DESC:TITLE OF THE INVENTION
Pharmaceutical composition comprising Rivaroxaban

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321066401 filed on October 04, 2023.

FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition for oral administration containing a therapeutically effective amount of an anticoagulant agent such as Rivaroxaban or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof. The invention also relates to the use of said composition for the prophylaxis and treatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION:
Rivaroxaban, a factor Xa (FXa) inhibitor with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4- (3-oxo4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish
powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
Currently rivaroxaban formulation marketed under tradename XARELTO® with granules/powder for oral suspension and oral tablet dosage forms, and used for various thromboembolic disorders.
Rivaroxaban is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

Rivaroxaban can be used for the prophylaxis and/or treatment of various thromboembolic diseases, in particular heart attacks, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial disease, pulmonary embolism or deep venous thrombosis, venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the
Fontan procedure.

Rivaroxaban is a BCS Class II drug that poses challenging problems in pharmaceutical product development process because of its low solubility and dissolution rate. BCS Class II drugs require enhancement in solubility and dissolution rate especially in solid pharmaceutical dosage forms in
order to become bioavailable.

US patent no. 7,157,456 discloses rivaroxaban product generically as well as specifically.
PCT publication no. 2012080184A2 discloses a liquid pharmaceutical composition which contain
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin- 5-yl}-methyl)-2- thiophene carboxamide, the production thereof and the use thereof for the prophylaxis and/or treatment of diseases.

US patent publication no. 20220193085 A1 discloses method of thromboprophylaxis in a pediatric
patient after a Fontan procedure.

US patent no. 9,415,053 discloses a process for the preparation of a solid, orally administrable pharmaceutical composition, comprising 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)- phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide in hydrophilized form, and its use
for the prophylaxis and/or treatment of diseases.

US patent no. 9,539,218 discloses a method of treating a thromboembolic disorder comprising administering a direct factor Xa inhibitor that is 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl) phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide.

US patent no. 8,188,270 discloses rivaroxaban polymorph in the modification II. Also discloses rivaroxaban polymorph in the modification I.

US patent publication no. 20210267908A1 discloses a capsule composition comprising rivaroxaban or its pharmaceutically acceptable salts, ester, solvates, polymorphs thereof and one or more pharmaceutically acceptable excipients.

All of the compositions described have the disadvantage that they are solid, oral compositions such as tablets or capsules. Children, the elderly and people with physical disabilities have difficulty
swallowing solid dosage forms such as tablets or capsules whole. On the other hand, the compositions of the present invention are granules or pellets in sachets or bottle, which are easier to swallow to children.

Additionally, nitrosamine impurities are possible in the synthesis of rivaroxaban and its pharmaceutical salt thereof. The Nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of Nitrosamine impurities include, but are not limited to, N-Nitroso rivaroxaban, N-Nitrosodimethyl amine (“NDMA”), N-Nitroso Rivaroxaban Amide, N-Nitroso Rivaroxaban Open Ring Acid, N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). Nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the Nitrosamine impurities in drugs is generally low, some levels have been above the U.S. Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the health-related effects, stringent limitations have been placed upon the permissible amounts of nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
There is a need for improved pharmaceutical compositions of rivaroxaban which provide improved stability especially during the manufacturing process to ensure reproducibility and quantitative accuracy. Additionally, there is a need to develop pharmaceutically acceptable rivaroxaban compositions wherein the amount of nitrosamine impurity is less than the FDA acceptable intake limit of the nitrosamine impurity based on maximum daily dose of rivaroxaban.

SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising rivaroxaban or
pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the invention, the pharmaceutical composition comprises rivaroxaban or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from but not limited to diluents, buffering agents, binders, preservatives, suspending agents, sweetening
agents, flavouring agents, and colouring agents.

Another aspect of the present invention provides a pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof, diluents, buffering agents, binders, preservatives, suspending agents, sweetening agents, and flavouring agents.

