Note: Descriptions are shown in the official language in which they were submitted.
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IMMEDIATE RELEASE DOSAGE FORM OF BOSENTAN AND PROCESS OF
MANUFACTURING SUCH
FIELD OF THE INVENTION
The present invention relates to an immediate release oral pharmaceutical
dosage
form containing a high dose of a poorly water-soluble active ingredient. In
particular, the
present invention is directed to immediate release dosage forms containing
bosentan.
BACKGROUND OF THE INVENTION
The compound 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-
(pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide, also known as bosentan,
is a dual
endothelin receptor antagonist with affinity for both endothelin ETA and ETB
receptors
useful for the treatment or prevention of endothelin-receptor mediated
disorders, such as
pulmonary arterial hypertension ("PAH") in individuals with World Health
Organization
functional Class III or IV primary pulmonary hypertension and pulmonary
hypertension
secondary to scleroderma or congenital heart disease or human immunodeficiency
virus
(HIV) patients.
The bosentan monohydrate molecule has the following chemical formula:
H3C `O NH O,CIi3
O
. I / O
H3C CH N I I H2O
3N \ /
` N O
OH
Bosentan monohydrate is poorly soluble in water (1.0 mg/100 ml). This leads to
great difficulty in the formulation of immediate release dosage forms
containing such an
active ingredient. Poor water solubility and high dose content make it
difficult to develop a
robust formulation and manufacturing process.
Poor dissolution behaviour is observed for many water-insoluble drugs. Such
low
solubility and poor dissolution can often result in low bioavailability,
particularly given
limited transit times through the gastrointestinal tract.
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According to the World Standard Drug Database, the commercial available
formulation of bosentan, marketed under the name Tracleer , has the following
composition: bosentan (125 or 62.5 mg), corn starch, glyceryl behenate,
magnesium stearate,
povidone, pregelatinized starch and sodium starch glycolate; and film coating:
ethylcellulose, hydroxypropylmethylcellulose, iron oxide red, iron oxide
yellow, talc,
titanium dioxide and triacetin.
The preparation of bosentan is disclosed in the following patents: European
Patent
No. 0 526 708, Canadian Patent No. 2,071,193, United States Patent No.
5,292,740, Canadian
Patent No. 2,397,258 and United States Patent No. 5,883,254.
Various techniques to prepare immediate release dosage forms of drug products
such as bosentan have been described in the art.
For example, Canadian Patent Application No. 2,607,098, entitled "Dispersible
tablet", discloses a dispersible tablet, wherein the monohydrate form of
bosentan is used, for
paediatric formulation. The tablet disintegrates completely in water at 15-22
C in 5 minutes
or less. The dispersible tablets were obtained by using the method of direct
compression.
International Patent Application Publication No. WO 2004/012700, entitled
"Novel
Dosage Form', discloses a dosage form comprising a high dose, high solubility
active
ingredient, as modified release and a low dose active ingredient as immediate
release where
the weight ratio of immediate release active ingredient and modified release
active
ingredient is from 1:10 to 1:15000 and the weight of modified release active
ingredient per
unit is from 500 mg to 1500 mg. A process for preparing the dosage form is
also disclosed
(bosentan is not exemplified).
The pharmaceutical industry employs various methods for compounding
pharmaceutical agents into tablet formulations. Wet granulation methods are
known in the
art and have been described in detail by Dilip M. Parikh (Handbook of
Pharmaceutical
Granulation Technology, 2nd ed., 2005 ISBN: 0824726472). Wet granulation is
one of the most
prevalent methods, which can be used where the flow properties of a compound
such as an
active pharmaceutical ingredient ("API") are poor which result in content
uniformity issues
when formulated as a dry blend. Wet granulation is commonly used to improve
the
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processing characteristics of a powder blend, including improved flowability,
content
uniformity and more uniform particle size.
Canadian Patent Application No. 2,326,349, entitled "Process for the
manufacture of
(sub)micronized particles by dissolving in compressed gas and surfactants",
describes the
process for manufacturing a pulverous preparation of submicronized
biologically active
compounds (such as bosentan) using conventional powder processing techniques.
United States Patent Application 2006/0018934 to Vaya et at., issued January
26,
2006, entitled "Novel drug delivery system," discloses a novel modified
release dosage form
comprising a high solubility active ingredient, and optionally, another active
ingredient as
an immediate release form, as well as the process for preparing same.
Canadian Patent Application No. 2,603,316, entitled "Combined-step process for
pharmaceutical compositions", relates to a process for the solid oral
pharmaceutical
formulation of the pharmaceutically active ingredient, levetiracetam. The
process
exemplified comprises a wet granulation of levetiracetam and simultaneous
fluid bed
drying such that it is simultaneously dried, thus preventing it from becoming
a paste.
