Note: Descriptions are shown in the official language in which they were submitted.
CA 02671778 2009-07-10
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 poorly soluble active ingredient, more specifically the present
invention is directed to
dosage forms containing Bosentan_
BACKGROUND OF THE INVENTION
Bosentan is used for the treatment or prevention of endothelin-receptor
mediated disorder, as
pulmonary arterial hypertension (PAH).
Bosentan monohydrate being a poorly water soluble drug (1mg/100mi), leads to
the great difficulty
in the formulation of immediate release dosage form containing such. Poor
water solubility and high
dose content makes it difficult to develop a robust formulation and
manufacturing process.
Poor dissolution behavior is observed for many water-insoluble drugs, which
limits their
bioavallability. Such low solubility can often result in low bioavailability,
particularly given limited
transit times through the gastrointestinal tract.
The Bosentan molecule has the following chemical formula:
0s0
'NH C1~CH3
HaC I õr
CHI N I Hz0
N 0
OH
~
BOSENTAN (Tracleer ) is a dual endothelin receptor antagonist important in the
treatment of
pulmonary artery hypertension (PAH, functional class III or IV), accordingly
to World Health
Organisation (WHO) and secondary to congenital heart disease and to human
immunodeficiency
virus (HIV).
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The preparation of Bosentan is disclosed in the following patents EP 0 526
708, CA 2,071,193, US
5,292,740, CA 2,397,258 and US 5,883,254.
Accordingly to the World Standard Drug Database, the commercial available
formulation of Tracleer
has the following composition' Bosentan (the API) (125 or 62.5mg) and tablet
contents: 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 various techniques to make immediate release dosage form of drugs as
described in prior art
are as follows:
CA 2,607,098 disclosed a dispersible tablet, wherein Bosentan monohydrate form
is used for
pediatric formulation, which disintegrates completely in water at 15-22 C in
no more than 5 minutes.
The dispersible tablets were obtained by using the method of direct
compression.
WO 2004/012700 discloses a dosage form comprising of 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, but bosentan is not
exemplified).
The pharmaceutical industry employs various methods for compounding
pharmaceutical agents in
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,
2"d ed., 2005 ISBN00824726472). In particular, 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 processing characteristics of a powder blend,
including improved
flowability, content uniformity and more uniform particle size.
CA 2,326,349 describes the process for manufacturing a pulverous preparation
of a submicronized
biologically active compounds (such as bosentan) using conventional powder
processing
techniques.
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US 20060018934 discloses a novel modified release dosage form comprising of a
high solubility
active ingredient and optionally comprise another active ingredient as an
immediate release form
and process for preparing.
CA 2603316 relates to a process for the solid oral pharmaceutical formulation
of a pharmaceutically
active ingredient, levetiracetam, which is exemplified, comprising a wet
granulation of levetiracetam
and simultaneous fluid bed drying such that it is simultaneously dried, thus
preventing it from
becoming a paste.
US 20080026062 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, US 20080026040 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.
WO 2009/004374 relates to an improved process for the preparation of Bosentan.
In particular it
relates to a process for preparing bosentani 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 for the treatment
of PAH, a deadly
disease if untreated. The need to use active ingredients with different
mechanisms of action,
especially with immediate release dosage form, since the dose of Bosentan is
very high it makes it
very difficult to manufacture the product to obtain reproducible results.
Therefore, accordingly a need exists for a dosage form providing a highly
insoluble drug in an
immediate release dosage forms.
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An object of the present invention is a formulation, which gives accurate
dosing and is prepared by
advantageous and simple process.
A further object of the present invention is to provide a wet granulation
process for making such a
novel granulate that may be used in solid oral dosage forms as immediate
release tablets.
SUMMARY OF THE INVENTION
An object of the present invention provides for an immediate release oral
pharmaceutical dosage
form of a high dose poorly soluble active ingredient, wherein the in vitro
dissolution rate of the said
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 370 C.
