DESC:TITLE OF THE INVENTION

Pharmaceutical Composition of Apixaban

FIELD OF THE INVENTION

The present invention relates to a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban and one or more pharmaceutically acceptable excipients, such as but not limited to binder(s), surfactant(s) and the like. The present invention also relates to a bioequivalent pharmaceutical composition comprising Apixaban having PSD of D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Apixaban chemically described as 1-(4methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridine-3-carboxamide as shown in Formula I.

Apixaban is marketed under brand name Eliquis. It was approved by USFDA in December 2012 for treatment and secondary prophylaxis of deep vein thrombosis and pulmonary embolism.

It is generically claimed in US6413980 and in IN243917. It is specifically claimed in US6967208 and IN247381. US6413980 also claimed pharmaceutical composition comprising compounds claimed in that patent.

Both these patents are silent on stability aspects of composition and how to prepare the composition. They are also silent on the aspects of polymorphic stability of Apixaban or any PSD specifications, either as compound or when present in the composition.

US9326945 claims a solid pharmaceutical composition comprising a therapeutically effective amount of crystalline Apixaban particles and a pharmaceutically acceptable diluent or carrier, wherein the crystalline Apixaban particles have a D90 equal to or less than about 89 µm, and wherein at least 77 wt % of Apixaban dissolves within 30 minutes in a pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate. This patent also specifically claims various dosage forms of Apixaban where in Apixaban with predefined D90 is present in the composition.

This patent stipulates that formulations that were made using a wet granulation process as well as those using large particles of Apixaban drug substance resulted in less than optimal exposures and that it can present quality control challenges. Therefore invention and guidance provided by US9326945 is that compositions for tablets comprising up to 5 mg, Apixaban particles having a D90 (90% of the volume) less than 89µm (µ or microns or mu.m) lead to consistent in-vivo dissolution in humans (at physiologic pH). IN6587/DELNP/2012 guides in similar way.
US2015018386 and its equivalent IN592/MUM/2012 claim a composition and a process for preparation of a composition comprising an amorphous form of Apixaban.

WO2014027334 describes a composition of multiparticulate system.

WO2015121472 and US2016346267 describes a pharmaceutical composition comprising Apixaban and a polymer having low viscosity as binder.

WO2015097090 and US2017000799 describes a solid particle of a poorly soluble drug, having an average particle size of 100 µm or less, wherein a solubilizer is adsorbed on the surface of the poorly soluble drug.

US20160143894 claims a pharmaceutical composition comprising crystalline form N-1 of apixaban having an X-ray powder diffraction pattern comprising peaks expressed in degrees 2? (±0.2° 2?) at 8.40, 12.80, 13.80, 16.90, 18.30, 21.00, 22.00, 24.70, 25.30, 26.80 and 32.60 ±0.2 2?, having a mean particle size equal to or greater than 100 µm and one or more pharmaceutically acceptable excipients, diluents and carriers. Said application is silent about D90 specifications of the Apixaban. Secondly, although it has a general claim about composition, entire application is silent on bioavailability profile of the composition or does not affirmatively state that the composition is bioequivalent with that of innovator reference listed drug ELIQUIS.

Although prior art has taught Apixaban compositions, it has created severe restrictions in using Apixaban. It is taught that if Apixaban with D90 of less than 89 µm is not used, it would result in inadequate exposure and the composition in which such Apixaban is used would pose quality problems. In fact that is the invention of the innovator vide US9326945. Thus there is severe limitation in using Apixaban having D90 more than 89 µm.

It is well known that increase in crystal size or particle jeopardizes the solubility. As has been described in the prior art, it is the particle size distribution of the Apixaban which is of critical importance to produce desirable composition.
Therefore as per the teachings of the prior art it is difficult to prepare a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 89 µm.

There is a need to provide a pharmaceutical composition comprising Apixaban having D90 more than 89 µm. There is need to provide a process to prepare a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 89 µm.

