Claims:We claim:

1. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof comprising:
a. dissolving hypromellose in sodium lauryl sulphate and water to prepare granulating solution;
b. adding microcrystalline cellulose to granulating solution prepared in step-a to form microcrystalline granules;
c. drying of granules prepared in step-b;
d. dissolving Rivaroxaban in organic solvent to prepare Rivaroxaban solution;
e. spraying or adding Rivaroxaban solution prepared in step-d to dried microcrystalline cellulose granules of step-c;
f. drying of granules prepared in step-e;
g. mixing or blending lactose monohydrate and croscarmellose sodium with dried granules prepared in step-f;
h. lubricating blend prepared in step-g with magnesium stearate;
i. compressing lubricated blend prepared in step-h to prepare tablets;
j. optionally coating compressed tablets obtained in step-i.

2. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof comprising:
a. dissolving hypromellose in sodium lauryl sulphate and organic solvent to prepare granulating solution;
b. adding microcrystalline cellulose to granulating solution prepared in step-a to form microcrystalline granules;
c. dissolving Rivaroxaban in organic solvent to prepare Rivaroxaban solution;
d. spraying or adding Rivaroxaban solution prepared in step-c to microcrystalline cellulose granules of step-b;
e. drying of granules prepared in step-d;
f. mixing or blending lactose monohydrate and croscarmellose sodium with dried granules prepared in step-e;
g. lubricating blend prepared in step-f with magnesium stearate;
h. compressing lubricated blend prepared in step-g to prepare tablets;
i. optionally coating compressed tablets obtained in step-h.

3. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof comprising:
a. dissolving hypromellose in sodium lauryl sulphate and water to prepare granulating solution;
b. adding microcrystalline cellulose to granulating solution prepared in step-a to form microcrystalline granules;
c. drying of granules prepared in step-b;
d. mixing or blending Rivaroxaban, lactose monohydrate and croscarmellose sodium with dried granules prepared in step-c;
e. lubricating blend prepared in step-d with magnesium stearate;
f. compressing lubricated blend prepared in step-e to prepare tablets;
g. optionally coating compressed tablets obtained in step-f.

4. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof comprising:
a. dissolving hypromellose in sodium lauryl sulphate and organic solvent to prepare granulating solution;
b. adding microcrystalline cellulose to granulating solution prepared in step-a to form microcrystalline granules;
c. drying of granules prepared in step-b;
d. mixing or blending Rivaroxaban, lactose monohydrate and croscarmellose sodium with dried granules prepared in step-c;
e. lubricating blend prepared in step-d with magnesium stearate;
f. compressing lubricated blend prepared in step-e to prepare tablets;
g. optionally coating compressed tablets obtained in step-f.

5. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof comprising:
a. dissolving hypromellose in sodium lauryl sulphate and organic solvent to prepare granulating solution;
b. adding microcrystalline cellulose, lactose monohydrate and croscarmellose sodium to granulating solution prepared in step-a to form granules;
c. dissolving Rivaroxaban in an organic solvent;
d. adding Rivaroxaban solution of step-c to granules of step-b and mixed in rapid mixer granulator;
e. drying above mixture in fluidized bed processor;
f. size reducing the dried granules obtained in step-e;
g. lubricating size reduced dried granules of step-f with magnesium stearate;
h. compressing lubricated blend prepared in step-g to prepare tablets;
i. optionally coating compressed tablets obtained in step-h.

6. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof as claimed in claim-1 to 5, wherein optionally re-granulating pre-lubricated dried granules by adding methylene dichloride in rapid mixer granulator followed by drying and size reduction.

7. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof as claimed in claim-1 to 5, wherein organic solvent is selected from one or more from dimethyl sulfoxide or acetone or isopropyl alcohol or dimethyl sulfoxide.

8. An improved process for preparation of solid oral pharmaceutical dosage of Rivaroxaban or pharmaceutically acceptable salt thereof as claimed in claim-1 to 5, wherein lubricated blend is filled in capsule to produce Rivaroxaban capsule dosage form.

