Orally administrable modified-release pharmaceutical dosage form

Abstract

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

1 . Sodium (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate of the formula (II) 
       
         
           
           
               
               
           
         
       
     
     
         2 . Compound of the formula (II) according to  claim 1 , in crystalline form of modification 1, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 8.1, 17.2, 18.8, 22.3 and 22.6°. 
     
     
         3 . Compound of the formula (II) according to  claim 1 , in crystalline form of modification 1, characterized in that the IR spectrum of the compound has band maxima at 3381, 1691, 1565, 1524 and 1419 cm −1 . 
     
     
         4 . Preparation of the compound of the formula (II) in crystalline modification 1 according to  claim 1 , characterized in that the compound of the formula (I) 
       
         
           
           
               
               
           
         
         is dissolved in a polar aprotic solvent, a base selected from a list comprising sodium hydroxide or a sterically demanding sodium alkoxide is added and the precipitated solid is, after stirring, isolated and dried. 
       
     
     
         5 . Preparation of the compound of the formula (II) according to  claim 4 , characterized in that the polar aprotic solvent used is acetonitrile and the base used is sodium hydroxide in solid form. 
     
     
         6 . Preparation of the compound of the formula (II) according to  claim 4 , characterized in that the solvent used is acetonitrile and the base used is sodium tert-butoxide or sodium 2-methylbut-2-oxide. 
     
     
         7 . Preparation of the compound of the formula (II) according to  claim 4 , characterized in that the base is added in an amount of 0.7 to 1.0 molar equivalents, based on the compound of the formula (I). 
     
     
         8 . Compound according to  claim 1  for the treatment and/or prevention of diseases. 
     
     
         9 . Compound 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), disorders of the central nervous system, in particular dementia, bone disorders, in particular osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, impaired microcirculation, fibrotic disorders, in particular systemic sclerosis, inflammatory disorders, and metabolic disorders, in particular metabolic syndrome, dyslipidaemia and diabetes. 
     
     
         10 . Medicament, comprising the compound as defined in  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, antihypertensive agents, MR antagonists, IP receptor agonists, compounds having anti-inflammatory action, antidementives, antidiabetics, active compounds which modify fat metabolism and active compounds for the treatment of bone and muscle disorders. 
     
     
         11 . Osmotic release system consisting of a core and a shell, where the shell consists of a water-permeable material impermeable for the components of the core and has at least one orifice, and where the core comprises sodium (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate of the formula (II) 
       
         
           
           
               
               
           
         
         and at least one hydrophilic swellable polymer. 
       
     
     
         12 . Osmotic release system according to  claim 11 , where the core of the osmotic release system comprises
 0.5% by weight to 50% by weight of the compound of the formula (II),   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.   
     
     
         13 . Osmotic release system according to  claim 11 , where the core comprises a two-chamber system consisting of an active ingredient layer and an osmosis layer. 
     
     
         14 . Osmotic release system according to  claim 13 , where the active ingredient layer comprises
 1% by weight to 50% by weight of the compound of the formula (II),   20% by weight to 99% by weight of at least one hydrophilic swellable polymer,   optionally at least one osmotically active additive and optionally at least one pharmaceutically customary auxiliary   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 auxiliary.   
     
     
         15 . Osmotic release system according to  claim 11 , where at least one hydrophilic swellable polymer is selected from a list comprising polyethylene oxide, xanthan, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids. 
     
     
         16 . Osmotic release system according to  claim 11 , where the at least one hydrophilic swellable polymer is polyethylene oxide. 
     
     
         17 . Osmotic release system according to  claim 14 , where the at least one hydrophilic swellable polymer of the active ingredient layer is polyethylene oxide having a viscosity of 40 to 100 mPa·s (measured in a 5% strength aqueous solution, 25° C.) and the at least one hydrophilic swellable polymer of the osmosis layer is polyethylene oxide having a viscosity of 5000 to 8000 mPa·s (measured in a 1% strength aqueous solution, 25° C.). 
     
     
         18 . Osmotic release system according to  claim 11 , where the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol. 
     
     
         19 . Process for preparing an osmotic release system according to  claim 11 , 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 is finally provided with one or more orifices suitable for the compound of the formula (II) exiting. 
     
     
         20 . Process for preparing an osmotic release system according to  claim 13 , 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,   both sets of granules are subsequently compressed on a bilayer tablet press to give 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.   
     
     
         21 . Use of an osmotic release system according to  claim 11  for the treatment and/or prevention of diseases. 
     
     
         22 . Use of an osmotic release system according to  claim 21  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), disorders of the central nervous system, in particular dementia, bone disorders, in particular osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, impaired microcirculation, fibrotic disorders, in particular systemic sclerosis, inflammatory disorders, and metabolic disorders, in particular metabolic syndrome, dyslipidaemia and diabetes. 
     
     
         23 . 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), disorders of the central nervous system, in particular dementia, bone disorders, in particular osteogenesis imperfecta, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, impaired microcirculation, fibrotic disorders, in particular systemic sclerosis, inflammatory disorders, and metabolic disorders, in particular metabolic syndrome, dyslipidaemia and diabetes in humans and animals comprising administering an effective amount of the compound according to  claim 1  to a human or animal in need thereof.