Specification
TENELIGLIPTIN COMPOSITIONS
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent
Application number 759/MUM/2014 (filed on Mar 05, 2014), the contents of
which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to teneligliptin, process for preparation
thereof and pharmaceutical compositions of teneligliptin.
BACKGROUND OF THE INVENTION
Dipeptidyl peptidase-4 (DPP-IV) inhibitors is a class of anti-diabetic drugs
act by inhibiting the degradation of the incretins, glucagon-like peptide- 1 (GLP-1)
and glucose-dependent insulinotropic peptide (GIP). Generically these compounds
are termed as "gliptins".
DPP-IV inhibitors are commonly used in a combination therapy along with
other antidiabetic drugs.
International Patent Application No. WO0152825 discloses combinations
of a DPP-IV inhibitor and antidiabetic compounds, preferably selected from the
group consisting of insulin signalling pathway modulators, like inhibitors of
protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds
and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),
compounds influencing a dysregulated hepatic glucose production, like inhibitors
of glucose-6-phosphatase (G6Pase), inhibitors of fructose- 1,6-bisphosphatase (F-
1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor
antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK),
pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers,
insulin secretion enhancers, alpha -glucosidase inhibitors, inhibitors of gastric
emptying, insulin, and alpha 2-adrenergic antagonists, for simultaneous, separate
or sequential use in the prevention, delay of progression or treatment of conditions
mediated by dipeptidylpeptidase - IV (DPP-IV), in particular diabetes, more
especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT),
conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis,
arthritis, obesity and osteoporosis; and the use of such combination for the
cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of
body weight.
International Patent Application No. WO0197808 discloses combinations
of dipeptidyl peptidase IV inhibitors- L-threo-isoleucyl pyrrolidide, L-alloisoleucyl
thiazolidide, L-allo-isoleucyl pyrrolidide; and salts thereof or 1 [2- [ (5-
cyanopyridin-2-yl) aminoethylamino] acetyl-2- cyano-(S)-pyrrolidine and (2S)-1-
[(2S)-2-amino-3, 3-dimethylbutanoyl]-2pyrrolidinecarbonitrile and antidiabetic
agents such as alpha glucosidase inhibitor, a biguanide, an insulin secretagogue or
an insulin sensitiser.
Bo Ahren et al. in "Twelve and 52-week efficacy of the Dipeptidyl
Peptidase IV inhibitor LAF237 in Metformin treated patients with type 2 diabetes."
Diabetes care, Volume 27, Number 12, published December 2004 reports a study
on combination of DPP IV inhibitor (LAF237) and metformin for the treatment of
diabetes.
Teneligliptin is a novel DPP-IV inhibitor indicated for the treatment of type
2 diabetes mellitus and is represented by a structural formula (I)
Formula (I)
It is available in the form of 20 mg tablets in Japan by the trade name
Tenelia®. It is used in cases showing insufficient improvement in glycemic control
even after diet control and exercise or a combination of diet control, exercise, and
sulfonylurea or thiazolidine class drugs. In adults, teneligliptin is orally
administered at a dosage of 20 mg once daily, which can be increased up to 40 mg
per day. Teneligliptin is disclosed in United States Patents US7074794 and
US8003790.
United States Patent Application US20120276166 discloses that long-term
preservation of a teneligliptin-containing solid preparation having a particular
content for about several months causes delayed dissolution of teneligliptin or a
salt thereof, or a solvate thereof. As a solution to this problem, to provide an
elution-stabilized dosage form of teneligliptin, it offers a teneligliptin-containing
solid preparation independently comprising a teneligliptin-containing part
containing teneligliptin or a salt thereof, or a solvate thereof at a content
percentage 1.5- to 10-fold the content percentage desired for a solid preparation.
Teneligliptin-containing part is prepared by granulating teneligliptin with
excipients and further adding excipients to form a finished dosage form. When the
content percentage of teneligliptin or a salt thereof, or a solvate thereof in said part
is less than 1.5-fold that desired for the solid preparation of the present invention,
the object of prevention of delay in the dissolution of the active ingredient cannot
be achieved, whereas when it is higher than 10-fold, the lack of strength necessary
for maintaining the solid form of particles and the like is feared, and the possibility
of problem in the production cannot be denied.
Contrary to these teachings, the present invention discloses stable
pharmaceutical compositions of teneligliptin wherein the ratio of teneligliptin
content in the 'teneligliptin-containing part' to that of the solid preparation being
less than 1.5-fold or more than 10-fold. Also the inventors provide new alternative
methods to prepare teneligliptin compositions.
SUMMARY OF THE INVENTION
The invention relates to teneligliptin, process for preparation thereof and
pharmaceutical compositions of teneligliptin comprising teneligliptin and one or
more pharmaceutically acceptable excipients.
In one embodiment, the present invention provides 3-{(2S, 4S)-4-[4-(3-
methyl- 1-phenyl-5-pyrazolyl)- 1-piperazinyl]-2-pyrrolidinylcarbonyl }-1,3-
thiazolidine trifluoroacetate salt.
