Note: Descriptions are shown in the official language in which they were submitted.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
Solid oral dosage form containing olmesartan medoxomil
The present invention relates to a pharmaceutical solid oral dosage form
comprising
olmesartan medoxomil. More particularly, the present invention relates to
formulations,
processes for preparing these formulations, and to formulations for the
treatment or prevention
of hypertension, heart and circulatory diseases. Specifically, the present
invention relates to the
use of (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl-4-(2-hydroxypropan-2-yl)-2-
propyl-1-({4-[2-
(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-imidazole-5-carboxylate in
the preparation
of immediate release formulations.
BACKGROUND OF THE INVENTION
The compound (5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl-4-(2-hydroxypropan-2-
yl)-2-propyl-1-
({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl] phenyl}methyl)-1H-imidazole-5-
carboxylate is known by
the name of olmesartan medoxomil presented by the formula (I) below:
O H3C CH3
HO N H3C
O O
N N- 1H
H3C N 0 N
Formula (I)
EP0503785B1 discloses generically a series of 1-(biphenylmethyl)imidazole
derivatives having
an activity as angiotensin II receptor antagonist including olmesartan
medoxomil and a process
for its preparation.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
2
Olmesartan medoxomil is a prodrug that is hydrolyzed to olmesartan during
absorption from the
gastrointestinal tract. Olmesartan works by blocking the binding of
angiotensin II to the AT,
receptors in vascular muscle; it is therefore independent of angiotensin II
synthesis pathways,
unlike angiotension converting enzyme (ACE) inhibitors. Angiotensin I is
converted to
angiotensin II through removal of two terminal residues by the enzyme ACE.
The renin-angiotension system provides one of the important mechanisms for
maintaining the
homeostasis of blood pressure in living animals. When blood pressure is
reduced or the
sodium ion concentration of the body fluids falls, this system is activated.
As a result, the
enzyme renin and ACE are activated and act on angiotensinogen, which is first
decomposed by
renin to produce angiotensin I (Al). This Al is then converted by ACE to
angiotensin II (All). All
is the principal pressor agent of the renin-angiotensin system, with effects
that include
vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac
stimulation and
renal reabsorption of sodium.
By blocking the binding rather than blocking the synthesis of angiotensin II,
olmesartan inhibits
the negative regulatory feedback on renin secretion. As a result of this
blockage, olmesartan
reduces vasoconstriction and the secretion of aldosterone. This lowers blood
pressure by
producing vasodilation, and decreasing peripheral resistance.
The compound of formula (I) exists in different polymorphic forms like the
crystalline form G as
disclosed in US2006/0281800 Al, olmesartan medoxomil hemihydrate as disclosed
in
EP1801111 Al; Form B as provided by W02008/149160 Al and an amorphous form as
disclosed in W02007/017135 A2.
WO 2007/128478 A2 reports that olmesartan medoxomil is susceptible to
degradation under
basic conditions and also under highly acidic conditions while it is most
stable at a pH in the
range of 3-5. According to W02007/128478 A2 stabilization of a pharmaceutical
composition
containing olmesartan medoxomil can be achieved with pharmaceutically
acceptable
constituents where each of the constituents being incorporated into a
composition has a pH of
less than 8 and wherein one of the constituents is stearic acid.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
3
One object of the present invention is therefore to provide a solid oral
dosage form containing
olmesartan medoxomil which is sufficiently stable without the incorporation
into a composition
including pH lowering agents i.e. stearic acid as disclosed in WO 2007/128478
A2.
Surprisingly it was found that the neutral compound polyethylene glycol having
a molecular
weight of 1000 - 10000, without acid-base-buffer capacity has a stabilizing
effect on olmesartan
medoxomil.
SUMMARY OF THE INVENTION
The present invention relates to a solid oral dosage form comprising
olmesartan medoxomil
and polyethylene glycol having an average molecular weight of about 1000 -
10000.
Another aspect of the invention is a solid oral dosage form as described
herein for the
treatment and/or prevention of hypertension and disorders associated
therewith.
