FIELD OF INVENTION
Present invention relates to a stable pharmaceutical composition comprising alogliptin and
5 metformin with suitable pharmaceutically acceptable excipient/s; wherein alogliptin and
metformin are in intimate mixture. Invention also encompasses various processes of
preparing said pharmaceutical composition and its use in improving glycemic control in
adults with type 2 diabetes mellitus.
10 BACKGROUND
Alogliptin, 2-( { 6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl}methyl)benzonitrile, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic
drug which is approved in US as monotherapy or combination therapy with other
agents such as metformin, sulfonylurea, thiazolidinedione and insulin, for improving
15 glycemic control in adults with type 2 diabetes mellitus.
Metformin, N,N-Dimethylimidodicarbonimidic diamide, is an anti-diabetic drug belonging
to biguanide class and is approved in US for monotherapy or combination therapy with
other agents such as sulfonylureas, thiazolidinediones, meglitinides, DPP-IV inhibitors and
20 SGLT2 inhibitors, for improving glycemic control in adults with type 2 diabetes mellitus.
US8900638 discloses therapeutic combination for diabetes or obesity; compnsmg
dipeptidyl peptidase (DPP-IV) inhibitor alogliptin or a salt thereof and Metformin HCl;
wherein alogliptin or a salt thereof and metformin HCl are physically separated from each
25 other to provide stability to the formulation. It further describes the solid composition
wherein contact of alogliptin or a salt thereof and metformin HCl is inhibited by layering
approaches or by forming granules of alogliptin or a salt thereof and metformin HCl
separately using wet granulation process.
Composition of alogliptin and metformin IS either associated with manufacturing
30 complexities such as sticking with alogliptin and incompatibility of alogliptin and
metformin with each other or some of the excipients, which affects stability and dissolution
of the formulation. The available prior art though tried to overcome problem of decrease in
preservation stability by following different method of manufacturing such as different
layering approaches or formulating granules of alogliptin and metformin separately with
5
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purpose of inhibiting contact of alogliptin and metformin; these techniques with added
steps are tedious leading to increased complexity of manufacturing. Thus, there still
remains need for development of stable pharmaceutical composition of alogliptin and
metformin devoid of processing troubles with ease of manufacturing.
Present invention provides a stable, bioequivalent composition of alogliptin and metformin
which overcomes all the mentioned issues and is produced using robust, reproducible and
easily scalable process.
10 SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a stable pharmaceutical composition
comprising intimate mixture of alogliptin and metformin with suitable pharmaceutically
acceptable excipient/s.
15 Another aspect of the present invention is to provide a stable pharmaceutical composition
comprising intimate mixture of alogliptin and metformin and a stabilizer with other suitable
pharmaceutically acceptable excipient/s.
Another aspect of the present invention is to provide a stable pharmaceutical composition
20 comprising alogliptin and metformin according to present invention prepared by one or
more processes selected from direct compression, dry granulation and wet granulation.
25
Another aspect of the present invention is to provide process of preparation of
pharmaceutical composition according to present invention.
Another aspect of the present invention is to provide use of pharmaceutical composition
according to present invention for improving glycemic control in adults with type 2
diabetes mellitus.
30 DETAILED DESCRIPTION OF THE INVENTION
Present invention relates to a novel approach of providing pharmaceutical composition
comprising intimate mixture of alogliptin and metformin which provides a stable
composition with desired dissolution profile and thus a bioequivalent product.
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The following paragraphs detail various embodiments of the invention. For the avoidance
of doubt, it is specifically intended that any particular feature(s) described individually in
any one of these paragraphs (or part thereof) may be combined with one or more other
features described in one or more of the remaining paragraphs (or part thereof). In other
5 words, it is explicitly intended that the features described below individually in each
paragraph (or part thereof) represent important aspects of the invention that may be taken
in isolation and combined with other important aspects of the invention described
elsewhere within this specification as a whole, and including the examples. The skilled
person will appreciate that the invention extends to such combinations of features and that
10 these have not been recited in detail here in the interests of brevity.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein or
15 clearly contradicted by context.
The term "added" or "mixed" as used herein are to be interpreted inclusively, unless the
context requires otherwise. That is, the use of these words may imply mixing or addition of
one of the components/parts/excipient/mixture of excipients with other
20 component/part/excipients.