9. Pharmaceutical compositions of Rivaroxaban or pharmaceutically acceptable salt thereof comprising following formula:
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 2.50 10.00 15.00 20.00
Lactose monohydrate 48.09 192.36 288.54 384.72
Croscarmellose Sodium 7.00 7.00 7.00 7.00
MCC PH 101 5.98 5.98 5.98 5.98
Hypromellose 6 cps 1.25 1.25 1.25 1.25
Sodium Lauryl Sulphate 4.50 4.50 4.50 4.50
Magnesium Stearate 0.68 0.68 0.68 0.68

wherein above composition comprises Rivaroxaban in non-hydrophilized form and prepared as claimed in claim-1 to 5.

10. Pharmaceutical compositions of Rivaroxaban or pharmaceutically acceptable salt thereof comprising following formula:
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68

wherein above composition comprises Rivaroxaban in non-hydrophilized form and prepared as claimed in claim-1 to 5. , Description:“PHARMACEUTICAL COMPOSITIONS OF RIVAROXABAN AND IMPROVED PROCESSES THEREOF”

FIELD OF THE INVENTION:
The present invention relates to a solid oral dosage form comprising Rivaroxaban and microcrystalline cellulose granules prepared using hypromellose and one or more pharmaceutically acceptable excipient(s), wherein said microcrystalline cellulose granules are free of Rivaroxaban. The present invention further relates to improved processes for the preparation of Rivaroxaban whose incorporation gives high dissolution rate which helps Rivaroxaban to reach at the absorption site quickly and thereby providing increased therapeutic efficacy in shorter span.

BACKGROUND OF THE INVENTION:
Clinically, atrial Fibrillation is characterized by rapid and irregular heart beating. Non valvular atrial fibrillation is characterized by absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair. The main goals of treatment of atrial fibrillation are to prevent circulatory instability and stroke. Hence, prevention of coagulation is required for reducing the risk of strokes. Prevention of coagulation can be achieved by the use of anticoagulants like Heparin, Warfarin, Dabigatran, Rivaroxaban and Apixaban.
The present invention relates to pharmaceutical compositions of Rivaroxaban and improved processes for the preparation thereof. Rivaroxaban is a pharmaceutical agent that is used to reduce stroke risk in nonvalvular atrial fibrillation. It helps reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for treating deep vein thrombosis and pulmonary embolism. It also reduces in the risk of recurrence of the same. Specifically, rivaroxaban is used for the prophylaxis of deep vein thrombosis after knee or hip replacement surgery which may lead to pulmonary embolism.
Pharmacologically, Rivaroxaban is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex which leads to thrombus formation. It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action.
Chemically, Rivaroxaban is pure (S)-enantiomer, low molecular weight, orally administrable inhibitor of blood clotting factor Xa, which can be employed for the prophylaxis and/or treatment of various thromboembolic diseases. Rivaroxaban is chemically known as (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide having empirical formula is C19H18CIN3O5S and the molecular weight is 435.88. Chemical structure of Rivaroxaban may be structurally represented as:

