Claims:We Claim
1. An oral solid dosage form comprising Rivaroxaban which is having D (90) < 30µm and one or more pharmaceutical acceptable excipients, prepared by a process, comprising the steps of:
i) blending Rivaroxaban and one or more pharmaceutical acceptable excipients,
ii) granulating the blend of step (i) using solvent and 0.2 to 0.6% of binder,
iii) the granules of step (ii) are dried and sifted,
iv) blending the dried granules of step (iii) with extragranular materials, and
v) compress the granules obtained in step (iv) into solid dosage form.

2. The process as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, surfactants and combinations thereof.

3. The process as claimed in claim 2, wherein the diluent is selected from the group comprising of lactose, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof.

4. The process as claimed in claim 2, wherein the disintegrant is selected from the group comprising of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof.
5. The process as claimed in claim 2, wherein the binder is selected from the group comprising of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives, hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combination thereof.

6. The process as claimed in claim 2, wherein the surfactant is selected are selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and combination thereof.

7. The process as claimed in claim 2, wherein the lubricant is selected from the group comprising of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric. acid, sodium stearyl fumarate," stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.

8. The process as claimed in claim 2, wherein the solid dosage form is selected from tablet, film coated tablet or capsule.

9. An oral solid dosage form comprising Rivaroxaban which is having D (90) < 30µm and one or more pharmaceutically acceptable excipients, prepared by a process according to claim 1, comprising the steps of:

(i) blending Rivaroxaban, microcrystalline cellulose, lactose, croscarmellose sodium and in rapid mixer granulator,
(ii) prepare binder solution using purified water, (0.2 to 0.6%) of hypromellose and is stirred to dissolve completely, and then sodium lauryl sulfate is added without stirring and dissolved completely.
(iii) formulating the granules of step-i blend using the solution of step-ii, the wet mass thus obtained was milled, dried in fluidized bed drier, and sifted,
(iv) the granules of step-iii was then lubricated with magnesium stearate and Croscarmellose sodium and was compressed into tablets,
iv) Compressed solid dosage form optionally coated with coating materials.
, Description:TITLE OF THE INVENTION:
“ORAL COMPOSITION OF RIVAROXABAN”
FIELD OF THE INVENTION:
The present invention relates to a process of preparing oral composition of Rivaroxaban. The solid composition is used for prophylaxis of venous thromboembolic disorders, stroke and systemic embolisms and for prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism.
BACKGROUND OF THE INVENTION:
Rivaroxaban is an oral anticoagulant which is a factor Xa (FXa) inhibitor. It indirectly inhabits the platelet aggregation by decreasing thrombin generation. It was developed by Janssen Pharms and currently marketed in the United States under the trade name XARELTO.

Rivaroxaban is an oxazolidinone derivative compound, which is chemically known as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide. It is disclosed in US 7157456, US 7585860 and US 7592339.
The pharmaceutical industry uses various methods of manufacturing solid dosage forms by using different pharmaceutical agents. Among various such methods of manufacturing solid dosage forms, granulation technique is preferable.
Granulation is a process in which granules are formed from drug substance with excipients in order to improve the properties of drug substance or dosage form. Granules are solid agglomerates of powder particles. Granulation may be dry granulation or wet granulation.
Wet granulation differs from dry granulation in having a granulation liquid, an aqueous or non-aqueous solvents are used alone or in combination with any of the pharmaceutical excipients as granulating solution. It improves compatibility of powder excipients, uniform content of drug substance and good segregation of components.
IN 256522 disclose a process for the preparation of a solid, orally administrable pharmaceutical composition comprising Rivaroxaban in hydrophilized form, in which (a) first granules comprising the active compound in hydrophilized form are prepared by moist granulation and the granules are then converted into the pharmaceutical composition, with addition of pharmaceutically suitable additives. IN’522 states that the tablet produced by a fluidized bed granulation process showed superior bioavailability as compared to a tablet produced by direct tableting, while tablets produced via mixer granulation showed no significant difference in bioavailability as compared to a tablet produced by direct tableting.
IN 2562/DELNP/2008 discloses solid pharmaceutical dosage forms of Rivaroxaban in amorphous form which can be prepared by melting active ingredient with one or more excipients.
WO 2010146179 discloses solid pharmaceutical compositions of Rivaroxaban, prepared dry granulation of the Rivaroxaban with at least one excipient, co-milling Rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient. The mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
The above prior art references disclose different process for the preparation of oral composition of rivaroxaban. However, the inventors of the present invention developed simple, cost effective alternate process which is more advantageous by means of comparable dissolution and bioavailability with respect to the marketed formulation of Xarelto tablets and prior arts.

