ORALLY ADMINISTRABLE MODIFIED-RELEASED PHARMACEUTICAL DOSAGE FORM
20200237648 · 2020-07-30
Assignee
Inventors
- Anke Stroyer (Berlin, DE)
- Carmen Lobback (Schöneiche, DE)
- Peter Serno (Bergisch Gladbach, DE)
- Kia LOVIS (Düsseldorf, DE)
- Philipp Rubenbauer (Bensheim, DE)
- Helko SCHIRMER (Solingen, DE)
- Danja GROßBACH (Wuppertal, DE)
- Tia Jacobs (Wuppertal, DE)
- Britta Olenik (Bottrop, DE)
- Julia Küsel (Bochum, DE)
- Donald Bierer (Haan, DE)
Cpc classification
A61K9/0004
HUMAN NECESSITIES
C07C233/55
CHEMISTRY; METALLURGY
A61K31/196
HUMAN NECESSITIES
A61K9/2086
HUMAN NECESSITIES
International classification
A61K9/00
HUMAN NECESSITIES
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, pulmonary and ophthalmic 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, 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) ##STR00008## and at least one hydrophilic swellable polymer.
2. Osmotic release system according to claim 1, where the core comprises a two-chamber system consisting of an active ingredient layer and an osmosis layer.
3. Osmotic release system according to claim 2, 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.
4. Osmotic release system according to claim 1, where the at least one hydrophilic swellable polymer is polyethylene oxide.
5. Process for preparing 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 finally provided with one or more orifices suitable for the compound of the formula (II) exiting.
6. Process for preparing an osmotic release system according to claim 2, 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.
7. 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) ##STR00009##
8. Compound of the formula (II) according to claim 7, 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.
9. Compound of the formula (II) according to claim 7, 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.sup.1.
10. Preparation of the compound of the formula (II) in crystalline modification 1 according to claim 8, comprising dissolving the compound of the formula (I) ##STR00010## in a polar aprotic solvent, adding a base selected from the group consisting of sodium hydroxide and a sterically demanding sodium alkoxide, stirring the precipitated solid, isolating and drying the compound of formula (II).
11. Compound according to claim 7 for the treatment and/or prevention of diseases.
12. Compound according to claim 7 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), ophthalmic disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DME), 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.
13. Medicament, comprising the compound as defined in claim 7 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.
14. 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), ophthalmic disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DME), 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.
15. 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), ophthalmic disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DME), 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 as defined in claim 7 to a person in need thereof.
16. 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), ophthalmic disorders, in particular non-proliferative diabetic retinopathy (NPDR) and diabetic macular oedema (DME), 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 osmotic release system as defined in claim 1 to a person in need thereof.
Description
EXPERIMENTAL SECTION
Abbreviations and Acronyms
[0282] cp centipoise
HPLC high-pressure/high-performance liquid chromatography
K Kelvin
[0283] min minute
ml millilitre
l microlitre
mm millimetre
m micrometre
mPa millipascal
Ph. Eur. European Pharmacopeia
s second
r revolution
USP United States Pharmacopeia
[0284] UV ultraviolet
Working Examples
Exemplary Compound 1
Sodium (3 S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate in crystalline modification 1
[0285] ##STR00007##
[0286] Preparation Method 1
[0287] Under a nitrogen atmosphere, a reaction vessel was filled with 1425 g of the compound of the formula (I) (preparation disclosed in WO 2012/139888, Example 22 and EP17204842.3 (published as WO 2019/105881)) and 13.3 kg of acetonitrile. The mixture is stirred until a solution has formed. 117 g of solid sodium hydroxide are added and the resulting suspension is stirred vigorously for 25 hours. The suspension is filtered. The solids obtained are washed with 1.2 kg of acetonitrile and dried under reduced pressure at 30 C. for 19 hours.
