EP3826619A1

EP3826619A1 - Pharmaceutical dosage form which can be administered orally and has modified release

Info

Publication number: EP3826619A1
Application number: EP19740581.4A
Authority: EP
Inventors: Anke Stroyer; Carmen Lobback; Peter Serno; Tia JACOBS
Original assignee: Bayer AG; Bayer Pharma AG
Current assignee: Bayer AG; Bayer Pharma AG
Priority date: 2018-07-24
Filing date: 2019-07-19
Publication date: 2021-06-02
Also published as: WO2020020790A1; JP2021531297A; US20210283046A1; CN112469398A; CA3107174A1

Abstract

The invention relates to pharmaceutical dosage forms, which can be administered orally and have a modified release and contain (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid, and to processes for preparing the dosage forms and to the use thereof for treating and/or preventing diseases, in particular for treating and/or preventing cardiac, renal, pulmonary and ophthalmological disorders, disorders of the central nervous system, fibrotic and inflammatory disorders and metabolic diseases.

Description

Oral pharmaceutical dosage form with modified release

The present invention relates to orally administrable pharmaceutical dosage forms with modified release containing (3S) -3- (4-chloro-3 - {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3 methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid and process for the preparation of the dosage forms and their use for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiac, renal, pulmonary and ophthalmological diseases, diseases of the central nervous system, fibrotic and inflammatory diseases and metabolic diseases.

In WO 2012/139888 the compound (3S) -3- (4-chloro-3 - {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino is phenyl) -3-cyclopropylpropanoic acid of the formula (I),

and its preparation disclosed in Example 22. The compound of formula (I) acts as an activator of soluble guanylate cyclase. The document also discloses that the chemical compounds described can generally be converted into tablets, orally administrable suspensions and orally administrable solutions. These pharmaceutical dosage forms are only rapid-release pharmaceutical compositions.

For diseases that need to be treated over a longer period of time or for the long-term prophylaxis of diseases, it is desirable to keep the frequency of taking medication as low as possible. Not only is this more convenient for the patient, it also increases treatment safety by reducing the disadvantages of irregular earnings. The desired reduction in the frequency of administration, for example from twice a day to once a day, can be achieved by extending the therapeutically effective plasma level by means of modified release of active ingredients from the dosage forms. After taking dosage forms with modified active ingredient release, side effects can also be reduced by smoothing the course of the plasma level. By minimizing the so-called /? έn // M / UM «L ratio, that is, by avoiding high plasma drug concentrations, which can often be observed after administration of rapid-release dosage forms, the occurrence of undesirable side effects correlated with the concentration peaks can be reduced. Therefore, a drug form with modified release should be developed. An osmotic release system was selected to ensure the required profile of an even, long-lasting and complete release of active ingredient over a variable, previously defined period. Osmotic release systems differ from other delivery systems with delayed release, for example, in that the release profiles can be adjusted flexibly by adjusting the thickness of the sheath (Kaushal, AM, Garg, S. An Update on Osmotic Drug Delivery Patents. Pharmaceutical Technology. 2003. l3 (l): 8-97).

Osmotic release systems are also referred to as gastrointestinal therapeutic systems (GITS) or oral osmotic systems (OROS). The long-lasting and even release of an active ingredient is controlled by the osmotic pressure.

With osmotic release systems, a distinction can be made between single-chamber systems (elementary osmotic pump) and two-chamber systems (push-pull systems).

In the single-chamber system, one or more osmotically active substances are mixed with the active ingredient and pressed. These cores are surrounded by a semipermeable membrane that has at least one opening. This semipermeable membrane, hereinafter referred to as the shell, is impermeable to the components of the core, but allows the water to enter from the outside via osmosis. The penetrated water then releases the active ingredient in dissolved or suspended form from one or more openings in the shell via the osmotic pressure that arises. Overall drug release and release rate can be controlled essentially through the thickness and porosity of the shell, the composition of the core, and the number and size of the openings.

In the two-chamber system, one chamber contains the active substance, the other chamber the osmotically active substance. Both chambers can be separated by a flexible partition. This core is also surrounded by a sheath that has at least one opening on the side of the active substance-containing chamber.

Advantages, formulation aspects, application forms and information on manufacturing processes of osmotic release systems are u. a. described in the following publications:

• Kaushal, AM, Garg, p .: "An Update on Osmotic Drug Delivery Patents", Pharmaceutical Technology 2003, 13, 8-97. • Kumar, P. and Mishra, B.: "An OverView of Recent Patents on Oral Osmotic Drug Delivery Systems", Recent Patents on Drug Delivery & Formulation 2007, 1, 236-255.

• Verma, R.K., Mishra, B., Garg, S .: "Osmotically controlled oral drug delivery", Drug Development and Industrial Pharmacy 2000, 26, 695-708.

• Verma, R.K., Krishna, D.M., Garg, S.: "Formulation aspects in the development of osmotically controlled oral drug delivery Systems", Journal of Controlled Release 2002, 79, 7-27.

• Sareen. R "Jain, N" Kumar, D.: "An Insight to Osmotic Drug Delivery", Current Drug Delivery 2012, 9, 285-296.

• Malaterre, V., Ogorka, J "Loggia, N" Gumy, R.: "Oral osmotically driven Systems: 30 years of development and clinical use", European Journal of Pharmaceutics and Biopharmaceutics 2009, 73, 311-323.

• US 4,327,725

• US 4,765,989

US 20030161882

EP-A 1024793

In the context of the present invention, the compound of the formula (I) should be formulated in the form of an osmotic release system in order to achieve a long-lasting and uniform release.

Polyethylene oxide is usually used as the hydrophilic swellable polymer, particularly in two-chamber systems (WO 2006/072367). Unexpectedly, the compound of formula (I) cannot be formulated in the usual way in the form of an osmotic release system with polyethylene oxide as the hydrophilic swellable polymer. During the manufacturing process of the osmotic release system containing the compound of formula (I), melting phenomena occurred during the granulation. The resulting inefficient manufacturing process led to dosage forms that do not meet the requirements and specification of a pharmaceutical product.

When the compound of the formula (I) and polyethylene oxide were used as the hydrophilic swellable polymer, a change in the consistency of part of the granules obtained was observed during the dry granulation by means of a roller. The granulate components melted together to form a hard, plastic-like mass, similar to a solidified melt that could not be processed further. The planned manufacturing process had to be canceled. Shredding the solidified melt by rasping and sieving was only possible with great effort in terms of force, material and time, which made the manufacturing process inefficient and unreliable with regard to the reproducible pharmaceutical quality of the product.

Further processing occurred during the further processing of the elaborately sieved roller granules containing the active substance adverse effects when compressing the tablets. So-called bridging was already observed in the feed hopper, which describes the interlocking of the granules due to the coarse surface of the granules. The ready-to-press mixture could therefore not flow without additional agitation. As a result, continuous tableting of the granules as a ready-to-press mixture was not possible. Here, too, the manufacturing process had to be stopped. The parts of the tabletting machine, such as the punch, die and rotary table, showed strong buildup of the active ingredient-containing press mixture. The few tablets obtained showed a so-called inclination of the lid, the upper or lower part of the tablet being completely or partially detached horizontally from the main part when ejected from the tablet press or during the processing process and forming a cap. Such tablets do not meet the requirements for an acceptable pharmaceutical quality and are no longer usable.

Removal and analysis of various samples of the active ingredient-containing powder mixture before granulation, the plastic-like mass before sieving, the plastic-like mass after comminution and sieving and the residue on the grinding sieve showed strong fluctuations in the content of the compound of the formula (I). Starting from 100% of the declared active substance content in the active substance-containing powder mixture before granulation, the samples showed content values from 107% to 120% based on the declared active substance content. The consistently increased content values are probably due to the fact that only part of the roller granules melts during manufacture and the compound of the formula (I) is present in a heterogeneous distribution. A pharmaceutical dosage form with such deviations in the active substance content is not acceptable and cannot be used for further development. It can be assumed that the measured fluctuations in the content of the powder mixture also lead to fluctuations in the content of a tablet made from it, and that these tablets therefore do not meet the requirements of the pharmacopoeia, for example the uniformity of salary (Ph. Eur. Edition 9; 2.9.40 "Uniformity of Dosage Units ") correspond.

Surprisingly, by replacing the hydrophilic swellable polymer polyethylene oxide with a hydrophilic swellable polymer suitable according to the invention, an osmotic release system can be obtained which neither has the described disadvantageous properties of the osmotic release system containing the compound of formula (1) and polyethylene oxide, nor the disadvantages in the production described of the osmotic release system containing the compound of formula (1) and polyethylene oxide. Hydrophilic swellable polymers suitable according to the invention are preferably selected from a list consisting of xanthan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, vinyl pyrrolidone-vinyl acetate copolymer, polyacrylic acids or their salts and mixtures of the individual polymers. When the compound of the formula (1) is used together with hydrophilic polymers suitable according to the invention, no melting phenomena or other disadvantageous observations made during the individual manufacturing steps. The manufacturing process can be carried out completely without unplanned interruptions. The content determination gives results in line with specifications with regard to the declared active substance content.

