Claims:CLAIMS

We claim

1. A solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof, one or more diluent, one or more binding agent, disintegrant and other pharmaceutically acceptable excipients wherein the composition is free of wetting agent.

2. The pharmaceutical composition as claimed in claim 1 wherein, Rivaroxaban is in the range of 1 to 100 mg.

3. The pharmaceutical composition as claimed in claim 1 wherein, diluent is selected from microcrystalline cellulose, lactose, starch, mannitol.

4. The pharmaceutical composition as claimed in claim 1 wherein, binder is selected from Hypromellose, hydroxypropylcellulose, starch, polyvinylpyrrolidone, polyethylene oxide, gum acacia, gum arabica, gelatine, cellulose esters, cellulose ethers.

5. The pharmaceutical composition as claimed in claim 1 wherein, disintegrant is selected from sodium carboxymethylcellulose, croscarmellose sodium, celluloses, methylcellulose, cross-linked cellulloses, sodium starch glycolate, alginates, gums, agar, guar, locust bean, karaya, pectin, tragacanth gums, corn starch, potato starch, maize starch, modified starches, pregelatinized corn starches.

6. The pharmaceutical composition as claimed in claim 1 wherein one or more pharmaceutically acceptable excipients may be present and is selected from lubricant and film coating agents.

7. The pharmaceutical composition as claimed in preceding claims, wherein, the composition is comprising a) Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof in the range of 1 to 100 mg, Lactose monohydrate in the range of 35 to 80%, microcrystalline cellulose pH 101 in the range of 10 to 40%, Croscarmellose Sodium in the range of 1 to 15 %, Hypromellose 6 cps in the range of 0.5 to 10%.

8. A process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof wherein the composition is free of wetting agent, comprising steps of :
i. Mixing diluent, disintegrant with Rivaroxaban in the rapid mixer granulator,
ii. Adding binder solution to the dry mix of step i) in the rapid mixer granulator,
iii. Drying of the granules is done in Fluidized Bed Dryer till the LOD of the blend comes down to less than 2.5 % w/w,
iv. Sizing and milling of the dried granules,
v. Blending of the dried granules and adding extra granular disintegrant,
vi. Mixing lubricant to blend of step v),
vii. Compressing the lubricated blend of step vi) using punch tooling or optionally filling the blend in the capsule and
viii. Optionally film coating the tablet of step vii).

Dated this 18th January, 2021

, Description:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – PHARMACEUTICAL COMPOSITION OF RIVAROXABAN
2. Applicant(s)
NAME: PRECISE BIO PHARMA PVT. LTD
NATIONALITY: INDIAN
ADDRESS: PRECISE BIO PHARMA PVT. LTD., 209, Jhalawar, Patanwala Industrial Estate, LBS Marg, Ghatkopar (W), Mumbai-400086

3. PREAMBLE TO THE DESCRIPTION

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

PHARMACEUTICAL COMPOSITION OF RIVAROXABAN

FIELD OF THE INVENTION
The present invention is in the field of pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients wherein the composition is free of wetting agent. The present invention is also related to a process of preparing the pharmaceutical composition of Rivaroxaban wherein the composition is free of wetting agent.

BACKGROUND OF THE INVENTION
Rivaroxaban is an orally active factor Xa inhibitor marketed for the treatment or prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.

The IUPAC name of Rivaroxaban is (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl] oxazolidin-5-yl] methyl} thiophene-2-carboxamide and the chemical structure is as below:

Rivaroxaban is marketed as Xarelto® (by Janssen Pharmaceuticals, Inc) in 2.5, 10, 15 and 20 mg strengths immediate release tablets. Xarelto® contains Microcrystalline cellulose, Croscarmellose sodium, Lactose monohydrate, Hypromellose 2910, Sodium lauryl sulphate, Magnesium stearate in the tablet core and Macrogol 3350, Hypromellose 2910, Titanium dioxide (E 171), Iron oxide red (E 172) in film coat. XARELTO is indicated: i) to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
ii) for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.

