Note: Descriptions are shown in the official language in which they were submitted.
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A STABLE PHARMACEUTICAL FORMULATION COMPRISING
TELMISARTAN AND HYDROCHLOROTHIAZIDE
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical tablet formulation
comprising two active
ingredients. More specifically the present invention relates to a formulation
comprising
Telmisartan, which is an angiotensin II receptor antagonist, and
Hydrochlorothiazide, a
diuretic, and methods of manufacturing thereof.
BACKGROUND OF THE INVENTION
Telmisartan was first disclosed in European Patent No. 0 502 314 as an
angiotensin II
receptor antagonist and is indicated for treatment of mild to moderate
essential hypertension
in patients.
Its chemical name is 4'-[[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-
benzimidazolyl]methyl]-2-biphenylcarboxylic acid, with molecular formula
C33H30N402,
having following structure:
Telmisartan is a white to off-white, odorless crystalline powder. It is
practically insoluble in
water and in the pH range of 3 to 7, sparingly soluble in strong acid (except
HCI) and soluble
in strong base.
As disclosed in W02000/43370 (Canadian Patent No. 2,352,436) crystalline
telmisartan
exists in two polymorphic forms having different melting points. Under the
influence of heat
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and humidity, the lower melting polymorph B transforms irreversibly into the
higher melting
polymorph A.
Telmisartan is an orally active, AT1 selective angiotensin II receptor
antagonist. By
selectively blocking the binding of angiotensin II to the AT1 receptors,
telmisartan inhibits
the vasoconstrictor and aldosterone-secreting effects of angiotensin II.
Telmisartan blocks ATI receptors, and has essentially no affinity for the AT2
receptors. AT2
receptors have been found in many tissues; to date, they have not been found
to be
associated with cardiovascular homeostasis. Telmisartan does not inhibit
angiotensin
converting enzyme (ACE, also known as kininase II), the enzyme that converts
angiotensin I
to angiotensin II and degrades bradykinin, nor does it affect renin or other
hormone
receptors or ion channels involved in cardiovascular regulation of blood
pressure and
sodium homeostasis. In hypertensive patients, antagonism of angiotensin II AT1
receptors
results in two to three-fold increases in plasma renin and angiotensin II
plasma
concentrations. Long term effects of increased AT2 receptor stimulation by
angiotensin II
are unknown. Telmisartan is known on the market under the trade name Micardis
by
Boehringer Ingelheim Corporation.
Hydrochlorothiazide (HCTZ) is an orally administered thiazide diuretic which
was first
disclosed in the patent US 3163645 and is indicated in treatment of edema and
hypertension. The chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-
benzothiadiazine-7-
sulfonamide 1,1-dioxide, molecular formula is C7HBCIN304S2 with following
structure:
0 0 0 0
H2N S`N
N
iH
Hydrochlorothiazide is a white to practically white, crystalline powder which
is slightly soluble
in water and freely soluble in sodium hydroxide solution.
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Combination of Telmisartan and Hydrochlorothiazide is commercially available
under the
trade name Micardis Plus and is indicated for use in the treatment of
hypertension.
However, particularly with a combination of Telmisartan or a pharmaceutically
acceptable
salt thereof and HCTZ, this approach was not feasible due to the
incompatibility of HCTZ
with basic compounds such as, e.g., meglumine (N-methyl-D-glucamine) which is
a
conventional component of Telmisartan formulations and the reduced dissolution
rate of
HCTZ from the dissolving matrix as compared with dissolution from a
disintegrating tablet.
Formulations using a combination of these two drugs are described in the
following patents:
W02003/059327 (Canadian Patent No. 2,472,392), W02004/096215 (Canadian Patent
Application No. 2,524,091), W02006063737 (Canadian Patent Application No.
2,589,493),
W02007/060170 (Canadian Patent Application No. 2,625,404), W02007/144175
(Canadian
Patent Application No. 2,654,890), W02009/058950, and W02009/115301.
W02003/059327 (Canadian Patent No. 2,472,392) discloses a bilayer
pharmaceutical tablet
comprising a first layer containing Telmisartan in substantially amorphous
form in a
dissolving tablet matrix and a second layer containing a diuretic in a
disintegrating tablet
matrix. This bilayer tablet structure overcomes the stability problem caused
by the
incompatibility of a diuretic like HCTZ with basic constituents of the
Telmisartan formulation.
At the same time such a formulation provides for immediate release of the
diuretic from the
fast disintegrating matrix. However bilayer tablets as per W003/059327
(CA2472392) tend
to be slightly hygroscopic and, therefore, need to be packaged using a
moisture-proof
packaging material such as aluminium foil blister packs, or polypropylene
tubes and HDPE
bottles which preferably contain a desiccant.
