WO2023067620A1

WO2023067620A1 - Orally disintegrating pharmaceutical compositions of rivaroxaban

Info

Publication number: WO2023067620A1
Application number: PCT/IN2022/050920
Authority: WO
Inventors: Balvir SINGH; Ramesh SHINGALA; Milap PATEL; Anil KATHIRIA
Original assignee: Unison Pharmaceuticals Pvt. Ltd.
Priority date: 2021-10-18
Filing date: 2022-10-15
Publication date: 2023-04-27

Abstract

The present invention relates to an orally disintegrating pharmaceutical compositions of Rivaroxaban or a pharmaceutically acceptable salt thereof. The present invention specifically relates to a stable orally disintegrating pharmaceutical compositions comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the ratio of Rivaroxaban to the total weight of the composition is less than about 1:12 and wherein Rivaroxaban is present in an amount of more than about 8 % w/w of the total weight of the composition. Moreover, the present invention relates to a method of prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, prevention of stroke and systemic embolism in adult patients, treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults and treatment and prevention of venous thromboembolism (VTE) in children and adolescents by administering orally disintegrating compositions of Rivaroxaban.

Description

ORALLY DISINTEGRATING PHARMACEUTICAL COMPOSITIONS OF RIVAROXABAN

PRIORITY APPLICATION

This application claims the benefit of priority of our Indian patent application 202121047158 filed on October 18, 2021 which is incorporated herein by reference and disclosures of which is incorporated in the instant application.

FIELD OF INVENTION

The present invention relates to an orally disintegrating pharmaceutical dosage forms of Rivaroxaban or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, premix or prodrug thereof. The present invention specifically relates to a stable orally disintegrating pharmaceutical composition comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the ratio of Rivaroxaban to the total weight of the composition is less than about 1:12 and wherein Rivaroxaban is present in an amount of more than about 8 % w/w of the total weight of the composition. Moreover, the present invention relates to a method of prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, prevention of stroke and systemic embolism in adult patients, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults and treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents by administering an effective amount of orally disintegrating dosage forms of Rivaroxaban.

BACKGROUND OF THE INVENTION

Rivaroxaban is a competitive, selective, and a direct inhibitor of serine protease coagulation factor Xa (FXa). The activated FXa plays a central role in the cascade of blood coagulation. It is activated by both the intrinsic and extrinsic coagulation pathways. FXa directly converts prothrombin to thrombin through the prothrombinase complex, and ultimately, this reaction leads to fibrin clot formation and activation of platelets by thrombin.

Rivaroxaban is a an oxazolidinone derivative compound and its chemical name is 5 -Chloro-N-( { (5S )-2-oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] - 1 ,3 -oxzolidin-5- yl}methyl)-2-thiophene-carboxamide. It is represented by the following structure:

Fig. 1 : Chemical structure of Rivaroxaban

It is a white to yellowish powder with a molecular weight of 435.89 g/mol. Rivaroxaban is only slightly soluble in organic solvents (e.g. acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media with pH 1 - 9 (pH-independent 5 - 7 mg/L are soluble at 25 °C). The partition coefficient in octanol / water (log Po/w) is 1.5. Rivaroxaban crystallizes in three polymorphs. Polymorph I is the thermodynamically stable one and has been used in all tablet formulations and is also present in the commercial product.

Rivaroxaban was developed by Janssen Pharms and is commercially marketed in the US, Europe and other countries under the brand name of Xarelto®. Xarelto® is currently approved in form of 2.5 mg, 10 mg, 15 mg and 20 mg immediate release tablets and 1 mg/mL granules for oral suspension.

Xarelto® 2.5 mg co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers.

Xarelto® 2.5 mg, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events. Xarelto® 10 mg is indicated for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery and for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Xarelto® 15 mg and 20 mg are indicated for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age > 75 years, diabetes mellitus, prior stroke or transient ischaemic attack and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Xarelto® has also been approved for treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in paediatric population, wherein the 1 mg/ml granules for suspension is approved for use in term neonates, infants and toddlers, children, and adolescents aged less than 18 years and weighing less than 30 kg; the 15 mg tablet is approved for use in children and adolescents aged less than 18 years and weighing from 30 kg to 50 kg and the 20 mg tablet is approved for use in children and adolescents aged less than 18 years and weighing more than 50 kg, after at least 5 days of initial parenteral anticoagulation treatment.

Rivaroxaban was first disclosed in W02001/47919 (Bayer) wherein it describes Rivaroxaban and its pharmaceutically acceptable salts, hydrates, hydrates of the salts and prodrugs, along with its process of preparation, medicaments comprising Rivaroxaban and one or more pharmacologically acceptable auxiliaries or excipients and the use of Rivaroxaban for preparing medicaments or pharmaceutical compositions for the treatment of thromboembolic disorders, disorders which are influenced positively by inhibition of factor Xa.

W02003/000256 (Bayer) discloses combinations comprising Rivaroxaban and at least one further pharmaceutical active ingredient including acetyl salicylic acid, clopidogrel and ticlopidone and the use of such combinations in the manufacture of a medicament for the prophylaxis and/or treatment of thromboembolic disorders. W02005/060940 (Bayer) discloses method of producing solid, orally administrable pharmaceutical composition comprising Rivaroxaban in hydrophilized form, characterized in that firstly granules comprising Rivaroxaban in hydrophilized form are produced by fluidized bed wet granulation and then the granules are converted to the pharmaceutical composition, optionally with the addition of pharmaceutically suitable additives.

W02006/079474 (Bayer) discloses the use of a rapid-release tablet of the compound Rivaroxaban for the manufacture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days.

W02007/039132 (Bayer) discloses a Rivaroxaban in form of modification II having specific NIR peaks, its amorphous form and its process of preparation, pharmaceutical compositions and its use in the treatment of thromboembolic disorders.

W02008/052671 (Bayer) discloses a triple combination comprising Rivaroxaban, acetyl salicylic acid and clopidogrel and the use of the combination with synergistic antithrombotic effect for producing a medicament for the prophylaxis and/or treatment of thromboembolic disorders.