Throughout this specification and the appended claims it is to be understood that the words
"comprise", "have" and "include" and variations such as "comprises", "comprising",
"having" "includes", "including" are to be interpreted inclusively, unless the context
25 requires otherwise. That is, the use of these words may imply the inclusion of an element or
elements not specifically recited.
The term "alogliptin" as used herein includes alogliptin in free form, its pharmaceutically
acceptable salts and its isomers, enantiomers, polymorphs, hydrates and solvates or
30 mixtures thereof. Preferably, alogliptin present in the composition according to present
invention is alogliptin benzoate. Alogliptin present in the composition according to present
invention can be in crystalline form or amorphous form. Particle size distribution (PSDD90)
of alogliptin used according to present invention is less than 500 microns; preferably
D90 is less than 100 microns, more preferably D90 is less than 50 microns.
5
10
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The term "metformin" as used herein includes metformin in free form or its
pharmaceutically acceptable salts and its isomers, enantiomers, polymorphs, hydrates and
solvates or mixtures thereof. Preferably, metformin present in the composition according to
present invention is metformin hydrochloride.
The term "intimate mixture" as used herein means mixture prepared by physically mixing
required quantity of alogliptin and metformin together, preferably by sifting or milling. The
term "intimate mixing" as used herein means process of physically mixing alogliptin and
metformin which promotes contact of active ingredients with each other.
The term "stable pharmaceutical composition" means pharmaceutical composition
exhibiting total impurities not more than 1.0% at 40°C and 75%RH, when stored in High
Density Polyethylene (HDPE) container for one month.
The term "part comprising alogliptin" as used herein means powder, granules, pellets or
15 beads comprising alogliptin and optionally one or more pharmaceutically acceptable
excipient/s.
The terms "D90" as used herein means at least 90% of the particles respectively; have
volume diameter in the specified range when measured by a suitable method for example
laser diffraction using a Malvern Mastersizer® laser diffraction instrument.
20 Prior art discloses that physical separation is essential to prevent decrease in preservation
stability of composition comprising alogliptin and metformin. It suggests that contact of
alogliptin and metformin must be inhibited to obtain a stable pharmaceutical composition.
Hence to achieve a stable pharmaceutical composition various process techniques which
lead to physical separation of alogliptin and metformin are disclosed.
25
It was surprisingly found by inventors that opposed to disclosed in prior art, a stable
pharmaceutical composition comprising alogliptin and metformin was achieved, even when
alogliptin and metformin were mixed intimately.
30 The first embodiment of the present invention provides a stable pharmaceutical
composition comprising intimate mixture of alogliptin and metformin with suitable
pharmaceutically acceptable excipient/s.
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Another preferred embodiment of the present invention provides a stable pharmaceutical
composition comprising intimate mixture of alogliptin and metformin and a stabilizer with
other suitable pharmaceutically acceptable excipient/s.
5 Another preferred embodiment of the present invention provides a stable pharmaceutical
composition comprising intimate mixture of alogliptin and metformin; wherein metformin
is present in about 3.3 parts or more parts by weight relative to 100 parts by weight of the
total weight of part comprising alogliptin.
10 Another embodiment of present invention provides a stable pharmaceutical composition
comprising intimate mixture of alogliptin and metformin; wherein metformin is present in
about 3.3 parts to about 50.0 parts by weight, more preferably metformin is present in
about 4.0 parts to about 35.0 parts by weight and most preferably metformin is present in
about 4.5 parts to about 10.0 parts by weight; relative to 100 parts by weight of the total
15 weight of part comprising alogliptin.
Thus, a preferred embodiment of the present invention provides a stable pharmaceutical
composition comprising intimate mixture of alogliptin and metformin; wherein metformin
is present in about 4.5 parts by weight relative to 100 parts by weight ofthe total weight of
20 part comprising alogliptin.
Also, another preferred embodiment of the present invention provides a stable
pharmaceutical composition comprising intimate mixture of alogliptin and metformin;
wherein metformin is present in about 10.0 parts by weight relative to 100 parts by weight
25 of the total weight of part comprising alogliptin.
It was surprisingly found by inventors that intimate mixing of alogliptin and metformin
followed by addition of certain excipients; particularly stabilizers such as mannitol,
sorbitol, isomalt, L-arginine, glycine and meglumine intragranularly leads to a stable
30 pharmaceutical composition. Preferably stabilizer is mannitol, sorbitol or isomalt.
