WO2022049602A1

WO2022049602A1 - Rivaroxaban compositions

Info

Publication number: WO2022049602A1
Application number: PCT/IN2021/050855
Authority: WO
Inventors: Vaibhavi SHAH; Ravindranath Gampa; Asis MAITI
Original assignee: Inventia Healthcare Limited
Priority date: 2020-09-05
Filing date: 2021-09-04
Publication date: 2022-03-10
Also published as: EP4208462A1

Abstract

The present invention relates to non-granulated compositions comprising rivaroxaban for oral administration, wherein rivaroxaban is at a concentration of not more than 20% by weight of the composition. The said non-granulated compositions provide the desired dissolution, and storage stability of rivaroxaban, and are bioequivalent to commercially available granulated compositions of rivaroxaban. The present invention also provides a process for the preparation of such compositions.

Description

RIVAROXABAN COMPOSITIONS

Field of the Invention:

The present invention relates to non-granulated compositions comprising rivaroxaban. The present invention also provides a process for the preparation of such compositions.

Background of the Invention:

Rivaroxaban or 5-chloro-N-({(5S)-2-oxo-3-4-(3-oxo-4-morpholinyl)-phenyl-1 ,3-oxazolidin -5-yl)-methyl-2-thiophenecarboxamide is a low molecular weight, orally administrable drug, which is employed for the prophylaxis and/or treatment of various thromboembolic diseases. It is a potent inhibitor of blood clotting factor Xa. It is commercially available as tablets (XARELTO®) in dose strengths of 2.5mg, 10mg, 15mg and 20mg. Rivaroxaban being a potent drug with relatively poor water solubility (about 7 mg/L), shows poor oral bioavailability and increased variability in the gastrointestinal absorption rate. Development of a dosage form comprising a potent, low dose, low solubility drug such as rivaroxaban, needs to simultaneously address several factors such as solubility, dissolution, content uniformity oral bioavailability, and storage stability. Various processes and techniques have been used in prior art to increase the solubility, and dissolution, and improve oral bioavailability and stability of rivaroxaban.

U.S. Patent No. 9,415,053 discloses wet/moist granulation of rivaroxaban and excipients, using a granulating liquid containing solvent, hydrophilic binding agent and wetting agent, to give a hydrophilized form of rivaroxaban. Hydrophilized form of rivaroxaban in the formulation leads to a significant increase in the bioavailability of rivaroxaban. Hydrophilic additives/binding agents used in the granulation are hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolysed starch, alginates and xanthan gum. Table 2 of U.S. Patent No. 9,415,053 presents data that shows that tablets prepared by directly compressed tablet compositions (Tablet A) were found to be 35% less readily absorbed and less bioavailable than tablets prepared by moist granulation (Tablet B) where rivaroxaban is in the hydrophilized form. U.S. Patent Publication No. 2017/065526, PCT Publication No. WO/2016/166733, PCT Publication No. WO/2015/124995, PCT Publication No. WO/2017/146709, Indian Patent Application No. 201837032592 and Indian Patent Application No. 3369/CHE/2013 disclose compositions comprising hydrophilized form of rivaroxaban prepared using processes like fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation and centrifugal wet granulation. The said compositions use hydrophilic binding agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, maize starch, povidone, and pregelatinized starch.

PCT Publication No. WO/2016/144071 relates to pharmaceutical compositions comprising rivaroxaban in the form of a tablet or a capsule, wherein rivaroxaban along with other excipients is wet granulated with a binder (hypromellose) and non-aqueous solvents using a high shear mixer granulator, and the granules dried using a fluidized bed dryer.

European Patent No. 2442799, U.S. Patent Publication No. 2017/0049782 and U.S. Patent Publication No. 2012/0231076 disclose a melt granulation process for the preparation of a solid compositions comprising rivaroxaban. The compositions use hydrophilic matrix formers (solubilizers), carriers or binders such as povidone, copovidone, polyethylene glycol, and poloxamer.

U.S. Patent Publication No. 2016/0120870, Indian Patent Application No. 781/MUM/2014, Indian Patent Application No. 2777/MUM/2013, and Indian Patent Application No. 3370/CHE/2013 disclose co-milling/co-micronization of rivaroxaban with at least one hydrophilic binder or surfactant.

