Field of the invention
The present invention relates to stable compositions comprising apixaban. The present invention also relates to process for preparation of such stable compositions comprising apixaban. The present invention also relates to method of using the stable compositions comprising apixaban. The present invention also relates to the use of stable compositions . comprising apixaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, and/or for the prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients who have undergone hip or knee replacement surgery, and/or for the treatment of DVT and PE, and/or for the reduction in the risk of recurrent DVT and PE following initial therapy.

Background of the invention
Apixaban is a low molecular selective inhibitor of the enzyme Factor Xa participating in the blood coagulation system. Apixaban is classified as'an antithrombotic drug which can be administered orally. Therefore, it’s possible medical use are reported to be in thrombosis treatment and thrombosis prophylaxis after orthopedic operations as well as the prophylaxis of ischaemic apoplexia in case‘of atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
Apixaban appears as‘a white to pale. yellow, non hygroscopic crystalline powder, with'an aqueous solubility of 0.028 mg/ml at 24°C. Apixaban is a non-ionizable compound and its partition coefficient at 24°C is 44.7 (log Po/w = 1.65) at pH 7.4 (n-Octanol / aqueous buffer).
The molecule has no chiral centres, therefore no stereoisomers exist. As per the ‘Biopharmaceutical Classification System (BCS), it is classified as a Class 111 (high solubility/low permeability) compound. It shows polymorphism and a number of hydrates and solvates were identified.
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination ‘of apixaban in the feces. Apixaban has a total clearance of approximately 3.3 L/hou‘r and. an apparent half- life of approximately 12 hours following oral administration.
The IUPAC name for apixaban is [INN] 1-(4-Methoxyphenyl)47-oxo-6- [4-(2—oxopiperidin- 1-y1) phenyl]-4,5,6,7—tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-'carbamid. The chemical
structure of apixaban is shown in the formula (1) below:
Apixaban is currently available in the US. market as tablets for oral use containing 2.5 and 5 mg of apixaban under brand name Eliquis®. In Europe market also, it is currently available as tablets for oral use containing 2.5 and mg of apixaban.
US 2013/0045245 by Pfizer and Bristol Meyer Squibb discloses composition comprising crystalline apixaban particles having D90 equal to or less than 89 um and a phMaceutically acceptable carrier, useful for the treatment and/or prophylaxis of thromboembolism.

US 2006/0160841 by Bristol-Myers squibb discloses process for transforming a first . anhydrous polymorph of apixaban having particle size D90 greater than about 60 um into a second anhydrous polymorph of apixaban having particle size D90 of less than about 50 um.
WO 2013174498 by Ratiopharm discloses oral dosage form for modified release containing (a) particulate, crystalline apixaban and (b) matrix former, wherein the apixaban particle size distribution has a D90 value of 90 um or greater, in particular of 95 to 500 um.
2554159 by Ratiopharm discloses compositions and/or oral dosage forms comprising micronized apixaban and a content uniformity enhancer. It discloses that the D90 value of the integral volume distribution is from 0.5 to 30 um, preferably from 1 to 15 pm, more preferably from 2.5 to 10 um and especially from 3 to 8.5 um. Also disclosed is that the composition does not contain lactose, in particular anhydrous lactOSe, and/or microcrystalline llulose.
The inventors of the present invention have endeavored to develop stable formulation" comprising apixaban having particle size D90 of less than about 20 um. Also the inventors 'of the present invention have endeavored to develloplstable formulation comprising apixaban having particle size D90 of more than about 90 umf

Obiective of the invention
The main object of the invention is to provide an oral dosage form composition comprising apixaban and at least one pharrnaceutically acceptable excipient. Another object of the' invention is to provide composition comprising apixaban having particle size D90 of less than about 20 um.

Yet another object of the invention is to provide composition comprising apixaban having particle size D90 of more than about 90 um.

Yet another object of the invention is to- provide process for preparing compositions comprising apixaban haying particle size D90 of less than about 20 um.
Yet another object of the invention is to provide process for preparing compositions comprising apixaban having particle size D90 of more than about 90 um;

Yet another objective Of the present invention is to provide methods of using the compositions containing apixaban according to the present invention.

Summary of the invention
In an aspect, the present invention relates to oral dosage‘form compositions comprising;
(i) 0.1 to 10% by weight apixaban,
(ii) 5 to 98% by weight diluent(s),
(iii).1 to 30% by weight'disintegrant(s), and
(iv) 0.1 to 5% by weight 1ubricant(s).'
