PHA R MAC E UTICA L FOR M U LAT IO NS OF A PIXA BA N FIE L D O F T H E INV E NTION

The present invention relates to pharmaceutical compositions comprising Factor X a inhi bitors. Present invention particularly relates to pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient The present invention also relates to a process for the preparation of pharmaceutical composition comprising apixaban or a pharmaceutically acceptable salt thereof and the use of the pharmaceutical compositions for the treatment and/or prevention of thromboembolic disorders.

BAC K G R OU ND OF T H E INV E NT ION

The prevention and treatment of blood clot formation, expansion, and/or migration in the blood and blood vessels of individuals havi ng certain clinical history normally requires the use of anticoagulants. For the clinical management of the conditions such as venous thrombosis, pulmonary embolism, prosthetic (replacement or mechanical) heart valves, irregular heartbeat and those who have suffered a heart attack, anticoagulants are frequently prescribed which act as blood thinner and decrease the clotting abi lity of the blood. Vitamin K antagonists (V KAs) e.g. warfarin, unfractionated heparin (U FH), and low molecular weight heparin (L MWH) have been commonly prescribed anticoagulants. Newer agents such as fondaparinux and enoxapari n sodi um have been developed as more effective anticoagulants and reported to have substantial ly low risk for heparin- i nduced thrombocytopenia compared with L MWH or U FH.

While anticoagulants are effective in treating and reducing the risk of thromboembolic conditions, they are associated with significant limitations that may lead to the risk for related, and potentially serious or fatal, bleeding events affecting their clinical use and acceptability. These conventional anticoagulants like U FH, L MWH, and new agents like fondaparinux are administered parenterally, which is inconvenient and expensive with respect to the long-term use, and require a health care professional for its administration. Though V itami n K antagonists are available for oral administration, they usually have a narrow therapeutic window and unpredictable therapeutic effect Many research studies are conducted to develop newer, more effective anticoagulants that can be administered oral ly. One approach has been to devel op smal I mol ecul e di rect factor X a i nhi bitors which targets to inhibit single enzymes, unlike the traditional anticoagulants (U FH, L MWH, and V KAs) that target multiple enzymes in the coagulation cascade. Therefore, Factor X a inhi bitors are found to be a class of compounds more efficacious for the treatment of thromboembolic disorders. In this class of compounds, first agent developed was Rivaroxaban (X arelto÷ by j anssen Pharms) and approved by USFDA in 2011 for oral administration.

Apixaban is a selective direct inhibitor of factor X a that participates in the blood coagulation systenri without requiring antithrombin III - unlike other conventional agents. It is developed by Bristol Myers Squibb and approved by the U.S. FDA for reducing the risk of stroke and systemic embol ism in patients with nonvalvular atrial fibrillation, for the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism in cases of hip or knee replacement

The synthesis of apixaban was first described in WO 2003/026652. WO 2006/078331 rel ates to a process or apparatus for transform! ng a f i rst polymorph i nto a second polymorph of the same chemical material, and discloses the H2-2 form in a needle-shaped dehydrate. It further di scl oses the H 2-2 form to be I ess stabl e than the granul ar, non-sol vate N - 1 form This international patent application does not relate to pharmaceutical compositions or method of maki ng i t U S 2016/143894 descri bes processes for the preparati on of crystal I i ne Form N-1 of apixaban having a mean particle size equal to or greater than 100 =m WO 2010/147978 describes controlled release apixaban formulations that are mainly provided as osmotic- control led release oral delivery systems (OR OS-formulation) such formulations are known to be complex, involve time consuming processes and require high cost equi pment, such as a laser for drilling the holes into the dosage form WO 2013/174498 discloses modified release apixaban compositions containing crystalline apixaban with a particle size distribution preferably with D ₅ o value of 5 to 500 =m WO 2014/052678 describes liquid formulations of apixaban. US 2013/0045245 and US 2016/0243101 further disclose compositions comprising crystalline apixaban wherein the drug particles have a maximum size cutoff and a D90 of the active equal to or less than about 89 i m. According to the disclosure of the above appl ication, it was found that in a tablet composition, apixaban particles having a D 90 less than 89 i m lead to consistent in-vivo dissolution and consistent exposure of the active in humans. It is also disclosed that tablets made using larger particles had lower exposures and/or dissolution compared to tablets made using the same process but with particle size of D90 of 50 I m Therefore the invention of US 2013/0045245 is particularly restricted to the use of smaller sized apixaban particles, specifically having a D90 equal to or less than about 89 I m.