SUMMARY OF THE INVENTION:
The present invention relates to a process of preparing an oral pharmaceutical dosage form of Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts with one or more pharmaceutical acceptable excipients.
One aspect of the present invention provides the process of preparing oral composition of Rivaroxaban comprising the steps of
i) blending Rivaroxaban and one or more pharmaceutical acceptable excipients,
ii) granulating the blend of step (i) using solvent and 0.2 to 0.6% of binder,
iii) the granules of step (ii) are dried and sifted,
iv) blending the dried granules of step (iii) with extragranular materials, and
v) compress the granules obtained in step (iv) into solid dosage form.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process of preparing an oral composition of Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts with one or more pharmaceutical acceptable excipients.
One embodiment of the present invention provides the process of preparing oral composition of Rivaroxaban comprising the steps of
i) blending Rivaroxaban and one or more pharmaceutical acceptable excipients,
ii) granulating the blend of step (i) using solvent and 0.2 to 0.6% of binder,
iii) the granules of step (ii) are dried and sifted,
iv) blending the dried granules of step (iii) with extragranular materials, and
v) compress the granules obtained in step (iv) into solid dosage form.
In an embodiment Rivaroxaban as the active ingredient (a) is employed in a micronized form. That means, the active ingredient (a) of the pharmaceutical composition of the present invention has a volume mean particle size (D90) of 1 to 30 um, more preferably of 4 to 20 um, still more preferably of 8 to 15 um.
The term "pharmaceutical acceptable excipient" as used herein refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients. Suitable excipients include diluents, binders, disintegrants, surfactants, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included.
The term “composition” or “pharmaceutical composition” or “ solid dosage forms” such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.
The term ‘stable’ refers to formulations that substantially retain the label 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 articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
According to the embodiments of the present invention suitable "diluents" used according to the present invention are selected from water soluble or water insoluble or combination thereof. Suitable water soluble diluents include sucrose, dextrose, lactose, mannitol, sorbitol and the like and water insoluble diluents include starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium silicate and the like or combination thereof.
According to the embodiments of the present invention suitable binders used according to the present invention are selected from the group comprising of hydroxypropylmethylcellulose, maize starch, povidone, hydroxypropylcellulose, pregelatinized starch and the like or combination thereof.
According to the embodiments of the present invention suitable surfactants are selected from Tyloxapol®, Triton X-100®, polysorbates, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearates, sorbitan monolaureates, sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, propylene glycol and mixtures thereof.
According to the embodiments of the present invention suitable disintegrants used according to the present invention are selected from starch, crospovidone, sodium starch glycolate, croscarmellose sodium and the like or combination thereof.
According to the embodiments of the present invention suitable lubricants used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.
According to the embodiments of the present invention suitable film coating polymers used according to the present invention are selected from polyvinyl alcohol (part hydrolyzed), titanium dioxide, macrogol (polyethylene glycol 3350), Hypromellose, Lactose, Triacetin, Talc, Titanium oxide and iron oxide and the like or mixtures thereof.
In an embodiment, the present invention provides a process for preparing oral solid dosage form of rivaroxaban comprising the steps of:
(i) Mixing Rivaroxaban and one or more excipients in rapid mixer granulator.