In one embodiment, the present invention provides isolated 3-{(2S,4S)-4-
[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3-
thiazolidine trifluoroacetate salt characterized by a proton NMR spectrum having
peaks at 9.17(brs, 1H), 7.73-7.70(d, 2H), 7.46-7.41(t, 2H), 7.28-7.24(t, 1H), 5.78
(s, 1H), 4.69-4.39 (m, 3H), 3.85-3.35 (m, 6H), 3.09- 3.02(m, 4H), 2.75-2.64 (m,
5H), 2.12 (s, 3H), 1.63-1.60 (m, 1H).
In one embodiment the present invention provides a process for the
preparation of isolated 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-lpiperazinyl]-
2-pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt
comprising;
(a) reacting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
trifluoroacetic acid; and
(b) isolating the 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-lpiperazinyl]-
2-pyrrolidinylcarbonyl} -l-,3 -thiazolidine trifluoroacetate salt from
step a .
In one embodiment step (a) may be carried out in a solvent selected from
the group consisting of dichloromethane or ethylene dichloride or chloroform.
In one embodiment, the present invention provides crystalline 3-{(2S, 4S)-
1-tert-Butoxycarbonyl-4-[4-(3-methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-yl]
pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD)
spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2
degrees 2 theta.
In one embodiment, the present invention provides crystalline 3-{(2S, 4S)-
1-tert-Butoxycarbonyl-4-[4-(3-methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-yl]
pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD)
spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2
degrees 2 theta and having DSC of 248 ±2°C.
In one embodiment the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising;
a . deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin- l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
an acid to form an acid addition salt of teneligliptin; and
b. reacting the acid addition salt of teneligliptin with a base followed
by treatment with hydrobromic acid.
In one embodiment, the acid used for deprotection may be selected form
the group consisting of hydrochloric acid, sulfuric acid and trifluoro acetic acid.
In one embodiment, the base in step (b) may be selected from an organic
base or inorganic base.
In one embodiment, in step (b) the product obtained after treatment with a
base may be isolated and treated with hydrobromic acid, optionally in presence of
a solvent.
In one embodiment, in step (b) the product obtained after treatment with a
base may be isolated as a residue and then treated with hydrobromic acid,
optionally in presence of a solvent.
In one embodiment, in step (b) the product obtained after treatment with a
base may not be isolated before treatment with hydrobromic acid.
In one embodiment, in step (b) after treatment with base hydrobromic acid
or hydrobromic acid in acetic acid is used.
In one embodiment the present invention provides a process for the
preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-
pyrrolidinylcarbonyl}-l-,3-thiazolidine 2.5 hydrobromide or a hydrate thereof
comprising;
a . deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
hydrochloric acid to form teneligliptin hydrochloride; and
b. reacting the teneligliptin hydrochloride with a base followed by
treatment with hydrobromic acid.
In one embodiment, the hydrochloride obtained is 2, 2.5 or 3 hydrochloride
of teneligliptin.
In one embodiment the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising;
a . deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
hydrochloric acid to form 2.5 teneligliptin hydrochloride; and
b. reacting the 2.5 hydrochloride of teneligliptin with a base followed
by treatment with hydrobromic acid.
In one embodiment the 2.5 HC1 was obtained by deprotecting 3-{(2S, 4S)-
1-tert-Butoxycarbonyl -4- [4-(3 -methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-
yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid in a solvent
selected from the group consisting of isopropyl alcohol, tert-butanol, n- butanol,
methanol or mixture thereof.
In one embodiment the present invention provides a process for the
preparation of teneligliptin comprising
a . deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
an acid to form an acid addition salt of teneligliptin; and
b. reacting the acid addition salt of teneligliptin with a base.
In one embodiment, the present invention provides a process for
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof which comprises
treating teneligliptin with hydrobromic acid or hydrobromic acid in acetic acid in a
solvent selected from methanol, tertiary butanol and mixtures thereof.
In one embodiment, the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide hydrate comprising crystallising
teneligliptin 2.5 hydrobromide hydrate from a solvent selected from the group
consisting of methanol, n-butanol, tertiary butanol, propyl acetate, isopropyl
acetate, butyl acetate, ethers such as diethyl ether, tetrahydrofuran,
tetrahydropyran, diisopropyl ether, methyl tertiary butyl ether; ketones such as
acetone, methyl ethyl ketone, amide as such as N, N-dimethyl formamide, N, Ndimethyl
acetamide; nitriles such as acetonitrile, hydrocarbons such as toluene,
xylene, cyclohexane, methyl cylcohexane; halogenated hydrocarbons such as
methylene dichloride, chloroform, ethylene dichloride and mixtures thereof.
Preferably, the solvent is methanol or a mixture of a methanol and tertiary-butanol.