[0288] Yield: 1375 g (92%)
[0289] Content of the compound of the formula (II): 96.4% (HPLC Method 1)
[0290] Content of the compound of the formula (III): <0.20% (HPLC Method 2)
[0291] Sodium content: 4.8%
[0292] XRPD: modification 1
[0293] Preparation Method 2
[0294] Under a nitrogen atmosphere, a reaction vessel is filled with 34.4 kg of acetonitrile and 4.0 kg of the compound of the formula (I) (content determination 99.1%) (preparation disclosed in WO 2012/139888, Example 22 and EP17204842.3 (published as WO 2019/105881)). The mixture is stirred at 20 C. The resulting solution is filtered and the filter is washed with 3 kg of acetonitrile. The filtrate is cooled to 0 C. 3.9 kg of a tetrahydrofuran solution of sodium tert-butoxide (content determination 19.6%) are added slowly at a temperature of from 5 C. to +5 C. After addition of about of the sodium tert-butoxide solution, seed crystals of the compound of the formula (II) in crystalline modification 1 are added. After completion of the metered addition, the line used for the metered addition is rinsed with an additional 3.0 kg of tetrahydrofuran. The resulting mixture is stirred at 0 C. for 17 hours. The suspension is filtered and the solids obtained are washed twice with 5.6 kg of cold acetonitrile. The product is dried under reduced pressure at 40 C. for 16 hours.
[0295] Yield: 4.0 kg (97%)
[0296] Content of the compound of the formula (II): 98.7% (HPLC Method 1)
[0297] Content of the compound of the formula (III): 0.19% (HPLC Method 2)
[0298] Sodium content: 4.4%
[0299] XRPD: modification 1
[0300] Analytical Methods
[0301] HPLC Method 1:
[0302] The tests for content determination and for impurities are carried out on a reversed-phase HPLC column with UV detection at 210 nm. The stationary phase is a Zorbax Eclipse Plus RRHD C18 HPLC column (50 mm2.1 mm, particle size 1.8 m) or a suitable alternative.
[0303] Gradient elution was chosen for optimal separation of the maxima. The gradient of the mobile phase is shown in Table 1 below.
[0304] Mobile phase A is water with 0.1% trifluoroacetic acid, mobile phase B is acetonitrile with 0.1% trifluoroacetic acid.
TABLE-US-00001 TABLE 1 Time [min] % A % B 0.0 95 5 25.0 20 80
[0305] The flow rate is 1.0 ml/min, the column temperature is 20 C., the injection volume is 2 l. Test solutions are prepared by dissolution in a mixture of equal parts of acetonitrile and water to a concentration of 0.46 mg/ml.
[0306] Quantification is carried out either by external calibration using a reference standard or via mass balance. The retention time of the compound of the formula (II) is about 16.2 min, the retention time of the compound of the formula (III) is about 12.0 min.
[0307] HPLC Method 2:
[0308] The tests for impurities are carried out on a normal-phase HPLC column with UV detection at 220 nm. The stationary phase is a Chiralpak AD-H HPLC column (250 mm4.6 mm, particle size 5 m) or a suitable alternative.
[0309] Isocratic elution was chosen for optimal separation of the maxima.
[0310] The mobile phase consists of 93% by volume of isohexane and 7% by volume of a mixture of 2-propanol with 0.2% trifluoroacetic acid and 1% water.
[0311] The flow rate is 1.25 ml/min, the column temperature is 30 C., the injection volume is 5 l. Test solutions are prepared by dissolution in a mixture of isohexane and 2-propanol (3/1, by volume) to a concentration of 0.5 mg/ml.
[0312] Quantification is carried out by external calibration using a reference standard. The retention time of the compound of the formula (II) is about 11.4 min, the retention time of the compound of the formula (III) is about 9.7 min.
[0313] Method 3 (Sodium Analysis):
[0314] Sodium is analysed by an ICP-MS method as semiquantitative summary analysis. Sample preparation takes place by microwave digestion with nitric acid.