CN104644577 (Tianjin Hankang) merely discloses orally disintegrating tablet of Rivaroxaban and its composition comprising specific pharmaceutical excipients in specific weight portions. It however does not provide any results of disintegration, in-vitro dissolution or in-vivo bioavailability or its comparison with the marketed tablets.

CN110946835 (Hainan Simcere) merely discloses solid dispersible tablets comprising Rivaroxaban solid dispersion and at least one pharmaceutically acceptable excipient. It however does not provide any comparative results of disintegration, in-vitro dissolution or in-vivo bioavailability with the marketed tablets.

Xarelto® is a widely prescribed medicine across all geographies. A significant proportion of patients with thromboembolic disorders have difficulty in swallowing (dysphagia) in the acute phase and many have ongoing problems. This can potentially lead to a reduction in patient compliance when such patients are administered oral formulations that must be swallowed intact.

Other patients may also suffer from dysphagia as it is a common problem among all age groups and has been observed in about 35 % of the general population. It is more common and prevalent in pediatric and geriatric patients and is seen in up to 60 % of the elderly institutionalized patients.

Patients who have difficulty in swallowing the tablet may be motivated to break or crush the tablet for ease of administration, which may result into medication error and may have dangerous consequences in a serious disease like thromboembolic disorder.

Hence, there is an unmet need to increase patient compliance and provide exact required dose of the drug in such disease conditions.

Orally disintegrating tablets which can be administered without the need of swallowing the tablets intact may offer significant benefit to patients suffering from thromboembolic disorders specifically to patients who have difficulty in swallowing the intact tablet including pediatric and geriatric patients.

Further, commercially marketed Xarelto® tablets are manufactured by complex process involving prior hydrophilization of Rivaroxaban followed by granulation by fluidized bed granulation.

It is observed that commercially available Rivaroxaban formulations seems to have reduced patient compliance for patients suffering from thromboembolic disorders especially for pediatric and geriatric patients due to difficulty in swallowing and which may lead to reduced treatment adherence. Further, they are also produced by industrially complex process.

The publicly available literature and above prior arts do not suggest any solution to the problems associated with currently marketed products. Hence, it remains an unmet need and a challenge for industry to develop an orally disintegrating tablet of Rivaroxaban which is having a reduced tablet weight so as to offer ease of administration, and is manufactured by industrially feasible and simple process, and which improves patient compliance, increases treatment adherence and thus enhances the overall treatment efficiency. The inventors of the present invention have discovered a novel approach for solving above problems by developing an easy to administer, stable orally disintegrating pharmaceutical compositions of Rivaroxaban in which the ratio of the weight of the active pharmaceutical ingredient to the total weight of the composition is lower, the % drug content is higher and is manufactured by industrially feasible and simple process.

Further, the composition of the present invention, remain stable for a long period of time without compromising the therapeutic efficacy and increases patient compliance and treatment adherence and is bioequivalent with currently marketed Xarelto® tablets.

SUMMARY OF THE INVENTION

The present invention relates to orally disintegrating pharmaceutical dosage forms of FXa inhibitors for prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, for prevention of stroke and systemic embolism in adult patients, for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults and treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents.

More specifically, the present invention relates to orally disintegrating compositions of Rivaroxaban or a pharmaceutically acceptable salt or a solvate or a hydrate or any crystalline or amorphous polymorph or a prodrug or a premix thereof, and one or more pharmaceutically acceptable excipients for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, for prevention of stroke and systemic embolism in adult patients, for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults and treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents or a pharmaceutically acceptable salt or prodrug form thereof. The present invention also relates to orally disintegrating compositions comprising about 1 mg to about 100 mg of Rivaroxaban or a pharmaceutically acceptable salt or a solvate or a hydrate or any crystalline or amorphous polymorph or a prodrug or a premix thereof, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients.

The present invention further relates to a stable orally disintegrating compositions comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the composition remains stable at 40 + 2 °C and 75 + 5 % RH conditions for a time period of at least 6 months.

The present invention also relates to a stable orally disintegrating composition comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the composition is bioequivalent to commercially available Xarelto® tablets.

Further, the present invention relates to orally disintegrating compositions comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients, wherein the ratio of the active pharmaceutical ingredient to the total composition weight is at least less than about 1:12.

The present invention relates to orally disintegrating compositions comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients, wherein the % drug content is higher than about 8.5 % w/w.

Further, the present invention relates to orally disintegrating tablets comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients, wherein the said composition has hardness from about 10 N to about 200 N.

Moreover, the present invention relates to orally disintegrating tablets comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the said composition disintegrates in less than about 3 minutes. Moreover, the present invention relates to orally disintegrating tablets comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein at least 85 % Rivaroxaban dissolves in not more than 20 minutes.

The present invention also relates to an industrially feasible and simple non- hydrophilized process of preparing an orally disintegrating tablet comprising Rivaroxaban or a pharmaceutically acceptable salt or a solvate or a hydrate or any crystalline or amorphous polymorph or a prodrug or a premix thereof, with at least one disintegrating excipient and with one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

The present invention relates to an orally disintegrating pharmaceutical dosage forms of FXa inhibitors for the treatment of thromboembolic disorders.

The present invention specifically relates to stable and bioequivalent orally disintegrating compositions comprising about 1 mg to about 100 mg of Rivaroxaban or a pharmaceutically acceptable salt or a solvate or a hydrate or any crystalline or amorphous polymorph or a prodrug or a premix thereof, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients for prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery, for prevention of stroke and systemic embolism in adult patients, for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults and treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents.

As used herein, the term "Rivaroxaban" refers to Rivaroxaban which may present in base form or in the form of the pharmaceutically acceptable salts or solvate or hydrate or any crystalline or amorphous polymorph or anhydrous form or prodrug or premix or metabolite or analog or isomer or like thereof.

As used herein, the term “at least one disintegrating excipient” or “disintegrant” or “disintegrating agent” refers to any inactive excipient which cause a rapid break-up of solid dosage forms when they come into contact with moisture. The disintegrating excipient may include a portion which acts as disintegrating agent and another portion may contain one or more of additional excipient selected from the group consisting of diluent, binder, surfactant, lubricant, glidant or a like thereof. In context of the composition of present invention disintegrating excipient is considered to include whole mixture of disintegrating agent and other excipient mixed or co-processed with it.

