DESC:TITLE OF THE INVENTION:
“STABLE PHARMACEUTICAL COMPOSITION OF EDOXABAN”
FIELD OF THE INVENTION:
The present invention relates to stable pharmaceutical composition comprising edoxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient; wherein the present invention is devoid of sugar alcohols. The present invention further relates to methods of preparing and administering such pharmaceutical compositions.

BACKGROUND OF THE INVENTION:
Edoxaban is chemically known as N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzenesulfonate) monohydrate, represented by the chemical structure:

Edoxaban, a factor Xa inhibitor approved by USFDA as SAVAYSA Tablets indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation.

Inactive ingredients in the SAVAYSA tablets consist of mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, carnauba wax, hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow.

The solubility of Edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practically insoluble at pH 8 to 9. Edoxaban is a basic compound, and thus can be solubilized in strong acidic aqueous solution, however when the pH of the aqueous media is shifted to less acidic, neutral or basic values, the dissolution profile of edoxaban diminishes considerably.

US Patent US9149532, discloses oral solid dosage forms, namely tablets comprising edoxaban together with a sugar alcohol (mannitol) and a water-swelling additive and other excipients. However, use of sugar alcohols may be problematic in patients showing intolerance against these compounds, such as mannitol. Furthermore, document US9149532 discloses that compositions where the sugar alcohol is replaced by other excipients, such as a combination of a saccharide (lactose), and a starch (cornstarch) the dissolution profile of the resulting compositions at pH 4 (strong acidic medium) is not satisfactory.

Patent document US9918975, discloses that keeping the water content during granulation of edoxaban-containing material to 10% or less, leads to an improved dissolution profile in the neutral region of the pH scale. However, this improvement is only obtained in formulations having a sugar alcohol in its composition. As mentioned above, many patients show intolerance against sugar alcohols, such as mannitol. Yet, it is further known that these excipients also increase the gastrointestinal motility, leading to a decrease in drug absorption, which involves the risk of lower efficacy of the therapeutic ingredient.

Patent application US2017231969 Al, discloses tablet compositions comprising edoxaban in combination with a water-soluble vinylpyrrolidone polymer (copovidone, povidone) and a cellulose ether, free of a sugar alcohol. However, no experimental data is provided detailing the dissolution profile of said compositions, thus there is no information on the influence of the disclosed compositions in the dissolution of edoxaban at any pH value.

As can be seen there is still a need for novel oral dosage forms such as tablets, with an adequate dissolution profile, which are devoid of sugar alcohols in its composition as sugar alcohols causes spike in sugar levels in blood. Therefore, it is an object of this invention to provide a tablet formulation comprising edoxaban or a pharmaceutically acceptable salt thereof, devoid of sugar alcohols in its composition, with good dissolution properties.

Therefore, there exists need to prepare alternate compositions of Edoxaban that shows improved stability, dissolution and bioavailability with simple, reproducible and cost effective manufacturing process for pharmaceutical composition of Edoxaban tablet, which also offers desired pharmaceutical technical attributes.

In order to solve the above problem, the present inventors have developed compositions, which provides Edoxaban product having improved stability, dissolution and bioavailability. The present invention relates to stable pharmaceutical compositions with good dissolution properties.

SUMMARY OF THE INVENTION:

The present invention relates to a stable pharmaceutical composition comprising Edoxaban or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient; wherein the compositions are devoid of sugar alcohols. The present invention further provides process for preparation of Edoxaban.

Accordingly, the preferred pharmaceutical composition of the present invention contains various quantities ranging from about 10 mg to about 100 mg of Edoxaban or a pharmaceutically acceptable salt thereof. Thus, for example, the preferred formulation can contain about 5mg to 100 mg of Edoxaban base.

OBJECTIVES OF INVENTION:

In one aspect, the stable pharmaceutical composition comprising Edoxaban or pharmaceutical acceptable salt thereof, and one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohols.

In another aspect, the present invention relates to oral stable pharmaceutical composition comprising Edoxaban or its pharmaceutically acceptable salt thereof, Sugar / Saccharide and one or more pharmaceutical acceptable excipients, wherein the composition is substantially devoid of sugar alcohols.