Thus, another preferred embodiment of the present invention provides a stable
pharmaceutical composition comprising intimate mixture of alogliptin and metformin;
wherein metformin is present in about 4.5 parts by weight relative to 100 parts by weight of
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the total weight of part comprising alogliptin and one or more pharmaceutically acceptable
excipient(s) selected from mannitol, sorbitol, isomalt, L-arginine, glycine and meglumine.
Another preferred embodiment of the present invention provides a stable pharmaceutical
5 composition comprising intimate mixture of alogliptin and metformin; wherein metformin
is present in about 10.0 parts by weight relative to 100 parts by weight of the total weight
of part comprising alogliptin and one or more pharmaceutically acceptable excipient(s)
selected from mannitol, sorbitol, isomalt, L-arginine, glycine and meglumine.
10 A generalized embodiment of the present invention provides a stable pharmaceutical
composition according to any of the embodiments, wherein said composition is prepared by
one or more processes selected from wet granulation, dry granulation and/or direct
compressiOn.
15 A preferred embodiment of the present invention provides a stable pharmaceutical
composition according to any of the embodiments, wherein said composition is prepared by
one or more processes selected from wet granulation and/or dry granulation.
Said compositions prepared by wet granulation or dry granulation process may have
20 intragranular component wherein said intragranular component comprises one or more
active pharmaceutical ingredient and excipients selected from diluent, disintegrant,
stabilizer and binder and an extra granular component. The Intragranular component
further comprises of two or more distinct parts, wherein any of the two or more distinct
parts can alternatively comprise intimate mixture of alogliptin with metformin and solely
25 metformin. At least one of such distinct part is present in the form of granules, pellets or
beads. Said granules, pellets or beads can be prepared by any known method of granulation
such as wet granulation i.e. by rapid mixing under high shear or low shear or fluidized bed
processing, melt granulation and the like or dry granulation or roller compaction. Wet
granulation can be either aqueous or non aqueous using suitable solvent. Dry granulation
30 may be carried out by slugging or by roller compaction. Any of the said granules can be
combined with other pharmaceutically acceptable excipients, generally referred as
extragranular component. Said extragranular component may be in the form of powder,
granules, pellets or beads. Preferably said extragranular component is in the form of
powder or granules. The extragranular component preferably comprises excipients selected
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from diluent, binder, disintegrant, lubricant and stabilizer and optionally an active
pharmaceutical excipient.
Any of said intragranular or extragranular components as stated herein above may
5 comprise alogliptin and/or metformin; preferably intragranular component comprises a part
comprising alogliptin and metformin in intimate mixture and suitable pharmaceutically
acceptable excipients and another part comprising metformin and suitable pharmaceutically
acceptable excipients. Optionally, the extragranular component may further comprise
metformin and suitable pharmaceutically acceptable excipients.
10
Intragranular component as stated herein above may comprise a part comprising alogliptin
and metformin in intimate mixture and one or more suitable pharmaceutically acceptable
excipient(s), particularly mannitol. Intragranular component may also comprise another
part comprising metformin and one or more suitable pharmaceutically acceptable
15 excipient(s), particularly sorbitol. Extragranular components may preferably comprise
diluents, disintegrant, lubricant and/or stabilizer.
20
25
Thus, another embodiment of present invention provides a stable pharmaceutical
composition comprising
1. Intragranular component comprising a part comprising alogliptin and metformin in
intimate mixture and one or more pharmaceutically acceptable excipient(s) and another part
comprising metformin and one or more pharmaceutically acceptable excipient(s) and
2. Extragranular component comprising one or more suitable pharmaceutically
acceptable excipient(s).
In a preferred embodiment, present invention provides pharmaceutical composition
compnsmg
1. Intragranular component comprising a part comprising alogliptin and metformin in
intimate mixture and one or more pharmaceutically acceptable excipient(s); wherein
30 metformin is present in about 3.3 parts or more parts by weight relative to 100 parts by
weight of the total weight of part comprising alogliptin and another part compnsmg
metformin and one or more pharmaceutically acceptable excipient(s) and
2. Extragranular component comprising one or more suitable pharmaceutically
acceptable excipient(s).
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In a most preferred embodiment, present invention provides pharmaceutical composition
compnsmg
1. Intragranular component comprising a part comprising alogliptin and metformin in
5 intimate mixture and one or more pharmaceutically acceptable excipient(s); wherein
metformin is present in about 10.0 parts by weight relative to 100 parts by weight of the
total weight of part comprising alogliptin and another part comprising metformin and one
or more pharmaceutically acceptable excipient(s) and
2. Extragranular component compnsmg one or more suitable pharmaceutically
10 acceptable excipient(s).