In another embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising teneligliptin and one or more
pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising teneligliptin hydrobromide hydrate and
one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipient, wherein the ratio of content of
teneligliptin in granule to that in the pharmaceutical composition is smaller than
1.5 and wherein the total weight of the composition is greater than 215 mg and less
than 600 mg.
In one aspect of this embodiment, teneligliptin is present in the form of
teneligliptin hydrobromide hydrate.
In one aspect of this embodiment, the pharmaceutical composition includes
one or more binders selected from the group consisting of hydroxypropylcellulose,
polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose;
one or more diluents selected from the group consisting of microcrystalline
cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate;
and; one or more lubricants selected from the group consisting of magnesium
stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and
esters of fatty acids.
In one aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-15% by weight of teneligliptin or its pharmaceutically acceptable
salt, l%-80% by weight of diluent, 0.1%-10% by weight of binder and 0.5%-30%
by weight of lubricant.
In a preferred aspect of this embodiment, the pharmaceutical composition
comprises 7%-10% by weight of teneligliptin or its pharmaceutically acceptable
salt, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%-
10% by weight of lubricant.
In another preferred aspect of this embodiment, the pharmaceutical
composition comprises about 8% by weight of teneligliptin or its pharmaceutically
acceptable salt, about 76% by weight of diluent, 9% by weight of binder and about
1% by weight of lubricant.
In another embodiment, the present invention relates to pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipients, wherein the ratio of content of
teneligliptin in granules to that in the pharmaceutical composition is greater than
10.
In one embodiment, the present invention relates to pharmaceutical
composition of teneligliptin comprising teneligliptin-containing granules and
metformin, wherein teneligliptin and metformin are present in separate portions
and wherein the ratio of content of teneligliptin in granules to that in the
pharmaceutical composition is greater than 10.
In one aspect of this embodiment, teneligliptin is present in the form of
teneligliptin hydrobromide hydrate.
In one aspect of this embodiment, the pharmaceutical composition includes
one or more binders selected from the group consisting of hydroxypropylcellulose,
polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose;
one or more diluents selected from the group consisting of microcrystalline
cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate;
and; one or more lubricants selected from the group consisting of magnesium
stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and
esters of fatty acids.
In one aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-5% by weight of teneligliptin, l%-50% by weight of diluent,
0.1%-10% by weight of binder and 0.1%-30% by weight of lubricant.
In another aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-2.5% by weight of teneligliptin or its pharmaceutically acceptable
salt, l%-25% by weight of diluent, 0.1%-3% by weight of binder and 0.1%-25%
by weight of lubricant.
In yet another aspect of this embodiment, the pharmaceutical composition
comprises about 2% by weight of teneligliptin or its pharmaceutically acceptable
salt, about 11% by weight of diluent, about 0.1% by weight of binder and about
0.5% by weight of lubricant.
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising granules
containing teneligliptin wherein the ratio of content of teneligliptin in granule to
that in the pharmaceutical composition is smaller than 1.5 and wherein the total
weight of the composition is greater than 215 mg and less than 600 mg comprising
the steps ofa)
mixing teneligliptin or a pharmaceutically acceptable salt with
pharmaceutically acceptable excipients;
b) adding a binder solution to the mixture of step a);
c) drying the wet mixture of step b) and sifting to form granules;
d) lubricating the granules of step c);
e) compressing the blend of step d) to form a tablet or filling of step d) the
blend into capsules.
In an aspect of this embodiment the process comprising the steps ofa)
dry mixing teneligliptin or a pharmaceutically acceptable salt with
pharmaceutically acceptable excipients to form a blend;
b) roll-compacting the blend of step a) one or more times to form flakes;
c) granulating and sieving the flakes of step b);
d) lubricating the granules of step c);
e) compressing the blend of step d); to form a tablet or filling the blend of step
d) into capsules.
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising the steps ofa)
mixing teneligliptin with pharmaceutically acceptable excipients to form a
blend for direct compression;
b) compressing the blend of step a) to form a tablet;
c) optionally coating the tablet of step b).
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin wherein the ratio of content of teneligliptin in
granules to that in the pharmaceutical composition is greater than 10; comprising
the steps ofgranulating
teneligliptin with pharmaceutically acceptable excipients;
a) lubricating the teneligliptin granules of step a);
b) granulating metformin with pharmaceutically acceptable excipients.
c) lubricating the metformin granules of step c);
d) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In one aspect of this embodiment the process comprising steps ofa)
spray granulating teneligliptin with pharmaceutically acceptable excipients;
b) lubricating the teneligliptin granules of step a);
c) granulating metformin with pharmaceutically acceptable excipients.
d) lubricating the metformin granules of step c);
e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In yet another aspect of this embodiment the process comprising the steps
ofa)
roll compacting and granulating teneligliptin with pharmaceutically
acceptable excipients;
b) lubricating the teneligliptin granules of step a);
c) granulating metformin with pharmaceutically acceptable excipients.
d) lubricating the metformin granules of step c);
e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In another embodiment the present invention relates to a process of
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin, comprising the steps ofa)
mixing teneligliptin with pharmaceutically acceptable excipients to form a
blend for direct compression;
b) granulating metformin with pharmaceutically acceptable excipients;
c) lubricating the metformin granules of step b);
d) compressing the blends of steps a) and c) to form a bi-layer tablet or filling
blends of steps a) and c) into capsules.