Several approaches to overcome the incompatibility problem have been reported
in
W02003/059327 (Canadian Patent No. 2,472,392). In one approach HCTZ particle
was
coated in a fluidized-bed granulator with a polymer solution containing water
soluble
polymers like hydroxypropylcellulose, hydroxypropylmethylcellulose or
polyvinylpyrrolidone,
thereby reducing the contact surface area of the HCTZ particles with the
Telmisartan
formulation during mixing and compressing. However, by this means it was not
possible to
reduce the surface contact area of HCTZ with the Telmisartan formulation in a
compressed
tablet to a degree sufficient to achieve the desired prolonged shelf life
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W02004/096215 relates to a medicament formulation of the crystalline sodium
salt of 4'-[2-
n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl) benzimidazol-1 -
ylmethyl]biphenyl-2-
carboxylic acid (Telmisartan) and methods for production thereof. The patent
discloses
pharmaceutical compositions containing the telmisartan sodium salt and a
diuretic.
W02006/063737 discloses a pharmaceutical composition comprising telmisartan
and
hydrochlorothiazide for the treatment of hypertension in patients with an
insufficient blood
pressure reduction upon treatment either with an angiotensin II receptor
antagonist, or a
pharmaceutical composition of an angiotensin II receptor antagonist and a low
dose of
hydrochlorothiazide, wherein the pharmaceutical composition contains the
component
telmisartan in a dissolving tablet matrix having instant release
characteristics and wherein
the diuretic hydrochlorothiazide forms is in a separate layer in a
disintegrating
pharmaceutical matrix.
W02007/144175 discloses a stable formulation of telmisartan and
hydrochlorothiazide
having both substances in separate units is prepared, exhibiting exceptional
stability when
subjecting to stress conditions.
W02009/058950 (Dr. Reddy's Laboratories) discloses the pharmaceutical tablets
comprising a first layer formulated for immediate release of telmisartan from
a dissolving
matrix and a second layer formulated for immediate release of
hydrochlorothiazide from a
dissolving matrix, methods for producing tablets and methods of use for
treating
hypertension.
The PCT application WO 2009/115301 discloses the solid pharmaceutical
composition
comprising at least two layers, wherein the first layer contains a non-peptide
angiotensin II
receptor antagonist or a pharmaceutically acceptable salt thereof in a
dissolving matrix and
the second layer contains a diuretic or a pharmaceutically acceptable salt
thereof,
characterized in that the second layer contains the diuretic or the
pharmaceutically
acceptable salt thereof in a dissolving matrix and the pharmaceutical
composition is
substantially free of disintegrants.
It is often desirable to combine multiple active ingredients in a single
pharmaceutical
composition. Inclusion of multiple ingredients in a single composition
generally reduces
costs and provides the convenience of consuming a single medication rather
than multiple
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medications for treating individual symptoms. However, a combination of
ingredients,
especially the stability of a composition might be compromised due to
incompatibility
between two active ingredients.
The solid pharmaceutical composition according to the present invention,
preferably in the
form of a tablet, provides an immediate release of the non-peptide angiotensin
II receptor
antagonist, in particular of the poorly water soluble Telmisartan or
pharmaceutically
acceptable salts thereof, and also provides an immediate release of a diuretic
from the
tablet matrix. At the same time the tablet structure overcomes the stability
problem caused
by the incompatibility of diuretics, like HCTZ, with basic excipients of the
conventional
Telmisartan formulation, e.g. meglumine.
It is known from the literature that telmisartan has very poor aqueous
solubility in the
physiological pH range of the gastrointestinal tract between pH 1 and 7, and
is soluble in
strong base. On the other hand, hydrochlorothiazide degrades in alkaline
conditions i.e
undergoes alkaline hydrolysis in the presence of heat and moisture. The major
degradation
product of Hydrochlorothiazide is 4-amino-6-chloro-1,3-benzenesulfonamide
("DSA") It is
advantageous to administer both drugs concomitantly or even better to
administer a
composition comprising both, to treat hypertension.
Difficulty results from the fact that both active substances need to be
released from the
composition substantially simultaneously. Preparation of fixed dose
combinations of
telmisartan and hydrochlorothiazide with adequate stability poses a challenge
to
formulators. Hence there is need for simple and stable fixed dose compositions
containing
telmisartan and hydrochlorothiazide.
