PHARMACEUTICAL DOSAGE FORM WHICH CAN BE ADMINISTERED ORALLY AND HAS MODIFIED RELEASE

Abstract

The present invention relates to orally administrable modified-release pharmaceutical dosage forms comprising (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 producing the dosage forms and to the use thereof for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiac, renal, pulmonary and ophthalmological disorders, disorders of the central nervous system, fibrotic and inflammatory disorders and metabolic disorders.

Claims

1. Osmotic release system consisting of a core and a shell, wherein the shell consists of a water-permeable material impermeable to the components of the core and has at least one orifice and wherein the core comprises (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) ##STR00002## and at least one hydrophilic swellable polymer, wherein the hydrophilic swellable polymer is not polyethylene oxide.

2. Osmotic release system according to claim 1, wherein the core of the osmotic release system comprises 0.5% by weight to 50% by weight of the compound of the formula (I), 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 excipient.

3. Osmotic release system according to claim 1, wherein the core comprises 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 excipient and optionally at least one osmotically active additive.

4. Osmotic release system according to claim 1, wherein the core comprises a two-chamber system consisting of an active ingredient layer and an osmosis layer.

5. Osmotic release system according to claim 4, wherein the active ingredient layer comprises 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, and optionally at least one osmotically active additive and optionally at least one pharmaceutically customary excipient, and the osmosis layer comprises 40% by weight to 90% by weight of at least one hydrophilic swellable polymer, 10% by weight to 60% by weight of an osmotically active additive, and optionally at least one pharmaceutically customary excipient.

6. Osmotic release system according to claim 1, wherein at least one hydrophilic swellable polymer is selected from a list consisting of xanthan, cellulose derivatives, for example hydroxypropylcellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose, 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.

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

8. Process for producing an osmotic release system according to claim 1, characterized in that the components of the core are mixed with one another, granulated and tableted, the resulting core is coated with a shell and the shell is then provided with one or more orifices suitable for the escape of the compound of the formula (I).

9. Process for producing an osmotic release system according to claim 4, 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, the two granulates are then pressed on a bilayer tablet press to obtain a bilayer tablet, the resulting core is then coated with the shell and the shell is, on the active ingredient side, provided with one or more orifices.

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

11. Osmotic release system according to claim 1 for the treatment and/or prevention of renal and cardiorenal disorders, in particular chronic kidney disease (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular disorders, in particular heart failure (HFpEF and HFrEF), myocardial infarction, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary disorders, in particular pulmonary hypertension (PH), ophthalmological disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DMO), disorders of the central nervous system, in particular dementia, bone disorders, in particular osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, microcirculation impairment, fibrotic disorders, in particular systemic sclerosis, inflammatory disorders, and metabolic disorders, in particular metabolic syndrome, dyslipidaemia and diabetes.

12. Osmotic release system according to claim 1 in combination with one or more other active ingredients selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, antithrombotics, antihypertensives, MR antagonists, IP receptor agonists, anti-inflammatory active substances, antidementia drugs, antidiabetics, active substances that modify fat metabolism and active substances for the treatment of bone and muscle disorders.

13. Method for the treatment and/or prevention of renal and cardiorenal disorders, in particular chronic kidney disease (CKD) and diabetic kidney disease (DKD), cardiac and cardiovascular disorders, in particular heart failure (HFpEF and HFrEF), myocardial infarction, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, pulmonary and cardiopulmonary disorders, in particular pulmonary hypertension (PH), ophthalmological disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DMO), disorders of the central nervous system, in particular dementia, bone disorders, in particular osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, microcirculation impairment, fibrotic disorders, in particular systemic sclerosis, inflammatory disorders, and metabolic disorders, in particular metabolic syndrome, dyslipidaemia and diabetes in humans and animals comprising administering a therapeutically effective amount of the osmotic release system according to claim 1 to a human or animal in need thereof.

Description

EXPERIMENTAL

[0221] Dissolution Profile

[0222] The dissolution of the active ingredient from the tablets is determined by the US Pharmacopoeia (USP 39) method (Chapter <711> Dissolution) using Apparatus 2 (paddle test). For the determination of the dissolution rate, a tablet is introduced into each receptacle of USP Apparatus 2 and the amount of active ingredient that has gone into solution after the undissolved constituents have been filtered off is determined by HPLC. The dissolution medium used is phosphate buffer pH 6.8 without addition of surfactant, and the paddle stirrer of the USP Apparatus 2 has a speed of rotation of 100 revolutions per minute. Unless otherwise stated, the dissolution rate of at least six test specimens is determined. In each case, the average amount of active ingredient released is reported.

