Note: Descriptions are shown in the official language in which they were submitted.
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SOLID COMPOSITION CONTAINING ORAL ANTICOAGULANT
FIELD OF INVENTION
The present invention relates to the field of Oral pharmaceuticals.
The invention specifically relates to solid oral anticoagulant compositions
and
methods for the preparation of the same.
The present invention more specifically relates to composition of Rivaroxaban
Oral tablets and methods for the preparation of the same.
This invention also relates to the composition of Rivaroxaban Oral tablets
prepared by drug layered spheres.
This invention also relates to the composition of Rivaroxaban tablets prepared
by Non-aqueous granulation using Organic solvent and Hydroalcoholic
granulation.
BACKGROUND OF INVENTION
The active ingredient in the present invention is Rivaroxaban chemically
known as "5-Chloro-N-({(5S)-2-oxo-344-(3-oxo-4-morpholinyl) phenyl]-1, 3-
oxazolidin-5-yll methyl)-2-thiophenecarboxamide" and has an empirical chemical
formula C19H18C1N305S with a structural formula shown below:
0 N 410 N-ILO
s ci
0
Rivaroxaban is a low molecular weight, orally administrable anticoagulant
indicated for reduction of risk of stroke and systemic embolism in nonvalvular
atrial
fibrillation and prophylaxis of deep vein thrombosis. It is an orally
bioavailable factor
Xa inhibitor that selectively blocks the active site of factor Xa and does not
require a
cofactor (such as Anti-thrombin III) for activity. Activation of factor X to
factor Xa
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(FXa) via the intrinsic and extrinsic pathways plays a central role in the
cascade of
blood coagulation.
US 7157456 discloses rivaroxaban product with method of use as anticoagulant
and different crystalline polymorphic forms of Rivaroxaban are disclosed in
various
patents and patent applications like US 8188270, US 20100168111, WO 2012004245
and W02013041651.
US 2008/0026057 disclose a solid, orally administrable pharmaceutical
composition, comprising rivaroxaban in hydrophilized form. This application
further
discloses a process for the preparation of composition comprising Rivaroxaban
in
hydrophilized form, in which (a) first granules comprising the Rivaroxaban in
hydrophilized form are prepared by moist granulation (b) and the granules are
then
converted into the pharmaceutical composition, if appropriate with addition of
pharmaceutically suitable additives.
US 2010/0151011 disclose rapid release solid pharmaceutical dosage form of
rivaroxaban containing drug in amorphous form or thermodynamically metastable
crystal modification form. Use of these modified forms increases the
solubility and the
oral bioavailability of rivaroxaban.
US 2011/0300214 disclose pharmaceutical compositions of rivaroxaban
comprising a solubilizer and a pseudo-emulsifier.
US 2012/0231076 disclose process for producing a pharmaceutical composition
of rivaroxaban. The process involves mixing rivaroxaban, a matrix former, and
a
disintegrant, melting the mixture, and granulating the melted mixture.
US 2013/0064888 disclose pharmaceutical dosage forms of rivaroxaban having
a compressed inert core, an optional subcoat over the compressed inert core, a
drug
layer over the compressed core.
WO 2010/146179 disclose solid pharmaceutical compositions of rivaroxaban,
prepared by dry mixing or dry granulation of the rivaroxaban with at least one
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excipient, co-milling rivaroxaban with the excipients, hot melt granulation
with a
molten excipient, or hot melt extrusion with an excipient. The mixture may
then be
agglomerated, granulated with a granulation liquid, or milled before
compressing to
form a tablet.
WO 2015/124995 Al disclose an oral solid dosage form of rivaroxaban,
prepared by a process, comprising the steps of blending, granulation, drying,
milling
and formulating the blend obtained into solid dosage form.
The above prior art references discloses different process for the preparation
of
solid oral dosage form of rivaroxaban. However, the inventors of the present
invention
have formulated a simple formulation with simple process which will provide
enhanced dissolution and bioavailability of drug.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide an oral solid dosage
form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable
salts and
one or more pharmaceutically acceptable excipients.
Another objective of the present invention is to provide a process for the
Preparation of solid dosage form of rivaroxaban its solvates, hydrates and/or
pharmaceutically acceptable salts.
Another objective of the invention is to provide an alternative pharmaceutical
composition of rivaroxaban and its method of preparation which will enhance
the
dissolution and oral bioavailability of the drug.
