DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of edoxaban tosylate which is devoid of sugar alcohol. Further, the present invention relates to a process for the preparation of pharmaceutical composition of edoxaban tosylate.
BACKGROUND OF THE INVENTION
Edoxaban tosylate is a factor Xa inhibitor, chemically known as N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl4,5,6,7tetrahydro [1,3] thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl]oxamide mono(4-methyl benzene sulfonate) monohydrate and its structural formula is given below:

According to the biopharmaceuticals classification system (BCS), edoxaban is a Class 4 substance with low aqueous solubility and low permeability. Edoxaban is a white to pale yellowish-white crystalline powder. 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 tosylate is marketed in US, Europe and other countries under the brand name SAVAYSA and LIXIANA, which is indicated as reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
The linear approach of preparation of edoxaban and its pharmaceutically acceptable salts has been first time reported in US Patent 7,365,205. However, the said patent is silent about any pharmaceutical compositions of edoxaban.
US Patent 9,149,532 discloses an oral pharmaceutical composition of edoxaban comprising sugar alcohol, water-swelling additive, coating agent and other excipient wherein sugar alcohol is present in an amount of 40 to 60 wt. % with respect to the total weight of the pharmaceutical composition. The ratio of water-swelling additive to sugar alcohol in the preparation is 1.5 to 4 parts by weight (sugar alcohol) to 1 part by weight (water-swelling additive). The tablet is coated with at least one coating agent selected from the group consisting of hypomellose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and polyvinyl alcohol, and wherein the coating agent is present in the amount of 1.5 to 5 wt. % with respect to the total weight of the pharmaceutical composition.
Another US Patent 9,918,975 unveils a process of preparing a pharmaceutical composition containing edoxaban or a pharmaceutically acceptable salt or a solvate thereof, one or more excipients selected from the group consisting of a sugar alcohol, water-swelling additive, disintegrant and a binder under conditions for keeping the maximum water content of the granules during granulation at 10% or less.
In the above said patents, sugar alcohol is used as a dissolution enhancer. However, the use of sugar alcohol may cause problems to patients because of its intolerance activity to human beings. It is further known that sugar alcohol also increases gastrointestinal motility, leading to a decrease in drug absorption, which involves the risk of lower efficacy of the therapeutic ingredient.
A US Patent Publication 2017/0231969 discloses a pharmaceutical composition comprising edoxaban, or a pharmaceutically acceptable salt thereof, a water soluble vinylpyrrolidone polymer selected from the group consisting of povidone copovidone, and cellulose ether. The said composition is devoid of 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.
An Indian Patent Publication 202141043435 discloses a pharmaceutical composition comprises intragranular and extragranular portion whereas intragranular portion comprises edoxaban and one or more excipients. However, this process is not suitable for compounds and excipients that are moisture sensitive, dissolution rate of tablets produced by wet granulation may decrease with aging.
In most of the above-mentioned prior arts, a pharmaceutical composition of edoxaban comprises sugar alcohol as a dissolution enhancer. However, use of sugar alcohol may cause digestive upset for many people, especially those with irritable bowel syndrome (IBS). So, the use of sugar alcohol should be avoided because of its intolerance activity to human beings, and it may cause problems to patients.
In order to overcome aforementioned drawbacks, there is a need to provide an advantageously feasible process for the preparation of pharmaceutical composition of edoxaban and its pharmaceutically acceptable salts or solvates thereof, wherein the composition is substantially free of sugar alcohol. Therefore, a stable pharmaceutical composition for oral administration is desired with enhanced technical formulation attributes such as dissolution profile, stability, bioequivalence and which is simple, reproducible and commercially viable at industrial scale.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide a pharmaceutical composition comprising edoxaban tosylate, wherein the composition is substantially free of sugar alcohol.
Another object of the present invention is to provide a pharmaceutical composition comprising edoxaban tosylate, wherein sugar alcohol is not used as a dissolution enhancer.
Another object of the present invention is to provide a process for the preparation of pharmaceutical composition of edoxaban tosylate with superior content uniformity of the active agent along with desired dissolution profile, flowability and bioavailability.
Another object of the present invention provides a pharmaceutical composition of edoxaban tosylate wherein the impurity profile and stability comply with the regulatory/ICH guidelines.
In another object of the present invention is to provide an efficient industrially feasible and economical process for the preparation of pharmaceutical composition of edoxaban tosylate thereof.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a pharmaceutical composition of edoxaban tosylate.
According to an embodiment, the present invention provides a pharmaceutical composition comprises of an intragranular part, extragranular part and one or more pharmaceutically acceptable excipients.
According to another embodiment, the present invention provides a pharmaceutical composition comprises of an intragranular part, an extragranular part and one or more pharmaceutically acceptable excipients wherein the extragranular part includes active pharmaceutical ingredient.