U.S. Patent Publication No. 2017/0000799 relates to adsorption of a solubilizer on the surface of a poorly soluble drug like rivaroxaban.

PCT Publication No. 2014/016842 and Indian Patent Application No. 2992/CHE/2012 disclose stable amorphous co-precipitates of rivaroxaban and hydrophilic excipients such as hypromellose and its derivatives. U.S. Patent Publication No. 2013/0281457 relates to a pharmaceutical composition comprising rivaroxaban, a solubilizer and a pseudo-emulsifier, the said compositions prepared by a pellet layering process.

U.S. Patent Publication No. 2018/0214453 and European Patent Publication No. 3505160 disclose rivaroxaban immediate release tablet comprising a non-ionic surfactant like poloxamer, at least one hydrophilic binder like hydroxypropyl methylcellulose and hydroxypropyl cellulose, at least one filler, at least one disintegrant and at least one lubricant. The said compositions are prepared using a roll compaction, slug compaction or direct compression.

In summary, prior art uses the following approaches to improve dissolution of rivaroxaban:

• Hydrophilization of rivaroxaban with one or more hydrophilic polymers (e.g. HPMC, HPC), using wet I moist granulation, melt extrusion, co-milling, or co-precipitation techniques (bringing hydrophilic polymers in close contact with the hydrophobic drugs to increase their solubility and dissolution rate)

• Use of hydrophilic binders like hydroxypropyl methylcellulose and hydroxypropyl cellulose, solubilizers, emulsifiers, hydrophilic matrix formers, or hydrophilic carriers

In commercially available rivaroxaban tablets, the process of wet/moist granulation is used to hydrophilize rivaroxaban with hydrophilic polymer- hypromellose.

It has surprisingly been found that the compositions of the present invention do not use any of the above approaches, and yet achieve the desired dissolution, bioavailability and stability.

Contrary to the teachings of the prior art, the compositions of the present invention are in the form of non-granulated compositions of rivaroxaban and yet achieve the desired dissolution, bioavailability and storage stability of rivaroxaban. The said compositions accomplish this by comprising rivaroxaban at low concentrations of about 20% or less (by weight of the composition), and diluent(s) at high concentrations of about 70% or more (by weight of the composition). The composition further comprises 1 % or less of surfactant (by weight of the composition). Further, despite the compositions comprising a low dose drug like rivaroxaban in a low concentration, they achieve the desired drug blend uniformity and content uniformity.

OBJECTS OF THE INVENTION

The principal object of the present invention is to provide non-granulated, compositions of rivaroxaban for oral administration, wherein rivaroxaban is at a concentration of not more than 20% by weight of the composition.

Another object of the present invention is to provide non-granulated compositions of rivaroxaban for oral administration, wherein the said compositions are bioequivalent to the commercially available granulated compositions of rivaroxaban.

Yet another object of the present invention is to provide non-granulated compositions of rivaroxaban, wherein the dissolution of rivaroxaban from the said compositions is not less than 90% in 45 minutes.

Yet another object of the present invention is to provide non-granulated compositions of rivaroxaban for oral administration, wherein the total impurities content in the said compositions, as determined by liquid chromatography, is not more than 3%.

Yet another object of the present invention is to provide a process for preparation of the said non-granulated compositions of rivaroxaban.

SUMMARY OF THE INVENTION

The present invention relates to non-granulated compositions of rivaroxaban, comprising rivaroxaban at a concentration of not more than 20% by weight of the composition. The present invention also provides a process for the preparation of such compositions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides non-granulated compositions of rivaroxaban for oral administration.

The term ‘non-granulated’ used herein refers to rivaroxaban that is not in the form of granules or granulates, but is in the form of a powder, or a powder blend of rivaroxaban with at least one excipient, the said powder or powder blend capable of being further compressed into tablets and/or filled into capsules. In the ‘non-granulated’ compositions, rivaroxaban is not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, comilling, co-crystallization, solvent evaporation, or co-precipitation.