Preferably, the poorly soluble active ingredient is Bosentan or a
pharmaceutically acceptable salt
thereof.
More preferably, wherein said active ingredient is in monchydrate form, which
is present in a high
dose about of 125 mg.
Preferably, the process used to make the immediate release oral pharmaceutical
dosage form is a
wet granulation process which allows to get good granules and flow properties.
Another object of the present invention provides for 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 370C.
USP Paddle Method is the Paddle Method described, e.g., in U.S Pharmacopoeia
XXII (1990).
An object of the present invention provides an immediate release oral
pharmaceutical dosage form
of a high dose poorly soluble active ingredient, wherein said active
ingredient is fully dissolved
within 60 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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Yet another object of the present invention also provides a process for the
preparation of an
immediate release oral pharmaceutical dosage form containing a high dose of a
poorly soluble
active ingredient, wherein said process comprises the following steps;
(1) - screening the active ingredient and pharmaceutical 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 (8)1-
(8) - adding to the granules of step (7) pharmaceutically acceptable
excipients;
(9) - mixing the mixture of step (8) using a suitable blender;
(10) - compressing the content of step (9).
Preferably, the poorly soluble active ingredient is Bosentan monohydrate and
according to the
process, wherein the content from step1 comprises: as active pharmaceutical
ingredient -
Bosentan monohydrate and as pharmaceutically acceptable excipients:
pregelatinized starch,
Povidone-K30, Sodium starch glycolate and magnesium stearate.
Also, preferably the content of step (1) is passed through a 20 mesh manual
screen and than dry
mixed in small high shear for 3 minutes, wherein the binder solution is
prepared by adding
Povidone K30 to purified water and mixing for 30 minutes or until a clear
solution is obtained,
wherein the drying of the wet mass is carried out in a small fluid bed dryer
for a period of about 45
minutes and wherein the granules obtained from step (7), are passed through
0.045 inches comill
screen at low speed, wherein a pregelatinized starch and sodium starch
glycolate are added to said
granules and mixed for 2 minutes using a suitable blender, then a lubricant is
added and mixed with
mixture obtained from step (9), prior to compression, such as Magnesium
stearate which is passed
through a 40 mesh manual screen, added to the mixture obtained from step (9)
and mixed for 3
minutes using a suitable blender, prior to compression.
An object of the present invention also provides a process for the preparation
of an immediate
release oral pharmaceutical dosage form containing high dose of a poorly
soluble active ingredient.
wherein the in vitro dissolution rate of the said 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
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dissolution buffer with 1% SDS at 37 C, wherein said p cess comprising wet
granulation step and
fluid bed drying step as follows:
(1) - screening Bosentan monohydrate and pr gelatinized starch, povidone 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 Povione K30 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);
(5) - performing a granulation;
(6) - drying the wet mass obtained from step (5) in small fluid bed for a
period of
about 45 minutes;
(7) - screening the granules obtained from step (6);
(8) - adding to the granules of step (7) pregelatinized starch and sodium
starch glycolate;
(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;
(12) - compressing the content obtained from step (11).
The present invention is further related to a prrcess for the manufacturing of
an oral
pharmaceutical dosage form of a high dose of Bosentan monohydrate in an
immediate release
form, comprising a wet granulation step and a fluid bed drying step.
The present invention is further related to use of said di sage form for the
treatment or prevention of
endothelin-receptor mediated disorder, wherein the disorder is pulmonary
arterial hypertension.
DETAILED DESCRIPTION OF THE INVENTION
The resent invention relates to an Immediate r
p s release oral pharmaceutical dosage form of a high
dose poorly soluble active ingredient, using in the pro cess of manufacturing
the wet granulation
step and a fluid bed drying step in order to get good granules with excellent
flow properties and
desired dissolution profiles.
The term "immediate release" as used herein in relatipn to composition
according to the invention
or used in any other context means release which is (not modified release and
releases more than
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90% of the active ingredient within 30 minutes. The teen "immediate release
dosage form" as used
herein can be described as 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').