In another aspect of the invention, an oral pharmaceutical composition comprising about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 90 to about 99.5% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of diluent;
c) about 1 % w/w to about 5 % w/w of buffering agent;
d) about 0.5 % w/w to about 3 % w/w of binder;
e) about 1 % w/w to about 8 % w/w of preservative;
f) about 10 % w/w to about 30 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of diluent;
c) about 1 % w/w to about 5 % w/w of buffering agent;
d) about 0.5 % w/w to about 3 % w/w of binder;
e) about 1 % w/w to about 8 % w/w of preservative;
f) about 10 % w/w to about 30 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients; wherein said composition is stable for at least 24 months of storage at 25° C. and 60% relative humidity (RH).

In yet another aspect of the present invention provides a stable pharmaceutical composition
comprising rivaroxaban, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable limit based on maximum daily dose of rivaroxaban.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the
form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium; and
c) other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium; and
c) other pharmaceutically acceptable excipients;
wherein the ratio of blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium to Xanthan gum in a given composition is about 10:1 w/w.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of mannitol;
c) about 1 % w/w to about 5 % w/w of anhydrous citric acid;
d) about 0.5 % w/w to about 3 % w/w of hypromellose;
e) about 1 % w/w to about 8 % w/w of sodium benzoate;
f) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 0.5 % w/w to about 3 % w/w of sucralose;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 65 % w/w of mannitol;
c) about 2 % w/w of anhydrous citric acid;
d) about 1.5 % w/w of hypromellose;
e) about 3.5 % w/w of sodium benzoate;
f) about 24 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 1 % w/w of sucralose;
h) about 1.3 % w/w of flavouring agent.
In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 67 % w/w of mannitol;
c) about 1.75 % w/w of anhydrous citric acid;
d) about 1.5 % w/w of hypromellose;
e) about 3.6 % w/w of sodium benzoate;
f) about 22 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 0.85 % w/w of sucralose;
h) about 1.6 % w/w of flavouring agent.

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 20 mg to about 50 mg of mannitol;
b) about 0.5 mg to about 2 mg of anhydrous citric acid;
c) about 0.25 mg to about 2 mg of hypromellose;
d) about 0.5 mg to about 4 mg of sodium benzoate;
e) about 5 mg to about 20 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.25 mg to about 2 mg of sucralose;
g) about 0.25 mg to about 2 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients; wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable intake limit of the nitrosamine impurity i.e. less than 200 ppm based on maximum daily dose of rivaroxaban

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 33 mg of mannitol;
b) about 1 mg of anhydrous citric acid;
c) about 0.75 mg of hypromellose;
d) about 1.8 mg of sodium benzoate;
e) about 12 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.5 mg of sucralose;
g) about 0.7 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 34 mg of mannitol;
b) about 0.9 mg of anhydrous citric acid;
c) about 0.75 mg of hypromellose;
d) about 1.8 mg of sodium benzoate;
e) about 11 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.45 mg of sucralose;
g) about 0.8 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to the process for preparation of a granules for suspension, wherein process comprises steps of:
a) Sifting of diluent and buffering agent through sieve #30
b) Addition of preservative to the purified water under continuous stirring until clear solution is formed.
c) Addition of binder to the step b) under continuous stirring until clear solution is obtained.
d) Addition of rivaroxaban to the step c) under continuous stirring until uniform and lump free
dispersion is formed.
e) Loading of step, a) material in fluid bed processor and start granulation using dispersion obtained in step d).
f) Drying of wet granules and passing it through co-mill.
g) sweetening agent, flavor, suspending agents passed through sieve #30.
h) Loading of half quantity of step f) material, followed by step g) material and followed by remaining half quantity of step f) material and blending for about 20 minutes.
i) Filling of granules in bottle.

In yet another aspect, the present invention relates to the process for preparation of a granules for
suspension, wherein process comprises steps of:
a) Sifting of mannitol and citric acid anhydrous through sieve #30
b) Addition of sodium benzoate to the purified water under continuous stirring until clear solution is formed.
c) Addition of hypromellose to the step b) under continuous stirring until clear solution is obtained.
d) Addition of rivaroxaban to the step c) under continuous stirring until uniform and lump free dispersion is formed.
e) Loading of step, a) material in fluid bed processor and start granulation using dispersion obtained in step d).
f) Drying of wet granules and passing it through co-mill.
g) Sucralose, flavor, xanthan gum and mixture of microcrystalline cellulose and carboxymethylcellulose sodium passed through sieve #30.
h) Loading of half quantity of step f) material, followed by step g) material and followed by remaining half quantity of step f) material and blending for about 20 minutes.
i) Filling of granules in bottle.