The different behavior of a mixture of the compound of the formula (I) and polyethylene oxide compared to a mixture of the compound of the formula (I) and hydrophilic polymers suitable according to the invention can additionally be measured by DSC (differential scanning calorimetry) thermograms of the respective substances alone and in rubbings in a 1: 1 ratio (binary mixtures). The changes observed in the thermograms are indicative of the processability of the powder mixture. A trituration which contains the compound of the formula (I) and polyethylene oxide in equal parts shows no melting peak which can be assigned to the compound of the formula (I) (FIG. 1). A disappearance of the melting peak of the active ingredient, a broadening of the melting peak of the hydrophilic swellable polymer and an earlier start of melting correlate with the described defects in processability. The melting process therefore begins at a temperature between 50 ° C and 60 ° C. These temperatures can arise during the production of the osmotic release systems and cause the melting phenomena described. A trituration which contains the compound of formula (I) and xanthan in equal parts shows, in addition to the melting peak of xanthan, also an additional melting peak which can be assigned to the compound of formula (I) (FIG. 2). Binary mixtures of the compound of formula (I) with vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), polyvinylpyrrolidone (PVP 25), hydroxypropyl cellulose (HPC LM), anionic copolymers of methacrylic acid and methyl methacrylates (Eudragit L100, Eudragit RL PO) also show a melting peak , which is assigned to the compound of formula (I) and is in a high temperature range (FIGS. 3 to 7). Since these polymers are amorphous, no melting peak can be seen that can be assigned to the polymers. The thermogram of a trituration of the compound of formula (I) and polyacrylic acid shows no melting peak which can be assigned to the compound of formula (I) (FIG. 8). It is reasonable to assume that the compound of formula (I) dissolves with increasing temperature after the glass transition temperature of polyacrylic acid. Since the glass transition temperature is approx. 106 ° C, melting phenomena are not to be expected during the production of an osmotic release system with polyacrylic acid as the hydrophilic swellable polymer.

An object of the present invention is a solid, orally administrable, (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3 -methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of modified release pharmaceutical formulation of formula (I), characterized in that 80% of the compound of formula (I) are released in a period of 2 to 24, preferably 4 to 20 , measured according to the USP release method (USP 39; chapter <711> dissolution) with apparatus 2 (paddle) and the information in the chapter "Release behavior". Both bicameral systems (push-pull systems) and unicameral systems (elementary osmotic pump) are suitable for the formulation of the compounds of the formula (I) in the form of an osmotic release system. Both the two-chamber system and the one-chamber system consist of a core that is covered with a cover and optionally with a lacquer. The compound of formula (I) can be present in the osmotic release systems both in crystalline and in amorphous form or in mixtures with crystalline and amorphous components. The compound of formula (I) is preferably present in crystalline form in the osmotic release system. The compound of formula (I) is preferably present in micronized form in the osmotic release system.

An object of the present invention is a solid, orally administrable, (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3 -methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula (I), containing pharmaceutical dosage form with modified release, characterized in that the pharmaceutical dosage form is based on an osmotic release system.

An object of the present invention is a solid, orally administrable pharmaceutical dosage form containing the compound of formula (I) with modified release, characterized in that the pharmaceutical dosage form is based on an osmotic unicameral system.

An object of the present invention is a solid, orally administrable pharmaceutical dosage form containing the compound of formula (I) with modified release, characterized in that the pharmaceutical dosage form is based on an osmotic two-chamber system.

In one embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening, and the core being the compound of the formula (1) and at least one hydrophilic swellable polymer contains. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening and the core being the compound of the formula (1) and at least one hydrophilic swellable Polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and preferably selected from a methacrylate or copolymer List consisting of xanthan, Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,

Sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer.

In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening and the core being the compound of the formula (1), at least one hydrophilic swellable Polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and preferably selected from a methacrylate or copolymer List consisting of xanthan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,

Sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one pharmaceutically customary auxiliary and optionally an osmotically active additive. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening and the core being the compound of the formula (1), the hydrophilic swellable polymer Xanthan, optionally containing at least one further hydrophilic swellable polymer, optionally containing at least one customary pharmaceutical excipient and optionally containing an osmotically active additive. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening, and the core being 0.5% by weight to 50% by weight. % of the compound of the formula (1), 40% by weight to 99.5% by weight of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch,

Vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and polyacrylic acids or preferably selected from a list consisting of xanthan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, Contains vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one customary pharmaceutical excipient and optionally an osmotically active additive.

In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening, and the core being 1% by weight to 40% by weight of the Compound of the formula (1), 50% by weight to 99% by weight of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose,

Sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and polyacrylic acids or preferably selected from a list consisting of xanthan, hydroxypropyl cellulose,

Hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one pharmaceutically customary auxiliary and optionally an additive. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening, and the core being 2% by weight to 20% by weight of the Compound of the formula (1), 60% by weight to 90% by weight of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose,

Hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one pharmaceutically customary auxiliary and optionally an additive. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening and the core being 2% by weight to 10% by weight of the compound of the formula (I), 70% by weight up to 85% by weight of at least one hydrophilic swellable polymer selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose,

Sodium carboxymethylcellulose, starch derivatives such as sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, such as methacrylic acid-methyl methacrylate copolymer, and polyacrylic acids, or preferably selected from a list consisting of xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or a mixture of xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one pharmaceutically customary auxiliary and optionally an osmotically active additive.

In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material with at least one opening that is impermeable to the components of the core, and wherein the core

0.5% by weight to 50% by weight of the compound of the formula (I),

10% by weight to 50% by weight of xanthan,

• 5% by weight to 40% by weight of a vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one further hydrophilic swellable polymer, optionally containing at least one further pharmaceutically customary auxiliary and optionally containing an osmotically active additive.

The percentages by weight relate in each case to the total mass of the core.

The osmotic single-chamber system preferably contains the hydrophilic water-swellable polymer xanthan as one of the essential components of the core. This is an anionic heteropolysaccharide, which is commercially available, for example, under the name Rhodigel® (manufactured by Rhodia) or “Xanthan FN food quality normal” (manufactured by Jungbunzlauer Ladenburg GmbH). It is present in an amount of 10 to 50% by weight, preferably 25 to 40% by weight, based on the total mass of the core components.

Another essential component of the core is the vinyl pyrrolidone-vinyl acetate copolymer. This copolymer is known per se and can be mixed with any ratio of monomers getting produced. The preferred commercially available Kollidon® VA64 (manufactured by BASF) is, for example, a 60:40 copolymer. It generally has a weight average molecular weight, as determined by light scattering measurements, from about 45,000 to about 70,000. The amount of the vinylpyrrolidone-vinyl acetate copolymer in the core is 5 to 40% by weight, preferably 15 to 25% by weight, based on the total mass of the core components.

Hydrophilic swellable polymers which may additionally be present in the core are, for example, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch, vinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone, methacrylic acid copolymers, for example methacrylic acid or methyl methacrylate copolymers or their methacrylate acids or methyl methacrylate copolymers.

Another object of the present invention is a method for producing an osmotic release system, characterized in that the components of the core are mixed with one another, granulated and tabletted, the resulting core is coated with a shell and the shell finally with one or more openings, suitable for Leaving the compound of formula (I) is provided.

The present invention furthermore relates to a process for producing an osmotic single-chamber system according to the invention, the components of the core being mixed with one another, granulated, if appropriate, moist or dry, then tabletted and the core thus produced being coated with the shell. The shell is provided with one or more openings on the active ingredient side. Alternatively, the introduction of the one or more openings in this process step can be omitted and first a varnish, for example a light protection and / or colored varnish, can be applied. In this case, both sides of the tablet are only coated after one or more further varnishes have been applied provided an opening, each of which extend from the outside to the inner core, ie Cross the paint and the shell and are suitable for the exit of the compound of formula (1). In a preferred embodiment of the present invention, the core components are subjected to wet granulation in the manufacture of the osmotic single-chamber system, since this process step brings about a better wettability of the constituents of the tablet core, as a result of which the gastrointestinal fluid entering penetrates the core better, which often leads to a faster and more complete release of the Active ingredient leads.

The shell and the optionally present lacquer of the osmotic drug release system of the present invention have at least one opening or passage through which the active ingredient gradually escapes together with the other core components. The opening is made in the shell by laser drilling, mechanical drilling or, for example, punching. It can be one or more There are openings in the casing. The size of the opening (diameter) is preferably 0.2 to 1.6 mm, particularly preferably 0.3 to 1.2 mm. The nature and the manufacturing method of the opening are known per se and described, for example, in US 4063064, US 4088864, US 3916899 or EP-A 0277092. In a further embodiment, the core of the osmotic release system consists of two layers, an active substance layer and an osmotic layer. Such an osmotic two-chamber system is described in detail, for example, in DE 3417113 C2, WO 2006/072367 or WO 2010/060564, the disclosure of which is hereby incorporated by reference. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening, and the core consisting of an active substance layer and an osmosis layer. In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material that is impermeable to the components of the core and having at least one opening, and wherein the core consists of an active substance layer and an osmosis layer and the active substance layer is 1% by weight .-% to 50 wt .-% of the compound of formula (1), 20 wt .-% to 99 wt .-% of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose .

Sodium carboxymethylcellulose, starch derivatives such as sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, such as methacrylic acid-methyl methacrylate copolymer, and polyacrylic acids, or selected from a list consisting of xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and Polyacrylic acids, preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer, optionally containing at least one osmotically active additive and optionally containing at least one customary pharmaceutical auxiliary. In a further embodiment, the active substance layer contains 1% by weight to 45% by weight, preferably 1% by weight to 30% by weight, particularly preferably 2% by weight to 20% by weight, of the compound of the formula ( 1), 30% by weight to 99% by weight, preferably 50% by weight to 99% by weight, particularly preferably 60% by weight to 98% by weight, of at least one hydrophilic swellable polymer, if appropriate at least an osmotically active additive and, if appropriate, at least one pharmaceutically customary auxiliary. In a further embodiment, the osmotic release system consists of a core and a shell, the shell of a water-permeable for the components of the core impermeable material with at least one opening and wherein the core consists of one of the previously described active ingredient layers and an osmosis layer, the osmosis layer 40 to 90 wt .-%, preferably 50 wt .-% to 80 wt .-% of at least one hydrophilic swellable Polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,

Starch derivatives, for example sodium carboxymethyl starch, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and polyacrylic acids or selected from a list consisting of xanthan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,

Sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer, and optionally containing at least one customary pharmaceutical excipient.

In a further embodiment, the osmotic release system consists of a core and a shell, the shell consisting of a water-permeable material with at least one opening that is impermeable to the components of the core, and wherein the core consists of an active substance layer and an osmosis layer, the active substance layer 1 % By weight to 50% by weight of the compound of the formula (1), 20% by weight to 99% by weight of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methylcellulose,

Sodium carboxymethylcellulose, starch derivatives such as sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, such as methacrylic acid-methyl methacrylate copolymer, and polyacrylic acids, or selected from a list consisting of xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and Polyacrylic acids, preferably xanthan, optionally containing at least one osmotically active additive and optionally at least one pharmaceutically customary excipient, and the osmosis layer 40% by weight to 90% by weight of at least one hydrophilic swellable polymer, preferably selected from a list consisting of xanthan, Cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,

Sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer and polyacrylic acids, preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer, and optionally containing at least one customary pharmaceutical excipient. In a further embodiment, the osmotic release system consists of one of the osmotic release systems described above, the shell consisting of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

In a further embodiment, the osmotic release system is one of the osmotic release systems described above, 80% of the compound of the formula (I) being released after 2 hours to 24 hours, preferably 4 hours to 20 hours, particularly preferably 5 hours to 16 hours according to the USP release method (USP 39; chapter <711> dissolution) with apparatus 2 (paddle) and the information in the chapter "Release behavior").

In the context of the present invention, hydrophilic swellable polymers are all pharmaceutically usable polymer compounds known to the person skilled in the art which swell up by absorbing water, with the exception of the hydrophilic swellable polymer polyethylene oxide. a hydrophilic swellable polymer is preferably at least selected from a list consisting of xanthan gum, cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose, starch derivatives such as sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, such as methacrylic acid-methyl methacrylate copolymer, and polyacrylic acids, or selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropylmethyl cellulose or sodium carboxymethyl cellulose, starch derivatives, for example sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone and methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer.

a hydrophilic swellable polymer is further preferably at least selected from a list consisting of xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone-vinyl acetate copolymer, and polyacrylic acids, or selected from a list consisting of xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch and vinylpyrrolidone Vinyl acetate copolymer is used, particularly preferably xanthan and vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof are used.

Furthermore, at least one hydrophilic swellable polymer is preferably selected from a list consisting of xanthan, Kollidon VA 64, PVP 25, Eudragit L100, Eudragit RL PO, HPC LM and polyacrylic acid or selected from a list consisting of xanthan, Kollidon VA 64, PVP 25, Eudragit L100, Eudragit RL PO and HPC LM are used.

In the context of the present invention, starch derivatives suitable as hydrophilic swellable polymers are corn, wheat, rice and potato starch, substituted starches such as carboxymethyl starch and its salt, hydroxyethyl starch or mixtures thereof. In the context of the present invention, cellulose derivatives suitable as hydrophilic swellable polymers are methyl cellulose (MC), hydroxymethyl propyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose sodium (Na-CMC), hydroxyethyl cellulose (HEC) or mixtures thereof.

The hydrophilic swellable polymers mentioned can be used alone or in combination with other hydrophilic swellable polymers.

Some hydrophilic swellable polymers can alternatively be used as pharmaceutically customary auxiliaries in the core, for example as binders or disintegrants. If the proportion of such a substance in the core is 10 or more percent based on the mass of the core, such a substance is considered a hydrophilic swellable polymer in the context of the present invention.

In the context of the present invention, osmotically active additives are, for example, all water-soluble substances whose use in pharmacy is harmless, e.g. the water-soluble excipients mentioned in Pharmakopoen, in "Hager" and "Remington Pharmaceutical Science" or other literature (Sareen. R., Jain, N., Kumar, D., Current Drug Delivery, 9, (2012), 285-296) , In particular, water-soluble salts of inorganic or organic acids or nonionic organic substances with high water solubility such as e.g. Carbohydrates, especially sugar, sugar alcohols or amino acids can be used. For example, the osmotically active additives can 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 phosphates, hydrogen or dihydrogen phosphates, acetates, succinates, benzoates, Citrate or ascorbate thereof. Pentoses 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 can also be used. The water-soluble amino acids include glycine, leucine, alanine or methionine. Sodium chloride is preferably used.

Pharmaceutically customary auxiliaries in the context of the present invention are, for example, buffer substances such as sodium bicarbonate, binders such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone or vinyl pyrrolidone-vinyl acetate copolymer (Kollidon® VA64), disintegrants such as sodium carboxymethyl starch, lubricants such as magnesium stearate, surfactant such as sodium disodium fluoride, and sodium laurate Protective colloids as described in EP-B-0277092 (page 5, lines 10-25), plasticizers as described for example in EP-B-0277092 (page 5, lines 29-32), surfactants such as described in EP-B-0277092 (page 5, lines 33-44), support materials as described, for example, in EP-B-0277092 (page 5, lines 45-47) and one or more color pigments such as iron oxide in one of the two layers for differentiating the active substance and osmosis layers. Suitable protective colloids are, for example, methylated Cellulose derivatives, for example methyl cellulose with a methoxy content of approx. 27.0 to 32.0% and a degree of substitution of approx. 1.75 to 2.1 or methyl hydroxypropyl cellulose with a content of approx. 16.0 - 30.0% methoxy and 4.0-32.0% hydroxypropoxy groups. Suitable plasticizers are, for example, glycerol, triethyl citrate, diethyl phthalate or diethyl sebacate. Suitable surfactants are, for example, anionic surfactants of the alkyl sulfate type, for example sodium, potassium or magnesium n-dodecyl sulfate, n-tetradecyl sulfate, n-hexadecyl sulfate or n-octa-decyl sulfate, alkyl ether sulfate, for example Sodium, potassium or magnesium n-dodecyloxyethyl sulfate, -n-tetradecyloxyethyl sulfate, -n-hexadecyl-oxyethyl sulfate or -n-octadecyloxyethyl sulfate or alkane sulfonate, for example sodium, potassium or magnesium n-dodecane sulfonate, -n-tetradecane n-hexadecane sulfonate or n-octadecane sulfonate. Suitable surfactants are also nonionic surfactants of the fatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxy alcohol esters such as polyoxyethylene sorbitan monolaurate, oleate palmitate, oleate palmitate tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, in particular ethylene oxide propylene oxide block polymers of the Pluronics® (BWC) or Synperonic® (ICI) type. Suitable carrier materials are, for example, lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, corn starch or amylopectin, or cellulose.

The shell of the osmotic drug delivery system consists of a water-permeable film-forming material that is impermeable to the components of the core in both the one-chamber and the two-chamber system. Such enveloping materials are known in principle and are described, for example, in EP 1024793. For example, acylated cellulose derivatives can be used as covering materials.

Acylated cellulose derivatives (cellulose esters) are substituted one to three times by acetyl groups or one to two times by acetyl groups and a further acyl radical other than acetyl, e.g. Cellulose acetate, cellulose triacetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate,

Cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate,

Cellulose acetate propionate, cellulose acetate diethylamino acetate, cellulose acetate acetate, cellulose acetate laurate, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, and shell materials from the group of cellulose ethers such as e.g. Ethyl cellulose or other cellulose acetate derivatives as well as agar acetate and amylose acetate.

Also suitable as material for the casing are ethyl cellulose and polymeric epoxies, copolymers of alkylene oxide and alkyl glycidyl ether, polyglycols and polylactic acid derivatives and other derivatives from that. Mixtures of per se water-insoluble acrylates (for example a copolymer of ethyl acrylate and methyl methacrylate) can also be used.

In the context of the present invention, cellulose acetate or mixtures of cellulose acetate and polyethylene glycol are preferably used as the covering material.

The amounts and the components used for the manufacture of the shell of the osmotic drug release system influence the rate of entry of the gastrointestinal fluid in a known manner. Basically, the rate of entry of the gastrointestinal fluid decreases with increasing amount of covering material.