RIVAROXABAN
Physico-chemically, Rivaroxaban 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.
Commercially, Rivaroxaban is available as XARELTO® tablets by Janssen Pharmaceuticals Inc in the United States market which is licensed from Bayer Healthcare AG. Each XARELTO® tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO® include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO® 10 mg tablets is Opadry® Pink and XARELTO® 15 mg tablets is Opadry® Red, containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO® 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
Pharmaceutically, Rivaroxaban is BCS class-II drug having relatively poor water solubility (about 7 mg/l), causing problems regarding dissolution of Rivaroxaban from the pharmaceutical composition and the oral bioavailability.
There are various methods available in prior art that can be used to enhance the dissolution profile of poorly soluble drugs such as hydrophilization, reduction of particle size, alteration of crystal habit, carrier dispersion of drugs, emulsification etc. There are situations where these techniques have no effect on bioavailability and therefore some other techniques or parameters are required for further improvement of dissolution of the drug. A properly designed composition should result in dissolution data that are not highly variable. High variability in results can make it difficult to anticipate in-vivo trends or effects and thus bioavailability of formulation.
IN211300 discloses Rivaroxaban molecule specifically for the first time. Further, this Indian patent also discloses Rivaroxaban and Rivaroxaban hydrate specifically. This patent is expected to expire on December 11, 2020.
IN256522 claims a process for preparation of Rivaroxaban wherein Rivaroxaban is converted into hydrophilized form. Here, in first step Rivaroxaban is wet-granulated using water. Hence, as per this patent, Rivaroxaban which is only in hydrophilized form can achieve required dissolution rate. However, this patent fails to disclose any other process wherein use of water may be avoided.
WO2010/146179 discloses process for preparation of Rivaroxaban wherein Rivaroxaban along with at least one excipient are hot melted for granulation or extrusion to provide granules of the same which are then compressed to form tablets. It may be important to note that Rivaroxaban exists in many crystalline forms and all the forms have vast difference in melting point as well. For example, Rivaroxaban modification-I melts at 230°C whereas modification I melts 203°C. Interestingly, for modification III, transition point is at about 127°C. Hence, final Rivaroxaban product may contain mixture of modifications and hence, use of hot-melt granulation technique may degrade some part of Rivaroxaban. Thus, this technique has very serious limitation.
WO2014/191446 discloses compositions of Rivaroxaban and process for preparation thereof. As per this patent, Rivaroxaban is dry milled with one or more excipients and then they are compressed to form tablet. This patent discloses use of dry granulation technique for the preparation of above-mentioned composition. As per disclosure in the patent, comparative dissolution of this product is slower and lesser than innovator product.
3369/CHE/2013 and 3370/CHE/2013 discloses Rivaroxaban compositions wherein Rivaroxaban is co-milled with surfactant. This mixture is then compressed to form tablet. However, it may be important to note that there are no analytical data reported in this patent application shows unsuccessful development of formulation.
2777/MUM/2013 claims process for preparation of Rivaroxaban composition wherein the said composition is prepared by intimate mixing of Rivaroxaban along with disintegrant and diluent. No stability data are reported in this patent which may be due to unsuccessful development.
781/MUM/2014 claims process for preparation of composition for Rivaroxaban. As per this patent, inert granules comprising hydrophilic polymer are prepared followed by addition of co-milled Rivaroxaban along with surfactant. This mixture is compressed to form tablets. This patent is similar to earlier patent where co-milling of Rivaroxaban and surfactant is reported.
WO2016/144071 discloses a rapid-release pharmaceutical formulation comprising Rivaroxaban-containing non-aqueous hydrophilic combined granules, wherein the granules are coated. Process for preparation of the same includes mixing Rivaroxaban with a low melting hydrophilic binder and granulating to prepare Rivaroxaban containing non-aqueous hydrophilic binding granules to form tablets.
IN201717037252 claims process for preparation of an oral pharmaceutical composition of Rivaroxaban in non-hydrophilized form, wherein the process comprises the steps of: a) dry mixing Rivaroxaban with pharmaceutically acceptable inert excipients to form a dry-mix; b) granulating the dry mix in step (a) in rapid mixer granulator to form granules; c) drying the granules formed in step (b) in fluidized bed dryer. This patent application discloses similar process that has been earlier reported.
WO2018/001914 discloses a pharmaceutical capsule composition comprising rivaroxaban with at least one pharmaceutically acceptable excipient. However, it may be important to note that there are no analytical data reported in this patent application shows unsuccessful development of formulation.
JP6574041 claims a solid pharmaceutical composition in the form of a tablet containing Rivaroxaban as an active ingredient, comprising a stirred granulation containing Rivaroxaban and lactose hydrate, and the content of crystalline cellulose in the granulated product is solid pharmaceutical composition.
WO2020/060336 claims a process for preparation of Rivaroxaban composition. This include preparing a solution comprising a solvent, rivaroxaban and a pharmaceutically acceptable cationic polymer; and converting the solution into a pharmaceutical composition.
In view of all these prior-art publications, there is still a need to prepare a stable pharmaceutical composition comprising Rivaroxaban prepared by simple and economically viable process, which provides desired dissolution profile with least deviation.
The inventors of the present invention have developed pharmaceutical compositions comprising Rivaroxaban wherein improved processes for preparation surprisingly maintain rapid dissolution rate even after 6 months of stability studies. This invention is further described in detail in later sections.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide a solid oral dosage form comprising Rivaroxaban and microcrystalline cellulose granules prepared using hypromellose and one or more pharmaceutically acceptable excipient(s), wherein said microcrystalline cellulose granules are free of Rivaroxaban.
One more objective of the present invention is to provide improved processes for the preparation of Rivaroxaban whose incorporation gives high dissolution rate which helps Rivaroxaban to reach at the absorption site quickly and thereby providing increased therapeutic efficacy in shorter span.
Another objective of the present invention is to provide Rivaroxaban composition wherein Rivaroxaban is not present in hydrophilized form.
Yet another objective of the present invention is to provide Rivaroxaban composition with improved economic processes wherein non-hydrophilized Rivaroxaban shows consistent dissolution profile at least over a period of six months stability storage condition.