In yet another preferred embodiment, present invention provides pharmaceutical
composition comprising
1. Intragranular component compnsmg a part consisting essentially of granules
15 comprising alogliptin and metformin in intimate mixture and one or more pharmaceutically
acceptable excipient(s) and another part consisting essentially of granules compnsmg
metformin and one or more pharmaceutically acceptable excipient(s) and
20
2. Extragranular component comprising one or more diluent, disintegrant, lubricant or
stabilizer.
Hence, a preferred embodiment, present invention provides pharmaceutical composition
compnsmg:
1. Intragranular component compnsmg a part consisting essentially of granules
comprising alogliptin and metformin in intimate mixture and microcrystalline cellulose,
25 povidone and mannitol; wherein metformin is present in about 10.0 parts by weight relative
to 100 parts by weight of the total weight of part comprising alogliptin and another part
consisting essentially of granules comprising metformin and microcrystalline cellulose,
povidone and sorbitol and
2. Extragranular component compnsmg microcrystalline cellulose, croscarmellose
30 sodium and magnesium stearate.
Compositions according to present invention may additionally compnse one or more
antidiabetic agent. The antidiabetic agent can be present in any of the intragranular or
extragranular component/s as described in the present invention. Such antidiabetic agents
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can be selected from biguanide, sulfonyl urea, thiazolidinediones, DPP-IV inhibitors, and
the like. Preferably, antidiabetic agent is pioglitazone or pharmaceutically acceptable salt
thereof.
5 Composition according to present invention can be prepared by any known method as
known to a skilled person. A generalized embodiment of present invention provides
process of preparing compositions according to present invention.
Another embodiment of present invention provides process of preparation of the stable
10 pharmaceutical composition comprising steps of:
1) Mixing alogliptin and metformin and optionally adding one or more
pharmaceutically acceptable excipient to the obtained mixture.
2) Optionally granulating the mixture of step 1.
3) Granulating metformin and optionally one or more pharmaceutical excipient(s).
15 4) Mixing mixture of step 1 or granules of step 2 and 3 and optionally adding one or
more pharmaceutical excipient(s).
5) Preparing pharmaceutical composition from the mixture obtained in step 4.
An embodiment of present invention provides process of preparing a stable pharmaceutical
20 composition comprising steps of:
1. Mixing metformin and at least one pharmaceutically acceptable excipient.
2. Granulating the mixture of step 1 with granulating fluid to prepare granules
3. Mixing alogliptin and metformin and optionally one or more pharmaceutically
acceptable excipient(s)
25 4. Mixing step 2 and 3 and optionally one or more pharmaceutical excipient(s).
5. Preparing pharmaceutical composition from the mixture obtained in step 4.
Another embodiment of present invention provides process of prepanng a stable
pharmaceutical composition comprising steps of:
30 1. Mixing alogliptin and metformin and optionally adding one or more
pharmaceutically acceptable excipient to the obtained mixture.
2. Granulating the mixture of step 1 with granulating fluid comprising one or more
binder(s) in one or more solvent(s).
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3. Granulating metformin and optionally one or more pharmaceutical excipient(s) with
granulating fluid comprising one or more binder in one or more solvent(s).
4. Mixing granules of step 2 and 3 and optionally adding one or more pharmaceutical
excipient(s).
5 5. Preparing pharmaceutical composition from the mixture obtained in step 4.
10
15
Another embodiment of present invention provides process of prepanng a stable
pharmaceutical composition comprising steps of:
1. Mixing metformin and povidone
2. Granulating the mixture of step 1 with water.
3. Mixing alogliptin and metformin and adding microcrystalline cellulose, mannitol
and croscarmellose sodium in said mixture.
4. Mixing step 2 and 3 and magnesium stearate.
5. Preparing pharmaceutical composition from the mixture obtained in step 4.
Another embodiment of present invention provides process of prepanng a stable
pharmaceutical composition comprising steps of:
1. Mixing alogliptin and metformin and adding mannitol to the obtained mixture.
2. Optionally adding L-arginine to the mixture obtained in step 1
20 3. Granulating mixture of step 1 or 2 with granulating fluid compnsmg aqueous
solution ofhydroxypropyl cellulose.
4. Granulating mixture of metformin and povidone with granulating fluid comprising
water
5. Mixing granules of step 3 and step 4 and adding microcrystalline cellulose and
25 croscarmellose sodium and magnesium stearate to the said mixture.
