DAPAGLIFLOZIN COMPOSITIONS
Field of the Invention
The present invention relates to pharmaceutical compositions comprising a solid dispersion
of dapagliflozin and. one or more pharmaceutically acceptable excipients, and processes for their
preparation. It further relates to a method of treating diabetes using said pharmaceutical
compositions.
Background of the Invention
Dapagliflozin is a SGLT2 inhibitor, chemically known as (2S,,37?,4/?,55',6i?)-2-[4-chloro-3-
(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2i/-pyran-3,4,5-triol. The commercially
available formulations of dapagliflozin contain the propanediol (propylene glycol) monohydrate
solvate of dapagliflozin as the active ingredient. The drug substance is crystalline in nature. In
contrast, dapagliflozin base is present in amorphous form.
U.S. Patent No. 6,515,117 discloses dapagliflozin as a compound. U.S. Patent No.
7,919,598 discloses the (S)-propylene glycol solvate of dapagliflozin and processes of preparation
thereof.
U.S. Patent Nos. 7,851,502, 8,221,786, and 8,361,972 disclose pharmaceutical compositions
comprising dapagliflozin or dapagliflozin propylene glycol hydrate and specific excipients in given
amounts. U.S. Patent No. 8,221,786 further discloses pharmaceutical compositions in the form of a
stock granulation comprising dapagliflozin propylene glycol hydrate and excipients in given
amounts.
PCT Publication No. WO 2012/163546 discloses pharmaceutical compositions comprising
cyclodextrin and dapagliflozin, preferably as an inclusion complex.
^ The dapagliflozin base is hygroscopic in nature. It absorbs moisture and forms sticky lumps
Q_ which are difficult to process and handle, and which may ultimately lead to content uniformity
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issues in the dosage form. The low solubility and stability of dapagliflozin base as compared to its
g solvates may lead to poor bioavailability of the drug.
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5 The inventors of the present invention have found that a solid dispersion of dapagliflozin is
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Summary of the Invention
The present invention relates to pharmaceutical compositions comprising a solid dispersion
of dapagliflozin and one or more pharmaceutically acceptable excipients. The solid dispersion
comprises dapagliflozin and a carrier, wherein the dapagliflozin is dispersed or dissolved in the
carrier.
The present invention also includes different processes for the preparation of said
pharmaceutical composition and a method of treating diabetes by administering said
pharmaceutical composition.
Detailed Description of the Invention
A first aspect of the present invention provides a pharmaceutical composition comprising a
solid dispersion of dapagliflozin and one or more pharmaceutically acceptable excipients.
According to one embodiment of this aspect, the solid dispersion comprises dapagliflozin
and a carrier, wherein the dapagliflozin is dispersed or dissolved in the carrier.
According to another embodiment of this aspect, the carrier comprises a hydrophilic
polymer and optionally one or more pharmaceutically acceptable excipients.
According to another, embodiment of this aspect, the weight ratio of dapagliflozin to the
carrier is about 1:0.1 to about 1:100.
According to another embodiment of this aspect, the pharmaceutically acceptable excipients
are selected from the group comprising diluents, binders, disintegrants, lubricants, glidants,
stabilizers, surfactants, solubility enhancers, coloring agents, flavoring agents, and mixtures
thereof.
According to another embodiment of this aspect, the solid dispersion is prepared by a
solvent method.
According to another embodiment of this aspect, the solid dispersion is prepared by a hotmelt
extrusion method.
According to another embodiment of this aspect, the pharmaceutical composition may be in
the form of caplets, pills, mini-tablets, granules, pellets, tablets, or capsules.
According to another embodiment of this aspect, the pharmaceutical composition is filmcoated.
