DESC:FIELD OF THE INVENTION

The present invention is related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.

BACKGROUND OF THE INVENTION

Edoxaban is a factor Xa inhibitor and is chemically described as N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide.

Formula I

Edoxaban is approved in the form of immediate release tablets and marketed by Daiichi Sankyo under the brand name LIXIANA® (Innovator product).

The immediate release tablets are approved in the strengths of 15 mg, 30 mg and 60 mg and are indicated in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age = 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA). Lixiana® is also indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults.

EP1405852 patent discloses an edoxaban as compound. The compounds of the patent are useful for treating and/or preventing thrombosis or embolism.

EP2140867 patent discloses a film coated tablet composition comprising edoxaban or a pharmacologically acceptable salt thereof or its hydrate, a sugar alcohol and a water-swelling additive; with improved dissolution property.

EP2548556 patent discloses a method for preparation of granules comprising edoxaban or a pharmaceutically acceptable salt thereof, or a solvate thereof, one or more excipients selected from the group consisting of a sugar alcohol and a water-swelling additive, a disintegrant and a binder, wherein the process is wet granulation and the maximum water content of the granules during granulation is 10% or less.

EP2742941 patent discloses a solid formulation containing edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof and one or more components selected from the group consisting of carmellose and fumaric acid, wherein a dosage form of the solid formulation is a tablet or a capsule which have an improved dissolution property.

EP2444087 patent discloses a tablet composition containing edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof, wherein the content of edoxaban is 0.5% by weight or more and less than 10% by weight with respect to the total weight of the pharmaceutical composition.

EP3549585 patent application discloses an orally disintegrating tablet comprising edoxaban or a pharmacologically acceptable salt thereof or a solvate thereof, an organic acid, a water soluble polymer and a disintegrant.

EP3177290 patent discloses the pharmaceutical composition comprising edoxaban or a pharmaceutically acceptable salt thereof, a water soluble vinylpyrrolidone polymer selected from the group consisting of povidone and copovidone, and a cellulose ether and not is devoid of sugar alcohol.

EP3744320 patent application discloses a tablet composition comprising edoxaban or a salt thereof or a hydrate, lactose as a water-soluble filler and crospovidone and sodium starch glycolate as disintegrants.

EP4076406 patent application discloses a tablet comprising edoxaban or a pharmaceutically acceptable salt thereof, a lactose as a first diluent and a starch as a second diluent.

The above prior art references disclose compositions comprising edoxaban. However, there still exists a need for the development of formulations comprising edoxaban. The present invention provides a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol and has comparable dissolution properties and is bioequivalent to innovator product (Lixiana®).

OBJECT OF THE INVENTION

The primary object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein D90 particle size of edoxaban is not more than 10 micron.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof, and wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more binders, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.

Another object of the present invention is to provide a process for preparation of pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutically acceptable excipients, wherein the said formulation is devoid of sugar alcohol.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 75% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition does not have more than 2.0% (w/w) of total impurity of edoxaban, after being stored at specific storage conditions.

Another object of the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is bioequivalent to innovator product (Lixiana®).

SUMMARY OF THE INVENTION

The present invention related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.

DETAILED DESCRIPTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention is related to a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron.

The term “Edoxaban” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with the said composition.

The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredient edoxaban is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.

The term “specific storage conditions” as used throughout the specification, refers to the pharmaceutical composition of present invention stored for at least 1 month at 40°C/75% RH. Preferably, the pharmaceutical composition of present invention can be stored for at least 6 month at 40°C/75% RH and 25° C/60% RH.

In accordance with the present invention, the term “about” shall mean a variation up to 10% (plus or minus 10%) of the particular term.

In accordance with the present invention, the term “D90” shall mean a pharmaceutical composition in which 90% of the edoxaban particles have a particle size of less than about 10 microns.

In accordance with the present invention, an assay value of edoxaban in pharmaceutical composition of edoxaban is within the limits of 95% to 105% after stability study according to ICH guidelines which is comparable when compared with reference product Lixiana®.

