WO2005117896A1

WO2005117896A1 - Formulations containing fasudil, a matrix and an envelope

Info

Publication number: WO2005117896A1
Application number: PCT/EP2005/005990
Authority: WO
Inventors: Heiko Kranz; Torsten Wagner
Original assignee: Schering Aktiengesellschaft
Priority date: 2004-06-03
Filing date: 2005-06-01
Publication date: 2005-12-15

Abstract

The invention relates to the use of a pharmaceutical formulation comprising 1-(5-isoquinolinesulfonyl)homopiperazine (FASUDIL) and derivatives thereof in a matrix body and an envelope surrounding the matrix body. The matrix body and envelope comprise poly vinyl pyrrolidone and poly vinyl acetate. Release occurs according to zero order reaction kinetics. The pharmaceutical formulation is used to treat diseases such as cardiovascular diseases, heart attacks, migranes, Alzheimer's disease, neuronal regeneration, tumours, erectile dysfunction, asthma, incontinence and menstrual complaints.

Description

FORMULATIONS CONTAINING FASUDIL, A MATRIX AND A COAT

The invention comprises a formulation for isoquinoline sulfonyl compounds such as 1- (5-isoquinoline sulfonyl) homopiperazine and 1- (6-hydroxyl-5-isoquinoline sulfonyl) homopiperazine, the preparation of such a formulation and the use of the formulation as a medicament, in particular for treatment from angina. PRIOR ART Isoquinoline sulfonly compounds: EP 0 187 371 A2 (Hidaka and Sone, filing date December 23, 1985) describes isoquinoline sulfonly compounds. These compounds are used as a drug. They are rho kinase inhibitors. They enlarge the diameter of blood vessels. They relax the smooth muscles of the blood vessels. You will e.g. used to treat angina, cerebrovascular thrombosis, hypertension, arteriosclerosis, cerebral apoplexy and vasospasm. The isoquinoline sulfonly compounds are vasodilators. These substances are rho kinase inhibitors and are used in the treatment of cardiovascular diseases, among others. with stable angina pectoris. They are also used for epileptic seizures.

They are very soluble in aqueous media. Due to this very good solubility in the intestinal tract and a short half-life of FASUDIL (one of the isoquinoline sulfonly compounds) and its salts in blood plasma, conventional oral formulations must be applied several times a day. Polyvinylpyrrolidone and polyvinyl acetate: Polyvinylpyrrolidone and polyvinyl acetate is described as a matrix in technical information see Kollidon SR, BASF, ME 397e, 2000. first order instead. This is expressly stated on pages 6 and 7 of the prospectus.

EP 1 138 321 A2 (filing date March 6, 2001) describes a formulation for active pharmaceutical ingredients that are released in a delayed manner. The diffusion-controlled release of the active pharmaceutical ingredient from the matrix is described by a first-order release. A mixture of polyvinyl acetate and polyvinylpyrrolidone is proposed, in particular in the case of very readily water-soluble active pharmaceutical ingredients, which surprisingly achieves slow release. The retardation can be increased by a jacket comprising polyvinyl acetate and polyvinylpyrrolidone, the release kinetics still corresponding to a first-order release.

WO 03/075896 A1 (published on September 18, 2003) describes a formulation which has a sealing jacket which contains 30 to 100% polyvinyl acetate as film former. In addition, polyvinyl acetate is also present in the core of the dosage form. Zero release order kinetics are achieved through the jacket. Various active ingredients are listed, which are incorporated into this formulation. WO 03/075896 describes that the rate of release of the active ingredients is regulated by the thickness of the jacket. A minimum thickness of 10 μm is essential to guarantee adequate mechanical stability. Usable layer thicknesses are in a range from 10 μm to 500 μm, preferably in a range from 30 μm to 300 μm. A highly water-soluble active ingredient requires a thicker coat to guarantee a usable release.

task

For these reasons, the task arises that the release of the active ingredient takes place in a controlled manner over a longer period of time in order to substantially extend the dosage intervals. At the same time, large-scale production of the drug must also be possible. In addition, the drug formulation must have adequate storage stability with regard to drug hold and drug release. In addition to zero order release, the stability of the coating should also be ensured.

Solution The object is achieved by using a formulation for releasing a pharmaceutical active substance according to the zero order, the formulation comprising at least one active substance in a matrix body and at least one sheath surrounding the matrix body, the sheath having a thickness of at most 7 μm, wherein the formulation comprises: an active ingredient in the matrix body, the active ingredient belonging to the group: FASUDIL group or hydroxyl FASUDIL group or a variant thereof, or a salt of the active ingredient, a matrix body with a matrix comprising a water-insoluble polyvinyl acetate, and a jacket comprising a water-insoluble polyvinyl acetate. A preferred use of the formulation according to the invention is one in which the matrix body has a matrix which, in addition to water-insoluble polyvinyl acetate, also comprises water-soluble polyvinylpyrrolidone.

Likewise preferred is a use of the formulation according to the invention, in which the casing also comprises water-soluble polyvinylpyrrolidone in addition to water-insoluble polyvinyl acetate.

The object is further achieved by using a pharmaceutical formulation for releasing a pharmaceutical active substance according to the zero order, the formulation comprising at least one active substance in one Includes matrix body and at least one sheath surrounding the matrix body, the sheath having a thickness of at most 7 μm, the formulation comprising: an active ingredient in the matrix body, the active ingredient being part of the group: FASUDIL group or hydroxyl FASUDIL group or a variant thereof, or a salt of the active ingredient, a matrix body with a matrix comprising a water-soluble polyvinylpyrrolidone and a water-insoluble polyvinyl acetate, and a jacket comprising a water-insoluble polyvinyl acetate.

The object is further achieved by using a pharmaceutical formulation for releasing a pharmaceutical active substance according to the zero order, the formulation comprising at least one active substance in a matrix body and at least one jacket surrounding the matrix body, the jacket having a thickness of at most 7 μm , the formulation comprising: an active ingredient in the matrix body, the active ingredient belonging to the group: FASUDIL group or hydroxyl FASUDIL group or a variant thereof, or a salt of the active ingredient, a matrix body with a matrix comprising a water-insoluble Polyvinyl acetate, and a jacket comprising a water-soluble polyvinylpyrrolidone and a water-insoluble polyvinyl acetate. The object is further achieved by using a pharmaceutical formulation for releasing a pharmaceutical active substance according to the zero order, the formulation comprising at least one active substance in a matrix body and at least one jacket surrounding the matrix body, the jacket having a thickness of at most 7 μm, wherein the formulation comprises: an active ingredient in the matrix body, the active ingredient belonging to the group: FASUDIL group or hydroxyl FASUDIL group or a variant thereof, or a salt of the active ingredient, a matrix body with a matrix comprising a water-soluble polyvinylpyrrolidone and a water-insoluble one Polyvinyl acetate, and a jacket comprising a water-soluble polyvinylpyrrolidone and a water-insoluble polyvinyl acetate.