A second aspect of the present invention provides a process for the preparation of a
pharmaceutical composition comprising a solid dispersion of dapagliflozin and one or more
pharmaceutically acceptable excipients, wherein the process comprises:
(a) dissolving a carrier in a solvent to obtain a solution;
(b) dispersing dapagliflozin in the solution of step (a) to obtain a dispersion;
(c) blending a diluent and optionally, a binder;
(d) granulating the blend of step (c) with the dispersion of step (b) to obtain drug coated
granules, followed by drying of the granules;
(e) blending the dried granules of step (d) with a disintegrant, a lubricant, and/or a
glidant; and
(f) compressing the lubricated granules of step (e) into tablets or filling into capsules.
The process of the second aspect of the invention may consist essentially of forming
granules by dissolving a carrier in a solvent to obtain a solution, dispersing the dapagliflozin in the
solution to obtain a dispersion, and granulating the dispersion with a blend of a diluent and an
optional binder to form granules. The process may then further include the steps of drying the
granules and then blending the dried granules with one or more of a disintegrant, lubricant and
glidant to form lubricated granules. The lubricated granules may then be compressed into a tablet
or filled into a capsule.
The process of the second aspect of the invention may consist of forming granules by
dissolving a carrier in a solvent to obtain a solution, dispersing the dapagliflozin in the solution to
obtain a dispersion, and granulating the dispersion with a blend of a diluent and an optional binder
to form granules. The granules thus prepared may be further processed by drying the granules and
blending the dried granules with one or more of a disintegrant, lubricant and glidant to lubricate the
granules. The lubricated granules may then be compressed into a tablet or filled into a capsule.
According to one embodiment of this aspect, the carrier is a hydrophilic polymer.
A third aspect of the present invention provides a process for the preparation of a
pharmaceutical composition comprising a solid dispersion of dapagliflozin and one or more
pharmaceutically acceptable excipients, wherein the process comprises:
(a) dissolving dapagliflozin in a carrier;
(b) blending a diluent and optionally, a binder;
(c) granulating the blend of step (b) with the solution of step (a) to obtain drug coated
granules, followed by drying of the granules;
(d) blending the.dried granules of step (c) with a disintegrant, a lubricant, and/or a glidant;
and
(e) compressing the lubricated granules of step (d) into tablets or filling into capsules.
The process of the third aspect of the invention may consist essentially of forming granules
by dissolving dapagliflozin in a carrier to obtain a solution and granulating the solution with a
blend of a diluent and an optional binder to form granules. The process may then further include
the steps of drying the granules, and then blending the dried granules with one or more of a
disintegrant, lubricant and glidant to form lubricated granules. The lubricated granules may then be
compressed into a tablet or filled into a capsule.
The process of the third aspect of the invention may consist of forming granules by
dissolving dapagliflozin in a carrier to obtain a solution and granulating the solution with a blend of
a diluent and an optional binder to form granules. The granules thus prepared may be further
processed by drying the granules and blending the dried granules with one or more of a
disintegrant, lubricant and glidant to lubricate the granules. The lubricated granules may then be
compressed into a tablet or filled into a capsule.
According to one embodiment of this aspect, the carrier is a hydrophilic polymer.
A fourth aspect of the present invention provides a process for the preparation of a
pharmaceutical composition comprising a solid dispersion of dapagliflozin and one or more
pharmaceutically acceptable excipients, wherein the process comprises:
(a) blending dapagliflozin, a carrier, and a glidant in a rapid mixer granulator;
(b) loading the blend of step (a) into a hot-melt extruder to obtain extrudates;
(c) milling the extrudates of step (b) and blending the milled extrudates with a diluent, a
binder, a disintegrant, a glidant, and/or a lubricant; and
(d) compressing the blend of step (c) into tablets or filling into capsules.
The process of the fourth aspect of the invention may consist essentially of forming
extrudates by blending dapagliflozin, a carrier, and a glidant in a rapid mixer granulator to form a
blend and then loading the blend of into a hot-melt extruder to obtain extrudates. The process may
then further include the steps of milling the extrudates, and then blending the milled extrudates with
one or more of a diluent, binder, disintegrant, lubricant and glidant to form a lubricated blend. The
lubricated blend may then be compressed into a tablet or filled into a capsule.