6. Preparing pharmaceutical composition from the mixture obtained from step 5.
Another preferred embodiment of present invention provides process of preparing a stable
pharmaceutical composition comprising steps of
30 1. Mixing alogliptin and metformin and adding mannitol, povidone and
microcrystalline cellulose to the obtained mixture.
2. Granulating the mixture of step 1 with granulating fluid comprising water.
3. Granulating mixture of metformin, povidone and microcrystalline cellulose with
granulating fluid comprising water and sorbitol.
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4. Mixing granules of step 2 and 3 and adding microcrystalline cellulose,
croscarmellose sodium and magnesium stearate.
5. Preparing pharmaceutical composition from the mixture obtained in step 4
Another embodiment of present invention provides process of preparing a stable
5 pharmaceutical composition comprising steps of
1. Mixing of alogliptin and about 3.3 parts or more parts by weight of metformin
relative to 100 parts by weight of the total weight of part comprising alogliptin and adding
one or more pharmaceutically acceptable excipient to the obtained mixture.
2. Optionally granulating the mixture of step 1.
10 3. Granulating the remaining quantity of metformin and one or more pharmaceutical
excipient(s).
4. Mixing mixture of step 1 or granules of step 2 and 3 and adding one or more
pharmaceutical excipient( s).
5. Preparing pharmaceutical composition from the mixture obtained in step 4.
15 In another embodiment, mixing of alogliptin and 10.0 parts by weight of metformin relative
to 100 parts by weight of the total weight of part comprising alogliptin and adding of one or
more pharmaceutically acceptable excipient is preferred.
Hence, a preferred embodiment of present invention provides process of preparing a stable
20 pharmaceutical composition comprising steps of
25
1. Mixing ofalogliptin and 10.0 parts by weight ofmetformin relative to 100 parts by
weight of the total weight of part comprising alogliptin and adding mannitol, povidone and
microcrystalline cellulose to the obtained mixture.
2. Granulating the mixture of step 1 with granulating fluid comprising water.
3. Granulating the remaining quantity of metformin and povidone and microcrystalline
cellulose with granulating fluid comprising water and sorbitol.
4. Mixing granules of step 2 and 3 and adding microcrystalline cellulose,
croscarmellose sodium and magnesium stearate.
5. Preparing pharmaceutical composition from the mixture obtained in step 4.
30 In a general embodiment present invention provides pharmaceutical composition prepared
by process as described herein above.
In another general embodiment the present invention may further comprise a coating.
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The pharmaceutical composition as described in the present invention may have functional
or non-functional coating, preferably coating is non-functional coating. Non-functional
coating comprises a film forming polymer and one or more excipients suitable for said
coating such as film former, plasticizer, glidant, opacifier or colorant. Example and suitable
5 amount of said excipient is known to a skilled person or as given in Handbook of
pharmaceutical excipients (sixth edition, 2009).
It was observed that addition of one or more plasticizer/s or humectant/s in coating avoided
the problem of logo bridging and peel off effect during tablet manufacturing. The
10 plasticizer/s or humectant/s according to the present invention includes mannitol, sorbitol,
xylitol, isomalt, liquid petrolatum, propylene glycol, glycerine, polyethylene glycol,
polyethylene glycol monomethyl ether, acetyl tributyl citrate, acetyl triethyl citrate, castor
oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, triacetin, tributyl
citrate or triethyl citrate; or mixtures thereof.
15
Hence, in yet another generalized embodiment, the present invention further comprises a
coating comprising one or more plasticizer/s.
Pharmaceutically acceptable excipients according to any of the embodiment of present
20 invention comprise diluent, disintegrant, binder, lubricant, pH adjuster/acidulant, stabilizer
and/or mixtures thereof and the like.
Composition according to present invention may optionally further comprises one or more
surfactant, glidant, coloring agent, flavoring agent, preservative, antioxidant and the like.
25 Example and suitable amount of said optional excipient is known to a skilled person or as
given in Handbook of pharmaceutical excipients (sixth edition, 2009).
A diluent according to present invention includes powdered cellulose, microcrystalline
cellulose, silicified microcrystalline cellulose, starch, pre-gelatinized starch, dibasic
30 calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium silicate,
precipitated calcium carbonate; sugars such as dextrose, lactose or sucrose; sugar alcohols
such as mannitol, sorbitol, xylitol, isomalt or erythritol; or mixtures thereof. Preferably
diluent is selected from mannitol, microcrystalline cellulose, silicified microcrystalline
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cellulose, isomalt and pre-gelatinized starch. Pharmaceutical composition compnses
diluent in the amount of5.0-30.0% w/w ofthe total composition.