Advantages The present invention solves the problem of controlled and pH-independent release with simultaneous large-scale producibility by means of a formulation comprising an active ingredient or a salt thereof, in particular a pharmaceutical formulation. The spatial combination of a matrix and one or more auxiliaries and a jacket is particularly well suited for the targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the drug form. The particle sizes of the powder mixtures are 90% in the range between 1 and 750 μm, preferably 50 and 500 μm, more preferably 60 and 400 μm, more preferably 90 and 300 μm and most preferably 150 and 250 μm. It is essential that the strength of the jacket is designed in such a way that the jacket does not allow the jacket to tear, despite the pharmaceutical load, parts of the jacket do not come off and the jacket does not become so thin for the release that the release is no longer inhibited in a planned manner becomes. The formulation according to the invention leads to a controlled release of the active ingredient or a salt thereof. While with a conventional formulation consisting of FASUDIL or a salt thereof, mannitol, maize starch, polyvinylpyrrolidone, croscarmellose, sodium and magnesium stearate, 100% of active ingredient are released after about 60 minutes, the formulation according to the invention can be used to release the drug 60 minutes can be reduced to below 10%. The advantage of the pharmaceutical formulation according to the invention is also evident in clinical studies. Compared to a conventional oral formulation, the plasma levels of FASUDIL or active metabolites of the treated persons are constant over a longer period when the formulation according to the invention is administered, so that the frequency of application of the drug formulation can be reduced.

This controlled release is based on the fact that, contrary to the description in the manufacturer's prospectus, it has surprisingly been found that a matrix of a mixture of polyvinylpyrrolidone and polyvinyl acetate with a jacket of the same mixture with a modified mixture ratio results in zero order release for the pharmaceutical active ingredient having.

In patent EP 1 138 321, a mathematical equation is mentioned on page 3, which describes a release from Kollidon SR matrices according to the root-time law. This type of release represents a release order in which a higher amount of drug is released at the start of the release than at later release points. This order is in contrast to a zero order release order in which the same amounts of drug are released within the same times. EP 1 138 321 does not describe that the release order changes as a result of the coating of the jacket. The applicant of EP 1 138 321 is also the manufacturer of the products Kollidon SR and Kollicoat SR and also dering further patent applications in this technical field. It thus represents the experts who are leaders in this technical field. An assessment of these experts with regard to the kinetics (first order in EP 1 138 321) and the usable jacket thickness (> 10μm in WO 03/75896) is therefore not the statement of any working group, but the statement of the leading experts, which brings the experts into the Direction is led to achieve a first-order release with the help of polyvinyl acetate and polyvinylpyrrolidone and, if necessary, also to achieve a zero-order release if the jacket thickness is greater than 10 μm. The applicant has formed the general and widespread view and preconceived opinion about this notion of release kinetics over a longer period of time and has promoted and maintained it through market dominance (cf. prospectus).

If one follows the technical teaching in international patent application WO 03/075896, the sheath around the core, in which the active pharmaceutical ingredient is also, must have a thickness of at least 30 μm in order to ensure a desired zero order release. Two effects are to be achieved here. On the one hand the slow release and on the other hand the strength of the jacket. It is expressly emphasized that the coat must have a pronounced thickness when the active pharmaceutical ingredient is water-soluble. FASUDIL is very soluble in water. If it is contained in the matrix, the matrix can be surrounded with a jacket that has a layer thickness of 30 μm. Such a formulation has the advantage that the jacket is stable. However, such a formulation is completely unusable as a medicament, since even after 10 hours, not even 10% of the active substance mass has diffused from the matrix through the jacket into the surrounding medium. The technical teaching of WO 03/075896 may be applicable to many active pharmaceutical ingredients, but the active ingredient FASUDIL behaves completely unexpectedly in this formulation according to the invention. Other publications deal with the release of active substances from a matrix of polyvinyl acetate and polyvinylpyrrolidone. Draganoiu et al. (2001, Pharm. Ind. 63, No. 6, 624-629) the release of propanolol hydrochloride from a matrix of polyvinyl acetate and polyvinyl pyrrolidone. All of the drug formulations described in the article result in a first order drug release. Drug formulations consisting of a matrix of polyvinyl acetate and polyvinylpyrrolidone, which have zero-order active ingredient release, have not hitherto been described in the literature.

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

A mixture for the sheath, which in addition contains sodium lauryl sulfate is sold as an aqueous polymer dispersion, for example under the trade name Kollicoat ^® SR 30 D. (Kollicoat ^® SR 30 D, Technical Information, ME 396 e, BASF, June 1999, polyvinyl acetate dispersion stabilized with polyvinylpyrrolidone and sodium lauryl sulfate) Commercially available Kollicoat SR 30 D contains a small percentage of polyvinylpyrrolidone. The aqueous polymer dispersion is applied to the solid pharmaceutical formulation in accordance with this invention by means of suitable pharmaceutical processes (eg spray drying processes). The applied additional polymer shell serves to specifically influence the release of FASUDIL HCI hemihydrate (see Fig. 3-4).

The BASF brochure only includes systems with a matrix (Kollidon SR). The person skilled in the art assumes that systems which only contain the matrix already sufficiently retard. These systems show first order release. Due to the properties of polyvinyl acetate and polyvinyl pyrrolidone, the application of an additional coat is not obvious. The prospectus raises the prejudice that a matrix with polyvinyl acetate and polyvinylpyrrolidone or only a jacket with polyvinyl acetate and polyvinylpyrrolidone corresponds to a first order release. The invention stands against this: the release takes place through the matrix and the coating according to the zero order. Specification of the active ingredients