According to another embodiment, the present invention provides a pharmaceutical composition of edoxaban tosylate, which comprises of
i. an intragranular part comprises diluent, disintegrant, binder solution and combinations thereof,
ii. an extragranular part comprises edoxaban tosylate, solubilizer, diluent, disintegrant, lubricant and/or glidant or combinations thereof.
According to an embodiment, the present invention provides an efficient process for the preparation of pharmaceutical composition of edoxaban tosylate, which comprises the steps of:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution of one or more pharmaceutically acceptable excipients in a suitable solvent,
iii. granulating the dry mixed powder obtained in step (i) with the solution of step (ii) to form intragranular part,
iv. drying the granules,
v. blending the dried granules with extragranular part comprises of edoxaban tosylate and one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a pharmaceutical composition of edoxaban tosylate, which comprises of an intragranular part comprises diluent, disintegrant, binder solution and combinations thereof and an extragranular part comprises edoxaban tosylate, solubilizer, diluent, disintegrant, lubricant and/or glidant or combinations thereof.
The present invention further provides an efficient process for the preparation of pharmaceutical composition of edoxaban tosylate comprising diluent, disintegrant, solvent, binder, solubilizer, lubricant, and coating agents wherein the intragranular part is free from active pharmaceutical ingredient (edoxaban tosylate).
The term “intragranular” means the part of the formulation which constitutes the granules. The term “intragranular part” used herein does not substantially contain any active pharmaceutical ingredient (API) and comprises of diluent, disintegrant, binder and/or solubilizer and optionally one or more pharmaceutically acceptable excipients. Preferably, the intragranular part comprises diluent, disintegrant and binder. According to the present invention, the intragranular part can be prepared by any known process in the art. More preferably, intragranular part is prepared by wet granulation.
The term "extragranular part" is the part of the proposed formulation which is not a part of granules. The extragranular part is added to the granules to form solid dosage forms specifically tablet. The extragranular part comprises of active pharmaceutical ingredients (edoxaban tosylate), solubilizer, diluent, disintegrant, lubricant and/or glidant and optionally one or more pharmaceutically acceptable excipients. In a preferred invention, the extragranular part comprises active pharmaceutical ingredients (edoxaban tosylate), solubilizer, diluent, disintegrant, lubricant and/or glidant.
The term “solubilizer” as used herein is an excipient which improves the solubility and dissolution of the active pharmaceutical ingredient.
The term “pharmaceutical composition” as used herein means a product comprising an active compound or a salt thereof together with pharmaceutical excipients such as binder, diluent, solubilizer, disintegrant, lubricant optionally a glidant. Thus pharmaceutical composition is also distinguished in the art as a pharmaceutical formulation.
The term “free of sugar alcohol” as used herein means that sugar alcohol as an excipient has not been added in intragranular and/or extragranular part of the composition.
The term "solid dosage form" as used herein may include conventionally used dosage forms such as tablets, capsules and the like.
The term "stable" as used herein refers to chemical stability of edoxaban tosylate in solid dosage forms wherein there is no significant change in assay values and dissolution when the dosage form is kept at 40°C/75% RH for 6 months.
The term “coating agent” refers to film coating agents that are a group of substances that form a coating which provides a barrier to protect drugs from e.g., the pH environment of the stomach, and non-functional coating agents.
In a preferred embodiment of the present invention provide a solid oral pharmaceutical composition comprising intragranular part, extragranular part, edoxaban tosylate and one or more pharmaceutically acceptable excipients, wherein intragranular part is free from edoxaban tosylate.
In one of the preferred embodiments, the invention provides a process for preparation of pharmaceutical composition of edoxaban tosylate which comprises of the following steps:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution of one or more pharmaceutically acceptable excipients in a suitable solvent,
iii. granulating the dry mixed powder obtained in step (i) with the solution of step (ii) to form intragranular part,
iv. drying the granules,
v. blending the dried granules with extragranular part comprises of edoxaban tosylate and one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.
In another embodiment of the present invention provides a stable pharmaceutical composition comprising edoxaban tosylate in an amount of 5% to 40% w/w, diluent ranging from 20% to 80% w/w, binder ranging from 0.5% to 5% w/w, disintegrant ranging from 1% to 10% w/w, solubilizer ranging from 1 % to about 5 %, optionally glidant ranging from 1% to 10.0% w/w, lubricant ranging from 0.5% to 5% w/w and film coat ranging from 0% to 5% w/w, relative to the total weight of the pharmaceutical dosage form, wherein the pharmaceutical composition is devoid of sugar alcohol.
In a preferred embodiment, intragranular part comprising a diluent and one or more pharmaceutically acceptable excipient(s).
In a preferred embodiment of the present invention suitable "diluents" are selected from lactose, lactose monohydrate, sucrose, dextrose, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof. Typically, the weight of the diluent can be within the range of 20% to 80% w/w, relative to the total weight of the pharmaceutical dosage form.