[0315] Method 4X-Ray Diffractometry for the Measurement of the Compound of the Formula (I) in Crystalline Form of Modification 1:
Sample preparation: sample as even powder layer between two films.
Instrument: X-ray powder diffractometer (STOE STADI P)
Generator: 40 kV/40 mA
Detector: location-sensitive detector
Radiation: germanium-monochromatized CuKal radiation
Measurement mode: transmittance
Measurement range: 2240
Step width: 0.5
Measurement time: 15 s/step
TABLE-US-00002 TABLE 2 X-ray diffractometry of the compound of the formula (I) in crystalline modification 1 Reflections Modification 1 6.5 17.2 24.1 28.6 32.7 38.1 7.6 17.5 24.4 28.8 33.1 38.5 8.1 18.0 24.7 29.0 33.7 38.7 9.6 18.8 25.1 29.3 34.0 38.9 10.3 19.4 25.2 29.5 34.7 39.4 11.0 19.8 25.5 29.8 35.5 39.6 14.7 21.0 25.8 30.4 35.8 39.8 15.1 21.4 26.5 30.8 36.1 15.6 21.7 26.8 31.2 36.3 16.0 22.3 27.2 31.6 36.7 16.4 22.6 28.1 32.3 37.7
[0316] The X-ray diffractogram of the compound of the formula (I) in crystalline modification 1 is shown in
[0317] Method 5IR Spectroscopy for the Measurement of the Compound of the Formula (I) in Crystalline Form of Modification 1:
TABLE-US-00003 Sample preparation: Sample was prepared as KBr disc Instrument Bruker Vertex 80v Number of scans 32 Resolution 2 cm.sup.1 Technique transmission
TABLE-US-00004 TABLE 3 IR spectra of the compound of the formula (I) in crystalline modification 1 Band maximum [cm.sup.1] Modification 1 3381 1524 1245 975 735 532 3066 1492 1185 937 721 516 2997 1458 1169 906 712 492 2975 1419 1135 895 669 447 2954 1389 1108 844 654 422 2914 1376 1101 827 628 1691 1312 1069 817 593 1595 1286 1044 788 566 1565 1263 1022 753 546
[0318] The IR spectrum of the compound of the formula (I) in crystalline modification 1 is shown in
[0319] Osmotic release systems and the preparation thereof are shown below. The osmotic release systems always contain excess active ingredient since, for technical reasons, some of the active ingredient remains in the osmotic release system.
[0320] Osmotic Release System 1 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0321] Tablet Composition in Mg/Tablet:
TABLE-US-00005 Core Active ingredient layer compound of the formula (II), micronized 2.75 mg hydroxypropylmethylcellulose (5 cp) 5.70 mg polyethylene oxide* 100.45 mg finely divided silica (Aerosil 200, Degussa) 0.90 mg magnesium stearate 0.30 mg 110.1 mg Osmosis layer hydroxypropylmethylcellulose (5 cp) 3.69 mg sodium chloride 21.51 mg polyethylene oxide** 47.60 mg iron oxide red 0.72 mg magnesium stearate 0.18 mg 73.70 mg total (core) 183.8 mg Shell cellulose acetate 12.40 mg polyethylene glycol 3350 1.60 mg 14.0 mg total (osmotic release system) 197.8 mg
[0322] After about 5 to 6 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 1 is shown in
[0323] Osmotic Release System 2 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0324] Tablet Composition in Mg/Tablet:
TABLE-US-00006 Core Active ingredient layer compound of the formula (II), micronized 6.00 mg hydroxypropylmethylcellulose (5 cp) 5.70 mg polyethylene oxide* 97.40 mg finely divided silica (Aerosil 200, Degussa) 0.90 mg magnesium stearate 0.30 mg 110.3 mg Osmosis layer hydroxypropylmethylcellulose (5 cp) 3.69 mg sodium chloride 21.51 mg polyethylene oxide** 47.60 mg iron oxide red 0.72 mg magnesium stearate 0.18 mg 73.7 mg total (core) 184.0 mg Shell cellulose acetate 12.60 mg polyethylene glycol 3350 1.40 mg 14.0 mg total (osmotic release system) 198.0 mg
[0325] After about 6 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 2 is shown in
[0326] Osmotic Release System 3 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0327] Tablet Composition in Mg/Tablet:
[0328] The composition of the active ingredient layer and the osmosis layer (core) corresponds to Working Example 2.