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In one aspect, the present invention relates to compositions comprising apixaban having
particle size D90 of less than about 20 um and. at least one pharmaceutically acceptable
excipient.
In another aspect, the present invention relates to compositions. comprising apixaban having
particle size D90 of more than about 90 um and at least one pharrnaceutically acceptable
excipient.
. In yet another aspect, the present invention describes the process for preparing the said
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pharmaceutical compositions comprising apixaban and at least one pharmaceutically
acceptable excipient.
Another aspect of the present invention provides methods of using the compositions
comprising apixaban by administering to a subject in need thereof a stable pharmacieutical
formulation comprising apixaban and one or more pharmaceutically acceptable excipients.
The oral dosage form compositions of the present invention are useful in reducing the risk of
stroke and systemic embolism in patients with non valvular atrial fibrillation, for the ,
prophylaxis of deep vein thrombosis, for the treatment
.of
deep vein thrombosis and
pulmonary embolism, and for the reduction in the‘risk of recurrent deep vein thrombosis and
pulmonary embolism following initial therapy.
Detailed description of the~invention
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated.
The term ‘stable’ refers to formulations that substantially retain the label amount of the
therapeutically active ingredient during storage for commercially relevant times, and the
drug-related impurity contents in the formulations remain within acceptable limits. Further,
the term .‘stable’ also optionally refers to formulations that contain polymorphically stable
active ingredient. The phrase “substantially pure polymorphic form of Apixaban”, unless .
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pseudopolymorphic forms at amounts detectable with typical analytical methods such as X-
ray powder diffraction and/or solid state infrared absorption, i.e. containing less than 10% of
other polymorphic and/orpseudo-polymorphic forms.
“Pharmaceutically acceptable” refers to those properties and/or substances which are
acceptable to the patient from a pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point of view regarding
compOSition, formulation, stability, patient acceptance and bioavailability.
The term “polymorphic form, polymorph, polymorph form, crystalline. polymorph or
crystalline formof Apixaban” in the present invention refers
to'a
crystalline 'anhydrOus N-l
form of ApiX’aban, which can be characterized by analytical methods such as X-ray powder
diffraction pattern, Fourier transform infrared ’spectroscopy (FT-IR), thermo-gravimetric
'analysis (TGA),'differential scanning calorimetry (DSC), by its melting point or other‘
techniques.
The term “composition” or “pharmaceutical composition” or “dosage form” or “formulation”
or “pharmaceutical composition”, as used herein or otherwise, synonymously include solid.
‘
dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres,
tablets, capsules, mini-tablets, layered tablets, beads, particles and the like; and liquid dosage
forms. such as solutions, suspensions, emulsions, colloids and the like, meant for oral
administration.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the
active drug (e.g. apixaban), which is sufficient to elicit an appreciable biological response
when administered to the patient.
In accordance with the present invention, the term “Apixaban” unless indicatedotherwise in
the entire-specification refers to ,Apixaban in the form of free base or itspharmaceutically
'
acceptable salt, amorphous, various polymorphs or any isomer or derivative, hydrate or
.
solvate, prodrug or combinations thereof; Preferably “Apixaban” as used alone denotes the
crystalline N31form, and the term can be used interchangeably for the purpose :of this
invention. In an embodiment, the polymorphic form, is substantially retained in the 3"28-Apr-2016/14451/2162-CHE-2015/De'scription(Complete)
The term “particles” refers to individual drug substance particles whether the particles exist singly or are agglomerated.
The term “partiCle size” unless indicated otherwise in the specification relates to particles of Apixaban free base as well as pharmaceutically acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof.
Apixaban particles having “a mean particle size” (herein also used interchangeably with “VMD” for “volume mean diameter”) equal to or less than a given diameter or'lbeing within a given particle size range means that the average of all Apixaban particles in the sample have an estimated volume, based on an assumption of spherical shape, less than or equal to the volume calculated for a spherical particle lwith a diameter equal to the given diameter.
Particle size distribution can be measured by laser light scattering technique as known to those skilled in the art.
The term “D90” unless indicated otherwise in the specification is defined as the size value corresponding to cumulative size. distribution at 90%, which represents the size of particles below which 90% of the sample lies. The known particle size‘analysis methods are suitable for determining the particle size, for example, particle size measurement using light-
scattering methods such as by Malvem or Horiba. The term “excipient” means a pharmacologically-inactive component such as a diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non—toxic and are acceptable for veterinary as wellas human pharmaceutical use. Reference to an excipient includes both one and more than one such
excipient.