The invention further relates to a process for the manufacture of a solid oral
dosage form
containing olmesartan medoxomil as a pharmaceutically active agent and
polyethylene glycol
having a molecular weight of about 1,000 - 10,000 as a stabilizer, comprising
wet granulation.
Another aspect of this invention is a process for the manufacture of a solid
oral dosage form
containing olmesartan medoxomil as a pharmaceutically active agent comprising
the steps of
a) dry mixing the active agent(s) with a diluent,
b) adding an aqueous solution containing a stabilizer and a binder
c) wet granulation of the mixture to obtain granules,
d) wet sifting the granules using a comill
e) drying and additionally sifting the granules,
f) blending the granules with a lubricant and
g) optionally compressing the blend to a tablet.
A disintegrant is preferably added either to the mixture of the active agent
and the diluent, i.e.
step (a) or to the blend of the granules and the lubricant, i.e. step (f).
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
4
Another aspect of this invention is a solid oral dosage form obtainable by the
process of the
present invention.
Yet another aspect of the invention is the use of polyethylene glycol as a
stabilizer of
olmesartan medoxomil in a solid dosage form.
DETAILED DESCRIPTION OF THE INVENTION
The terms "dissolution profile" and "release profile" are used interchangeably
in this application.
Also the terms "sifting" and "sieving" are used interchangeably herein.
The term "solid ingredient" refers to any constituent of the composition of
the solid oral dosage
form according to the present invention that is in the solid state under
standard conditions, i.e.
at 25 C and at a pressure of 1 atm (101.325 kPa).
Generally, the phrase "Immediate release formulation" refers to any solid oral
formulation that
after taking, by the time olmesartan medoxomil leaves the stomach, olmesartan
medoxomil is
either in solution or it is in the form of a suspension of fine particles,
e.g., in a form in which
olmesartan can be readily absorbed. More specifically, the in vitro
dissolution profiles for the
immediate release formulations were generated using the paddle method USP
Apparatus II at
a stirring speed of 50 rpm in 0.1 HCI or phosphate buffer with a pH 6.8 at 37
C.
Generally, in the case of orally administered pharmaceuticals, bioavailability
of active
ingredients contained therein is quite important, and exerting a constant
efficacy is also
required. For that purpose, assuring uniformity, e.g. bioequivalence among
formulation batches
is required. In pharmacopoeias, procedures for testing disintegration or
dissolution properties of
solid formulations are defined for assuring a constant quality and
bioequivalence of the
formulations. Accordingly, pharmaceuticals are requested to meet
specifications as defined
based on such tests.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
Active agent(s)
The solid oral dosage form of the present invention preferably contains a unit
dose in the range
of about 10 to 250 mg, more preferably in the range of about 10 to 40 mg,
particularly of 10, 20
or 40 mg of the active agent olmesartan medoxomil.
Another object of the present invention is to provide a solid oral dosage form
containing
olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ),
amlodipine or
hydrochlorothiazide and amlodipine and a process of forming the same.
Amlodipine may
formulated in form of pharmaceutical acceptable salts thereof, e.g. the
besylate, mesylate or
maleate salt. With mentioning the term amlodipine the free base and all
pharmaceutically
acceptable salts are included.
Hydrochlorothiazide is a known therapeutic agent which is useful in the
treatment of
hypertension. It acts by inhibiting the kidneys' ability to retain water. This
reduces the volume of
the blood, decreasing blood return to the heart and thus cardiac output and,
by other
mechanisms, is believed to lower peripheral vascular resistance.
Amlodipine is known as a long-acting calcium channel blocker and used as an
anti-
hypertensive and in the treatment of angina. Like other calcium channel
blockers, amlodipine
acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral
resistance and
hence reducing blood pressure; in angina it increases blood flow to the heart
muscle.
The present invention particularly relates to a solid oral dosage form, which
contains a unit
dose in the range of about 10 to 250 mg, preferably in the range of about 10
to 40 mg,
particularly of 10, 20 or 40 mg of the active ingredient olmesartan medoxomil
and a unit dose in
the range of about 6 to 60 mg, preferably in the range of about 10 to 30 mg,
particularly of 12.5
or 25 mg of the active ingredient hydrochlorothiazide.