In yet another aspect, the present invention relates to a pharmaceutical composition for oral administration comprising an intragranular portion and an extragranular portion, wherein the intragranular portion comprises rivaroxaban or pharmaceutically acceptable salt thereof, mannitol, citric acid, hypromellose, and sodium benzoate and the extragranular portion comprises blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium, sucralose, xantham gum, and flavor.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt used for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart
disease after the Fontan procedure.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt used for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart
disease after the Fontan procedure.

In yet another aspect, the present invention relates to a method of treating venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with
congenital heart disease after the Fontan procedure by a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt.

In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure.

DESCRIPTION OF THE INVENTION:
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or
more," "at least one," and "one or more than one."

The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.

The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug- related impurity contents in the formulations remain within acceptable limits.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.

As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.

“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, diluent, binder, disintegrant, lubricant/glidants, antioxidant, plasticizer, surfactants, solvent/vehicle, flavors or colorants, coating materials and any other excipient known to the art for making solid oral pharmaceutical composition.

The term “core” as used herein, refers to an interior compartment of a unit dosage form.

The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term “excipient” means a pharmacologically inactive component such as a binder, solvent, diluent, disintegrant, carrier, lubricant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.

By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or
"composition" or "formulation" as used herein refers to a solid dosage form comprising rivaroxaban suitable for administration such as a granule, hard or soft gelatin capsule, tablet, caplet, mini-tablets, pellets, pills, granules or powder for suspension, suspension and the like. The pharmaceutical dosage form can be prepared by methods known in the art, such as dry granulation or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent. The material obtained by suitable methods known in the art can be filled into sachets, bottles, capsules or made into tablets.

The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. rivaroxaban and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.

The term “rivaroxaban” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms. Pharmaceutically acceptable salts of rivaroxaban include but not limited to oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, mesylate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, palmitate, and gluconate salts.

The present invention provides a rivaroxaban or pharmaceutically acceptable salt thereof may be present in an amount of about 0.5 to about 10 % w/w, preferably about 1 to about 5 % w/w, more preferably about 1.5 to 2.5 % w/w of the composition. The present invention also provides a pharmaceutical composition comprising rivaroxaban in an amount of about 1 mg/mL upon reconstitution.
The present invention provides a rivaroxaban or pharmaceutically acceptable salt thereof having D90 particle size in the range of 1 to 50 µm. Preferably, the D90 particle size can be between 5 and 15 µm.
The present invention provides a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises rivaroxaban or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from the group consisting of diluents, buffering agents, binders, preservatives, suspending agents,
sweetening agents, and flavouring agents.

In one aspect of the invention, an oral stable pharmaceutical composition comprising about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In another aspect, there is provided a pharmaceutical composition comprising: a) about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof; b) about 90 to about 99.5% w/w of pharmaceutically acceptable excipients.

Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, mannitol, sorbitol or other sugar alcohols, isomalt, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is mannitol. Diluent may be present in an amount of about 50 % w/w to about 80 % w/w, preferably about 60 % w/w to about 75% w/w, more preferably about 65 % w/w to about 70 % w/w of the composition.

Buffering agents according to the present invention are selected from, but not limited to, sodium bicarbonate, citric acid, maleic acid, phosphoric acid, citrate, tartrate, acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate and the like used either alone or in combinations thereof and the most preferably used buffering agent is citric acid. Buffering agent may be present in an amount of about 1 % w/w to about 5 % w/w, preferably about 1 % w/w to about 3% w/w of the composition.

In some embodiments, the buffering agent is present to maintain a pH of about 3.3-5.3.