The use of a formulation according to the invention comprises the FASUDIL group and the hydroxyl FASUDIL group, the active ingredient belonging to the group: FASUDIL group: FASUDIL = 1- (5-isoquinolinesulfonyl) homopiperazine (described in US Pat. No. 4,678,783 B1) FASUDIL hydrochloride 1- (5-isoquinolinesulfonyl) homopiperazine hydrochloride (described in EP 1 110 553); - FASUDIL hydrates (hemihydrate) = 1- (5-isoquinolinesulfonyl) - homopiperazine hydrates; FASUDIL hydrochloride hydrates (hemihydrate) = 1- (5-isoquinolinesulfonyl) homopiperazine hydrochloride hydrate (described in US Pat. No. 5,942,505) hydroxyl - FASUDIL - group: M3 (hydroxyl - FASUDIL) = 1- (6-hydroxyl-5-isoquino-line -sulfonyl) homopiperazines (described in US 4,678,783); M3 hydrochloride = 1- (6-hydroxyl-5-isoquinolinesulfonyl) homopiperazine hydrochloride; - M3 hydrates (hemihydrates) = 1- (6-hydroxyl-5-isoquinolinesulfonyl) homopiperazine hydrates; M3 hydrochloride hydrates (hemihydrate) = 1- (6-hydroxyl-5-iso-quinolinesulfonyl) homopiperazine hydrochloride hydrates.

definitions

SALTS: Salts from the active pharmaceutical ingredient are e.g. B. the hydrochloride, hydrochloride hemihydrate, hydrochloride hydrate, hydrochloride trihydrate, dihydrogen phosphate, hydrogen phosphate, phosphate, hydrogen sulfate, sulfate, mesylate, ethyl sulfonate, malate, fumarate and tartrate. FORMULATIONS: Formulations, in particular formulations as a medicament, in the sense of the invention are single-unit systems, such as. B. tablets, and multiparticulate systems. Multiparticulate systems can e.g. B. granules, pellets or mini tablets. These can be filled into hard or soft gelatin capsules and pressed into tablets. The original formation usually breaks down into many subunits in the stomach. The mini-depots then pass successively from the stomach into the intestine. The mini-depots can usually pass the pylorus with the sphincter closed. OTHER SUBSTANCES OF THE MATRIX AND THE COAT: A polymer matrix can be selected from the group consisting of cellulose derivatives [eg methyl cellulose, hydroxypropyl methyl cellulose (eg hydroxypropyl methyl cellulose K 4 M, hydroxypropyl methyl cellulose K 15 M), hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose (for example ethyl cellulose 100), cellulose acetate (for example cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate (for example cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate cellulose, hydroxypropyl cellulose methylate, hydroxypropyl cellulose hydroxyl, hydroxypropyl cellulose hydroxyl cellulose hydroxyl cellulose hydroxyl cellulose hydroxyl, cellulose hydroxyl cellulose, cellulose cellulose - Derivatives [eg polyacrylates, cross-linked polyacrylates (eg polmethacrylates, polyethyl acrylates, polymethyl acid ethyl acrylates, polymethyl acid methyl methacrylates, polymethyl acid methyl methacrylates, polymethyl acrylate trimethylammonium ethyl methacrylate chlorides, polyethyl acrylate trimethyl ammonium methyl methacrylate, methyl acrylate inoethyl methacrylate methacrylate copolymers, Carbopol ^® 971 P, Carbopol ^® 974 P, Carbopol ^® 71 G)], vinyl polymers (e.g. polyvinyl acetate phthalates), polyethylene glycols, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (e.g. xanthanes), xanthanes, , Zuckerester (eg Saccharomyces sestearat, Saccharosepaimitat, charoseoleat sucrose laurate, sucrose behenate, Sac, Saccharoseerucat and Saccharoseester with mixed fatty acids), diethylene glycol monoethyl ether (Transcutol ^® P eg), diethylene glycol monopalmitostearat (eg Hydrines ^®), ethylene glycol-monopalmitostearat (e.g. Monthyle ^® ), Gycerol behenate and Gycerol dibehenate (e.g. Compritol ^® 888 ATO, Compritol ^® HD 5 ATO and Compritol ^® E), glycerol distearate, glycerol di palmitostearate and glycerol palmitostearate (e.g. Precirol ^® ATO 5 and Precirol ^® WL 2155), glycerol monooleate 40 (e.g. Peceol ^® ), glycerol monostearate 40-55 (e.g. Geleol ^® ), macrogolglycerol laurate (e.g. Gelucire ^® 44 / 14 and Labrafil ^® M 2130 CS), macrogol glycerol stearates (eg Gelucire ^® 50/13), propylene glycol monopalmitostearate (eg Monosteol ^® ), chitosan, galactomannan, pectin, shellac and alginates.

Furthermore, the solid pharmaceutical formulation in the sense of this invention can be coated with a further polymer shell for further release modification. This is usually selected from the group of cellulose derivatives [eg methyl cellulose, hydroxypropyl methyl cellulose (eg hydroxypropyl methyl cellulose K 4 M, hydroxypropyl methyl cellulose K 15 M), hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose (eg ethyl cellulose 100), cellulose acetate (eg Cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate (e.g. cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acrylate, poly (ethyl acetate) - Acid methyl methacrylates, polymethyl acid methyl methacrylates, polymethyl acrylate trimethylammonium ethyl methacrylate chlorides, polyethyl acrylate trimethyl ammonium methyl methacrylate chlorides, dimethyl aminoethyl methacrylate methacrylate copolymers, Carbopol ^® 971 P, carb opol ^® 974 P, Carbopol ^® 71 G)], vinyl polymers (e.g. polyvinyl acetate phthalates), polyethylene glycols, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (e.g. xanthans, xanthan gum), sugar esters (e.g. Sac - charosestearat, Saccharosepaimitat, sucrose laurate, sucrose behenate, saccharose oleate, Saccharoseerucat and Saccharoseester with mixed fatty acids), diethylene glycol monoethyl ether (for example Transcutol ^® P), diethylene glycol monopalmitostearate (eg Hydrines ^®), Ethylenglycolmonopalmito- stearate (eg Monthyle ^®), Gycerol behenate and gycerol dibehenate (e.g. Compritol ^® 888 ATO, Compritol ^® HD 5 ATO and Compritol ^® E), glycerol distearate, glycerol dipalmitostearate and glycerol palmitostearate (e.g. Preci- rol ^® ATO 5 and Precirol ^® WL 2155), glycerol monooleate 40 (e.g. Peceol ^® ), glycerol monostearate 40-55 (e.g. Geleol ^® ), macrogolglycerol laurate (e.g. Gelucire ^® 44/14 and Labrafil ^® M 2130 CS ), Macrogolglycerol stearate (eg Gelucire ^® 50/13), propylene glycol monopalmitostearate (eg Monosteol ^® ), chitosan, galactomannan, pectin, shellac and alginates can be selected.