In a preferred formulation of the present invention suitable “disintegrants” are selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof. Typically, the weight of the disintegrant can be within the range of 1% to 10% w/w, relative to the total weight of the pharmaceutical dosage form.
In a preferred formulation of the present invention suitable “binders” are hydrophilic polymers whereas hydrophilic polymers are selected from polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, pregelatinized starch and combination thereof. Typically, the weight of the binder can be within the range of 0.5% to 5% w/w, relative to the total weight of the pharmaceutical dosage form.
In one of the preferred embodiments, the intragranular part is prepared by granulation technique. The granulation technique used herein may include but not limited to aqueous granulation, non-aqueous or dry granulation. Preferably the intragranular part is prepared by aqueous granulation.
In a preferred formulation, the suitable “solvents” is water and /or alcohol. Especially in the present invention, the preferred solvent is water.
In a preferred embodiment, extragranular part comprising edoxaban tosylate and one or more pharmaceutically acceptable excipient(s). In a preferred invention, the excipient comprises solubilizer, diluent, disintegrant, lubricant and/or glidant or combination thereof.
In a preferred formulation of the present invention, extragranular part contains the weight of the edoxaban tosylate within the range of 5% to 40% w/w, relative to the total weight of the pharmaceutical dosage form.
In a preferred formulation of the present invention suitable “solubilizer” are selected from derivatives of cellulose (hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, polyvinylpyrrolidone, preferably having a weight average molecular weight of 10,000 to 60,000 g/mol, copolymers of polyvinylpyrrolidones, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g. Povidon VA 64; BASF), preferably having a weight average molecular weight of 40,000 to 70,000 g/mol, polyoxyethylene alkylethers, polyethylene glycol, co-blockpolymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic®). Especially, preferred solubilizer in the present invention is SEPITRAP 80 (polysorbate and magnesium aluminometasilicate), sodium lauryl sulphate and combination thereof.
In a preferred embodiment, the formulation uses SEPITRAP 80 as a preferred solubilizer, wherein SEPITRAP 80 is a micro-encapsulated solubilizer in powder form which is designed to simplify the manufacturing of solid oral form drugs. It is manufactured by adsorption of the solubilizer in liquid form on a porous support. It is both a solid solubilizer and a compression agent. It is a functional excipient designed specifically to simplify manufacturing of dry-form drugs while improving bioavailability of the active ingredient. SEPITRAP 80 consists of polysorbate 80 (45-65%) and magnesium aluminometasilicate (35-55%). Typically, the weight of the solubilizer can be within the range of 1% to 5.0% w/w, relative to the total weight of the pharmaceutical dosage form. Preferably about 3.0% to about 4.0 % by weight relative to the total weight of the composition.
In a preferred formulation of the present invention suitable “lubricants” are selected from calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof. Typically, the weight of the lubricant can be within the range of 0.5% to 5.0% w/w, relative to the total weight of the pharmaceutical dosage form.
In the present invention, the formulation uses AquaPolish® P yellow (922.03), AquaPolish® P orange (932.01) and AquaPolish® P pink (942.04) as a coating agent. Typically, the weight of the coating material can be within the range of 0% to 5.0% w/w, relative to the total weight of the pharmaceutical dosage form. Preferably about 3.0% to about 5.0 % by weight relative to the total weight of the composition.
According to the present invention, the composition may or may not contain sugar alcohol as a part of coating material.
In a preferred formulation, the suitable “glidant” can be selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and combination thereof. Typically, the weight of the glidant can be within the range of 1% to 10.0% w/w, relative to the total weight of the pharmaceutical dosage form.
The pharmaceutical composition of the present invention is solid oral dosage form containing edoxaban in conventional pharmaceutical dosages for example tablet, capsules, pellets and granules.
In another embodiment, pharmaceutical composition of the present invention exhibits greater than 70% of drug release within 30 minutes. The dissolution profile of the final dosage form complies with the regulatory requirements. Specifically, the pharmaceutical composition of the present invention exhibits more than 70% of drug release within 30 minutes in 500 ml of 0.1 N HCl (Office of Generic Drugs dissolution database) using a USP I apparatus (basket) at a temperature of 37±0.5° C. and a rotation speed of 100 revolutions per minute.
The pharmaceutical composition of the present invention boosts dissolution properties at physiologic pH. The dissolution studies of compositions comprising edoxaban tosylate, having dissolution more than 70% within 30 minutes wherein edoxaban tosylate is present in an amount of 5 to 40% w/w of the total weight of the pharmaceutical composition.
In accordance with another embodiment of the present invention, there is provided a pharmaceutical composition which is stable at 40°C and 75% relative humidity. The level of impurities is controlled within the composition as per regulatory guidelines.
The following example, which includes preferred embodiments, will serve to illustrate the practice of the invention, it is to be understood that the examples are provided solely for purposes of illustration and should not be regarded as limiting the scope of the invention in any manner.
Examples
Example 1: Tablet containing 60 mg of edoxaban
S. No. Ingredients
mg/tablet
Intragranular