The process of the fourth aspect of the invention may consist of forming extrudates by
blending dapagliflozin, a carrier, and a glidant in a rapid mixer granulator to form a blend and then
loading the blend of into a hot-melt extruder to obtain extrudates. The process may then further
include the steps of milling the extrudates,.and then blending the milled extrudates with one or
more of a diluent, binder,, disintegrant, lubricant and glidant to form a lubricated blend. The
lubricated blend may then be compressed into a tablet or filled into a capsule.
According to one embodiment of this aspect, the carrier is a hydrophilic polymer.
A fifth aspect of the present invention provides a method of treating diabetes by
administering a pharmaceutical composition comprising a solid dispersion of dapagliflozin and one
or more pharmaceutically acceptable excipients.
According to one embodiment of this aspect, the method of treatment further comprises
administration of an additional anti-diabetic agent.
The term "dapagliflozin," as used herein, refers to dapagliflozin base. The dapagliflozin
base is hygroscopic in nature, which is less stable and has low solubility as compared to its
solvates. It quickly absorbs moisture, degrades, discolors, and causes sticking problems. Further,
absorption of moisture results in lump formation which may ultimately lead to content uniformity
issues in the dosage form. Hence, the pharmaceutical composition of the present invention is
prepared in the absence of water.
The term "pharmaceutically acceptable excipients," as used herein, includes diluents,
binders, disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring
agents, flavoring agents, and mixtures thereof.
The term "about," as used herein, refers to any value which lies within the range defined by
a variation of up to ±10% of the value.
The term "solid dispersion," as used herein, refers to a group of solid products consisting of
at least two different components, generally a carrier and a drug. The carrier can be crystalline or
amorphous. The drug can be dispersed or dissolved in the carrier. The solid dispersion of
dapagliflozin is more stable, has superior solubility, and better processing abilities as compared to
dapagliflozin base.
The solid dispersion of dapagliflozin may be prepared by dissolving or dispersing the
dapagliflozin base in the carrier. The carrier used for forming the solid dispersion comprises a
hydrophilic polymer and, optionally, one or more pharmaceutically acceptable excipients. The
weight ratio of the dapagliflozin to the carrier is in the range of about 1:0.1 to about 1:100;
particularly in the range of about 1:0.25 to about 1:20; more particularly in the range of about 1:0.5
to about 1:10. The solid dispersion of the present invention may be prepared by a hot-melt
extrusion method, by a solvent method, or by a combination of both.
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In the solvent method, the solid dispersion of the dapagliflozin is loaded on to the
excipients; in the hot-melt extrusion method, the solid dispersion of the dapagliflozin is converted
to a particulate form. In the solvent method, the drug is dissolved/dispersed in the carrier or the
drug along with the carrier is dissolved/dispersed in a solvent. The solution or dispersion is then
used for granulating the blend of one or more pharmaceutical^ acceptable excipients. The granules
are then dried to obtain the solid dispersion of the drug loaded on to the excipients. In an alternate
method, the drug is dissolved/dispersed in the carrier or the drug along with the carrier is
dissolved/dispersed in a solvent. The solvent is then evaporated by freeze drying or spray drying.
As the solvent evaporates, supersaturation occurs, followed by simultaneous precipitation of both
the carrier and the drug in solid form. The resulting precipitate, which has the drug dissolved or
suspended in a carrier, is then dried to produce a solid dispersion of the invention. In the hot-melt
extrusion method, the drug and the carrier are loaded in a hot-melt extruder and the resulting
extrudates are milled to obtain a solid dispersion in a particulate form.
Suitable hydrophilic polymers are selected from the group comprising cellulose or
derivatives thereof, e.g., methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate
succinate, carboxymethylethyl cellulose, carboxylmethyl cellulose sodium, and hydroxyethyl
cellulose; synthetic polymers, e.g., polyethylene glycol (e.g., Macrogol 400, Macrogol 1500,
Macrogol 4000, and Macrogol 6000), polyvinyl alcohol, polyvinylpyrrolidone, polyvinylacetal
diethylaminoacetate, acrylic polymers, and carboxylvinyl polymer; natural polymers or sugars, e.g.,
gum arable, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum;
and mixtures thereof.