Hence, it was an object of the present i nventi on to provide oral dosage forms of apixaban using the larger sized particles. In particular, it was an object of the present i nvention to provide apixaban oral dosage forms using a larger particle size than disclosed in the prior art. Inventors of this invention have surprisingly found, in contrast to that the teaching of the prior art; the desi red dissolution and bioavailability profiles can be achieved using apixaban with a I arger parti cl e size. It was another obj ect of the present i nventi on to provi de simple, less time consuming and cost-effective processes for the preparation of the pharmaceutical compositions.

SU M MA RY OF T H E INV E NTIO N

The present invention provides pharmaceutical compositions for oral administration comprising a therapeutically effective amount of a selective factor X a inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention is directed to pharmaceutical compositions comprising apixaban or a pharmaceuti cal ly acceptabl e salt thereof and a pharmaceutical ly acceptabl e carrier, wherei n the apixaban particles have a D90 more than 89 =m.

Accordingly, the present invention particularly provides pharmaceutical compositions comprising apixaban particles having a D90 more than 89 =m as measured by any suitable technique known i n the prior art and a pharmaceutically acceptable diluent or carrier. Suitable techniques known in the prior art for particle size determination that can be used in this invention include, but are not limited to microscopy, sieving, sedimentation and/or laser light scattering methods.

In one of the aspect of the present i nventi on, the parti cl e si ze of the apixaban i s determi ned by using Malvern light scattering.

Another aspect of the present invention provides a process for manufacturing a solid oral dosage form of a pharmaceutical composition comprising the steps of: i) blending apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof with at least one pharmaceutically acceptable carrier to form a blend; wherein apixaban particles have a D90 more than 89 =nr ii) granulating the blend to form a granulate, iii) addi ng one or more extragranular excipients, and iv) compressing the blend into solid oral dosage form and opti onal ly coati ng the dosage form with a f i I m coati ng.

In another aspect of the present invention, the pharmaceutical composition is prepared by a dry granulation process.

In yet another aspect of the present invention, the pharmaceutical composition is prepared by wet granulation.

Y et another aspect of the present invention provides a pharmaceutical composition comprising apixaban particles havi ng a D90 more than 89 =nr which releases at least 85 wt % of apixaban withi n 30 mi nutes.

Another aspect of the present invention comprises the use of at least one surfactant as a pharmaceuti cal carri er i n an amount of from about 0.1 % to about 5% by weight

Another aspect of the present invention provides a method of treating or preventing thromboembolic disorders, comprising administering to a subject in need thereof, a therapeutically effective amount of apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof and a pharmaceutically acceptable carrier, wherein apixaban particles have a D90 more than 89 =m

In another aspect of the present invention, it provides an easy and commercial ly viable process for manufacturing pharmaceutical composition of apixaban or a pharmaceutically acceptable salt, enantiomer, polymorph, ester or derivative thereof, characterized by apixaban particles having a D90 more than 89 =m DE TAIL E D DE SC R IPT ION O F T H E I NV E NT IO N

The present invention provides an immediate release pharmaceutical composition comprising Factor Xa inhibitors. The present invention provides pharmaceutical composition(s) comprising apixaban having a larger particle size than disclosed in the prior art.

The term ^" apixaban _, herein comprises various forms such as crystalline, amorphous, hydrates, anhydrates, solvates, pharmaceutical acceptable salts, enantiomers, polymorphs, esters, or derivatives thereof.

Apixaban may be obtained directly via the synthesis described in U.S. Pat. No. 6,967,208 and/or US 2006/0069258 (based on U.S. application Ser. No. 11/235,510 filed Sep. 26, 2005) or any other known process.

In an aspect of the present invention, apixaban in crystalline form is used. Various crystal line forms of apixaban known i n the prior art are within the scope of this invention, including but not limiting to, Form N-1, Form H2-2, Form M and others.

As used herein, the term ^" immediate release _, means that at least 70 wt % of a compound initially present in the dosage form is released within one hour or less following introduction to a use environment. A ^" use environment _, as used herein, can either mean various in- vivo fluids, such as the GI tract or the in- vitro environment of a test solution, such as phosphate buffered sal i ne.