As used herein, the term "pharmaceutically acceptable" refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the term "pharmaceutically acceptable salts" refer to derivatives of the Rivaroxaban wherein the Rivaroxaban is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to mineral or organic salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids and the like thereof. Further, the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts. The conventional non-toxic salts include inorganic or organic acids, for example those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like thereof; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like thereof.

As used herein, the term “premix” refers to physical mixture or dispersions or complex of Rivaroxaban with a premixing agent which include, but are not limited to lactose, mannitol, xylitol, erythritol, microcrystalline cellulose, DCP, silicon dioxide, talc, starch, CCS, SSG, crospovidone, polyvinyl pyrrolidone, PVA, HPC, HPMC, methyl cellulose, carboxymethyl cellulose, SCMC, hydroxyethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, hypromellose phthalate (HPMCP), lactose monohydrate, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, sugars, N-vinyl lactams, polyacrylates or polymethacrylates, polyethylene oxide, PEG, oligo- or polysaccharides, poloxamers, graft copolymers of polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate, water soluble and water insoluble polymers and combinations comprising one or more of the foregoing hydrophilic carriers.

As used herein, the term “prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

The term "orally disintegrating" refers to a composition which disintegrates within 3 minutes in water (37+2°C), as determined according to the disintegration test disclosed in the European/US Pharmacopoeia, preferably within 1 minute, and more preferably within 30 seconds.

The term "orally disintegrating dosage form” is interchangeable with the term “orally disintegrating tablet" (ODT) or with the term "rapidly disintegrating tablet" (RDT) or with the term “fast disintegrating tablet” or with the term “orally dispersible tablet” or with the term “rapidly dispersible tablet” or with the term “fast dispersible tablet” or with the term “orodispersible tablets”. It refers to a solid dosage form composed of a tablet that is designed to disintegrate or dissolve rapidly in the oral cavity when it comes in contact with saliva without need for chewing tablets or swallowing with liquids. Preferred orally disintegrating tablets have the characteristics set forth by the U.S. Food & Drug Administration in Guidance for Industry: Orally Disintegrating Tablets (Dept, of Health and Human Services, U.S. FDA Center for Drug Evaluation and Research, December 2008). Generally, the preferred tablets of the invention exhibit in vitro disintegration times of 60 seconds or less when evaluated using the USP Disintegration Test described in USP 24-NF 19 or an equivalent alternative test.

The term “stable” means a drug substance and/or pharmaceutical composition for pharmaceutical use which remains stable as per ICH guidelines. The term “ICH guidelines” means drug substance and composition remains stable at 25°C + 2°C and 60 % RH + 5 % RH, 30°C + 2° C and 65% RH + 5% RH, and 40° C ± 2° C and 75% RH + 5% RH conditions for a period of at least 6 months or longer.

As used herein, the term “impurity” include total impurities or individual, known or unknown impurities.

As used herein, the terms "bioequivalence" is defined as a pharmacokinetic (PK) comparison of the present pharmaceutical composition to that of the approved formulation. The pharmaceutical composition of the present invention must display drug pharmacokinetics that fall within a range of 80-125% (0.8-1.25) when one computes the ratio of the drug PK of the present invention composition with respect to approved marketed formulation. The PK parameters that are used for this comparison are the maximum concentration achieved in the blood (Cmax) and the area-under-the-curve (AUC). The AUC is determined by plotting the concentration of the active ingredient in the blood over time. It is accepted as bioequivalent if the present invention composition PK falls within the 80 - 125% range when compared to the approved marketed drug formulation PK.

As used herein, the terms “about” and “approximately” should be understood to mean within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean a range of up to 30 % or up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. The orally disintegrating dosage form in the present invention includes but not limited to tablets, mini-tablets, pellets, granules, powders, films, beads, sachets, cachets; troches; lozenges, wafers, tablets in capsules, tablets in tablets, in-lay tablets or a like thereof.

The orally disintegrating tablet is a drug dosage form designed to be dissolved/disintegrate rapidly within the oral cavity. Orally disintegrating tablets include sublingual tablets and buccal tablets, the former are placed under the tongue and the latter are placed in the buccal pouch, and allowed to be dissolved in saliva.

It has been observed that commercially available Rivaroxaban formulations seems to have reduced patient compliance for patients suffering from thromboembolic disorders especially for pediatric and geriatric patients due to difficulty in swallowing and which may lead to reduced treatment adherence. Further, they are also produced by industrially complex process.

The available literature and prior arts do not suggest any solution to the problems associated with the currently marketed products. Hence, it remains an unmet need and a challenge for industry to develop an orally disintegrating tablet of Rivaroxaban which offers ease of administration, and is manufactured by industrially feasible and simple process, and which improves patient compliance, increases treatment adherence and thus enhances the overall treatment efficiency.

The inventors of the present invention, have surprisingly invented a novel approach for solving above problems by developing easy to administer, stable pharmaceutical orally disintegrating composition of Rivaroxaban which has a lower ratio of the weight of the active pharmaceutical ingredient to the total weight of the composition, has a higher % drug content and is manufactured by industrially feasible and simple process.

In one embodiment of the present invention, the Rivaroxaban may present in any one form or can be a mixture of crystalline, metastable, amorphous, hydrated, solvated, anhydrous, non-solvated, pre-mix with excipients or mixtures thereof.

In one embodiment of the present invention, the orally disintegrating tablets comprises Rivaroxaban in an amount from about 0.5 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 2.5 mg to about 20 mg.

In one embodiment, the composition of the present invention has a lower ratio of the weight of the active pharmaceutical ingredient to the total weight of the composition. In the composition of the present invention, the ratio of Rivaroxaban to the total weight of the composition is lower than about 1:12, preferably is lower than about 1:10, more preferably is lower than about 1:8, and still more preferably is even lower than about 1:6. In one aspect of the embodiment, the ratio of Rivaroxaban to the total weight of the composition is about 1:5.5.