TABLE-US-00007 Shell cellulose acetate 25.20 mg polyethylene glycol 3350 2.80 mg 28.0 mg total (osmotic release system) 212.0 mg
[0329] After about 11 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 3 is shown in
[0330] Osmotic Release System 4 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0331] Tablet Composition in Mg/Tablet:
[0332] The composition of the active ingredient layer and the osmosis layer (core) corresponds to Working Example 2.
TABLE-US-00008 Shell cellulose acetate 34.20 mg polyethylene glycol 3350 3.80 mg 38.0 mg total (osmotic release system) 222.0 mg
[0333] After about 15 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 4 is shown in
[0334] Osmotic Release System 5 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0335] Tablet Composition in Mg/Tablet:
TABLE-US-00009 Core Active ingredient layer compound of the formula (II), micronized 5.75 mg hydroxypropylmethylcellulose (5 cp) 5.70 mg polyethylene oxide* 97.65 mg finely divided silica (Aerosil 200, Degussa) 0.90 mg magnesium stearate 0.30 mg 110.3 mg Osmosis layer hydroxypropylmethylcellulose (5 cp) 3.69 mg sodium chloride 21.51 mg polyethylene oxide** 47.60 mg iron oxide red 0.72 mg magnesium stearate 0.18 mg 73.7 mg total (core) 184.0 mg Shell cellulose acetate 27.00 mg polyethylene glycol 3350 3.00 mg 30.0 mg total (osmotic release system) 214.0 mg
[0336] The osmotic release system 5 was tested for the content of the compound of the formula (II) (active ingredient content) (n=10). Based on 100% of the declared active ingredient content, a minimum active ingredient content of 93.8% and a maximum active ingredient content of 103.7% were measured. The standard deviation was 3.1%.
[0337] After about 10 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 5 is shown in
[0338] Osmotic Release System 6 (Two-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0339] Tablet Composition in Mg/Tablet:
TABLE-US-00010 Core Active ingredient layer compound of the formula (II), micronized 17.24 mg hydroxypropylmethylcellulose (5 cp) 5.70 mg polyethylene oxide* 86.16 mg finely divided silica (Aerosil 200, Degussa) 0.90 mg magnesium stearate 0.30 mg 110.3 mg Osmosis layer hydroxypropylmethylcellulose (5 cp) 3.69 mg sodium chloride 21.51 mg polyethylene oxide** 47.60 mg iron oxide red 0.72 mg magnesium stearate 0.18 mg 73.70 mg total (core) 184.0 mg Shell cellulose acetate 27.00 mg polyethylene glycol 3350 3.00 mg 30.00 mg total (osmotic release system) 214.0 mg
[0340] The osmotic release system 6 was tested for the content of the compound of the formula (II) (active ingredient content) (n=10). Based on 100% of the declared active ingredient content, a minimum active ingredient content of 96.3% and a maximum active ingredient content of 101.2% were measured. The standard deviation was 1.4%.
