Orally administrable modified-release pharmaceutical dosage form

Patent metadata

Field	Value
Publication number	US-10905667-B2
Application number	US-201816043567-A
Country	US
Kind code	B2
Filing date	Jul 24, 2018
Priority date	Jul 24, 2018
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

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.

First claim

The invention claimed is:

1. A compound that is 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. The 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. The 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. A method for preparing the compound of the formula (II) of claim 1 in crystalline modification 1 comprising dissolving a compound of the formula (I)

in a polar aprotic solvent, adding a base selected from the group consisting of sodium hydroxide and a sterically demanding sodium alkoxide, stirring, filtering to obtain a solid, isolating and drying.

5. The method of claim 4 , wherein the polar aprotic solvent used is acetonitrile and the base used is sodium hydroxide in solid form.

6. The method of claim 4 , wherein the solvent used is acetonitrile and the base used is sodium tert-butoxide or sodium 2-methylbut-2-oxide.

7. The method of claim 4 , wherein the base is added in an amount of 0.7 to 1.0 molar equivalents, based on the compound of the formula (I).

8. A medicament comprising the compound of 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.

9. 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.

10. Osmotic release system according to claim 9 , 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.

11. Osmotic release system according to claim 9 , where the core comprises a two-chamber system consisting of an active ingredient layer and an osmosis layer.

12. Osmotic release system according to claim 11 , 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.

13. Osmotic release system according to claim 9 , where the at least one hydrophilic swellable polymer is selected from the group consisting of polyethylene oxide, xanthan, hydroxypropylcellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, vinylpyrrolidone/vinyl acetate copolymer and polyacrylic acids.

14. Osmotic release system according to claim 9 , where the at least one hydrophilic swellable polymer is polyethylene oxide.

15. Osmotic release system according to claim 12 , 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.).

16. Osmotic release system according to claim 9 , where the shell consists of cellulose acetate or a mixture of cellulose acetate and polyethylene glycol.

17. A process for preparing the osmotic release system of claim 9 , comprising mixing sodium (3 S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate of the formula (II) and the at least one hydrophilic swellable polymer together to form a resulting mixture, granulating the resulting mixture, tableting to form a resulting core, coating the resulting core with the shell, and providing the shell the shell with one or more orifices suitable for the compound of the formula (II) exiting.

18. A process for preparing the osmotic release system of claim 11 in which the osmosis layer has components, comprising
mixing sodium (3 S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate of the formula (II) and the at least one hydrophilic swellable polymer of the active ingredient layer together to form a resulting mixture,
granulating the resulting mixture to form a set of active layer granules,
mixing the components of the osmosis layer to form a resulting osmosis layer mixture,
granulating the resulting osmosis layer mixture to form a set of osmosis layer granules,
compressing the set of active layer granules and the set of osmosis layer granules on a bilayer tablet press to give a bilayer tablet,
coating the bilayer tablet with the shell and
providing the shell, on the active ingredient side, with one or more orifices.

19. A method for the treatment and/or prevention of one or more diseases and disorders selected from the group consisting of renal and cardiorenal disorders, cardiac and cardiovascular disorders, pulmonary and cardiopulmonary disorders, disorders of the central nervous system, bone disorders, thromboembolic disorders, muscular dystrophies, ischaemias, vascular disorders, impaired microcirculation, fibrotic disorders, inflammatory disorders, and metabolic disorders, in humans and animals comprising administering an effective amount of the compound of claim 1 to a human or animal in need thereof.

20. The method of claim 19 , wherein the renal and cardiorenal disorders are selected from the group consisting of chronic kidney disease (CKD) and diabetic kidney disease (DKD), the cardiac and cardiovascular disorders are selected from the group consisting of heart failure (HFpEF and HFrEF), myocardial infarction, angina pectoris, cardiomyopathies, hypertension and arteriosclerosis, the pulmonary and cardiopulmonary disorder is pulmonary hypertension (PH), the disorders of the central nervous system is dementia, the bone disorders is osteogenesis imperfect, the fibrotic disorders is systemic sclerosis, and the metabol

Assignees

• Bayer Pharma AG
• Bayer Ag

Inventors

• Stroyer Anke
• Lobback Carmen
• Serno Peter
• Rubenbauer Philipp
• Lovis Kai
• Schirmer Heiko
• Grossbach Danja
• Bierer Donald
• Olenik Britta
• Jacobs Tia
• Küsel Julia

Classifications

• A61K31/192 Primary

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title