It has now been unexpectedly found that Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ supports preparation of stable, reproducible and bioequivalent pharmaceutical compositions. It is also unexpectedly found that pharmaceutical compositions containing Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ also produce similar in-vitro and in-vivo profile as that of innovator composition.

It has been surprisingly found that even when D90 as prescribed by innovator in US9326945 is not followed, it is possible to produce a stable, reproducible and bioequivalent pharmaceutical compositions containing Apixaban and one or more pharmaceutically acceptable excipients, such as but not limited to binder(s), surfactant(s) and the like.
Surprisingly it is found that even when Apixaban of different D90 is used, i.e. D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ still it is possible to produce stable, reproducible and bioequivalent pharmaceutical compositions containing Apixaban by wet granulation technique.

It is also surprisingly found that wet granulation process produces a stable, reproducible and bioequivalent pharmaceutical compositions containing Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.

OBJECT OF THE INVENTION

The main object of present invention is to provide Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.

Another object of the invention is to provide a pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients such as but not limited to binder(s), surfactant(s) and the like.

Another object of the invention is to provide a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipient.

Yet another object of present invention is to provide a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipient and which is produced by spray granulation wet granulation.

Yet another object of present invention is to provide a process to produce a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 89 µm and one or more pharmaceutically acceptable excipient and which is produced by spray granulation wet granulation.

SUMMARY OF THE INVENTION

The present invention relates to Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.
Present invention also relates to pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients such as but not limited to binder(s), surfactant(s) and the like.

The present invention relates to a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients such as but not limited to binder(s), surfactant(s) and the like.

The present invention also relates to a process to prepare a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients such as but not limited to binder(s), surfactant(s) and the like.

Also the present invention particularly relates to a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipient and which is produced by spray granulation wet granulation.

The present invention also relates to a process for the preparation of a pharmaceutical composition comprising Apixaban and one or more pharmaceutically acceptable excipients, wherein the process comprising steps of:
a. Preparing granules comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ using wet granulation;
b. Adding one or more pharmaceutically acceptable excipients and compressing to form a tablet; and
c. Optionally coating the compressed tablets.

DETAILED DESCRIPTION OF THE INVENTION

According to main object of the invention, there is provided Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ. D90 more than 100 µ is to be interpreted as Apixaban having D90 from 100µ to 1000µ.

According to another aspect of the invention there is provided a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipients such as but not limited to binder(s), surfactant(s) and the like.

According to yet another aspect, there is provided a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ and one or more pharmaceutically acceptable excipient and which is produced by spray granulation wet granulation.

Terms microns or mu.m or µ or mum or µm are used interchangeably and mean the same. The term "composition" as used herein refers to equivalents thereof, including but not limited to cores, coated cores, pellets, micro-pellets, pills, compressed tablets, granules, spheres, capsules and the like.

The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term "tablet" is intended to encompass compressed pharmaceutical dosage forms of all shape and size, whether coated or uncoated.

The term “stable and reproducible” as used herein means that the composition is stable when stored at stability conditions as per ICH stability guidelines and that the process described when followed, produces a stable and bioequivalent formulation repeatedly.

The term “bioequivalent” as used herein means that a formulation that has the same pharmacologic potency and bioavailability as that of reference formulation containing same active agent at the same dose. Two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption i.e., bioavailability are the same.
The term 'similarity factor' or 'f2 factor' as used herein refers to one way of comparing dissolution profiles of two different products. This model-independent mathematical approach compares the dissolution profile of the two products: test and reference or two strengths. Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of two curves, and thus equivalent performance of the two products, in-vitro.

The term PSD means particle size distribution. Apixaban is milled and or micronized to produce the Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.

Novelty of the Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ resides in the fact that it was not reported in the prior art that Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ produces bioequivalent pharmaceutical composition. Non-obviousness of the invention resides in the fact that in the light of prior art teachings, nobody would ever imagine that Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ would ever produce bioequivalent pharmaceutical composition.

Prior art does teach wet granulation of Apixaban. But it severely and categorically limits the use of wet granulation of Apixaban having D90 as prescribed in US9326945.