SUMMARY OF THE INVENTION
A first object of the present invention is to provide a stable pharmaceutical
formulation
comprising telmisartan or a pharmaceutically acceptable salt and a diuretic
dispersed in a
matrix, said matrix comprising:
- at least one disintegrant in an amount ranging from 0.5 %-20% by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution
enhancing
agent to telmisartan of from 1:1 to 10:1;
- a water-insoluble diluent in an amount ranging from 15%-75% by weight; and
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at least one other pharmaceutically acceptable excipient /or adjuvant in an
amount
ranging from 0 - 25% by weight.
Preferably, the diuretic is HCTZ.
Preferably, the formulation according to the present invention comprises a
surfactant or
emulsifier present in an amount ranging from 0.5% -10% by weight.
According to another aspect of the present invention, there is provided a
stable
pharmaceutical formulation according to claim 1 wherein the in vitro
dissolution rate of said
formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and
at least 80 %
of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at
75 rpm in 900ml of pH 7.5 phosphate buffer.
Preferably, the disintegrant is selected from the group consisting of:
crospovidone,
croscarmellose sodium, sodium starch glycolate, starch, modified starch and a
combination
thereof. More preferably, the disintegrant is croscarmellose sodium.
The dissolution enhancing agent is preferably selected from the group
consisting of:
NaHCO3, KHCO3i NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO,
and
MgCO3. More preferably, the dissolution enhancing agent is MgO.
Preferably, the formulation further comprises a solubilizing agent selected
from the group
consisting of: alkali metal hydroxide such as NaOH and KOH. More preferably,
the
solubilizing agent is NaOH.
Preferably, the water insoluble diluent is selected from the group consisting
of:
microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline
cellulose, powdered
cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate,
magnesium silicate,
magnesium trisilicate, magnesium aluminium metasilicate (Neusilin), kaolin,
starch, starch
derivatives, and co-processed excipients. Also preferably, the co-processed
excipient is
selected from the group consisting of: Ludipress( (mixture of lactose and
3.2% Povidone
K30), Cellactose( (mixture of lactose and cellulose), and Silicified MCC
Prosolv (mixture
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of microcrystalline cellulose and silicon dioxide). More preferably, the co-
processed
excipient is silicified microcrystalline cellulose Prosoly .
Preferably, the formulation comprises less than 0.5% wt of 4-amino-6-chloro-
1,3
benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content
when
exposed to 40 C/75% relative humidity conditions in Blister as well as HDPE
pack. Also
preferably, the formulation according to claim 1, wherein the in vitro
dissolution rate remains
similar to the initial value for telmisartan and for the diuretic on stabiliy
as measured by using
USP type II apparatus at 75 rpm in 900m1 of pH 7.5 phosphate buffer.
According to another aspect of the present invention, there is provided a wet
granulation
process preferably a low shear granulation process for preparing the stable
pharmaceutical
composition.
According to another aspect of the present invention, there is provided a
process for the
preparation of a stable pharmaceutical formulation according to claim 1
comprising: an
angiotensin II receptor antagonist, a diuretic and a dissolution enhancing
agent in a matrix,
wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and
(5) - compression.
When the process has for starting material a salt form of an angiotensin II
receptor
antagonist said process comprises a dry mixing step and direct compression.
According to another aspect of the present invention, there is provided a use
of a stable
pharmaceutical formulation containing two active ingredients in a single
layer, in an
immediate release form for the treatment or prevention of hypertension.
Preferably, the formulation is in the form of a monolithic tablet or a single
layer tablet. Also
preferably, the formulation is in the form of a bilayer tablet dosage form
wherein a first layer
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is a placebo layer and the second layer contains the angiotensin II receptor
antagonist or a
pharmaceutically acceptable salt thereof, and a diuretic.
According to another aspect of the present invention further relates to stable
formulation
comprising telmisartan or acceptable salts and Hydrochlorothiazide, wherein
the telmisartan
or acceptable salt is in substantially amorphous form.
DETAILED DESCRIPTION OF THE INVENTION
An object of the present invention provides a pharmaceutical formulation
comprising two
active ingredients, wherein the in vitro dissolution rate of said formulation
provides at least
80% of a first active ingredient dissolved within 30 minutes and at least 80 %
of a second
active ingredient dissolved within 30 minutes as measured by USP type II
apparatus at 75
rpm in 900ml of pH 7, 5 phosphate buffer.
According to another object of the present invention there is provided a
pharmaceutical
formulation comprising a combination of Telmisartan and Hydrochlorothiazide
(HCTZ) in a
single layer, preferably with Magnesium Oxide, but does not degrade or
contribute to
degradation of HCTZ, and a manufacturing process in order to get suitable
stability
properties, without need of expensive packing.