In one another embodiment, the composition of the present invention has a higher % drug content. The composition of the present invention has Rivaroxaban content of more than about 8 % w/w, preferably more than about 12 % w/w, and still more preferably more than about 18 % w/w of the total composition weight. In one aspect of the embodiment the Rivaroxaban content is about 18.33 % w/w with respect to the total weight of the composition.

In another embodiment, the orally disintegrating pharmaceutical compositions has a total weight less than about 500 mg, preferably less than about 200 mg, more preferably is less than about 150 mg and still more preferably is less than about 100 mg and is even less than about 80 mg.

In another embodiment, the orally disintegrating pharmaceutical compositions comprising Rivaroxaban having a particle size D90 less than about 200 pm. The range of particle sizes preferred for use in the invention is D90 less than about 200 pm, more preferably D90 less than about 150 pm, even more preferably D90 less than about 100 pm, and most preferably D90 less than about 50 pm. The particle size distribution of Rivaroxaban particles may be measured using any technique known in the art, e.g. by microscopy or light scattering equipment such as a Malvern Zetasizer equipment.

In another embodiment, the tablets of the present invention has hardness from about 10 to about 200 N. Particularly, the tablet has hardness from about 10 to about 150 N, preferably from about 10 to about 100 N, or more preferably from about 10 to about 50 N. In a more preferred embodiment, the tablet of the invention has a hardness of from about 15 to about 60 N.

In one another embodiment, the tablets of the present invention has disintegration time of less than about 3 minutes, preferably less than about 2 minutes, or more preferably less than about 1 minute. In a particular embodiment, the tablets of the invention have a disintegration time of less than about 120, 75, 60, 55, 50, 45, 40, 35 or 30 seconds. The rapid disintegration in the mouth makes it possible in particular for a patient to administer Rivaroxaban without having to swallow the intact tablet and as well as without the need of simultaneously drinking any liquid in order to ingest the formulation. Additionally, the rapid disintegration allows Rivaroxaban to be more easily taken into the body by patients, particularly in paediatric and elderly patients as well as other patients that may have difficulty swallowing or in patients with restricted physical movement.

It is also important that orally disintegrating formulations maintain an acceptable rate of disintegration following storage. Disintegration time for tablets may be detrimentally affected by a number of factors, including exposure to gases, moisture, and light. Tablets may be administered to patients many months following their initial preparation, and the tablets of the invention have been found to maintain an acceptable disintegration time following storage.

In one another embodiment of the present invention, the orally disintegrating composition comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients remains stable at 25°C + 2°C and 60 % RH + 5 % RH, 30°C ± 2° C and 65% RH + 5% RH, and 40° C ± 2° C and 75% RH + 5% RH conditions for a period of at least 6 months or longer and wherein there is no significant change in content of Rivaroxaban and the composition retains at least 90 % of amount of Rivaroxaban initially present in the composition throughout its shelf life.

In one another embodiment of the present invention, the orally disintegrating composition comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients remains stable at 25°C + 2°C and 60 % RH + 5 % RH, 30°C ± 2° C and 65% RH + 5% RH, and 40° C ± 2° C and 75% RH + 5% RH conditions for a period of at least 6 months or longer and wherein the total, known and unknown impurities level remain in the limit as per the defined criteria of ICH & USP/EP monographs and wherein any of the unknown impurity is not more than 0.2 % and the total impurities are not more than 0.3 % w/w.

The present invention also relates to a stable orally disintegrating composition comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the composition shows optimum and comparable in-vitro dissolution to commercially available Xarelto® tablets.

Moreover, the present invention relates to orally disintegrating tablets comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein at least 85 % Rivaroxaban dissolves in not more than 20 minutes.

The present invention also relates to a stable orally disintegrating tablet comprising Rivaroxaban, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients wherein the composition shows optimum content uniformity.

In another preferred embodiment, the present invention relates to orally disintegrating tablets comprising 2.5 mg to 20 mg Rivaroxaban, wherein the % Rivaroxaban content is from more than about 8.5 % w/w to more than about 18 % w/w, wherein the ratio of the weight of Rivaroxaban to the total weight of the tablet is lower than about 1:12 to lower than about 1:6, and wherein the composition has at least one disintegrating excipient and one or more pharmaceutically acceptable excipients, and wherein the composition has a hardness from about 10 N to 200 N, preferably within 15 N to 60 N and disintegrates within 60 seconds, more preferably within 30 seconds and the composition is stable for its shelf life and is bioequivalent to the marketed tablets of Rivaroxaban.

The composition of the present invention are also suitable for nasogastric delivery to a patient. Nasogastric delivery requires the constituents of the tablet to be suspendable or soluble in water so that the tablet contents may be administered to the patient through a nasogastric tube.

In another embodiment, the present invention relates to a process of preparing orally disintegrating composition comprising formulating Rivaroxaban or a pharmaceutically acceptable salt or a solvate or a hydrate or any crystalline or amorphous polymorph or a prodrug or a premix thereof prodrug form thereof, at least one disintegrating excipient and one or more pharmaceutically acceptable excipients into suitable oral dosage forms.

In one aspect of the embodiment, the orally disintegrating composition of the present invention is bioequivalent to commercially available Xarelto® tablets despite its formulation using a simple, non-complex process wherein the API is not necessarily hydrophilized i.e. it is not necessarily dissolved in binder solution before converting it into a dosage form.

In one aspect of the embodiment, the process is a non -hydrophilized process, wherein the Rivaroxaban is not necessarily hydrophilized by dissolving it in a binder solution.

In another aspect of the embodiment, the process involves use of the API in powder form either in dry mix, either in intra-granular component or in extra- granular component without the need to hydrophilized it.

In another aspect of the embodiment, the blend of the composition prepared by the process, is having good flow properties, compressibility, reduced tableting or manufacturing problems like sticking and the composition shows optimum content uniformity.

The pharmaceutical composition of the present invention can be obtained by a known conventional methods like direct compression, wet granulation, dry granulation, roller compaction or slugging, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion, freeze drying (lyophilisation), Zydis technology, molding methods, or like thereof. The wet granulation process may involve shear granulators, high shear mixer granulators, twin screw granulators and Fluid Bed Granulators.