The present invention particularly relates to a solid oral dosage form, which
contains a unit
dose in the range of about 10 to 250 mg, preferably in the range of about 10
to 40 mg,
particularly of 10, 20 or 40 mg of the active agent olmesartan medoxomil and a
unit dose in the
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
6
range of about I to 20 mg, particularly of 5 or 10 mg of the active agent
amlodipine, calculated
as amlodipine free base.
The present invention particularly relates to a solid oral dosage form, which
contains a unit
dose in the range of about 10 to 250 mg, preferably in the range of about 10
and 40 mg,
particularly of 10, 20 or 40 mg of the active agent olmesartan medoxomil, a
unit dose in the
range of about 6 to 60 mg, preferably in the range of about 10 to 30 mg,
particularly of 12.5 or
25 mg of the active agent hydrochlorothiazide and a unit dose in the range of
about 1 to 20 mg,
particularly of 5 or 10 mg of the active agent amlodipine, calculated as
amlodipine free base.
The solid oral dosage forms containing olmesartan medoxomil in combination
with HCTZ
and/or amlodipine do also contain polyethylene glycol having a molecular
weight of 1000 -
10000 and are also preferably produced by the preferred process of the present
invention.
Polyethylene glycol
The pharmaceutical dosage form of the invention comprises at least one
stabilizer to prevent
the acid or base catalyzed decompositions of olmesartan medoxomil. The
preferred stabilizer
used in pharmaceutical composition is polyethylene glycol (PEG). The numbers
that are often
included in the names of PEGs indicate their average molecular weights. For
example, PEG
400 has an average molecular weight of 400 Da.
The stabilizer present in the pharmaceutical compositions of the present
invention is preferably
PEG having an average molecular weight from 1,000 to 10,000, more preferably
from 4,000 to
9,000, most preferably from 6,000 to 8,000.
The PEG is preferably present in an amount of 0.1 to 3 weight-%, more
preferably from 0.5 to
2.5 weight-%, e.g., about 1 weight-%, based on the total weight of the
composition.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
7
Further excipients
The solid oral dosage form according to the present invention can be in the
form of tablets,
capsules, caplets, sachets and soft capsules. In the case of tablets or
capsules, lubricants are
preferably added at the steps of filling or tabletting in consideration of
handling properties,
precision for filling and the like. Olmesartan medoxomil has potent adhesive
properties, and the
use of lubricants is therefore preferred. However, the use of the lubricants
causes delaying in a
dissolution time.
The pharmaceutical composition according to the present invention can further
comprise any
additional excipients and adjuvants, which are pharmaceutically acceptable,
and general
coating materials, which are preferably applied as a coating to the solid form
of the
pharmaceutical composition of the present invention. Such further excipients
and adjuvants are
known to the person skilled in the art, and can be referred to the standard
textbook by Fiedler
("Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete",
5th ed., 2002) or
to the "Handbook of Excipients", edited by the American Pharmaceutical
Association and Dr.
Arthur H. Kibbe, 3rd ed., 2000.
Preferably, the pharmaceutical composition of the solid oral dosage form
according to the
present invention comprises one or more diluents, binders, lubricants,
stabilizers and/or coating
materials and optionally colourants and/or surfactants, and in particular 1 to
90 weight-% of a
diluent, 0.5 to 10 weight-% of a binder, 0 to 3 weight-% of a lubricant, 0.1
to 3 weight-% of a
stabilizer, 0 to 5 weight-% of a coating material, and optionally 0 to 6
weight-% of a surfactant
and 0 to 3 weight-% colourants based on the total weight of the composition.
The further
excipients and adjuvants and optionally coating materials or colourants are
present in the
pharmaceutical composition of the present invention, such that the total
amount of the
pharmaceutical composition including the amount of the active agents results
in 100 weight-%.
In case of capsules, the capsule shell is excluded from the total amount of
the pharmaceutical
composition.