Binders according to the present invention are selected from, but not limited to, starch, pregelatinized starch, povidone, hydroxy propyl cellulose, polyethylene glycol, sorbitol, hypromellose (Methocel E5 Premium LV), and the like used either alone or in combinations thereof. A preferred binder of the present invention is hypromellose. Binder may be present in an amount of about 0.5 % w/w to about 3 % w/w, preferably about 1 % w/w to about 4 % w/w, more preferably about 1 % w/w to about 2 % w/w of the composition.

The term “preservative,” as used herein, refers to an agent or mixture of agents that is used to protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity. Preservatives include, but are not limited to, benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, sorbic acid, benzalkonium chloride, butyl paraben, methyl paraben, ethylparaben, propyl paraben, sodium propionate, and the like used either alone or in combinations thereof. A preferred preservative of the present invention is sodium benzoate. Preservative may be present in an amount of about 1 % w/w to about 8 % w/w, preferably about 2 % w/w to about 7 % w/w, more preferably about 3 % w/w to about 4 % w/w of the composition.

The term “suspending agent or viscosity enhancer,” as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby keeping the active ingredient suspended to allow accurate dosing. Suspending agent include, but are not limited to, xantham gum, guar gum, acacia, alginic acid, sodium alginate, propylene glycol alginate, carbomer, salts of carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, bentonite, carrageenan, sucrose, sorbitol, xylitol, dextrose, fructose, maltitol, gelatin, tragacanth, a polyvinyl alcohol, cetearyl alcohol, colloidal silicon dioxide, blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium (Avicel CL 611), and the like used either alone or in combinations thereof. A preferred suspending agent of the present invention is combination of xantham gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium. Suspending agent may be present in an amount of about 10 % w/w to about 30 % w/w, preferably about 15 % w/w to about 25 % w/w, more preferably about 20 % w/w to about 24 % w/w of the composition.

Suitable sweetening agents include, but are not limited to, natural sweeteners such as sugars e.g. fructose, glucose, sucrose, sorbitol or mixtures thereof and artificial sweeteners such as sodium saccharine, sucralose, sodium cyclamate, aspartame and the like used either alone or in combinations thereof. A preferred sweetening agent of the present invention is sucralose.
Sweetening agents may be present in an amount of about 0.5 % w/w to about 3 % w/w, preferably about 1 % w/w to about 4 % w/w, more preferably about 0.5 % w/w to about 1.5 % w/w of the composition.
The term “flavoring agent,” as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. Flavoring agents include, but are not limited to, artificial strawberry flavor, banana flavor, vanilla, artificial cream flavor and the like used either alone or in combinations thereof. A preferred flavoring agent of the present invention is cream/vanilla flavor. Flavoring agents may be present in an amount of about 0.5 % w/w to about 3 % w/w, preferably about 1 % w/w to about 4 % w/w, more preferably about 1 % w/w to about 2 % w/w of the composition.

Disintegrants according to the present invention are selected from, but not limited to, croscarmellose sodium, crospovidone, carmellose calcium, sodium starch glycolate, polacrilin potassium, starches, substituted hydroxypropyl cellulose, powdered agar and the like used either alone or in combinations thereof.
Lubricants according to the present invention are selected from, but not limited to, magnesium stearate, calcium stearate, aluminium stearate, sucrose stearate, sucrose fatty acid ester, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, talc, and the like used either alone or in combinations thereof.
Glidants according to the present invention are selected from, but not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, and the like used either alone or in combinations thereof.
Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the preparation. Suitable antioxidants for use in the present invention include but not limited to propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.

‘‘Plasticizer’’ refers to an excipient that can impart flexibility and/or stretchability to a coat or membrane. Examples of plasticizers include but are not limited to medium chain triglycerides, phthalates, phosphates, glycerol, citrates, adipates, sebacates, succinates, glycolates, and the like used either alone or in combinations thereof.
‘‘Surfactant’’ refers to one or more excipients that may be added to the pharmaceutical composition to facilitate dissolution of poorly soluble excipients and/or to increase dissolution rate of composition or components thereof. Examples of surfactants include but are not limited to sodium lauryl sulphate, glycerol monostearate, sorbitan monolaurate, tween 60, tween 80 (polysorbate 80) etc.