In another embodiment, the composition of the present invention comprises taste masking of Rivaroxaban particles (e.g., powder, particles, granules), wherein the taste masking agent is either added in the dry mix or Rivaroxaban is coated with a taste-masking layer to improve palatability of the composition. The taste-masking layer can be applied to the Rivaroxaban particles by any suitable method, for example microencapsulation, coacervation phase separation or fluidized bed coating methods.

The compositions of the present invention may be coated with one or more layers of membrane coating materials for sealing purposes, as is known in the art. An outer coating may also include one or more colorants to provide a coloured dosage form as desired and/or to improve the taste of the tablet. These coatings may be sugar coatings, film coatings, colour coatings, or the like.

The pharmaceutical compositions herein, e.g., orally disintegrating composition, can be of any suitable size and shape, and the invention is not limited in this regard. For example, the dosage forms may be of triangular, round, rectangular, square, capsule, almond, oval, diamond, biconvex, multi-layered, or have an irregular shape. There may also be letters or characters embossed or printed on the dosage form surface.

The present invention compositions can also be adapted for sublingual or buccal administration which may include buccal tablets, buccal films, sublingual tablets, sublingual films and the likes thereof.

In another embodiment, the orally disintegrating compositions of the invention may include one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants/super disintegrants, effervescent agents, lubricants, glidants, sweeteners, flavouring agents, coloring agents, antioxidants, surfactants/solubilizers, stabilizers, solvents, plasticizers, suitable taste masking agents, or a like thereof. The diluents according to the present invention include, but are not limited to starch (maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, and others), lactose (e.g., lactose monohydrate, such as Fast Flo® 316, lactose anhydrous and others), Dextrose, Pearlitol, cellulose derivatives includes crystalline celluloses such as microcrystalline cellulose, kaolin and powdered celluloses, confectioner's sugar, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, dicalcium phosphate, calcium sulfate, carmellose, sugar alcohols such as mannitol, maltodextrin, sorbitol, xylitol, inositol sucrose, inositol, polysaccharides polymers such as pullulan, or commercially available pre-mixes including but not limited to F-melt type C, Ludiflash, Solutab, Prosolv ODT G2 and mixtures thereof. Preferably, the diluent in present invention is microcrystalline cellulose, mannitol, dibasic calcium phosphate, starch, maltodextrin, lactose, sorbitol, F-melt type C, Ludiflash, Solutab, Prosolv ODT G2. The one or more diluents together may be present in an amount from about 1 to about 90 % w/w, preferably may be present in an amount from about 10 to about 80 % w/w, more preferably from about 20 to about 70 % w/w, still more preferably from about 35 to about 65 % w/w of the total weight of the composition. Every individual diluent may be present in an amount from about 5 to about 60 % w/w, preferably from about 10 to about 50 % w/w, more preferably from about 15 to about 45 % w/w of the total weight of the composition.

The binders according to the present invention include, but are not limited to corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, gelatin, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone and its derivatives in various grades such as povidone, copovidone and others, methyl cellulose, pre-gelatinized starch, hydroxy propyl cellulose in various grades, hydroxypropyl methyl cellulose in various grades, microcrystalline cellulose, and mixtures thereof. Preferably, the binder in present invention is hydroxy propyl cellulose and povidone. The binder may present in an amount from about 0.5 to about 20 % w/w, preferably from about 1 to about 10 % w/w, more preferably from about 1 to about 5 % w/w of the total weight of the composition.

In another embodiment, the oral disintegrating tablet of the present invention involves use of disintegrating excipient which are co-processed with other excipient such as filler, binder or diluent or which are in the pre-mix form. These type of disintegrating excipient can provide robustness, better compressibility, optimum disintegrating time, allowing rapid dissolution, smooth mouth feeling which make them particularly suitable for use in the tablets of the invention. Some of the commercially available co-processed disintegrating excipient include, but not limited to, PEARLITOL® Flash, F-melt type C, F-melt type M, Eudiflash, GalenlQ, Prosolv, StarEac® and Pharmaburst. PEARLITOE® Flash is a spray- dried mixture of mannitol (80%) and maize starch (20%). The co-processed disintegrating excipient is present either alone or in combination with other excipients and the preferred combination of disintegrating excipient is croscarmellose sodium and PEARLITOL® Flash. The disintegrating excipient may present in amount from about 0.5% w/w to about 95% w/w of the composition, preferably from about 2.0% w/w to about 95% w/w of the composition.

As mentioned above, the co-processed or pre-mix disintegrating excipient contains a portion which acts as disintegrating agent and another portion may contain one or more of additional excipient selected from the group consisting of diluent, binder, surfactant, lubricant, glidant or a like thereof. In context of the composition of present invention disintegrating excipient is considered to include whole mixture of disintegrating agent and other excipient mixed or processed with it.

The disintegrants/super disintegrants according to the present invention include, but are not limited to low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, alginic acid, calcium carbonate, croscarmellose sodium, crospovidone (Kollidon CL-F), polacrillin potassium, potato or tapioca starch, pre-gelatinized starch and mixtures thereof. Commercially available disintegrating excipient pre-mixes such as F-melt type C, F-melt type M, Ludiflash, GalenlQ, Solutab, Prosolv and Pharmaburst may also be used in the present invention composition. The disintegrant may be present either alone or in combination with other disintegrants and the preferred disintegrant is croscarmellose sodium and crospovidone. The one or more disintegrants together may be present in amount from about 1 to about 70 % w/w, preferably from about 10 to about 60 % w/w of the total weight of the composition. Every individual disintegrant may be present in an amount from about 1 to about 30 %, preferably from about 10 to about 20 % w/w of the total weight of the composition.

The lubricants according to the present invention include, but are not limited to magnesium stearate, glyceryl monostearates, glyceryl behenate, palmitic acid, talc, carnauba wax, calcium stearate, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, sodium stearyl fumarate and mixtures thereof. Preferably, the lubricant in present invention is magnesium stearate. The lubricants may present in amount from about 0.05 to about 5% w/w of the total weight of the composition, preferably from about 0.1 to about 3 % w/w of the total weight of the composition and more preferably from about 0.5 to about 1.5 % w/w of the total weight of the composition.