A disintegrant according to present invention includes calcium carboxymethyl cellulose
5 and its salt including sodium or calcium salt, cross-linked carboxymethyl cellulose sodium
(Croscarmellose sodium), cross-linked carboxymethyl cellulose calcium, cross-linked
polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch; low substituted
hydroxypropyl cellulose; or mixtures thereof. Preferably disintegrant is selected from
croscarmellose sodium and cross-linked polyvinylpyrrolidone. Pharmaceutical composition
10 comprises disintegrant in the amount of 0.5- 5.0% w/w of the total composition.
A binder according to present invention includes polyvinyl alcohol, polyvinyl pyrrolidone
(povidone), starch, pregelatinised starch; cellulose derivatives such as cellulose powder,
microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl
15 cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, zem,
polymethacrylates, sodium alginate, gums, synthetic resins or mixtures thereof. Preferably
binder is selected from hydroxypropyl cellulose, polyvinyl pyrrolidone and polyvinyl
alcohol. Pharmaceutical composition comprises binder in the amount of 1.0-10.0% w/w of
the total composition.
20
A lubricant according to present invention includes sodium stearyl fumarate, magnesium
stearate, calcium stearate, zinc stearate, glyceryl dibehenate, stearic acid, hydrogenated
castor oil, polyethylene glycol, magnesium silicate, sorbitan monostearate & sucrose
monopalmitate or mixtures thereof. Preferably lubricant is selected from magnesium
25 stearate and sodium stearyl fumarate. Pharmaceutical composition comprises lubricant in
the amount of0.5-3.0%w/w ofthe total composition.
A pH adjuster/acidulant according to present invention includes acetic acid, citric acid,
carbonic acid, fumaric acid, phosphoric acid, tartaric acid or mixtures thereof. Preferably
30 pH adjuster/acidulant is selected from acetic acid, citric acid and tartaric acid.
Pharmaceutical composition comprises pH adjuster/acidulant in the amount of 1.0-10.0%
w/w ofthe total composition.
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A stabilizer is any pharmacologically acceptable excipient which stabilizes the said
pharmaceutical composition and does not include stabilization by means of physical
separation. A stabilizer according to present invention includes amino acids such as Larginine,
glycine and others; sugar and sugar alcohols such as mannitol, sorbitol, xylitol,
5 isomalt, erythritol and others; alkalizing agents such as meglumine and others;
cyclodextrins, tetrasodium edetate or mixtures thereof. Preferably stabilizer is selected
from mannitol, sorbitol, isomalt, L-arginine, glycine and meglumine. Pharmaceutical
composition comprises stabilizer in the amount ofO.l-10.0% w/w ofthe total composition.
10 A solvent for granulation used according to present invention includes water, acetone,
methyl alcohol, ethyl alcohol, isopropyl alcohol, polyalcohols, methylene chloride,
chloroform, dichloromethane, ether and the like or combination thereof. Preferably solvent
selected is water.
15 Pharmaceutical compositions prepared according to present invention, comprises alogliptin
in the amount of 0.9 to 5.0%, preferably 3.0%, most preferably 1.3% w/w of the total
composition and metformin in the amount of 50.0 to 85.0%, preferably 70.0-80.0%, most
preferably 77.0% w/w of the total composition.
20 A pharmaceutical composition according to present invention is a solid composition for
immediate release for oral administration and it can be in the form of tablet, powder or
capsule. Preferably, said composition is in the form of tablet for oral administration.
Another embodiment of present invention provides use of the composition prepared
25 according to present invention for improving glycemic control in adults with type 2
diabetes mellitus.
The invention will be further illustrated by the following examples, however, without
restricting its scope to these embodiments.
30 Example 1
No I Ingredients I 0/ow/w
Intragranular Component
Granules 1:
1 I Alogliptin benzoate I 1.31
5
10
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2 Metformin HCl 0.57
3 Mannitol 3.40
4 L-Arginine 0.28
4 Hydroxypropyl cellulose 0.13
5 Water Q.S
Granules 2:
6 Metformin HCl 76.35
7 Povidone K30 3.98
8 Water Q.S
Extraganular Component:
9 Microcrystalline cellulose 12.43
10 Croscarmellose sodium 0.77
11 Magnesium stearate 0.77
Total 100.00
Intragranular Component: Alogliptin benzoate and Metformin HCl were mixed followed
by sifting with mannitol and L-Arginine through 20# sieve. Obtained mixture was
granulated with granulating fluid prepared by dissolving hydroxypropyl cellulose in water.