[0223] Thermoanalytical Investigation of Binary Physical Mixtures

[0224] In order to illustrate compatibilities in thermoanalytical investigations, a mortar was charged with equal parts of the compound of the formula (I) and of hydrophilic swellable polymers and the contents were ground with a pestle into a homogeneous powder mixture (trituration in a ratio of 1:1, binary mixture). The hydrophilic swellable polymers investigated were polyethylene oxide (meeting the requirements of the Ph. Eur. (9th edition) monograph “Macrogols, High Molecular Mass”; viscosity from 40 to 100 mPa.Math.s; measured in 5% aqueous solution 25° C.; POLYOX™ water-soluble resin NF WSR N-80; Dow), xanthan (“Xanthan FN food grade, normal” produced by Jungbunzlauer Ladenburg GmbH) meeting the requirements of the Ph. Eur. (9th edition) monograph “Xanthan gum”, vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64) meeting the requirements of the Ph. Eur. (9th edition) monograph “Copovidone”, polyvinylpyrrolidone (PVP 25) meeting the requirements of the Ph. Eur. (9th edition) monograph “Povidone”, methacrylic acid-methyl methacrylate copolymer (Eudragit® L100) meeting the requirements of the Ph. Eur. (9th edition) monograph “Methacrylic acid-Methyl Methacrylate Copolymer (1:1)”, methacrylic acid-methyl methacrylate copolymer (Eudragit® RL PO) meeting the requirements of the Ph. Eur. (9th edition) monograph “Ammonio Methacrylate Copolymer (Type A)”, hydroxypropylcellulose (HPC LM Nisso) meeting the requirements of the Ph. Eur. (9th edition) monograph “Hydroxypropylcellulose” and polyacrylic acid (meeting the requirements of the Ph. Eur. (9th edition) monograph “Carbomers”; designation: Polyacrylic acid, MW 1 080 000, aver. MN 135,000; Acros Organics).

[0225] The physical mixtures and the respective individual components were characterized thermoanalytically.

[0226] The thermograms were recorded on a DSC (differential scanning calorimeter). For this, about 5 mg of sample was in each case heated in an aluminium crucible under nitrogen (50 ml/min) at a heating rate of 10 K/min until the end of the melting point of the respective compound.

[0227] Unless specified more precisely, the substances used refer to the pharmaceutical excipients known to those skilled in the art under the name cited and, if listed in the respective pharmacopoeia, meet the respective requirements of the pharmacopoeial monographs of the European (Ph. Eur 9), US (USP 41 and NF 36) and/or Japanese (JP, 17th edition) pharmacopoeias.

[0228] FIG. 1 shows thermograms of the compound of the formula (I), of polyethylene oxide and of binary mixtures of the compound of the formula (I) with polyethylene oxide.

[0229] FIG. 2 shows thermograms of the compound of the formula (I), of xanthan and of binary mixtures of the compound of the formula (I) with xanthan.

[0230] FIG. 3 shows thermograms of the compound of the formula (I), of vinylpyrrolidone-vinyl acetate copolymer and of binary mixtures of the compound of the formula (I) with vinylpyrrolidone-vinyl acetate copolymer.

[0231] FIG. 4 shows thermograms of the compound of the formula (I), of PVP 25 and of binary mixtures of the compound of the formula (I) with PVP 25.

[0232] FIG. 5 shows thermograms of the compound of the formula (I), of Eudragit L100 and of binary mixtures of the compound of the formula (I) with Eudragit L100.

[0233] FIG. 6 shows thermograms of the compound of the formula (I), of Eudragit RL PO and of binary mixtures of the compound of the formula (I) with Eudragit RL PO.

[0234] FIG. 7 shows thermograms of the compound of the formula (I), of HPC LM and of binary mixtures of the compound of the formula (I) with HPC LM.

[0235] FIG. 8 shows thermograms of the compound of the formula (I), of polyacrylic acid and of binary mixtures of the compound of the formula (I) with polyacrylic acid.