The glidants according to the present invention include, but are not limited to silica such as colloidal anhydrous silica, colloidal silicon dioxide or kaolin, talc and mixtures thereof. Preferably, the glidant in present invention is colloidal silicone dioxide. The glidants may present in amount from about 0.05 to about 5 % w/w, preferably from about 0.1 to about 3 % w/w, more preferably from about 0.3 to about 0.8 % w/w of the total weight of the composition.

The sweeteners/sweetening according to the present invention include, but are not limited to sugar alcohols like mannitol, sorbitol, xylitol, Erythritol, sucralose, aspartame, saccharin sodium, acesulfame potassium, and mixtures thereof. Preferably, the sweeteners in present invention is aspartame. The sweeteners may present in an amount from about 0.1 to about 5 % w/w, preferably from about 0.5 to about 1.5 % w/w of the total weight of the composition. The flavouring agents according to the present invention include, but are not limited to pharmaceutically acceptable natural oils, natural flavours, and artificial flavours. Preferably, the flavouring agents are selected from menthol, peppermint, wintergreen, cherry, bubble gum, strawberry, cherry, pineapple, vanilla, almond and other nuts, and the like & mixtures thereof. The flavouring agents may present in the composition from about 0.1 to about 3 % w/w, preferably in an amount from about 0.5 to about 1.5 % w/w of the total weight of the composition. The colouring agents according to the present invention include, but are not limited to natural colorants, synthetic colorants or like thereof. Examples of natural colorants include pigments and dyes obtained from mineral, plant, and animal sources like red ferric oxide, titanium dioxide, Allura Red AC FDC Red 40, yellow ferric oxide, zinc oxide, indigo, and synthetic colorants include FD&C or D&C dye, an azo dye or like thereof. The coloring agents may present in the composition from about 0.05 to about 3.0 % w/w of the total weight of the composition.

The surfactants/solubilizers may be included in the compositions of the present invention include, but are not limited to cetostearyl alcohol, lecithin, cholesterol, medium-chain glyceride, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glyceryl monooleate, polyoxyethylene castor oil glycoside, isopropyl myristate, monoethanolamine, oleic acid, propylene glycol, polyethylene alkyl ether, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester, sodium docusate, sorbic acid, sorbitan fatty acid ester, stearic acid, polyoxyethylene alkyl ether, polyethylene sorbitan fatty acid ester, polysorbates, poloxamers, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine and mixtures thereof. Micro-encapsulated solubilizer in powder form like Sepitrap 80 which is polysorbate 80 adsorbed over magnesium aluminometasilicate can also be used as surfactant/solubilizer. Preferably the surfactant in the present invention is sodium lauryl sulphate. The surfactants/solubilizers may present in amount from about 0.05 to about 10 % w/w of the composition, preferably from about 0.1 to about 5 % w/w, still more preferably from about 0.5 to about 1.5 % w/w of the total weight of the composition.

The taste-masking agents/polymers may also be present according to present invention and include, but are not limited to water-soluble polymers, waterinsoluble polymers, or like thereof. Examples of polymers include ethylcellulose, cellulose acetate, cellulose acetate butyrate, pullulan, methacrylate copolymers available under the trade name of Eudragit (type RL, RS and NE30D), maltrin, an aminoalkyl methacrylate copolymer available under the trade name of Eudragit (type El 00 or EPO), polyvinylacetal diethylaminoacetate, sodium chloride, sucrose, povidone, polacrillin potassium and mixtures thereof. The taste masking agent may be present in an amount from about 1 % to about 25 %, preferably from about 2.5 to about 20 % w/w of the total weight of the composition.

Suitable effervescent agents may also be included in the compositions of the present invention, which includes but are not limited to citric acid (anhydrous), sodium bicarbonate and combinations of any of the foregoing. The effervescent agents may be present in an amount from about 0.5 % to about 15 %, preferably from about 1 to about 12 % w/w of the total weight of the composition.

The stabilizers or anti-oxidants may be optionally included in the compositions of the present invention include, but not limited to citric acid, benzoic acid, sodium benzoate, and the like. The stabilizers may present in amount from about 0.001 to about 10 % w/w of the total weight of the composition.

The solvents according to the present invention, but are not limited to for the purpose of film coating/granulation includes water, methanol, ethanol, acetone, isopropyl alcohol, dichloromethane, and any mixtures thereof.

The plasticizers according to the present invention include, but are not limited to, triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, polyethylene glycol, polypropylene glycol, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides and the like or mixtures thereof. The plasticizer may typically present in amount from about 10 to about 30 % w/w based on the weight of dry polymer. In another embodiment of the present invention, Rivaroxaban and/or other one or more active ingredient can be present in the dry mix intra-granularly, or can be dissolved or dispersed along with binder solution or can be added extra-granularly or if the tablets are coated, then can even be added in the coating solution.

The excipients described in the specification can serve as one or more function in the pharmaceutical compositions of the present invention.

The pharmaceutical composition of the present invention can be preferably packed into blisters or bottles or a like thereof. Preferred blisters are made of material or laminate, which ensures high protection against humidity, oxygen and UV radiation. It is preferred that blisters are made of PVC, OPA (oriented polyamide), aluminium foil, PCTFE (e.g. Aclar), PVDC (polyvinylidene chloride), PVDC-coated PVC, PVC/PE/PCTFE laminate, CFF (Cold-Form Foil), COC (Cyclic Olefin Copolymer) or combination thereof.

In one embodiment of the present invention, the orally disintegrating tablets of the present invention comprises Rivaroxaban in amount from about 2.0 to about 50 % w/w, one or more diluents together in an amount from about 35 to about 65 % w/w, one or more disintegrants together in an amount from about 10 to about 60 % w/w, one or more binder in an amount from about 1 to about 5 % w/w, one or more surfactant in an amount from about 0.5 to about 1.5 % w/w, one or more sweetening agent in an amount from about 0.5 to about 1.5 % w/w, one or more flavouring agent in an amount from about 0.5 to about 1.5 %, one or more glidant in an amount from about 0.3 to about 0.8 % w/w and one or more lubricant in an amount from about 0.5 to one or more 1.5 %.