SUMMARY OF THE INVENTION:
Despite of extensive research on Rivaroxaban as reported in prior-art publications, an oral composition of Rivaroxaban wherein Rivaroxaban is in non-hydrophilized form and yet stable composition has not been reported. Surprisingly, inventors of the present invention have derived following processes by using them a stable composition of Rivaroxaban may be obtained wherein Rivaroxaban is in non-hydrophilized form.
Accordingly, the present invention provides an oral composition of Rivaroxaban preferably as oral dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
In one general aspect, a pharmaceutical composition as per the present invention is in the form of tablet or capsule.
In yet another aspect, a pharmaceutical composition as per the present invention comprises Rivaroxaban and one or more pharmaceutically acceptable excipients wherein the Rivaroxaban is in non-hydrophilized form.
Another embodiment according to the present invention, wherein the formulated product manufactured contains Rivaroxaban in non-hydrophilized form, which results in to enhanced in-vitro dissolution release above 99% even after six months stability data.
In yet another embodiment of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process which may include wet-granulation which may be aqueous or non-aqueous.
In another embodiment of the present invention, wherein the microcrystalline cellulose granules present in the pharmaceutical composition enhances bioavailability of Rivaroxaban owing to their faster dissolution properties.
Embodiments of the pharmaceutical composition may include Rivaroxaban as an active ingredient with one or more selected from pharmaceutically acceptable excipients like fillers or diluents, binders, surfactants, disintegrants, lubricants, glidants, coloring agents and the like.
In another embodiment of the present invention, wherein Rivaroxaban is present in the final formulation in amount ranging from 1 mg to 50 mg along with pharmaceutically acceptable excipients.
In one embodiment, process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) dissolving hypromellose in sodium lauryl sulphate and water to prepare binder solution;
b) adding binder solution prepared in step-a to microcrystalline cellulose and granulating in rapid mixer granulator followed by drying of these granules;
c) dissolving Rivaroxaban in to organic solvent like DMSO (dimethyl sulfoxide) or acetone or IPA or MDC and spraying or adding this solution on dried granules obtained in step-b followed by continuous drying;
d) adding lactose monohydrate and croscarmellose sodium to above dried granules obtained in step-c followed by blending;
e) lubricating blend obtained in step-d using magnesium stearate;
f) compressing lubricated blend obtained in step-e to form tablets.
g) Optionally, coating tablets obtained in step-f using Opadry® ready mixture.

In another embodiment, process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) dissolving hypromellose in sodium lauryl sulphate and organic solvents like DMSO or acetone to prepare binder solution;
b) adding binder solution prepared in step-a to microcrystalline cellulose and granulating in rapid mixer granulator;
c) dissolving Rivaroxaban in to organic solvent like DMSO (dimethyl sulfoxide) or acetone and spraying or adding this solution on granules obtained in step-b followed by continuous drying;
d) adding lactose monohydrate and croscarmellose sodium to above dried granules obtained in step-c followed by blending;
e) lubricating blend obtained in step-d using magnesium stearate;
f) compressing lubricated blend obtained in step-e to form tablets.
g) Optionally, coating tablets obtained in step-f using Opadry® ready mixture.

In one more embodiment, process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) dissolving hypromellose in sodium lauryl sulphate and water to prepare binder solution;
b) adding binder solution prepared in step-a to microcrystalline cellulose for granulation in rapid mixer granulator followed by drying of these granules;
c) adding Rivaroxaban, lactose monohydrate and croscarmellose sodium to above dried granules obtained in step-b followed by blending;
d) lubricating blend obtained in step-c using magnesium stearate;
e) compressing lubricated blend obtained in step-d to form tablets;
f) optionally, coating tablets obtained in step-e using Opadry® ready mixture.