SUMMARY OF INVENTION
One embodiment of the present invention provides an oral pharmaceutical
composition comprising Rivaroxaban its solvates, hydrates and/or
pharmaceutically
acceptable salts prepared by drug layering technology.
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In another embodiment of the present invention provides an oral
pharmaceutical composition comprising Rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts prepared by non-aqueous granulation and
hydroalcoholic granulation.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising Rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts prepared by non-aqueous granulation/
Hydroalcoholic granulation containing cremophore.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising Rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts, diluents/fillers, binders, disintegrants,
glidants,
lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving excipients in mixture of ethanol and Purified water,
b) Dispersing drug in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets, and
d) Adding extragranular materials to step 3 pellets and blend followed by
compression and optional coating.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium
lauryl sulphate in mixture of ethanol and Purified water,
b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer,
d) Adding extragranular materials to step 3 pellets and blend,
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e) Compressing the tablets using step 4 blend,
f) Dispersing Opadry brown in Purified water, and
g) Coating the tablets of step 5 with step 6 dispersion.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution,
b) Dispersing Drug in step 1 solution until smooth dispersion forms,
c) Sifting and blending the excipients,
d) Spraying step 2 dispersion on to step 3 blend until proper granules
obtains,
and
e) Adding extragranular materials and compression with optional coating.
In another embodiment of the present invention provides an oral
pharmaceutical composition comprising rivaroxaban its solvates, hydrates
and/or
pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose and Cremophor in ethanol or mixture
of Ethanol and Purified water,
b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
c) Sifting Croscarmellose sodium, Lactose monohydrate and microcrystalline
cellulose,
d) Spraying step 2 dispersion on to step 3 blend in Fluid bed dryer until
proper
granules obtained,
e) Adding extragranular materials to step 4 granules and blend, and
f) Compressing the tablets using step 5 blend.
DETAILED DESCRIPTION OF THE INVENTION
The invention specifically relates to oral anticoagulant compositions and
methods for the preparation of the same.
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One embodiment of the present invention provides an oral pharmaceutical
composition comprising Rivaroxaban its solvates, hydrates and/or
pharmaceutically
acceptable salts, diluents, binders, disintegrants, glidants, lubricants,
surfactants,
solubilizers and other excipients.
In another embodiment of the present invention provides process for the
preparation of oral solid composition comprising rivaroxaban its solvates,
hydrates
and/or pharmaceutically acceptable salts, diluents, binders, disintegrants,
glidants,
lubricants, surfactants and other excipients.
The term "rivaroxaban" includes various forms of rivaroxaban such as hydrates,
solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters,
prodrugs, complexes or mixture thereof and all other forms known in the art.
Rivaroxaban can be present in different physical forms, e.g. in an amorphous
form, in
one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms),
in the
form of mixture of different crystal forms (e.g. anhydrous, solvated or
hydrated forms)
or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous,
solvated or
hydrated forms). Each of these forms is included in the term "rivaroxaban" as
used in
the present invention.
The term "comprising", which is synonymous with "including", "containing",
or "characterized by" here is defined as being inclusive or open-ended, and
does not
exclude additional, unrecited elements or method steps, unless the context
clearly
requires otherwise.
The composition according to the invention comprise diluents such as
microcrystalline cellulose, powdered cellulose, lactose (anhydrous or
monohydrate),
compressible sugar, fructose, dextranes, other sugars such as mannitol,
sorbitol,
lactitol, saccharose or a mixture thereof, siliconised microcrystalline
cellulose,
calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures
thereof.
A preferred further diluent that also causes reduced sticking properties of
tablets to the
equipment used for tabletting is silica, preferably colloidal or fumed silica.
Preferably,
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the excipients include at least one diluent selected from microcrystalline
cellulose and
lactose monohydrate.
The composition according to the invention comprise binders, such as
polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl
alcohol, polymers of acrylic acid and its salts, starch, celluloses and
celluloses
derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose,
hydroxyl
propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose,
carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution,
acacia,
tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised
starch, partially
hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures
thereof. It is
preferable to use a binder with good water solubility. In a preferred
embodiment of the
invention the excipients include at least one binder selected from
hydroxypropyl
cellulose and povidone.