The invention provides pharmaceutical compositions comprising apixaban particles having a D90 more than 89 i m and a pharmaceutically acceptable diluent or carrier. T he ranges of particle size preferred for use in the present invention is D90 more than 89 i m, more preferably D 90 i s at I east about 100 1 m, even more preferably D 90 i s at I east about 110 1 m. In an aspect of the present i nventi on, the D 90 i s between about 89 1 m to about 250 1 m T he particle size distribution of apixaban particles as described in the specification is characterized by D90 values. "Dgo _, is defined as 90% of the volume of particles havi ng a diameter less than a specified diameter.

Use of apixaban particles having particle size distribution more than that disclosed in the prior arts, particularly D90 more than 89 i m is a typical feature of this invention. As specified above in the background, patent application US 2013/0045245 is restricted to the use of smaller sized apixaban particles, specifically having D90 equal to or less than about 89 1 m i n order to achi eve consistent dissol uti on. T he compositi ons of the present i nvention use apixaban particles havi ng the size higher than that disclosed in above application, but it still achieves consistent desired dissolution profile.

The particle size distribution stipulated herein refers to the particle sizes determined by using any known suitable techniques such as microscopy, sieving, sedimentation and/or laser light scattering techniques.

The term "particles" refers to individual drug substance particles. T he particles may exist as single particles or as agglomerations, however, if the size of the primary apixaban particles comprising the agglomerate are more than 89 ι m individually, then the agglomerate itself is considered to meet the particle size requirements as described in this specification.

The present invention provides solid oral pharmaceutical compositions comprising apixaban with a D90 more than 89 1 m. Solid oral pharmaceutical compositions of the present invention include, but are not limited to, tablets, pellets, granules, powders, capsules, microcapsules, microspheres, spheroids, pel lets filled in capsules, tablets in capsules, multilayer tablets, bi layer tablets, tri layer tablets, or premixed powders filled in capsul es. In a preferred embodi ment of the present i nventi on, the sol i d oral dosage form i s a tablet.

T his i nvention further provides a pharmaceutical composition comprisi ng the use of at least one surfactant or wetting agent The term ^" wetting agent_ or ^" surfactant _, , as used herei n, refers to a surface active agent or a mixture of agents that lower the interfacial tension between a solid & a liquid or two liquids. In pharmaceutical formulations, surfactants aid in wetting of a hydrophobic drug i n a solid formulation to ensure efficient dissolution of the drug. T he surfactant may be natural or synthetic in origin. Further, it may be non- ionic, anionic, cationic or amphoteric in nature. Representative examples of surfactants that can be used in the present invention include, but are not l imited to, cremophors, polyethylene glycols, poloxamers, polysorbates, sodium lauryl sulphate, tragacanth, and/or mixtures thereof.

In an embodiment of the present invention, the surfactant used is sodium lauryl sulfate. In another embodiment of the present invention, the surfactant is a poloxamer. In yet another embodiment of the present invention, the surfactant is a mixture of sodi um lauryl sulfate and a poloxamer in an appropriate amount The present invention comprises the use of one or more surfactants from about 0.1% to 5% by weight. In an embodiment of the present invention, surfactants used in the compositions range from about 2% to 4%. In an embodiment of the present invention, the formulations exhibit and in vitro dissolution profile such that the amount of the drug equivalent to 85 wt% dissolves within 30 minutes. To study the dissolution criterion, the suitable dissolution test is selected and it is carried out i n an aqueous media non-buffered or buffered to a pH range (1 to 7.6) found in the gastroi ntesti nal tract and control I ed at 37°C ( e 10°C ) . V ari ous dosage forms, such as tabl ets and capsules, can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a tablet typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets. The amount of dissolved apixaban can be determined using suitable analytical techniques such as UV or H PLC.

Since in-vivo-in-vitro relationships are established, the dissolution (in-vitro) test, in addition to its application as a quality control technique, can more preferably be used to predict the biological (in-vivo) performance of the tablet

In one embodiment of the present invention, the dissolution test is performed in 900 mL of dissolution medium at 37° C, using USP Apparatus 2 (paddles) at a rotation speed of 75 rpm Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for apixaban. 0.1 N HCI or 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulphate (SLS) solution has been used as dissolution medium The formulations of the present invention lead to consistent i n-vitro dissolution profiles. This is one of the advantages of the present invention.