In another embodiment the present invention relates to a process of
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin, comprising the steps ofa)
granulating metformin with pharmaceutically acceptable excipients;
b) lubricating the metformin granules of step a);
c) compressing the metformin blend of step b) to form a core;
d) preparing a teneligliptin containing polymer solution or suspension;
e) coating the core of step c) with the solution or suspension of step d).
BRIEF DESCRIPTION OF FIGURES
Fig 1. Proton MR spectrum of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-
l-piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt.
Fig 2. X-ray Diffraction of 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl}thiazolidine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions of
teneligliptin comprising teneligliptin and one or more pharmaceutically acceptable
excipients.
The terms used herein are defined as follows. If a definition set forth in the
present application and a definition set forth later in a non-provisional application
claiming priority from the present provisional application are in conflict, the
definition in the non-provisional application shall control the meaning of the terms.
The term "teneligliptin" as used herein, unless mentioned otherwise
mentioned, means {(2S, 4S)-4-[4-(3-Methyl-l-phenyl-lH-pyrazol-5-yl)-lpiperazinyl]-
2-pyrrolidinyl} (1, 3-thiazolidin-3-yl) methanone, hydrate or a salt
thereof.
The term "metformin" as used herein, unless mentioned otherwise, means
metformin, hydrate or a salt thereof.
The term "salt" or "pharmaceutically acceptable salt" as used herein, means
those salts which are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of humans and lower animals without undue toxicity,
irritation, and allergic response, commensurate with a reasonable benefit to risk
ratio, and effective for their intended use. Representative acid additions salts
include hydrochloride, dihydrochloride, hydrobromide, sulphate, bisulphate,
acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate,
ascorbate, glucoheptonate, lactobionate, trifluoroacetate and lauryl sulphate salts.
Representative alkali or alkaline earth metal salts include the sodium, calcium,
potassium and magnesium salts.
In another embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising teneligliptin and one or more
pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising teneligliptin hydrobromide hydrate and
one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipient, wherein the ratio of content of
teneligliptin in granule to that in the pharmaceutical composition is smaller than
1.5 and wherein the total weight of the composition is greater than 215 mg and less
than 600 mg.
In one aspect of this embodiment, teneligliptin is present in the form of
teneligliptin hydrobromide hydrate
In one aspect of this embodiment, the pharmaceutical composition includes
one or more binders selected from the group consisting of hydroxypropylcellulose,
polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose;
one or more diluents selected from the group consisting of microcrystalline
cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate;
and; one or more lubricants selected from the group consisting of magnesium
stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and
esters of fatty acids.
In one aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-15% by weight of teneligliptin or its pharmaceutically acceptable
salt, l%-80% by weight of diluent, 0.1%-10% by weight of binder and 0.5%-30%
by weight of lubricant.
In a preferred aspect of this embodiment, the pharmaceutical composition
comprises 7%-10% by weight of teneligliptin or its pharmaceutically acceptable
salt, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%-
10% by weight of lubricant.
In another preferred aspect of this embodiment, the pharmaceutical
composition comprises about 8% by weight of teneligliptin or its pharmaceutically
acceptable salt, about 76% by weight of diluent, 9% by weight of binder and about
1% by weight of lubricant.
In another embodiment, the present invention relates to pharmaceutical
composition of teneligliptin comprising granules containing teneligliptin and one
or more pharmaceutically acceptable excipients, wherein the ratio of content of
teneligliptin in granules to that in the pharmaceutical composition is greater than
10.
In one embodiment, the present invention relates to pharmaceutical
composition of teneligliptin comprising teneligliptin-containing granules and
metformin, wherein teneligliptin and metformin are present in separate portions
and wherein the ratio of content of teneligliptin in granules to that in the
pharmaceutical composition is greater than 10.
In one aspect of this embodiment, teneligliptin is present in the form of
teneligliptin hydrobromide hydrate.
In one aspect of this embodiment, the pharmaceutical composition includes
one or more binders selected from the group consisting of hydroxypropylcellulose,
polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose;
one or more diluents selected from the group consisting of microcrystalline
cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate;
and; one or more lubricants selected from the group consisting of magnesium
stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and
esters of fatty acids.
In one aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-5% by weight of teneligliptin, l%-50% by weight of diluent,
0.1%-10% by weight of binder and 0.1%-30% by weight of lubricant.
In another aspect of this embodiment, the pharmaceutical composition
comprises 1.5%-2.5% by weight of teneligliptin or its pharmaceutically acceptable
salt, l%-25% by weight of diluent, 0.1%-3% by weight of binder and 0.1%-25%
by weight of lubricant.