If necessary, a varnish, for example a light protection and / or colored varnish, can be applied to the casing. Particularly suitable materials are, for example, polymers such as polyvinyl alcohol, hydroxypropyl cellulose and / or hydroxypropyl methyl cellulose, optionally in combination with suitable plasticizers such as polyethylene glycol or polypropylene glycol and pigments such as titanium dioxide or iron oxides. The coating with a film coating may be mentioned by way of example, for which polyvinyl alcohol and polyethylene glycol 3350 are first dissolved in water at room temperature and mixed with stirring. Talc, titanium dioxide and iron oxide are gradually added with stirring. Lacquer suspensions can, for example, with a suitable painting unit, e.g. a Glatt-Coater, on which tablet cores are applied. Alternatively, coating can be carried out instead of coating. In general, such a coating is applied by an aqueous or organic application medium. In the context of the present invention, the term coating additionally also denotes coatings on the casing which are applied by an alternative process, for example a solvent-free process ,

So-called "ready-made paints" can also be used as paints. These already contain a mixture of auxiliary substances and are dissolved and applied in water. Opadry 11 85F230009 Orange (Colorcon PVA-based finish) is mentioned as an example, which contains partially hydrolyzed polyvinyl alcohol, talc, polyethylene glycol (PEG 3350), titanium dioxide, red iron oxide, yellow iron oxide and polysorbate 80 (Tween 80).

The shell of the osmotic drug delivery system of the present invention has at least one opening or passage through which the active ingredient together with the other core components gradually escapes. The opening is made in the shell by laser drilling, mechanical drilling or, for example, punching. There may be one or more openings in the shell. The size of the opening (diameter) is preferably 0.2 to 1.6 mm, particularly preferably 0.3 to 1.2 mm. The nature and the manufacturing method of the opening are known per se and described, for example, in US 4063064, US 4088864, US 3916899 or EP-B-0277092. The optional paint can also have one or more openings. In the described embodiments, at least one water-soluble salt of inorganic or organic acids, particularly preferably sodium chloride, is preferably used as the osmotically active additive.

In the embodiments described, binders such as, for example, hydroxypropyl cellulose, lubricants such as, for example, magnesium stearate, flow regulating agents, such as, for example, highly disperse silicon dioxide and color pigments such as, for example, iron oxide are preferably used as pharmaceutically customary auxiliaries.

To produce the osmotic two-chamber system, for example, the components of the active ingredient layer can be mixed and granulated moist or dry, preferably dry, the components of the osmotic layer can be mixed and granulated, and then both granules can be compressed into a two-layer tablet on a two-layer tablet press. The resulting inner core is then coated with a shell. The shell is provided with one or more openings on the active ingredient side. Alternatively, the introduction of the one or more openings in this process step can be omitted. In this case, only after coating with one or more lacquers are both sides of the tablet provided with an opening, each of which extends from the outside to the inner core, i.e. Cross the varnish and casing.

During the production of the osmotic two-chamber system, both the components of the active substance layer and the components of the osmotic layer are each granulated, in particular with the aid of roller granulation.

The dosage forms according to the invention have valuable pharmacological properties and can be used for the treatment and / or prevention of diseases in humans and animals. For the purposes of the present invention, the term “treatment” or “treat” includes inhibiting, delaying, stopping, alleviating, weakening, restricting, reducing, suppressing, suppressing or curing a disease, ailment, a disease, an injury or a health-related Disorder, development, course or progression of such conditions and / or symptoms of such conditions. The term "therapy" is understood here as synonymous with the term "treatment".

The terms "prevention", "prophylaxis" or "prevention" are used synonymously in the context of the present invention and mean avoiding or reducing the risk, an illness, a disease, an illness, an injury or a health disorder, an unfolding or a To progress, experience, suffer, or have symptoms of such conditions and / or the symptoms of such conditions. The treatment or prevention of an illness, a condition, an illness, an injury or a health disorder can take place partially or completely.

The dosage forms according to the invention lead to vascular relaxation, to a platelet inhibition of aggregation, to a lowering of blood pressure and to an increase in the coronary blood flow and the microcirculation. These effects are mediated by direct, heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP levels.

The dosage forms according to the invention are particularly suitable for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular diseases, in particular heart failure (HFpEF and HFrEF), heart attack , Angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary diseases, in particular pulmonary hypertension (PH), diseases of the central nervous system, in particular dementia, bone diseases, in particular osteogenesis imperfecta, thromboembolic diseases, muscular dystrophies, ischemia, vascular disorders, fibrous disorders, fibrosis Diseases in particular of systemic sclerosis, in particular age-related macular degeneration, inflammatory diseases, and metabolic diseases, in particular of the metabolic syndrome, dyslipidemia and D iabetes.

The dosage forms according to the invention can be used for the treatment and / or prevention of cardiac, cardiovascular and cardiopulmonary diseases, for example high blood pressure (hypertension), heart failure, coronary heart disease, stable and unstable angina pec toris, pulmonary arterial hypertension (PAH) and secondary forms of pulmonary Hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal hypertension, peripheral and cardiac vascular diseases, arrhythmias, arrhythmias of the atria and the ventricles as well as conduction disorders, for example atrio-ventricular blockages of grade I-III, supraventricular tachyflammatory arrhythmia , Ventricular fibrillation, ventricular tachyarrhythmia, torsade de pointes tachycardia, extrasystoles of the atrium and ventricle, AV junctional extrasystoles, sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff- Parkinson-White- syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock.

The dosage forms according to the invention can be used for the treatment and / or prevention of thromboembolic diseases and ischemia, such as myocardial ischemia, myocardial infarction, rash, cardiac hypertrophy, transistoric and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema e.g. pulmonary edema, himedema, renal edema or edema due to cardiac insufficiency, peripheral circulatory disorders, reperfusion damage, arterial and venous thrombosis, microalbuminuria, cardiac muscle weakness, endothelial dysfunction, micro- and macrovascular damage (vasculitis), as well as for preventing thrombosis after restenosis , percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, bypass surgery and micro and macro vascular damage (vasculitis), increased levels of fibrinogen and low-density LDL, as well as increased concentrations of plasminogen activator inhibitor 1 (PAI-l), as well as for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction. For the purposes of the present invention, the term "pulmonary hypertension" encompasses both primary and secondary sub-forms thereof, as defined by the Dana Point classification according to their respective aetiology [see D. Montana and G. Simonneau, in: AJ Peacock et al. (Ed.), Pulmonary Circulation. Diseases and Their treatment, 3 ^rd edition, Hodder Arnold Publ, 2011, pp 197-206. MM Hoeper et al., J Am. Coli. Cardiol. 2009, 54 (1), S85-S96] This includes in particular group 1 pulmonary arterial hypertension (PAH), which includes idiopathic and familial forms (1PAH and FPAH), acute pulmonary hypertension, especially that Acute respiratory distress syndrome (ARDS), acute lung injury (AL1) and neonatal respiratory distress syndrome (infant respiratory distress syndrome - 1RDS). Furthermore, PAH also includes persistent pulmonary hypertension in newborns and associated pulmonary arterial hypertension (AP AH), which is associated with collagenosis, congenital systemic pulmonary shunt vitamins, portal hypertension, HIV infections, the use of certain drugs and medications ( for example, by appetite suppressants), with diseases with a significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary-capillary hemangiomatosis, or with other diseases such as thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasis, hemoglobino-pathological diseases, myelop splenectomy. Group 2 of the Dana Point classification comprises PH patients with a causative left heart disease, such as ventricular, atrial or valvular diseases. Group 3 includes forms of pulmonary hypertension associated with a lung disease, e.g. chronic obstructive pulmonary disease (COPD), interstitial lung disease (1LD), pulmonary fibrosis (1PF), and / or hypoxemia, sleep apnea, alveolar hypoventilation, chronic altitude sickness, association-related disorders are. Group 4 includes PH patients with chronic thrombotic and / or embolic diseases, for example with thromboembolic obstruction of proximal and distal pulmonary arteries (CTEPH) or with non-thrombotic embolizations (e.g. as a result of tumor diseases, parasites, foreign bodies). Less common forms of pulmonary hypertension, such as those with sarcoidosis, histiocytosis X or lymphangiomatosis, are in group 5 summarized.

For the purposes of the present invention, the term "heart failure" encompasses both acute and chronic manifestations of heart failure as well as specific or related forms of the disease, such as acute congestive heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophy, hypertrophy, hypertrophy Cardiomyopathy, congenital heart defects, heart valve defects, heart failure with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, myocardial myocardial insufficiency, myocardial myocardial insufficiency, myocardial myocardial insufficiency, heart failure alcohol-toxic cardiomyopathy, cardiac storage diseases as well as diastolic and systolic heart failure, He or insufficiency with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF).

The dosage forms according to the invention are also suitable for the treatment and / or prevention of metabolic diseases. In the context of the present invention, metabolic diseases are, for example, diseases of the glucose metabolism and diseases and complications which are associated with a disturbed glucose metabolism. Diseases of the glucose metabolism are, for example, diabetes mellitus (type 1 or type 2), insulin resistance, impaired glucose tolerance, hyperglycaemia, hypoglycaemia, hyperinsulinemia or hypoinsulinemia. Diseases associated with a disturbed glucose metabolism are, for example, micro- and macroangiopathies, diabetic retinopathies, diabetic neuropathies, diabetic nephropathies, delayed / impaired wound healing, diabetic foot, tissue ischemia, ulcers on the extremities, gangrene, metabolic acidosis, ketidemia, dysiasis , Myocardial infarction, acute coronary syndrome, stable or unstable angina pectoris, cardiomyopathies, heart failure, cardiac arrhythmia, vascular restenosis, peripheral arterial disease, obesity, syndrome X, fat metabolism disorders, arteriosclerosis or high blood pressure. The compound of formula (1) according to the invention and the dosage forms according to the invention are also suitable for maintaining, improving and restoring the functions of cells of the pancreas, in particular for maintaining, improving and restoring the number and size of the β-cells of the pancreas. Within the scope of the present invention, metabolic diseases are also diseases of the fat metabolism such as lipid metabolism disorders, hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipidemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia, adiposity, obesity (obesity), obesity (obesity), obesity (obesity), obesity, fat loss , Atherosclerosis and the metabolic syndrome. The dosage forms according to the invention are also suitable for the treatment and / or prevention of cardiovascular Diseases associated with a metabolic disorder.