In one another embodiment of the present invention, the pharmaceutical composition may comprise Rivaroxaban, along with one or more diluent which may include but is not limited to pearlitol flash, microcrystalline cellulose, dibasic calcium phosphate, starch, maltodextrin, lactose, mannitol, sorbitol, F-Melt Type C, Ludiflash, Solutab, Prosolve, ODT G2, one or more disintegrants which may include but is not limited to croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, polacrillin potassium, pregelatinized starch, carboxymethylcellulose sodium, one or more binder which may include but is not limited to polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, starch, gelatin, one or more surfactant which may include but is not limited to sodium lauryl sulphate, polysorbate, poloxamer, one or more lubricant which may include but is not limited to magnesium stearate, stearic acid, sodium stearyl fumerate, one or more glidant which may include but is not limited to colloidal silicon dioxide, colloidal anhydrous silica, talc, one or more sweetener which may include but is not limited to sucralose, aspartame, acesulfame potassium, sodium saccharin, one or more flavouring agent which may include but is not limited to powdarome peppermint premium, vanilla, pineapple flavour.

In one aspect of the embodiment, the orally disintegrating dosage form of the present invention comprises 18.18 % w/w Rivaroxaban, 21.82 % w/w microcrystalline cellulose, 21.31 % w/w Pearlitol flash, 13.64 % w/w croscarmellose sodium, 3.46 % w/w hydroxypropyl methyl cellulose, 0.78 % w/w sodium lauryl sulphate, 17.82 % w/w crospovidone, 0.91 % w/w aspartame, 1.1 % w/w powdarome peppermint premium, 0.36 % w/w colloidal silicon dioxide and 0.64 % w/w magnesium stearate.

In one another aspect of the embodiment, the orally disintegrating dosage form of the present invention comprises 20 mg Rivaroxaban, 24 mg microcrystalline cellulose, 23.44 mg Pearlitol flash, 13.64 mg croscarmellose sodium, 3.8 mg hydroxypropyl methyl cellulose, 0.86 mg sodium lauryl sulphate, 19.6 mg crospovidone, 1 mg aspartame, 1.2 mg powdarome peppermint premium, 0.4 mg colloidal silicon dioxide and 0.7 mg magnesium stearate.

The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention. EXAMPLES

Example 1: Orally Disintegrating Tablets of Rivaroxaban by Direct Compression

Orally disintegrating tablets of Rivaroxaban were prepared using direct compression (DC) process for simplicity of processing and cost effectiveness. The composition details are given in table 1.

Table 1: Composition of OD tablets of Rivaroxaban by DC process (mg/tab)

Manufacturing Procedure:

1. Required quantity of Rivaroxaban and dibasic calcium phosphate/microcrystalline cellulose were co-sifted through sieve # 30.

2. Blend of step 1 was then co-sifted with required quantity of lactose/pearlitol flash, croscarmellose sodium, hypromellose, SLS, crospovidone, aspartame, peppermint flavour and colloidal silicon dioxide through sieve # 30 and was blend mixed in a blender for 30 minutes.

3. Required quantity of magnesium stearate was sifted through sieve # 60 and was used to lubricate blend of step 2 in a blender for 5 minutes.

4. Tablet compression could not be performed due to very poor flow properties of the lubricated blend. Example 2: Orally Disintegrating Tablets of Rivaroxaban by Wet Granulation

Orally disintegrating tablets of Rivaroxaban were prepared using wet granulation (WG) process for improving flow of the blend, compressibility and prevent manufacturing problems associated with direct compression. The composition details are given in table 2.

Table 2: Composition of OD tablets of Rivaroxaban by WG process (mg/tab)

Manufacturing Procedure:

1. Required quantity of Rivaroxaban, microcrystalline cellulose/dibasic calcium phosphate, lactose/pearlitol flash and croscarmellose sodium were co-sifted through sieve # 30 and were blend mixed in a rapid mixer granulator for 10 minutes.

2. Binder solution was prepared by dissolving required quantity of hypromellose in purified water under stirring. Required quantity of SLS was then mixed with the binder solution. The blend of step 1 was then granulated with binder solution in a RMG. Wet mass was milled through through a co-mill. 3. The granules of step 2 were then dried in a fluidized bed dryer till desired LOD was obtained and were further milled through co-mill.

4. Crospovidone, optionally Sepitrap 80, aspartame, peppermint flavour & aerosil were co-sifted through sieve # 40 & were blended with granules of step 3 in a blender.

5. Required quantity of magnesium stearate was sifted through sieve # 60 and was used to lubricate blend of step 4 in a blender. The lubricated blend was then compressed into tablets using a rotary compression machine.

Example 3: Evaluation of batches WG 1 to WG 4.

The tablets of batches WG 1 to WG 4 were compressed at optimum hardness and high hardness. The tablets were then evaluated for in-vitro disintegration time.

The results are summarized in below Table 3.

Table 3: In-vitro disintegration time for WG 1 to WG 4

As seen from the results, the tablets of batches WG 2, WG 3 and WG 4 showed a disintegration time of more than 30 seconds, whereas the tablets of batch WG 1 showed a disintegration time of less than 30 seconds and thus tablets of batch WG 1 were selected for further study.

Example 4: Orally Disintegrating Tablets of Rivaroxaban with Different Binder, Different Disintegrant and Different Concentration of Disintegrant Orally disintegrating tablets of Rivaroxaban were prepared using wet granulation (WG) process by using different binder, different disintegrant and at different concentration of disintegrant. The composition details are given in table 4. Table 4: Composition of OD tablets of Rivaroxaban with Different Binder,

Different Disintegrant and Different Cone. Of Disintegrant (mg/tab)

Tablets were prepared by wet granulation process similar to the process described in example 2. The tablets of batch WG 5 were prepared using Povidone K 30 as a binder. Whereas Sodium starch glycholate was used as a disintegrant in batch WG 6. The tablets of batch WG 7 used Crospovidone as disintegrant, but at a lower concentration than that in batch WG 1. Example 5: Evaluation of batches WG 5, WG 6 and WG 7

The tablets of batches WG 5, WG 6 and WG 7 were compressed at optimum hardness and high hardness. The tablets were then evaluated for in-vitro disintegration time. The results are summarized below in Table 5. Table 5: In-vitro disintegration time for WG 5, WG 6 and WG 7

As seen from the results, changing binder from hypromellose to Povidone K 30 increased the disintegration time from 21 seconds up to 95 seconds at optimum hardness and from 30 seconds to 118 seconds at high hardness. Whereas although the tablets of batch WG 6 with sodium starch glycholate as disintegrant showed an acceptable disintegration time of 28 seconds at optimum hardness, but at high hardness, it was found to be 58 seconds. Lowering the concentration of total disintegrant from 32 % w/w to 10 % w/w negatively impacted the disintegration time as it increased from 21 seconds to 48 seconds at optimum hardness and from 30 seconds to 75 seconds at high hardness.