T he i nventi on further provi des processes for prepari ng pharmaceuti cal composi ti ons of the present invention.

In one embodi ment of the present i nventi on, the pharmaceuti cal compositi ons are prepared by a dry granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, granulati ng the blend using a dry granulation process, adding one or more extragranular excipients, compressing the blend i nto tabl ets and opti onal ly f i I m coati ng the tabl et

In another embodiment of the present i nvention, the pharmaceutical compositions are prepared by a dry granul ati on process comprises the steps of bl endi ng the apixaban parti cl es of a predetermined size with one or more excipients, adding a binder, disintegrant, and other fillers, and carrying out dry granulation by compacti ng the blend to ribbons of density in the range of 1.0 to 1.2 g/cc and then sizing the compacted ribbons using a roller compactor.

In further embodiment of the present invention, the pharmaceutical compositions are prepared by a wet granulation process comprising the steps of blending apixaban particles of a predetermined size with one or more excipients, adding a binder, disintegrant, and other fillers, and carrying out wet granulation using a solution comprising the bi nder in a suitable solvent followed by sizing the granules by passing them through a mill such as a screen mill. The granules are then dried using a convection oven or a fluid- bed dryer, and optionally sized by passing them through a mill such as a screen mill. A suitable disintegrant is then added as an extragranular material and mixed. The blend is then compressed i nto tabl ets. Opti onal ly, a f i I m coati ng i s appl i ed to the tabl ets.

Various pharmaceutically acceptable carriers or excipients are used in the compositions of the present invention, including fillers or diluents, binders, disintegrants, lubricants, glidants, and colorants.

^" Fil lers or diluents _, may be selected from the group comprising carbohydrates, confectioners sugar, compressible sugars, dextrose, dextrates, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. Fillers or diluents may be used in the range of 10-90% w/w of the total weight of the oral pharmaceutical composition.

^" Binders _, may be selected from the group comprisi ng potato starch, wheat starch, corn starch, microcrystall ine cellulose, cellulose, including hydroxy propyl cellulose, hydroxy propyl methyl cellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums including acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth; or combinations thereof. Binders may be used in the range of 1-15% w/w of the total weight of the oral pharmaceutical composition.

^" Disintegrants _, may be selected from the group comprising alginic acid, carboxymethyl cellulose calcium, carboxy methyl eel I ulose sodium, croscarmel lose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium algi nate, sodium starch glycolate, starches or combi nations thereof. Disintegrants may be used in the range of 1- 20% w/W of the total weight of the oral pharmaceuti cal composition.

" L ubri cants_ may be sel ected from the group comprisi ng al umi ni um stearate, zi nc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetabl e oi I , steari c aci d, magnesi um al umi num si I i cate, sodi um stearyl f umarate, glyceryl behenate, sodium benzoate or mixtures thereof. Lubricants may be used in the range of 0.1 - 5 % w/W of the total weight of the oral pharmaceutical composition.

"Glidants _, may be selected from the group comprising silicon dioxide, magnesium tri si licate, powdered cellulose, starch, talc, tri basic calcium phosphate, calcium silicate, magnesi um si I i cate, col I oi dal si I i con di oxi de, si I i con hydrogel or mixtures thereof. G I i dants may be used in the range of 0.01 ^" 4% w/W of the total weight of the oral pharmaceutical composition.

^" Colorants _, may be selected from the group comprising iron oxide yellow, iron oxide red, titanium dioxide or mixtures thereof. Colorants may be used in the range of 0.01 ^" 1.5% w/W of the total weight of the oral pharmaceutical composition.

The pharmaceutical compositions of the present invention may have one or more coati ngs such as f i I m coati ngs and/or sugar coati ngs. T he coati ng may compri se from about 1 - 4.5% w/W of the total weight of the pharmaceutical composition. ^" Coating agents _, which are useful in the coating process, may be selected from the group comprising water sol uble polymers including, polyvinylpyrrolidone or water soluble cellulose including, hydroxy propyl methyl cellulose or hydroxy propyl cellulose. Coating agents may be selected from the group comprising soluble agents such as polysorbate 80, polysaccharides such as, acacia, corn, sucrose, gelatin, shel lac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrol idone, vinyl acetate or combinations thereof. These may be applied from aqueous or non- aqueous systems or combi nations of aqueous and non-aqueous system as appropriate.