Suitable solvents used for the preparation of the solid dispersion may be a single solvent or
mixture of solvents, and the order of dissolution or dispersion of dapagliflozin with the carrier in
J the solvent may be varied. Particularly, the solvent is an organic solvent. Suitable solvents are
2 selected from the group comprising alcohols, e.g., methanol, ethanol, and isopropyl alcohol;
carboxylic acids, e.g., formic acid, acetic acid, and propionic acid; halogenated hydrocarbons, e.g.,
dichloromethane, dichloroethane, and methylene chloride; ketones, e.g., acetone, dimethyl ketone,
ethyl methyl ketone, and methyl iso-butyl ketone; amides, e.g., N,N- dimethylformamide and N,Ndimethylacetamide;
sulphoxides, e.g., dimethyl sulfoxide and diethyl sulphoxide; ethers, e.g.,
diethyl ether, ethyl methyl ether, di-isopropyl ether, tetrahydrofuran, and 1,4-dioxane; cyclic ethers,
e.g., tetrahydrofuran; and mixtures thereof.
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Suitable diluents are selected from the group comprising lactose, e.g., lactose anhydrous and
lactose monohydrate; cellulose, e.g., microcrystalline cellulose, co-processed microcrystalline
cellulose, and powdered cellulose; starch, e.g., pregelatinized starch, maize starch, rice starch,
potato, starch, and wheat starch; sugar alcohols, e.g., mannitol, sorbitol, xylitol, and erythritol;
inorganic salts, e.g., calcium carbonate, calcium phosphate, calcium sulfate, dibasic calcium
phosphate, dibasic calcium phosphate anhydrate, dibasic calcium phosphate dihydrate, and tribasic
calcium phosphate; and mixtures thereof. The diluents may act as a binder.
Suitable binders are selected from the group comprising povidone, copovidone,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose,
ethyl cellulose, carboxymethyl cellulose sodium, xanthan gum, gum acacia, gum arable, tragacanth,
sorbitol, dextrose, sucrose, lactose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol,
polyvinyl alcohol, corn starch, modified corn starch, maize starch, pregelatinized starch,
methacrylates, carboxyvinyl polymers, waxes, and mixtures thereof.
Suitable disintegrants are selected from the group comprising croscarmellose sodium,
hydroxypropyl cellulose, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline
cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, gums, alginic acid or
alginates, starch, corn starch, pregelatinized starch, modified starch, sodium starch glycolate,
carboxymethyl starch, polyacrylates, and mixtures thereof.
Suitable lubricants are selected from the group comprising stearic acid, magnesium stearate,
calcium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol, talc, hydrogenated
vegetable oils, fatty acids, waxes, and mixtures thereof.
Suitable glidants or anti-sticking agents are selected from the group comprising talc, silicon
dioxide, colloidal silicon dioxide (colloidal anhydrous silica), calcium silicate, magnesium silicate,
hydrated silica, and mixtures thereof.
Suitable stabilizers are selected from the group comprising cellulose derivatives, e.g.,
hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl
cellulose phthalate, carboxymethyl cellulose sodium, and carboxymethyl cellulose calcium; vinyl
polymers, e.g., polyvinylpyrrolidone, copovidone, and polyvinyl alcohol; polyethylene glycol;
block copolymers of ethylene oxide and/or propylene oxide; gums, e.g., xanthan gum, gum arabic
and/or derivatives thereof; pectins; alginates; acacia; tragacanth and/or derivatives thereof;
carrageenans; agar and/or derivatives thereof; polysaccharides from microbiological sources;
starches; arabinogalactans; galactomannans; dextrans; and mixtures thereof. The stabilizers may
also act as crystallization inhibitors.