An additional polymer shell consisting of polyvinyl acetate and polyvinylpyrrolidone is particularly suitable. This mixture, which additionally contains sodium lauryl sulfate, is sold as an aqueous polymer dispersion, for example under the trade name Kollicoat ^® SR 30 D (Kollicoat ^® SR 30 D, Technical Information, ME 396 e, BASF, June 1999, polyvinyl acetate dispersion stabilized with polyvinylpyrrolidone and sodium lauryl sulfate) The aqueous polymer dispersion is applied to the solid pharmaceutical formulation in the sense of this invention by means of suitable pharmaceutical processes (eg spray drying processes). The applied additional polymer shell serves to specifically influence the release of FASUDIL HCI hemihydrate (see Fig. 3-4).

AUXILIARY AGENTS: For targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the dosage form, water-soluble or water-insoluble auxiliaries such as e.g. Lactose, calcium diphosphate, mannitol, sorbitol, sucrose, fructose, glucose, starch or a starch derivative can be used. Mixtures of one or more auxiliaries can also be used. Lactose is preferred. Coarse-grain lactose is particularly advantageous.

Cellulose or cellulose derivatives can be used as an additional aid for the targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the drug form. Microcrystalline cellulose is particularly advantageous. This swells in an aqueous environment and leads to an accelerated pH-independent release of the active ingredient and its salts. LUBRICANTS: The single-unit dosage forms, such as tablets, can also contain lubricants to reduce interparticle friction and be added to reduce the sliding friction between the wall of the material and the die. Substances are used as lubricants which, due to their lamellar structure, have layers that can be easily moved against each other. Organic substances that can be used pharmaceutically are, for example, the divalent metal soaps, the higher fatty alcohols and the polyethylene glycols with higher molecular weights. The magnesium and calcium salts of higher fatty acids are particularly advantageous.

FLOW REGULATORS: In the case of single-unit dosage forms, a flow regulator can be added to improve the flow properties of the material to be tabletted. This means that the material to be tabletted regularly fills the die of the machine with sufficient packing density. The addition of a flow control agent may be necessary in particular for direct tableting. Substances with a purely flow-regulating effect are mainly the highly disperse silicas, ie the micronized silica gels and the pyrolytically produced silicas. Starches and talc are substances that can be used as flow regulators as well as disintegrants or as lubricants. PARTICLE SIZES OF THE POWDER MIXTURES (GRAIN SIZE DISTRIBUTION): In the case of the single-unit dosage form, it is important for their industrial production that the material to be tabletted has properties similar to granules such as good flowability, high bulk density and defined grain size distribution. The grain size of the material to be tabletted depends on the size of the tablets to be produced and generally varies between 1 μm and 750 μm. The grain size refers to the size of the matrix. The coat is not included in the description of the grain size. A grain size distribution that is as uniform as possible within the material to be tabletted is important in order to prevent segregation (eg when the tablet machine is shaking) and thus an accumulation of larger particles in the upper part of the material, since otherwise larger fluctuations in the dosage can occur. A defined particle size and particle size distribution is achieved by classification (e.g. wet or dry sieving) or by granulation of the starting materials. The particle size can be measured using the method described in Example 14. The particle sizes 90% should be in the range between 1 μm - 750 μm. A preferred range is from 20 μm to 400 μm. Another preferred range is from 50 to 500 microns, more preferably from 60 to 400 microns, even more preferably from 90 to 300 microns, and most preferably 150 and 250 microns.

The particle size is determined by means of laser diffractometry (R.H. Müller, R. Schuhmann, particle size measurement in laboratory practice, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996). The volume distribution of the particle sizes was used as the measurement parameter. COAT THICKNESS: The coat thickness of the jacket should be less than / equal to 7 μm (layer thickness <7 μm). A layer thickness of less than / equal to 6 μm (layer thickness <6 μm) is preferred, more preferred is a layer thickness of less than / equal to 5 μm (layer thickness <5 μm), even more preferably less than / equal to 4 μm (layer thickness <4 μm) , a layer thickness of less than / equal to 3 μm (layer thickness <3 μm) is most preferred. The layer thickness is measured using scanning electron microscopy. Commercial devices are e.g. manufactured by Philips (Philips Electronics, Einhoven, The Netherlands). The layer thickness of the films can also be measured with a film thickness measuring device (e.g. Minitest 600, Erichsen GmbH, Hemer, Germany).

The layer thickness varies on a particle in a range of 20% of the layer thickness, preferably in a range of 15% of the layer thickness and most preferably in a range of 10% of the layer thickness. The layer thickness varies from particle to particle in a range of 30% of the layer thickness, preferably in a range of 20% of the layer thickness and most preferably in a range of 10% of the layer thickness.

Further embodiments of the formulation

A use of the formulation according to the invention is preferred, the matrix being a mixture comprising the active ingredient, the matrix former, lubricant and, under certain circumstances, further auxiliaries. A further embodiment of the use of the formulation according to the invention is that the particle sizes of the powder mixtures are 90% in the range between 1 μm and 750 μm, a preferred form is in the range from 20 μm to 400 μm. An advantageous use of the formulation according to the invention is that the matrix has the following composition: 10.0% -80.0%, preferably 20.0% -70.0%, more preferably 30.0% -60.0%, am most preferably 40.0% - 50.0% polyvinyl acetate, 0% -46.0%, preferably 0% -36.0% more preferably 0% - 26.0%, most preferably 6.0% - 16.0 % Polyvinylpyrrolidone, (the lower limit of polyvinylpyrrolidone can also be 1%, preferably 1.5% or 2.5%.) 0% -40.0%, preferably 0% -30.0%, more preferably 0% - 20.0 %, most preferably 0% - 10.0% lactose, 0% - 5.0%, preferably 0% - 3.5% more preferably 0% - 2.5%, most preferably 0.5% - 1, 5% magnesium stearate and 0% - 5.0%, preferably 0% - 3.5% more preferably 0% - 2.5%, most preferably 0.5% - 1.5% silicon dioxide, each in a mixture a sum of 100% based on the matrix.

An advantageous use of the formulation according to the invention is that the coat has the following composition: 40.0% -100.0%, preferably 60.0% -100.0% more preferably 80.0% - 100.0%, most preferably 90.0% - 100.0% polyvinyl acetate, 0% -40.0%, preferably 0% -30.0% more preferably 0% - 20.0%, most preferably 0% - 10.0% Polyvinylpyrrolidone, (The lower limit of polyvinylpyrrolidone can also be 1%, preferably 1.5% or 2.5%.), 0% -2.0%, preferably 0% -1.0%, more preferably 0% - 0.5 %, most preferably 0% - 0.3% sodium lauryl sulfate, 0% -40.0%, preferably 0% -30.0% more preferably 0% - 20.0%, most preferably 0% - 10.0% triethyl citrate and, 0% - 20.0%, preferably 0% - 10.0% more preferably 0% - 5.0%, most preferably 0% - 2.5% silicon dioxide, each in a mixture forming a sum of 100%, based on the jacket.