The dosage forms according to the invention are also suitable for the treatment and / or prevention of muscular or neuromuscular diseases. The term "muscular or neuromuscular diseases" refers to a medical condition that affects the muscles and / or their direct control of the nervous system. They can be acquired or be of genetic origin. In particular, muscular or neuromuscular diseases are Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, Miyoshi myopathy, Emery tripod muscular dystrophy, facioscapulohumeral muscular dystrophy, muscular dystrophy, myotomy, muscular dystrophy, myotomy Muscular dystrophy, oculopharyngeal muscular dystrophy, myasthenia gravis, Lambert-Eaton myasthenic syndrome and Charcot-Marie-Tooth disease.

Furthermore, the dosage forms according to the invention can be used for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculation disorders, claudication, hearing disorders, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, CREST syndrome, erythematosis, onychomycosis and rheumatism ,

The dosage forms according to the invention can also be used for the treatment and / or prevention of ischemia and / or reperfusion-related damage to organs or tissues and as additives for perfusion and preservation solutions of organs, organ parts, tissues or tissue parts of human or animal origin, in particular during surgical interventions or find use in the field of transplant medicine.

The dosage forms according to the invention are also suitable for the treatment and / or prevention of kidney diseases, in particular of kidney insufficiency and kidney failure. For the purposes of the present invention, the terms kidney insufficiency and kidney failure include both acute and chronic manifestations (chronic kidney disease; CKD) thereof as well as the basis thereof or related kidney diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, kidney inflammation, kidney inflammation, and kidney disease-related diseases such as osseous transplantation disorders, kidney disease, osteoarthritis diseases, osteoarthritis disorders, and kidney disease-related diseases such as nebuclear transplantation disorders such as kidney disease, osteoarthritis disorders, and kidney disease-related disorders such as kidney inflammation and immunological transplant disorders induced nephropathy, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, diabetic kidney crane (DKD), pyelonephritis, kidney cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which are diagnosed, for example, by abnormally reduced creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of Kidney enzymes, for example glutamyl synthetase, changed urinosmolarity or urine quantity, increased microalbuminuria, macroalbuminuria, lesions on glomerula and arterioles, tubular dilatation, hyperphosphataemia and / or the need for dialysis can be characterized. The present invention also includes the use of the dosage forms according to the invention for the treatment and / or prevention of sequelae of renal insufficiency, for example hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (for example hyperkalemia, hyponatremia) and disorders in the bone and carbohydrate metabolism.

In addition, the dosage forms according to the invention are suitable for the treatment and / or prevention of diseases of the genitourinary system, for example benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorders (BOO), lower hamstring syndromes (LUTS), interstitial cystitis, neurogenic overactive bladder (OAB), incontinence, e.g. mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain and erectile dysfunction, female sexual dysfunction, vaginal atrophy, dyspareunia or atrophic vaginitis.

The dosage forms according to the invention are also suitable for the treatment and / or prevention of asthmatic diseases, chronic obstructive pulmonary diseases (COPD), acute respiratory syndrome (ARDS) and acute lung damage (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis , pulmonary emphysema (emphysema for example, cigarette smoke-induced lung), pulmonary venous hypertension, interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, coagulation disorders, chronic thromboembolism, tumor-associated pulmonary embolism, connective tissue disease, lupus , Schistosomiasis, sarcoidosis, chronic bronchitis, capillary pulmonary hemangiomatosis; Histiocytosis X, lymphangiomatosis and compressed lung vessels due to adenopathy, fibrotic mediastinitis and cystic fibrosis (CF).

The dosage forms according to the invention described in the present invention also represent dosage forms for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving perception, concentration, learning or memory after cognitive disorders, as they occur in particular in situations / diseases / syndromes such as "mild cognitive impairment", age-associated learning and memory disorders, age-associated memory loss, dementia, vascular dementia, mixed forms the dementia, dementia that occurs after strokes ("post stroke dementia"), post-traumatic craniocerebral trauma, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's dementia, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, with schizophrenia Dementia or Korsakoff psychosis, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (iCADASIL or CADASIL syndrome), asymptomatic neurocognitive disorder (including MSI), MSI (MSI), asymptomatic neurocognitive disorder (ANI) Syndrome (CIS), relapsing MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS), multisystem atrophy (MSA), Parkinson's disease, Parkinsonism Plus, progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome) ), Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) They are also suitable for the treatment and / or prevention of diseases of the central nervous system such as anxiety, tension and depression, central nervous-related sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders in the intake of food, beverages and addictive substances. They are also suitable for the treatment and / or prevention of injuries, for example traumatic traumas (TBI), including e.g. B. Concussions and traumatic encephalopathies (CTE), or non-traumatic strokes (including ischemic strokes, aneurysms or hypoxia), brain damage, cognitive impairments, brain injuries, neurodegenerative diseases or neuropathic pain. They are also suitable for the treatment and / or prevention of dystonia, for example generalized, focal, segmental, vegetative, acute dystonic reactions and genetic / primary dystonia and dyskinesia, including acute, chronic / tardive and non-motor and levo-dopa-induced Dyskinesia (LID). They are also suitable for the treatment and / or prevention of diseases which are characterized by a reduction in the synaptic plasticity and the synaptic processes, for example Fragil-X syndrome, Rett syndrome, Williams syndrome, Renpenning syndrome, autism spectrum disorders including autism, Asperger syndrome, or profound developmental disorders. They are also suitable for the treatment and / or prevention of mental, affective or psychological disorder, for example bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusion, schizoaffective disorder, obsessive-compulsive disorder (OCD), depressive disorders, anxiety disorders, panic disorders or post-traumatic stress disorder (PTSD).

Furthermore, the dosage forms according to the invention are also suitable for regulating cerebral blood flow and are therefore effective means for combating migraines. They are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke, cerebral ischemia and cranial and trauma. The dosage forms according to the invention can also be used to combat painful conditions.

In addition, the dosage forms according to the invention have anti-inflammatory effects and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid diseases and inflammatory skin diseases be used.

The dosage forms according to the invention are also suitable for the treatment and / or prevention of acute pain, central pain syndrome, chemotherapy-induced neuropathy and neuropathic pain, diabetic neuropathy, fibromyalgia, inflammatory pain, neuropean pain, postoperative pain, tonic pain or visceral pain.

The dosage forms according to the invention are also suitable for the treatment and / or prevention of fibrous diseases of the internal organs, such as the lungs, heart, kidneys, bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic diseases of the eye. For the purposes of the present invention, the term “fibrotic diseases” particularly includes such diseases as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic diseases, scleroderma, systemic sclerosis, mor , Keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitroretinopathy and diseases of the connective tissue (e.g. sarcoidosis). The dosage forms according to the invention can also be used for the treatment of steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), for promoting wound healing, for combating postoperative scarring, for example after glaucoma operations, and for cosmetic purposes in the case of aging and cornified skin.

Furthermore, the dosage forms according to the invention are suitable for the treatment and / or prevention of bone diseases such as, for example and preferably, osteogenesis imperfecta (oil), bone fractures, bone healing disorders, rickets, osteomalacia, avascular bone necrosis, Paget's disease, osteodystrophy, osteopenia, osteolytic lesions due to bone metastases, radiation therapy or chemotherapy, periodontitis, hypercalcemia, osteonecrosis, osteosarcoma, osteolytic metastases, familial expansive osteolysis, expansile skeletal and idiopathic hyperplasia, hyperostosis corticalis deformans juvenilis, Camurati-Engelmann disease, prosthetic loosening, periprosteletic osteomalysis, multiplyolitic osteolysis, dressol Bone loss, bone loss due to immobilization or lack of sex hormones, bone loss associated with a disease selected from the group consisting of cachexia, anorexia, alopecia and inflammatory Diseases selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, psoriasis, spondyloarthritis, SLE, systemic sclerosis, metastatic cancer and inflammatory bowel disease, osteoarthritis, impaired bone healing after osteotomy, idiopathic bone loss in childhood, curvature of the spine, osteoporosis, primary osteoporosis, secondary osteoporosis and especially osteoporosis, primary osteoporosis or secondary osteoporosis, which is not caused by a lack of sex hormones.

Furthermore, the dosage forms according to the invention are suitable for the treatment and / or prevention of dysfunctions of gastrointestinal sphincters, such as achalasia, sphincter spasms and hypertensive sphincters, in particular lower esophageal sphincters (LES) achalasia, esophageal achalasia, spastic LES, hypertensive LES (HTussphinks), hypertensive PES (HTusslesink) Pylorus) achalasia, pyloric spasm (pylorospasm), hypertensive pylorus, ileocecal sphincter or valve (ICV) achalasia, hypertensive ICV, spastic ICV or ICV spasm, sphincter of Oddi dysfunction (SOD), sphincter Oddi's sphincter, Oddi's hypertensive sphincter, internal anal sphincter (IAS) achalasia, hypertensive IAS, spastic IAS or IAS cramp. In a further embodiment, the mentioned dysfunctions of gastrointestinal sphincters can be attributed to a neurological, metabolic, endocrine or neurodegenerative disease.