The composition according to the invention comprise disintegrants, such as
is carboxymethylcellulose,
carboxymethylcellulose calcium (CMC-Ca),
carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl
cellulose as e.g. Ac-Di-Sol , PrimeHose , Pharmacelt XL, Explocel , and
Nymcel ZSX having a molecular weight of 90 000-700 000, sodium starch
glycolate
e.g. ExplosolO, ExplotabO, Glycolys , Primojel , Tablo , Vivastar0 P, in
particular having molecular weight is 500000-11000000, crosslinked
polyvinylpolypyrrolidone (Plasone-XL , Polyplasdone XL and KolEdon CL) in
particular having a molecular weight in excess of 1000000, more particularly
having a
particle size distribution of less than 400 microns or less than 74 microns,
microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose),
sodium
carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed
starch,
wheat starch, maize starch, rice starch or potato starch, cornstarch,
pregelatinized
starch, crospovidone, for example, POLYPLASDONE XL (International Specialty
Products), magnesium aluminium silicate or mixtures thereof.
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The composition according to the invention also comprise lubricants, such as
stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate,
hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate,
macrogols, or mixtures thereof.
The composition according to the invention also comprise glidants, such as
talc,
fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate
either
alone or in combination thereof.
The composition according to the invention also comprise surfactants, such as
sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or
sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid
esters of
polyhydric alcohols such as glycerol monostearate, glyceryl monooleate,
glyceryl
monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also
known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene
polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237,
Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of
sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan
monooleate,
sorbitan stearate, sorbitan monolaurate etc. such as Span or Arlacel ,
Emsorb@,
Capmul , or Sorbester , Triton X-200 etc.; or a fatty acid esters of
polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g.
polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20)
sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monopalmitate
(Tween 40), polyoxyethylene (20) sorbitan monolaurate (Tween 20); or
polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200
dilaurate,
PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate;
alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate
(Lauroglycol ); or hydrogenated castor oil and polyoxyethylene castor oil
derivates,
e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil
(Cremophor@ EL;
BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol
40
hydrogenated castor oil (Cremophor RH 40) or polyethylenglycol 60
hydrogenated
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castor oil (Cremophor RH 60); or sucrose fatty acid esters, such as sucrose
stearate,
sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate
butyrate; or
vitamin E and its derivatives such as Vitamin E-TPGS (d-alpha-tocopheryl
polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids
(lecithins, kephalins, phosphatidyl serine), glyceroglycolipids
(galactopyransoide),
sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides,
gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium,
SDS
(sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic
acid,
sodium caprylate; or bile acids and salts thereof; or ethoxylated
triglyceiides; or
quaternary ammonium salts such as cetyl-trimethylammonium bromide,
cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and
triacetin; or
triethanolamine, lecithin, monohydric alcohol esters such as trialkyl
citrates, lactones
and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol
fatty acid
esters such as mono-, di- and triglycerides and a cetylated mono- and di-
glycerides;
propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or
derivatives
thereof, lecithins, alcohols and glycine or taurine conjugates,
ursodeoxycholic acid,
sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate,
N-
Hexadecyl-N, N-dimeth y1-3- ammonio- 1 -propanesulfonate,
anionic (alkyl-
arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine,
lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine,
choline,
serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-
derivatives of
lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl
derivatives of
lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of
the
polar head group, that is cholines, ethanolamines, phosphatidic acid, serines,
threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP,
BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic
surfactants (e.g. N- alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-
cholamido-l-
propyldimethylammonio-1 -propanesulfonate, dodecylphosphocholine, myristoyl
lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants
(quarternary
ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate
etc.),
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long-chain falty acids and salts thereof C6-C2 (eg. oleic acid and caprylic
acid),
acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine
or histidine,
or side-chain acylated derivatives of lysine or arginine, N-a-acylated
derivatives of
dipeptides comprising any combination of lysine, arginine or histidine and a
neutral or
acidic amino acid, N-a-acylated derivative of a tripeptide comprising any
combination
of a neutral amino acid and two charged amino acids, or the surfactant may be
selected
from the group of imidazoline derivatives, or mixtures thereof. Each one of
these
specific surface-active agent constitutes an alternative embodiment of the
invention.
The composition according to the invention also comprise solubilizers such as
.. sugar alcohols like isomalt, sorbitol, xylitol or mannitol, cellulose
derivatives
(especially hydroxypropylmethyl cellulose (HPMC) and/or hydroxypropyl
cellulose
(HPC)), sugar alcohols (especially isomalt), polyethoxylated castor oil
(Cremophor),
polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone are used as
solubilizer.