15 The granules so obtained were dried and sized through 0.8mm screen of oscillating
granulator. Metformin HCl and povidone K30 were co-sifted through 24# sieve, mixed and
granulated in rapid mixer granulator using water. The granules so obtained were dried and
sized through 0.8mm screen of oscillating granulator.
Extragranular Component: Both granules as obtained from above mentioned processes
20 were mixed for 10 minutes. Microcrystalline cellulose and croscarmellose sodium were
sifted through 30# sieve and mixed with blend of obtained granules. The obtained blend
was lubricated with magnesium stearate and was compressed by rotary compression
machine to form tablet.
25 Example 2
No Ingredients 0/ow/w
Intragranular Component
Granules 1:
1 Alogliptin benzoate 1.31
2 Metformin HCl 0.26
3 Mannitol 3.71
4 L-Arginine 0.28
4 Hydroxypropyl cellulose 0.13
5 Water Q.S
Granules 2:
6 Metformin HCl 76.67
7 Povidone K30 3.98
5
10
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8 Water Q.S
Extraganular Component:
9 Microcrystalline cellulose 12.12
10 Croscarmellose sodium 0.77
11 Magnesium stearate 0.77
Total 100.00
Example 2 can be prepared following similar procedure as described in Example 1.
Examples 3 and 4
Ex.3 Ex. 4
No Ingredients 0/ow/w 0/ow/w
Intragranular Component
Granules 1:
1 Alogliptin benzoate 1.31 1.31
2 Metformin HCl 0.26 0.57
3 Mannitol 3.99 3.68
4 Hydroxypropyl cellulose 0.14 0.14
5 Water Q.S Q.S
Granules 2:
6 Metformin HCl 76.67 76.35
7 Povidone K30 6.00 3.99
8 Water Q.S Q.S
Extragranular Component:
9 Microcrystalline cellulose 10.10 12.43
10 Croscarmellose sodium 0.77 0.77
11 Magnesium stearate 0.77 0.77
Total 100.00 100.00
Intragranular Component: Alogliptin benzoate and Metformin HCl were mixed followed
by sifting with mannitol through 20# sieve. Obtained mixture was granulated with
15 granulating fluid prepared by dissolving hydroxypropyl cellulose in water. The granules so
obtained were dried and sized through 0.8mm screen of oscillating granulator. Metformin
HCl and povidone K30 were co-sifted through 24# sieve, mixed and granulated in rapid
mixer granulator using water. The granules so obtained were dried and sized through
0.8mm screen of oscillating granulator.
20 Extragranular Component: Both granules as obtained from above mentioned processes
were mixed for 10 minutes. Microcrystalline cellulose and croscarmellose sodium were
sifted through 30# sieve and mixed with blend of obtained granules. The obtained blend
5
10
15
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17
was lubricated with magnesmm stearate and was compressed by rotary compressiOn
machine to form tablet.
Examples 5
No Ingredients 0/ow/w
Intragranular Component
Granules 1:
1 Alogliptin benzoate 1.32
2 Metformin HCl 0.62
3 Microcrystalline Cellulose 0.82
4 Mannitol 3.27
5 Povidone 0.19
6 Water Q.S
Granules 2:
6 Metformin HCl 77.14
7 Microcrystalline Cellulose 2.33
8 Povidone K30 4.03
9 Sorbitol 0.47
10 Water Q.S
Extragranular Component:
11 Microcrystalline cellulose 8.26
12 Croscarmellose sodium 0.78
13 Magnesium stearate 0.78
Total 100.00
20 Intragranular Component: Alogliptin benzoate and Metformin HCl were mixed followed
by sifting with microcrystalline cellulose, mannitol and povidone K30 through 20# sieve.
Obtained mixture was granulated with granulating fluid - water. The granules so obtained
were wet milled, dried and sized through l.Omm screen of Quadro co-mill. Metformin HCl,
povidone K30 and microcrystalline cellulose were co-sifted through 20# sieve, mixed and
25 granulated in rapid mixer granulator using granulating fluid prepared by dissolving sorbitol
in water. The granules so obtained were wet milled, dried and sized through 0.5mm screen
of oscillating granulator.