The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredient edoxaban is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.

The term “bioequivalence” as used throughout the specification, refers to an extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action.

The term "Cmax" as used throughout the specification, refers to the highest (peak) concentration of a drug in the bloodstream or other part of the body after drug administration. Cmax is a key pharmacokinetic measure and informs dosing schedules.

The term "AUC" as used throughout the specification, refers an area under the curve that means the area under the plasma drug concentration-time curve reflects the actual body exposure to drug after administration of a dose of the drug. The information is useful for determining dosing and for identifying potential drug interactions.

The term "AUC0-inf" as used throughout the specification, refers an area under the curve extrapolated to infinity.

The term "AUC0-t" as used throughout the specification, refers an area under the curve from time zero to the last measurable time point.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, and wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, wherein D90 particle size of edoxaban is not more than 10 micron, wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof, and wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more binders, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.

The water-swelling additive employed in the present invention refers to an additive for pharmaceuticals which swells with water added thereto. Examples of the water-swelling additive in the present invention include diluents and bases which are water-swellable. The water swelling additive can be selected from the group comprising of but not limited to microcrystalline cellulose, pregelatinized starch, a-starch, sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, soybean lecithin, low-substituted hydroxypropyl cellulose, powdered tragacanth, bentonite and combinations thereof. The water swelling additive can be present in a concentration of from about 40% to about 80% by weight of the total weight of the composition.

The sugar alcohol can refer to mannitol, xylitol, erythritol.

The diluents can be selected from the group comprising of but not limited to dibasic calcium phosphate anhydrous, corn starch, sucrose or other sugar or sugar derivatives, low substituted HPC or mixture thereof.

The disintegrant can be selected from the group comprising of but not limited to croscarmellose sodium, crospovidone, sodium starch glycolate, starch, corn starch or mixture thereof, more preferably crospovidone. The disintegrant can be present in a concentration of from about 2% to about 8% by weight of the total weight of the composition.

The binder can be selected from the group comprising of but not limited to polyvinylpyrrolidone, povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, maize starch or mixture thereof, more preferably hydroxypropyl cellulose. The binder can be present in a concentration of from about 2% to about 6% by weight of the total weight of the composition.

The lubricant can be selected form the group comprising of agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, sodium stearyl, sorbitol, stearic acid, talc, and zinc stearate or mixture thereof, more preferably magnesium stearate. The lubricant can be present in a concentration of from about 1% to about 4% by weight of the total weight of the composition.

The solvent can be selected from the group of pharmaceutically acceptable solvents comprising of purified water, dichloromethane, isopropyl alcohol or mixtures thereof.

In one of the embodiments, the present invention is to provide a process for preparation of pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutically acceptable excipients, wherein the said formulation is devoid of sugar alcohol. Further, one of the process for preparation of pharmaceutical composition of edoxaban according to the present invention comprising following steps:
1. Co-sifting edoxaban with water-swelling additive and disintegrant.
2. Preparation of binder solution wherein binder was dissolved into solvent under gentle stirring to get a clear solution.
3. Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
4. Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
5. Granules of step 4 were dried in rapid dryer.
6. Dried granules of step 5 were milled through co-mill.
7. Extra granular material, i.e., disintegrant was sifted and mixed with sized granules of step 6 in the blender.
8. Lubricant was sifted and mixed with the blend of step 7 in the blender.
9. The common blend of step 8 was bifurcated for compression of tablets.
10. Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
11. The tablets were coated with coating agent using auto coater.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said formulation is devoid of sugar alcohol, and wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Acetate buffer pH 4.5 in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the release of edoxaban is in line with the innovator product (Lixiana®) when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein edoxaban is released more than 75% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition does not have more than 2.0% (w/w) of total impurity of edoxaban, after being stored at specific storage conditions.

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is having a ratio of test vs reference value of more than 90 % with the innovator product (Lixiana®).

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition having coefficient of variation less than 30 % with the innovator product (Lixiana®).