In another aspect, the present invention relates to the oral stable dosage composition comprising Edoxaban or its pharmaceutical salt thereof, Sugar / Saccharide, Starch, Crospovidone, Povidone Magnesium Stearate and one or more pharmaceutical acceptable excipients or combinations thereof.

In another aspect, the present invention relates to oral stable composition comprising Edoxaban or its pharmaceutical salt thereof, wherein the composition is devoid of sugar alcohol.

In another aspect, the present invention relates to oral stable composition of Edoxaban comprising Edoxaban or its pharmaceutical salt thereof, solubilizing agent, one or more diluents, disintegrant, binder, lubricant and optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another aspect, the present invention relates to oral stable composition of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from about 10 % to about 60 % of solubilizing agent.
(c) from about 5 % to about 60 % of one or more diluents;
(d) from about 1 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another aspect, the present invention relates to the oral stable pharmaceutical composition as defined above for the treatment of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

In another aspect, the present invention relates to oral stable pharmaceutical composition as defined above having dissolution more than 90% within 30 minutes.

DETAILED DESCRIPTION OF THE INVENTION:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term "Edoxaban" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, colorants, solubulizers, plasticizer or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as Starch, cornstarch, granulated cornstarch, pregelatinized starch, lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "disintegrant" employed in a composition of the present invention is capable of facilitating the breakup of a pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, powdered cellulose or croscarmellose; iron exchange resin such as amberlite, gums such as agar, locust bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate, Crospovidone, povidone or starch.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "solubilizing agent" employed in a composition of the present invention is capable of increasing solubility of drug (Edoxaban). Example of solubilizing agent of instant invention includes, but are not limited to Maltodextrin, polyethylene glycols, Tween 80 (polysorbate 80), Tween 20 (polysorbate 20), talc, Dibasic Calcium Phosphate (DCP; Fujicalin), sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Aerosil 200, Amorphous micronized silica (Sylysia 350), diethylene glycol monoethyl ether (Transcutol P), propylene glycol, tocopherols (tocopheryl polyethylene glycol 1000 succinate), propylene glycol, monocaprylate, caprylocaproyl macrogol-8 glycerides, glycerylcaprylate, poloxamers, PEG-40 hydrogenated castor oil, lecithin, propylene glycol stearates, and polyethylene glycol glycerides, sodium lauryl sulfate, anionic emulsifying wax, glycerol, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, stearic acid, sulfobutylether b-cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "excipient" means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Edoxaban and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Edoxaban or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The term "Parenteral dosage forms” includes all conventional oral solid dosage forms like a
Intramuscular injection, Intravenous injection, subcutaneous injection any other Parenteral dosage forms comprising Edoxaban or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The present invention relates to a stable pharmaceutical compositions comprising Edoxaban or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients.

In one embodiment, the present invention relates to solid oral pharmaceutical composition comprising Edoxaban or its pharmaceutical salt thereof, solubilizing agents and one or more pharmaceutical acceptable excipients, wherein the composition is substantially devoid of sugar alcohol.

In certain exemplary embodiments, the pharmaceutical composition comprises Edoxaban, or is in the form of a pharmaceutically acceptable salt, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).

In certain exemplary embodiments, the exemplary compound (Edoxaban) contain an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.

In certain embodiments, the present invention relates to a pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein, pharmaceutical composition is in the form of solid dosage form, semi-solid dosage form, liquid dosage form, gaseous dosage form, oral dosage forms, topical dosage forms and parenteral dosage forms.

In certain embodiments compounds described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, or lotions and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to lotions, ointments, creams, and gels. In a preferred embodiment, the topical formulation is a gel.

In another embodiment, the solid oral pharmaceutical composition is in the form of tablet comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of capsule comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of Syrups comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of Suspension comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of Intramuscular injection comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of Intravenous injection comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of subcutaneous injection comprising Edoxaban or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention relates to oral stable composition of Edoxaban comprising Edoxaban or its pharmaceutical salt thereof, solubilizing agent, one or more diluents, disintegrant, binder, lubricant and optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In a yet another embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising Edoxaban or its pharmaceutical salt thereof, Maltodextrin, Crospovidone, Povidone, Starch, Magnesium stearate and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of sugar alcohol.