Novelty and non-obviousness of the invention resides in the fact that prior art teachings neither teach nor do they ever support imagination that the process of wet granulation of Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ would produce a stable, reproducible bioequivalent pharmaceutical composition.

The pharmaceutical composition of the present invention comprise one or more pharmaceutically acceptable excipients which include, diluents, binders, surfactants, disintegrants, lubricants, glidants, coating agents, plasticizers, coloring agent, viscosity enhancers, and the like and the combinations thereof.

Diluents include, but are not limited to microcrystalline cellulose (MCC), microfine cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, starch, pre-gelatinized starch, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, dextrates, dextrin, dextrose, kaolin, maltodextrin, mannitol, sucrose, methyl dextrin and sorbitol and the combinations thereof.

Binders include, but are not limited to cellulose derivatives such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium carboxy methyl cellulose, methyl cellulose, ethyl cellulose and polyvinylpyrrolidone, polyethyleneglycol, polyvinyl alcohols, pregelatinized starch, starch paste, sucrose, glucose, acacia, tragacanth, gelatin, alginic acid and sodium alginate and the combinations thereof.

Disintegrants include, but are not limited to carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, polacrilin potassium, sodium alginate and sodium starch glycolate and the combinations thereof.

Lubricants include but are not limited to magnesium stearate, aluminium stearate, sucrose stearate, calcium stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like and the combinations thereof.

Surfactant include but are not limited to self-emulsifying glyceryl monooleate, docusate sodium, emulsifying wax BP, sodium lauryl sulfate (SLS), benzethonium chloride, cetrimide, cetylpyridinium chloride, lauric acid, myristyl alcohol, sorbic acid, emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers (macrogol cetostearyl ether, macrogol lauryl ether, macrogol oleyl ether, macrogol stearyl ether), polyoxyethylene castor oil derivatives (macrogolglycerol ricinoleate, macrogolglycerol hydroxystearate), polyoxyethylene sorbitan fatty acid esters (polysorbate 20, 40, 60, and 80), polyoxytehylene stearates, polyoxylglycerides (caprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoyl polyoxylglycerides and stearoyl polyoxylglycerides), sorbitan esters (sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitan trioleate), triethyl citrate and mixtures thereof and other surfactants known to those skilled in the art.

Pharmaceutically acceptable non-toxic solvents include but are not limited to Purified water, Methylene dichloride, Iso propyl alcohol, or any combinations thereof.

In one embodiment there is provided Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ. As per the embodiment, the Apixaban produced in bulk drug plant was milled and micronized to get the PSD of D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ. The milling and or micronization of Apixaban produced from bulk drug plant is useful to prepare the Apixaban of required PSD.
In one embodiment the present invention provides a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.

In an embodiment the present invention provides a wet granulation process to produce a stable, reproducible and bioequivalent pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ.

The relative % of the ingredients used may be selected as per related FDA guidelines for lower strengths.

The pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ provides a stable and reproducible formulation which shows similarity factor value of more than 50 when dissolution of the formulation is compared with innovators product reference listed drug ELIQUIS. So also when different strengths are compared, f2 value or similarity factor value of more than 50 is observed.