“Pharmaceutically acceptable excipient(s)” are components added to pharmaceutical formulation in addition» to the active ingredient Apixaban. Excipients may be added to facilitate manufacture, enhance stability, enhance ,product characteristics, enhance bioavailability, enhance patient aCceptability, etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, one or more of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, "dispersing ggéntléfiilrrflfd’firfi‘efs,{flats/(1m, pririitirri‘g'i'rilksfletc;
In the specification, singular forms, including the singular forms a," "an" and "the",
specifically also encompass theplural referents of the terms to which they refer unless the
context clearly dictates otherwise. In addition, as used herein, unless specifically indicated-
otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive"
sense of "either/or".
As used in this specification, whether in a transitional phrase or in the body of a claim, the
terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended
meaning; That is, the terms are to be interpreted synonymously with the phrases "having at
least" or "including at least". When used in the context of a process, the' term "comprising"
means that the process includes at least the recited steps, but may include additional steps.
When used in the context of a compound or composition, the term "comprising" means that
the compound or composition includes at least-the recited features or components, but may
also include additional features or components.
The present invention provides oral dosage forms comprising Apixaban and at least one
‘pharrnaceutically acceptable excipient(s).
In an embodiment, the said composition comprises apixaban wherein the D90 of the apixaban
particles 13 less than about 20 pm
The said particle size limit may be achieved by virtue of
the process of synthesis of apixaban, or by using mechaniCal means such as milling or other
techniques known to those skilled 1n the art.
Yet another embodiment of the present invention. relates to compoSitions comprising
.
apixaban wherein D90 of Apixaban particles is more that about 90 um.
Yet another embodiment of the present invention provides. stable pharmaceutical
compositions comprising apixaban and one or more other pharmaceutically acceptable
excipient(s).
Another embodiment of the present invention provides an oral dosage form composition
comprising:
(i) 0.1 to 10% by weight apixaban, .
J»28-Apr-2016/14451/2162-CHE-2015/Description(Complete)
(ii) 5 to 98% by weight diluent(s),
(iii) 1 to 30% by weight disintegrant(s), and
(iv) 0.1 to 5% by weight 1ubricant(s).
In yet another'embodiment the oral dosage form of the present invention comprises:
(i) 1.5 to 6 % by weight apixaban,
i
(ii) 30 to 90 % by weight diluent(s),
(iii) 3 to 20 % by weight disintegrant(s), and
(iv) 0.5 to 3 % by weight 1ubricant(s).
Another embodiment of the present invention provides a stable solid oral composition
comprising apixaban and one or more pharmaceutically acceptable excipient, 'wherein the
composition contains optionally a surfactant.
-
The said dosage form further comprises one or more of the following lexcipients such as dry
binders, disintegrants, glidants, lubricants, diluents, sweeteners, .thickening agents,
preservatives, flavoring agents and combinations thereof.
In another embodiment, the present invention relates.
'to a pharmaceutical formulation
comprising apixaban having D90 less than about 20 pm, at least one diluent, surfactant and
one or more other pharmaceutically acceptable excipients.
In another embodiment, the present invention relates. to a pharmaceutical formulation
comprising apixaban having D90 more than about 90 pm, at least one diluent, surfactant and
one or more other pharmaceutically acceptable excipients.
In an embodiment, the present invention provides pharmaceutical compositions wherein the
ratio of the active agent apixaban to diluents is from about 1:100 toabout 100:1.
In an embodiment, the present invention provides pharmaceutical compositions wherein the .
ratio of two diluents that is lactose to microcrystalline cellulose is from about 1:50 to about
The compositions of the present invention can. be in the form of tablets, capsules, granules
and powder for oral suspensions.
In a preferred embodiment, the tablet of the present application can be film-coated. For this
purpose, methods known in the art for film-coating a tablet may be employed. In a preferred
embodiment of the present invention the film-coating can be a film-coating, essentially
without affecting the release of the active agent, or a film-coating affecting the release of the
active agent.
In'the present invention, the processes have been designed to especially handle particles of
drug having particle size less than 20 pm or more than 90 um,
The compositions of the present invention can be prepared by any of the methods known to
the art such as direct compression, dry granulation or wet granulation.
According to the present invention, the compositions comprising apixaban are prepared by
dry process such as blending or blending followed optionally by other processes such as
direct compression, slugging-deslugging or roller compaction as per the 'need of the dosage
form.