[0341] After about 10 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 6 is shown in
[0342] Osmotic Release System 7 (Two-Chamber System, Kollidon VA 64 as Hydrophilic Swellable Polymer)
[0343] Tablet Composition in Mg/Tablet:
TABLE-US-00011 Core Active ingredient layer compound of the formula (II), micronized 5.75 mg hydroxypropylmethylcellulose (5 cp) 5.70 mg Kollidon VA 64 97.65 mg finely divided silica (Aerosil 200, Degussa) 0.90 mg magnesium stearate 0.30 mg 110.3 mg Osmosis layer hydroxypropylmethylcellulose (5 cp) 3.69 mg sodium chloride 21.51 mg polyethylene oxide** 47.60 mg iron oxide red 0.72 mg magnesium stearate 0.18 mg 73.70 mg total (core) 184.0 mg Shell cellulose acetate 27.00 mg polyethylene glycol 3350 3.00 mg 30.00 mg total (osmotic release system) 214.0 mg
[0344] After about 8.5 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 7 (which is additionally coated with 6 mg of a coating composition, as described below) is shown in
[0345] Osmotic Release System 8 (One-Chamber System, Kollidon VA 64 and Xanthan Gum as Hydrophilic Swellable Polymers)
[0346] Tablet Composition in Mg/Tablet:
TABLE-US-00012 Core compound of the formula (II), micronized 6.00 mg xanthan gum (60 mesh) 100.0 mg Kollidon VA 64 55.0 mg sodium chloride 55.0 mg sodium bicarbonate 17.0 mg sodium carboxymethyl starch (Explotab) 23.0 mg hydroxypropylmethylcellulose (3 cp) 10.0 mg finely divided silica (Aerosil 200, Degussa) 1.50 mg magnesium stearate 1.50 mg total (core) 269.0 mg Shell cellulose acetate 12.00 mg polyethylene glycol 3350 8.00 mg 20.00 mg total (osmotic release system) 289.0 mg
[0347] After about 18 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 8 is shown in
[0348] Osmotic Release System 9 (One-Chamber System, Polyethylene Oxide as Hydrophilic Swellable Polymer)
[0349] Tablet Composition in Mg/Tablet:
TABLE-US-00013 Core compound of the formula (II), micronized 5.75 mg hydroxypropylmethylcellulose (5 cp) 10.0 mg polyethylene oxide* 60.65 mg polyethylene oxide** 57.0 mg sodium chloride 25.0 mg finely divided silica (Aerosil 200, Degussa) 1.0 mg magnesium stearate 0.6 mg total (core) 160.0 mg Shell cellulose acetate 21.6 mg polyethylene glycol 3350 2.4 mg 24.00 mg total (osmotic release system) 184.0 mg
[0350] After about 14 hours, 80% of the compound of the formula (II) had been released. The release profile of the compound of the formula (II) from the osmotic release system 9 is shown in
[0353] Optionally, a coat may be applied to the osmotic release systems presented. For the osmotic release systems 5, 6 and 7, a coat of the following composition was prepared and applied in an amount of 6 mg per osmotic release system.
TABLE-US-00014 Coat polyvinyl alcohol 2.4 mg polyethylene glycol 3350 1.212 mg talc 0.888 mg titanium dioxide 1.02 mg iron oxide yellow 0.2784 mg iron oxide red 0.2016 mg total (coat) 6.0 mg
[0354] The person skilled in the art is aware that the amount of coat can be adjusted depending, for example, on the size and the surface of the osmotic release system. Here, the composition of the components of the coat in percentage terms remains unchanged.
[0355] Preparation of the Osmotic Release Systems 1 to 6:
[0356] To produce the active ingredient layer, the compound of the formula (II) in micronized form, hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose, viscosity 5 mPa.Math.s; measured in a 2% strength aqueous solution, 25 C.) and polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography Macrogols, High Molecular Mass; viscosity 40 to 100 mPa.Math.s; measured in a 5% strength aqueous solution, 25 C.; POLYOX Water-Soluble Resin NF WSR N-80; Dow) were mixed in a blender. This premix was sieved, mixed again and then subjected to dry granulation by roller granulation and finally sieved. Granules obtained were mixed with finely divided silica (corresponds to Ph. Eur. (Edition 9) monography Silica, colloidal anhydrous; silicon dioxide, Aerosil 200). Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by a final mixing to yield the mixture ready for compression.