As diluent one or more components can be used, which contribute a part of the
tablet to reach
the necessary total mass of the tablet. Preferred diluents are inorganic
phosphates, like dibasic
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
8
calcium phosphate, sugars or sugar analogues and derivatives thereof, in
particular lactose,
such as lactose monohydrate or water-free lactose, dextrose, sorbitol,
mannitol, saccharose,
maltodextrin, isomalt and Tablettose . Celluloses like microcrystalline
cellulose or powdered
cellulose are further preferred diluents according to the present invention.
Preferably the
pharmaceutical composition according to the present invention comprises 1 to
90 weight-%,
more preferable 40 to 90 weight-%, in particular 60 to 85 weight-%, e.g. about
80 weigth-% of a
diluent, based on the total weight of the composition.
As binders, i.e. a compound enabling granulation of the active ingredient and
the further
excipients and adjuvants into granules, to be used in the pharmaceutical
composition of the
present invention, gelatine, povidone (N-vinylpropylidone polymer), copovidone
(copolymer of
N-vinyl-2-pyrrolidone and vinyl acetate) and in particular hydroxypropyl
cellulose or polyvinyl
pyrrolidone can be exemplified, the latter being particularly preferred. The
binder is preferably
present in an amount of 0.5 to 10 weight %, more preferably 0.5 to 5 weight %,
in particular I
to 3 weight-%, based on the total weight of the composition.
As lubricants to be used in the pharmaceutical compositions of the present
invention fatty acids
or fatty acid derivates, such as alkali and earth alkali salts of stearic,
lauric and/or palmitic acid,
in particular magnesium stearate, glycerol monostearate or glycerol
tristearate, glyceryl
palmitate/stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc
stearate, hydrogenated
plant oil (Lubritab ), natriumbenzoate, or polyethylen glycol are exemplified,
sodium stearyl
fumarate and magnesium stearate are especially preferred. The lubricant is
preferably present
in an amount of 0 to 3 weight-%, more preferably 0.5 to 2.5 weight-%, such as
about I weight-
based on the total weight of the composition.
The pharmaceutical composition of the present invention preferably comprises
at least 1
weight-%, more preferably 1-10 weight-% and even more preferably 1-5 weight-%
of a
disintegrant, based on the total weight of the composition. Some disintegrants
are known in the
art which may also be used as binders, diluents or as further excipients or
adjuvants different to
disintegrants. Preferably used disintegrants according to the present
invention are
croscarmellose sodium, low substituted hydroxypropyl cellulose, crospovidone,
sodium starch
glycolate and polacrilin potassium.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
9
Stabilizers used in pharmaceutical compositions to prevent the acid or base
catalyzed
decompositions of olmesartan medoxomil are, e.g. polyethylene glycol (PEG),
see supra. As
stabilizer to be used in the pharmaceutical compositions of the present
invention PEG having
the molecular weight 1000-10000, preferably 4000-9000, in particular 6000-8000
are especially
preferred. The stabilizer is preferably present in an amount of 0.1-3 weight-
%, more preferably
0.5-2.5 weight-%, such as about 1 weight-%, based on the total weight of the
composition.
In a specific embodiment, the pharmaceutical formulation of the invention does
not contain
stearic acid. In another embodiment, the pharmaceutical formulation of the
invention does not
contain stearic acid or a salt thereof.
Release profile
A particular advantage of the tablets of this invention is their advantageous
dissolution profile.
The tablets release a substantial portion of the active ingredient, olmesartan
medoxomil, within
20 or 30 minutes, using USP Apparatus II, in 900 ml 0.05 M Phosphate Buffer,
pH 6.8 at 37 C
and 50 rpm. In a first embodiment, the tablets exhibit the following release
of olmesartan
medoxomil: at least 15% within 5 minutes, at least 50% within 10 minutes, at
least 60% within
15 minutes, and at least 80% within 30 minutes, using USP Apparatus II, in 900
ml 0.05 M
Phosphate Buffer, pH 6.8 at 37 C and 50 rpm.
In a second embodiment related to the dissolution profile at pH 6.8, the
tablets exhibit the
following release of olmesartan medoxomil: 20 to 40% within 5 minutes, 50 to
75% within 10
minutes, 60 to 90% within 15 minutes, and at least 80% within 30 minutes,
determined
according to USP Apparatus II, in 900 ml 0.05 M Phosphate Buffer, pH 6.8 at 37
C and 50 rpm.