Furthermore, the dosage forms according to the invention are suitable for the treatment and / or prevention of ophthalmic diseases, which in the sense of the invention are understood to mean, for example, the following diseases: age-related macular degeneration (AMD) including dry (non-exudative) and moist (exudative, neovascular) AMD , choroidal neovascularization (CNV), choroidal neovascular membranes (CNVM), cystoid macular edema (CME), epiretinal membranes (ERM) and macular perforations, myopia-associated choroidal neovascularization, angioid and vascular stripes, retinal detachment, diabetic retina Non-proliferative diabetic retinopathy (NPDR), diabetic macular edema (DME), atrophic and hypertrophic changes in the retinal pigment epithelium, retinal venous occlusion, choroidal retinal venous occlusion, macular edema, macular edema associated with retinal venous occlusion, retinitis pigmentosa, Stargardt's Disease, premature retinopathy, glaucoma, inflammatory diseases of the eye, for example uveitis, scleritis or endophthalmitis, cataract, refractive anomalies, for example myopia, hyperopia, astigmatism or keratoconus, coma angiogenesis as a result of, for example, keratitis, corneal transplantation, or keratoplasty as keratoplasty Consequences of hypoxia (e.g. through extensive contact lens wear), pterygium conjunctivae, subcomeal edema and intracomeal edema.

Due to their active profile, the dosage forms according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiopulmonary diseases such as primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris and hypertension, and of thromboembolic diseases, ischemia, vascular diseases, microcirculatory disorders, renal failure, fibrot Diseases and arteriosclerosis. The dosage forms according to the invention are preferably suitable for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular diseases, in particular heart failure (HFpEF and HFrEF), heart attack, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary diseases, especially pulmonary hypertension (PH), ophthalmological diseases, especially non-proliferative diabetic retinopathy (NPDR) and diabetic macular edema (DME), diseases of the central nervous system, especially dementia Bone diseases, in particular osteogenesis imperfecta, thromboembolic diseases, muscular dystrophies, ischemia, vascular diseases, microcirculation disorders, fibrotic diseases, in particular systemic sclerosis, inflammatory diseases, and metabolism diseases, in particular the metabolic syndrome, dyslipidemia and diabetes.

The dosage forms according to the invention are preferably suitable for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD).

The dosage forms according to the invention are preferably suitable for the treatment and / or prevention of ophthalmic diseases, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular edema (DME).

The dosage forms according to the invention are preferably suitable for treatment and / or

Prevention of cardiovascular diseases, especially heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).

Prevention of cardiopulmonary diseases, especially pulmonary hypertension.

Prevention of diseases of the central nervous system, especially dementia, including vascular dementia and mixed forms of dementia.

Prevention of "muscular or neuromuscular diseases", especially Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Another object of the present invention is the use of the dosage forms according to the invention for the treatment and / or prevention of sickle cell anemia, traumatized Patients receive a synthetic blood substitute and for the preservation of blood substitutes.

Another object of the present invention is the use of the invention

Dosage forms for the treatment and / or prevention of polycystic ovary syndrome (PCOS).

Another object of the present invention is the use of the invention

Dosage forms for the treatment and / or prevention of preeclampsia.

Another object of the present invention is the use of the invention

Dosage forms for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the invention

Dosage forms in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using at least one dosage form according to the invention.

The dosage forms according to the invention can be used alone or, if necessary, in combination with other active ingredients. The present invention furthermore relates to medicaments containing at least one of the dosage forms according to the invention and one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases. Examples of suitable combination active ingredients which may be mentioned are:

• Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, as well as inhaled NO;

• Other substances that increase the cGMP concentration, such as protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives;

• NO synthase substrates, such as N-hydroxyguanidine derivatives, L-arginine derivatives, N-alkyl-N'-hydroxyguanidine derivatives, N-aryl-N'-hydroxyguanidine derivatives or guanidine derivatives;

• Compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4, 5, 9 and / or 10, in particular PDE-4- Inhibitors such as Roflumilast or Revamilast and PDE-5 inhibitors such as Sildenafil, Vardenafil, Tadalafil, Udenafil, Dasantafil, Avanafil, Mirodenafil or Lodenafil; • NO-independent but heme-dependent stimulators of guanylate cyclase, in particular riociguat, nelociguat, vericiguat, praliciguat (IW-1973), oleinciguat (IW-1701) and those in WO 00/06568, WO 00/06569, WO 02/42301 , WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549;

• prostacyclin analogs and IP receptor agonists, by way of example and preferably iloprost, berastro, treprostinil, epoprostenol, NS-304, Selexipag or Ralinepag;

Endothelin receptor antagonists, by way of example and preferably bosentan, darusentan, ambrisentan, macicentan or sitaxsentan;

• Inhibitors of human neutrophil elastase (HNE), for example and preferably Sivelestat or DX-890 (Reltran);

Compounds which inhibit the signal transduction cascade, in particular from the group of tyrosine kinase inhibitors, by way of example and preferably dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefibinib, gefitinib, Canertinib, lestaurtinib, pelitinib, semaxanib, masitinib or tandutinib;

Rho-kinase inhibitors, by way of example and with preference Fasudil, Y-27632, SLx-21 19, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;

• anti-obstructive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example and preferably by inhalation or systemically used beta-receptor mimetics (e.g. Bedoradrin) or inhalation-applied anti-muscarinic substances;

Anti-inflammatory and / or immunosuppressive agents, such as those used for the treatment of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, for example and preferably systemically or inhalatively applied corticosteroids, flutiform, pirfenidone, acetylcysteine, azathioprine or BIBF- l 120;

• chemotherapeutic agents, such as those used for the therapy of neoplasms of the lungs or other organs;

• Active substances that are used for the systemic and / or inhalation treatment of lung diseases, for example for cystic fibrosis (alpha-1 -antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amikacin, levofloxacin), chronic obstructive pulmonary diseases (COPD) (LAS40464, PT003, SUN-101), acute respiratory syndrome (ARDS) and acute lung damage (ALI) (interferon-beta-la, traumakine), obstructive sleep apnea (VI-0521), bronchiectasis (mannitol, ciprofloxacin), bronchiolitisporiterans (bronchiolitisporiterans , Aztreonam) and sepsis (Pagibaximab, Voluven, ART-123); • Active substances that are used to treat muscular dystrophy, for example idebenone;

• antithrombotic agents, for example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;

Active substances that change the fat metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha -, PPAR-gamma and / or PP AR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists;

Active ingredients which inhibit neoangiogenesis, by way of example and preferably inhibitors of the VEGF and / or PDGF signaling pathways, inhibitors of the integrin signaling pathways, inhibitors of the angiopoietin-tie signaling pathways, inhibitors of the PI3K-Akt-mTor signaling pathways, inhibitors of the Ras Raf-Mek-Erk signaling pathways, inhibitors of the MAPK signaling pathways, inhibitors of the FGF signaling pathways, inhibitors of the sphingosine-l-phosphate signaling pathways, inhibitors of endothelial cell proliferation or apoptosis-inducing active substances;

• Active substances that reduce the vascular wall permeability (edema formation), for example and preferably corticosteroids, inhibitors of the ALKl-Smadl / 5 signaling pathway, inhibitors of the VEGF and / or PDGF signaling pathways, cyclooxygenase inhibitors, inhibitors of the kallikrein-kinin system or inhibitors the sphingosine-l-phosphate signaling pathways;

• Active substances which reduce damage to the retina in the case of oxidative stress, for example and preferably inhibitors of the complement system, in particular antagonists of the complement C5a receptor, or agonists of the 5-HTLA receptor;

• antioxidants and radical scavengers;

• Blood pressure lowering active ingredients, for example and preferably from the group of calcium antagonists, angiotensin-all antagonists, ACE inhibitors, beta-receptor-B loose, alpha-receptor-B loose, diuretics, phosphodiesterase inhibitors, sGC stimulators , Enhancers of cGMP levels, ECE inhibitors, vasopeptidase inhibitors and / or mineralocorticoid receptor antagonists;

• antiarrhythmics, such as sodium channel blockers, beta-receptor blockers, potassium channel blockers or calcium channel blockers;

• alpha-1 adrenoceptor antagonists;

• Central-acting alpha-2 adrenoceptor agonists;

• imidazoline 1-1 receptor agonists;

• Dopamine Dl receptor agonists;

• 5-HT2 antagonists; • vasopressin antagonists;

• calcium channel sensitizer;

• bronchodilators, such as, for example, beta-2 adrenoceptor agonists, anticholinergics, theopylline or PDE inhibitors;

Corticosteroids such as prednisolone;

• PGD2 receptor antagonists;

Nonsteroidal antiasthmatics, such as beta-2 adrenoceptor agonists or combinations of beta-2 adrenoceptor agonists and corticosteroids;

• Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors;