In a preferred embodiment of the invention, there is provided bilayer
pharmaceutical
formulation comprising two active ingredients, wherein the first active
ingredient is
Telmisartan or a pharmaceutically acceptable salt thereof, which is
practically insoluble in
water (pH 3- 9), soluble in strong base. Preferably, the second active
ingredient is
hydrochlorothiazide, which is soluble in sodium hydroxide solution, slightly
soluble in water.
The term "active ingredient" refers to an agent or substance that has
measurable specified
or selected physiologic activity when administered to a subject in a
pharmaceutically
significant or effective amount. The active agent can be a therapeutic, a
prophylactic, or a
diagnostic agent. These terms of art are well-known in the pharmaceutical and
medicinal
arts.
The term "stability" refers to the extent to which a product retains, within
specified limits and
throughout its period of storage and use, the same properties and
characteristics that it
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possessed at the time of its manufacture. There are five general types of
stability defined by
the United States Pharmacopoeia: Chemical, Physical, Microbiological,
Therapeutic and
Toxicological.
Additionally, the formulation of the present invention preferably further
comprises
pharmaceutically acceptable excipients. Excipients are added to the
composition for a
variety of purposes. One or more pharmaceutically acceptable excipients may be
present in
the composition of the present invention, such as for example diluents,
binders, lubricants,
disintegrants, glidants, acidifying agents.
Particularly preferred, as pharmaceutically acceptable excipients to use in
the present
invention are: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90
(Prosoly ),
colloidal silicon dioxide (Aerosil ), dibasic calcium phosphate Hydrous,
croscarmellose
sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose
and iron
oxides.
Suitable diluents include for example pharmaceutically acceptable inert
fillers such as
microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium
phosphate,
saccharides, and/or mixtures of the foregoing.
Suitable binders may be selected from amongst povidone, Copovidone, alginic
acid; sodium
alginate; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxy
propyl
cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose;
gelatin; and starch or
starch derivatives.
Suitable lubricants are selected from the group consisting of: Mg-, Al- or Ca-
stearate, stearic
acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty
acid, glyceryl
monostearate hydrogenated vegetable oil, polyethylene glycol,and mixtures
thereof.
Suitable disintegrants may be selected from one or more compounds such as:
croscarmellose sodium, sodium starch glycolate, maize starch, CMC-Ca, CMC-Na,
microcrystalline cellulose, cross-linked PVP, alginic acid, sodium alginate,
pregelatinized
starch and low-substituted hydroxy propyl cellulose.
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Suitable dissolution enhancing agents are preferably selected from the group
consisting of:
NaHCO3i KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO,
and
MgCO3. More preferably, the dissolution enhancing agent is MgO.
Suitable anti-adherents may be selected from one or more compounds that are
capable of
preventing stickiness to surfaces of the punches. Examples of anti-adherents
include silicon-
containing compounds such as colloidal silicon dioxide, magnesium trisilicate
and talc.
According to another object of the invention, there is pharmaceutical
formulation comprising
Telmisartan or a pharmaceutically acceptable salt thereof and a second active
ingredient,
wherein at least 60 % of Telmisartan is dissolved within 5 minutes as measured
by USP
Paddle Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also,
preferably at
least 80 % of Telmisartan is dissolved within 10 minutes as measured by USP
Paddle
Method at 75 rpm at pH 7,5 dissolution phosphate buffer at 37 C. Also,
preferably at least
90 % of Telmisartan is dissolved within 30 minutes as measured by USP Paddle
Method at
75 rpm at pH 7,5 dissolution phosphate buffer at 37 C.
According to another object of the invention, there is provided a
pharmaceutical formulation
comprising Telmisartan or a pharmaceutically acceptable salt thereof and
Hydrochlorothiazide, wherein at least 55 % of Hydrochlorothiazide is dissolved
within 5
minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution
phosphate
buffer at 37 C. Also, preferably at least 75 % of Hydrochlorothiazide is
dissolved within 10
minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution
phosphate
buffer at 37 C. Also, preferably at least 80 % of Hydrochlorothiazide is
dissolved within 30
minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution
phosphate
buffer at 37 C. Also, preferably at least 85 % of Hydrochlorothiazide is
dissolved within 60
minutes as measured by USP Paddle Method at 75 rpm at pH 7,5 dissolution
phosphate
buffer at 37 C.