[0357] To produce the osmosis layer, iron oxide red (for example CAS number 1309-37-1), hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose; viscosity 5 mPa.Math.s; measured in a 2% strength aqueous solution, 25 C.), polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography Macrogols, High Molecular Mass; viscosity 5000 to 8000 mPa.Math.s; measured in a 1% strength aqueous solution, 25 C.; POLYOX Water-Soluble Resin NF WSR Coagulant; Dow) and sodium chloride (corresponds to Ph. Eur. (Edition 9) monography Sodium Chloride) were mixed in a blender. This premix was subjected to dry granulation and then sieved. Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by final mixing to yield the mixture ready for compression.
[0358] The bilayer tablets were produced by tabletting on a bilayer tabletting press. First, the tabletting press was adjusted to the tabletting weight of the active ingredient layer (lower part of the tablet). Then the granules for the osmosis layer (upper part of the tablet) were added to the pre-pressed lower part of the tablet such that the respective total tablet weight of the bilayer tablet core (diameter about 8 mm) was obtained.
[0359] To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9) monography Cellulose acetate) was dissolved in acetone. An aqueous solution comprising polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) was added to the cellulose acetate solution and they were mixed. Using a coating unit suitable for organic coatings, this solution was sprayed onto the tablet cores of the bilayer tablets.
[0360] A hole having an approximate size (diameter) of 1 mm was drilled into the shell on the side of the active ingredient layer using, for example, a semiautomatic drill. Differentiation of the active ingredient layer from the osmosis layer was possible by the colour. The active ingredient layer was white to slightly orange. Owing to the added iron oxide, the osmosis layer was orange-red.
[0361] Optionally, a coat may be applied which for its part may optionally comprise auxiliaries such as pigments for colouring. To this end, polyvinyl alcohol (corresponds to Ph. Eur. (Edition 9) monography Poly(vinyl alcohol)) and polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) are dissolved in water at room temperature and mixed with stirring. With stirring, talc (corresponds to Ph. Eur. (Edition 9) monography Talc), titanium dioxide (corresponds to Ph. Eur. (Edition 9) monography Titanium dioxide) and iron oxide (for example CAS number 1309-37-1 for iron oxide red and CAS numbers 51274-00-1 or 20344-49-4 for iron oxide yellow) are added a little at a time. The coat suspension obtained is applied to the tablet cores using a suitable coating unit, e.g. a Glatt coater. Such a coating was carried out in the case of osmotic release systems 5 and 6.
[0362] Preparation of the Osmotic Release System 7:
[0363] To produce the active ingredient layer, the compound of the formula (II) in micronized form, hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose; viscosity 5 mPa.Math.s; measured in a 2% strength aqueous solution, 25 C.) and Kollidon VA 64 (corresponds to Ph. Eur. (Edition 9) monography Copovidone) were mixed in a blender. This premix was sieved, mixed again and then subjected to dry granulation by roller granulation and finally sieved. The granules obtained were mixed with finely divided silica (corresponds to Ph. Eur. (Edition 9) monography Silica, colloidal anhydrous; silicon dioxide, Aerosil 200). Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by final mixing to yield the mixture ready for compression.
[0364] To produce the osmosis layer, iron oxide red (for example CAS number 1309-37-1), hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose; viscosity 5 mPa.Math.s; measured in 2% strength aqueous solution, 25 C.), polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography Macrogols, High Molecular Mass; viscosity 5000 to 8000 mPa.Math.s; measured in a 1% strength aqueous solution, 25 C.; POLYOX Water-Soluble Resin NF WSR N-80; Dow) and sodium chloride (corresponds to Ph. Eur. (Edition 9) monography Sodium Chloride) were mixed in a blender.
[0365] This premix was subjected to dry granulation and then sieved. Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by final mixing to yield the mixture ready for compression.
[0366] The bilayer tablets were produced by tabletting on a bilayer tabletting press. First, the tabletting press was adjusted to the tabletting weight of the active ingredient layer (lower part of the tablet). Then the granules for the osmosis layer (upper part of the tablet) were added to the pre-pressed lower part of the tablet such that the respective total tablet weight of the bilayer tablet core (diameter about 8 mm) was obtained.