In an embodiment, the present invention provides prOcess for the preparation of stable oral
pharmaceutical compositions of apixaban by a direct compression method.
In anotherembodiment, the present invention provides process for the preparation of stable
oral pharmaceutical compositions of apixaban by dry granulation method.
In yet another embodiment, therpresent invention provides process for the- preparation of
stable oral pharmaceutical compositions of apixaban by a wet granulation method.
In an embodiment, the present invention provides process for the preparation of stable oral
pharmaceutical compositions, wherein the process comprises of the following steps:
'(i) treating apixaban with at least one pharmaceutically acceptable excipient(s),

(ii) optionally adding one or more other pharmaceutically acceptable excipients, and
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28¥Apr-2016/14451/2162-CHE-2015/Description(Compléte)28-Apr-201_6l14451l2162-CHE-2015/Description(Complete)
In yet another embodiment, the present invention provides process for the preparation of
pharmaceutical composition, wherein the process comprises of the following steps:
(i) treating apixaban with at least one phannaceutically acceptable excipient(s) including
diluent(s), disintegrant(s) and lubricant(s),
(ii) optionally adding one or more other pharmaceutically acceptable excipient(s), and
(iii) formulating the material of step (i) and (ii) into a suitable dosage form. In another embodiment, the present invention also relates to a method of reducing the risk of stroke and systemic embolism in 'patients. with non valvular atrial fibrillation, for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery, for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy.
In yet another embodiment, the oral dosage form compositions of the present invention are useful in reduCing the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation, for the prophylaxis of deep vein thrombosis, for the treatment of deep vein thrombosis and pulmonary embolism, and' for the reduction in the risk of recurrent deep vein thrombosis and pulmonary embolism following initial therapy.
Diluents or fillers increase the bulk of the composition. Diluents are present alone or in combination in the range of about 95% by weight. Diluents are selected from a group comprising of but not limited to’ lactose, sucrose, glucose, dextrose, mannitol, xylitol, erythritol, dulcitol, ribitol, sorbitol, powdered cellulose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dehydrate, tribasic calcium phosphate, kaolin, magnesium oxide, magnesium carbonate, and the like, and mixtures thereof In addition, lubricants may be used. Lubricants are generally used in order to reduce sliding friction.
particular, the intention is‘ to reduce the sliding friction found during tablet pressing between the punch moving up and down in the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand. Suitable lubricants are selected from group comprising of but not limited to stearic acid,-adipic acid, sodium stearyl fumarate and/or magnesium stearate, and the like, and mixtures thereof. Lubricants are '1ll28-Apr-2o16/14451/2162-0HE-é015/Description(CompIété) generally used in an amount of 0.1 to 3 % by weight, based on the total weight of dosage from Disintegrants according to the present invention are selected from but not limited to group.
comprising, water swellable substances, for example, cellulose and its derivatives including
low-substituted hydroxypropyl Cellulose; cross-linked‘polyvinylpyrrolidone; cross-linked
sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium
carboxymethylcellulose, calcium‘carboxy methylcellulose, microcrystalline cellulose; sodium.
starch 'glycolate;.ion-exchange resins; starch and modified starches including pregelatinized
starch; formalin-casein; alginates, gums, and the like, and mixtures thereof. Disintegrants can
be present in an amount of O to 50 wt%, preferably 2 to 40 wt%, more preferably 2.5 to 30
wt% and still more preferably 3 to 25 wt% of the dosage form.
. A glidant is a substance that is added to apowder to improve its flowability. “Glidants” are
selected from group comprising of, but not limited to, colloidal silica, calcium silicate,
magnesium silicate, silicon hydrogel, cornstarch, talc, corn starch, DL—leucine and the like,
and mixtures thereof.
Binders can be present in an amount of 1 to 40%, preferably 5 to 25% by weight. Binders
hold the ingredients in the composition together. “Binders” include, but are not limited to,
-.
hydroxypropyl cellulose,- hydroxypropyl methylcellulose, low-substituted hydroxypropyl.
cellulose, povidone, starches such ascorn starch, potato starch, modified starches, sugars,
guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxyethyl
cellulose, copolyVidone, carboxymethylcellulose sodium, ethyl cellulose, gelatin, liquid
glucose and pregelatinized starch and the like used either alone Or in combinations thereof.
The binder may be used in the range of about. 05-10% by weight of the composition.
