DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

SOLID COMPOSITION CONTAINING ORAL ANTICOAGULANT

We, ALPHAMED FORMULATIONS PVT. LTD.,
a company incorporated under the companies act, 1956 having address at Survey No. 225, Sampanbole village, Shamirpet Mandal, RR Dist. Hyderabad- 500078, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to the field of Oral pharmaceuticals.
The invention specifically relates to solid oral anticoagulant compositions and methods for the preparation of the same.
The present invention more specifically relates to composition of Rivaroxaban Oral tablets and methods for the preparation of the same.
This invention also relates to the composition of Rivaroxaban Oral tablets prepared by drug layered spheres.
This invention also relates to the composition of Rivaroxaban tablets prepared by Non-aqueous granulation using Organic solvent and Hydroalcoholic granulation.
BACKGROUND OF INVENTION
The active ingredient in the present invention is Rivaroxaban chemically known as “5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l, 3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide” and has an empirical chemical formula C19H18ClN3O5S with a structural formula shown below:

Rivaroxaban is a low molecular weight, orally administrable anticoagulant indicated for reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis. It is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.
US 7157456 discloses rivaroxaban product with method of use as anticoagulant and different crystalline polymorphic forms of Rivaroxaban are disclosed in various patents and patent applications like US 8188270, US 20100168111, WO 2012004245 and WO2013041651.
US 2008/0026057 disclose a solid, orally administrable pharmaceutical composition, comprising rivaroxaban in hydrophilized form. This application further discloses a process for the preparation of composition comprising Rivaroxaban in hydrophilized form, in which (a) first granules comprising the Rivaroxaban in hydrophilized form are prepared by moist granulation (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.
US 2010/0151011 disclose rapid release solid pharmaceutical dosage form of rivaroxaban containing drug in amorphous form or thermodynamically metastable crystal modification form. Use of these modified forms increases the solubility and the oral bioavailability of rivaroxaban.
US 2011/0300214 disclose pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier.
US 2012/0231076 disclose process for producing a pharmaceutical composition of rivaroxaban. The process involves mixing rivaroxaban, a matrix former, and a disintegrant, melting the mixture, and granulating the melted mixture.
US 2013/0064888 disclose pharmaceutical dosage forms of rivaroxaban having a compressed inert core, an optional subcoat over the compressed inert core, a drug layer over the compressed core.
WO 2010/146179 disclose solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or 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.
WO 2015/124995 A1 disclose an oral solid dosage form of rivaroxaban, prepared by a process, comprising the steps of blending, granulation, drying, milling and formulating the blend obtained into solid dosage form.
The above prior art references discloses different process for the preparation of solid oral dosage form of rivaroxaban. However, the inventors of the present invention have formulated a simple formulation with simple process which will provide enhanced dissolution and bioavailability of drug.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide an oral solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
Another objective of the present invention is to provide a process for the Preparation of solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts.
Another objective of the invention is to provide an alternative pharmaceutical composition of rivaroxaban and its method of preparation which will enhance the dissolution and oral bioavailability of the drug.
SUMMARY OF INVENTION
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by drug layering technology.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation and hydroalcoholic granulation.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation/ Hydroalcoholic granulation containing cremophore.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving excipients in mixture of ethanol and Purified water,
b) Dispersing drug in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets, and
d) Adding extragranular materials to step 3 pellets and blend followed by compression and optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water,
b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer,
d) Adding extragranular materials to step 3 pellets and blend,
e) Compressing the tablets using step 4 blend,
f) Dispersing Opadry brown in Purified water, and
g) Coating the tablets of step 5 with step 6 dispersion.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution,
b) Dispersing Drug in step 1 solution until smooth dispersion forms,
c) Sifting and blending the excipients,
d) Spraying step 2 dispersion on to step 3 blend until proper granules obtains, and
e) Adding extragranular materials and compression with optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose and Cremophor in ethanol or mixture of Ethanol and Purified water,
b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
c) Sifting Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose,
d) Spraying step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtained,
e) Adding extragranular materials to step 4 granules and blend, and
f) Compressing the tablets using step 5 blend.
DETAILED DESCRIPTION OF THE INVENTION
The invention specifically relates to oral anticoagulant compositions and methods for the preparation of the same.
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides process for the preparation of oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants and other excipients.
The term "rivaroxaban" includes various forms of rivaroxaban such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Rivaroxaban can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "rivaroxaban" as used in the present invention.
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
The composition according to the invention comprise diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
The composition according to the invention comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.
The composition according to the invention comprise disintegrants, such as carboxymethylcellulose, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000-11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL®, Polyplasdone® XL and Kollidon® CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL® (International Specialty Products), magnesium aluminium silicate or mixtures thereof.
The composition according to the invention also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.
The composition according to the invention also comprise glidants, such as talc, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.
The composition according to the invention also comprise surfactants, such as sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span or Arlacel , Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®60), polyoxyethylene (20) sorbitan monopalmitate (Tween®40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-l -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-C2 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.
The composition according to the invention also comprise solubilizers such as sugar alcohols like isomalt, sorbitol, xylitol or mannitol, cellulose derivatives (especially hydroxypropylmethyl cellulose (HPMC) and/or hydroxypropyl cellulose (HPC)), sugar alcohols (especially isomalt), polyethoxylated castor oil (Cremophor), polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone are used as solubilizer.
The composition according to the invention also comprise solvents such as methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.
Other excipients commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.
The pharmaceutical composition of the present invention can be present in the form of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule, a sachet and other dosage forms suitable for oral administration.
The granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/ dissolution of the film.
Other additives used in the preparations to the compositions of this invention, the following can be used and there were no limitations: stabilizer, surfactant, plasticizer, lubricant, reducing agent, buffer agent, sweetening agent, base, adsorbent, corrigent, binder, suspending agent, antioxidant, polish, coating, wetting agent, wet modifier, filler, antifoaming agent, refrigerative agent, coloring matter, flavoring agent, perfume, sugar coating agent, isotonizing agent, softener, emulsifying agent, foaming agent, pH modifier, anti-frothing agents, diluent, excipient, dispersing agent, disintegrator, fragrance, desiccant, antiseptics, preservative, solubilizing agent, solubilizer
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
Example 1
S.No Ingredients Quantity in mg per tablet
Example 1A Example 1B
1. Sugar Spheres (#60/80) 33.0 33.0
2. Rivaroxaban 20.0 20.0
3. Croscarmellose sodium 7.0 -
4. Hydroxy propyl cellulose 2.5 2.5
5. Sodium lauryl sulphate 0.5 0.5
6. Lactose monohydrate 55.0 62.0
7. Colloidal silicon dioxide 1.0 1.0
8. Magnesium Stearate 1.0 1.0
9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0
Film Coating
11. Opadry brown 3.0 3.0
12. Purified Water QS QS
Total Weight (mg) 123.0 123.0