A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a suspension or solution. Examples include but not limited to purified water, alcoholic solvents methanol, ethanol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ethers such as
dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.

In some embodiments, coloring agents may be used to introduce a uniformity of appearance to the product and/or to protect any light-sensitive ingredients. Suitable coloring agents include all
pigments, dyes and lakes approved by the U.S. Food and Drug Administration (e.g., FD&C colorants), including but not limited to FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, iron oxide yellow, tartrazine, erythrosine, amaranth lake, titanium dioxide, opadry systems, or any combination thereof.

In another aspect of the invention, an oral pharmaceutical composition comprising about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 0.5 to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 90 to about 99.5% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of granules for suspension.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of diluent;
c) about 1 % w/w to about 5 % w/w of buffering agent;
d) about 0.5 % w/w to about 3 % w/w of binder;
e) about 1 % w/w to about 8 % w/w of preservative;
f) about 10 % w/w to about 30 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of diluent;
c) about 1 % w/w to about 5 % w/w of buffering agent;
d) about 0.5 % w/w to about 3 % w/w of binder;
e) about 1 % w/w to about 8 % w/w of preservative;
f) about 10 % w/w to about 30 % w/w of suspending agents;
g) about 0.5 % w/w to about 3 % w/w of sweetening agent;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients;
wherein said composition is stable for at least 24 months of storage at 25° C and 60% relative humidity (RH).

In yet another aspect of the present invention provides a stable pharmaceutical composition
comprising rivaroxaban, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable limit based on maximum daily dose of rivaroxaban.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the
form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium; and
c) other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium; and
c) other pharmaceutically acceptable excipients;
wherein the ratio of blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium to Xanthan gum in a given composition is about 10:1 w/w.

In yet another aspect of the present invention provides pharmaceutical composition comprising:
a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 50 % w/w to about 80 % w/w of mannitol;
c) about 1 % w/w to about 5 % w/w of anhydrous citric acid;
d) about 0.5 % w/w to about 3 % w/w of hypromellose;
e) about 1 % w/w to about 8 % w/w of sodium benzoate;
f) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 0.5 % w/w to about 3 % w/w of sucralose;
h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and
i) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 65 % w/w of mannitol;
c) about 2 % w/w of anhydrous citric acid;
d) about 1.5 % w/w of hypromellose;
e) about 3.5 % w/w of sodium benzoate;
f) about 24 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 1 % w/w of sucralose;
h) about 1.3 % w/w of flavouring agent.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 67 % w/w of mannitol;
c) about 2 % w/w of anhydrous citric acid;
d) about 1.5 % w/w of hypromellose;
e) about 3.5 % w/w of sodium benzoate;
f) about 22 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 1 % w/w of sucralose;
h) about 1.3 % w/w of flavouring agent.

In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of granules for suspension dosage form comprising:
a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof;
b) about 67 % w/w of mannitol;
c) about 1.75 % w/w of anhydrous citric acid;
d) about 1.5 % w/w of hypromellose;
e) about 3.6 % w/w of sodium benzoate;
f) about 22 % w/w of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
g) about 0.85 % w/w of sucralose;
h) about 1.6 % w/w of flavouring agent.

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 20 mg to about 50 mg of mannitol;
b) about 0.5 mg to about 2 mg of anhydrous citric acid;
c) about 0.25 mg to about 2 mg of hypromellose;
d) about 0.5 mg to about 4 mg of sodium benzoate;
e) about 5 mg to about 20 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.25 mg to about 2 mg of sucralose;
g) about 0.25 mg to about 2 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 33 mg of mannitol;
b) about 1 mg of anhydrous citric acid;
c) about 0.75 mg of hypromellose;
d) about 1.8 mg of sodium benzoate;
e) about 12 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.5 mg of sucralose;
g) about 0.7 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients.