The term ‘non-granulated composition’ as used herein refers to compositions that comprise rivaroxaban not in the form of granules or granulates, but in the form of a powder, or a powder blend with at least one excipient. In the ‘non-granulated’ compositions, rivaroxaban is not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or coprecipitation. The ‘non-granulated composition’ can be in the form of powder, powder blend, tablet, directly compressed tablet, capsule, or combinations thereof.

The term ‘directly compressed’, as used herein, refers to non-granulated compositions of rivaroxaban wherein rivaroxaban is in the form of powder or powder blends, which has been directly incorporated into tablets by compression.

The present invention provides compositions of rivaroxaban, wherein rivaroxaban is nongranulated.

The non-granulated compositions of the present invention may be in the form of powder blends, tablets, or capsules.

In one aspect, the non-granulated compositions of rivaroxaban are in the form of directly compressed tablets and/or capsules. In another aspect, the non-granulated compositions of rivaroxaban are blended with inert excipient granules. The blend can be further compressed into tablets and/or filled into capsules. The term “inert excipient granules” as used herein, refers to inactive and inert excipients in the form of granules or granulates, the said g ran ules/g ran ulates being free of rivaroxaban.

In an aspect, the non-granulated compositions of rivaroxaban provide rapid release, extended-release, sustained-release, controlled-release, prolonged release, delayed- release, enteric-release, timed-release, pulsed-release, or a combination thereof.

Rivaroxaban as used herein includes rivaroxaban, and its pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates thereof. Rivaroxaban can be in crystalline and/or amorphous form.

Rivaroxaban is used herein in concentrations ranging from about 0.25% to about 20%, preferably from about 0.5% to about 15%, more preferably from about 0.75% to about 10%, and most preferably from about 1 % to about 10% by weight of the composition.

Rivaroxaban used in the non-granulated compositions has a particle size distribution wherein 90% by volume (d (0.9)) of rivaroxaban particles have a particle size of not more than 100 microns, preferably not more than 50 microns, more preferably not more than 25 microns, and most preferably not more than 20 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

Rivaroxaban used in the non-granulated compositions has a particle size distribution wherein 50% by volume (d (0.5)) of rivaroxaban particles have a particle size of not more than 50 microns, preferably not more than 30 microns, more preferably not more than 20 microns, and most preferably not more than 10 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

In one aspect, the non-granulated compositions comprise a powder blend of rivaroxaban and at least one diluent. Diluent in the non-granulated compositions is selected from water-soluble diluents, waterinsoluble diluents, and mixtures thereof. Water-soluble diluents are selected from mannitol, sorbitol, and lactose. The preferred water-soluble diluent is lactose. Waterinsoluble diluents are selected from microcrystalline cellulose and dibasic calcium phosphate. The preferred water-insoluble diluent is microcrystalline cellulose.

The non-granulated compositions comprise diluent(s) in concentrations ranging from about 70% to about 99%, preferably from about 75% to about 99%, and more preferably from about 80% to about 99% by weight of the composition. In one embodiment the concentration of diluent(s) is not less than 70% by weight of the composition. In another embodiment, the concentration of diluent(s) is not less than 75% by weight of the composition. In yet another embodiment, the concentration of diluent(s) is not less than 80% by weight of the composition.

In one embodiment, the non-granulated compositions of rivaroxaban comprise at least two diluents. The weight ratio of the diluents can range from about 1 :0.25 to about 1 :2.5.

In one embodiment, the non-granulated compositions of rivaroxaban comprise at least two diluents, wherein the first diluent is a water-insoluble diluent, and the second diluent is a water-soluble diluent.

In an aspect, the weight ratio of water-insoluble diluent to water-soluble diluent, in the non-granulated compositions of rivaroxaban, can range from about 1 :1 to 1 :2.5, preferably from about 1 :1 to 1 :2.

In one embodiment, the non-granulated rivaroxaban composition comprises rivaroxaban and at least two diluents, wherein rivaroxaban is not more than 20% by weight of the composition, and wherein the weight ratio of the diluents range from 1 : 0.25 to 1 : 2.5

In an aspect, the non-granulated compositions of the present invention comprise at least one surfactant.