When in-vivo testing and comparison is done, the composition of the present invention shows similarity factor of more than 50 when compared with innovator product ELIQUIS. Cmax, AUC are depicted in the tables titled “Bioequivalence Summary Table of Cmax” and “Bioequivalence Summary Table of AUC0_72”
The pharmaceutical composition of the invention is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule, granules in capsule and other like dosage forms suitable for oral administration. The tablets may further be coated with film forming polymers.
The process to prepare pharmaceutical composition by wet granulation is provided.
A process for the preparation of a pharmaceutical composition comprising Apixaban and one or more pharmaceutically acceptable excipients, wherein the process comprising steps of:
a. Preparing granules comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ using wet granulation;
b. Adding one or more pharmaceutically acceptable excipients and compressing to form a tablet; and
c. Optionally coating the compressed tablets.
In a preferred embodiment the pharmaceutical composition of the present invention is prepared by wet granulation process, wherein the process comprised the steps:
a. Co-sifting of one or more diluent and one or more disintegrant through # 40 sieve to prepare dry mix;
b. Preparing a drug solution by adding Apixaban into methylene chloride (MDC) and isopropyl alcohol (IPA);
c. Spraying the drug solution prepared in step b. on the dry mix of step a. in fluidized bed processor (FBP) to granulate it;
d. Drying a granules in fluidized bed processor to prepare dried granules;
e. Dissolving surfactant(s) in purified water to prepare surfactant solution;
f. Spraying the surfactant solution prepared in step e. on the dried granules prepared in step d to prepare surfactant coated granules.
g. Drying the surfactant coated granules of step f. in FBP to prepare dried granules;
h. Sifting the dried granules of step g. using # 30 sieve to prepare sifted granules;
i. Pre-Lubricating the sifted granules prepared in step h. with pharmaceutical ingredients to prepare the pre-lubricated granules;
j. Lubricating the pre-lubricated granules prepared in step i., to prepare lubricated blend;
k. Compressing the lubricated blend prepared in step j. to prepare compressed tablets; and
l. Optionally coating the compressed tablets prepared in step k.
The tablets may optionally be coated with a film coat, which provides an aesthetic appeal. Film coat also provides moisture protection, taste masking etc. Coating agents include, but not limited to Opadry®. Preferred Opadry® is Opadry II Pink (32K540052).

Another embodiment explains the process to prepare the pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ by wet granulation process, wherein the process comprised co-sifting Apixaban with other ingredients and wet granulating it, followed by drying, lubricating and compressing. Multiple Bioequivalence Studies proved that the compositions prepared as per invention are stable, reproducible and bioequivalent. The present invention is described in more detail by following examples, but scope of the present invention is not limited thereto.

EXAMPLES

Example 1: Apixaban produced in bulk drug plant, having far bigger particle is milled and or micronized to produce Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ. Milling and micronization is carried out by known equipments such as multimill. The PSD is determined by Malvern Mastersizer 2000. Wet methods using liquid paraffin or sunflower oil are useful. This Apixaban having D90 more than 100 µ, more preferably more than 300µ to 1000µ and most preferably more than 350µ to 800µ is used in subsequent examples to prepare the Pharmaceutical compositions.

Example 2: Wet granulation method (by using fluidized bed processor)

Sr. No. Ingredients 5 mg
(mg/Tab) 2.5 mg
(mg/Tab) % w.r.t. core tab % w.r.t. coated tab
Part I (Dry Mix/Intra-granular)
1 Microcrystalline Cellulose 79 39.5 39.5 38.35
2 Lactose Anhydrous 98.5 49.25 49.25 47.82
3 Croscarmellose Sodium 4 2 2 1.94
Part-II (Drug Solution)
4 Apixaban ( D90=100 micron) 5 2.5 2.5 2.43
5 Methylene Chloride* q.s. q.s. - -
6 Iso Propyl Alcohol* q.s. q.s. - -
Part-III (Binder Solution)
7 Sodium Lauryl Sulphate 2 1 1 0.97
8 Polyvinylpyrrolidone (Povidone K-25) 6 3 3 2.91
9 Purified Water* q.s. q.s. - -
Part -IV (Pre-lubrication/ Extra-granular) - - - -
10 Croscarmellose Sodium 4 2 2 1.94
Part-V(Lubrication/Extra-granular)
11 Magnesium Stearate 1.5 0.75 0.75 0.73
Total Weight of Core Tablet 200 100 100 -
Part -VI (Coating ) - - - -
12 Opadry Pink/Yellow 6 3 - 2.91
13 Purified Water* q.s. q.s. - -
Total Weight of Coated Tablet 206 103 - 100
* Removed during processing & only traces will be present in final product
Manufacturing process:

a) Part-I (Dry Mix): Microcrystalline Cellulose, Lactose Anhydrous, Croscarmellose sodium were sifted through #40 sieve and mixed to prepare the dry mix.
b) Part-II: Apixaban was added to MDC under stirring to form clear solution, then IPA was added and stirred. Clear drug solution of Apixaban was sprayed on dry mix prepared in Part - I in FBP by Top Spray method.
c) Part-III: SLS and Povidone K-25 were dissolved in Purified water to form binder solution.
Binder solution spraying: solution is sprayed on contents of Fluidized Bed Processor by Top Spray, to prepare the granules.
d) Drying and sizing: Granules were dried in Fluidized Bed Processor for 15 minutes and sized using #30 sieve.
e) Pre-Lubrication: Croscarmellose Sodium was sifted through # 40 sieve and in Double Cone Blender, sized granules prepared in step d) were Pre-Lubricated to prepare pre-lubricated blend.
f) Lubrication: Magnesium Stearate was sifted through # 60 sieve and pre-lubricated blend prepared in step e) was lubricated to prepare lubricated blend.
g) Compression: Lubricated blend prepared in step f) was compressed into tablets using appropriate punch set.
h) Coating: Compressed tablets prepared in step g) were coated by Opadry pink/yellow suspension to achieve required weight gain for different strengths.

Example 3: Wet granulation method (by using fluidized bed processor)

Sr. No. Ingredients 5 mg
(mg/Tab) 2.5 mg
(mg/Tab) % w.r.t. core tab % w.r.t. coated tab
Part I (Dry Mix/Intra-granular)
1 Apixaban ( D90=100 micron) 4 2 2 1.94
2 Microcrystalline Cellulose 79 39.5 39.5 38.35
3 Lactose Anhydrous 98.5 49.25 49.25 47.82
4 Croscarmellose Sodium 4 2 2 1.94
Part-II (Drug Solution) - - - -
5 Apixaban ( D90=100 micron) 1 0.5 0.5 0.49
6 Methylene Chloride* q.s. q.s. - -
7 Iso Propyl Alcohol* q.s. q.s. - -
Part-III (Binder Solution) - - - -
8 Sodium Lauryl Sulphate 2 1 1 0.97
9 Polyvinylpyrrolidone (Povidone K-25) 6 3 3 2.91
10 Purified Water* q.s. q.s. - -
Part -IV (Pre-lubrication/ Extra-granular) - - - -
11 Croscarmellose Sodium 4 2 2 1.94
Part-V(Lubrication/Extra-granular) - - - -
12 Magnesium Stearate 1.5 0.75 0.75 0.73
Total Weight of Core Tablet 200 100 100 -
Part -VI (Coating ) - - - -
13 Opadry Pink/Yellow 6 3 - 2.91
14 Purified Water* q.s. q.s. - -
Total Weight of Coated Tablet 206 103 - 100
* Removed during processing & only traces will be present in final product
Manufacturing process:

a) Part-I (Dry Mix): Apixaban, Microcrystalline Cellulose, Lactose anhydrous, Croscarmellose sodium were sifted through #40 sieve and mixed to prepare the dry mix.
b) Part-II: Apixaban was added to MDC under stirring to form clear solution, then IPA was added and stirred. Clear drug solution of Apixaban was sprayed on dry mix prepared in Part - I in FBP by Top Spray method.
c) Part-III: Sodium Lauryl Sulphate and Povidone K-25 were dissolved in Purified water to form binder solution.
Binder solution spraying: solution is sprayed on contents of Fluidized Bed Processor by Top Spray, to prepare the granules.
d) Drying and sizing: Granules were dried in Fluidized Bed Processor for 15 minutes and sized using #30 sieve.
e) Pre-Lubrication: Croscarmellose Sodium was sifted through # 40 sieve and in Double Cone Blender, sized granules prepared in step d) were Pre-Lubricated to prepare pre-lubricated blend.
f) Lubrication: Magnesium Stearate was sifted through # 60 sieve and pre-lubricated blend prepared in step e) was lubricated to prepare lubricated blend.
g) Compression: Lubricated blend prepared in step f) was compressed into tablets using appropriate punch set.
h) Coating: Compressed tablets prepared in step g) were coated by Opadry pink/yellow suspension to achieve required weight gain for different strengths.