A preferred use of the formulation according to the invention in which the auxiliary is lactose, calcium diphosphate, mannitol or a starch.

Furthermore, it is advantageous to use the formulation according to the invention in which microcrystalline cellulose is used as an additional aid.

Properties when used as a drug

The formulation of the invention shows pharmacological activity and can be used as a therapeutic agent or as a medicament. The invention comprises an inventive use of the formulation as a medicament, the active substance being a pharmaceutical active substance.

A formulation according to the invention is preferred together with at least one physiologically compatible, pharmacological auxiliary or carrier. Pharmacological adjuvants and excipients are at Remington's

Pharmaceutical Science, 15 ^th ed. Mack Publishing Company, Easton Pennsylvania (1980).

The formulation of the invention is suitable for the treatment of various indications. Preferred is the use of the formulation as a therapeutic agent for the treatment of cardiovascular diseases (eg angina, high blood pressure, atherosclerosis, Reynauds syndrome, heart attack), stroke, migraine, Alzheimer's, neuronal regeneration, tumors, erectile dysfunction, asthma, incontinence, menstrual disorders , It is more preferred to use the composition as a therapeutic agent for treating treatment of cardiovascular diseases (e.g. angina, high blood pressure), stroke and erectile dysfunction together with at least one physiologically compatible, pharmacological auxiliary or carrier. Treatment includes prophylactic and therapeutic measures.

(i) The invention further provides (α) the use according to the invention of the formulation of the invention for the manufacture of a medicament for the treatment of cardiovascular diseases (eg angina, high blood pressure, atherosclerosis, Reynauds syndrome, heart attack), stroke, migraine, Alzheimer's, neuronal Regeneration, tumors, erectile dysfunction, asthma, incontinence and menstrual cramps. (ß) a procedure for the treatment of cardiovascular diseases (e.g. angina, high blood pressure, atherosclerosis, Reynauds syndrome, heart attack), stroke, migraine, Alzheimer's, neuronal regeneration, tumors, erectile dysfunction, asthma, incontinence and menstrual disorders. which method comprises administering a formulation according to the invention, the amount suppressing the disease, and the formulation being given to a patient in need of such a medicament; (γ) a formulation for the treatment of cardiovascular diseases (eg angina, high blood pressure, atherosclerosis, Reynauds syndrome, heart attack), stroke, migraines, Alzheimer's, neuronal regeneration, tumors, erectile dysfunction, asthma, incontinence and menstrual disorders. which treatment comprises a formulation of the invention and at least one pharmaceutically acceptable carrier and additive. The suitable dose for these therapeutic effects is different and depends, for example, on the concentration of the individual elements in the pharmaceutical composition, the type of administration and the type and severity of the conditions to be treated.

The formulation of the invention can be administered orally in systemic treatment.

The pharmaceutical composition of the invention can be processed with the additives and / or carrier substances customary in galenical pharmacy according to methods known per se to the usual oral administration forms.

A physical mixture consisting of water-insoluble polyvinyl acetate and water-soluble polyvinylpyrrolidone as a matrix is particularly suitable. This mixture, which in addition contains sodium lauryl sulfate and silicon dioxide, for example, is sold under the trade name Kollidon SR ^® sold (Kollidon SR, Technical Information, ME 397e, BASF, July 2000: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0, 2% silicon dioxide). The matrix is then coated with a jacket consisting of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and optionally triethyl citrate.

Furthermore, the solid pharmaceutical formulation in the sense of this invention can be coated with a color varnish for optical and taste reasons. This usually consists of a binder (e.g. hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyethylene glycol), lubricant (e.g. talc) and color pigment (e.g. iron oxide pigment, titanium dioxide).

Another preferred use of the solid pharmaceutical formulation contains fasudil or a salt thereof, lactose, Kollidon SR ^®, silicon dioxide and magnesium stearate, whereby 90% of the particles in the range of 1 - are 750 microns and the matrix then, with a coat consisting of polyvinyl acetate, polyvinyl pyrrolidone Sodium lauryl sulfate and optionally triethyl citrate is coated. A formulation of this type shows, for example, an 80% release of the active ingredient after 6 hours.

Embodiments of the production process A process for producing a formulation according to the invention is preferred, with the following steps: the active ingredient or a salt thereof is mixed with the matrix and optionally with one or more auxiliaries, (ie: the active ingredient or a salt thereof is ( i) mixed with the matrix or (ii) mixed with the matrix and one or more auxiliaries) the flow regulating agent is added, the lubricant is added, the mixture is tabletted and the coat is applied (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac, particularly preferred Polyvinylpyrrolidone and polyvinyl acetate).

The direct production of tablets basically takes place by mixing the powder components, dosing via the filling device of the tablet machine and then compressing the powder mixture. In direct tableting, the particle size and particle size distribution of the active ingredient used and its salts, matrix and auxiliaries have a considerable influence on the large-scale manufacture of the tablets. These must therefore be classified individually before mixing the powder components (e.g. by sieving). Alternatively, the entire powder mixture or individual constituents of the powder mixture can be classified together (e.g. sieved). The powder constituents, as mentioned in the examples, are weighed out and mixed over a sufficiently long period in a free-fall mixer (eg turbulent mixer, V mixer) or compulsory mixer (eg ploughshare mixer, planetary mixer kneader). In particular, the addition of the flow regulation means and lubricant (both together are also referred to as FST complex) is only carried out shortly before the tabletting machine is loaded. The FST complex is to be finely sifted onto the premixed tablet material and mixed in as described above, whereby the mixing time must not be too short (inhomogeneous distribution) or too long (total mixing of the material).

Furthermore, the invention relates to a method for producing a solid pharmaceutical formulation according to the invention, the active substance or a salt thereof, the matrix and the auxiliaries being subjected to a process known as granulation before mixing and tableting. After granulating and adding the lubricant, tablets are made as described above. The granulation can be carried out by gradually enlarging or agglomerating primary particles of the powder mixture to the desired secondary size (build-up granulation) or by dividing a pasted powder mass to the desired granule grain size (breakdown granulation). Build-up granulation includes e.g. B. the plate granulation and the fluidized bed granulation. The degrading granulation can e.g. by compacting the raw materials and then mechanically dividing and sieving the compressed materials. The degradation or build-up granulation can take place moist (e.g. adhesive or crust granules) or dry (e.g. briquette or melt solidification granules).