In other embodiment, process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) dissolving hypromellose in sodium lauryl sulphate and organic solvents like DMSO or acetone to prepare binder solution;
b) adding binder solution prepared in step-a to microcrystalline cellulose for granulation in rapid mixer granulator followed by drying of these granules;
c) adding Rivaroxaban, lactose monohydrate and croscarmellose sodium to above dried granules obtained in step-b followed by blending;
d) lubricating blend obtained in step-c using magnesium stearate;
e) compressing lubricated blend obtained in step-d to form tablets;
f) optionally, coating tablets obtained in step-e using Opadry® ready mixture.

In another embodiment, process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps:
a) granulating microcrystalline cellulose, lactose monohydrate and croscarmellose sodium using hypromellose, surfactant and water;
b) dissolving Rivaroxaban in organic solvents like IPA, DMSO or acetone;
c) adding dissolved Rivaroxaban in granules obtained in step-a followed by drying;
d) optionally, dissolving dried granules of step-c in MDC and re-granulating followed by drying;
e) size reducing dried granules of step-c or step-d;
f) lubricating granules obtained in step-e using magnesium stearate;
g) compressing lubricated blend obtained in step-f to form tablets;
h) optionally, coating tablets obtained in step-e using Opadry® ready mixture.

The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
In accordance with the present invention, a pharmaceutical composition of Rivaroxaban comprising of Rivaroxaban as an active ingredient with pharmaceutically acceptable excipients.
The term "Rivaroxaban" as used herein includes Rivaroxaban free base, its pharmaceutically acceptable salt. Preferably, Rivaroxaban is Rivaroxaban free base. Rivaroxaban can be used in any crystalline, partly crystalline or amorphous form or modification. Rivaroxaban can be used in non-micronized form.
The term "pharmaceutically acceptable excipient(s)" as used herein refers to additive(s) useful for converting pharmacologically active compound into pharmaceutical dosage forms which are suitable for administration to patients. Suitable pharmaceutically acceptable excipients include fillers or diluents, binders, surfactants, disintegrants, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included.
The term "microcrystalline cellulose (MCC) granules" which is free of Rivaroxaban as used herein means a component wherein Rivaroxaban is not added during processing. Inert granules according to present invention can be prepared by any known process in the art. Preferably, inert granules are prepared by wet granulation, wherein Rivaroxaban is not added during granulation. Further, these MCC granules are free of lactose as well as disintegrants. The inventors of the present invention during development process surprisingly observed that plain MCC granules were having good compressibility and dissolution rate even after six months of stability storage condition when compared with the MCC granules containing lactose or disintegrant or both.
MCC have swelling tendencies and excellent water imbibing or wicking action. This property makes MCC as also an excipient of choice for wet granulation. When used MCC in wet granulation method, it had produced uniform granules and drying was more homogeneous which remove the hardening of granules. Hardening is a phenomenon which is observed in incompletely dried granules. This case happened when the granules are dried at a high temperature, from which the inside part of the granules remains wet, while the surface seems dried. The granules are often hard and resist disintegration. When coming to compaction process, the compression forces will break the granules and deform plastically to form soft tablets due to the moisture coming out of the incompletely dried granules. When MCC was employed, faster disintegration from granules and tablets was obtained. Basically, using MCC in wet granulation included wetting MCC with water followed by drying.
The term "added" or "mixed" or "adding" or "mixing" as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing or adding or granulating Rivaroxaban or one or more pharmaceutically acceptable excipient(s) with said inert granules or other pharmaceutically acceptable excipient(s) to prepare mixture or blend.
The term “granulation” includes aqueous granulation, non-aqueous granulation as well as dry granulation.
The term “organic solvent” includes dimethyl sulfoxide, isopropyl alcohol (IPA), methylene dichloride (MDC), acetone or mixture thereof.
In an embodiment, the solid oral dosage form of Rivaroxaban comprises MCC granules comprising a hypromellose and surfactant, only. Surprisingly, it was found that hypromellose when used in the MCC granules, it significantly improved dissolution profile of Rivaroxaban composition, without opting for hydrophilization of Rivaroxaban.
A pharmaceutical composition according to present invention is a solid composition for immediate release for oral administration and it can be in the form of tablet, powder or capsule. Preferably, said composition is in the form of tablet for oral administration.
For a pharmaceutical composition, it is always desirable to have stable dissolution profile over six months stability date to get consistent therapeutic efficacy. To the surprise of inventors, use of hypromellose in the inert granules (which excludes lactose and disintegrants) not just improves the dissolution profile of the composition but also was stable over more than six-month stability storage condition.
Diluent may be selected from cellulose derivatives such as powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate; saccharides such as lactose, sucrose or dextrose; sugar alcohols such as mannitol, sorbitol or erythritol and mixtures thereof The formulation may incorporate one or more of the above fillers, preferably, lactose and microcrystalline cellulose forms the filler. The diluent may be present in an amount ranging from 1% to 90% by weight of the composition.
Surfactant may be selected from anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. The preferred surfactants according to present invention may include, but not limited to Sodium lauryl sulfate, polyoxyehtylene polyoxypropylene glycol, polyethylene glycol, polyoxyehtylene glycol and ethers, polysorbates (tweens), glycerol, Sorbitan esters. The preferred surfactant in the present invention is sodium lauryl sulfate. The surfactant may be present in an amount ranging from 0.5% to 25% by weight of the composition.