In yet another aspect of the present invention provides granules for oral suspension of rivaroxaban containing 1 mg/mL of rivaroxaban upon reconstitution comprising:
a) about 34 mg of mannitol;
b) about 0.9 mg of anhydrous citric acid;
c) about 0.75 mg of hypromellose;
d) about 1.8 mg of sodium benzoate;
e) about 11 mg of combination of xanthan gum, and blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium;
f) about 0.45 mg of sucralose;
g) about 0.8 mg of flavouring agent; and
h) optionally other pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to the process for preparation of a granules for suspension, wherein process comprises steps of:
a) Sifting of diluent and buffering agent through sieve #30;
b) Addition of preservative to the purified water under continuous stirring until clear solution is formed.
c) Addition of binder to the step b) under continuous stirring until clear solution is obtained.
d) Addition of rivaroxaban to the step c) under continuous stirring until uniform and lump free
dispersion is formed.
e) Loading of step, a) material in fluid bed processor and start granulation using dispersion obtained in step d).
f) Drying of wet granules and passing it through co-mill.
g) sweetening agent, flavor, suspending agents passed through sieve #30.
h) Loading of half quantity of step f) material, followed by step g) material and followed by remaining half quantity of step f) material and blending for about 20 minutes.
i) Filling of granules in bottle.

In yet another aspect, the present invention relates to the process for preparation of a granules for
suspension, wherein process comprises steps of:
a) Sifting of mannitol and citric acid anhydrous through sieve #30
b) Addition of sodium benzoate to the purified water under continuous stirring until clear solution is formed.
c) Addition of hypromellose to the step b) under continuous stirring until clear solution is obtained.
d) Addition of rivaroxaban to the step c) under continuous stirring until uniform and lump free dispersion is formed.
e) Loading of step, a) material in fluid bed processor and start granulation using dispersion obtained in step d).
f) Drying of wet granules and passing it through co-mill.
g) Sucralose, flavor, xanthan gum and mixture of microcrystalline cellulose and carboxymethylcellulose sodium passed through sieve #30.
h) Loading of half quantity of step f) material, followed by step g) material and followed by remaining half quantity of step f) material and blending for about 20 minutes.
i) Filling of granules in bottle.

In yet another aspect, the present invention provides a pharmaceutical composition comprising 1mg/mL of rivaroxaban upon reconstitution with purified water.
In yet another aspect, the present invention relates to the administration of a pharmaceutical composition by medicine dispensing device, comprising: a syringe having a barrel configured to contain a liquid medicine to be dispensed by the medicine dispensing device; and a plurality of color-coded dosing indicia spaced around the surface of the barrel.

In yet another aspect, the present invention relates to the administration of a particular dose of pharmaceutical composition by medicine dispensing device by calculating, using a conversion factor based upon the volumetric capacity, a width for each individual color-coded zone of the plurality of color-coded zones of syringe that represent the appropriate drug doses that correspond to the one or more physical characteristics of the patient.

In yet another aspect, the present invention provides a pharmaceutical composition of rivaroxaban, which is bioequivalent to the marketed rivaroxaban product. In yet another aspect, the present invention provides a process for preparation of a stable, reproducible and bioequivalent pharmaceutical composition of rivaroxaban.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt used for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt used for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure.

In yet another aspect, the present invention relates to a method of treating venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure by a pharmaceutical composition comprising rivaroxaban or pharmaceutically acceptable salt.

In yet another aspect, the present invention relates to a use of pharmaceutical composition
comprising rivaroxaban or pharmaceutically acceptable salt for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years and for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure.
The composition of the invention can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.

EXAMPLES
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example - 1: Rivaroxaban granules for oral suspension (1 mg/mL after reconstitution)-Table-1

Sr Ingredients % w/w mg/mL
Intragranular Portion
1 Mannitol 65.05 33.023
2 Citric acid, anhydrous 2.00 1.016
Binder Dispersion
3 Rivaroxaban 1.97 1.000
4 Hypromellose 1.50 0.763
5 Sodium benzoate 3.54 1.800
6 Purified water - Q.S.
Extragranular Portion
7 Blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium 21.65 11.000
8 Sucralose 1.00 0.508
9 Xanthan gum 2.00 1.016
10 Cream/Vanilla Flavor 1.34 0.681
Total Fill weight 100.00 50.8