Extragranular Component: Total granules of 1 (X) and granules of 2 as obtained from
above mentioned processes were mixed in the quantity of IX and 3X, respectively and
30 further co-sifted with microcrystalline cellulose and croscarmellose sodium through 20#
sieve. The obtained blend was then sandwiched between remaining part of metformin HCl
granules in blender and blended for 30 minutes. The obtained blend was lubricated with
magnesium stearate and was compressed by rotary compression machine to form tablet.
5
10
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The tablets of example 1, 3, 4 and 5 were exposed to following conditions:
40°C and 75%RH for 1 month in HDPE container
The impurity profile of the tablets was determined by Shimadzu High Performance Liquid
Chromatograph using gradient method.
The following table provides the amount of total impurities at the initial stage, and at the
end of 1 month.
Initial
40°C;75%RH

Claims:
1. A stable pharmaceutical composition comprising intimate mixture of alogliptin and
metformin and optionally with pharmaceutically acceptable excipient/s; wherein metformin
is present in about 3.3 parts or more parts by weight relative to 100 parts by weight of the
5 total weight of part comprising alogliptin.
2. The stable pharmaceutical composition as claimed in claim 1 comprising intimate
mixture of alogliptin and metformin; wherein metformin is present in about 3.3 parts to
about 50.0 parts by weight, more preferably metformin is present in about 4.0 parts to
about 35.0 parts by weight and most preferably metformin is present in about 4.5 parts to
10 about 10.0 parts by weight; relative to 100 parts by weight of the total weight of part
comprising alogliptin.
3. The stable pharmaceutical composition as claimed in claims 1 or 2 comprising
intimate mixture of alogliptin and metformin; wherein metformin is present in about 10.0
parts by weight relative to 100 parts by weight of the total weight of part comprising
15 alogliptin.
4. The stable pharmaceutical composition as claimed in any of the claims 1 to 3,
further comprising a stabilizer.
5. The stable pharmaceutical composition as claimed in claim 4, wherein stabilizer is
selected from mannitol, sorbitol, isomalt, L-arginine, glycine and meglumine.
20 6. A stable pharmaceutical composition comprising:
1) Intragranular component comprising a part comprising alogliptin and metformin in
intimate mixture and one or more pharmaceutically acceptable excipient(s) and another part
comprising metformin and one or more pharmaceutically acceptable excipient(s) and
2) Extragranular component comprising one or more suitable pharmaceutically
25 acceptable excipient(s).
7. The stable pharmaceutical composition as claimed in claim 6, comprising:
1) Intragranular component comprising a part comprising alogliptin and metformin in
intimate mixture and one or more pharmaceutically acceptable excipient(s); wherein
metformin is present in about 3.3 parts or more parts by weight relative to 100 parts by
30 weight of the total weight of part comprising alogliptin and another part comprising
metformin and one or more pharmaceutically acceptable excipient(s) and
2) Extragranular component comprising one or more suitable pharmaceutically
acceptable excipient(s).
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8. A process of preparation of the stable pharmaceutical composition compnsmg
intimate mixture of alogliptin and metformin, comprising:
1) Mixing alogliptin and metformin and optionally adding one or more
pharmaceutically acceptable excipient to the obtained mixture.
5 2) Optionally granulating the mixture of step 1.
3) Granulating metformin and optionally one or more pharmaceutical excipient(s).
4) Mixing mixture of step 1 or granules of step 2 and 3 and optionally adding one or
more pharmaceutical excipient(s).
5) Preparing pharmaceutical composition from the mixture obtained in step 4.
10 9. A process of preparation of the stable pharmaceutical composition comprising
intimate mixture of alogliptin and metformin as claimed in claim 8, comprising:
1) Mixing of alogliptin and about 3.3 parts or more parts by weight of metformin
relative to 100 parts by weight of the total weight of part comprising alogliptin and adding
one or more pharmaceutically acceptable excipient to the obtained mixture.
15 2) Optionally granulating the mixture of step 1.
3) Granulating the remaining quantity of metformin and one or more pharmaceutical
excipient(s).
4) Mixing mixture of step 1 or granules of step 2 and 3 and adding one or more
pharmaceutical excipient( s).
20 5) Preparing pharmaceutical composition from the mixture obtained in step 4.
10. A stable pharmaceutical composition according to any of the preceding claims,
additionally comprising one or more antidiabetic agent.