The tablets release a substantial portion of the active ingredient, olmesartan
medoxomil, within
or 15 minutes, using USP Apparatus II, in 900 ml 0.1 N HCI, pH 1.1 at 37 C and
50 rpm. In
a first embodiment, the tablets exhibit the following release of olmesartan
medoxomil: at least
30% within 5 minutes, at least 70% within 10 minutes, at least 80% within 15
minutes, and at
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
least 90% within 30 minutes, using USP Apparatus II, in 900 ml 0.1 N HCI, pH
1.1 at 37 C and
50 rpm.
In a second embodiment related to the dissolution profile at pH 1.1, the
tablets exhibit the
following release of olmesartan medoxomil: 40 to 70% within 5 minutes, 75 to
95% within 10
minutes and at least 85 to 100% within 15 minutes, using Apparatus II, in 900
ml 0.1 N HCI, pH
1.1 at 37 C and 50 rpm.
Use
According to another aspect of the invention, the solid oral dosage form of
the present
invention and all its embodiments are provided for the treatment or prevention
of hypertension
and diseases related thereto. Diseases related to hypertension are diseases
caused by high
blood pressure, like angina pectoris and diseases of the heart, the kidney and
the
cerebrovascular system.
Process of manufacture
Generally any known process in the art can be used for the manufacture of the
solid oral
dosage forms of the present invention.
Surprisingly, however, it has been found that solid oral dosage forms
comprising olmesartan
medoxomil and polyethylene glycol having an average molecular weight of about
1000 - 10000
formed from sized granules obtained by wet mass sifting during a wet
granulation process
show stable and excellently reproduceable immediate release profiles with each
batch.
Therefore, the present invention further provides a preferred process for the
manufacture of a
solid oral dosage form containing olmesartan medoxomil and preferably
polyethylene glycol
having an average molecular weight of about 1000 - 10000. The preferred
process of the
invention is a wet granulation process and more preferably the wet granules
obtained in the wet
granulation are subjected to wet sifting subsequently by wet granulation.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
11
In cases where formulations are prepared by a dry process, electrostatic
charges are
generated by physical irritations caused through processes such as
pulverization, agitation,
blending, granulation and the like, which in turn cause a decrease in fluidity
of pulverized,
blended or granulated materials, worsen handling properties, and decrease
precision for
content uniformity of an active ingredient.
The process for the manufacture of the solid oral dosage form according to the
present
invention is therefore preferably carried out in the presence of water, i.e.
it is preferably a wet
granulation method.
Further, and even more preferred, the wet granules are subjected to wet mass
sifting, in order
to obtain sized wet granules.
In a preferred embodiment of the present invention the pharmaceutical
composition is in the
form of a tablet which can be obtained by wet granulation followed by wet mass
sifting.
The granules obtained by the preferred process of wet sifting using a comill
of the present
invention have a particle size of 10 to 1 mm, preferably 7 to 3 mm, in
particular 4 mm after wet
sifting. The preferred sieves to be used during the wet mass sifting are mesh
7L156Q03746
with a square hole size of 3.96 mm x 3.96 mm .
In another embodiment of the present invention there is provided a process for
the manufacture
of the solid oral dosage form according to the present invention comprising
the steps of
a) dry mixing the active agent with a diluent,
b) adding an aqueous solution containing a stabilizer and a binder and
granulation of the
mixture to get granules
c) wet sifting using a comill, drying and additionally sifting the granules,
d) blending the granules together with a lubricant,
A disintegrant is preferably added either to the mixture of the active agent
and the diluent, i.e.
step (a) or to the blend of the granules and the lubricant, i.e. step (d).
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
12
All solid ingredients are preferably sieved before being employed in the
process. More
preferably the disintegrant and lubricant are sieved before being employed in
the process.
In a preferred embodiment of the process, the blend obtained in step (iv) is
compressed to
tablets. The compression of the granulates to tablet cores can be carried out
using a
conventional tabletting machine or a rotary compression machine. The tablet
cores may vary in
shape and be, for example, round, oval, oblong, cylindrical or any other
suitable shape, and
may also vary in size depending on the concentration of the therapeutic
agents. Preferably, the
tablets are coated by suitable coating methods well-known in the art.