In yet another aspect of this embodiment, the pharmaceutical composition
comprises about 2% by weight of teneligliptin or its pharmaceutically acceptable
salt, about 11% by weight of diluent, about 0.1% by weight of binder and about
0.5% by weight of lubricant.
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising granules
containing teneligliptin wherein the ratio of content of teneligliptin in granule to
that in the pharmaceutical composition is smaller than 1.5 and wherein the total
weight of the composition is greater than 215 mg and less than 600 mg comprising
the steps ofa)
mixing teneligliptin or a pharmaceutically acceptable salt with
pharmaceutically acceptable excipients;
b) adding a binder solution to the mixture of step a);
c) drying the wet mixture of step b) and sifting to form granules;
d) lubricating the granules of step c);
e) compressing the blend of step d) to form a tablet or filling of step d) the
blend into capsules.
In an aspect of this embodiment the process comprising the steps ofa)
dry mixing teneligliptin or a pharmaceutically acceptable salt with
pharmaceutically acceptable excipients to form a blend;
b) roll-compacting the blend of step a) one or more times to form flakes;
c) granulating and sieving the flakes of step b);
d) lubricating the granules of step c);
e) compressing the blend of step d); to form a tablet or filling the blend of step
d) into capsules.
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising the steps ofa)
mixing teneligliptin with pharmaceutically acceptable excipients to form a
blend for direct compression;
b) compressing the blend of step a) to form a tablet;
c) optionally coating the tablet of step b).
In another embodiment, the present invention relates to a process for
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin wherein the ratio of content of teneligliptin in
granules to that in the pharmaceutical composition is greater than 10; comprising
the steps ofa)
granulating teneligliptin with pharmaceutically acceptable excipients;
b) lubricating the teneligliptin granules of step a);
c) granulating metformin with pharmaceutically acceptable excipients.
d) lubricating the metformin granules of step c);
e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In one aspect of this embodiment the process comprising the steps ofa)
spray granulating teneligliptin with pharmaceutically acceptable excipients;
b) lubricating the teneligliptin granules of step a);
c) granulating metformin with pharmaceutically acceptable excipients.
d) lubricating the metformin granules of step c);
e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In yet another aspect of this embodiment the process comprising the steps
ofa)
roll compacting and granulating teneligliptin with pharmaceutically
acceptable excipients;
b) lubricating the teneligliptin granules of step a);
c) granulating metformin with pharmaceutically acceptable excipients.
d) lubricating the metformin granules of step c);
e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling
blends of steps b) and d) into capsules.
In another embodiment the present invention relates to a process of
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin, comprising the steps ofa)
mixing teneligliptin with pharmaceutically acceptable excipients to form a
blend for direct compression;
b) granulating metformin with pharmaceutically acceptable excipients;
c) lubricating the metformin granules of step b);
d) compressing the blends of steps a) and c) to form a bi-layer tablet or filling
blends of steps a) and c) into capsules.
In another embodiment the present invention relates to a process of
preparation of teneligliptin pharmaceutical composition comprising teneligliptincontaining
granules and metformin, comprising the steps ofa)
granulating metformin with pharmaceutically acceptable excipients;
b) lubricating the metformin granules of step a);
c) compressing the metformin blend of step b) to form a core;
d) preparing a teneligliptin containing polymer solution or suspension;
e) coating the core of step c) with the solution or suspension of step d).
Teneligliptin granules as contemplated by this invention can be made of
Teneligliptin in association with one or more of a diluent, lubricant, binder,
fluidizing agent, disintegrating agent, solubilizing agent and the like.
Suitable diluents include but are not limited to, mannitol, sorbitol, xylitol,
starch, lactose, cellulose, calcium hydrogen phosphate, carboxymethyl cellulose
sodium and the like. The diluents can be quantitatively adjusted to manipulate the
percentage content of teneligliptin in granules as well as the finished dosage form.
Suitable lubricants include but are not limited to, magnesium stearate,
colloidal silicon dioxide, hydroxypropylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, starch, calcium stearate, talc, stearic acid, sucrose,
ester of fatty acid and the like.
Suitable binders include but are not limited to, hydroxypropylcellulose,
polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose
and the like.
Finished formulations containing Teneligliptin 1.5-15%, diluent 1-80%,
binder 0.1-10% and lubricant 0.5-30%, more preferably Teneligliptin 7-10%,
diluent 60-70%, binder 0.5-2% and lubricant 0.5- 10% can be prepared by the
methods mentioned below. The percentages are so adjusted that, the total weight of
the composition is between 215 mg to 600 mg.