According to another object of the invention, there is provided a process for
the preparation
of a pharmaceutical formulation containing two active ingredients in a single
layer
comprising the following steps:
(1) - dissolving Telmisartan in purified water with sodium hydroxide;
(2) - dissolving binder in isopropyl alcohol;
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(3) - mixing the content of step (1) with the content of step (2);
(4) - blending pharmaceutical excipients;
(5) - granulating the blend of step (4) with the content of step (3);
(6) - drying the wet granules obtained from step (5);
(7) - screening the dried granules obtained from step (6);
(8) - mixing the granules of step (7) with additional pharmaceutically
acceptable
excipients;
(9) - preparing a mixture of a second active ingredient and pharmaceutically
acceptable
excipients;
(10) - adding the content of step (9) to the content of step (8); and
(11) - compressing the blend of step (10).
According to another object of the invention, there is provided a process for
the preparation
of a pharmaceutical formulation comprising two active ingredients, wherein the
in vitro
dissolution rate of the said formulation provides at least 80 % of a first
active ingredient
dissolved within 30 minutes and at least 80 % of a second active ingredient
dissolved within
30 minutes as measured by USP Paddle Method at 75 rpm at pH 7, 5 dissolution
phosphate
buffer at 37 C, wherein said process comprises the following steps:
(1) - dissolving Telmisartan in purified water with sodium hydroxide;
(2) - dissolving, povidone (K-30) in isopropyl alcohol;
(3) - mixing the solution of step (1) with the solution of step (2);
(4) - dry mixing the following pharmaceutical excipients: silicified MCC
90(Prosolv ),
dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon
dioxide;
(5) - screening the content obtained from step (4) and then blending;
(6) - adding to the blend of step (5) to the granulation solution of step (3);
(7) - drying the wet granules in a fluid bed drier;
(8) - screening the dried granules obtained from step (7);
(9) - mixing the granules of step (8) with magnesium oxide heavy and the
colloidal silicon
dioxide (Aerosil ) and screening the obtained mixture;
(10) - screening Hydrochlorothiazide, microcrystalline cellulose PH102 (Avicel
) and
croscarmellose sodium, and blending with the granules of step (9);
(11) - dispersing a portion of blend with magnesium stearate and screening;
(12) - blending the content of step (11) together with the granules of step
(9);
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(13) - separately screening the microcrystalline cellulose, yellow iron oxide,
colloidal
silicon dioxide and croscarmellose sodium, through #40 sieve (400pm) and
blending
the content;
(14) - screening magnesium stearate and blending with the blend of step (12);
(15) - compressing the lubricated blend of step (14) and the blend of step
(12), using a
bilayer compression machine.
Preferably, the process for the preparation of a pharmaceutical formulation
comprises two
active ingredients - Telmisartan and Hydrochlorothiazide, the pharmaceutically
acceptable
excipients: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90
(Prosoly ),
colloidal silicon dioxide (Aerosil ), dibasic calcium phosphate hydrous,
croscarmellose
sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose
and
colorants.
Preferably, the granulation solution is prepared by dissolving gradually
Telmisartan under
stirring in purified water with sodium hydroxide. More preferably, wherein
isopropyl alcohol
and povidone (K-30) is dissolved in a separate vessel. Then, the content of
solution of step
(1) is mixed with the content of the solution of step (2).
Preferably, the obtained content is dry mixed and then screened with the
following
pharmaceutical excipients: silicified MCC 90 (Prosolv ), dibasic calcium
phosphate
hydrous, croscarmellose sodium and colloidal silicon dioxide.
Preferably, to the blend of step (5) is added to the content of step (3) and
the granulation is
carried out in a ribbon blender.
Preferably, the wet granules are dried in a fluid bed drier at inlet
temperature of 50 C 5 C
until a loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer
set at 105 C
for 10 minutes.
Preferably, the dried granules obtained from step (7) are screened through a
comill
equipped with 0.039R screen (1000 pm).
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Preferably, the granules of step (8) are mixed with magnesium oxide heavy and
colloidal
silicon dioxide (Aerosil ) and screened through #30 sieve (600pm).
Preferably, Hydrochlorothiazide, microcrystalline cellulose PH102 (Avicel )
and
croscarmellose sodium are screened through #40 sieve (400pm), added to the
granules of
step (9) and blended for 20 minutes.
Preferably, a portion of the blend obtained from step (10) is dispersed with
magnesium
stearate, and then screened manually through #40 sieve (400pm) and blended for
3
minutes.
Preferably, microcrystalline cellulose PH102, yellow iron oxide, colloidal
silicon dioxide and
croscarmellose sodium are screened through #40 sieve (400pm) and blended for
15
minutes.
Preferably, magnesium stearate is passed through a 40 (400pm) mesh screen, is
introduced
into the bin blender and blended for 3 minutes with mixture obtained from step
(12), prior to
compression.
Preferably, the lubricated blend is compressed using capsule shaped tooling at
average
weight of 700 mg on a stokes bilayer compression machine.