In a yet another embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising Edoxaban or its pharmaceutical salt thereof, lactose monohydrate, Crospovidone, Povidone, Starch, Magnesium stearate and one or more pharmaceutically acceptable excipients; wherein the composition is devoid of sugar alcohol.

In yet another embodiment, the pharmaceutical composition of the present invention can be formulated as dosage forms which include, but are not limited to, powders, granules, pills, tablets, coated tablets, capsules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

In another embodiment, the pharmaceutical composition of the present invention can be formulated as oral dosage forms selected from powders, granules, tablets, and capsules, powders for reconstitution, granules for reconstitution.

In another embodiment, the present invention relates to the oral stable pharmaceutical composition comprising Edoxaban or its pharmaceutical salt thereof, wherein the composition is in the form of tablet or capsule.

In another embodiment, the present invention relates to oral stable tablet dosage form composition comprising 10mg to 100mg of Edoxaban base.

In another embodiment, the present invention composition relates to the oral stable pharmaceutical composition having excellent stability, good purity profile with improved dissolution profile and bioavailability.

In further embodiments of the present invention, the pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Edoxaban, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the Edoxaban.

The composition of the present invention can be produced by sizing and milling a mixture of the drug substance with excipients. For example, one method for the production includes mixing the Edoxaban with the materials for the preparation by a suitable mixer, and lubrication the mixture to tablet or capsule.

The pharmaceutical compositions can be prepared by using any suitable method known in the art such as direct compression, dry or wet granulation (aqueous/non-aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

The pharmaceutical composition is meant for once daily or twice daily administration.

In another embodiment, the present invention relates to the oral stable composition comprising
Edoxaban or its pharmaceutical salt thereof, having dissolution more than 90% within 30 minutes.

In another embodiment, the present invention relates to the pharmaceutical composition as defined above for the treatment of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

In another aspect, the present invention relates to oral stable composition comprising Edoxaban or its pharmaceutical salt thereof, wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to the oral stable dosage composition comprising Edoxaban or its pharmaceutical salt thereof, Maltodextrin, Maize Starch, crospovidone, Povidone, Magnesium stearate and one or more pharmaceutical acceptable excipients or combinations thereof; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to the oral stable dosage composition comprising Edoxaban or its pharmaceutical salt thereof, Lactose monohydrate, Maize starch, crospovidone, Povidone, Magnesium stearate and one or more pharmaceutical acceptable excipients or combinations thereof; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable dosage composition comprising: Edoxaban or its pharmaceutical salt thereof, solubilizing agent, one or more diluents, disintegrant, binder, lubricant and optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable dosage composition of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of solubilizing agent.
(c) from about 5 % to about 60 % of one or more diluents;
(d) from 1 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable tablet of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 45 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of solubilizing agent;
(c) from about 5 % to about 60 % of one or more diluents;
(d) from 1 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant;
(g) optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable tablet of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of Maltodextrin;
(c) from about 5 % to about 60 % of Starch;
(d) from about 1 % to about 15 % Crospovidone;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable tablet of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of lactose monohydrate;
(c) from about 5 % to about 60 % of Starch;
(d) from about 1 % to about 15 % Crospovidone;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients; wherein the composition is devoid of sugar alcohol.

In another embodiment, the present invention relates to oral stable tablet of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of Lactose;
(c) from about 1 % to about 10 % of Colloidal silicon dioxide;
(d) from about 1 % to about 15 % of Starch;
(e) from about 1 % to about 10 % of Povidone;
(f) from about 0.5 % to about 2 % of Sodium starch glycolate;
(g) from about 0.5 % to about 2 % of Magnesium stearate;
(h) optionally one or more pharmaceutical acceptable excipients; wherein the said composition is devoid of sugar alcohol.

In another embodiment, the weight ratio of Edoxaban tosylate to solubilizing agent is from about 1:1 to about 1:10.

In another embodiment, the present invention relates to a pharmaceutical stable dosage form composition comprising immediate release tablet.