In another aspect, the non-granulated compositions comprise rivaroxaban, at least one diluent, and at least one surfactant. In an embodiment, the surfactant(s) is selected from ionic surfactants known in the art. In a preferred embodiment, the ionic surfactant is sodium lauryl sulphate.

In another embodiment, the non-granulated compositions are free of non-ionic surfactants.

The non-granulated compositions comprise surfactant(s) in concentrations ranging from about 0.05% to about 1 % by weight of the composition. Preferably the concentration of the surfactant(s) ranges from about 0.1 % to about 0.75% by weight of the composition.

In an aspect, the concentration of the surfactant(s) is not more than about 1 %, preferably not more than about 0.75% and more preferably not more than about 0.5% by weight of the composition.

The non-granulated compositions comprise surfactant(s) in concentrations of about 1% to about 50% by weight of rivaroxaban.

The non-granulated compositions comprise rivaroxaban and surfactant in a weight ratio ranging from 1 :0.01 to 1 :0.5.

In an aspect, the non-granulated compositions comprise at least one disintegrant.

In another aspect, non-granulated compositions are in the form of rapid release compositions and comprise rivaroxaban, at least one diluent, and at least one disintegrant.

Disintegrant(s) may be present in concentrations from about 1 % to about 20% by weight of the composition, and are selected from those known in the art such as sodium starch glycolate, crospovidone, and croscarmellose sodium.

Lubricant(s) may be present in concentrations from about 0.25% to about 5% by weight of the composition, and are selected from those known in the art such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, palmitic acid, talc, and glyceryl behenate. Glidant(s) may be present in concentrations from about 0.1 % to about 10% by weight of the composition, and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, stearic acid, and talc.

The non-granulated compositions may optionally be film coated with a film-coating layer comprising film-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants or mixtures thereof. The film coating materials are selected from those known in the art.

In an aspect, the non-granulated compositions of rivaroxaban comprise rivaroxaban in the non-hydrophilized form. The non-granulated compositions are free of hydrophilic components such as hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolysed starch, alginates and xanthan gum.

In another aspect, the non-granulated compositions are free of binders such as hydrophilic binding agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, maize starch, povidone, and pregelatinized starch.

In yet another aspect, the non-granulated compositions are free of hydrophilic matrix formers (solubilizers), carriers or binders such as povidone, copovidone, polyethylene glycol, and poloxamer.

In an embodiment, the non-granulated compositions comprise rivaroxaban, at least one diluent, at least one surfactant and at least one disintegrant.

In another embodiment, the non-granulated compositions comprise rivaroxaban, at least two diluents, at least one surfactant, and at least one disintegrant. In another embodiment, the non-granulated compositions comprise rivaroxaban, at least two diluents, at least one ionic surfactant, and at least one disintegrant.

In another embodiment, the non-granulated compositions comprise rivaroxaban, at least one water-insoluble diluent, at least one water-soluble diluent, at least one surfactant, and at least one disintegrant.

In another embodiment, the non-granulated compositions consist essentially of rivaroxaban, two diluents, a surfactant, a disintegrant, and a lubricant.

In another embodiment, the non-granulated, rapid release compositions consist essentially of rivaroxaban, two diluents, a surfactant, a disintegrant, and a lubricant.

In another embodiment, the non-granulated compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, a surfactant, a disintegrant, and a lubricant.

In another embodiment, the non-granulated, rapid release compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, a surfactant, a disintegrant, and a lubricant.

In another embodiment, the non-granulated compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, an ionic surfactant, a disintegrant, and a lubricant.

In another embodiment, the non-granulated, rapid-release compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, an ionic surfactant, a disintegrant, and a lubricant.

The process for preparing the non-granulated compositions comprises one or more of the following steps: a) sifting rivaroxaban, diluent(s) and optionally other excipients; b) co-sifting rivaroxaban with at least one surfactant and optionally at least one diluent to obtain a powder blend; c) sequentially blending rivaroxaban of step a) or the mixture of step b) with sifted diluent(s), and optionally other sifted excipients to obtain a powder blend ; d) optionally re-sifting and re-blending powder blends after a sequential blending process to obtain a powder blend; e) optionally directly compressing the powder blend from step b), c) or d) into tablets; f) optionally film-coating and/or seal-coating the tablets of step e) g) optionally filling the powder blend from step b), c) or d) into capsules.