Disintegrant may be selected from calcium carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, carboxymethylcellulose sodium, sodium starch glycolate, pregelatinized starch; low-substituted hydroxypropylcellulose; and mixtures thereof. The disintegrant may be present in an amount ranging from 1% to 20% by weight of the composition.
Lubricant may be selected from stearic acid or its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearyl Fumarate, talc and colloidal silicon dioxide respectively. The lubricant may be present in an amount ranging from 0.25% to 5% by weight of the composition.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch, microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.
Solvents include, but are not limited to purified water, acetone, ethyl alcohol, isopropyl alcohol, dichloromethane and other materials known to one ordinarily skilled in the art and mixtures thereof.
It should be appreciated that there is considerable overlap between the above-listed excipients in common usage, since a given excipient is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed excipients should be taken as merely exemplary, and not limiting, of the types of excipients that can be included in compositions of the present invention. One or more of these excipients can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden. The amount of each type of excipients employed may vary within ranges conventional in the art.
In another embodiment for the preparation of Rivaroxaban composition comprises of preparing microcrystalline cellulose granules using hypromellose, surfactant and water using aqueous wet-granulation process. Above granules are first dried. Rivaroxaban is then dissolved in an organic solvent and then sprayed or added on above granules followed by continuous drying. Remaining excipients are added to above dried granules which are then lubricated and followed by compression to form tablets. These tablets are optionally coated. In some cases, above mentioned mixture is filled in capsule instead of compressing the same as tablets.
In yet another embodiment for the preparation of Rivaroxaban composition comprises of preparing microcrystalline cellulose granules using hypromellose, surfactant and organic solvent using non-aqueous wet-granulation process. Rivaroxaban is then dissolved in an organic solvent and then sprayed or added on above wet granules followed by continuous drying. Remaining excipients are added to above dried granules which are then lubricated and followed by compression to form tablets. These tablets are optionally coated. In some cases, above mentioned mixture is filled in capsule instead of compressing the same as tablets.
In an embodiment, the process for preparation of solid oral dosage form of Rivaroxaban comprises addition of Rivaroxaban with one or more pharmaceutically acceptable excipient(s). Then, microcrystalline cellulose granules are prepared using hypromellose, surfactant and water using aqueous wet-granulation process. Further, above microcrystalline cellulose granules are dried and then mixed with Rivaroxaban dry mix followed by lubrication and compression to form tablets. These tablets are optionally coated. In some cases, above mentioned mixture is filled in capsule instead of compressing the same as tablets.
In yet another embodiment for the preparation of Rivaroxaban composition comprises of preparing microcrystalline cellulose granules using hypromellose, surfactant and organic solvent using non-aqueous wet-granulation process. Above granules are first dried. Rivaroxaban is then mixed with other excipients including lubricants and mixed well followed by compression to form tablets. These tablets are optionally coated. In some cases, above mentioned mixture is filled in capsule instead of compressing the same as tablets.
In other embodiment for the preparation of Rivaroxaban composition comprises of preparing granules of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium using hypromellose, surfactant and water using aqueous wet-granulation process. Rivaroxaban is dissolved in isopropyl alcohol and this solution was added to above granules. Above granules are dried in fluidized bed dryer. Optionally, these dried granules optionally re-granulated using methylene chloride in rapid mixer granulator and dried. These dried granules were lubricated with magnesium stearate followed by compression to form tablets. These tablets are optionally coated. In some cases, above mentioned mixture is filled in capsule instead of compressing the same as tablets.
In yet another aspect of the embodiment, the process comprises the steps of compressing into suitable dosage form and optionally coating the same. Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan. The coating may be functional or non-functional.
After experimenting more than dozen type of possible processes, inventors of the present invention observed only these processes surprisingly maintain the similar dissolution rate even after storage under stability conditions for six months. This is the main advantage of above-mentioned processes. Because it is the prime motive of each scientist to develop a formulation which is stable over a longer period of time. This motive is fulfilled in this invention. In addition, due to maintenance of fast dissolution rate over six-month stability period, this composition would reach faster and completely to the site of absorption and thereby increasing bioavailability in shorter span.
Inventors of the present invention also noted that sequence of above processes is also crucial. Inventors tried to change the sequence which led to poor dissolution results than the earlier one. Hence, not only the processes but also the sequence of these processes does play a significant role in development of stable pharmaceutical formulation of Rivaroxaban wherein Rivaroxaban is not present in hydrophilized form.
One embodiment of the present invention may include a pharmaceutical composition comprising about 1 mg to 50 mg of Rivaroxaban with pharmaceutically acceptable excipients.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Means, the foregoing examples are illustrative embodiments and are merely exemplary. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.