(ii) Preparing a solution comprising solvent, 0.2 to 0.6% of binder, and surfactant.
(iii) Granulating the blend of step (i) with the solution of step (ii).
(iv) Blending the granules of step (iii) with one or more extragranular excipients.
(v) Formulating the blend obtained in step (iv) into solid dosage form.
According to embodiment of the present invention composition will provide stable product, as well as improved content uniformity, blend uniformity and bioavailability.
The process details of the invention is provided in the example given below, which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Examples-1
Table 1
S.No. Ingredients Qty per Unit (mg)
10 mg % w/w 15 mg % w/w 20 mg % w/w
1. Rivaroxaban 10.00 9.804 15.00 14.706 20.00 19.608
2. Cellulose, microcrystalline 101 56.00 54.90 53.5 52.45 51.0 50.00
3. Lactose monohydrate 26.90 26.373 24.40 23.922 21.90 21.471
4. Croscarmellose sodium 4.00 3.922 4.00 3.922 4.00 3.922
Binder Solution
5. Hypromellose 0.5 0.49 0.5 0.49 0.5 0.49
6. Sodium lauril sulfate 1.00 0.982 1.00 0.981 1.00 0.980
7. Purified water QS QS QS QS QS QS
Extra granular
8. Croscarmellose sodium 3.00 2.941 3.00 2.941 3.00 2.941
9. Magnesium stearate 0.60 0.588 0.60 0.588 0.60 0.588
Core Tablet Mass (mg) 102.00 -- 102.00 -- 102.00 --
10. Opadry II 85F540176 Pink 3.06 -- -- -- -- --
11. Opadry II 85F565119 Brown -- -- 3.06 -- -- --
12 Opadry II 85F550037 Rexd -- -- -- -- 3.06 --
13. Purified water QS -- QS -- QS --
Coated Tablet Mass (mg) 105.06 -- 105.06 -- 105.06 --
The processing steps involved in manufacturing of oral composition of Rivaroxaban given in example 1 is given below:
Sifting
i. Co-sift Rivaroxaban, Cellulose, microcrystalline, Lactose monohydrate and Croscarmellose sodium through sieve # 20 ASTM.
Dry mixing and Granulation
ii. Load the sifted materials of step-i in Rapid Mixer Granulator and mix for 10 minutes using impeller at slow speed and chopper off.
Binder Solution Preparation
iii. Dissolve hypromellose in purified water under stirring and add sodium lauril sulfate without stirring.
iv. Granulate step-ii dry mix by using step-iii binder solution.
Drying
v. Unload the wet mass from RMG and mill through co-mill fitted with 6.0 mm screen at slow speed (700 ± 50 RPM).
vi. Dry the granules at inlet temperature of 55°C ± 10°C in FBD until the LOD of the granules reaches 1.0 - 3.0 % m/m at 105°C.
Sizing and Milling
vii. Sift the step-vi dried granules through sieve #30 ASTM (595µm).
viii. Mill the retentions of step-vii by using co-mill fitted with 1.0 mm screen at slow speed (700 ± 50 RPM) and sift through sieve #30 ASTM (595 µm). Continue this to mill the granules with 1.0 mm screen until all the material passes through sieve # 30 ASTM (595 µm).
Sifting of extra-granular material
ix. Sift Croscarmellose sodium through sieve #40 ASTM (420 µm).
x. Sift Magnesium stearate through sieve #60 ASTM (250 µm).
Blending and Lubrication
xi. Load the granules of step-viii and step-ix materials in blender and mix for 10 minutes at slow speed (12 ± 2 RPM).
xii. Add pre sifted magnesium stearate of step-x to above material and mix for 5 minutes at slow speed (12 ± 2 RPM).
Compression
xiii. Compress the lubricated blend of step-xii.
Film Coating:
xiv. Disperse Opadry II in purified water (15% m/m solids) under stirring and continue stirring for 45 minutes to form uniform dispersion.
xv. Load the core tablets of step-xiii in coating pan and coat the tablets for 3.0 ± 1.0% m/m with following coating parameters. After achieving the desired mass gain dry the coated tablets for 15 minutes with low inlet temperature.

Dissolution profile results:
Table 2. Dissolution profile of Rivaroxaban Tablets, 10mg, 15mg & 20mg (RLD Vs Test) in office of generic drugs (OGD) media.
Strength 10 mg 15mg 20mg
Time (min) Reference Test Reference Test Reference Test
10 78 82 87 90 86 86
15 83 86 90 93 88 89
20 85 87 92 94 90 90
30 88 89 93 94 92 91
45 90 91 94 95 92 91

Figure 1. Comparison of dissolution profiles of Rivaroxaban Tablets, 10 mg (Test Vs RLD).

Figure 2. Comparison of dissolution profiles of Rivaroxaban Tablets, 15 mg (Test Vs RLD).

Figure 3. Comparison of dissolution profiles of Rivaroxaban Tablets, 20 mg (Test Vs RLD).