United States Patent Application 2008/0026062 to Farr et al., issued January
31, 2008,
entitled "Pharmaceutical compositions including nano-sized active agent,"
describes a
pharmaceutical composition which comprise a water-soluble or partially water-
soluble
polymer matrix; and a plurality of nano-sized particles of active agent which
are sparingly
water-soluble to water-insoluble dispersed in the water-soluble or partially
water-soluble
polymer matrix. The particulate pharmaceutical composition can be micronized
or in the
form of a film that can be rolled up. If micronized, the individual micron-
sized particles can
have a plurality of nano-sized particles present in the micron-sized
particles.
Similarly, United States Patent Application 2008/0026040 to Farr et al.,
issued
January 31, 2008, entitled "Active agent-releasing dosage forms," describes a
pharmaceutical
composition which is provided having a plurality of polymeric film layers heat
sealed
together as a multilayer structure and having an active agent dispersed within
the
multilayer structure. The multilayer structure is configured to release the
active agent upon
administration to a subject, either in a controlled release or immediate
release manner.
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International Patent Application Publication No. WO 2009/ 004374, entitled
"Process
for introduction of hydroxyethoxy side chain in bosentan", relates to an
improved process
for the preparation of Bosentan. In particular it relates to a process for
preparing bosentan
substantially free from impurities and to a pharmaceutical composition
comprising
bosentan and its use in the treatment of endothelin-receptor mediated
disorders.
Bosentan monohydrate is currently being marketed as a tablet under the name
Tracleer for the treatment of PAH, a deadly disease if untreated.
The need to use a high dose of a poorly water soluble active ingredient, such
as
bosentan, with an immediate release dosage form makes it very difficult to
manufacture the
product to obtain reproducible results.
Therefore, a need exists for a dosage form providing a highly insoluble drug
in an
immediate release dosage forms.
SUMMARY OF INVENTION
According to one aspect of the present invention, there is provided a
formulation
comprising a high dose of a poorly water soluble active ingredient, such as
bosentan, which
gives accurate dosing and immediate release dosage forms.
According to a further aspect of the present invention, there is provided a
wet
granulation process for preparing a novel granulate comprising a high dose of
a poorly
water soluble active ingredient, such as bosentan, that can be used in solid
oral dosage
forms such as immediate release tablets.
In a further aspect of the present invention there is provided an immediate
release
oral pharmaceutical dosage form comprising a high dose of a poorly water
soluble active
ingredient wherein the in vitro dissolution rate of the dosage form provides
at least 90% of
the active ingredient dissolved within 30 minutes as measured by USP Paddle
Method at 50
rpm at 900 ml of dissolution buffer with 1 % SDS at 37 C.
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There is further provided a process for the manufacturing of an immediate
release
oral pharmaceutical dosage form comprising a high dose of poorly water soluble
active
ingredient, preferably bosentan monohydrate, comprising the following steps:
(1) screening the active ingredient and one or more pharmaceutically
acceptable
excipients;
(2) dry mixing the content of step (1);
(3) preparing a binder solution;
(4) adding the binder solution of step (3) to the dry blend of step (2);
(5) performing a granulation;
(6) drying the wet mass obtained from step (5);
(7) screening the granules obtained from step (6);
(8) adding pharmaceutically acceptable excipients to the granules of step (7);
(9) mixing the mixture of step (8) using a suitable blender;
(10) compressing the content of step (9).
The present invention is further related to the use of said dosage form for
the
treatment or prevention of endothelin-receptor mediated disorder, wherein the
disorder is
pulmonary arterial hypertension.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an immediate release oral pharmaceutical
dosage
form of a high dose, poorly water-soluble active ingredient. The process for
manufacturing
the immediate release oral pharmaceutical dosage form of the present invention
utilizes a
wet granulation step and a fluid bed drying step in order to prepare good
granules with
excellent flow properties and desired dissolution profiles.
The term "immediate release" as used herein in relation to the compositions
according to the present invention, or used in any other context herein, means
release which
is not a modified release and releases 90%, or more, of the active ingredient
within 30
minutes. The term "immediate release dosage form' as used herein can be
described as a
dosage form which allows the drug to dissolve in the gastrointestinal
contents, with no
intention of delaying or prolonging the dissolution or absorption of the drug
(as per US
FDA guideline for "SUPAC-MR : Modified Release Solid Oral Dosage Forms").
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The term "dosage form" is intended to denote any form of the formulation that
contains an amount sufficient to achieve a therapeutic effect with a single
administration.
The term "active ingredient" refers to an Active Pharmaceutical Ingredients
(API)
which are active chemicals used in the manufacturing of drugs. The active
agent can be a
therapeutic, a prophylactic, or a diagnostic agent. These terms of art are
well-known to the
person skilled in the pharmaceutical and medicinal arts.