EXAMPLES
EXAMPLE-1:
Table-1
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68
Total 85.00 85.00 85.00 85.00

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and water to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose and was granulated in rapid mixer granulator followed by drying of these granules.
3. Rivaroxaban was then dissolved in to organic solvent like DMSO (dimethyl sulfoxide) or acetone and this solution was sprayed or added on dried granules obtained in step-2 followed by continuous drying.
4. Lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-3 and blended.
5. Blend obtained in step-4 was then lubricated using magnesium stearate.
6. Lubricated blend obtained in step-5 was then compressed to form tablets.
7. Tablets obtained in step-6 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-2:
Table-2
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68
Total 85.00 85.00 85.00 85.00

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and organic solvent like DMSO or acetone to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose and was granulated in rapid mixer granulator.
3. Rivaroxaban was then dissolved in to organic solvent like DMSO or acetone and this solution was sprayed or added on granules obtained in step-2 followed by continuous drying.
4. Lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-3 and blended.
5. Blend obtained in step-4 was then lubricated using magnesium stearate.
6. Lubricated blend obtained in step-5 was then compressed to form tablets.
7. Tablets obtained in step-6 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-3:
Table-3
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68
Total 85.00 85.00 85.00 85.00

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and water to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose and was granulated in rapid mixer granulator followed by drying of these granules.
3. Rivaroxaban, lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-2 and blended.
4. Blend obtained in step-3 was then lubricated using magnesium stearate.
5. Lubricated blend obtained in step-4 was then compressed to form tablets.
6. Tablets obtained in step-5 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-4:
Table-4
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68
Total 85.00 85.00 85.00 85.00

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and organic solvent like DMSO or acetone to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose and was granulated in rapid mixer granulator followed by drying of these granules.
3. Rivaroxaban, lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-2 and blended.
4. Blend obtained in step-3 was then lubricated using magnesium stearate.
5. Lubricated blend obtained in step-4 was then compressed to form tablets.
6. Tablets obtained in step-5 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-5 to 8:

Table-5
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 2.50 10.00 15.00 20.00
Lactose monohydrate 48.09 192.36 288.54 384.72
Croscarmellose Sodium 7.00 7.00 7.00 7.00
MCC PH 101 5.98 5.98 5.98 5.98
Hypromellose 6 cps 1.25 1.25 1.25 1.25
Sodium Lauryl Sulphate 4.50 4.50 4.50 4.50
Magnesium Stearate 0.68 0.68 0.68 0.68
Total 70.00 280.00 420.00 560.00