Teneligliptin granules can be prepared by mixing teneligliptin and
pharmaceutically acceptable excipients; adding a binder solution to the mixture of
teneligliptin and pharmaceutically acceptable excipients and drying the wet
mixture of teneligliptin and pharmaceutically acceptable excipients followed by
sieving to form granules. Alternatively, after mixing teneligliptin and
pharmaceutically acceptable excipients a binder solution can be sprayed on the
mixture in a fluidized bed-processor followed by drying of the wet granules and
subsequent optional sieving. As another alternative, teneligliptin flakes can be
prepared by dry mixing teneligliptin and pharmaceutically acceptable excipients to
form a blend; roll-compacting the blend one or more times to form flakes followed
by granulating and sieving the flakes. The teneligliptin granules or flakes can be
lubricated with any of the lubricants mentioned above. This mixture can then be
punched in a tabletting machine or can be filled into capsules by a capsule-filling
machine. Optionally, a coating can be applied to the tablet. The coating solution or
suspension contains excipients like hypromellose, polyethylene glycol, colorant
such as red or yellow iron oxide, titanium dioxide and talc. These tablets can be
alternatively, filled into capsules of suitable size. The capsule volume can be
suitably selected, ranging from 0.13- 1.37 ml to accommodate the teneligliptin
containing lubricated blend or tablets.
In an alternative, a direct compression process for producing teneligliptin
tablets is also contemplated by the invention. The tablets are prepared by mixing
teneligliptin with one or more pharmaceutically acceptable excipients to prepare a
blend for direct compression; compressing the blend of to form a tablet; optionally
a coating can be applied to the tablet, as described above.
In an embodiment, the invention also relates to teneligliptin pharmaceutical
composition comprising teneligliptin containing granules and a pharmaceutically
acceptable excipient, wherein the percentage ratio of teneligliptin in the granules to
teneligliptin in the total composition is greater than ten times wherein
thecomposition can quantitatively contain teneligliptin 1.5-15%, diluent 1-80%,
binder 0.1-10% and lubricant 0.5-30%, more preferably Teneligliptin 7-10%,
diluent 50-70%, binder 0.5-5% and lubricant 0.5-10%> and can be prepared by the
methods mentioned above.
Teneligliptin can be formulated with metformin in a single dosage form.
The content of metformin or salt thereof can be suitably selected so as to deliver a
dose of metformin in the range of 1-2000 mg, preferably 250-1000 mg. Such a
pharmaceutical composition contains teneligliptin and metformin in separate
portions. For example, a multi-layered composition containing teneligliptin and
metformin in separate layers of a bi- or tri-layered tablet; a composition containing
metformin in the core and teneligliptin in the coating and other similar variants
thereof. Such a composition can quantitatively contain Teneligliptin 1.5-5%,
diluent 1-50%, binder 0.1- 10% and lubricant 0.1-30%, preferably Teneligliptin
1.5-25%, diluent 1-20%, binder 0.1-3% and lubricant 0.1-25%. Suitable diluents,
binders and lubricants can be selected as described above.
Such teneligliptin and metformin compositions can be prepared by a
process comprising the steps of- granulating teneligliptin with pharmaceutically
acceptable excipients; lubricating the teneligliptin granules with a lubricant to form
a lubricated teneligliptin blend; granulating metformin with pharmaceutically
acceptable excipients; lubricating the metformin granules with a lubricant to form a
lubricated metformin blend; compressing the teneligliptin blend and metformin
blend to form a bilayer tablet or filling the blend into capsules. Alternatively,
multi-layered tablets can be prepared by introducing, in addition to the teneligliptin
blend and metformin blend, a blend of pharmaceutically acceptable excipients, at
the compression stage of the above process. Also, the teneligliptin granules used in
the above process can be alternatively prepared by methods, mentioned earlier.
In the alternative, teneligliptin and metformin compositions can be
prepared by a process comprising the steps of granulating metformin with
pharmaceutically acceptable excipients; lubricating the metformin granules with a
lubricant to form a lubricated metformin blend; compressing the metformin blend
to form a core; preparing a teneligliptin containing polymer solution or suspension;
coating the core of metformin with the teneligliptin containing polymer solution or
suspension. Such a composition can quantitatively contain Teneligliptin 1.5- 10%,
diluent 1-80%, binder 0.1- 10% and lubricant 0.1-30%, preferably, Teneligliptin
1.5-2.5%, diluent 1-20%, binder 0.1-3% and lubricant 1-25%. The percentages are
so adjusted that the intragranular content of teneligliptin is more than ten times that
of teneligliptin in the finished composition. The suitable diluents, binders and
lubricants can be selected as described above.
In a separate embodiment the pharmaceutical composition of the present
invention may be useful in treatment or prophylaxis of diabetes, obesity, HIV
infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis,
autoimmune disease and the like.
In a separate embodiment, the present invention provides 3-{(2S, 4S)-4-[4-
(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3-
thiazolidine tnfluoroacetate salt.
In one embodiment, the present invention provides isolated 3-{(2S,4S)-4-
[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3-
thiazolidine trifluoroacetate salt characterized by a proton NMR spectrum having
peaks at 9.17(brs, 1H), 7.73-7.70(d, 2H), 7.46-7.41(t, 2H), 7.28-7.24(t, 1H), 5.78
(s, 1H), 4.69-4.39 (m, 3H), 3.85-3.35 (m, 6H), 3.09- 3.02(m, 4H), 2.75-2.64 (m,
5H), 2.12 (s, 3H), 1.63-1.60 (m, 1H).