Suitable surfactants are selected f™™ tu~ ~
dodecy! sulfate am • , ^ ^ " " ^ S ° d i U m 'aUryJ sulfate- sodi™
y. su,fate, a « » , „ talyl sulfete> b e n z a | k o n i um ^
copo,yme, of poly(et„y,e„e oxide) and ^(propylene ox.de) commercially! d a 1 ^
« poloxamines, p o | y v i n y | a|coho, ( p V A x &tty a k o h o | S ] ^ J ox
polyoxyethylene a.Mary, ether, polyethyle„e glyCo, fatty acd ester, a,Me„e glyc„, attyt d r 3 r crr fattiac,d ester'sorb,an ** - - -•—- i* «
or Span 80), po,yoxyethy,e„e sorbitan fatty acid ester (polysorba.es), mi m i x h l r e s t J J
Suitable solubility enhancers are selected from the group comprising sodium lauryl sulfate
P o l y e n e glyco,, pr0pyle„e g,ycol, „ , glycero, monosteal, glycero " t e
. . g ^ n d e s , mono-alcohols, higher a>coho,s, dimethvlsulfoxide, dimeth^amide N N
- J:!:::::::8 agems and flavoring agm,s a r e — * ™ - - — —
may further be f„m c Z P*armaceu„cal composition of the present invention
ay further be film-coated usmg ,eeh„iques we,, known in the art such as spray coating i„ .
nvent.onal coating pa„ or . f l u i d i z e d bed pm ^ ^ -
formmg polymers and one or more coating additives.
Suitable film-forming polymers are selected from the group comprising cellulose
nvattves , , , methy, cellulose, hydroxymethy, cellulose, hydroxyethy, cellulose, hydro
cellulose, „d ethy! cellulose; vmy, polymers, e.g., polyvinylpyrrolidones; acryhc polymers- and
— tltereof. Alternatively, comtneroally available coatmg c ^ s J l J J ^
fotmmg polymers marketed under various trade names,,.,, Opadry®, may be used for c o ^
The coating additives comprise one or more of plasticizers, glidants or flow regulators
lubricants, coloring agents, and opacifies »°w regulators,
Suitable plasticizers are selected ir^m tu~
, . the grouP ""nprising castor oil diacetvlated
jnoglycertdes, dibuty, sebacate, d,ethy, phthalate, glycerin, Methylene glycols p p
lycols, tr,acet,„, ,riethy, citrate, and mixtures thereof. An opacifier such as t i t l urn d i o x l !
also be present in the coating. uioxiae may
Examples of solvents used for preparing the coating solution are selected from methyl
alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform,
methylene chloride, and mixtures thereof.
The composition of the present invention is used for treating diabetes. The pharmaceutical
composition of the present invention may be administered in combination with other anti-diabetic
agents.
The present invention is illustrated below by reference to the following examples.
However, one skilled in the art will appreciate that the specific methods and results discussed are
merely illustrative of the invention, and not to be construed as limiting the invention, as many
variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Example 1
Ingredients Percent (%) w/w
Part A (Drug Coated Granules)
Dapagliflozin base
Polyethylene glycol
Isopropyl alcohol
Methylene chloride
Lactose anhydrous
Macrocrystalline cellulose
4.05
8.09
q.s.
q.s.
20.23
40.45
Part B
Drug Coated Granules of Part A
Microcrystalline cellulose
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
72.82
18.20
4.05
1.21
0.81
Film coating
Opadry® coating 2.91
Procedure:
1. Lactose anhydrous and intragranular microcrystalline cellulose were blended.
2. Polyethylene glycol was dissolved in a solvent mixture (isopropyl alcohol:methylene
chloride mixture (1:1.5 ratio)), followed by the dispersion of dapagliflozin base while
stirring.
3. The material of step 1 was granulated with the dispersion of step 2, followed by
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The dried granules of step 3 were blended with-extragranular microcrystalline
cellulose and crospovidone, followed by the addition of colloidal silicon dioxide and
magnesium stearate.