Another object of the invention is a method for producing a solid multiparticulate formulation according to the invention, wherein the active ingredient or a salt thereof, the matrix, and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by means of extrusion and subsequent spheronization.

A method for producing a formulation according to the invention is advantageous, with the following steps: the active ingredient or a salt thereof is extruded with the matrix and optionally one or more auxiliaries, (ie: the active ingredient substance or a salt thereof is (i) extruded with the matrix or (ii) with the matrix and at least one auxiliary)

the mixture is then processed into pellets by spheronization and then coated with the jacket (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac, particularly preferably polyvinylpyrrolidone and polyvinyl acetate).

Under certain circumstances, the active ingredient-containing pellets can be coated with a subcoat [coating adjacent to the matrix] (preferably cellulose derivatives and vinyl polymers such as polyvinylpyrrolidone) before the polymer matrix is applied. The function of the subcoat is to prevent incompatibilities between the active substance or a salt thereof and the matrix or to prematurely diffuse the active substance or a salt thereof into the matrix during pellet storage.

Furthermore, the invention relates to a method for producing a solid pharmaceutical formulation according to the invention, the active ingredient or a salt thereof, the matrix and the auxiliaries being processed into pellets by means of direct pelleting. The raw materials are mixed and processed into pellets using a binder solution (wet granulation) or melted additives (e.g. fats). The coat is then applied (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac, particularly preferably polyvinylpyrrolidone and polyvinyl acetate).

A method for producing a formulation is also preferred, comprising the following steps: the active substance or a salt thereof is mixed with the matrix and optionally one or more auxiliary substances, (ie: the active substance or a salt thereof is (i) mixed with the matrix or (ii) mixed with the matrix and at least one auxiliary) the mixture is processed into pellets by spray drying or solidification and the coat is applied (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac, particularly preferably polyvinylpyrrolidone and polyvinyl acetate).

A method for producing a formulation is advantageous, with the following steps: the active substance or a salt thereof is mixed with the matrix and optionally one or more auxiliary substances (ie: the active substance or a salt thereof is (i) mixed with the matrix or (ii) mixed with the matrix and at least one auxiliary agent) the mixture is processed into pellets by means of rotor granulation, and the jacket is applied (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac, particularly preferably polyvinylpyrrolidone and polyvinyl acetate).

Furthermore, the invention relates to a method for producing a solid formulation according to the invention, the matrix and the auxiliaries being processed into pellets by applying them in layers to the active ingredient or a salt thereof (layering).

Furthermore, the invention relates to a process for filling the pellets produced into pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules) or for pressing the pellets produced into tablets. The pellets can be filled into capsules or the pellets can be processed into tablets, optionally with the addition of other auxiliaries (preferably cellulose, cellulose derivatives, lactose, lubricants and flow regulators). The invention further relates to a process for the preparation of a solid formulation according to the invention, the active ingredient or a salt thereof being mixed with the matrix, the lubricant and the auxiliaries and then processed into mini-tablets (preferred tablet diameter 1-5 mm) by direct tableting.

Furthermore, the invention relates to a method for producing a solid formulation according to the invention, the active ingredient or a salt thereof, the matrix and the auxiliaries being subjected to a process known as granulating before mixing and tableting. After granulating and adding the lubricant, the starting materials are processed into mini tablets (preferred tablet diameter 1 - 5 mm).

The invention further relates to a method for filling the mini tablets produced into pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules). The mini tablets can be filled into capsules, if appropriate, with the addition of further auxiliaries (preferably cellulose, cellulose derivatives, lactose).

PICTURES:

Fig. 1 shows the effect of the polymer matrix (%, based on the total weight of the tablet) on the release of FASUDIL HCI hemihydrate from matrix tablets in pH 6.8 phosphate buffer solution (33% FASUDIL HCI hemihydrate, based on the total weight of the tablet) ) (Examples 1-5).

Fig. 2 shows the effect of the polymer matrix (%, based on the total weight of the tablet) on the release of FASUDIL HCI hemihydrate from matrix tablets in pH 6.8 phosphate buffer solution (41% FASUDIL HCI hemihydrate, based on the total weight of the tablet) ) (Examples 6-7). Fig. 3 shows the effect of the polymer coating (%, based on the total weight of the core tablet) on the release of the FASUDIL HCI hemihydrate from matrix tablets in pH 6.8 phosphate buffer solution (33% FASUDIL HCI hemihydrate, based on the total weight of the core tablet) ( Examples 1, 8-9).

Fig. 4 shows the effect of the polymer coating (%, based on the total weight of the core tablet) on the release of FASUDIL HCI hemihydrate from mini tablets in phosphate buffer solution pH 6.8 (33% FASUDIL HCI hemihydrate, based on the total weight of the core tablet ) (Examples 10-12).

Fig. 5 shows the particle size distribution of a typical powder molding compound for direct tabletting determined by laser diffractometry. Fig. 6 shows the influence of the jacket thickness on the release of FASUDIL from mini tablets in pH 6.8 phosphate buffer solution (Example 15). % Release based on the total amount of FASUDIL HCI hemihydrate in the core tablet. The jacket thickness is given in μm.

Fig. 7 shows the sufficient mechanical stability of the film coating with different almond thicknesses, the release in phosphate buffer solution pH 6.8 being measured before and after mechanical stress in an abrasion tester. % Release based on the total amount of FASUDIL HCI hemihydrate in the core tablet. The jacket thickness is given in μm. Examples Example 1

Production of a matrix tablet by means of direct tabletting

Composition per basic unit: 100 mg FASUDIL HCI hemihydrate 117.5 mg lactose 75 mg Kollidon SR ^® 3 mg highly disperse silicon dioxide 4.5 mg magnesium stearate

Lactose, FASUDIL HCI hemihydrate and Kollidon SR ^® are sieved individually and mixed in the above order in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is then tabletted using an eccentric or rotary tablet press. The release from these matrix tablets is then measured using the method mentioned in Example 13.

Example 2

Production of a matrix tablet by means of direct tabletting

Composition per basic unit: 100 mg FASUDIL HCI hemihydrate 192.5 mg Kollidon SR ^®

3 mg fumed silica 4.5 mg magnesium stearate

FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is then tabletted using an eccentric or rotary tablet press. The release from these matrix tablets is then measured using the method mentioned in Example 13.