In one embodiment the present invention provides a process for the
preparation of isolated 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-lpiperazinyl]-
2-pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt
comprising;
(a) reacting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
trifluoroacetic acid; and
(b) isolating the 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-lpiperazinyl]-
2-pyrrolidinylcarbonyl} -l-,3 -thiazolidine trifluoroacetate salt from
step a .
In one embodiment step a may be carried out in a solvent selected from the
group consisting of dichloromethane or ethylene dichloride or chloroform.
In one embodiment, the present invention provides crystalline 3-{(2S, 4S)-
1-tert-Butoxycarbonyl-4-[4-(3-methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-yl]
pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD)
spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2
degrees 2 theta.
In one embodiment, the present invention provides crystalline 3-{(2S, 4S)-
1-tert-Butoxycarbonyl-4-[4-(3-methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-yl]
pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD)
spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2
degrees 2 theta and having DSC of 248 ±2°C.
Advantageously, when crystalline 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-
(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1-yl] pyrrolidin-2-ylcarbonyl}
thiazolidine is used as a starting material for the synthesis of teneligliptin
2.5 hydrobromide or a hydrate thereof, the product is obtained in high yield and
purity as compared to the use of non crystalline form of the starting material.
In one embodiment the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising;
a . deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin- l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
an acid to form an acid addition salt of teneligliptin; and
b. reacting the acid addition salt of teneligliptin with a base followed
by treatment with hydrobromic acid.
In one embodiment, the acid used for deprotection may be selected form
the group consisting of hydrochloric acid, sulfuric acid and trifluoro acetic acid.
In one embodiment, the base in step b may be selected from an organic
base or inorganic base.
A suitable base may be selected from organic or an inorganic base. The
inorganic base may be selected from, but is not limited to hydroxides such as
sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate,
potassium carbonate; bicarbonates such as sodium bicarbonate, potassium
bicarbonate, hydrides such as sodium hydride, alkoxides such as sodium
methoxide, potassium methoxide, potassium tert-butoxide; while the organic base
may be selected from, but is not limited to triethyl amine, trimethyl amine,
pyridine, diisopropyl amine and dimethyl amino pyridine.
In one embodiment, in step b the product obtained after treatment with a
base may be isolated and treated with hydrobromic acid, optionally in presence of
a solvent.
In one embodiment, in step b the product obtained after treatment with a
base may be isolated as a residue and then treated with hydrobromic acid,
optionally in presence of a solvent.
In one embodiment, in step b the product obtained after treatment with a
base may not be isolated before treatment with hydrobromic acid.
In one embodiment, in step b after treatment with base hydrobromic acid or
hydrobromic acid in acetic acid is used.
In one embodiment the present invention provides a process for the
preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-
pyrrolidinylcarbonyl}-l-,3-thiazolidine 2.5 hydrobromide or a hydrate thereof
comprising;
a . deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
hydrochloric acid to form teneligliptin hydrochloride; and
b. reacting the teneligliptin hydrochloride with a base followed by
treatment with hydrobromic acid.
In one embodiment, the hydrochloride obtained is 2, 2.5 or 3 hydrochloride
of teneligliptin.
In one embodiment the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising;
a . deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
hydrochloric acid to form 2.5 teneligliptin hydrochloride; and
b. reacting the 2.5 hydrochloride of teneligliptin with a base followed
by treatment with hydrobromic acid.
In one embodiment the 2.5 HC1 was obtained by deprotecting 3-{(2S, 4S)-
1-tert-Butoxycarbonyl -4- [4-(3 -methyl- 1-phenyl-lH-pyrazol-5-yl) piperazin- 1-
yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid in a solvent
selected from the group consisting of isopropyl alcohol, tert-butanol, n- butanol,
methanol or mixture thereof.
In one embodiment the present invention provides a process for the
preparation of teneligliptin comprising
a . deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-lphenyl-
lH-pyrazol-5-yl) piperazin- l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with
an acid to form an acid addition salt of teneligliptin; and
b. reacting the acid addition salt of teneligliptin with a base.
In one embodiment, the present invention provides a process for
preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof which comprises
treating teneligliptin with hydrobromic acid or hydrobromic acid in acetic acid in a
solvent selected from methanol, tertiary butanol and mixtures thereof.
In one embodiment, teneligliptin is dissolved in a mixture of methanol and
tertiary butanol.