The blend of step 4 was compressed into tablets.
The tablets of step 5 were coated with Opadry®.
Example 2
Ingredients Percent (%) w/w
Part A (Drug Coated Granules)
Dapagliflozin base
Polyethylene glycol
Hydroxypropylmethyl cellulose
Isopropyl alcohol
Methylene chloride
Lactose anhydrous
Microcrystalline cellulose
4.05
4.05
4.05
q.s.
q.s.
20.23
40.44
PartB
Drug Coated Granules of Part A
Microcrystalline cellulose
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
72.82
18.20
4.05
1.21
0.81
Film coating
Opadry® coating 2.91
Lactose anhydrous and intragranular microcrystalline cellulose were blended.
Polyethylene glycol and hydroxypropylmethyl cellulose were dissolved in a solvent
mixture (isopropyl alcohol:methylene chloride mixture (1:1.5 ratio)), followed by the
dispersion of dapagliflozin base while stirring.
The material of step 1 was granulated with the dispersion of step 2, followed by
drying of the granules.
The dried granules of step 3 were blended with extragranular microcrystalline
cellulose and crospovidone, followed by the addition of colloidal silicon dioxide and
magnesium stearate.
The blend of step 4 was compressed into tablets.
The tablets of step 5 were coated with Opadry®.
Example 3
Ingredients
Part A (Drug Coated Granules)
Dapagliflozin base
Polyethylene glycol (PEG 400)
Lactose anhydrous
Mierocrystalline cellulose
PartB
Drug Coated Granules of Part A
Mierocrystalline cellulose
Crospovidone Colloidal silicon dioxide
Magnesium stearate
Film coating
Opadry® coating
Percent (%) w/w
4.05
8.09
20.23
40.45
72.82
18.20
4.05
1.21
0.81
2.91
Procedure:
1. Lactose anhydrous and intragranular mierocrystalline cellulose were blended.
2. Dapagliflozin base was added to polyethylene glycol (PEG 400) while stirring to form
a single phase solution.
3. The material of step 1 was granulated with the solution of step 2, followed by drying
of the granules.
4. The dried granules of step 3 were blended with extragranular mierocrystalline
cellulose and crospovidone, followed by the addition of colloidal silicon dioxide and
magnesium stearate.
5. The blend of step 4 was compressed into tablets.
6. The tablets of step 5 were coated with Opadry®.
Example 4
Ingredients
Part A (Drug Coated Granules)
Dapagliflozin base
Hydroxypropylmethyl cellulose
Isopropyl alcohol
Methylene chloride
Lactose anhydrous
Macrocrystalline cellulose
PartB
Drug coated granules of part A
Microcrystalline cellulose
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
Film coating
Opadry® coating
Percent {%) w/w
4.05
4.05
q.s. .
q.s.
20.23
42.46
70.79
19.82
4.05
1.46
0.97
2.91
Procedure:
1. Lactose anhydrous and intragranular microcrystalline cellulose were blended.
2. Hydroxypropylmethyl cellulose was dissolved in a solvent mixture (isopropyl alcohol
methylene chloride mixture (1:1.5 ratio)), followed by the dispersion of dapagliflozin
base while stirring.
3. The material of step 1 was granulated with the dispersion of step 2, followed by
drying of the granules.
4. The dried granules of step 3 were blended with extragranular microcrystalline
cellulose and crospovidone, followed by the addition of colloidal silicon dioxide and
magnesium stearate.
5. The blend of step 4 was compressed into tablets.
6.. The tablets of step 5 were coated with Opadry®.
Example 5
Ingredients
Intragranular
Dapagliflozin base
Polyethylene glycol
Macrocrystalline cellulose
Lactose anhydrous/monohydrate
Crospovidone
Colloidal silicon dioxide
Sodium stearyl fumarate
Film coating
Opadry® coating
Percent (%) w/w
4.05
16.18
50.56'
20.23
4.05
1.21
0.81
2.91
Procedure:
1. Sift and mix dapagliflozin base, polyethylene glycol, and half of the colloidal silicon
dioxide.