Example 4: Wet granulation method (by using rapid mixer granulator)

Sr. No. Ingredients 5 mg
(mg/Tab) 2.5 mg
(mg/Tab) % w.r.t. core tab % w.r.t. coated tab
Part I (Dry Mix/Intra-granular)
1 Microcrystalline Cellulose 79 39.5 39.5 38.35
2 Lactose Anhydrous 98.5 49.25 49.25 47.82
3 Croscarmellose Sodium 4 2 2 1.94
Part-II ( Binder/Drug dispersion) - - - -
4 Apixaban ( D90=100 micron) 5 2.5 2.5 2.43
5 Sodium Lauryl Sulphate 2 1 1 0.97
6 Polyvinylpyrrolidone (Povidone K-25) 6 3 3 2.91
7 Purified Water* q.s. q.s. - -
Part -III (Pre-lubrication/ Extra-granular) - - - -
8 Croscarmellose Sodium 4 2 2 1.94
Part-IV(Lubrication/Extra-granular) - - - -
9 Magnesium Stearate 1.5 0.75 0.75 0.73
Total Weight of Core Tablet 200 100 100 -
Part -V (Coating) - - - -
10 Opadry Pink/yellow 6 3 - 2.91
11 Purified Water* q.s. q.s. - -
Total Weight of Coated Tablet 206 103 - 100

* Removed during processing & only traces will be present in final product.

Manufacturing process:

a) Part-I (Dry Mix): Microcrystalline Cellulose, Lactose Anhydrous, Croscarmellose sodium were sifted through #40 sieve and mixed to prepare the dry mix.
b) Part-II: Sodium lauryl sulphate and Povidone K-25 were dissolved in water. Apixaban was dispersed in obtained solution. This dispersion was sprayed on dry mix prepared in step a) in RMG to prepare the granules.
c) Drying and sizing: Granules were dried in rapid dryer for 15 minutes and sized using #30 sieve.
d) Pre-Lubrication: Croscarmellose Sodium was sifted through # 40 sieve and in Double Cone Blender, sized granules prepared in step c) were pre-Lubricated to prepare pre-lubricated blend.
e) Lubrication: Magnesium Stearate was sifted through # 60 sieve and pre-lubricated blend prepared in step d) was lubricated to prepare lubricated blend.
f) Compression: Lubricated blend prepared in step e) was compressed into tablets using appropriate punch set.
g) Coating: Compressed tablets prepared in step f) were coated by Opadry pink/yellow suspension to achieve required weight gain for different strengths.

Example 5: Wet granulation method (by using rapid mixer granulator)

Sr. No. Ingredients 5 mg
(mg/Tab) 2.5 mg
(mg/Tab) % w.r.t. core tab % w.r.t. coated tab
Part I (Dry Mix/Intra-granular)
1 Apixaban ( D90=100 micron) 4 2 2 1.94
2 Microcrystalline Cellulose 79 39.5 39.5 38.35
3 Lactose Anhydrous 98.5 49.25 49.25 47.82
4 Croscarmellose Sodium 4 2 2 1.94
Part-II ( Binder/Drug dispersion) - - - -
5 Apixaban ( D90=100 micron) 1 0.5 0.5 0.49
6 Sodium Lauryl Sulphate 2 1 1 0.97
7 Polyvinylpyrrolidone (Povidone K-25) 6 3 3 2.91
8 Purified Water* q.s. q.s. - -
Part -III (Pre-lubrication/ Extra-granular) - - - -
9 Croscarmellose Sodium 4 2 2 1.94
Part-IV (Lubrication/Extra-granular) - - - -
10 Magnesium Stearate 1.5 0.75 0.75 0.73
Total Weight of Core Tablet 200 100 100 -
Part -V (Coating) - - - -
11 Opadry Pink/yellow 6 3 - 2.91
12 Purified Water* q.s. q.s. - -
Total Weight of Coated Tablet 206 103 - 100
* Removed during processing & only traces will be present in final product.