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition having confidence interval value more than 80 % with the innovator product (Lixiana®).

In one of the embodiments, the present invention is to provide a pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is bioequivalent to innovator product (Lixiana®).

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.

Example 1:

Sr. No Ingredients % w/w
1 Edoxaban 15.0 - 25.0
2 Water Swelling Additive 40.0 - 80.0
3 Disintegrant 2.0 - 8.0
4 Binder 2.0 - 6.0
6 Lubricant 1.0 - 4.0
7 Solvent q.s.
Core tablet weight 100

Manufacturing process:
1. Co-sifting edoxaban with water swelling additive and disintegrant.
2. Preparation of binder solution wherein binder was dissolved in the solvent under gentle stirring to get clear solution.
3. Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
4. Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
5. Granules of step 4 were dried in rapid dryer.
6. Dried granules of step 5 were milled through co-mill.
7. Extra granular material disintegrant was sifted and mixed with sized granules of step 6 in the blender.
8. Lubricant was sifted and mixed with blend of step 7 in the blender.
9. Common blend of step 8 was bifurcated for compression of tablets.
10. Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.

Example 2:

Sr. No Ingredients % w/w
1 Edoxaban 15.0 - 25.0
2 Water Swelling Additive 40.0 - 80.0
3 Disintegrant 2.0 - 8.0
4 Binder 2.0 - 6.0
6 Lubricant 1.0 - 4.0
7 Solvent q.s.
Core tablet weight 100
8 Coating Agent q.s.
Coated tablet weight -

Manufacturing process:
1. Co-sifting edoxaban with water-swelling additive and disintegrant.
2. Preparation of binder solution wherein binder was dissolved in the solvent under gentle stirring to get clear solution.
3. Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
4. Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
5. Granules of step 4 were dried in rapid dryer.
6. Dried granules of step 5 were milled through co-mill.
7. Extra granular material disintegrant was sifted and mixed with sized granules of step 6 in the blender.
8. Lubricant was sifted and mixed with blend of step 7 in the blender.
9. Common blend of step 8 was bifurcated for compression of tablets.
10. Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
11. The tablets were coated with coating agent using auto coater.

Example 3:

Sr. No Ingredients % w/w
1 Edoxaban 15.0 - 25.0
2 Microcrystalline cellulose 40.0 - 60.0
3 Pregelatinized starch 15.0 - 25.0
4 Crospovidone 2.0 - 8.0
5 Hydroxy Propylcellulose 2.0 - 6.0
6 Magnesium Stearate 1.0 - 4.0
7 Purified water q.s.
Core tablet weight 100
8 Coating Agent q.s.
Coated tablet weight -

Manufacturing process:
1. Co-sifting edoxaban with microcrystalline cellulose, pregelatinized starch, and crospovidone.
2. Preparation of Hydroxypropyl cellulose solution wherein Hydroxypropyl cellulose was dissolved into purified water under gentle stirring to get clear solution.
3. Sifted material of step 1 was transferred to rapid mixer granulator and dry mixed.
4. Dry mix material of step 3 was granulated using binder solution of step 2 in the rapid mixer granulator.
5. Granules of step 4 were dried in rapid dryer.
6. Dried granules of step 5 were milled through co-mill.
7. Extra granular material crospovidone was sifted and mixed with sized granules of step 6 in the blender.
8. Magnesium stearate was sifted and mixed with blend of step 7 in the blender.
9. Common blend of step 8 was bifurcated for compression of tablets.
10. Lubricated blend was compressed at theoretical weight of tablet by using appropriate tooling in compression machine.
11. The tablets were coated with coating agent using auto coater.

DISSOLUTION STUDY:
The composition of example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using 0.1 M Hydrochloric acid in 900 mL of volume and gave the following results as Table 1.