2. Transfer the material of step 1 to a hot-melt extruder to obtain extruded material,
followed by milling.
3. Blend microcrystalline cellulose, crospovidone, lactose monohydrate, and the
remaining half of the colloidal silicon dioxide.
4. Blend the material of step 2 and step 3, followed by the addition of sodium stearyl
fumarate.
5. Compress the blend of step 4 into tablets.
6. Film coat the tablets of step 5 with Opadry ®
Example 6:
Ingredients
Intragranular
Dapagliflozin base
Copovidone
Microcrystalline cellulose
Lactose anhydrous/monohydrate
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
Film coating
Opadry® coating
Percent (%) w/w
4.05
16.18
50.56
20.23
4.05
1.21
0.81
2.91
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Procedure:
lv Sift and mix dapagliflozin base, copovidone, and half of the colloidal silicon dioxide.
2. Transfer the material of step 1 to a hot-melt extruder to obtain extruded material,
followed by milling.
3. Blend microcrystalline cellulose, crospovidone, lactose monohydrate, and the
remaining half of the colloidal silicon dioxide.
4. Blend the material of step 2 and step 3, followed by the addition of magnesium
stearate,
5. Compress the blend of step 4 into tablets.
6. Film coat the tablets of step 5 with Opadry®.

WE CLAIM:
1.. A pharmaceutical composition, comprising a solid dispersion of dapagliflozin and one or
more pharmaceutical^ acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the solid dispersion
comprises dapagliflozin and a carrier.
3. The pharmaceutical composition according to claim 2, wherein the carrier comprises a
hydrophilic polymer and optionally one or more pharmaceutical^ acceptable excipients.
4. The pharmaceutical composition according to claim 2, wherein the weight ratio of the
dapagliflozin to the carrier is about 1:0.1 to about 1:100.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically
acceptable excipients are selected from the group comprising diluents, binders,
disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring
agents, flavoring agents, and mixtures thereof.
6. The pharmaceutical composition according to claim 1, wherein the composition is in the
form of caplets, pills, mini-tablets, granules, pellets, tablets, or capsules.
7. A process for the preparation of the pharmaceutical composition according to claim 2,
wherein the process comprises:
(a) dissolving a carrier in a solvent to obtain a solution;
(b) dispersing dapagliflozin in the solution of step (a) to obtain a dispersion;
(c) blending a diluent and optionally, a binder;
(d) granulating the blend of step ,(c) with the dispersion of step (b) to obtain drug coated
granules, followed by drying of the granules;
(e) blending the dried granules of step (d) with a disintegrant, a lubricant, and/or a glidant;
and
(f) compressing the lubricated granules of step (e) into tablets or filling into capsules.
8. A process for the preparation of the pharmaceuticalcomposition of claim 2, wherein the
process comprises:
(a) dissolving dapagliflozin in a carrier;
(b) blending a diluent and optionally, a binder;
(c) granulating the blend of step (b) with the solution of step (a) to obtain drug coated
granules, followed by drying of the granules;
(d) blending the dried granules of step (c) with a disintegrant, a lubricant, and/or a glidant;
and
(e)- compressing the lubricated granules of step {d) into tablets or filling into capsules.
9. A process for the preparation of the pharmaceutical composition according to claim 2,
wherein the process comprises:
(a) blending dapagliflozin, a carrier, and a glidant in a rapid mixer granulator;
(b) loading the blend of step (a) in a hot-melt extruder to obtain extrudates;
(c) milling the extrudates of step (b) and blending the milled extrudates with a diluent, a
binder, a disintegrant, a glidant, and/or a lubricant; and
(d) compressing the blend of step (c) into tablets or filling into capsules.
10. A pharmaceutical composition comprising a solid dispersion of dapagliflozin and one or
more pharmaceutically acceptable excipients substantially as described and illustrated
herein.