The term "high dose" as used herein refers to the percentage by weight of
active
ingredient present in the dosage form. In the preferred embodiments of the
present
invention, the high dose immediate release pharmaceutical dosage form
comprises more
than about 70% by weight of the active ingredient.
In a preferred embodiment of the present invention, the active ingredient in
the
dosage form is bosentan monohydrate or a pharmaceutically acceptable salt
thereof.
In addition to the active ingredient, the pharmaceutical composition of the
present
invention contains pharmaceutically acceptable excipients 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, and acidifying agents. As understood by a person
skilled in the art,
these excipients are conventional excipients which are well known in the
pharmaceutical
art.
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.
Solid pharmaceutical compositions that are compacted into a dosage form, such
as a
tablet, may include excipients whose functions include helping to bind the
active ingredient
and excipients together before compression. These excipients are referred to
as binders.
Suitable binders include, for example, starch, povidone,
hydroxypropylmethylcellulose,
pregelatinized starch, hydroxypropylcellulose and/or mixtures of the
foregoing.
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The preferred lubricants to be used according to the present invention,
include the
following: magnesium, aluminum or calcium stearate, stearic acid, sodium
stearyl fumarate,
talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate, and
mixtures
thereof.
The dissolution rate of a compacted solid pharmaceutical composition in the
patient's stomach may be increased by the addition of a disintegrant to the
composition.
Suitable disintegrants according to the present invention include, for
example,
croscarmellose sodium, sodium starch glycolate, maize starch, CMC-Ca, CMC-Na,
microcrystalline cellulose, cross-linked PVP, alginic acid, sodium alginate,
pregelatinized
starch and guar gum.
A composition for tabletting or capsule filling may be prepared by wet
granulation.
In wet granulation, the active ingredient and excipients in powder form are
blended and
then further mixed in the presence of a liquid, typically water, that causes
the powders to
clump into granules. The granules are screened and/or milled, dried and then
screened
and/or milled to the desired particle size. The granules may then be
compressed into
tablets, or other excipients may be added prior to tabletting, such as a
glidant and/or a
lubricant.
In a preferred embodiment of the present invention, the immediate release oral
pharmaceutical dosage form comprises a high dose of bosentan monohydrate as
the active
ingredient (a poorly water soluble active ingredient) or a pharmaceutically
acceptable salt
thereof, and the following pharmaceutically acceptable excipients:
pregelatinized starch,
povidone K-30, sodium starch glycolate and magnesium stearate.
Oral dosage forms which may be employed with the present invention include
granules, spheroids or pellets in a capsule or in any other suitable solid
form. Preferably,
however the oral dosage form is a tablet.
The oral dosage form preferably contains a dose of about 125 mg of bosentan
monohydrate. Alternatively, the dosage form may contain molar equivalent
amounts of
other pharmaceutically acceptable bosentan salts.
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The granules can be manufactured in accordance with conventional techniques in
which the active ingredient and other pharmaceutically acceptable excipients
are mixed and
granulated by adding solution of binder in a low or high shear mixer or by
fluidized bed
granulation. The granules are then dried, preferably in a fluidized bed dryer.
The dried
granules are sieved and mixed with lubricants and disintegrants.
Alternatively, the
manufacture of granules can be made by direct mixing of the directly
compressible
excipients or by roller compaction.
Bosentan monohydrate is poorly soluble in water (1.0 mg/100 ml) and poorly
soluble in aqueous solutions at low pH, particularly when present at a high
dose.
Notwithstanding this, the present invention was able to obtain an immediate
release dosage
form using a wet granulation process to obtain good granules and flow
properties.
Povidone K-30 plays a very important role as binder used in solution in order
to get good
granules when used in the range of about 2 to about 10 % w/w of the
composition.
In one embodiment of the present invention, there is provided an immediate
release
oral pharmaceutical dosage form of a high dose poorly soluble active
ingredient, wherein
the in vitro dissolution rate of the dosage form provides at least 90% of the
active ingredient
dissolved within 30 minutes as measured by USP Paddle Method at 50 rpm at 900
ml of
dissolution buffer with 1 % SDS at 37 C.
In another embodiment of the present invention, there is provided an immediate
release oral pharmaceutical dosage form of', a high dose poorly soluble active
ingredient,
wherein said active ingredient is fully dissolved within 45 minutes as
measured by USP
Paddle Method at 50 rpm at 900 ml of dissolution buffer with 1% SDS at 37 C.
In one embodiment of the present invention, the process for manufacturing an
oral
pharmaceutical dosage form containing a high dose of a poorly water soluble
active
ingredient in an immediate release form comprises the following steps:
(1) screening the active ingredient and pharmaceutically acceptable
excipients;
(2) dry mixing the content of step (1);
(3) preparing a binder solution;
(4) adding the binder solution of step (3) to the dry blend of step (2);
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(5) performing a granulation;
(6) drying the wet mass obtained from step (5);
(7) screening the granules obtained from step (6);
(8) adding to the granules of step (7) pharmaceutically acceptable excipients;
(9) mixing the mixture of step (8) using a suitable blender; and
(10) compressing the content of step (9).