Flow properties and compressibility, of the non-granulated compositions in the form of powder blend, were evaluated using the parameters of angle of repose, compressibility index and Hausner ratio, the said parameters being determined in accordance to the United States Pharmacopeia (USPNF-2021 -Issue 1 (1174) Powder Flow).

The non-granulated compositions comprise powder blends with a compressibility index of not more than 31 %, preferably not more than 25%, and more preferably not more than 15%.

The non-granulated compositions comprise powder blends with a Hausner ratio of not more than 1 .45, preferably not more than 1 .34, and most preferably not more than 1 .25.

The non-granulated compositions comprise powder blends with an angle of repose of not more than 45°, preferably not more than 40°, and most preferably not more than 35°.

The non-granulated compositions comprising a powder blend can further be compressed into tablets, or filled into capsules.

In another aspect, the compressibility of the non-granulated compositions was evaluated by determining the hardness and friability of the compressed tablets.

Hardness of the non-granulated, compressed tablets of the present invention was evaluated at periodic time intervals of the compression cycle (initial, middle and end), and at various compression speeds (low speed, optimum speed, high speed). The hardness of the said tablets was in the range of about 3 kilopond (kp) to about 9 kilopond (kp), preferably from about 4 kilopond (kp) to about 8 kilopond (kp). Friability testing of the non-granulated, compressed tablets was evaluated in accordance to United States Pharmacopeia (USPNF-2021 -Issue 1 , (1216) Tablet Friability). Friability was determined using the Drum Friability Tester. 20 tablets were carefully dusted before testing, and weighed. The tablets were placed in the drum of friability tester and rotated at the speed of 25 ± 1 rotations per minute for 4 minutes (100 rotations). After 100 rotations the tablets were de-dusted and re-weighed, and the friability percentage calculated. Acceptance criteria is that the loss in weight of the tablets, at the end of the test, should be not more that 1 %.

The non-granulated compositions are evaluated in terms of rivaroxaban content, total impurities, blend uniformity, content uniformity, average cumulative % dissolution of rivaroxaban, and oral bioavailability.

Rivaroxaban content (assay) in the non-granulated compositions of rivaroxaban, as determined by liquid chromatography, ranges from about 90% to about 1 10%, preferably from about 95% to about 105% of the label claim.

Blend analysis was conducted on the powder blend by sampling (in triplicate) from three different locations of the blender using a unit dose sampler. Acceptance criteria is that average % rivaroxaban content of individual sample at all locations is within 90%-110% of the target content, and the relative standard deviation of all samples is not more than 5%.

Content Uniformity was conducted during tablet compression or capsule filling by sampling (in triplicate) at 20 time-points which correspond to equally distributed time intervals during the compression or filling of the batch respectively. Acceptance criteria is that the average % rivaroxaban content of tablets at each time-point is within 90%-1 10% of the target content, % rivaroxaban content of individual tablet at each time-point is within 75%-125% of the target content, and the relative standard deviation for all tablets is less than or equal to 4%.

Dissolution of rivaroxaban from the non-granulated compositions was studied in 900ml of acetate buffer pH 4.5 (with 0.2%-0.4% sodium lauryl sulphate) using USP - Type II (Paddle) apparatus at 75rpm, and calculated in terms of average cumulative percentage dissolution of rivaroxaban at various time-points.

Dissolution of rivaroxaban from the non-granulated compositions, for rapid release, is not less than 90% in 45 minutes, preferably not less than 90% in 30 minutes, preferably not less than 85% in 20 minutes, more preferably not less than 85% in 15 minutes and most preferably not less than 80% in 10 minutes.

Total impurities content in the non-granulated compositions, as determined by liquid chromatography, is not more than 3%, preferably not more than 2.5%, more preferably not more than 2%, and most preferably not more than 1 .5%.