Rivaroxaban is practically insoluble in water (about 7 mg/L) and has high permeability, thus being a BCS class II compound. According to the CHMP assessment report for Xarelto®, rivaroxaban is slightly soluble in organic solvents (1.0 - 10.0 g/L). Due to the low solubility of rivaroxaban, the use of small particle size is required in order to obtain bioavailable compositions. Small particle size may adversely impact blend flowability, which makes the manufacturing process of the rivaroxaban pharmaceutical composition difficult, especially with regard to reproducibility and content uniformity. Thus, to improve the solubility of this poorly soluble drug molecule, various techniques are disclosed in the below cited art.

IN 256522 discloses solid oral formulation of Rivoroxaban and the process of making in hydrophilzed form, which involves moist granulation of rivaroxaban with wetting agent and hydrophilic binding agent, wherein the wetting agent (0.1%-5%), hydrophilic binding agent (1%-15%).

WO2013022924 A1 discloses a tablet composition having an inert core, a drug layer over compressed core and a sub coat, having a water solubility at 25°C.

IN 201717037252 discloses a process for preparation of an oral formulation comprising Rivaroxaban in non-hydrophyllized form, wherein they have prepared dry mix with non-aqueous granulation by use of fluidized bed dryer.

IN 201641023129 discloses a pharmaceutical oral composition containing Rivaroxaban wherein the process of preparation of the same is provided. The said patent discloses the composition prepared spraying the rivaroxaban solution on sugar pellet which is compressed in to tablet.

WO2017021482 A1 discloses an immediate release tablet comprising rivaroxaban, a non-ionic surfactant and optionally one or more pharmaceutically acceptable excipients obtainable by using a dry process.

US20120231076 discloses a pharmaceutical composition prepared by melting a mixture of rivaroxaban in crystalline form along with suitable hydrophilic matrix former and a disintegrant.

WO2010003641 discloses a formulation preferably a film coated tablet of rivaroxaban and salts along with pharmaceutically accepted excipients and which is a solubiliser, a pseudo-emulsifier forming a suspension which is sprayed on the pellet core.

WO2010017948 A2 discloses a formulation of rivaroxaban and its salts preferably in a crystalline form, a solubiliser having solubility of more than 10 mg/1 at 25 °C, a pseudo emulsifier, a gum and a non-erodible polymer having solubility of 10 mg/1 or less at 25 °C and a pore forming substance of water solubility more than 100 mg/l at 25 °C.

WO2014005934 A1 discloses solid, orally administrable pharmaceutical dosage form containing rivaroxaban, characterized in that it consists of a combination of rapid and controlled release, wherein the controlled-release drug dose is incorporated in a two-chamber osmotic system, and the osmotic delivery system with a drug (I ) rapidly releasing active substance-containing film coating or a drug-containing powder or granule coat (sheath-core tablet) is combined molding blend, wherein the molding blend has a pH value at least about 5; and forming the molding blend into a gummy dosage composition.

To improve the solubility of Rivaroxaban, various techniques incorporating, solubiliser, Wetting Agents, Hydrophilic matrix former, osmotic system, drug layering on tablet core, drug layering of pellet have been disclosed in the prior art.

Wetting agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is the most commonly used in tablet formulation, however it is known to hazardous to environment and carcinogenic in nature as per literature.

Therefore, there still exists a need of simple, stable and cost effective pharmaceutical composition of Rivaroxaban which solves the problems of poor solubility and stability issues. The present inventors have found that even without using a wetting agent or surfactant, or without incorporating any complex method a Rivaroxaban tablet is easily prepared which rapidly releases the drug and shows equivalent dissolution profile as well as bio availability.

The present inventors have developed a pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients wherein the composition is free of wetting agents as described herein.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof, one or more diluent, one or more binding agent, disintegrant and other pharmaceutically acceptable excipients wherein the composition is free of wetting agent.

One more object of the present invention is to provide a process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof along with pharmaceutically acceptable excipients, wherein the composition is free of wetting agent.

One more object of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban, which is simple and cost effective.

One more object of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban which shows high stability even without use of wetting agent.

One more object of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban for the treatment of treatment of deep vein thrombosis and pulmonary embolism.

SUMMARY OF THE INVENTION
Main aspect of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof, one or more diluent, one or more binding agent, disintegrant and other pharmaceutically acceptable excipients wherein the composition is free of wetting agent.

Another aspect of the present invention is to provide a process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients, wherein the composition is free of wetting agent.

DESCRIPTION OF THE INVENTION
The present invention is about a solid oral pharmaceutical composition comprising Rivaroxaban without wetting agent.

