Solid, modified-release pharmaceutical dosage forms which can be administered orally
The present invention relates to solid, modified-release pharmaceutical dosage forms which can be administered orally and comprise 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, and process for their production, their use as medicaments, their use for the prophylaxis, secondary prophylaxis and/or treatment of disorders, and their use for producing a medicament for the prophylaxis, secondary prophylaxis and/or treatment of disorders.
1 . A solid, modified-release pharmaceutical dosage form which can be administered orally and comprises 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I), characterized in that 80% of the active ingredient (I) are released in a period of from 2 to 24 hours in the USP release method with apparatus 2 (paddle).
2 . The pharmaceutical dosage form according to claim 1 , characterized in that 80% of the active ingredient (I) are released in a period of from 4 to 20 hours in the USP release method with apparatus 2 (paddle).
3 . The pharmaceutical dosage form according to claim 1 , characterized in that the active ingredient (I) is present in crystalline form.
4 . The pharmaceutical dosage form according to claim 3 , comprising the active ingredient (I) in micronized form.
5 . The pharmaceutical dosage form according to claim 4 , comprising the active ingredient (I) in hydrophylized form.
6 . The pharmaceutical dosage form according to claim 1 , characterized in that the active ingredient (I) is present in amorphous form.
7 . The pharmaceutical dosage form according to claim 6 , characterized in that the active ingredient (I) has been amorphized by melt extrusion.
8 . The pharmaceutical dosage form according to claim 7 , characterized in that the polymer employed in the melt extrusion is hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP), the proportion of polymer in the melt extrudate is at least 50%, and the active ingredient (I) is present in the melt extrudate in a concentration of from 1 to 20%.
9 . The pharmaceutical dosage form according to claim 7 , characterized in that at least one pharmaceutically suitable substance is added in a concentration of from 2 to 40% as plasticizer and/or to depress the melting point of the active ingredient (I).
10 . The pharmaceutical dosage form according to claim 9 , characterized in that the pharmaceutically suitable additive is a sugar alcohol.
11 . The pharmaceutical dosage form according to claim 1 , wherein said dosage form is based on an erosion matrix system.
12 . The pharmaceutical dosage form according to claim 11 , characterized in that the active ingredient (I) is present in amorphous form.
13 . The pharmaceutical dosage form according to claim 1 , comprising hydroxypropylcellulose or hydroxypropylmethylcellulose or mixtures of hydroxypropylcellulose and hydroxypropylmethylcellulose as hydrophilic matrix former.
14 . The pharmaceutical dosage form according to claim 11 , characterized in that the active ingredient (I) is present in a concentration of between 1 and 50%.
15 . A process for producing a pharmaceutical dosage form according to claim 11 , comprising producing an extrudate comprising the active ingredient (I) by melt extrusion, grinding and mixing it with further tabletting excipients and then compressing it to tablets by direct tabletting.
16 . A multiparticulate pharmaceutical dosage form according to claim 1 .
17 . The multiparticulate pharmaceutical dosage form according to claim 16 , characterized in that the active ingredient (I) is present in amorphous form.
18 . The multiparticulate pharmaceutical dosage form according to claim 16 , comprising hydroxypropylcellulose as hydrophilic matrix former.
19 . The multiparticulate pharmaceutical dosage form according to claim 18 , characterized in that hydroxypropylcellulose is present as hydrophilic matrix former in a concentration of between 10 and 99%.
20 . The multiparticulate pharmaceutical dosage form according to claim 16 , characterized in that the active ingredient (I) is present in a concentration of between 1 and 30%.
21 . The multiparticulate pharmaceutical dosage form according to claim 16 , characterized in that the diameter of the particles is between 0.5 and 3.0 mm.
22 . The multiparticulate pharmaceutical dosage form according to claim 21 , characterized in that the diameter of the particles is between 1.0 and 2.5 mm.
23 . A pharmaceutical dosage form comprising multiparticulate pharmaceutical dosage forms according to claim 16 .
24 . The pharmaceutical dosage form according to claim 23 in the form of a capsule, of a sachet or of a tablet.
25 . A process for producing a multiparticulate pharmaceutical dosage form as defined in claim 16 , comprising producing by melt extrusion an extrudate strand comprising the active ingredient (I) and cutting said strand.
26 . The process according to claim 25 , further comprising roundings the articles obtained after cutting the extrudate strand.
27 . The process according to claim 25 , further comprising coating said articles.
28 . The pharmaceutical dosage form according to claim 1 , wherein said dosage form is based on an osmotic release system.
29 . The pharmaceutical dosage form according to claim 28 , characterized in that the active ingredient (I) is present in amorphous form.
30 . The pharmaceutical dosage form according to claim 28 , consisting of an osmotic single-chamber system comprising a core comprising
2 to 30% active ingredient (I)
20 to 50% xanthan,
10 to 30% of a vinylpyrrolidone-vinyl acetate copolymer,
and a shell consisting of a water-permeable material which is impermeable for the components of the core and has at least one orifice.
31 . The pharmaceutical dosage form according to claim 30 , additionally comprising sodium chloride as osmotically active additive in the core.
32 . The pharmaceutical dosage form according to claim 30 , characterized in that the shell consists of cellulose acetate or of a mixture of cellulose acetate and polyethylene glycol.
33 . A process for producing an osmotic single-chamber system as defined in claim 30 , comprising mixing together the components of the core, granulating and tabletting them, coating the core produced in this way with a shell, and finally providing the shell with one or more orifices.
34 . The pharmaceutical dosage form according to claim 28 , consisting of an osmotic two-chamber system comprising a core having an active ingredient layer comprising
1 to 40% active ingredient (I),
50 to 95% of one or more osmotically active polymers,
and an osmosis layer comprising
40 to 90% of one or more osmotically active polymers,
10 to 40% of an osmotically active addition,
and a shell consisting of a water-permeable material which is impermeable for the components of the core and has at least one orifice.
35 . The pharmaceutical dosage form according to claim 34 , which comprises polyethylene oxide having a viscosity of from 40 to 100 mPa·s (5% strength aqueous solution, 25° C.) as osmotically active polymer in the active ingredient layer in the core, and comprises polyethylene oxide having a viscosity of from 5000 to 8000 mPa·s (1% strength aqueous solution, 25° C.) as osmotically active polymer in the osmosis layer in the core.
36 . The pharmaceutical dosage form according to claim 34 , characterized in that the shell consists of cellulose acetate or of a mixture of cellulose acetate and polyethylene glycol.
37 . A process for producing an osmotic two-chamber system as defined in claim 34 , comprising
mixing and granulating the components of the active ingredient layer and
mixing and granulating the components of the osmosis layer,
subsequently compressing the two granules in a bilayer tablet press to a bilayer tablet.
coating the core produced in this way with the shell, and
providing the shell with one or more orifices on the active ingredient side.
38 . A medicament comprising a solid pharmaceutical dosage form which can be administered orally and has a modified release, as defined in claim 1 , of the active ingredient (I).
39 . A method for the prophylaxis, secondary prophylaxis and/or treatment of a thromboembolic disorder, comprising administering to a patient a therapeutically effective amount of the pharmaceutical dosage form of claim 1 .
40 . The method of claim 39 , wherein the thromboembolic disorder is myocardial infarction, angina pectoris, reocclusion and restenosis following an angioplasty or aortocoronary bypass, stroke, transient ischaemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.