Manufacturing process for example 1:
a) Sifting of mannitol and citric acid anhydrous through sieve #30
b) Addition of sodium benzoate to the purified water under continuous stirring until clear solution is formed.
c) Addition of hypromellose to the step b) under continuous stirring until clear solution is obtained.
d) Addition of rivaroxaban to the step c) under continuous stirring until uniform and lump free dispersion is formed.
e) Loading of step, a) material in fluid bed processor and start granulation using dispersion obtained in step d).
f) Drying of wet granules and passing it through co-mill.
g) Sucralose, flavor, xanthan gum and blend of microcrystalline cellulose and carboxymethylcellulose sodium passed through sieve #30.
h) Loading of half quantity of step f) material, followed by step g) material and followed by remaining half quantity of step f) material and blending for about 20 minutes.
i) Filling of granules in bottle.

Example - 2: Rivaroxaban granules for oral suspension (1 mg/mL after reconstitution)- Table-2

Sr Ingredients % w/w mg/mL
Intragranular Portion
1 Mannitol 66.97 34.02
2 Citric acid, anhydrous 1.75 0.90
Binder Dispersion
3 Rivaroxaban 1.97 1.00
4 Hypromellose 1.5 0.76
5 Sodium benzoate 3.64 1.85
6 Purified water - Q.S.
Extragranular Portion
7 Blend/mixture of microcrystalline cellulose and carboxymethylcellulose sodium 19.68 10.00
8 Sucralose 0.85 0.43
9 Xanthan gum 2.00 1.02
10 Cream/Vanilla Flavor 1.64 0.83
Total Fill weight 100.00 50.8

Manufacturing process for example 2: As per example 1.
Example - 3: Stability Study: Stability study conducted on compositions in order to ensure the stable composition for longer period of time and data is given in Table as below:
Table-3: Stability study results of example 1 at 25°C / 60% RH:

Sr Attributes Initial 3 months 6 months 12 months
1 Description
1.1 For Powder: PET bottle Off white granular powder Off white granular powder Off white granular powder Off white granular powder
1.2 For reconstituted suspension: PET bottle Off white opaque flavored homogeneous
suspension Off white opaque flavored homogeneous
suspension Off white opaque flavored homogeneous
suspension Off white opaque flavored homogeneous
suspension
2 Assay (w/w, by HPLC)
2.1 Rivaroxaban 102.9% 104.1% 101.1% 103.7%
2.2 Sodium benzoate 100.0% 102.4% 98.8% 100.6 %
3 Dissolution (By HPLC) Minimum:95% Maximum:97% Average:96% Minimum:101% Maximum: 102% Average:101% Minimum:102%
Maximum: 103% Average:103% Minimum:99% Maximum: 100% Average:99%
4 pH 4.3 4.1 4.2 4.2
5 Water determination (w/w, By K.F. Titration) 1.0 % 1.4 % 1.3 % 0.9%
6 Organic impurities (w/w, By HPLC)
6.1 Specified
degradation Stage-II
identified product: 0.07% 0.06% 0.06 % 0.06 %
6.2 Specified degradation
KSM-III
identified product: Below LOQ (0.051%) ND Below LOQ (0.051%) ND
6.3 Specified identified
degradation product Deschloro Rivaroxaban Below LOQ (0.053%) Below LOQ (0.053%) Below LOQ (0.053%) Below LOQ (0.053%)
6.4 Any individual
unspecified degradation product 0.06% 0.05% 0.05% 0.05%
6.5 Total products
degradation 0.2% 0.2% 0.1 % 0.1 %
7 Dose uniformity by Assay of redispersibility (Top, middle, and Bottom) (w/w, by HPLC) Top:102.9%
Middle:102.9% Bottom:102.7% Top-104.0%,
Middle-103.8%, Bottom-103.7% Top-99.6%
Middle-100.6% Bottom-100.0% Top-99.4%
Middle-99.6% Bottom-99.5%

LOQ: Limit of Quantification; ND: Not Detected;

The above stability results show that the pharmaceutical composition prepared in Example 1 is stable for at least 12 months.