In one embodiment, the present invention provides a process for the
preparation of teneligliptin 2.5 hydrobromide hydrate comprising crystallising
teneligliptin 2.5 hydrobromide hydrate from a solvent selected from the group
consisting of methanol, n-butanol, tertiary butanol, propyl acetate, isopropyl
acetate, butyl acetate, ethers such as diethyl ether, tetrahydrofuran,
tetrahydropyran, diisopropyl ether, methyl tertiary butyl ether; ketones such as
acetone, methyl ethyl ketone, amide as such as N, N-dimethyl formamide, N, Ndimethyl
acetamide; nitriles such as acetonitrile, hydrocarbons such as toluene,
xylene, cyclohexane, methyl cylcohexane; halogenated hydrocarbons such as
methylene dichloride, chloroform, ethylene dichloride and mixtures thereof.
Preferably, the solvent is methanol or a mixture of a methanol and tertiary-butanol.
The compounds were characterized and analyzed by following techniques
Proton NMR spectra was recorded in DMSO-d6 using NMR instrument-
Varian 300 MHZ.
Instrumental settings for XRPD: The measurements were performed on
Philips X-Ray Diffractometer model XPERT-PRO (PANalytical) Detector:
X'celerator [1] using Cu lamp with type and wavelength of the X-ray radiation: K-
Documents
Orders
| Section |
Controller |
Decision Date |
|
|
|
Application Documents
| # |
Name |
Date |
| 1 |
693-MUMNP-2015-US(14)-HearingNotice-(HearingDate-13-01-2021).pdf |
2021-10-18 |
| 1 |
Form 5.pdf |
2018-08-11 |
| 2 |
693-MUMNP-2015-Written submissions and relevant documents [27-01-2021(online)].pdf |
2021-01-27 |
| 2 |
Form 3.pdf |
2018-08-11 |
| 3 |
Form 2.pdf |
2018-08-11 |
| 3 |
693-MUMNP-2015-FER (By Post).pdf |
2018-12-10 |
| 4 |
Drawings.pdf |
2018-08-11 |
| 4 |
693-mumnp-2015-ABSTRACT [23-08-2018(online)].pdf |
2018-08-23 |
| 5 |
693-MUMNP-2015.pdf |
2018-08-11 |
| 5 |
693-mumnp-2015-CLAIMS [23-08-2018(online)].pdf |
2018-08-23 |
| 6 |
693-MUMNP-2015-FER.pdf |
2018-08-11 |
| 6 |
693-mumnp-2015-COMPLETE SPECIFICATION [23-08-2018(online)].pdf |
2018-08-23 |
| 7 |
693-MUMNP-2015-RELEVANT DOCUMENTS [23-08-2018(online)].pdf |
2018-08-23 |
| 7 |
693-mumnp-2015-CORRESPONDENCE [23-08-2018(online)].pdf |
2018-08-23 |
| 8 |
693-MUMNP-2015-PETITION UNDER RULE 137 [23-08-2018(online)].pdf |
2018-08-23 |
| 8 |
693-mumnp-2015-DRAWING [23-08-2018(online)].pdf |
2018-08-23 |
| 9 |
693-mumnp-2015-FER_SER_REPLY [23-08-2018(online)].pdf |
2018-08-23 |
| 9 |
693-mumnp-2015-OTHERS [23-08-2018(online)].pdf |
2018-08-23 |
| 10 |
693-mumnp-2015-FER_SER_REPLY [23-08-2018(online)].pdf |
2018-08-23 |
| 10 |
693-mumnp-2015-OTHERS [23-08-2018(online)].pdf |
2018-08-23 |
| 11 |
693-mumnp-2015-DRAWING [23-08-2018(online)].pdf |
2018-08-23 |
| 11 |
693-MUMNP-2015-PETITION UNDER RULE 137 [23-08-2018(online)].pdf |
2018-08-23 |
| 12 |
693-mumnp-2015-CORRESPONDENCE [23-08-2018(online)].pdf |
2018-08-23 |
| 12 |
693-MUMNP-2015-RELEVANT DOCUMENTS [23-08-2018(online)].pdf |
2018-08-23 |
| 13 |
693-mumnp-2015-COMPLETE SPECIFICATION [23-08-2018(online)].pdf |
2018-08-23 |
| 13 |
693-MUMNP-2015-FER.pdf |
2018-08-11 |
| 14 |
693-mumnp-2015-CLAIMS [23-08-2018(online)].pdf |
2018-08-23 |
| 14 |
693-MUMNP-2015.pdf |
2018-08-11 |
| 15 |
693-mumnp-2015-ABSTRACT [23-08-2018(online)].pdf |
2018-08-23 |
| 15 |
Drawings.pdf |
2018-08-11 |
| 16 |
693-MUMNP-2015-FER (By Post).pdf |
2018-12-10 |
| 16 |
Form 2.pdf |
2018-08-11 |
| 17 |
693-MUMNP-2015-Written submissions and relevant documents [27-01-2021(online)].pdf |
2021-01-27 |
| 17 |
Form 3.pdf |
2018-08-11 |
| 18 |
Form 5.pdf |
2018-08-11 |
| 18 |
693-MUMNP-2015-US(14)-HearingNotice-(HearingDate-13-01-2021).pdf |
2021-10-18 |
Search Strategy
| 1 |
SEARCHREPORT_23-02-2018.pdf |