• Medicines for obesity and obesity such as methamphetamine, amfepramon, pheniermin, benzphetamine, phendimetrazine, mazindol, orlistat, sibutramine or rimonabant and combinations such as phentetmin / topiramate, bupropion / naltrexone, sibutramine / metformin, zupolionin SR, bupropion SR, bupropion / fluticasone; Lorcaserin, Phentermin / Topiramat, Cetilistat, Exenatid, Liraglutid, Metformin, Sibutramin / Metformin, Bupropion SR / Zonisamidc SR, CORT-108297, Canagliflozin, Chromium Picolinat, GSK-1521498, LY-37760in, S7T3, Nine3, Nine3, Nine3, Nine3, Mine3 -821, salmeterol xinafoat / fluticasone, somatropin (recombinant), tesamorelin, tesofensin, velneperit, zonisamide, beloranib, resveratrol, sobetirom, tetrahydrocannabivarin and beta-lapachone;

Adenylate cyclase inhibitors, such as colforsin dapropat;

• positive inotropic substances, such as digoxin;

Drugs for the treatment of erectile dysfunction, such as alprostadil;

• anti-dementia drugs such as acetylcholinesterase inhibitors, such as donepezil, galantamine and rivastigmine; or NMDA receptor antagonists, such as, for example, memantine;

Medicines to treat mental disorders, such as dopamine D4

Receptor antagonists such as clozapine, Dopamine D2 receptor antagonists such as Nemonaprid, mixed dopamine Dl / D2 receptor antagonists such as Zuclopenthixol, GABA A-

Receptor modulators such as carbamazepine, sodium channel inhibitors such as lamotrigine, monoamine oxidase inhibitors such as moclobemide, tricyclic antidepressants such as amitriptyline, desipramine, imipramine, amoxapine, nortriptyline or clomipramine, selective serotonin reuptake or fluoroquinoxinoxinone or ritrinodinoxin (R) or paroxysinoxinoxin (R), paroxysinoxinoxinoxinoxinoxinoxinoxinoxinoxyloxinoxinoxinoxin , selective norepinephrine reuptake inhibitors (SNRls) such as venlafaxine or dopaminergic antidepressants such as bupropion; Inhibitors of neural endopeptidase (NEP inhibitors) such as sacubitril, omapatrilat or methylene blue, AVE-7688, or in a dual combination ('ARNIs') with angiotensin receptor blockers (for example valsartan), for example LCZ696;

Natriuretic peptides, e.g. "atrial natriuretic peptides" (ANP, anaritides), "B-type natriuretic peptides" or "brain natriuretic peptides" (BNP, nesiritide), "C-type natriuretic peptides" (CNP) and urodilatin;

• Antidiabetics, by way of example and preferably from the group of the insulins and insulin derivatives, sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, PPAR-gamma agonists, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK1 - receptor agonists, inhibitors of dipeptidyl peptidase 4 (gliptins), SGLT-2 inhibitors, leptin receptor agonists, potassium channel antagonists and inhibitors of liver enzymes which are involved in stimulating gluconeogenesis and / or glycogenolysis;

• Anti-infectives, by way of example and preferably from the group of antibacterial, antifungal and / or antiviral substances; and or

• Substances for the treatment of glaucoma, for example and preferably from the group of adrenergics, beta-receptor blockers, carbonic anhydrase inhibitors, parasympathomimetics and prostaglandins; and or

• Substances for the treatment of bone diseases, for example and preferably bisphosphonates, vitamin D or its metabolites, strontium ranelate, selective estrogen receptor modulators (SERM), parathyroid hormone or its analogues and / or RANKL (receptor activator of nuclear factor kappa-B ligand) modulators.

Antithrombotic agents are preferably understood to mean compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a thrombin inhibitor, for example and preferably ximelagatran, melagatran, dabigatran, bivalirudin or Clexane, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a GPIIb / IIIa antagonist, exemplarily and preferably Tirofiban or Abciximab, administered. In a preferred embodiment of the invention, the dosage forms according to the invention are used in combination with a factor Xa inhibitor, for example and preferably rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-l76b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the invention

Dosage forms administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a vitamin K antagonist, for example and preferably coumarin, phenprocumon or warfarin administered.

The antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor-B loose, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics understood.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a calcium antagonist, exemplarily and preferably nifedipine, amlodipine, verapamil or diltiazem, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an alpha-1 adrenoceptor antagonist, exemplary and preferably prazosin, administered.

In a preferred embodiment of the invention, the invention

Dosage forms, in combination with a beta-receptor blockers, for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, Carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an angiotensin AII antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan or embursatan, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an ACE inhibitor, exemplary and preferably enalapril, Captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an endothelin antagonist, for example and preferably as Bosentan, Darusentan, Ambrisentan or Sitaxsentan, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a renin inhibitor, for example and preferably aliskiren, SPP-600 or SPP-800, administered.

The dosage forms according to the invention are administered in combination with a mineralocorticoid receptor antagonist, for example spironolactone or eplerenone, particularly preferably with a non-steroidal mineralocorticoid receptor antagonist such as finerenone.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a diuretic, by way of example and preferably furosemide, bumetanide, torasemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazonol, metholazonol, metholazonol, metholazonol, metholazonol, methazolidon, metholazonol, methazazidol, methazolidon, methazolazon, methazolazon, metholazonol, methazolidon, methazolazon, metholazon, metholazon, metholazonol, methazazol Amiloride or Triamteren administered.

Compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR are preferably included among the fat metabolism-changing agents gamma and / or PP AR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoproteins antagonists are understood.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a CETP inhibitor, for example and preferably torcetrapib (CP-5294/4), JJT-705 or CETP -vaccine (Avant), administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a thyroid receptor agonist, by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitiroma (CGS 26214).

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an HMG-CoA reductase inhibitor from the statin class, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a squalene synthesis inhibitor, by way of example and preferably BMS-1 88494 or TAK-475, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an ACAT inhibitor, for example and preferably avasimib, melinamide, pactimib, eflucimib or SMP-797, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with an MTP inhibitor, for example and preferably Implitapid, BMS-201038, R-103757 or JTT-130, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a PPAR-gamma agonist, exemplary and preferred as pioglitazone or rosiglitazone, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a PPAR delta agonist, exemplary and preferably GW 501516 or BAY 68-5042, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a cholesterol absorption inhibitor, exemplary and preferably ezetimibe, tiqueside or pamaqueside, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a lipase inhibitor, by way of example and preferably orlistat, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a polymeric bile acid adsorber, for example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a bile acid reabsorption inhibitor, by way of example and preferably ASBT (= IBAT) inhibitors, e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with a lipoprotein (a) antagonist, exemplary and preferred wise Gemcabene calcium (CI-1027) or nicotinic acid administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with acetylcholinesterase inhibitors, for example and preferably as donepezil, galantamine or rivastigmine, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with NMDA receptor antagonists, exemplary and preferably memantine, administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with sGC stimulators, for example and preferably Riociguat, Nelociguat, Vericiguat, Praliciguat (IW-1973) or Olinciguat (IW-1701) administered.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with antidiabetic agents, exemplarily and preferably administered metformin.

In a preferred embodiment of the invention, the invention

Dosage forms in combination with SGLT-2 inhibitors, for example and preferably dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and / or tofogliflozin administered.

In a preferred embodiment of the invention, the dosage forms according to the invention are used in combination with substances for the treatment of bone diseases such as, for example and preferably, vitamin D or its metabolites, strontium ranelate, selective estrogen receptor modulators (SERM) and / or RANKL modulators.

In a preferred embodiment of the invention, the dosage forms according to the invention are used in combination with bisphosphonates, such as, for example and preferably, etidronates, clodronates, tiludronates, teriparatides, pamidronates, neridronates, olpadronates, alendronates, ibandronates, risedronates, zoledronates.

Another object is the use of an osmotic release system according to the invention containing the compound of formula (I) for the treatment and / or prevention of diseases.

Another object is the use of an osmotic release system according to the invention containing the compound of formula (I) for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular diseases, especially the Heart failure (HFpEF and HFrEF), heart attack, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary diseases, especially pulmonary hypertension (PH), diseases of the central nervous system, especially dementia, bone diseases, especially osteogenesis imperfecta, thromboembolic disorders , Vascular diseases, microcirculation disorders, fibrotic diseases, in particular systemic sclerosis, ophthalmological diseases, inflammatory diseases, and metabolic diseases, in particular metabolic syndrome, dyslipidemia and diabetes.

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD).

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of cardiac and cardiovascular diseases, in particular heart failure (HFpEF and HFrEF), heart attack, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis.

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of pulmonary and cardiopulmonary diseases, in particular pulmonary hypertension (PH).

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of diseases of the central nervous system, in particular dementia.

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of diseases of the central nervous system, in particular vascular and Alzheimer's dementia.

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) for the treatment and / or prevention of metabolic diseases, in particular the metabolic syndrome, dyslipidemia and diabetes.

Another object is the use of an osmotic according to the invention

Release system containing the compound of formula (I) as described above in combination with one or more further active substances selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, antithrombotic agents, antihypertensive agents, MR antagonists, IP receptor agonists, anti-inflammatory agents, anti-dementia drugs, anti-diabetic agents, agents that change fat metabolism and agents for the treatment of bone and muscle disorders.