"Additives _, may be selected along with film formers to obtain satisfactory films. These additives may be selected from the group comprising plasticizers such as di butyl phthalate, tri ethyl citrate, polyethylene glycol, or the I ike; antitacking agents such as, talc, stearic acid, magnesi um stearate, col I oi dal si I i con di oxi de or the I i ke; f i 11 ers such as tal c or preci pitated calcium carbonate; polishing agents such as beeswax, carnauba wax or synthetic chlorinated wax; opacifying agents such as titanium dioxide; or colorants, etc. Antitacking agents may be used in the range of 0.1 - 15% w/w of the total weight of the oral pharmaceutical composition.

^" Solvents _, may be any pharmaceutical ly acceptable, non-toxic agent or a mixture of agents i n the form of a I i qui d, whi ch i s used for di ssol vi ng another sol i d or I i qui d, or as a di spersi ng or granulating media. Solvents employed in the present invention may be aqueous, alcoholic, hydroalcohol ic or organic in nature with varying polarity. Representative examples of solvents employed i ncl ude acetone, dichloromethane, ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.

The amount of apixaban contained in a tablet, capsule, or other dosage form containing a composition of this invention will contain therapeutically effective amount of apixaban. ^" Therapeutically effective amount _, refers to amount of the active agent which halts or reduces the progress of the condition being treated or which otherwise partly, cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routi ne experimentation and with an undue burden.

Therapeutically effective amount of apixaban in the respect of this invention is usually between 2.5 and 5 mg, usually administered orally twice a day, although amounts outside thi s range and different f requenci es of admi ni strati on are f easi bl e for use i n therapy under prescribed medical conditions. The pharmaceutical compositions of the present invention are useful, inter alia, in the prevention and/or treatment of thromboembolic disorders, for example, deep vei n thrombosis, acute coronary syndrome, stroke, and pulmonary embolism

The present invention should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and compl ete, and wi 11 f ul ly convey the scope of the i nventi on to those ski 11 ed i n the art. Other features and embodi ments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its i ntended scope.

EXAM PL E S

E xample 1 Ingredients mg/ tablet

Intra-granular

Apixaban 2.5

Lactose 49.5

M i crocrystal I i ne eel I ul ose 39.5

C roscarmel I ose sodi um 3.0

Magnesi um stearate 0.5

Extra - granular

Poloxamer 2.0

C roscarmel I ose sodi um 2.5

Magnesi um stearate 0.5

Film coating

Opadry pink II

Opadry yellow II 3.5

Brief manufacturing procedure:

1. Co- sift apixaban, lactose, mi crocrystal line cellulose, croscarmel I ose sodium through 40 #AST M S.S. sieve.

2. Mix the step- 1 blend in suitable blender for 25 minutes.

3. Sift magnesium stearate through 60# ASTM S.S. sieve and add to step 2 blend and I ubricate the blend for 5 mi nutes.

4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.

5. Load the milled material on the vibratory sifter. Collect the undersize of #25 mesh (710 m) S.S. sieve and oversize of #60 mesh (250 m) S.S. sieve.

6. Pass the undersize of #60 mesh material of step-5 again through roller compactor to get compacted flakes. 7. Repeat steps 4 to 6 until the granules (#25 mesh) and fines (#60 mesh) attain ratio of 60 e 5.0%: 40 e 5.0%.

8. Load granules and fines, in suitable blender and mix for 10 minutes.

9. Sift croscarmel lose sodium and poloxamer through 40# AST M S.S. seive and load to step 8 blend and mix for 10 minutes.

10. Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.

11. Compress the tablet with step- 10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.

C oati ng sol uti on preparati on:

12. A dd and di sperse quantity of opadry yel I ow under conti nuous sti rri ng i n purif i ed water and sti r for 45 mi nutes to get 10% w/w dispersi on.

13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet ai r temperature 55 e 5°C till 3.5% w/w e 0.25% weight build up is attained.