According to another object of the invention, there is provided a process for
the preparation
of a pharmaceutical formulation containing two active ingredients in a single
layer, wherein
said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and
(5) - compression.
Preferably, the step of preparation of a granulation solution further
comprises dissolving
Telmisartan under stirring in purified water with sodium hydroxide.
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Preferably, the step of preparation of a granulation solution further
comprises dissolving
povidone (K-30) in Isopropyl Alcohol.
Preferably, the step of preparation of a granulation solution further
comprises mixing the
content of step (1) with the content of step (2) for 15 minutes.
Preferably, the step of dry mixing further comprises: dry mixing silicified
MCC 90 (Prosolv
), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal
silicon dioxide
in a ribbon blender for 5 min.
Preferably, the step of dry mixing further comprises screening the content
obtained from
step (2) through a comill equipped with 0.045R screen (1190 pm) and then mix
for 5 minutes
to yield an excipient blend.
Preferably, the step of granulation further comprises adding to the blend
obtained from the
dry mixing step the granulation solution.
Preferably, the step of granulation further comprises drying the wet granules
in a fluid bed
drier at an inlet temperature of 50 C 5 C till a loss on drying value of
3.8% 0.4% is
obtained on a moisture analyzer set at 105 C for 10 minutes.
Preferably, the step of granulation further comprises screening the dried
granules through a
comill equipped with 0.039R screen (1000 pm).
Preferably, the step of lubrication comprises mixing magnesium oxide heavy and
the
colloidal silicon dioxide (Aerosil ) and screening through #30 sieve (600pm).
Preferably, the step of lubrication further comprises screening
Hydrochlorothiazide,
microcrystalline cellulose PH102 (Avicel(D) and croscarmellose sodium, through
#40 sieve
(400pm) and adding to the granules of Telmisartan and blending to yield a HCTZ
blend.
Preferably, the step of lubrication further comprises dispersing a portion of
the HCTZ blend
with magnesium stearate and screening the obtained content through #40 sieve
(400pm) to
yield a lubricated HCTZ blend.
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Preferably, the step of lubrication further comprises adding the lubricated
HCTZ blend to the
Telmisartan granules and blending for 3 minutes to yield the actives blend.
Preferably, the step of blending placebo blend further comprises screening
microcrystalline
cellulose, yellow or red iron oxide, colloidal silicon dioxide and
croscarmellose sodium,
through #40 sieve (400pm) and blending the content for 15 minutes to obtain an
excipient
placebo blend.
Preferably, the step of compression further comprises compressing the
excipient blend and
actives blend, to form a bilayer pharmaceutical formulation.
According to another object of the present invention, there is provided the
use of a
pharmaceutical formulation containing two active ingredients in a single
layer, in an
immediate release form, for the treatment or prevention of hypertension.
While several embodiments of the invention have been described, it will be
understood that
the present invention is capable of further modifications and this application
is intended to
cover any variations uses or adaptations of the invention following in general
the principles
of the invention and including such departures from the present disclosure as
to come within
knowledge customary practices in the art to which the invention pertains, as
may be applied
to the essential features herein before set forth and falling within the scope
of the invention.
The following examples illustrate the preferred embodiment and various aspects
of the
present invention.
Example 1
IMMEDIATE RELEASE DOSAGE FORM OF TELMISARTAN/HCTZ ACCORDING TO A
PREFERRED EMBODIMENT OF THE PRESENT INVENTION
1. Preparation Of Granulating Solution:
1. In a vessel to purified water was added sodium hydroxide and dissolved
under stirring.
The required quantity of Telmisartan was added gradually and dissolved under
stirring.
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2. In another vessel to isopropyl alcohol was added Povidone (K-30) and
dissolved under
stirring.
3. The granulation solution is prepared by adding to the content of
Telmisartan solution (1)
the Povidone K30 solution (2) and mixing for 15 minutes.
Dry Mixing
4. Silicified MCC 90 (Prosoly ), Dibasic Calcium phosphate Hydrous,
Croscarmellose
sodium and Colloidal Silicon Dioxide (Aerosil ) was introduced into a ribbon
blender
and blended for 5 minutes. The blend was screened through a comill screen
0.045R
(1190 pm). This blend was reintroduced into the ribbon blender and blended for
5
minutes.
Granulation
5. The blend of step 4 was granulated with solution of step 3 in a ribbon
blender.
6. The wet granules were dried in a fluid bed drier at an inlet temperature of
50 C 5 C
till a Loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer
set at
105 C for 10 minutes.
7. The dried granules were screened through a co mill screen 0.039R screen
(1000
pm) for further processing.