The excipients as mentioned in the specification should be taken as merely exemplary, and not limiting, of the types of excipients that can be included in composition of the present invention. One or more of these excipients can be selected and used by the person skilled in the art 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.

The term “pharmaceutically acceptable excipient” as used herein refers to a component of a pharmaceutical composition or formulation which has one or more functions and is suitable to be administered to any animal including mammals and humans. Some of the functions that the excipient may perform are: diluent, binder, disintegrant, glidant, lubricant, coating, colorant, flavouring agent, sweetener, and the like.

The main embodiment the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof, one or more diluent, one or more binding agent, disintegrant and other pharmaceutically acceptable excipients wherein the composition is free of wetting agent.

The inventors have found that even without using a wetting agent or surfactant, a solid oral tablet of Rivaroxaban can be prepared which rapidly releases the drug and shows high stability.

The term "Rivaroxaban" refers to rivaroxaban, pharmaceutically acceptable salt, hydrates, esters, polymorphs, derivatives or solvates of thereof. Rivaroxaban can be in crystalline and amorphous form, preferably it is in crystalline form. In present invention, Rivaroxaban can be present in the pharmaceutical composition preferably in the range of 1 to 100 mg, more preferably in the range of 1.5 to 50 mg, most preferably in the range of 2 to 25 mg.

The term “Pharmaceutically acceptable salt” refers to a salt which is acceptable for administration to a patient, such as mammal (eg. Salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutical acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

Another one embodiment of the present invention is to provide a pharmaceutical composition of Rivaroxaban that can be administered orally in the form of tablet, capsule, and granules, liquid dosage form like solution, syrup and suspension.

Another preferred embodiment of the present invention is to provide an oral solid pharmaceutical composition of Rivaroxaban, preferably in the form of tablet.

A “diluent” is an inert pharmaceutically acceptable excipient that provides bulk to the pharmaceutical composition, facilitates the manufacturing process of the dosage form as well as improves the uniformity of content of the active ingredient in the composition. Suitable examples of diluents are selected from microcrystalline cellulose, lactose (including but not limited to lactose USP, anhydrous lactose USP and spray-dried lactose USP, lactose monohydrate), starch (including but not limited to maize starch, hydrolyzed starch, mannitol and the like. The diluent selected for the present invention is in range from 15mg to 150mg, preferably the range is from 30mg to 120mg, most preferably the range is 40mg to 90mg.

A “binder” is a pharmaceutically acceptable excipient that holds the components of a solid pharmaceutical composition together, such as granules or tablets. Suitable binders are selected from starch (including but not limited to maize starch and pregelatinized starch), gum acacia, gum arabica, gelatine, cellulose and derivatives thereof (including but not limited to cellulose esters, cellulose ethers and hydroxypropylcellulose, Hypromellose such as Hypromellose 3 CPS, Hypromellose 5 CPS, Hypromellose 6 CPS , Hypromellose 15 CPS, Hypromellose 50 CPS) polyvinylpyrrolidone, polyethylene oxide and the like. The binder selected for the present invention is in range from 0.1mg to 10mg, preferably the range is from 0.5mg to 5mg, most preferably the range is 0.8mg to 3mg.

A “disintegrant” is a pharmaceutically acceptable excipient that included in solid pharmaceutical forms, such as tablets or granules, facilitate its break up or disintegration in an aqueous environment. Suitable disintegrants are starches (including but not limited to sodium starch glycolate, corn starch, potato starch, maize starch, modified starches and pregelatinized corn starches, celluloses (including but not limited to purified cellulose, methylcellulose and carmellose sodium (also known as sodium carboxymethylcellulose), cross-linked cellulloses, such as cross-linked carmellose (croscarmellose) and its salts, including sodium croscarmellose), alginates, gums (such as agar, guar, locust bean, karaya, pectin, and tragacanth gums) and the like. The disintegrant, selected for the present invention is in range from 0.5mg to 35mg, preferably the range is from 1mg to 25mg, most preferably the range is 2mg to 10mg.

Another embodiment of the present invention is to provide the solid pharmaceutical composition of Rivaroxaban wherein one or more pharmaceutically acceptable excipients may be present and is selected from lubricant and film coating agents.

A “lubricant” is pharmaceutical excipient that prevents the ingredients from sticking to the tablet dies and punches. Suitable lubricants are sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, magnesium lauryl sulfate, talc, and the like.