Surfactants are compounds which are capable of
improving the wetting of the drug and/or
enhancing the dissolution. The‘surfactants can be selected from hydrophilic surfactants or
lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic,
and zwitterionic surfactants. Surfactants according to the present invention are selected from
group comprising of . but not limited to, polpyethylene alkylaryl ethers such as
polyoxyethylene lauryl ether, polyoxyethylene cetyl
I
ether, polyoxyethylene stearyl ether;
RIT
‘pblyefhy—lérfielg’fyegol (liliifififdttiii geld ester—s sauchEasfiPEé gadnéi'laurate; PE‘E} LIiiilaurate, PEG
1228-Apr-2016/14451/2162-CHE-2'015/Description(Co_mplete)
. distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysOrbate 40,
polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate,
sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil
derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl
sulphate and the like, and mixtures thereof.
In an embodiment, the tablet compositions of the present invention may be film coated. A
film forming agent mayprovide smooth film-forming coating suspensions and enhance the
rheological mechanical strength properties of film coating gel matrices. Film-forming agents
include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers.
A cellulosic polymer may include a molecule comprisingat least one cellulose polymer or
derivative modified with small amounts of propylene glycol ether groups attached to the
cellulose anhydroglucose chain affording binding properties that enhance the reinforcing film
properties of film applications. Examples of cellulosic polymers include, but are not limited

to, hydroxypropyl methyl cellulose (“HPMC”), carboxymethyl cellulose (“CMC”) or salts
thereof, hydroxypropyl cellulose (“HPC”), methylcellulose (“MC”), hydroXyethyl cellulose
(“HEC”), and the like. In addition, cellulosic polymers may be characterized as ionic or non-
ionic. Ionic cellulosic polymers include, for example, sodium CMC. Non-ionic cellulosic
polymers include, for example, HPMC, HPC, HEC, and MC. Varieties of commercially -
available cellulosic polymers exist and may include, for example, Spectracel® HPMC
compOsitions (available from Sensient Technologies). Further, other'commercially available
coating materials are available marketed under the brand name Opadry® for example Opadry
Gray which contains: lactose monohydrate NF,,hypromellose type 2910 USP, titanium
dioxide USP; triacetin USP, and iron oxide‘black JPE; Opadry II Pink which contains:
hypromellose type 2910 USP, titanium dioxide USP, lactose monohydrate NF, polyethylene
glycol 3350 NF, triacetin USP, and FD&C Red #40; Opadry 11 Blue which contains:
hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol
3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10;
Opadry 11 ,Yellow which contains: hypromellose type 2910 USP, lactose monOhydrate NF,
.titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin
USP; Opadry II Purplewhich contains: hypromellose type 2910 USP, lactose monohydrate
NF, titanium dioxide USP, D&C Red #27, polyethylene glycol 3350 NF, triacetin USP, and
FD&C Blue #1 and the like.
substitute the equivalent excipients as described in this specification or with the one known to
In an embodiment, the compositions of the present invention may additionally comprise of a
colorant in order to produce a desirable color. Colors known to be 'FD&C’ certified may be
used to provide coloring to the product and are within the purview of the present invention.
Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral,
plant, and animal sources.
Examples of natural colorants include red ferric oxide, yellow' ferric oxide, annattenes,
alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used,- which is
typically an FD&C or D&C dye, e.g., an approved dye selected from the. so-called ‘cdal—tar’
dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a
xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or-
a ‘lake’ thereof, i.e.-an aluminum or calcium salt thereof. Particularly preferred colorants are
food colorants in the 'GRAS'-(Generally Regarded as Safe) category.
The tablets in accordance with the present invention can be prepared by [either direct
compression, dry granulation like slugging or roller compaction, or by wet granulation.
The wet granulation method may comprise use of aqueous solvent such as water or an
organic solvent (non-aqueous) such as dichloromethane, ethanol, acetone, methylene chloride
and the like, or a mixture’thereof, as the granulating aid.
The compositions of 'the present invention can be packed into suitable containers such as
bottles, blisters or.pouch._Further, the packages may optionally: contain, a dessicant or an
antioxidant‘or oxygen absorbant or combinations thereof.
The followmg examples further exemplify the invention and are not intended to limit the
scope of the invention.
It is obvious to those skilled in the art to find out the composition for other dosage forms and
the industry.
Opadry® c0ating system'comprises lactose monohydrate, hypromellose, triacetin, titanium
dioxide, red iron oxide/ yellow iron oxide.