Example 6: Orally Disintegrating Tablets of Rivaroxaban by Wet Granulation in Fluidized Bed Processor

Orally disintegrating tablets of Rivaroxaban were prepared using wet granulation (WG) process in fluidized bed processor (FBP) to further improve tablet properties. The composition details are given in table 6.

Table 6: Composition of OD tablets of Rivaroxaban by in FBP (mg/tab)

Manufacturing Procedure:

1. Required quantity of Rivaroxaban, microcrystalline cellulose, pearlitol flash and croscarmellose sodium were co-sifted through sieve # 30 and were loaded in a fluidized bed processor (FBP).

2. Binder solution was prepared by dissolving required quantity of hypromellose in purified water under stirring. Required quantity of SLS was then mixed with the binder solution.

3. The blend of step 1 was then granulated with binder solution of step 2 in FBP with top spray granulation. The granules were then dried in FBP till desired LOD was obtained and were further milled through co-mill.

4. Required quantity of crospovidone, optionally Sepitrap 80 aspartame, peppermint flavour and aerosil were co-sifted through sieve # 40 and were blended with granules of step 3 in a blender.

5. Required quantity of magnesium stearate was sifted through sieve # 60 and was used to lubricate blend of step 4 in a blender. The lubricated blend was then compressed into tablets in a rotary compression machine.

Example 7: Evaluation of disintegration time of batches WGF 1

The tablets of batches WGF 1 were compressed at optimum hardness and high hardness. The tablets were then evaluated for in-vitro disintegration time. The results are summarized in below Table 7. As seen from the results, the disintegration time of batch WGF 1 was found to be within acceptable limits.

Table 7: In-vitro disintegration time for WGF 1

Example 8: In-vitro dissolution of batch WG 1 and WGF 1

The tablets of finalized batches WG 1 and WGF 1 were studied for in-vitro drug dissolution study in USP paddle type dissolution test apparatus using 900 ml of pH 4.5 acetate buffer + 0.4 % SLS (OGD media) at 75 RPM. The results summarized in table 8 clearly indicate that the tablets of both batches showed good in-vitro drug dissolution and were comparable to the reference product.

Table 8: In-vitro dissolution study of WG 1 and WGF 1

Example 9: Accelerated Stability Study of WG 1 The orally disintegrating tablets of batch WG 1 were packed in Alu-Alu blisters and were stored at 40 °C/75 % RH. The tablets were evaluated at initial, after 3 months and after 6 months for any increase in any unknown or total impurities and for other physico-chemical parameters. The results are summarized in table 9 shows that the tablets of batch WG 1 remained stable and there was no significant increase in any unknown or total impurities. The in-vitro dissolution, assay, water content and disintegration time also remained within acceptable limits.

Table 9: Accelerated stability studies of WG 1

Claims

We Claim:

1. An orally disintegrating pharmaceutical composition comprising a therapeutically effective amount of Rivaroxaban or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, premix or a prodrug thereof and at least one disintegrating excipient.

2. The orally disintegrating pharmaceutical composition as claimed in claim 1, wherein the ratio of Rivaroxaban or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, premix or a prodrug thereof to the total weight of the composition is lower than about 1:12, preferably lower than about 1:6, or more preferably about 1:5.5.

3. The orally disintegrating pharmaceutical composition as claimed in claim 1, wherein Rivaroxaban or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, premix or a prodrug thereof is present in an amount of more than about 8 % w/w, preferably more than about 12 %, or preferably more than about 18 % w/w of the total weight of the composition.

4. The orally disintegrating pharmaceutical composition as claimed in claim 1, wherein the disintegrating excipient is present in an amount from about 10 % w/w to about 90 % w/w of the total weight of the composition.

5. The orally disintegrating pharmaceutical composition as claimed in claims 1 to 4, wherein the composition has a hardness of about 10 N to about 100 N, or preferably about 15 N to about 60 N.

6. The orally disintegrating pharmaceutical composition as claimed in claims 1 to 4, wherein the composition has a disintegration time of less than about 3 minutes, preferably less than about 2 minutes, more preferably less than about 90 seconds, or more preferably less than about 60 seconds.

7. The orally disintegrating pharmaceutical composition as claimed in any of the preceding claims, wherein the disintegrating excipient comprises one or more disintegrant and optionally comprises one or more additional excipients selected from the group consisting of diluent, binder, surfactant, lubricant, glidant, or a like thereof. The orally disintegrating pharmaceutical composition as claimed in claim 7, wherein the disintegrating excipient is selected from group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, polacrillin potassium, pregelatinized starch, carboxymethylcellulose sodium, mannitol, starch, microcrystalline cellulose, lactose, dibasic calcium phosphate, sorbitol, xylitol or premixes or mixtures thereof. The orally disintegrating pharmaceutical composition as claimed in any of the preceding claims, wherein the binder is selected from a group consisting of polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, starch. The orally disintegrating pharmaceutical composition as claimed in any of the preceding claims, wherein the composition comprises 15-25 % w/w Rivaroxaban, 15-30 % w/w microcrystalline cellulose, 12-24 % w/w mannitol, 3-6 % w/w starch, 10-20 % w/w croscarmellose sodium, 2-6 % w/w hydroxypropyl methyl cellulose, 0.5- 1.5 % w/w sodium lauryl sulphate, 10-30 % w/w crospovidone, 0.2-1 % w/w colloidal silicon dioxide, 0.5-2 % w/w magnesium stearate, 0.5-1.5 % w/w aspartame, 0.5-1.5 % w/w peppermint flavour.