Manufacturing process:

a) Part-I (Dry Mix): Apixaban. MCC, Lactose Anhydrous, Croscarmellose sodium were sifted through #40 sieve and mixed to prepare the dry mix.
b) Part-II : Sodium lauryl sulphate and Povidone K-25 were dissolved in water. Apixaban was dispersed in obtained solution. This dispersion was sprayed on dry mix prepared in step a) in RMG to prepare the granules.
c) Drying and sizing: Granules were dried in rapid dryer for 15 minutes and sized using #30 sieve.
d) Pre-Lubrication: Croscarmellose Sodium was sifted through # 40 sieve and in Double Cone Blender, sized granules prepared in step c) were pre-Lubricated to prepare pre-lubricated blend.
e) Lubrication: Magnesium Stearate was sifted through # 60 sieve and pre-lubricated blend prepared in step d) was lubricated to prepare lubricated blend.
f) Compression: Lubricated blend prepared in step e) was compressed into tablets using appropriate punch set.
Coating: Compressed tablets prepared in step f) were coated by Opadry pink/yellow suspension to achieve required weight gain for different strengths.
,CLAIMS:We Claim:

1. Apixaban having D90 more than 100 µ, more preferably D90 ranging from 300µ to 1000µ and most preferably D90 ranging from 350µ to 800µ.

2. A pharmaceutical composition comprising Apixaban having D90 more than 100 µ, more preferably D90 ranging from 300µ to 1000µ and most preferably D90 ranging from 350µ to 800µ and one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition as claimed in claim 2, wherein pharmaceutically acceptable excipients are selected from the group comprising a diluent, a binder, a disintegrant, a surfactant, a lubricant, a glidant, a coating agent, a plasticizer, a coloring agent and a viscosity enhancer.

4. The pharmaceutical composition as claimed in claim 2, wherein the composition is in the form of caplets, pills, mini-tablets, granules, pellets, tablets or capsules.

5. The pharmaceutical composition as claimed in claim 3, wherein the diluent is selected from the group comprising microcrystalline cellulose, lactose monohydrate, micro fine cellulose, powdered cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, starch, pre-gelatinized starch, calcium carbonate, calcium sulphate, magnesium carbonate, and combination thereof.

6. The pharmaceutical composition as claimed in claim 3, wherein the binder is selected from the group comprising polyvinyl pyrrolidone, polyethylene glycol, pregelatinized starch, starch, cellulose derivatives (such as hydroxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl methyl cellulose), hydrogenated vegetable oil, and combination thereof.

7. The pharmaceutical composition as claimed in claim 3, wherein the disintegrant is selected from the group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, polacrilin potassium, sodium alginate, sodium starch glycolate, and combination thereof.

8. The pharmaceutical composition as claimed in claim 3, wherein the surfactant is selected from the group comprising self-emulsifying glyceryl monooleate, docusate sodium, emulsifying wax BP, sodium lauryl sulphate (SLS), and combination thereof.

9. The pharmaceutical composition as claimed in claim 3, wherein the lubricant is selected from the group comprising magnesium stearate, aluminium stearate, sucrose stearate, calcium stearate stearic acid, talc, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, and combination thereof.

10. A process for preparation of pharmaceutical composition comprising apixaban and one or more pharmaceutical acceptable excipients, wherein the process comprises:
a) co-sifting a diluent and a disintegrant through a sieve to prepare a dry mix;
b) mixing a surfactant, a binder and a purified water to produce a binder solution;
c) dispersing apixaban having a D90 particle size more than 100 microns in the binder solution obtained in step (b) to produce a drug solution;
d) spraying the drug solution obtained in step (c) on the dry mix of step (a) to produce drug granules;
e) drying the drug granules obtained in step (d) in dryer to produce dried granules and sift the granules;
f) pre-lubrication of the sifted granules obtained in step (e) to produce lubricated blend
g) Compressing the lubricated blend obtained in step (f) to produce uncoated tablet and optionally coating the tablets.