In another embodiment, the present invention relates to the pharmaceutical composition as defined above for the treatment of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1
S.No. Ingredients mg/Tablet % w/w
15 mg 30 mg 60 mg
Intra-granular agents
1. Edoxaban tosylate 20.25 40.50 81.00 20.25
2. Maltodextrin 49.55 99.10 198.20 49.55
3. Maize Starch 21.00 42.00 84.00 21.00
4. Crospovidone 5.35 10.70 21.40 5.35
Binder solution
5. Povidone K-30 3.05 6.10 12.20 3.05
6. Purified water q.s q.s q.s --
Extra granular agents
7. Magnesium Stearate 0.80 1.60 3.20 0.80
Total weight of uncoated tablets 100.00 200.00 400.00 100.00
Film coating ( 5.0% w/w weight build up)
8. Opadry orange (HPMC based) 5.00 -- -- --
9. Opadry red (HPMC based) -- 10.00 -- --
10. Opadry yellow (HPMC based) -- -- 20.00 --
11. Purified water q.s q.s q.s --
Total weight of film coated tablets 105.00 210.00 420.00 --
q.s = quantity sufficient.

Example – 2:
S.No. Ingredients mg/Tablet % w/w
15 mg 30 mg 60 mg
Intra-granular agents
1. Edoxaban tosylate 20.25 40.50 81.00 20.25
2. Lactose monohydrate 49.55 99.10 198.20 49.55
3. Maize Starch 21.00 42.00 84.00 21.00
4. Crospovidone 5.35 10.70 21.40 5.35
Binder solution
5. Povidone K-30 3.05 6.10 12.20 3.05
6. Purified water q.s q.s q.s --
Extra granular agents
7. Magnesium Stearate 0.80 1.60 3.20 0.80
Total weight of uncoated tablets 100.00 200.00 400.00 100.00
Film coating ( 5.0% w/w weight build up)
8. Opadry orange (HPMC based) 5.00 -- -- --
9. Opadry red (HPMC based) -- 10.00 -- --
10. Opadry yellow (HPMC based) -- -- 20.00 --
11. Purified water q.s q.s q.s --
Total weight of film coated tablets 105.00 210.00 420.00 --
q.s = quantity sufficient.

The Edoxaban tablet composition of examples 1 and 2 are prepared by direct compression wet or dry granulation.
BRIEF MANUFACTURING PROCESS OF EXAMPLE 1 AND 2:
Sifting:
I. Co-sift Edoxaban tosylate, Lactose monohydrate, Maize starch, Povidone K30 and Crospovidone through 40 # mesh.
II. Load the step I into the blender and mix for 15 minutes.
III. Sift Magnesium stearate through 60 # mesh.

Lubrication:
IV. Blend the step III materials with step III for 5 minutes.

Compression:
V. Compress the step IV blend according to their individual weights by using suitable punches.

Film Coating:
VI. The coating dispersion was prepared strength wise by dispersing Opadry orange, Opadry red and Opadry yellow in purified water under stirring and coat the compressed tablets of step viii with the coating dispersion.

Example-3:
S.No. Ingredients Functional category mg/Tablet % w/w
15 mg 30 mg 60 mg
Intra-granular agents
1. Edoxaban tosylate API 20.20 40.41 80.82 20.20
2. Lactose monohydrate Diluent 35.00 69.99 139.98 35.00
3. Colloidal Silicon dioxide Glidant 2.00 4.00 8.00 2.00
Binder solution
4. Povidone K-30 Binder 2.00 4.00 8.00 2.00
5. Purified water Solvent q.s q.s q.s --
Extra granular agents
6. Lactose monohydrate Diluent 20.00 40.00 80.00 20.00
7. Maize Starch Diluent/ solubilizing agent 10.00 20.00 40.00 10.00
8. Sodium starch glycolate Disintegrant 10.00 20.00 40.00 10.00
9. Magnesium Stearate Lubricant 0.80 1.60 3.20 0.80
Total weight of uncoated tablets 100.00 200.00 400.00 100.00
Film coating ( 5.0% w/w weight build up)
10. Opadry orange (HPMC based)

Coating material 3.00 -- -- --
11. Opadry pink (HPMC based) -- 6.00 -- --
12. Opadry yellow (HPMC based) -- -- 12.00 --
13. Purified water solvent q.s q.s q.s --
Total weight of film coated tablets 105.00 210.00 420.00 --
q.s = quantity sufficient.