Example 3

Production of a matrix tablet by direct tablet composition per basic unit:

100 mg FASUDIL HCI hemihydrate

87.5 mg lactose

105 mg Kollidon SR ^®

3 mg fumed silica 4.5 mg magnesium stearate

Example 4

Production of a matrix tablet by direct tableting

Composition per basic unit: 100 mg FASUDIL HCI hemihydrate 57.5 mg lactose 135 mg Kollidon SR ^® 3 mg fumed silica 4.5 mg magnesium stearate

Example 5

Production of a matrix tablet by means of direct tabletting

Composition per basic unit: 100 mg FASUDIL HCI hemihydrate 27.5 mg lactose

165 mg Kollidon SR ^®

3 mg of highly disperse silicon dioxide

4.5 mg magnesium stearate

Lactose, FASUDIL HCI hemihydrate and Kollidon SR ^® are sieved individually and mixed in the above order in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is then tabletted using an eccentric or rotary tablet press. Then the release measured from these matrix tablets using the method mentioned in Example 13.

Example 6 Production of a matrix tablet by direct tableting

Composition per basic unit: 123.3 mg FASUDIL HCI hemihydrate 94.2 mg lactose 75 mg Kollidon SR ^®

3 mg fumed silica 4.5 mg magnesium stearate

Example 7 Production of a matrix tablet by direct tableting

Composition per basic unit: 123.3 mg FASUDIL HCI hemihydrate 169.2 mg Kollidon SR ^® 3 mg highly disperse silicon dioxide 4.5 mg magnesium stearate FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is then tabletted using an eccentric or rotary tablet press. The release from these matrix tablets is then measured using the method mentioned in Example 13.

Example 8

Production of a matrix tablet by direct tableting with subsequent film coating

Composition per basic unit: 100 mg FASUDIL HCI hemihydrate 117.5 mg lactose 75 mg Kollidon SR ^® 3 mg highly disperse silicon dioxide

4.5 mg magnesium stearate 17.1 mg Kollicoat SR ^® 30 D corresponding to aqueous dispersion 57 mg 0.9 mg triethyl citrate

3.6 mg polyvidone 25

Lactose, FASUDIL HCI hemihydrate and Kollidon SR ^® are sieved individually and mixed in the above order in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powder molding compound is tabletted using an eccentric or rotary tablet press (tablet cores). Polyvidon 25 and triethyl citrate are stirred into the aqueous Kollicoat SR ^® 30 D dispersion using an Ultra-Turrax mixer or a colloid mill (film varnish). The film varnish produced (= jacket) is sprayed onto the tablet cores with the application of heat in a drum coater, the water used evaporating. The release from these matrix tablets is then measured using the method mentioned in Example 13.

Example 9 Production of a matrix tablet by direct tableting with subsequent film coating

Composition per basic unit:

100 mg FASUDIL HCI hemihydrate

117.5 mg lactose 75 mg Kollidon SR ^®

3 mg of highly disperse silicon dioxide

4.5 mg magnesium stearate

8.55 mg Kollicoat SR ^® 30 D corresponding to aqueous dispersion 28.5 mg 0.45 mg triethyl citrate

1.8 mg polyvidone 25

Lactose, FASUDIL HCI hemihydrate and Kollidon SR ^® are sieved individually and mixed in the above order in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powder molding compound is tabletted using an eccentric or rotary tablet press (tablet cores). Polyvidon 25 and triethyl citrate are mixed into the aqueous Kollicoat SR ^® 30 D dispersion using an Ultra-Turrax mixer or a colloid mill. stirred (film lacquer). The film varnish produced is sprayed onto the tablet cores with the application of heat in a drum coater, the water used evaporating. The release from these matrix tablets is then measured using the method mentioned in Example 13.

Example 10

Manufacture of mini tablets by direct tableting

2.74 mg FASUDIL HCI hemihydrate 3.76 mg Kollidon SR ^® 0.067 mg finely divided silica 0.10 mg magnesium stearate

FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 minutes. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is tabletted into mini tablets (corresponds to a matrix tablet) by means of an eccentric or rotary tablet press. The mini tablets produced are filled into hard gelatin capsules. The release from these mini tablets is then measured using the method mentioned in Example 13.

Example 11 Production of mini tablets with subsequent film coating

Composition per basic unit: 2.74 mg FASUDIL HCI hemihydrate 3.76 mg Kollidon SR ^® 0.067 mg highly disperse silicon dioxide 0.10 mg magnesium stearate 0.316 mg Kollicoat SR ^® 30 D corresponding to aqueous dispersion 1.05 mg 0.017 mg triethyl citrate 0.033 mg Polyvidon 25

FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is tabletted into mini tablets using an eccentric or rotary tablet press.

Polyvidon 25 and triethyl citrate are stirred into the aqueous Kollicoat SR ^® 30 D dispersion using an Ultra-Turrax mixer or a colloid mill (film varnish). The film varnish produced is sprayed onto the tablet cores with the application of heat in a fluidized bed coater, the water used evaporating. The release from these mini tablets is then measured using the method mentioned in Example 13.

Example 12 Production of mini tablets with subsequent film coating

Composition per basic unit:

2.74 mg FASUDIL HCI hemihydrate

3.76 mg Kollidon SR ^®

0.067 mg finely divided silica 0.10 mg magnesium stearate

0.632 mg Kollicoat SR ^® 30 D corresponding to 2.1 mg aqueous dispersion

0.034 mg triethyl citrate

0.066 mg polyvidone 25 FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 min. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is tabletted into mini tablets using an eccentric or rotary tablet press.

Example 13 Measurement of the release of FASUDIL HCl hemihydrate

The active ingredient release from matrix tablets is measured using a one-compartment method (blade stirrer apparatus), as described in the American Pharmacopoeia USP XXV. The active ingredient release from mini tablets is measured by a one-compartment method (basket apparatus), as described in the American Pharmacopoeia USP XXV. The release of FASUDIL HCl hemihydrate was examined in phosphate buffer solution pH 6.8 (composition see USP XXV).

Example 14 Measurement of particle size

The particle size of fasudil HCI hemihydrate, Kollidon SR ^® or the powder mixtures described in Example 1 to 12 lactose was by means of laser diffractometry (Muller, RH, Schuhmann, R., particle size measurement in the laboratory practice, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1996) be - Right. The volume distribution of the particle sizes was used as the measurement parameter. Example 15

Measurement of the release of FASUDIL from mini tablets taking into account different shell thicknesses.

Mini tablets are produced by direct tableting as described in Example 10.