A “film coating” is a thin layer (of about 0.02-0.5 mm) that surrounds the tablet. The coating may perform different functions: aesthetic, ease the swallowing, modify the release of the drug (e.g. enteric coating, sustained release, etc). Suitable coatings include commercial coating agents based on hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol) (PVA), Isopropyl alcohol and Dichloromethane, povidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and polyvinyl alcohol.

Unless otherwise indicated, the percentage used in the present invention refers to the weight percentage.

One of the embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients, wherein diluent is selected from microcrystalline cellulose, lactose monohydrate, starch, one or more binding agent is selected from Hypromellose, starch, hydroxypropylcellulose, disintegrant is selected from croscarmellose, sodium starch glycolate, corn starch, lubricant is selected from magnesium stearate, calcium stearate, magnesium lauryl sulfate, talc and optionally comprising film coating based on hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol) (PVA) or Isopropyl alcohol and Dichloromethane and the composition is free of wetting agent.

One of the preferred embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising a) Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof in the range of 1 to 100 mg, Lactose monohydrate in the range of 35 to 80%, microcrystalline cellulose pH 101 in the range of 10 to 40%, Croscarmellose Sodium in the range of 1 to 15 %, Hypromellose 6 cps in the range of 0.5 to 10% wherein the composition is free of wetting agent.

Another embodiment of the present invention provides a process of preparing the solid pharmaceutical composition comprising Rivaroxaban along with pharmaceutically acceptable excipients wherein the composition is free of wetting agent.

There are various methods through which oral solid dosage forms of Rivaroxaban can be prepared like, direct compression, dry granulation, drug layering of pellets and wet granulation. However there are various disadvantages associated with methods known in the prior art therefore granulation is one of the preferred method of tablet preparation wherein wet granulation is the most preferred method for tablet preparation of poorly soluble drug.

Direct compression (or direct compaction) is used to define the process by which tablets are compressed directly from powdered active drug substance and suitable excipients into a firm compact without employing the process of granulation. There are certain demerits associated with direct compression process as given below:
1. High-dose drugs may present problems with direct compression if it is not easily compressible by itself.
2. The choice of excipients used in the manufacture of tablets by direct compression technology is highly restricted since most materials do not have inherent binding properties.
3. Low-dose drugs may not be uniformly blended.
4. Direct compression excipients are often more expensive than other tablet excipients used in wet granulation or slugging.

Granulation, the process of particle enlargement by agglomeration technique, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. Granulation process transforms fine powders into free-flowing, dust free granules that are easy to compress. Granulation process can be divided into two types: wet granulation that utilize a liquid in the process and dry granulation that requires no liquid.

In dry granulation process the powder mixture is compressed without the use of heat and solvent. The dry granulation process is used to form granules without a liquid solution because the product granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. A swaying granulator or a roll compactor can be used for the dry granulation. Dry granulation can be conducted under two processes; either a large tablet (slug) is produced in a heavy duty tableting press or the powder is squeezed between two counter-rotating rollers to produce a continuous sheet or ribbon of material. When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying density. Some disadvantages associated are:
1. The main disadvantage of dry granulation is that since it does not form granules, it may not have better flow properties.
2. The dry granulation method leads to low flowability, compressibility, and cohesiveness of the powder, causing the powder to not easily flowing and compressed.
3. The process produces a lot of dust which can lead to cross-contamination.
4. It requires a special heavy-duty apparatus for granulation.
5. Dry granulation tablets are softer than wet granulation tablets which make them difficult to tablet coating or film coating.
6. It extensively damages the sieving screening and other tools which are used in the process.

Wet granulation is a widely used technique that produces granules via wet massing of the active pharma ingredient (API) and granulation liquid with or without a binder. Wet granulation is carried out in two ways – one method is to moisten the powder or powder mixture and pass it through a screen of the mesh size needed to produce granules in the desired size using dry heat. The second type used a fluid bed processor in which particles are placed and vigorously dispersed and suspended while liquid excipient is sprayed onto the particles and dried. Depending on molecule sensitivity, aqueous (water) or non-aqueous (organic) solvents are used for the granulation process. Aqueous processes are considered safer and cost-effective.