Manufacturing Process:
Sifting:
I. Co-sift Edoxaban tosylate monohydrate, Lactose monohydrate, Colloidal silicon dioxide through 30 # mesh and blended the mixture for 15 minutes in Rapid mixer granulator.
Binder Solution:
II. Binder Solution is prepared by dissolving povidone K-30 in purified water by stirring until clear solution obtained.

Granulation:
III. Granulating the dry mix of step I material using step II binder solution.

IV. Dry the granules of step III, until the % LOD of the granules reaches NMT 2.0% w/w at 105ºC.
Sizing and Milling:
V. Sift and mill the dried granules of step IV through 30# mesh.
Extragranular agents:
VI. Co-sift Anhydrous Lactose, Povidone K-30, Maize Starch, Sodium Starch Glycolate and Magnesium stearate through 40 # mesh.

Lubrication:
VII. The dried granules of step V are blended with Extragranular agents of step VI and lubricated for 5 minutes using magnesium stearate.

Compression:
VIII. Compress the Step VII blend by using suitable punches.
Film Coating:
IX. The coating dispersion was prepared by strength wise by dispersing Opadry Orange, Opadry pink and Opadry Yellow in purified water under stirring and Coat the compressed tablets of step VIII with the suitable coating dispersion.

Table 1: Comparative dissolution profile of innovator edoxaban (Lixiana) tablets and example 3 (15mg) of instant invention:

,CLAIMS:We Claim:

1. A solid oral pharmaceutical composition comprising:
(a) an intragranular portion comprising Edoxaban or its pharmaceutical salt thereof, atleast one diluent and one or more pharmaceutical acceptable excipients or combinations thereof;
(b) an extragranular portion comprising atleast one lubricant and one or more pharmaceutical acceptable excipients or combinations thereof; wherein said the composition is devoid of sugar alcohol.

2. A solid oral pharmaceutical composition as claimed in claim 1, the sugar alcohol is selected from the group consisting of mannitol, xylitol, sorbitol, erythritol, and combinations thereof.

3. A solid oral pharmaceutical composition as claimed in claim 1, the diluent is selected from the group consisting of dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; Starch, cornstarch, granulated cornstarch, pregelatinized starch, lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, microcrystalline cellulose and combinations thereof.

4. A solid oral pharmaceutical composition as claimed in claim 1, the lubricant is selected from the group of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid and combinations thereof.

5. A solid oral pharmaceutical composition of Edoxaban, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of solubilizing agent.
(c) from about 5 % to about 60 % of one or more diluents;
(d) from 1 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % of binder;
(f) from about 0.5 % to about 2 % of lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients; wherein the said composition is devoid of sugar alcohol.

6. The oral stable dosage composition as claimed in claim 5, comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of lactose monohydrate;
(c) from about 5 % to about 60 % of Starch;
(d) from about 1 % to about 15 % of Crospovidone;
(e) from about 1 % to about 10 % of Povidone;
(f) from about 0.5 % to about 2 % of Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients; wherein the said composition is devoid of sugar alcohol.

7. The oral stable dosage composition as claimed in claim 5, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of Maltodextrin;
(c) from about 5 % to about 60 % of Starch;
(d) from about 1 % to about 15 % of Crospovidone;
(e) from about 1 % to about 10 % of Povidone;
(f) from about 0.5 % to about 2 % of Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients; wherein the said composition is devoid of sugar alcohol.

8. The oral stable dosage composition as claimed in claim 5, wherein said composition comprises on a total of 100 % by weight:
(a) from about 5 % to about 60 % of Edoxaban or its pharmaceutical salt thereof,
(b) from 10 % to about 60 % of Lactose;
(c) from about 1 % to about 10 % of Colloidal silicon dioxide;
(d) from about 1 % to about 15 % of Starch;
(e) from about 1 % to about 10 % of Povidone;
(f) from about 0.5 % to about 2 % of Sodium starch glycolate;
(g) from about 0.5 % to about 2 % of Magnesium stearate;
(h) optionally one or more pharmaceutical acceptable excipients; wherein the said composition is devoid of sugar alcohol.

9. A oral stable composition as claimed in claim 5 comprising Edoxaban or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.

10. A oral stable composition as claimed in claim 5, for the treatment of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.