In an aspect the total impurities in the non-granulated compositions is not more than 1 %, preferably not more than 0.8%, more preferably not more than 0.5%, and most preferably not more than 0.25%.

In another embodiment the total impurities in the non-granulated compositions is not more than 0.2%.

Storage stability of the non-granulated compositions of the present invention was studied in one or more of the following conditions:

Accelerated Storage Conditions: i) 40°C ± 2°C and 75% ± 5 % relative humidity (40°C/75%RH)

Room Temperature Storage Conditions: ii) 30°C ± 2°C and 75% ± 5 % relative humidity (30°C/75%RH) iii) 25°C ± 2°C and 60% ± 5 % relative humidity (25°C/60%RH)

After specific time-periods of storage, the compositions were analyzed for % rivaroxaban content, % total impurities and average cumulative % dissolution of rivaroxaban.

The invention is now illustrated with non - limiting examples.

Example 1

Rivaroxaban tablets 2.5mg tablets: Rivaroxaban (d(0.5) of 5 microns; d(0.9) of 12 microns) (1.20%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.00%w/w) to give a first blend. Microcrystalline cellulose (17.75%w/w), lactose (56.22%w/w) and croscarmellose sodium (1 1 ,48%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend. The second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes. Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend. The powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling. The compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide yellow).

Flow Properties of the lubricated powder blend was evaluated, and was found to have a compressibility index of 25%, a Hausner ratio of 1 .33 and an angle of repose of 39^s.

Blend uniformity analysis of 3 batches manufactured according to Example 1 was conducted on the lubricated blend. ‘Average % rivaroxaban content’ met the acceptance criteria. The relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.20% to 1 .10%.

Content uniformity analysis of 3 batches manufactured according to Example 1 was conducted on the non-granulated, directly compressed tablets. Each time-point average % rivaroxaban content and individual tablet % rivaroxaban content met the acceptance criteria. Relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.6% to 1 .2%.

Friability of the non-granulated, directly compressed tablets of Example 1 , when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.32%.

Hardness of the non-granulated, directly compressed tablets of Example 1 , when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 12 rpm; optimum speed of 15 rpm; high speed of 18 rpm), was found to be in the range of about 3 kp to about 9 kp.

Average cumulative % dissolution of rivaroxaban from non-granulated, directly compressed tablets prepared according to Example 1 was 94% in 10 minutes.

Example 2

Rivaroxaban tablets 10mg tablets:

Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 9 microns) (4.78%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend. Microcrystalline cellulose (17.75%w/w), lactose (52.63%w/w) and croscarmellose sodium (1 1 ,48%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend. The second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes. Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend. The lubricated powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling. The compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).

Flow Properties of the lubricated powder blend of Example 2 was evaluated, and was found to have a compressibility index of 23.5%, a Hausner ratio of 1 .3 and an angle of repose of 42^s.

Content uniformity analysis of 3 batches manufactured according to Example 2 was conducted on the non-granulated, directly compressed tablets. Each time-point ‘average % rivaroxaban content’ and individual tablet '% rivaroxaban content’ met the acceptance criteria. Relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.9% to 1 .5%.

Friability of the non-granulated, directly compressed tablets of Example 2, when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.23%. Hardness of the non-granulated, directly compressed tablets of Example 1 , when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 12 rpm; optimum speed of 15 rpm; high speed of 18 rpm), was found to be in the range of about 3 kp to about 9 kp.

Average cumulative % dissolution of rivaroxaban from non-granulated, directly compressed tablets prepared according to Example 2 was 96% in 15 minutes.

Example 3

Rivaroxaban tablets 20mg tablets:

Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 11 microns) (9.57%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend. Microcrystalline cellulose (17.75%w/w), lactose (47.85%w/w) and croscarmellose sodium (1 1 ,48%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend. The second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes. Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend. The lubricated powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling. The compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).

Blend uniformity analysis of 3 batches manufactured according to Example 3 was conducted on the lubricated blend. ‘Average % rivaroxaban content’ met the acceptance criteria. The relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.63 to 0.96%.