Table 1:
Sr. No. Time Points (minutes) Edoxaban tablets
60 mg (Lixiana®) 15 mg 30 mg 60 mg
EU CA
1 5 25 16 60 41 45
2 10 77 67 93 85 84
3 15 97 98 98 97 93
4 20 98 99 99 99 94
5 30 100 99 100 100 95
6 45 101 99 101 100 97
7 60 101 99 101 101 97

The above dissolution study shows the release of edoxaban tablet is comparable to the innovator product (Lixiana®).

The composition of example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using Acetate buffer pH 4.5 in 900 mL of volume and gave the following results as Table 2.

Table 2:
Sr. No. Time Points (minutes) Edoxaban tablets
60 mg (Lixiana®) 15 mg 30 mg 60 mg
EU CA
1 5 44 31 76 58 78
2 10 100 90 96 93 90
3 15 101 97 100 101 94
4 20 102 97 102 101 96
5 30 102 97 102 102 97
6 45 102 97 102 102 98
7 60 102 97 103 103 98

The above dissolution study shows the release of edoxaban tablet is comparable to the innovator product (Lixiana®).

The composition of example 4 was tested for dissolution study as per USP Apparatus 2 (Paddle type) at 50 rpm using Phosphate buffer pH 6.8 in 900 mL of volume and gave the following results as Table 3.

Table 3:
Sr. No. Time Points (minutes) Edoxaban tablets
60 mg (Lixiana®) 15 mg 30 mg 60 mg
EU CA
1 5 11 9 22 7 27
2 10 47 42 40 36 43
3 15 60 57 50 48 53
4 20 68 66 58 56 58
5 30 75 75 68 65 65
6 45 81 81 77 74 72
7 60 85 85 83 80 77

The above dissolution study shows the release of edoxaban tablet is comparable to the innovator product (Lixiana®).

STABILITY STUDY
Table 4: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 1 month time interval at condition of 40°C / 75 % RH in Alu- Alu Blister.

Strength Assay Related substances Limit Alu Alu Blister Pack
15 mg 101.2% Total impurity Not more than 2.0% 0.052%
30 mg 100.0% Total impurity Not more than 2.0% 0.051%
60 mg 100.0 % Total impurity Not more than 2.0% BQL (0.05 %)

Table 5: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 1 month time interval at condition of 40°C / 75 % RH in HDPE bottle.

Strength Assay Related substances Limit HDPE Bottle
15 mg 99.8% Total impurity Not more than 2.0% 0.053 %
30 mg 99.5% Total impurity Not more than 2.0% 0.050%
60 mg 99.6% Total impurity Not more than 2.0% BQL (0.05 %)

The above data shows a total impurity not more than 2% in the formulation and assay value within the range of ICH guideline, indicative of stability of edoxaban in the drug product.

Table 6: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 40°C / 75 % RH in Alu- Alu Blister.

Alu Alu Blister 40° C/75% RH
Strength Test Limit 3 Months 6 Months
15 mg Assay 95.0% to 105.0% 101.5% 100.7%
Total Impurity Not more than 2.0% 0.060% 0.063%
30 mg Assay 95.0% to 105.0% 101.5% 100.8%
Total Impurity Not more than 2.0% 0.062% 0.17%
45 mg Assay 95.0% to 105.0% 100.2% 99.2%
Total Impurity Not more than 2.0% BQL (0.05 %) 0.158%

Table 7: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 25° C / 60% RH in Alu- Alu Blister.

Alu Alu Blister 25° C/60% RH
Strength Test Limit 3 Months 6 Months
15 mg Assay 95.0% to 105.0% 100.9% 99.2%
Total Impurity Not more than 2.0% 0.055% 0.057%
30 mg Assay 95.0% to 105.0% 99.0% 100.0%
Total Impurity Not more than 2.0% 0.051% 0.136%
45 mg Assay 95.0% to 105.0% 101.7% 102.2%
Total Impurity Not more than 2.0% BQL (0.05 %) 0.136%

Table 8: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 40°C / 75 % RH in HDPE bottle.