Lubrication
8. The dried screened granules of step 7 was added to a bin blender.
9. Magnesium oxide heavy and Colloidal Silicon Dioxide (Aerosil ) were
dispersed
and screened through #30 sieve (600pm).This sieved dispersion was added to the
bin blender of step 8.
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10. Hydrochlorothiazide, Microcrystalline Cellulose PH102 (Avicel(D)and
croscarmellose
sodium was screened through #40 sieve (400pm).This sieved dispersion was
introduced into the bin blender of step 8 and blended for 20 minutes.
11. Magnesium stearate was dispersed with a portion of the blend of step 10 in
a
polyethylene bag and screened manually through #40 sieve (400pm).This sieved
dispersion was introduced into the bin blender of step 8 and blended for 3
minutes.
II. Manufacturing of Yellow Placebo Blend
12. Microcrystalline Cellulose PH 102 (Avicel ), Yellow oxide iron, Colloidal
Silicon
Dioxide (Aerosil ) and croscarmellose sodium was screened through #40 sieve
(400pm) and introduced into the bin blender and blended for 15 minutes.
13. Magnesium stearate was screened through #40 sieve (400pm) and introduced
into
the bin blender of step 12 and blended for 3 minutes.
Compression
14. The lubricated blend of step 11 and stepl 3 was compressed using capsule
shaped
tooling at an average weight of 700 mg on a stokes bilayer compression
machine.
The formulation of Example 1 is set out in Table 1 below.
Table 1
Formulation according to the present invention
No. Ingredient mg/Tablet
(Telmisartan and Hydrochlorothiazide granules)
1 Telmisartan 80.0
2 Sodium Hydroxide 6.624
3 Povidione (k30) 4.80
4 Purified water 110.0*
Isopropyl Alcohol 12.7**
6 Silicified MCC 90 ( Prosoly ) 168.0
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No. Ingredient mg/Tablet
7 Colloidal Silicon Dioxide (Aerosil ) 4.8
8 Dibasic Calcium phosphate Hydrous 72.0
9 Croscarmellose Sodium 19.2
Magnesium Oxide Heavy 24.0
11 Colloidal Silicon Dioxide (Aerosil ) 2.4
12 Hydrochlorothiazide 25.0
13 Microcrystalline Cellulose PH 102 (Avicel ) 70.23
14 Croscarmellose Sodium 19.2
Magnesium Stearate 3.75
Total 500.0
Yellow Placebo granules
16 Microcrystalline Cellulose PH 102 (Avicel ) 194.65
17 Yellow oxide iron 0.35
18 Colloidal Silicon Dioxide (Aerosil ) 0.5
19 Croscarmellose sodium 4.0
Magnesium Stearate 0.5
Total 200.0
Total of both layers 700.0
* & **: Evaporates during processing. Does not appear in the final
formulation.
Dissolution:
The tablets obtained from Example 1 were subsequently tested for in vitro
dissolution rate,
measured by Apparatus II (USP Paddle Method), using the following parameters:
Speed: 75 rpm
Media: 900 ml pH 7.5 Phosphate buffer
Temperature: 37 C.
The dissolution results are set out in Table 2 and 3 below.
Table II and III provides a comparative dissolution of telmisartan and
hydrochlorothiazide
from Micardis Plus 80/25 mg where Telmisartan and Hydrochlorothiazide are
dispersed in
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two separate layers) versus formulation of present invention (where
Telmisartan and
hydrochlorothiazide are dispersed in a single layer)
Table II
Media :900 ml,7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
Micardis Plus 80/25 mg
Time
Lot no :810094 Example 1
minutes % Telmisartan Dissolved % Telmisartan Dissolved
0 0 0
34 66
60 84
78 89
30 98 90
45 99 91
60 99 92
ITP 99 96
Table III :
Media :900m1, 7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
Micardis Plus 80/25 mg
Time Lot No :810094 Example 1
% Hydrochlorothiazide % Hydrochlorothiazide
min Dissolved Dissolved
0 0 0
5 93 59
10 95 79
15 97 83
30 98 86
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45 99 87
60 98 89
ITP 98 95
Stability
Stability of formulation of present invention (Examplel) was evaluated in two
types of
packaging at 40 C /75% RH conditions. The following parameters were
evaluated.
1) Degradation of Telmisartan and Hydrochlorothiazide in the formulation as
per the
present invention.
2) Dissolution of Telmisartan and Hydrochlorothiazide in the formulation as
per the
present invention.
3) Moisture content of the formulation as per the present invention.
The results of degradation, dissolution and Moisture content are tabulated in
Tables IV, V, VI, VII,
VIII and IX.