Content uniformity analysis of 3 batches manufactured according to Example 3 was conducted on the non-granulated, directly compressed tablets. Each time-point ‘average % rivaroxaban content’ and individual tablet '% rivaroxaban content’ met the acceptance criteria. Relative standard deviation calculated for the batches met the acceptance criterial and was in the range of 0.8% to 1 .0%. Average cumulative % dissolution of rivaroxaban from the tablets of Example 3 was 90% of label claim in 10 minutes.

Example 4

Rivaroxaban tablets 15mg tablets:

Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 9 microns) (9.55%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend. Microcrystalline cellulose (17.71%w/w), lactose (47.77%w/w) and croscarmellose sodium (1 1 ,46%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend. The second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes. Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend. The lubricated powder blend was directly compressed into using 7.0 mm, round, standard concave punch tooling. The compressed tablets were film-coated to 2.55% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).

Flow Properties of the lubricated powder blend of Example 4 was evaluated, and was found to have a compressibility index of 25%, a Hausner ratio of 1 .33 and an angle of repose of 38^s.

Blend uniformity analysis of 3 batches manufactured according to Example 4 was conducted on the lubricated blend. ‘Average % rivaroxaban content’ met the acceptance criteria. The relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.63% to 0.96%.

Content uniformity analysis of 3 batches manufactured according to Example 4 was conducted on the non-granulated, directly compressed tablets. Each time-point ‘average % rivaroxaban content’ and individual tablet '% rivaroxaban content’ met the acceptance criteria. Relative standard deviation calculated for the batches met the acceptance criterial and was in the range of 0.7% to 1 .2%. Average cumulative % dissolution of rivaroxaban from the non-granulated, directly compressed tablets manufactured in accordance with Example 4 was 95% of label claim in 10 minutes.

Bioequivalence Study under Fasting Conditions:

A two-way, crossover, fasting bioequivalence study of rivaroxaban tablets 10 mg of example 2 and commercially available rivaroxaban tablets 10 mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) was performed in 1 1 volunteers. Table 1 provides the pharmacokinetic parameters of the bioequivalence study under fasting conditions.

Table 1 : Pharmacokinetic parameters of fasting bioequivalence study of 10mg rivaroxaban tablets

As seen in Table 1 , the non-granulated and directly compressed rivaroxaban tablets 10 mg of example 2 of the present invention was found to be bioequivalent to the commercially available rivaroxaban tablets 10mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) in a fasting bioequivalence study.

Bioequivalence Study under Fed Conditions:

A two-way, crossover, fed bioequivalence study of rivaroxaban tablets 20 mg of example 3 and commercially available rivaroxaban tablets 20 mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) was performed in 12 volunteers. Table 2 provides the pharmacokinetic parameters of the bioequivalence study under fed conditions. Table 2: Pharmacokinetic parameters of fed bioequivalence study of 20mg rivaroxaban tablets

As seen in Table 2, the non-granulated and directly compressed rivaroxaban tablets 20 mg of example 2 of the present invention was found to be bioequivalent to the commercially available rivaroxaban tablets 20 mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) in a fed bioequivalence study.

Storage Stability

The tablets of examples 1 , 2, 3 and 4 were packed in PVC-PVDC blister packs and subjected to storage stability studies. After specified time intervals, the tablets were analyzed for rivaroxaban content, total impurities and dissolution. Table 3 provides the % rivaroxaban content, % total impurities, and average cumulative % dissolution of rivaroxaban at 30 minutes, of the non-granulated and directly compressed tablets of examples 1 , 2, 3 and 4, after 6 months of storage. Table 4 provides the % rivaroxaban content, % total impurities and average cumulative % dissolution of rivaroxaban at 30 minutes, of the non-granulated and directly compressed tablets of examples 1 , 2, 3 and 4, after 24 months of storage at room temperature conditions.

Table 3: Stability of non-granulated tablets of examples 1 , 2, 3 and 4 after 6 months of storage

Table 4: Stability of non-granulated tablets of Examples 1 , 2, 3 and 4 after 24 months of storage

BQL: Below Quantification Level

Thus the non-granulated compositions of the present invention, comprising rivaroxaban at low concentrations and diluents at high concentrations, were found to provide the desired flow properties, blend uniformity, content uniformity, dissolution, and storage stability. The non-granulated compositions of the present invention are bioequivalent to the commercially available rivaroxaban compositions (prepared by granulation).