Production of mini tablets with subsequent film coating (coat layer thickness = 30 μm):

Composition per basic unit:

2.74 mg FASUDIL HCI hemihydrate

3.76 mg Kollidon SR ^®

0.067 mg highly disperse silicon dioxide 0.10 mg magnesium stearate

0.948 mg Kollicoat SR ^® 30 D corresponding to 3.15 mg aqueous dispersion

0.051 mg triethyl citrate

0.099 mg polyvidone 25

Production of mini tablets with subsequent film coating (coat layer thickness = 6 µm):

Composition per basic unit: 2.74 mg FASUDIL HCI hemihydrate

3.76 mg Kollidon SR ^® 0.067 mg finely divided silica

0.10 mg magnesium stearate

0.2844 mg Kollicoat SR ^® 30 D corresponding to aqueous dispersion 0.945 mg

0.0153 mg triethyl citrate 0.0297 mg polyvidone 25 Production of mini tablets with subsequent film coating (coat thickness 3 µm):

Composition per basic unit: 2.74 mg FASUDIL HCI hemihydrate 3.76 mg Kollidon SR ^®

0.067 mg colloidal silica 0.10 mg magnesium stearate 0.1422 mg Kollicoat SR ^® 30 D corresponding to aqueous dispersion 0.4725 mg 0.00765 mg triethyl citrate 0.01485 mg polyvidone 25

FASUDIL HCI hemihydrate and Kollidon SR ^® are individually sieved and mixed in the turbula for 10 min. Highly disperse silicon dioxide, sieved, is added and all components are mixed in the turbula for a further 5 minutes. Magnesium stearate, sieved, is sprinkled on and all components are mixed in the turbula for a further 30 seconds. The powdered molding compound is tabletted into mini tablets using an eccentric or rotary tablet press.

Polyvidon 25 and triethyl citrate are stirred into the aqueous Kollicoat SR ^® 30 D dispersion using an Ultra-Turrax mixer or a colloid mill (film varnish). The film varnish produced is sprayed onto the tablet cores with the application of heat in a fluidized bed coater, the water used evaporating. The release from these mini tablets is then measured using the method mentioned in Example 13. The example shows that coat thicknesses of 3 and 6 μm result in a satisfactory release of FASUDIL from the matrix body. Sheath layer thicknesses of 30 μm cannot be used as medication, since no therapeutically effective plasma level is reached in the patient. Example 16

Measurement of the mechanical stability of the casing at different layer thicknesses, the release of FASUDIL from the matrix tablet being measured before and after the mechanical treatment. The jacket thickness is measured using scanning electron microscopy (e.g. with a device from Philips, Philips Electronics, Einhoven, the Netherlands). In addition, the film thickness is measured using a film thickness measuring device, as described in Siepmann et al. Journal of Controlled Release, Vol. 60, Issue 2-3, pages 379-389, 1999. The mini tablets are produced as described in Example 15. The mechanical stability of the jacket is investigated using the abrasion test method described in the general method section of the European Pharmacopoeia 2002 on page 247. The active ingredient release from the mini tablets, before and after abrasion testing, is measured using the method mentioned in Example 13.

The example shows that coat thicknesses of 3 and 6 μm result in a satisfactory release of FASUDIL from the matrix body both before and after the mechanical treatment. These tests show that mechanically stable film coatings are achieved even with a film thickness of less than 10 μm.

Claims

claims

1 . Use of a pharmaceutical formulation for releasing a pharmaceutical active substance according to zero order, the formulation comprising at least one active substance in a matrix body and at least one sheath surrounding the matrix body, the sheath having a thickness of at most 7 μm, the formulation comprising: an active ingredient in the matrix body, the active ingredient belonging to the group: FASUDIL group or hydroxyl FASUDIL group or a variant thereof, or a salt of the active ingredient, a matrix body with a matrix comprising a water-insoluble polyvinyl acetate and water-soluble polyvinylpyrrolidone and a jacket comprising a water-insoluble polyvinyl acetate and water-soluble polyvinyl pyrrolidone.

2. Use of a formulation according to claim 1, wherein the active ingredient belongs to the group:

FASUDIL - group: FASUDIL = 1- (5-isoquinolinesulfonyl) homopiperazine; FASUDIL hydrochloride = 1- (5-isoquinolinesulfonyl) homopiperazine hydrochloride; - FASUDIL hydrates (hemihydrates) = 1- (5-isoquinolinesulfonyl) - homopiperazine hydrates; FASUDIL Hydrochloride Hydrate (Hemihydrate) = 1- (5-isoquinolinesulfonyl) homopiperazine hydrochloride hydrate; Hydroxyl - FASUDIL - group: M3 (hydroxyl - FASUDIL) = 1- (6-hydroxyl-5-isoquino-line sulfonyl) homopiperazines; M3 hydrochloride = 1- (6-hydroxyl-5-isoquinolinesulfonyl) homopiperazine hydrochloride; - M3 hydrates (hemihydrates) = 1- (6-hydroxyl-5-isoquinolinesulfonyl) homopiperazine hydrates; M3 hydrochloride hydrates (hemihydrate) = 1- (6-hydroxyl-5-isoquinolinesulfonyl) homopiperazine hydrochloride hydrate. Use of a formulation according to one of the preceding claims, wherein the matrix is a mixture comprising the active ingredient, the matrix former, lubricant and at least one further auxiliary. Use of a formulation according to one of the preceding claims, wherein the particle sizes of the powder mixtures are 90% in the range between 1 μm and 750 μm. Use of a formulation according to one of the preceding claims, wherein the matrix has the following composition:

10% -80% polyvinyl acetate, 0% -46% polyvinylpyrrolidone, 0% - 40% lactose, 0% - 5% magnesium stearate and

0% - 5% silicon dioxide, each in a mixture forming a sum of 100%, based on the matrix. Use of a formulation according to any one of the preceding claims, wherein the coat has the following composition:

40.0% -100.0% polyvinyl acetate, 0% -40.0% polyvinylpyrrolidone, 0% -2.0% sodium lauryl sulfate, 0% -40.0% triethyl citrate and, 0% - 20.0% silicon dioxide, each in a mixture forming a sum of 100%, based on the jacket. Use of a formulation according to any one of the preceding claims, wherein the adjuvant is lactose, calcium diphosphate, mannitol or a starch. Use of a formulation according to one of the preceding claims, wherein microcrystalline cellulose is used as an additional auxiliary. Use of a formulation according to any one of the preceding claims for the manufacture of a medicament for the treatment of cardiovascular diseases, stroke, migraines, Alzheimer's, neuronal regeneration, tumors, erectile dysfunction, asthma, incontinence and

menstrual cramps