Pack I: HDPE pack with desiccant ( Trisorb )
Pack II: Cold forming ALU/ALU blisters.
Table IV: Degradation of formulation of Example I in HDPE bottles at 40 C/75%
RH
Pack I : HDPE pack with desiccant (Trisorb )
Lot No: Formulation as per Example 1
Parameter Initial (T=0) 1 Month 2 Months
Moisture content (%) 3.71% 3.58% 3.34%
Degradation of Telmisartan
Known Impurities
Comp 3 - - -
Comp 4 - - -
Comp 5 - - -
Comp 6 0.07% 0.07% 0.06%
Comp 7 - - -
Unknown RRT % RRT % RRT %
Impurities
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0.87 0.03 0.87 0.03 1.40 0.03
1.41 0.03 1.40 0.03 1.41 0.10
1.42 0.07 1.41 0.09
Degradation of Hydrochlorothiazide
Known Impurities
Comp 1* 0.07% 0.07% 0.06%
Comp 2 0.04% 0.04% 0.04%
Unknown Impurities RRT % RRT % RRT %
2.60 0.04 2.58 0.04 2.58 0.05
* DSA Impurity
Table V: Dissolution of Telmisartan from formulation as per example 1 in HDPE
pack at
40 C/75% RH
Media :900 ml,7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
T=0 I Month 2 Months
Time % Telmisartan % Telmisartan % Telmisartan
in minutes Dissolved Dissolved Dissolved
0 0 0 0
66 70 71
84 89 91
89 93 92
30 90 95 92
45 91 95 92
60 92 95 92
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Table VI: Dissolution of Hydrochlorothiazide from formulation as per example 1
in HDPE
pack at 40 C/75% RH
Media :900ml, 7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
T=0 I Month 2 Months
Hydrochlorothiazide Hydrochlorothiazide Hydrochlorothiazide
Time Dissolved Dissolved Dissolved
0 0 0 0
59 65 68
79 86 89
83 91 90
30 86 93 92
45 87 94 93
F 60 89 94 94
Table VII: Comparative Degradation of Example I and Micardis Plus in ALU/ALU
Blisters
at 40 C/75% RH.
Pack If : ALU/ALU Blister pack
Example I Micardis Plus 80/25 mg
Lot No 810094
Parameter Initial (T=0) 1Month 2 Months Initial (T=0) 1Month
Moisture 3.71% 3.8% 3.5% 1.74% 1.71%
content (%)
Degradation of Telmisartan
Known
Impurities
Comp 3 - - - - -
Comp 4 - - - - -
Comp 5 - - - - -
Comp 6 0.07% 0.07% 0.06% - -
Comp 7 - - -
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Unknown RRT % RRT % RRT % RRT % RRT %
Impurities
0.87 0.03 0.87 0.03 0.87 0.03 1.46 0.03 1.46 0.03
1.41 0.03 1.41 0.09 1.40 0.04 1.47 0.04 1.47 0.03
1.42 0.07 1.41 0.10
Degradation of Hydrochlorothiazide
Known
Impurities
Comp l 0.07% 0.06% 0.07% 0.10% 0.12%
Comp 2 0.04% 0.04% 0.04% 0.03% 0.03%
Unknown RRT % RRT % RRT % RRT % RRT %
Impurities
2.60 0.04 2.58 0.04 2.60 0.05 2.58 0.05 2.58 0.05
Table VIII: Dissolution of Telmisartan from formulation as per example 1 in
ALU/ALU Blister
pack at 40 C/75% RH
Media :900m1, 7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
T=0 1 Month 2 Months
Time
in %Telmisartan % Telmisartan %Telmisartan
minutes Dissolved Dissolved Dissolved
0 0 0 0
66 64 73
84 90 90
89 93 94
30 90 93 95
45 91 93 95
60 92 94 96
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Table IX: Dissolution of Hydrochlorothiazide from formulation as per example 1
in ALU/ALU
Blister pack at 40 C/75% RH
Media :900m1,7.5 Phosphate buffer
Apparatus: USP Type II
RPM : 75
T=0 I Month 2 Months
% Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide
Time Dissolved Dissolved Dissolved
0 0 0 0
59 60 75
79 86 90
83 90 92
30 86 91 94
45 87 92 95
60 89 92 96
Based on the data from the above tables the following can be concluded:
1) From Tables IV & VII the formulation as per the present invention has
comparable
stability in both blister as well as HDPE pack with that of the reference
product (Micardis
Plus 80/25 mg).
2) From Tables V, VI, VIII and IX the dissolution rate of Hydrochlorothiazide
and Telmisartan
from formulation as per-the present invention is not affected on stability.