Example 2
S.No Ingredients Quantity in mg per tablet
Example 2A Example 2B
1. Sugar Spheres (#60/80) 33.0 33.0
2. Rivaroxaban 10.0 10.0
3. Croscarmellose sodium 6.4 6.4
4. Hydroxy propyl cellulose 4.0 4.0
5. Sodium lauryl sulphate 0.5 0.2
6. Lactose monohydrate 37.1 37.4
7. Colloidal silicon dioxide 1.0 1.0
8. Magnesium Stearate 1.0 1.0
9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 85.0 85.0
Film Coating
11. Opadry brown 2.5 2.5
12. Purified Water QS QS
Total Weight (mg) 87.5 87.5

Example 3
S.No Ingredients Quantity in mg per tablet
Example 3A Example 3B
1. Sugar Spheres (#60/80) 34.0 34.0
2. Rivaroxaban 20.0 20.0
3. Croscarmellose sodium 7.0 7.0
4. Hydroxy propyl cellulose 2.0 4.0
5. Sodium lauryl sulphate 0.5 0.5
6. Lactose monohydrate 54.5 52.5
7. Colloidal silicon dioxide 1.0 1.0
8. Magnesium Stearate 1.0 1.0
9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0
Film Coating
11. Opadry brown 3.0 3.0
12. Purified Water QS QS
Total Weight (mg) 123.0 123.0

Example 4
S.No Name of the ingredients Quantity/ tablet in mg
20 mg strength 15 mg strength 10 mg strength 2.5 mg strength
Intra-granular
1. Sugar Spheres (#60/80) 34.0 39.0 44.0 51.5
2. Rivaroxaban 20.0 15.0 10.0 2.5
3. Croscarmellose sodium 7.0 7.0 7.0 7.0
4. Hydroxy propyl cellulose 2.0 2.0 2.0 2.0
5. Sodium lauryl sulphate 0.5 0.5 0.5 0.5
6.
7. Lactose monohydrate 54.5 54.5 54.5 54.5
8. Colloidal silicon dioxide 1.0 1.0 1.0 1.0
9. Magnesium Stearate 1.0 1.0 1.0 1.0
10. Ethanol QS QS QS QS
11. Purified Water QS QS QS QS
Core tablet weight 120.0 120.0 120.0 120.0
Film coating
12. Opadry brown 3.0 3.0 3.0 3.0
13. Purified Water QS QS QS QS
Coated Tablet Weight 123.0 123.0 123.0 123.0

Manufacturing Process:
1. Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water,
2. Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer,
4. Adding extragranular materials to step 3 pellets and blend,
5. Compressing the tablets using step 4 blend,
6. Dispersing Opadry brown in Purified water, and
7. Coating the tablets of step 5 with step 6 dispersion.