Common Process for preparation of Example-5 to 8:
1. A) Hypromellose was dissolved in sodium lauryl sulphate and organic solvent like DMSO or acetone to prepare binder solution.
OR
B) Hypromellose was dissolved in sodium lauryl sulphate and water to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose and was granulated in rapid mixer granulator followed by drying of these granules.
3. A) Rivaroxaban was then dissolved in to organic solvent like DMSO or acetone and this solution was sprayed or added on dried granules obtained in step-2 followed by continuous drying. Lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-3A and blended.
OR
B) Rivaroxaban, lactose monohydrate and croscarmellose sodium were added to above dried granules obtained in step-2 and blended.
4. Blend obtained in step-3 was then lubricated using magnesium stearate.
5. Lubricated blend obtained in step-4 was then compressed to form tablets.
6. Tablets obtained in step-5 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-9:
Table-6
Ingredients 2.5 mg 10 mg 15 mg 20 mg
Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet) Weight
(mg / tablet)
Rivaroxaban 02.50 10.00 15.00 20.00
Lactose monohydrate 63.09 55.59 50.59 45.59
Croscarmellose Sodium 07.00 07.00 07.00 07.00
MCC PH 101 05.98 05.98 05.98 05.98
Hypromellose 6 cps 01.25 01.25 01.25 01.25
Sodium Lauryl Sulphate 04.50 04.50 04.50 04.50
Magnesium Stearate 00.68 00.68 00.68 00.68
Total 85.00 85.00 85.00 85.00

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and water to prepare binder solution.
2. Binder solution prepared in step-1 was added to microcrystalline cellulose, lactose monohydrate and croscarmellose sodium were granulated in rapid mixer granulator.
3. Rivaroxaban was dissolved in organic solvent like isopropyl alcohol or dimethyl sulfoxide or acetone in separate vessel.
4. Dissolved Rivaroxaban obtained in step-3 was mixed with granules obtained in step-2.
5. Granules obtained in step-4 are dried in fluidized bed dryer.
6. Dried granules obtained in step-5 were optionally re-granulated using methylene chloride in rapid mixer granulator and dried.
7. Dried granules obtained in step-5 or step-6 were then lubricated with magnesium stearate.
8. Lubricated blend obtained in step-7 was then compressed to form tablets.
9. Tablets obtained in step-5 was optionally coated using Opadry® ready mixture which was dissolved in isopropyl alcohol and dichloromethane.

EXAMPLE-10: Comparative dissolution profile:
Dissolution of 20 mg tablet of example-3 was compared with XARELTO® which were performed in 900 ml of 4.5 pH acetate buffer and 0.4% sodium dodecyl sulfate (SDS) at 75 rpm using paddle (type-II USP). Following results were obtained at specific time intervals.
Initial samples of example-3 (20 mg tablet) was compared with XARLETO® 20 mg tablets for dissolution profile. In addition, these tablets were also subjected to the stability studies as per ICH guideline stored at 25°C/60% RH (relative humidity) and following results were observed.
Table-7
Sample % Drug dissolved at following time points
5 min 10 min 15 min 20 min 30 min 45 min
XARLETO® 20 mg tablet
Initial 55.52 85.00 89.12 92.47 95.72 97.24
After 1 month 53.68 84.58 88.56 91.89 95.43 96.99
After 3 months 53.76 84.10 88.14 91.42 95.08 96.57
After 6 months 53.21 83.88 87.45 90.98 94.34 96.08
Example-3 (20 mg tablet)
Initial 53.32 84.41 88.56 91.71 96.99 99.56
After 1 month 53.54 84.62 88.76 91.85 96.71 99.51
After 3 months 52.80 84.56 88.39 91.98 96.56 99.25
After 6 months 52.24 84.12 88.88 91.36 96.11 99.05

From above data, it may be easily concluded that composition of Rivaroxaban prepared as per the present invention has better and consistent dissolution profile over a period of time. Similar results were also obtained in other examples as well.
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
The above-mentioned examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.