[0367] To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9) monography Cellulose acetate) was dissolved in acetone. An aqueous solution comprising ethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) was added to the cellulose acetate solution and they were mixed. Using a coating unit suitable for organic coatings, this solution was sprayed onto the tablet cores of the bilayer tablets.
[0368] A hole having an approximate size (diameter) of 1 mm was drilled into the shell on the side of the active ingredient layer using a semiautomatic drill. Differentiation of the active ingredient layer from the osmosis layer was possible by the colour. The active ingredient layer was white to slightly orange. Owing to the added iron oxide, the osmosis layer was orange-red.
[0369] Subsequently, coating was carried out using a coat comprising pigments for colouring. To this end, polyvinyl alcohol (corresponds to Ph. Eur. (Edition 9) monography Poly(vinyl alcohol) and polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) were dissolved in water at room temperature and mixed with stirring. With stirring, talc (corresponds to Ph. Eur. (Edition 9) monography Talc), titanium dioxide (corresponds to Ph. Eur. (Edition 9) monography Titanium dioxide) and iron oxide (for example CAS number 1309-37-1 for iron oxide red and CAS numbers 51274-00-1 or 20344-49-4 for iron oxide yellow) were added a little at a time. Alternatively, a finished coat of the same composition may be suspended in water. In a suitable coating unit, the aqueous coat suspension obtained was sprayed onto the tablet cores.
[0370] Preparation of the Osmotic Release System 8:
[0371] The compound of the formula (II) in micronized form, xanthan (Xanthan FN Lebensmittelqualitat normal (produced by Jungbunzlauer Ladenburg GmbH) corresponding to Ph. Eur. (Edition 9) monography Xanthan gum, Kollidon VA 64 (corresponds to Ph. Eur. (Edition 9) monography Copovidone), sodium chloride (corresponds to Ph. Eur. (Edition 9) monography Sodium Chloride), sodium bicarbonate and sodium carboxymethyl starch (Explotab) were mixed in a blender (premix). Hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose; viscosity 3 mPa.Math.s; measured in a 2% strength aqueous solution, 25 C.) was dissolved in water (granulation liquid).
[0372] The premix was introduced into a fluidized-bed granulator and, in the fluidized bed, granulated with the granulation liquid. The granules were then dried in the fluidized bed. The dried and sieved granules were mixed with finely divided silica (corresponds to Ph. Eur. (Edition 9) monography Silica, colloidal anhydrous; silicon dioxide, Aerosil 200). Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by final mixing to yield the mixture ready for compression.
[0373] Tabletting was carried out using a tablet diameter of about 9 mm and a tablet breaking strength of about 50-60 N.
[0374] To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9) monography Cellulose acetate) was dissolved in acetone. An aqueous solution comprising polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) was added to the cellulose acetate solution and they were mixed. Using a coating unit suitable for organic coatings, the solution was sprayed onto the tablet cores.
[0375] A hole having an approximate size (diameter) of 1 mm was drilled into the shell using a semiautomatic drill.
[0376] Preparation of the Osmotic Release System 9:
[0377] To produce the tablet cores, the compound of the formula (II) in micronized form, hydroxypropylmethylcellulose (corresponds to Ph. Eur. (Edition 9) monography Hypromellose; viscosity 5 mPa.Math.s; measured in a 2% strength aqueous solution, 25 C.), sodium chloride (corresponds to Ph. Eur. (Edition 9) monography Sodium Chloride) and polyethylene oxide were mixed in a blender. This premix was sieved, mixed again and then mixed with finely divided silica (corresponds to Ph. Eur. (Edition 9) monography Silica, colloidal anhydrous; silicon dioxide, Aerosil 200). Addition of sieved magnesium stearate (corresponds to Ph. Eur. (Edition 9) monography Magnesium Stearate) was followed by final mixing to yield the mixture ready for compression. Alternatively, the premix can be subjected to dry granulation by roller granulation and finally sieved.