14. Dry the tablet of step- 10 for 60 minutes at inlet air temperature 55 e 5°C with intermittent jogging.

E xample 2

Ingredients mg/ tablet

Intra-granu lar

Apixaban 5.0

Lactose 99.0

M i crocrystal I i ne eel I ul ose 79.0

C roscarmel I ose sodi um 6.0

Magnesium stearate 1.0

Extra - granular

Poloxamer 4.0

C roscarmel I ose sodi um 5.0 Magnesium stearate 1.0

Film coating

Opadry pink II 7.0

Opadry yellow II

Brief manufacturing procedure:

1. Co-sift apixaban, lactose, microcrystalline cellulose, croscarmel lose sodium through 40 #AST M S.S. sieve.

2. Mix the step- 1 blend in suitable blender for 25 minutes.

3. Sift Magnesium stearate through 60# AST M S.S. sieve and add to step 2 blend and I ubricate the blend for 5 mi nutes.

4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.

5. L oad the mi 11 ed materi al on the vi bratory sifter. C ol I ect the undersi ze of #25 mesh (710 m) S.S. Sieve and oversize of #60 mesh (250 m) S.S. sieve.

6. Pass the undersi ze of #60 mesh material of step-5 again through roller compactor to get compacted flakes.

7. Repeat steps 4 to 6 until the granules (#25 mesh) and fines (#60 mesh) attain ratio of 60 e 5.0%: 40 e 5.0%.

8. Load granules and fines, in suitable blender and mix for 5 minutes.

9. Sift croscarmel lose sodium and poloxamer through 40# AST M S.S. seive and load to step 8 blend and mix for 10 minutes.

10. Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.

11. Compress the tablet with step-10 blend usi ng 9.8 x 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.

C oati ng sol uti on preparati on:

12. Add and disperse quantity of opadry pink under continuous stirring in purified water and sti r for 45 mi nutes to get 10% w/w dispersi on. 13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet ai r temperature 60 e 5°C till 3.5% w/w e 0.25% weight build up is attained.

14. Dry the tablet of step- 10 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.

T able 1 : Dissolution data of the formulations of Example 1 and Example 2:

E xample 3

Ingredients mg/ tablet

Intra-g ranular

Apixaban 5.0

Lactose 93.4

Microcrystalline

79.0

cellulose

Croscarmellose

5.0

sodi um

Magnesium stearate 1.5

Extra - granular

Poloxamer 4.0 Sodium lauryl sulfate 6.0

Croscarmel lose

5.0

sodi um

Magnesium stearate 1.1

Film coating

Opadry pink II 7.0

Brief manufacturing procedure:

1. Co-sift apixaban, lactose, mi crocrystal line cellulose, croscarmel lose sodium through 40# AST M S.S. seive.

2. Mix the step- 1 blend in suitable blender for 25 minutes.

3. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 2 blend and I ubricate the blend for 5 mi nutes.

4. Load the step-3 blend on roller compactor and compact the material of step-3 on roller compactor to get desi red compacted flakes and milled through oscillating granulator.

5. Load the milled material on the vibratory sifter. Collect the undersize of #25 mesh (710 m) S.S. sieve and oversize of #60 mesh (250 m) S.S. sieve.

6. Pass the undersize of #60 mesh material of step-5 again through roller compactor to get compacted flakes.

7. Repeat steps 4 to 6 until the granules (#25 mesh) and fines (#60 mesh) attain ratio of 60 e 5.0%: 40 e 5.0%.

8. Load granules and fines, in suitable blender and mix for 5 minutes.

9. Sift croscarmel lose sodium, poloxamer and sodium lauryl sulfate through 40# AST M S.S. seive and load to step 8 blend and mix for 10 minutes.

10. Sift magnesium stearate through 60# AST M S.S. seive and add to step 9 blend and I ubricate the blend for 5 mi nutes.

11. Compress the tablet with step- 10 blend using 9.8 B 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.

C oati ng sol uti on preparati on: 12. Add and disperse quantity of opadry pink under continuous stirring in purified water and sti r for 45 mi nutes to get 10% w/w dispersi on.

13. L oad the tabl ets of step-11 i nto perforated coati ng pan and coat the tabl et with an i nl et ai r temperature 60 e 5°C till 3.5 % w/w e 0.25% weight build up is attained.

14. Dry the tablet of step-10 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.

T able 2: Dissolution data of the formulation of E xample 3:

E xample 4

Ingredients mg/ tablet

Intra-g ranular

Apixaban 2.5

Poloxamer 2.5

Lactose 47.75

Microcrystalline

28.75

cellulose

Croscarmellose

3.00

sodi um Isoprop l alcohol Q.S.