1 Microcrystalline cellulose 160.000
2 Pregelatinized starch 42.000
3 Crospovidone 12.000
Binder

4 Hydroxypropyl cellulose 12.000
5 Purified Water QS
Extragranular

6 Edoxaban Tosylate Monohydrate 80.820
7 Sepitrap 80 12.000
8 Microcrystalline cellulose 19.180
9 Pregelatinized starch 42.000
10 Crospovidone 12.000
Lubrication
11 Magnesium stearate 8.000
Weight Core tablet
400.000
Film Coating
12 Aquapolish P Yellow 922.03 STA 16.00
13 Purified water QS
Weight of Film Coated tablet
416.000

Procedure:
1. Microcrystalline cellulose, pregelatinized starch, crospovidone were sifted through sieve and mixed uniformly.
2. The dry mixed powder prepared in step 1 was granulated with hydroxypropyl cellulose and purified water to obtain granules of intragranular part.
3. The granules of step 2 were dried and passed through sieve followed by milling to obtain dried and sized granules.
4. Edoxaban tosylate monohydrate, sepitrap 80, microcrystalline cellulose, pregelatinized starch and crospovidone were sifted through sieve and mixed with granules obtained from step 3 in the blender.
5. Magnesium stearate was sifted and mixed with the material obtained in step 4 for the lubrication.
6. The lubricated blend was compressed into tablet of an average weight of 400 mg.
7. The compressed tablet obtained in step 6 was coated by using Aquapolish P Yellow 922.03 STA and water to get tablets of an average weight of 416 mg.