Aqueous granulation process uses water as a solvent. It includes sifting, mixing and granulation in a Rapid Mixer Grinder with aqueous binder solution, drying in a Fluid Bed Dryer or Processor, milling using a Multi-mill or Co-mill and final mixing in a blender suitable for the task.

Non-aqueous granulation process uses organic solvents like Isopropyl alcohol, Dichloromethane, Chloroform as a binder solution as some molecules are sensitive to temperature and moisture, and not suited for dry mixing. Safety is critical during this process and any equipment used must be flameproof and situated in a dedicated area, and all safety measures adhered to.

The present invention provides a process of wet granulation as it has the advantages over other methods, as given below:
1. Wet granulation modifies the properties of formulation ingredients to overcome their tableting deficiencies. Granules formed are relatively more spherical than the powders and have better flow properties.
2. Improved compressibility of powders resulting from wet granulation process allows the use of low pressure during compression. This reduces machine wear and thus improves the life of the machine.
3. The process makes use of conventional excipients and therefore is not dependent on the inclusion of special grades of excipients.
4. It ensures better content uniformity, especially for soluble low-dose drugs.
5. The process may improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of the granules. The presence of water in the form of moisture can help to improve the dissolution rate of hydrophobic drugs.
6. Wet granulation prevents segregation of components of a homogenous powder mix during processing, transferring, handling and/or storage, leading to reduced intra- and inter-batch variability.
7. Wet granulation reduces the level of dust present during manufacturing process thereby reducing the incidence of cross-contamination and risk to workers.
8. Wet granulation reduces the amount of air entrapment thereby increasing powder compressibility.
9. It maintains the same density of all granules since good material uniformity is maintained due to particle segregation prevention.
10. Tablets made from a wet granulation process are ideal for tablet coating.

One of the embodiment of the present invention provides a process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof wherein the composition is free of wetting agent, comprising steps of:
i. Mixing diluent, disintegrant with Rivaroxaban in the rapid mixer granulator,
ii. Adding binder solution to the dry mix of step i) in the rapid mixer granulator,
iii. Drying of the granules is done in Fluidized Bed Dryer till the LOD of the blend comes down to less than 2.5 % w/w,
iv. Sizing and milling of the dried granules,
v. Blending of the dried granules and adding extra granular disintegrant,
vi. Mixing lubricant to blend of step v),
vii. Compressing the lubricated blend of step vi) using punch tooling or optionally filling the blend in the capsule and
viii. Optionally film coating the tablet of step vii).

Another embodiment of the present invention provides a process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban or a pharmaceutically acceptable salt or solvate thereof wherein the composition is free of wetting agent by top spray granulation process.

Top spray granulation is most commonly used to improve the flow characteristics of powder. Other advantages include increasing particle size, density, and surface area as well as reducing dust emissions.

Another embodiment of the present invention provides a process of preparing a solid oral pharmaceutical composition comprising Rivaroxaban in a fluid bed equipment by spraying appropriate amounts of aqueous binder solution of Hypromellose on the dry mix bled to obtain dried granules which is lubricated to provide final bend for tablet preparation or filling in capsule dosage form.

One of the preferred embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising Rivaroxaban, microcrystalline cellulose, lactose monohydrate, Hypromellose, croscarmellose sodium, magnesium stearate and optionally comprising film coating based on Isopropyl alcohol and Dichloromethane wherein the composition is free of wetting agent.

Another preferred embodiment of the present invention is to provide a process of preparing the solid oral pharmaceutical composition comprising Rivaroxaban wherein the composition is free of wetting agent, comprising steps of:
i. Mixing of Rivaroxaban along with Lactose Monohydrate, Microcrystalline cellulose pH 101, Croscarmellose Sodium in the rapid mixer granulator for about 15 minutes,
ii. Adding binder solution of HPMC 6 CPS to the dry mix of step i) in the rapid mixer granulator at slow speed,
iii. Drying of the granules is done in Fluidized Bed Dryer till the LOD of the blend comes down to less than 2.5 % w/w,
iv. Sizing the dried granules, in a vibratory sifter for using a 30 mesh screen and milling through a multimill with a 1.0 mm screen,
v. Blending of the dried granules in a bin blender at slow speed by adding extra granular disintegrant, Croscarmellose Sodium after sieving through 40 mesh screen,
vi. Mixing Magnesium stearate as lubricant to blend of step v) and mixing in bin blender at slow speed,
vii. Compressing the lubricated blend of step vi) using punch tooling and
viii. Optionally film coating the tablet of step vii) by applying the coating composition comprising coating agents in solution/suspension based on Isopropyl alcohol and Dichloromethane by spray coating in a conventional coating pan.