Claims

WE CLAIM

1 . A non-granulated rivaroxaban composition comprising rivaroxaban and at least two diluents, wherein rivaroxaban is not more than 20% by weight of the composition, and wherein the weight ratio of the diluents range from 1 : 0.25 to 1 : 2.5.

2. The non-granulated rivaroxaban composition as claimed in claim 1 , wherein the first diluent is water-insoluble, and the second diluent is water-soluble.

3. The non-granulated rivaroxaban composition as claimed in claim 1 , wherein the composition comprises not less than 70% by weight of diluent.

4. The non-granulated rivaroxaban composition as claimed in claim 1 , wherein rivaroxaban has a particle size distribution such that 90% by volume (d (0.9)) of rivaroxaban particles have a particle size not more than 25 microns.

5. The non-granulated rivaroxaban composition as claimed in claim 1 , wherein the composition further comprises ionic surfactant at not more than 1 % by weight of the composition.

6. The non-granulated rivaroxaban composition as claimed in claim 1 , wherein the composition further comprises at least one excipient selected from disintegrant, glidant and lubricant.

7. A non-granulated rivaroxaban composition comprising rivaroxaban and at least two diluents, wherein rivaroxaban is not more than 20% by weight of the composition, and wherein the dissolution of rivaroxaban from the said composition is not less than 90% in 30 minutes.

8. The non-granulated rivaroxaban composition as claimed in claim 7, wherein the weight ratio of the diluents range from 1 : 0.25 to 1 : 2.5.

. The non-granulated rivaroxaban composition as claimed in claim 7, wherein the first diluent is water-insoluble, and the second diluent is water-soluble. 0. The non-granulated composition as claimed in claim 7, wherein the composition comprises not less than 70% by weight of diluent. 1. The non-granulated rivaroxaban composition as claimed in claim 7, wherein rivaroxaban has a particle size distribution such that 90% by volume (d (0.9)) of rivaroxaban particles have a particle size not more than 25 microns. 2. The non-granulated rivaroxaban composition as claimed in claim 7, wherein the composition further comprises ionic surfactant at not more than 1 % by weight of the composition. 3. The non-granulated rivaroxaban composition as claimed in claim 7, wherein the composition further comprises at least one excipient selected from disintegrant, glidant and lubricant. 4. A non-granulated rivaroxaban composition comprising rivaroxaban and at least two diluents, wherein rivaroxaban is not more than 20% by weight of the composition, and wherein the said non-granulated composition is bioequivalent to a granulated composition of rivaroxaban. 5. The non-granulated rivaroxaban composition as claimed in claim 14, wherein the weight ratio of the diluents range from 1 : 0.25 to 1 : 2.5. 6. The non-granulated rivaroxaban composition as claimed in claim 14, wherein the first diluent is water-insoluble, and the second diluent is water-soluble. 7. The non-granulated rivaroxaban composition as claimed in claim 14, wherein the composition comprises not less than 70% by weight of diluent.

18. The non-granulated rivaroxaban composition as claimed in claim 14, wherein rivaroxaban has a particle size distribution such that 90% by volume (d (0.9)) of rivaroxaban particles have a particle size not more than 25 microns.

19. The non-granulated rivaroxaban composition as claimed in claim 14, wherein the composition further comprises ionic surfactant at not more than 1% by weight of the composition.

20. The non-granulated rivaroxaban composition as claimed in claim 14, wherein the composition further comprises at least one excipient selected from disintegrant, glidant and lubricant.

21 . The non-granulated rivaroxaban composition as claimed in claims 1 , 7 or 14, wherein the composition is in the form of powder blend, tablet, directly compressed tablet, capsule, or a combination thereof.

22. The non-granulated rivaroxaban composition as claimed in claim 21 , wherein the composition is in the form of powder blend which has a compressibility index of not more than 31% and an angle of repose of not more than 45°.

23. The non-granulated rivaroxaban composition as claimed in claim 22, wherein the powder blend is compressed into tablets by direct compression.