Example 2: Tablet containing 60 mg of edoxaban
S. No. Ingredients
mg/tablet
Intragranular
1 Microcrystalline cellulose 160.000
2 Pregelatinized starch 42.000
3 Crospovidone 12.000
Binder
4 Hydroxypropyl cellulose 12.000
5 Purified Water QS
Extragranular
6 Edoxaban Tosylate Monohydrate 80.820
7 Sepitrap 80 12.800
8 Microcrystalline cellulose 19.180
9 Pregelatinized starch 42.000
10 Crospovidone 12.000
Lubrication
11 Sodium stearyl fumarate 7.200
Weight Core tablet
400.000
Film Coating
12 Aquapolish P Yellow 922.03 STA 16.00
13 Purified water QS
Weight of Film Coated tablet
416.000

Procedure:
1. Microcrystalline cellulose, pregelatinized starch, crospovidone were sifted through sieve and mixed uniformly.
2. The dry mixed powder prepared in step 1 was granulated with hydroxypropyl cellulose and purified water to obtain granules of intragranular part.
3. The granules of step 2 were dried and passed through sieve followed by milling to obtain dried and sized granules.
4. Edoxaban tosylate monohydrate, sepitrap 80, microcrystalline cellulose, pregelatinized starch and crospovidone were sifted through sieve and mixed with granules obtained from step 3 in the blender.
5. Sodium stearyl fumarate was sifted through sieve and mixed with the material obtained in step 4 for the lubrication.
6. The lubricated blend was compressed into tablet of an average weight of 400 mg.
7. The compressed tablet obtained in step 6 was coated by using Aquapolish P Yellow 922.03 STA and water to get tablets of an average weight of 416 mg.
Example 3: Tablet containing 60 mg of edoxaban
S. No. Ingredients
mg/tablet
Intragranular

1 Microcrystalline cellulose 160.000
2 Pregelatinized starch 42.000
3 Crospovidone 12.000
Binder

4 Hydroxypropyl cellulose 12.000
5 Purified Water QS
Extragranular

6 Edoxaban Tosylate Monohydrate 80.820
7 Sepitrap 80 13.200
8 Microcrystalline cellulose 20.380
9 Pregelatinized starch 42.000
10 Crospovidone 12.000
Lubrication
11 Magnesium stearate 5.600
Weight Core tablet
400.000
Film Coating
12 Aquapolish P Yellow 922.03 STA 16.00
13 Purified water QS
Weight of Film Coated tablet
416.000

Procedure:
1. Microcrystalline cellulose, pregelatinized starch, crospovidone were sifted through sieve and mixed uniformly.
2. The dry mixed powder prepared in step 1 was granulated with hydroxypropyl cellulose and purified water to obtain granules of intragranular part.
3. The granules of step 2 were dried and passed through sieve followed by milling to obtain dried and sized granules.
4. Edoxaban tosylate monohydrate, sepitrap 80, microcrystalline cellulose, pregelatinized starch and crospovidone were sifted through sieve and mixed with granules obtained from step 3 in the blender.
5. Sodium stearyl fumarate was sifted through sieve and mixed with the material obtained in step 4 for the lubrication.
6. The lubricated blend was compressed into tablet of an average weight of 400 mg.
7. The compressed tablet obtained in step 6 was coated by using Aquapolish P Yellow 922.03 STA and water to get tablets of an average weight of 416 mg.
Stability Study
The composition of edoxaban tosylate monohydrate was stored at 40°C/75% RH and was tested for impurities at specific intervals.
The result is as below:

Example 3 Specification
Assay
(95.0 to 105.0%) Individual unspecified impurity
Total impurity

Initial 99.20 0.06 0.22
3 Months 99.10 0.09 0.23

Dissolution Study
Dissolution study of edoxaban tosylate monohydrate was conducted in 500 mL 0.1N HCl media with USP Apparatus II (Paddle) and release of edoxaban tosylate monohydrate at time point of 30 minutes on stability at 40° C/75% RH.
The result is as below:

% Drug Release
Initial 3 Months (40° C /75% RH)
84% 82%

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples are provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:WE CLAIM
1. A pharmaceutical composition of edoxaban tosylate, which comprises of:
i. an intragranular part comprises diluent, disintegrant, binder and combinations thereof,
ii. an extragranular part comprises edoxaban tosylate, solubilizer, diluent, disintegrant, lubricant and/or glidant or combinations thereof.
2. The pharmaceutical composition as claimed in claim 1, wherein intragranular part in step (i) comprises binder ranging from 0.5% to 5% w/w, relative to the total weight of the pharmaceutical dosage form; wherein extragranular part in step (ii) comprising edoxaban tosylate in an amount of 5% to 40% w/w, solubilizer ranging from 1% to about 5%, optionally glidant ranging from 1% to 10.0% w/w, lubricant ranging from 0.5% to 5% w/w, relative to the total weight of the pharmaceutical dosage form.
3. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutical composition comprises diluent ranging from 20% to 80% w/w and disintegrant ranging from 1% to 10% w/w, relative to the total weight of the pharmaceutical dosage form, wherein the pharmaceutical composition is devoid of sugar alcohol.
4. The pharmaceutical composition as claimed in claim 1, further comprising film coat ranging from 0% to 5% w/w, relative to the total weight of the pharmaceutical dosage form.
5. The pharmaceutical composition as claimed in claim 2, binder is hydrophilic polymers wherein hydrophilic polymers are selected from polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates, pregelatinized starch and combination thereof.
6. The pharmaceutical composition as claimed in claim 2, solubilizer is selected from derivatives of cellulose (hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, polyvinylpyrrolidone, preferably having a weight average molecular weight of 10,000 to 60,000 g/mol, copolymers of polyvinylpyrrolidones, preferably copolymers comprising vinylpyrrolidone and vinylacetate units, preferably having a weight average molecular weight of 40,000 to 70,000 g/mol, polyoxyethylene alkylethers, polyethylene glycol, co-blockpolymers of ethylene oxide and propylene oxide, SEPITRAP 80, sodium lauryl sulphate and combination thereof; lubricant is selected from calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof; wherein glidant is selected from calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and combination thereof.
7. The pharmaceutical composition as claimed in claim 3, wherein diluent is selected from lactose, lactose monohydrate, sucrose, dextrose, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof; wherein disintegrant is selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof.
8. The pharmaceutical composition as claimed in claim 4, wherein film coating material is selected from AquaPolish® P yellow, AquaPolish® P orange and AquaPolish® P pink.
9. A process for the preparation of pharmaceutical composition of edoxaban tosylate, which comprises the steps of:
i. dry mixing of one or more pharmaceutically acceptable excipients,
ii. preparing a solution of one or more pharmaceutically acceptable excipients in a suitable solvent,
iii. granulating the dry mixed powder obtained in step (i) with the solution of step (ii) to form intragranular part,
iv. drying the granules,
v. blending the dried granules with extragranular part comprises of edoxaban tosylate and one or more pharmaceutical acceptable excipients,
vi. lubricating the above blend of step (v) with a suitable lubricant,
vii. compressing the lubricated blend into solid dosage form, and
viii. optionally, coating the solid dosage form.
10. The pharmaceutical composition as claimed in proceeding claims, wherein edoxaban tosylate is present in an amount of 5% to 40% w/w of the total weight of the pharmaceutical composition having dissolution more than 70% within 30 minutes.