Tablets for oral suspension containing rivaroxaban

Abstract

A tablet for oral suspension formulation suitable for reconstitution is disclosed. The tablet contains a disintegrant, a wetting agent, a lubricant and other excipients in selected amounts to provide fast disintegration and dissolution in water. Also disclosed is a method of treating a disease by administering to a subject in need thereof a tablet disclosed herein.

1 . A tablet for oral suspension formulation, suitable for reconstitution with a pharmaceutically acceptable carrier to form a suspension, comprising
 rivaroxaban or a pharmaceutically acceptable salt thereof, and   excipients comprising a disintegrant, a wetting agent, a hydrophilic lubricant and a binder;   wherein the excipients and their amounts in the tablet are so selected and configured that the tablet disintegrates within about 1 minute in 100 ml water at room temperature and a resulting suspension passes through mesh aperture of 710 μm, and the tablet provides an in vitro release of at least 75% of the rivaroxaban within about 30 minutes under United States Pharmacopeia (USP) dissolution apparatus 2, in 900 ml of pH 4.5 water medium comprising 0-0.4% sodium lauryl sulfate (SLS) at 75 rpm stirring rate,   wherein the disintegrant is crospovidone ranging from about 5% to about 15% by weight, the lubricant is sodium stearyl fumarate ranging from about 1% to about 3%, the binder ranges from 1% to about 3% by weight in the tablet,   wherein “about” as used herein includes the referenced numeric indication plus or minus 10% of that referenced numeric indication.   
     
     
         2 . The tablet of  claim 1 , wherein the rivaroxaban or the pharmaceutically acceptable salt is present in the amount ranging from about 1 mg to about 50 mg. 
     
     
         3 . The tablet of  claim 1 , wherein the disintegrant agent is present in the amount ranging from about 6% to about 10% in the tablet by weight. 
     
     
         4 . (canceled) 
     
     
         5 . The tablet of  claim 1 , wherein the lubricant is present in the amount ranging from about 1.3% to about 2.2%. 
     
     
         6 . The tablet of  claim 1 , further comprising a glidant in the amount ranging from about 0.5% to about 3% in the tablet by weight. 
     
     
         7 . The tablet of  claim 6 , wherein the glidant is selected from the group consisting of silicon dioxide, starch and talc and any combination thereof. 
     
     
         8 . The tablet of  claim 1 , wherein the wetting agent of the tablet is present in the amount ranging from about 0.1% to about 1% in the tablet by weight. 
     
     
         9 . The tablet formulation of  claim 1 , wherein the binder is hypromellose. 
     
     
         10 . (canceled) 
     
     
         11 . The tablet of  claim 1 , wherein the wetting agent is selected from the group consisting of sodium dodecyl sulfate (SDS), poloxamers, polysorbate 80 and any combination thereof. 
     
     
         12 . The tablet of  claim 1 , wherein the binder is selected from the group consisting of Polyvinylpyrrolidone (PVP), Hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and any combination thereof. 
     
     
         13 . The tablet of  claim 1 , further comprising a filler comprising microcrystalline cellulose and lactose monohydrate, wherein the ratio between the microcrystalline cellulose and the lactose monohydrate ranges from about 1:1 to about 2:1 by weight. 
     
     
         14 . (canceled) 
     
     
         15 . The tablet of  claim 1 , wherein the excipients and their amounts in the tablet are so selected that the tablet provides an in vitro release of at least 90% of the rivaroxaban within about 20 minutes under USP dissolution apparatus 2, in 900 ml of pH 4.5 water medium comprising 0-0.4% SLS at 75 rpm stirring rate. 
     
     
         16 . The tablet of  claim 1 , wherein the excipients and their amounts in the tablet are so selected that the tablet provides an in vitro release of at least about 90% of the rivaroxaban within about 10 minutes under USP dissolution apparatus 2, in 900 ml of pH 4.5 water medium comprising 0-0.2% SLS at 75 rpm stirring rate, wherein the tablet comprises 2.5 or 10 mg of rivaroxaban. 
     
     
         17 . The tablet of  claim 1 , which is prepared according to the following:
 (a) preparing a granulation liquid comprising the wetting agent and a first portion of the binder;   (b) mixing rivaroxaban or a pharmaceutically acceptable salt thereof with one or more excipients comprising a second portion of the binder and the disintegrant to prepare a dry mixture;   (c) mixing the granulation liquid and the dry mixture to obtain a wet granule and dry the wet granule to obtain a dry granule; and   (d) milling the dry granule and mixing the milled granule with an external phase comprising one or more additional excipients,   wherein the first portion of binder ranges from about ¼ to about ½ in the total amount of the binder.   
     
     
         18 . The tablet of  claim 17 , wherein the binder is hypromellose, the first portion is about ¼ of the total amount of the binder. 
     
     
         19 . The tablet of  claim 17 , wherein the granulation liquid of step (a) and the dry mixture of step (b) are substantially free from silicon dioxide. 
     
     
         20 . A method of treating or reducing the risk of a disease comprising:
 (a) preparing a suspension from the tablet of  claim 1 ; and   (b) administering the suspension to a subject in need thereof, wherein the disease is stroke or systemic embolism associated with nonvalvular atrial fibrillation, deep vein thrombosis (DVT), pulmonary embolism (PE), or myocardial infarction (MI) or stroke associated with with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).   
     
     
         21 . A method of preparing the tablet of  claim 1 , comprising
 (a) preparing a granulation liquid comprising a wetting agent and a first portion of binder;   (b) mixing rivaroxaban or a pharmaceutically acceptable salt thereof with one or more excipients comprising a second portion of the binder to prepare a dry mixture;   (c) mixing the granulation liquid and the dry mixture to obtain a wet granule and dry the wet granule to obtain a dry granule; and   (d) milling the dry granule and mixing the milled granule with one or more additional excipients,   wherein the first portion of binder ranges from about ¼ to about ½ in the total amount of the binder.   
     
     
         22 . The tablet formulation of  claim 1 , wherein the binder is present in the amount ranging from about 2% to about 3% by weight. 
     
     
         23 . The tablet formulation of  claim 1 , which is free from croscarmellose sodium. 
     
     
         24 . The tablet formulation of  claim 1 , which is free from magnesium stearate. 
     
     
         25 . The tablet formulation of  claim 1 , which is prepared by wet granulation.