In a preferred embodiment of the present invention, the active ingredients and
pharmaceutically acceptable excipients for use in step (1) are the following:
bosentan or a
pharmaceutically acceptable salt, such as the sodium salt (t he active
ingredient) and a
diluent, a binder and a disintegrant (the pharmaceutically acceptable
excipients).
Preferably, the bosentan is in the monohydrate form, and the diluent is
pregelatinized
starch, the binder is povidone K-30, and the disintegrant is sodium starch
glycolate.
In one embodiment, the content of step (1) is passed through a 20 mesh manual
screen and then dry mixed in small high shear for 3 minutes (step (2)). The
binder solution
is prepared by adding povidone K-30 to purified water and mixing for 30
minutes or until a
clear solution is obtained. In step (6), the wet mass is dried in a small
fluid bed dryer for a
period of about 45 minutes. In step (7) the granules obtained from step (6)
are passed
through 0.045 inches comill screen at low speed, wherein pregelatinized starch
and sodium
starch glycolate are added to said granules and mixed for 2 minutes using a
suitable blender
(steps (8) and (9)), then a lubricant, such as magnesium stearate, is passed
through a 40
mesh manual screen and added and mixed with the mixture obtained from step
(9), prior to
compression (step (10).
In a further embodiment, the process for preparing the immediate release oral
pharmaceutical dosage form containing a high does of bosentan monohydrate
comprises the
following steps:
(1) screening bosentan monohydrate and pregelatinized starch, povidone K-30
and sodium starch glycolate through a 20 mesh manual screen;
(2) dry mixing the content of step (1) in a small high shear for 3 minutes;
(3) preparing a binder solution by adding povidone K-30 to a sufficient
quantity of purified water and mixing for 30 minutes or until a clear
solution is obtained;
(4) adding the binder solution of step (3) to the dry blend of step (2);
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(5) performing a granulation;
(6) drying the wet mass obtained from step (5) in a small fluid bed for a
period
of about 45 minutes;
(7) screening the granules obtained from step (6);
(8) adding pregelatinized starch and sodium starch glycolate to the granules
of step (7);
(9) mixing the mixture obtained from step (8) for 2 minutes using a suitable
blender;
(10) screening magnesium stearate through a 40 mesh manual screen;
(11) mixing the content obtained from step (9) with the content from step (10)
for 3 min using a suitable blender; and
(12) compressing the content obtained from step (11).
The following example illustrates the preferred embodiment and various aspects
of
the present invention.
Example 1
Immediate Release Dosage Form of Bosentan According to a Preferred Embodiment
of the
Present Invention
The required quantities of bosentan monohydrate, pregelatinized starch,
povidone
and sodium starch glycolate are passed through a 20 mesh manual screen and
then the
content is dry mixed in a small high shear for.3 minutes.
The binder solution is prepared by adding povidone K-30 to a sufficient
quantity of
purified water and mixing for 30 minutes or until a clear solution is
obtained.
The binder solution is then added to the dry blend mixture followed by
granulation.
The wet mass of obtained granules are then dried in a small fluid bed for a
period of about
45 minutes and then passed through 0.045 inches co-mill screen at low speed.
The required quantity of pregelatinized starch and sodium starch glycolate are
added to obtain granules and mixed for 2 minutes using a suitable blender.
The granulate is then lubricated by mixing the required quantity of magnesium
stearate, which is screened through a 40 mesh manual screen, then added to the
obtained
mixture, and mixed for 3 min using a suitable blender prior to compression.
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The tablets are compressed on a suitable tabletting machine.
The formulation of Example 1 is set out in Table 1 below.
Table 1- Formulation According to the Preferred Embodiment
Name of Ingredients
No. Intra-granular components % w/w mg/tablet
1. bosentan monohydrate 73.53 125.0
2. pregelatinized starch 9.97 16.949
3. povidone K-30 3.0 5.1
4. povidone K-30 3.0 5.1
5. sodium starch glycolate 5.0 8.5
Extra-granular components
6. pregelatinized starch 5.0 8.5
7. magnesium stearate 0.5 0.85
TOTAL 100 170
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:
o Speed: 50 rpm
o Media: purified with 1 % SDS
o Dissolution medium (buffer) - 900m1
o Temperature: 37 C.
The dissolution results are set out in Table 2 below.
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Table 2 - Dissolution Rate of Bosentan Monohydrate Formulation of Example 1
Time (min) Reference product Tablets from
(% dissolved) Example I
(% dissolved)
70 49
91 75
97 90
100 99
45 100 102
60 101 103