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 refers to the % with respect to total dosage form
of weight.
In a preferred embodiment of the invention, the present invention provides a
dosage form wherein
the said active ingredient 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.
Preferably, according to the present invention 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 referred to as
binders and other excipients together before the compression.
Preferably, according to the present invention suitable binders include for
example starch,
povidone, hydroxypropylmethylcellulose, pregelatinized starch,
hydroxypropylcellulose and/or
mixtures of the foregoing.
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Preferably, according to the present invention for suitable lubricants are
selected from the group
consisting. of. Mg-, Al- or Ca-stearate, steanc 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.
Preferably, according to the present invention suitable disintegrants include
for example
croscarmellose sodium, sodium starch glycolate, maize starch, CIVIC-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 step. 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 aspect of the invention, an immediate release oral
pharmaceutical dosage form of a
high dose poorly soluble active ingredient comprises as active ingredient
Bosentan monohydrate or
a pharmaceutically acceptable salt thereof and as pharmaceutically acceptable
excipients:
pregelatinized starch, povidone-K30, 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.
In a preferred aspect of the invention, oral dosage form preferably contains a
dose about of 125 mg
of Bosentan monohydrate. Alternatively, the dosage form may contain molar
equivalent amounts of
other pharmaceutically acceptable bosentan salts.
The granules can be manufactured in accordance with usual 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
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lubricants and disintegrants. Alternatively, the manufacture of granules can
be made by direct
mixing of the directly compressible excipients or by roller compaction.
Since Bosentan monohydrate is poorly soluble in water (1 mg/100ml) and in
aqueous solutions at
low pH, and especially in high dose, it was an achievement to obtain an
immediate release dosage
form, using wet granulation process to get 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 (2-10) % w/w in the composition.
According to an object of the present invention, the process for the
manufacturing of an oral
pharmaceutical dosage form of a high dose of Bosentan monohydrate in an
immediate release
form comprises the following steps:
(1) - screening the active ingredient and pharmaceutical 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 to the granules of step (7) pharmaceutically acceptable
excipients;
(9) - mixing the mixture of step (8) using a suitable blender;
(10) - compressing the content of step (9).
The following example illustrates the preferred embodiment and various aspects
of the present
invention.
Example I
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 dry mixed
the content in a
small high shear for 3 minutes;
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The binder solution is prepared by adding Povidone K30 to a sufficient
quantity of purified water
and mixing for 30 minutes or until a clear solution is obtained.
Then adding the binder solution to the dry blend mixture performing a
granulation. The wet mass of
obtained granules are then dried in small fluid bed for a period of about 45
minutes and then
passed through 0.045. inches comill 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
screening through a 40 mesh manual screen; then added to the obtained mixture
mixing for 3 min
using a suitable blender prior to compression.
The tablets are compressed on a suitable tabletting machine.
The formulation of Example 1 is set out in Table I below.
Table I
Formulation according to the present invention
Name of Ingredients
No. Intra-granular components % wlw mgltablet'
1. Bosentan monohydrate 73.53 125.0
2. Pregelatinized starch 9.97 16.949
3. Povidone-K30 3.0 5.1
4. Povidone-K30 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
E TOTAL 100 170
The tablets obtained from Example 1 were subsequently tested for in vitro
dissolution rate,
measured by Apparatus If (USP Paddle Method), using the following parameters:
CA 02671778 2009-07-10
Speed: 50 rpm
Media: purified with 1 % SDS
Dissolution medium (buffer) - 900ml
Temperature: 37 C.
The dissoluti n results are set out in Table 2 below.
T bole 2
Dissolution Rate of Bosentan Monohydrate Formulation of Example 1
Time (min) Reference product Tablets from
(% dissolved) Example I
(% dissolved)
10 70 49
91 75
97 90
100 99
45 100 102
60 101 103
25
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