Another preferred embodiment of the present invention provides a solid oral pharmaceutical composition of Rivaroxaban wherein the lubricated blend may be filled into capsule by the conventional process to provide capsule dosage form of Rivaroxaban for oral administration.

Another preferred embodiment of the present invention provides a solid oral pharmaceutical composition of Rivaroxaban for the treatment of deep vein thrombosis and pulmonary embolism.

Another preferred embodiment of the present invention provides a solid oral pharmaceutical composition of Rivaroxaban to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.

One of the preferred embodiment of the present invention is to provide a solid oral rapid releasing tablet comprising Rivaroxaban, microcrystalline cellulose, lactose monohydrate, Hypromellose, croscarmellose sodium, magnesium stearate and optionally comprising film coating based on Isopropyl alcohol and Dichloromethane wherein the composition is free of wetting agent.

The inventors of present invention have surprisingly found that using simple wet granulation process and easily available excipients which are cost effective, an oral solid dosage composition of Rivaroxaban can be prepared which shows bioequivalence and comparable in-vitro dissolution profile of the drug release as compared to the standard drug. Therefore Rivaroxaban tablets for oral administration can be prepared without using any wetting agent or solubiliser or surfactant or any other pore forming agents or utization of complex technologies like osmotic tablet, drug layering of tablets core, drug layering on pellets as mentioned in the prior art.
The following examples are illustrated to describe the scope of the invention.
Example 1: Preparation of solid dosage forms of Rivaroxaban
1.1 Composition of Various Strengths of Rivaroxaban Tablet
Ingredients (Qty./tab (mg)) 20 mg 15 mg 10 mg 2.5 mg
Rivaroxaban 20 15 10 2.5
Lactose monohydrate 46.52 51.52 56.52 64.02
Microcrystalline cellulose pH 101 25 25 25 25
Croscarmellose Sodium 3.5 3.5 3.5 3.5
Dry mix weight 95.02 95.02 95.02 95.02
Hypromellose 6 cps 0.8 0.8 0.8 0.8
Purified Water 21.22 21.22 21.22 21.22
Granular Weigh. 95.82 95.82 95.82 95.82
Croscarmellose Sodium 3.5 3.5 3.5 3.5
Magnesium Stearate 0.68 0.68 0.68 0.68
Total weight of Uncoated tablet 100 100 100 100
Instacoat Universal 2.5 NA NA NA
SheffCoat White NA 2.5 NA NA
SheffCoat Pink NA NA 2.5 NA
Instacoat Universal NA NA NA 2.5
Dichloromethane 33.25 33.25 33.25 33.25
Isopropyl alcohol 14.25 14.25 14.25 14.25
Total weight of Coated tablet (Considering 2% w/w gain) 102 102 102 102

1. All the materials was weighed accurately in separate containers.
2. Weighed amount of Rivaroxaban, Lactose Monohydrate, Croscarmellose Sodium and MCC pH 101 were passed separately through sieve #40.
3. All the dry ingredients were mixed in Rapid mixer granulator with impeller 110 RPM Speed for about 15 min.
4. Binder solution Preparation: In separate container, weighed amount of HPMC 6 cps was dissolved in purified water.
5. Binding: Binder solution was added to step 3 in RMG with the help of peristaltic pump at slow speed of Impeller.
6. Drying of granulated wet mass in Fluid bed dryer at 55° C ±5° C till the LOD of the blend comes down to less than 2.5 % w/w.
7. Dried granules were sifted through # 30 sieves in shifter and collect 30 # sifted granules in a S.S bin.
8. Oversized granules were passed through 1 mm Screen in multi mill and shifted through # 30 sieves in shifter and sifted granules were collected in a same S.S bin.
9. Previously weighed Croscarmellose Sodium was passed through sieve # 40 and mixed with above Blend for 15 minutes in Conta Blender at 15 RPM.
10. Previously weighed Magnesium stearate was passed through sieve # 40 and transferred it to Conta blender & run for another 5 mins at 15 RPM.
11. The blend was compressed with medium compression force with 6.0 mm Standard concave round shape punch.
12. Coating was performed with accurately weighed amount of 5% w/w Ready mix coating material in separate containers & dispersed in mixture of 28.5% w/w IPA & 66.5% w/w MDC. The coating was performed till the weight gain reaches up to approx. 1.75 % to 2.25% of the core tablet weight.