The composition according to the invention also comprise solvents such as
methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and
the like
and mixtures thereof.
Other excipients commonly used in pharmaceutical composition may be used
and reference is made to the extensive literature on suitable substances [see
in
particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe,
.. Paul J Sheskey & Sian C Owen (2006)1 the content of which is incorporated
herein by
reference.
The pharmaceutical composition of the present invention can be present in the
form of a tablet, a capsule, powder, a disc, a caplet, granules, pellets,
granules in a
capsule, minitablets, minitablets in a capsule, pellets in a capsule, a sachet
and other
dosage forms suitable for oral administration.
The granules may be prepared by methods such as, but not limited to, wet
granulation, melt granulation, dry granulation or roll compaction or the like.
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Optionally, cores/tablets can be coated with conventional materials used for
film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995,
edited
by Graham Cole. Film coating formulations usually contain the following
components: polymer (s), plasticizer (s), colourant (s) /opacifier (s),
vehicle (s). In
film coating suspension the minor quantities of flavours, surfactants and
waxes can be
used. The majority of the polymers used in film coating are either cellulose
derivatives, such as the cellulose ethers, or acrylic polymers and copolymers.
Occasionally encountered are high molecular weight polyethylene glycols,
polyvinyl
pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers
are
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose
and
methylcellulose. Acrylic polymers comprise a group of synthetic polymers with
diverse functionalities. Some of them can be further modified to enhance
swelling and
permeability by the incorporation of materials such as water soluble cellulose
ethers
and starches in order to ensure complete disintegration/ dissolution of the
film.
is Other
additives used in the preparations to the compositions of this invention,
the following can be used and there were no limitations: stabilizer,
surfactant,
plasticizer, lubricant, reducing agent, buffer agent, sweetening agent, base,
adsorbent,
corrigent, binder, suspending agent, antioxidant, polish, coating, wetting
agent, wet
modifier, filler, antifoaming agent, refrigerative agent, coloring matter,
flavoring
agent, perfume, sugar coating agent, isotonizing agent, softener, emulsifying
agent,
foaming agent, pH modifier, anti-frothing agents, diluent, excipient,
dispersing agent,
disintegrator, fragrance, desiccant, antiseptics, preservative, solubilizing
agent,
solubilizer
The following examples describes the nature of the invention and are given
only for the purpose of illustrating the present invention in more detail and
are not
limitative and relate to solutions which have been particularly effective on a
bench
scale.
Example 1
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S.No Ingredients Quantity in mg per
tablet
Example 1A Example 1B
1. Sugar Spheres (#60/80) 33.0 33.0
2. Rivaroxaban 20.0 20.0
3. Croscarmellose sodium 7.0
4. Hydroxy propyl cellulose 2.5 2.5
5. Sodium lauryl sulphate 0.5 0.5
6. Lactose monohydrate 55.0 62.0
7. Colloidal silicon dioxide 1.0 1.0
8. Magnesium Stearate 1.0 1.0
9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0
Film Coating
11. Opadry brown 3.0 3.0
12. Purified Water QS QS
Total Weight (mg) 123.0 123.0
Example 2
S.No Ingredients Quantity in mg per
tablet
Example 2A Example 2B
1. Sugar Spheres (#60/80) 33.0 33.0
2. Rivaroxaban 10.0 10.0
3. Croscarmellose sodium 6.4 6.4
4. Hydroxy propyl cellulose 4.0 4.0
5. Sodium lauryl sulphate 0.5 0.2
6. Lactose monohydrate 37.1 37.4
7. Colloidal silicon dioxide 1.0 1.0
8. Magnesium Stearate 1.0 1.0
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9. Ethanol QS QS
10. Purified Water
QS QS
Core tablet weight 85.0 85.0
Film Coating
11. Opadry brown
2.5 2.5
12. Purified Water
QS QS
Total Weight (mg) 87.5 87.5
Example 3
S.No Ingredients Quantity in mg per
tablet
Example 3A Example 3B
1. Sugar Spheres
(#60/80) 34.0 34.0
2. Rivaroxaban 20.0 20.0
3. Croscarmellose
sodium 7.0 7.0
4. Hydroxy propyl
cellulose 2.0 4.0
5. Sodium lauryl
sulphate 0.5 0.5
6. Lactose
monohydrate 54.5 52.5
7. Colloidal silicon
dioxide 1.0 1.0
8. Magnesium Stearate
1.0 1.0
9. Ethanol QS QS
10. Purified Water
QS QS
Core tablet weight 120.0 120.0
Film Coating
11. Opadry brown
3.0 3.0
12. Purified Water
QS QS
Total Weight (mg) 123.0 123.0
Example 4
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S.No Quantity/ tablet in mg
Name of the ingredients 20 mg 15 mg 10 mg 2.5 mg
strength strength strength strength
Intra-granular
1. Sugar Spheres (#60/80) 34.0
39.0 44.0 51.5
2. Rivaroxaban 20.0 15.0 10.0 2.5
3. Croscarmellose sodium 7.0 7.0
7.0 7.0
4. Hydroxy propyl cellulose 2.0 2.0
2.0 2.0
5. Sodium lauryl sulphate 0.5 0.5
0.5 0.5
6.