[0378] Tabletting was carried out using a tablet diameter of about 8 mm and a tablet breaking strength of about 80-110 N.
[0379] To produce the shell, cellulose acetate (corresponds to Ph. Eur. (Edition 9) monography Cellulose acetate) was dissolved in acetone. An aqueous solution comprising polyethylene glycol 3350 (corresponds to Ph. Eur. (Edition 9) monography Macrogols; mean molecular mass 3350 g/mol) was added to the cellulose acetate solution and they were mixed. Using a coating unit suitable for organic coatings, the solution was sprayed onto the tablet cores.
[0380] A hole having an approximate size (diameter) of 1 mm was drilled into the shell using, for example, a semiautomatic drill.
[0381] Unless specified in more detail, the substances used for preparing the osmotic release systems refer to pharmaceutical auxiliaries known to the person skilled in the art under the name employed and, if listed in one of the pharmacopeias, meet the respective requirements of the pharmacopeia monographies of the European (Ph. Eur. 9), American (USP 41 and NF 36) and/or Japanese (JP, 17th edition) pharmacopeia.
[0382] Release Characteristics
[0383] The release of the active ingredient from the tablets was determined by the method of US Pharmacopoeia USP 39 (Chapter <711> Dissolution) using apparatus 2 (paddle test). To determine the release rate, a tablet was introduced into each release vessel of the 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 release medium used was phosphate buffer pH 6.8 without addition of surfactant, and the paddle stirrer of the USP apparatus 2 had a speed of rotation of 100 revolutions per minute. Unless stated otherwise, the release rate of at least six test specimens was determined. In each case, the mean amount of active ingredient released is reported.
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[0393] Thermoanalytical Investigation of Binary Physical Mixtures
[0394] In order to represent compatibilities in thermoanalytical investigations, the compounds of the formulae (II) and (I) were initially charged with equal parts of hydrophilic swellable polymers in a flat round bowl and, using a pestle, ground to a homogeneous powder mixture (trituration in a ratio of 1:1, binary mixture). Investigated as hydrophilic swellable polymers were polyethylene oxide (corresponds to Ph. Eur. (Edition 9) monography Macrogols, High Molecular Mass; viscosity 40 to 100 mPa.Math.s; measured in a 5% strength aqueous solution, 25 C.; POLYOX Water-Soluble Resin NF WSR N-80; Dow), xanthan (Xanthan FN Lebensmittelqualitat normal produced by Jungbunzlauer Ladenburg GmbH), corresponds to Ph. Eur. (Edition 9) monography Xanthan gum, vinylpyrrolidone/vinyl acetate copolymer (Kollidon VA 64), corresponds to Ph. Eur. (Edition 9) monography Copovidone, polyvinylpyrrolidone (PVP 25), corresponds to Ph. Eur. (Edition 9) monography Povidone, methacrylic acid/methyl methacrylate copolymer (Eudragit L100), corresponds to Ph. Eur. (Edition 9) monography Methacrylic acid-Methyl Methacrylate Copolymer (1:1), methacrylic acid/methyl methacrylate copolymer (Eudragit RL PO), corresponds to Ph. Eur. (Edition 9) monography Ammonio Methacrylate Copolymer (TYPE A), hydroxypropylcellulose (HPC LM Nisso), corresponds to Ph. Eur. (Edition 9) monography Hydroxypropylcellulose and polyacrylic acid (corresponds to Ph. Eur. (Edition 9) monography Carbomers; Name: Polyacrylic acid, MW 1,080,000 aver. MN 135,000; Acros Organics).
[0395] The physical mixtures and the respective individual components were characterized thermoanalytically. The thermograms were recorded on a differential scanning calorimeter. To this end, in each case about 5 mg of the sample were heated in an aluminium pan under nitrogen (50 ml/min) using a heating rate of 10 K/min to the end of the melting point of the compound in question.
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