Manufacturing process:
Sift Lactose Monohydrate and/or Microcrystalline Cellulose, Apixaban,
CrOsCarmellose sodium and/or Sodium Lauryl Sulfate through #30 mesh. ,
Sift magnesium stearate through #60 mesh.
Mix step-1 material in 10w shear blender for 10 mins.
Lubricate the step-3 material with step-2 material for 5 mins.‘
Compress into tablet.
B. Film Coating; .
Disperse the Opadty iii-purified water under stirring.
Load‘thecore tablets in perforated pan coater and fire-warm the tablets for 10—1 5
minutes.
Coat the tablet until the'target weight build up is achieVed.
QuantilyzSuflicient‘
Opadry® coating system comprises lactose mOnohyldrateglhyprOmellose; triacetin, titanium
dioxide, rediron oxide/ yellow‘ iron oxide,
5%; Ji‘ ~ U"! W.28-Apr-2016/14451/2162-CHE-2015/Descri'ption(Complete)
Manufacturing process:
A. Core Tablet:
1.
iowsowew'sv
Sift Lactose Monohydrate'and/or Microcrystalline Cellulose, Apixaban,
Croscarmellose sodium and/or Sodium Lauryl' Sulfate through #30 mesh.‘
Sift half quantity of magnesium stearate through #60 mesh.
~Mix step-1 material in low sh‘ear blender for 10 mins.
Compact the mixed material of step-4 using Roll Compactor.
Pass the cempacts through :Oscillating Granulator fitted with required sieve.
Sift the milled granules the required sieve. 4
Sift half quantity of magnesium stearate through #60 mesh.
Lubricate the step-6 material with step-7 material for 5 mins.
Compress into tablet.
_ B. Film Coating:
1.
2.
Disperse the Opadry in purified water (12% w/w solids) under stim'ng.
Load the core tablets in perforated pan coater and- pre-warm the tablets for 10-15
Minutes.
Coat the tablet until the target weight build ‘up'is achieved.

[28-Apr-201'6I1
4451/2162-CHE-201
5IC|aims
We claim:
,1.
:
11111111111111
Oral dosage form compositions comprising:
(i) 0.1 to 10% by weight apixaban,
‘
(ii) 5 to 98% by weight diluent(s),
(iii) 1 to 30% by weight disintegrant(s), and
.
(iv) 0.1 to 5% by weight lubricant(s).
The oral dosage form compositions according to claim 1, wherein'the 13.90 of the
apixaban particles is less than about 20 pm.
The oral dosage form compositions according to claim 1,
'wherein'
the D90 of the
apixaban particles is more that about 90 pm.
The oral dosage form compositions according to claims 1-3, wherein the Composition
contains optionally a surfactant.
The oral dosage form compositions according to claim 1, wherein the composition
further comprises oneor more of the excipients selected from group comprising dry
binders, glidants, sweeteners, thickening agents, preservatives, flavoring agents and
combinations thereof.
‘
The oral dosage form “compositions according to: claim 1, comprising apixaban having
'
D90 'less than about 20 pm, at least one surfactant(s), and one or more other
pharmaceutically acceptable excipients.
The orali dosage form compositions according to claim 1, comprising apixaban having
D90 more than' about 90 um,
‘at least one surfactant(s), and one or more other
'
pharmaceutically acceptable eXcipients.
The oral dosage form compositions according to claims 1-7, wherein the ratio of the
1
active agent apixaban to diluent(s) is from about 1:100 to'about 100:1.
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.125. U128-Apr-20'1'6I14451/2162V-CHE-2015IC|aims
9.
10.
'A
process for the preparation of pharmaceutical compositions according to claim 1,
wherein the prdcess comprises of the following steps:
(iv) ,
treating apixaban With at least one'pharmaceutically acceptable excipient(s)
- including -diluent(s)', disintegrant(s) and lubricant(s),
(v) optionally adding one or more other'phannaceutically acceptable.excipient(s),
and
'
(vi) formulating the material of step (i) and (ii) into a suitable dosage form.
The oral dosage form compositions according to claim 1, which is useful in reducing
‘
the risk of stroke and systemic embolism in patients. with non valvular atrial
fibrillation, for the prophylaxis of deep vein thrombosis, for the treatment of deep
'vein thrombosis and pulmonary embolism, and for the reduction in the risk of
/
recurrent deep vein thrombosis and pulmonary embolism following initial therapy.
Dated this
'
aé dayof RVYf/ 2016
'
For Aurobindo Pharma Limited
'
r._M. Sivakumaran
Director;
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