1.2 Various strengths of Rivaroxaban were prepared by the process as given below:

1.3 Physical Parameters of Rivaroxaban Tablet
1.3.1 Uncoated Tablet
Average Weight 100 mg ± 7.5%
Diameter 6.0 mm ± 0.2 mm
Hardness NLT 2.5 Kg/cm2
Disintegration Time NLT 15 Min

1.3.2 Coated Tablet
Average Weight 102 mg ± 7.5%
Diameter 6.1 mm ± 0.2 mm
Disintegration Time NLT 30 Min

1.4 Comparative Dissolution profile of various Strengths of Rivaroxaban Tablet
1.4.1 Comparative Dissolution profile of 2.5 mg Tablet in pH 4.5 Buffer media with Xarleto
Rivaroxaban - 2.5 mg tablet
Official Dissolution Media details Time Point in Minutes Present
Invention
(Example 1) Xarleto
10 85.5 84.22
Medium 900 ml, Buffer pH 4.5 15 88.98 87.29
Speed 75 RPM 20 94.29 89.24
Apparatus Type-II, Paddle 30 95.38 91.39
45 95.2 93.48

1.4.2 Comparative Dissolution profile of 10 mg Tablet in pH 4.5 Buffer media with Xarleto
Rivaroxaban - 10 mg tablet
Official Dissolution Media details Time Point in Minutes Present Invention
(Example 1) Xarleto
10 94.41 85.9
Medium 900 ml, Buffer pH 4.5 & 0.2% SLS 15 96.8 94.79
Speed 75 RPM 20 97.05 97.12
Apparatus Type-II, Paddle 30 98.25 97.66
45 98.88 97.79

1.4.3 Comparative Dissolution profile of 15 mg Tablet in pH 4.5 & 0.4% SLS Buffer media with Xarleto
Rivaroxaban - 15 mg tablet
Official Dissolution Media details Time Point in Minutes Present Invention
(Example 1) Xarleto
10 82.46 74.98
Medium 900 ml, Buffer pH 4.5 & 0.4% SLS 15 92.8 94.9
Speed 75 RPM 20 95.02 97.2
Apparatus Type-II, Paddle 30 95.23 97.53
45 95.86 97.35
1.4.4 Comparative Dissolution profile of 20 mg Tablet in pH 4.5 & 0.4% SLS Buffer media with Xarleto
Rivaroxaban - 20 mg tablet
Official Dissolution Media details Time Point in Minutes Present Invention
(Example 1) Xarleto
10 91.86 88.56
Medium 900 ml, Buffer pH 4.5 & 0.4% SLS 15 100.72 103.01
Speed 75 RPM 20 103.23 104.93
Apparatus Type-II, Paddle 30 102.74 105.37
45 104.05 105.84

1.5 Stability study of various strengths of Rivaroxaban Tablet (Example 1)
1.5.1 Stability study of 2.5 mg Rivaroxaban Tablet
Storage Condition 40°C ± 2°C RH 75% ± 5% RH
Test Specification Initial 1 month 3 month 6 month
Description Yellow color round shaped film coated tablet
with both side plain Yellow color round shaped film coated tablet
with both side plain Yellow color round shaped film coated tablet with both side plain Yellow color round shaped film coated tablet
with both side plain Yellow color round shaped film coated tablet
with both side plain
Disintegration NMT 30 Minute 1 Min 40 Sec 01Min 25sec 01Min 50sec 01 min 55 sec
Average weight 105 mg ± 5% 103.31 mg 103.63% 103.62mg 102.93 mg
Dissolution NLT 75 % (Q) of the stated amount Min.:85.41 %,Max.:99.52 %,Avg.:92.87 % Min.: 80.67%, Max.: 87.22%, Avg.: 83.15% Min.: 81.25%,Max.: 85.48%, Avg.: 84.07% Min.: 81.14 %,Max.: 84.07 %, Avg.: 82.67 %
Related substances Any other impurity : NMT 0.5 %
Total impurity :NMT 1.0 % 0.08%
0.08% 0.08%
0.08% 0.09%
0.22% 0.09%
0.22%
Assay 90.0 % - 110.0 % of the stated amount 104.64% 103.74% 107.64% 103.20%