7. Lactose monohydrate 54.5 54.5
54.5 54.5
8. Colloidal silicon dioxide 1.0 1.0
1.0 1.0
9. Magnesium Stearate 1.0 1.0 1.0
1.0
10. Ethanol QS QS QS QS
11. Purified Water QS QS QS
QS
Core tablet weight 120.0 120.0 120.0 120.0
Film coating
12. Opadry brown 3.0 3.0 3.0
3.0
13. Purified Water QS QS QS
QS
Coated Tablet Weight 123.0 123.0 123.0 123.0
Manufacturing Process:
1. Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl
sulphate in mixture of ethanol and Purified water,
2. Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer,
4. Adding extragranular materials to step 3 pellets and blend,
5. Compressing the tablets using step 4 blend,
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6. Dispersing Opadry brown in Purified water, and
7. Coating the tablets of step 5 with step 6 dispersion.
Example 5
S.No. Ingredients Quantity/ tablet in mg
EX 5A EX 5B EX 5C
1. Rivaroxaban 20.0 20.0 20.0
2. Microcrystalline cellulose
28.0 35.0 37.0
3. Lactose monohydrate 22.9
22.9 22.9
4. Croscarmellose sodium 2.0
3.0 2.0
5. Hydroxy propyl cellulose 1.0
3.0 2.0
6. Cremophor 0.5 0.5 0.5
7. Ethanol QS QS QS
8. Microcrystalline cellulose
10.0
9. Magnesium Stearate 0.6
0.6 0.6
Core tablet weight 85.0 85.0 85.0
Film Coating
10. Opadry brown 2.5
2.5 2.5
11. Purified Water QS QS
QS
Coated Tablet Weight (mg) 87.5 87.5 87.5
Manufacturing process:
1. Dissolving Hydroxypropyl cellulose and Cremophor in ethanol,
2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Sift together Croscarmellose sodium, Lactose monohydrate and
Microcrystalline
cellulose,
4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper
granules
obtains,
5. Add extragranular materials to step 4 granules and blend,
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6. Compress the tablets using step 5 blend,
7. Disperse Opadry brown in Purified water, ad
8. Coat the tablets of step 6 with step 7 dispersion.
Example 6
S.No. Ingredients
Quantity/ tablet in mg
EX 6A EX 6B
1.
Rivaroxaban 20.0 20.0
2.
Microcrystalline cellulose 35.0 35.0
3. Lactose
monohydrate 22.9 22.9
4. Croscarmellose sodium 3.0
5. Hydroxy
propyl cellulose 3.0 6.0
6.
Cremophor 0.5 0.5
7. Ethanol
& Purified Water QS QS
8.
Magnesium Stearate 0.6 0.6
Core tablet weight 85.0 85.0
Film Coating
9. Opadry
brown 2.5 2.5
10. Purified
Water QS QS
Coated Tablet Weight (mg) 87.5 87.5
Manufacturing process:
1. Dissolve Hydroxypropyl cellulose and Cremophor in mixture of ethanol and
Purified water,
2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms,
3. Sift together Croscarmellose sodium, Lactose monohydrate and
microcrystalline
cellulose,
4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper
granules
obtains,
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CA 03028346 2018-12-18
WO 2018/007945
PCT/IB2017/054031
5. Add extragranular materials to step 4 granules and blend,
6. Compress the tablets using step 5 blend,
7. Disperse Opadry brown in Purified water, and
8. Coat the tablets of step 6 with step 7 dispersion.
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