According to a further aspect of the present invention, a solid oral dosage
form obtainable by
the preferred processes of the present invention is provided.
Within the present invention, percentages given are referred to the weight,
based on the total
weight of the composition, if not indicated otherwise or obvious for the
person skilled in the art.
There now follows a series of examples which serve to illustrate the
invention. The following
examples are not to be limiting:
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
13
Examples
Example 1
Olmesartan tablet
Ingredients Function mg/Tab % w/w
Intra Granular Material
Olmesartan medoxomil Active 40.0 9.5
PEG 6000 Stabilizer 4.0 1.0
Lactose monohydrate Diluent 291.0 69.5
Microcrystalline cellulose Diluent 47.5 11.3
Low substituted hydroxypropyl cellulose Disintegrant 12.0 2.9
Hydroxypropyl cellulose Binder 7.0 1.7
Extra Granular Material
Magnesium stearate Lubricant 3.0 0.7
Coating
Opadry 14.5 3.5
material
Total Weight 419.0 100.0
Preparation process:
The tablets of example 1 were prepared using a wet granulation process:
The active agent(s), the diluent, e.g. lactose monohydrate and
microcrystalline cellulose and
optionally the disintegrant, e.g. low substituted hydroxypropyl cellulose were
weighted out as
indicated in the table. The powder blend was then mixed, followed by
granulation with the
binder solution, e.g. aqueous solution of a binder e.g. PVP and/or
hydroxypropyl cellulose and
a stabilizer e.g. PEG 6000, in a mixer/granulator and sieved 7L156Q03746 to
form the
"intragranular material". The wet granules were dried (in a fluid bed dryer)
until a LOD (loss of
drying) of typically 2.5% or less was reached, followed by passing the dried
granules through a
round hole screen 7LO55RO3732 with a diameter of 1.40 mm using a comill.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
14
In a final step, the lubricant magnesium stearate and optionally the
disintegrant, e.g.
croscarmellose sodium were weighted and mixed with the granule blend described
above. This
final blend was then compressed into tablets using the tablet press and then
optionally coated
with the coating material Opadry.
Example 2
Olmesartan tablet
Ingredients Function mg/Tab % w/w
Intra Granular Material
Olmesartan medoxomil Active 40.0 9.6
PEG 6000 Stabilizer 4.0 1.0
Lactose monohydrate Diluent 287.5 69.1
Microcrystalline cellulose Diluent 49.0 11.8
PVP Binder 11.0 2.6
Extra Granular Material
Croscarmellose sodium Disintegrant 7.0 1.7
Magnesium stearate Lubricant 3.0 0.7
Coating
Opadry 14.5 3.5
material
Total Weight 416.0 100.0
The tablets were prepared using a process similar to the process described in
example 1.
CA 02785920 2012-06-28
WO 2011/083112 PCT/EP2011/050061
Example 3
Olmesartan/Hydrochlorothiazide tablet
Ingredients Function mg/Tab % w/w
Intra Granular Material
Olmesartan medoxomil Active 20.0 9.1
Hydrochlorothiazide Active 25.0 11.3
PEG 6000 Stabilizer 2.0 0.9
Lactose monohydrate Diluent 131.7 59.5
M icrocrysta I line cellulose Diluent 24.0 10.9
PVP Binder 5.5 2.5
Extra Granular Material
Croscarmellose sodium Disintegrant 3.5 1.6
Magnesium stearate Lubricant 1.5 0.7
Coating
Opadry 7.8 3.5
material
Total Weight 221.0 100.0
The tablets were prepared using a process similar to the process described in
example 1.
Example 4
Tablets prepared according to example 1 were further analyzed. A dissolution
profile of the
active ingredient was obtained by dissolving a tablet in an USP-Apparatus II
in 900 ml 0.05M
phosphate buffer pH 6.8 or OA N HCI at 37 C and stirring speed of 50 rpm. The
dissolution
tests were carried out using USP-Apparatus II.
The release profile is shown in Figure 1 and 2.