Example - 4: Evaluation of Nitrosamine Impurities.
As per FDA release guidance on Control of Nitrosamine Impurities in Human Drugs, rivaroxaban granules for suspension, as prepared in Examples 1, and 2 (Initial composition) were evaluated using GC-MS/MS and LC-MS/MS techniques, and results of the same as mentioned in table-4:
Table-4: Results of nitrosamine testing.
Name of Impurity Specification Observed result in ppm
N-Nitrosodimethylamine (NDMA) NMT 1.92 ppm Not Detected
N-Nitrosodiethylamine (NDEA) NMT 0.53 ppm Not Detected
N-Nitrosodibutylamine (NDBA) NMT 0.53 ppm Not Detected /
Below detection limit
N-Nitroso Rivaroxaban Amide NMT 50.0 PPM Not Detected
N-Nitroso Rivaroxaban Open Ring Acid NMT 50.0 PPM 9 ppm

The above results as mentioned in Table-4 for nitrosamine impurity demonstrated that, there is undetectable or less amount of the nitrosamine impurities present in the rivaroxaban composition.

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We claim:
1. A pharmaceutical composition comprising a) about 0.5 % w/w to about 10 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof; b) about 50 % w/w to about 80 % w/w of mannitol; c) about 1 % w/w to about 5 % w/w of anhydrous citric acid; d) about 0.5 % w/w to about 3 % w/w of hypromellose; e) about 1 % w/w to about 8 % w/w of sodium benzoate; f) about 10 % w/w to about 30 % w/w of combination of xanthan gum, and mixture of microcrystalline cellulose and carboxymethylcellulose sodium; g) about 0.5 % w/w to about 3 % w/w of sucralose; h) about 0.5 % w/w to about 3 % w/w of flavouring agent; and optionally other pharmaceutically acceptable excipients wherein the composition is administered in the form of granules for oral suspension.

2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises a) about 1.97 % w/w of rivaroxaban or pharmaceutically acceptable salt thereof; b) about 67 % w/w of mannitol; c) about 2 % w/w of anhydrous citric acid; d) about 1.5 % w/w of hypromellose; e) about 3.5 % w/w of sodium benzoate; f) about 22 % w/w of combination of xanthan gum, and mixture of microcrystalline cellulose and carboxymethylcellulose sodium; g) about 1 % w/w of sucralose; h) about 1.3 % w/w of flavouring agent.

3. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises a) about 20 mg to about 50 mg of mannitol; b) about 0.5 mg to about 2 mg of anhydrous citric acid; c) about 0.25 mg to about 2 mg of hypromellose; d) about 0.5 mg to about 4 mg of sodium benzoate; e) about 5 mg to about 20 mg of combination of xanthan gum, and mixture of microcrystalline cellulose and carboxymethylcellulose sodium; and f) optionally other pharmaceutically acceptable excipients.

4. The pharmaceutical composition as claimed in claim 1, wherein the ratio of mixture of microcrystalline cellulose and carboxymethylcellulose sodium to Xanthan gum in a given composition is about 10:1 w/w.

5. The pharmaceutical composition as claimed in claim 1, wherein the rivaroxaban having D90 particle size in the range of 5 µm to 15 µm.

6. The pharmaceutical composition as claimed in claim 1, wherein the buffering agent is present to maintain a pH of about 3.3-5.3.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition is stable for at least 24 months of storage at 25° C. and 60% relative humidity (RH).

8. A method of preparing a pharmaceutical composition as claimed in claim 1, wherein the composition is manufactured using wet granulation process.

9. A pharmaceutical composition for oral administration comprising an intragranular portion and an extragranular portion, wherein the intragranular portion comprises rivaroxaban or pharmaceutically acceptable salt thereof, mannitol, citric acid, hypromellose, and sodium benzoate and the extra granular portion comprises microcrystalline cellulose and carboxymethylcellulose sodium, sucralose, xantham gum, and flavor.

10. A pharmaceutical composition comprising rivaroxaban for oral administration, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the 200 ppm based on maximum daily dose of rivaroxaban.

Dated this 3rd day of October 2024

Mr. Thirupathi Bendram VP & Head - IPR
Alkem Laboratories Limited