1.5.2 Stability study of 10 mg Rivaroxaban Tablet (Example 1)
Storage Condition 40°C ± 2°C RH 75% ± 5% RH
Test Specification Initial 1 month 3 month 6 month
Description Pink color round shaped each film coated tablets having both side plain. Pink color round shaped each film coated tablets having both side plain. Pink color round shaped each film coated tablets having both side plain. Pink color round shaped each film coated tablets having both side plain. Pink color round shaped each film coated tablets having both side plain.
Disintegration NMT 30 Minute 01Min 36 Sec 01 min 30 sec 01min 52sec 50 Sec
Average weight 105 mg ± 5% 103.78mg 102.97 mg 102.72mg 103.08 mg
Related substances Any other impurity : NMT 0.5 %
Total impurity :NMT 1.0 % 0.09%
0.09% 0.08%
0.15% 0.13%
0.24% 0.26%
0.47%
Dissolution NLT 75 % (Q) of the stated amount Min.: 85.15%, Max.: 107.06%, Ave.: 94.05% Min.:87.74 %, Max.:111.96 %, Ave.:98.54 % Min.: 89.15%, Max.: 109.83%, Ave.: 97.82% Min.:95.03%, Max.:98.04%, Ave.:96.12%
Assay 90.0 % - 110.0 % of the stated amount 100.30% 104.10% 106.13% 101.65%

1.5.3 Stability study of 15 mg Rivaroxaban Tablet (Example 1)
Storage Condition 40°C ± 2°C RH 75% ± 5% RH
Test Specification Initial 1 month 3 month 6 month
Description White colored film coated round shaped tablet having both side plain White colored film coated round shaped tablet having both side plain White colored film coated round shaped tablet having both side plain White colored film coated round shaped tablet having both side plain White colored film coated round shaped tablet
having both side plain
Disintegration NMT 30 Minute 01Min 40sec 01Min 30sec 1min 40sec 01 Min 05 Sec
Average weight 105 mg ± 5% 102.99mg 102.51mg 103.11 mg 103.64 mg
Related substances Any other impurity : NMT 0.5 %
Total impurity :NMT 1.0 % Not Detected
Not Detected Not Detected
Not Detected 0.13 %
0.23 % 0.25%
0.39%
Dissolution NLT 75 % (Q) of the stated amount Min.: 81.03%, Max.: 87.33%, Ave.: 83.31% Min.:83.46%,Max.:89.71%,Ave.: 86.27% Min.:81.64 %, Max.:87.50 %, Ave.:83.87 % Min.:86.19%, Max.:87.07%, Ave.:86.63%
Assay 90.0 % - 110.0 % of the stated amount 102.84% 102.49% 99.10% 100.60%

1.5.4 Stability study of 20 mg Rivaroxaban Tablet (Example 1)
Storage Condition 40°C ± 2°C RH 75% ± 5% RH
Test Specification Initial 1 month 3 month 6 month
Description Brown color round shaped film coated tablet with both side plain Brown color round shaped film coated tablet with both side plain Brown color round shaped film coated tablet with both side plain Brown color round shaped film coated tablet with both side plain Brown color round shaped film coated tablet with both side plain
Disintegration NMT 30 Minute 01Min;30sec 01 min 25 sec 01min 58sec 2 Minute
Average weight 105 mg ± 5% 102.45 mg 102.30 mg 101.61mg 102.19 mg
Dissolution NLT 75 % (Q) of the stated amount Min.: 85.09%,Max.: 103.66%, Avg.: 89.62% Min.: 90.89 %, Max.: 95.48 %, Ave.: 93.17 % Min.: 84.13%, Max.: 88.68%, Avg.: 86.09% Min.: 85.10%,Max.: 85.58%,Avg.:85.24%
Related substances Any other impurity : NMT 0.5 %
Total impurity :NMT 1.0 % Not Detected
Not Detected Not Detected
Not Detected 0.09%
0.09% 0.09%
0.16%
Assay 90.0 % - 110.0 % of the stated amount 101.21% 103.18% 100.47% 103.56%