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 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, 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: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 embodiment of the present invention provides the process of preparing oral solid dosage form 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 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, 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 54.50 53.431 52.00 50.980 49.50 48.529
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 2.00 1.961 2.00 1.961 2.00 1.961
6. Sodium lauril sulfate 1.00 0.980 1.00 0.980 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 solid dosage form 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