In the dosage forms according to the invention, the compound of the formula (I) is preferably in an amount of about 1 to 240 mg, particularly preferably in an amount of about 1 mg to 120 mg, very particularly preferably in an amount of about 2.5 mg to 50 mg included. The present invention relates to the pharmaceutical dosage forms according to the invention mentioned above, the compound of the formula (I) preferably in an amount of 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg , 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg and 240 mg is included. The amounts of the compound of the formula (I) denote the nominal amounts in the pharmaceutical administration form, under certain circumstances an excess of up to 20% of the amount of active ingredient may additionally be present.

In general, it has been found beneficial to administer approximately 0.01 to 10 mg / kg body weight per day for effective results.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

Experimental part

F release behavior

The release of the active ingredient from the tablets is determined according to the method of US Pharmacopoeia USP 39 (chapter <711> dissolution) using apparatus 2 (paddle test). To determine the rate of release, a tablet is introduced into each release vessel of the USP apparatus 2 and the amount of active ingredient dissolved is determined after filtering off the undissolved constituents by means of HPLC. Phosphate buffer pH 6.8 without the addition of surfactant is used as the release medium and the blade stirrer of USP apparatus 2 has a rotation speed of 100 revolutions per minute. Unless otherwise stated, the release rate of at least six test specimens is determined. The average of the amount of active substance released is given in each case. Thermal analysis of binary physical mixtures

In order to show comparability in thermoanalytical investigations, the compound of the formula (I) with hydrophilic swellable polymers was placed in equal parts in a fantasy dish and ground into a homogeneous powder mixture using a pestle (trituration in a ratio of 1: 1, binary mixture). Polyethylene oxide (according to Ph. Eur. (Edition 9) monograph "Macrogols, High Molecular Mass"; viscosity from 40 to 100 mPa-s; measured in 5% aqueous solution, 25 ° C; POLYOX ™ Water -Soluble Resin NF WSR N-80; Dow), xanthan ("Xanthan FN food quality normal" manufactured by Jungbunzlauer Ladenburg GmbH), according to Ph. Eur. (Edition 9) monograph "Xanthan gum", vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64), according to Ph. Eur. (Edition 9) monograph "Copovidone", polyvinylpyrrolidone (PVP 25), according to Ph. Eur. (Edition 9) monograph "Povidone", methacrylic acid-methyl methacrylate copolymer (Eudragit® L100), corresponding Ph. Eur. (Edition 9) monograph "Methacrylic acid - methyl methacrylate copolymer (1: 1), methacrylic acid-methyl methacrylate copolymer (Eudragit® RL PO) according to Ph. Eur. (Edition 9) monograph" ammonio methacrylate copolymer (TYP E A), hydroxypropyl cellulose (HPC LM Nisso), according to the Ph. Eur. (Edition 9) monograph "Hydroxypropyl cellulose" and polyacrylic acid (according to the Ph. Eur. (Edition 9) monograph "Carbomers"; Name: Polyacrylic acid, MW 1,080,000, aver. MN 135,000; Acros Organics).

The physical mixtures and the individual components were characterized thermoanalytically. The thermograms were recorded on a DSC (dynamic differential calorimeter, English: differential scanning calorimeter). For this purpose, approx. 5 mg of the sample were heated in an aluminum pan under nitrogen (50 ml / min) at a heating rate of 10 K / min until the melting temperature of the respective compound had ended.

If not specified in more detail, the substances used refer to pharmaceutical auxiliaries known to the person skilled in the art under the abovementioned name and, if listed in the respective pharmacopoeias, meet the respective requirements of the pharmacopoeia monographs of the European (Ph. Eur 9), American (USP 41 and NF 36) and / or Japanese (JP, 17th edition) pharmacopoeia.

Fig. 1 shows thermograms of the compound of formula (I), of polyethylene oxide and of the binary mixtures of the compound of formula (I) with polyethylene oxide.

Fig. 2 shows thermograms of the compound of formula (I), of xanthan and of the binary mixtures of the compound of formula (I) with xanthan.

Fig. 3 shows thermograms of the compound of formula (I), of vinyl pyrrolidone-vinyl acetate Copolymer and of the binary mixtures of the compound of formula (I) with vinylpyrrolidone-vinyl acetate copolymer.

Fig. 4 shows thermograms of the compound of formula (I), of PVP 25 and of the binary mixtures of the compound of formula (I) with PVP 25. Fig. 5 shows thermograms of the compound of formula (I), of Eudragit L100 and of the binary mixtures of the compound of formula (I) with Eudragit L100.

6 shows thermograms of the compound of formula (I), of Eudragit RL PO and of the binary mixtures of the compound of formula (I) with Eudragit RL PO.

Fig. 7 shows thermograms of the compound of formula (I), of HPC LM and of the binary mixtures of the compound of formula (I) with HPC LM.

8 shows thermograms of the compound of formula (I), of polyacrylic acid and of the binary mixtures of the compound of formula (I) with polyacrylic acid.

Claims

claims

1. Osmotic release system consisting of a core and a shell, the shell consisting of a water-permeable material which is impermeable to the components of the core and having at least one opening and the core (3S) -3- (4-chloro-3 - {[ (2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3 -cyclopropylpropanoic acid

Formula (I)

and contains at least one hydrophilic swellable polymer, the hydrophilic swellable polymer not being polyethylene oxide.

2. Osmotic release system according to claim 1, wherein the core of the osmotic release system

0.5% by weight to 50% by weight of the compound of the formula (I),

Contains from 40% by weight to 99.5% by weight of at least one hydrophilic swellable polymer and optionally at least one osmotically active additive and optionally at least one pharmaceutically customary auxiliary.

3. Osmotic release system according to one of claims 1 or 2, wherein the core

0.5% by weight to 50% by weight of the compound of the formula (I),

• 10% by weight to 50% by weight of xanthan, »5% by weight to 40% by weight of a vinylpyrrolidone-vinyl acetate copolymer, optionally at least one further hydrophilic swellable polymer, optionally at least one further pharmaceutically customary auxiliary and optionally at least contains an osmotically active additive.

4. Osmotic release system according to one of claims 1 or 2, wherein the core comprises a two-chamber system consisting of an active substance layer and an osmotic layer.

5. Osmotic release system according to claim 4, wherein the drug layer

1% by weight to 50% by weight of the compound of the formula (I),

• 20% by weight to 99% by weight of at least one hydrophilic swellable polymer, optionally containing at least one osmotically active additive and optionally at least one customary pharmaceutical excipient, and the osmosis layer

40% to 90% by weight of at least one hydrophilic swellable polymer,

• 10 wt .-% to 60 wt .-% of an osmotic active additive, and optionally contains at least one customary pharmaceutical excipient.

6. Osmotic release system according to one of claims 1 to 5, wherein at least one hydrophilic swellable polymer is selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose, starch derivatives, for example

Sodium carboxymethyl starch, vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, methacrylic acid copolymers, for example methacrylic acid-methyl methacrylate copolymer and polyacrylic acids.

7. Osmotic release system according to one of claims 1 to 6, wherein the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

8. A method for producing an osmotic release system according to any one of claims 1 to 7, characterized in that the components of the core are mixed together, granulated and tableted, the core thus formed is coated with a shell and the shell finally with one or more openings , suitable for the exit of the compound of formula (I).

9. A method for producing an osmotic release system according to any one of claims 4 to 7, characterized in that • the components of the active ingredient layer are mixed and granulated and

The components of the osmosis layer are mixed and granulated,

Then both granules are pressed into a two-layer tablet on a two-layer tablet press,

• The resulting core is then coated with the shell and

• The shell is seen on the active ingredient side with one or more openings.

10. Osmotic release system according to one of claims 1 to 7 for the treatment and / or prevention of diseases.

11. Osmotic release system according to one of claims 1 to 7 for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular diseases, in particular heart failure (HFpEF and HFrEF ), Heart attack, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary diseases, in particular pulmonary hypertension (PH), ophthalmological diseases, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular edema (DME), diseases of the central nervous system , especially dementia, bone diseases, especially osteogenesis imperfecta, thromboembolic diseases, muscular dystrophies, ischemia, vascular diseases, microcirculation disorders, fibrotic diseases, especially systemic sclerosis, inflammatory diseases, and St metabolic disorders, especially the metabolic syndrome, dyslipidemia and diabetes.

12. Osmotic release system according to one of claims 1 to 7 in combination with one or more further active ingredients selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of

Guanylate cyclase, antithrombotic agents, antihypertensive agents, MR antagonists, IP receptor agonists, anti-inflammatory agents, anti-dementia drugs, anti-diabetic agents, agents that change fat metabolism and agents for the treatment of bone and muscle disorders.

13. Process for the treatment and / or prevention of renal and cardiorenal diseases, in particular chronic kidney failure (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular diseases, in particular heart failure (HFpEF and HFrEF), heart attack, angina pectoris, cardiomyopathies , Hypertension and Arteriosclerosis, pulmonary and cardiopulmonary diseases, in particular pulmonary hypertension (PH), ophthalmic diseases, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular edema (DME), diseases of the central nervous system, in particular dementia, bone diseases, in particular osteogenesis imperfecta, thromboembolic disorders,

Muscular dystrophies, ischemia, vascular diseases, microcirculation disorders, fibrotic diseases, in particular systemic sclerosis, inflammatory diseases, and metabolic diseases, in particular metabolic syndrome, dyslipidemia and diabetes in humans and animals by administration of an osmotic

Release system as defined in any one of claims 1 to 7.