HDPE Bottle 40° C/75% RH
Strength Test Limit 3 Months 6 Months
15 mg Assay 95.0% to 105.0% 100.5% 101.0%
Total Impurity Not more than 2.0% 0.067% 0.125%
30 mg Assay 95.0% to 105.0% 101.0% 100.7%
Total Impurity Not more than 2.0% 0.062% 0.194%
45 mg Assay 95.0% to 105.0% 100.3% 98.9%
Total Impurity Not more than 2.0% 0.05% 0.173%

Table 9: Stability data of edoxaban tablet 15mg, 30mg & 60mg under 3 month & 6 month time interval at condition of 25° C / 60% RH in HDPE bottle.

HDPE Bottle 25° C/60% RH
Strength Test Limit 3 Months 6 Months
15 mg Assay 95.0% to 105.0% 100.4% 100.3%
Total Impurity Not more than 2.0% 0.054% 0.059%
30 mg Assay 95.0% to 105.0% 100.1% 99.3%
Total Impurity Not more than 2.0% 0.051% 0.152%
45 mg Assay 95.0% to 105.0% 99.2% 99.9%
Total Impurity Not more than 2.0% 0.054% 0.135%

The above data shows a total impurity not more than 2% in the formulation and assay value within the range of ICH guideline, indicative of stability of edoxaban in the drug product.

Tablet 10: Bioequivalence data of edoxaban tablets 60mg in fasting condition of healthy adult human.

Pharmacokinetic Parameters % Ratio (T/R) % CV 90% CI (Lower-Upper)
Cmax 95.5 28.2 80.3 – 113.7
AUC0-t 99.6 13.6 91.4 – 108.4
AUC0-inf 100 13.1 91.4 – 108.4
Bioequivalence Yes Yes Yes

The above data shows a value of Cmax, AUC0-t & AUC0-inf within the range of FDA guideline, indicative of bioequivalent of edoxaban tablet with Lixiana® edoxaban tablets 60 mg.
,CLAIMS:We claims:

1. A pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is devoid of sugar alcohol.

2. The pharmaceutical composition of edoxaban as claimed in claim 1, wherein the said water swelling additive is selected from the group consisting of microcrystalline cellulose, pregelatinized starch and combinations thereof.

3. The pharmaceutical composition of edoxaban as claimed in claim 1, wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more binders, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.

4. The pharmaceutical composition of edoxaban as claimed in claim 1, wherein D90 particle size of edoxaban is not more than 10 micron.

5. The pharmaceutical composition of edoxaban as claimed in claim 1, wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M hydrochloric acid in 900 mL of volume, or wherein edoxaban is released more than 95% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in acetate buffer pH 4.5 in 900 mL of volume, or wherein edoxaban is released more than 75% at 60 minutes when the said composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in phosphate buffer pH 6.8 in 900 mL of volume.

6. The pharmaceutical composition of edoxaban as claimed in claim 1, wherein the said composition does not have more than 2.0% (w/w) of total impurity of edoxaban, after being stored at 40°C/75% for at least 6 months.

7. The process for preparation of a pharmaceutical composition of edoxaban as claimed in claim 1, comprising the steps of:
a) co-sifting edoxaban with water-swelling additive and disintegrant,
b) preparation of binder solution wherein binder was dissolved into solvent under gentle stirring to get a clear solution,
c) sifted material of step a) was transferred to granulator and dry mixed,
d) dry mix material of step c) was granulated using binder solution of step b) in granulator and dried,
e) dried granules of step d) were milled through co-mill,
f) extra granular material, i.e., disintegrant was sifted and mixed with sized granules of step e) in the blender,
g) lubricant was sifted and mixed with the blend of step f) in the blender and further compressed to obtained tablets
h) the tablets were coated with coating agent to obtain coated tablets

8. A pharmaceutical composition of edoxaban comprising edoxaban or its pharmaceutically acceptable salt thereof, water swelling additive and one or more pharmaceutical acceptable excipient, wherein the said composition is devoid of sugar alcohol and the said composition is bioequivalent to innovator product (Lixiana®).