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ORAL PHARMACEUTICAL COMPOSITIONS OF A THIOPHENE-2-CARBOXAMIDE DERIVATIVE

IP.com Disclosure Number: IPCOM000249349D
Publication Date: 2017-Feb-20
Document File: 6 page(s) / 130K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present invention discloses processes for preparing pharmaceutical formulations comprising a thiophene-2-carboxamide derivative in the form of solid oral dosage formulations

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 19% of the total text.

1

ORAL PHARMACEUTICAL COMPOSITIONS OF A THIOPHENE-2-CARBOXAMIDE DERIVATIVE

The present invention relates to processes for preparing pharmaceutical formulations comprising rivaroxaban in the form of solid oral dosage formulations.

Rivaroxaban (compound I) is the international commonly accepted name for (S)-5- chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl)methyl}thiophene-2-carboxamide and has an empirical formula of C19H18N3O5SCl and a molecular weight of 435.88 g/mol.

Rivaroxaban is available as Xarelto® film-coated tablets containing 2.5 mg, 10 mg, 15 mg or 20 mg of rivaroxaban which is used as a treatment for deep vein thrombosis, pulmonary embolism, and for the reduction in the risk of recurrence of the same. Xarelto® film-coated tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium laurilsulfate (core), and macrogol, hypromellose, titanium dioxide and iron oxide (film-coat)

The prior art discloses various approaches for formulating rivaroxaban to improve its bioavailability. WO2005/060940 teaches the use of the wet granulation technique in combination with the use of hydrophilic matrix formers in order to hydrophilize the rivaroxaban and to improve bioavailability.

Preferred solid oral dosage formulations of rivaroxaban are capsules, tablets or sachets. More preferably, solid oral dosage formulations of rivaroxaban are tablets. The present invention is related to processes for the preparation of rivaroxaban oral dosage forms, preferably tablets, wherein rivaroxaban has a d90 value of not more than 30 µm, preferably not more than 15 µm, and most preferably not more than 10 µm.

The term “d90,” as used herein, means that 90% of the particles are less than the specified particle size value based on volume. Rivaroxaban in the solid oral formulations obtained according to the processes of the present invention may be present in crystalline form, amorphous form, anhydrous form, hydrate form, solvate form, or as mixtures thereof.

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The starting rivaroxaban used for the preparation of the solid oral formulations according to the present invention may be in a crystalline form, amorphous form, anhydrous form, hydrate form, solvate form, or as mixtures thereof. Preferably, the starting rivaroxaban used for the preparation of the solid oral formulations according to the present invention is in crystalline form I as disclosed in WO2007/039132.

The weight ratio of rivaroxaban to pharmaceutically acceptable inert excipients in the solid oral formulations, preferably tablets, obtained according to the processes of the present invention is 1:0.1 to 1:50, more preferably 1:3 to 1:35. The rivaroxaban tablets as reported herein release more than 85% of rivaroxaban in 30 minutes when measured in a USP type II dissolution apparatus, paddle rotating at 75 RPM, at a temperature of 37°C ±0.5°C, in 900 mL of pH 4.5 acetate buff...