Methylene di chloride Q.S.

Extra - granular

Microcrystalline

12.00

cellulose

Croscarmellose

2.50

sodi um

Magnesium stearate 0.50

Film coating

Opadry pink

Opadry yellow 3.50

Brief manufacturing procedure:

1. Sift lactose, microcrystalli ne cellulose, croscarmellose sodium through 40# AST M S.S. seive.

2. Load the step 1 blend in fluidised bed process.

3. Dissolve apixaban in methylene di chloride.

4. Dissolve poloxamer in isopropyl alcohol.

5. A dd step 4 sol uti on to step 3 sol uti on under sti rri ng and mi x the sol uti on for 15 mi nutes.

6. Granulate step 2 blend with using step 5 solution i n fluidised bed process with suitable parameters.

7. D ry the granul es after granul ati on for 15 mi nutes at bed temperature of 35-40eC .

8. Pass the dried granules through AST M #25 mesh.

9. Sift croscarmellose sodium and microcrystalline cel lulose 102 through 40#AST M S.S. sieve and load to step 8 blend and mix for 10 minutes.

10. Sift magnesium stearate through 60# AST M S.S. sieve and add to step 9 blend and I ubricate the blend for 5 mi nutes.

11. Compress the tablet with step- 10 blend using 6.0 mm round shaped bevel concave punches on a compression machine with suitable parameter.

C oati ng sol uti on preparati on: 12. A dd and di sperse quantity of opadry yel I ow under conti nuous sti rri ng i n purif i ed water and sti r for 45 mi nutes to get 10% w/w dispersi on.

13. Load the tablets of step-11 into perforated coating pan and coat the tablet with an inlet ai r temperature 55e 5eC till 3.5% w/w e 0.25% weight build up is attained.

14. Dry the tablet of step- 10 for 60 minutes at i nlet air temperature 55e 5eC with intermittent jogging.

T able 3: Dissolution data of the formulation of E xample 4:

E xample 5

Ingredients mg/ tablet

Intra-grar lular

Apixaban 5.0

Lactose 91.0

Microcrystalline

79.0

cellulose

C roscarmel I ose sodi um 6.0

Binder solution

Hydroxy propyl methyl

5.0

cellulose E 5 Purified water Q.S.

Extra - granular

C roscarmel I ose sodi um 5.0

Magnesium stearate 1.0

Film coating

Opadry pink II 7.0

Opadry yellow II

Brief manufacturing procedure:

1. Co-sift apixaban, lactose, mi crocrystal line cellulose, croscarmel I ose sodium through 40# AST M S.S. seive.

2. Load the step 1 blend in rapid mixer granulator and mix the blend for 15 minutes at slow i mpel I or speed and chopper off.

3. Add and dissolve hydroxy propyl methyl cellulose E5 in purified water under stirring.

4. Granulate the step 2 blend with addition of step 3 binder solution under slow impel I or and chopper speed.

5. Dry the wet granules in rapid dryer at 55°C till LOD becomes below 1.5 to 2.0% at 105°C for 10 mi nutes.

6. Pass the dried granules of step-5 through 25#and load to the suitable blender.

7. Sift croscarmel I ose sodium through 40#AST M S.S. seive and load to step 6 blend and mix for 10 minutes.

8. Sift magnesium stearate through 60# ASTM S.S. seive and add to step 7 blend and I ubricate the blend for 5 mi nutes.

9. Compress the tablet with step-8 blend using 9.8 B 5.2 mm oval shaped bevel concave punches on a compression machine with suitable parameter.

C oati ng sol uti on preparati on:

10. Add and disperse quantity of opadry pink under continuous stirring in purified water and sti r for 45 mi nutes to get 10% w/w dispersi on. 11. L oad the tabi ets of step-9 i nto perforated coati ng pan and coat the tabi et with an i nl et ai r temperature 60 e 5°C till 3.5% w/w e 0.25% weight build up is attained.

12. Dry the tablet of step- 11 for 60 minutes at inlet air temperature 50 e 5°C with intermittent jogging.

T able 4: Dissolution data of the formulation of E xample 5:

Dissolution (Dissolution media volume: 900 mL, Paddle, 75 R PM) pH 6.8 Phosphate buffer with 0.05% SLS

T ime (M inutes) % Dissolved

5 27

10 41

15 55

30 70