Example 5
S.No. Ingredients Quantity/ tablet in mg
EX 5A EX 5B EX 5C
1. Rivaroxaban 20.0 20.0 20.0
2. Microcrystalline cellulose 28.0 35.0 37.0
3. Lactose monohydrate 22.9 22.9 22.9
4. Croscarmellose sodium 2.0 3.0 2.0
5. Hydroxy propyl cellulose 1.0 3.0 2.0
6. Cremophor 0.5 0.5 0.5
7. Ethanol QS QS QS
8. Microcrystalline cellulose 10.0 - -
9. Magnesium Stearate 0.6 0.6 0.6
Core tablet weight 85.0 85.0 85.0
Film Coating
10. Opadry brown 2.5 2.5 2.5
11. Purified Water QS QS QS
Coated Tablet Weight (mg) 87.5 87.5 87.5

Manufacturing process:
1. Dissolving Hydroxypropyl cellulose and Cremophor in ethanol,
2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Sift together Croscarmellose sodium, Lactose monohydrate and Microcrystalline cellulose,
4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains,
5. Add extragranular materials to step 4 granules and blend,
6. Compress the tablets using step 5 blend,
7. Disperse Opadry brown in Purified water, ad
8. Coat the tablets of step 6 with step 7 dispersion.
Example 6
S.No. Ingredients Quantity/ tablet in mg
EX 6A EX 6B
1. Rivaroxaban 20.0 20.0
2. Microcrystalline cellulose 35.0 35.0
3. Lactose monohydrate 22.9 22.9
4. Croscarmellose sodium 3.0 -
5. Hydroxy propyl cellulose 3.0 6.0
6. Cremophor 0.5 0.5
7. Ethanol & Purified Water QS QS
8. Magnesium Stearate 0.6 0.6
Core tablet weight 85.0 85.0
Film Coating
9. Opadry brown 2.5 2.5
10. Purified Water QS QS
Coated Tablet Weight (mg) 87.5 87.5

Manufacturing process:
1. Dissolve Hydroxypropyl cellulose and Cremophor in mixture of ethanol and Purified water,
2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Sift together Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose,
4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains,
5. Add extragranular materials to step 4 granules and blend,
6. Compress the tablets using step 5 blend,
7. Disperse Opadry brown in Purified water, and
8. Coat the tablets of step 6 with step 7 dispersion.
,CLAIMS:We Claim:
1. An oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by drug layering technology.
2. The composition claimed in claim 1, further comprising one or more excipients which are selected from diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
3. The composition as claimed in claims 1 and 2, wherein said diluents is microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
4. The composition as claimed in claims 1 and 2, wherein said binder is polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.
5. The composition as claimed in claims 1 and 2, wherein said disintegrants is carboxymethylcellulose, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000-11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL®, Polyplasdone® XL and Kollidon® CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL® (International Specialty Products), magnesium aluminium silicate or mixtures thereof.
6. The composition as claimed in claims 1 and 2, wherein said glidant is talc, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.
7. The composition as claimed in claims 1 and 2, wherein said lubricant is stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.
8. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of::
a) Dissolving excipients in mixture of ethanol and Purified water,
b) Dispersing drug in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets, and
d) Adding extragranular materials to step 3 pellets and blend followed by compression and optional coating.
9. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of::
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water,
b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer,
d) Adding extragranular materials to step 3 pellets and blend,
e) Compressing the tablets using step 4 blend,
f) Dispersing Opadry brown in Purified water, and
g) Coating the tablets of step 5 with step 6 dispersion.
10. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution,
b) Dispersing Drug in step 1 solution until smooth dispersion forms,
c) Sifting and blending the excipients,
d) Spraying step 2 dispersion on to step 3 blend until proper granules obtains, and
e) Adding extragranular materials and compression with optional coating.

Dated this Fourth (04th)day of July, 2017.

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883