Note: Descriptions are shown in the official language in which they were submitted.
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WO 00/66130 1 PCT/FR00/01086
Pharmaceutical comaosition in a unit form containing acetvlsalicvlic acid and
cloaido4rel hvdropenosulahate
The present invention relates to a pharmaceutical composition provided in a
unit
galenic form, containing a combination of active principles with platelet anti-
aggregating activity, which consists of aspirin and of clopidogrel
hydrogenosulphate.
The unit galenic form can be administered orally, and preferably consists of a
tablet, a
gelatin capsule or a single-dose sachet.
In the compositions according to the invention, the aspirin is used in its
acid form, and
the clopidogrel hydrogenosulphate can be used in either of its polymorphic
forms
which are known to date, and which are named Form 1 (F1 ) or Form 2 (F2).
Clopidogrel hydrogenosulphate Form 1 is the salt described in patent EP 281459
and
clopidogrel hydrogenosulphate Form 2 is that described in patent application
FR 98/07464.
The therapeutic interest of combining aspirin and clopidogrel is described,
inter alia, in
patent application WO 97/29753.
Pharmaceutical compositions are mentioned therein, without however ever
specifying
that the pharmaceutically acceptable salt used is the hydrogenosulphate of
clopidogrel.
This document indicates anyway that the composition can be used parenterally
or
orally, and that it is possible to administer the active principles according
to four
methods of administration, i.e. both orally, both parenterally or one orally
and the other
parenterally, or conversely.
However, no pharmaceutical composition which is provided in a unit galenic
form, and
which is suitable for a concomitant administration of aspirin and of
clopidogrel
hydrogenosulphate is described.
Given that it has been clearly determined that the doses of each one of the
platelet
anti-aggregating constituents of the combination can be prebound, and do not
require
adjusting as a function of the patients to be treated, it has been found to be
useful and
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advantageous to have a single medicinal form which can be administered orally,
and
which contains these two active principles.
Several combination studies have been carried out with aspirin and other
active
principles, but many drawbacks have been demonstrated during the production of
the
galenic forms, in particular tablets containing aspirin combined with salts of
an active
principle.
Thus, the publication which appeared in the International Journal of
Pharmaceutics
(Netherlands) 1984, 18, 287-298, demonstrates the incompatibility between
aspirin and
other solid active principles. Experimental confirmation of these models was
demonstrated using aspirin and mepyramine maleate. The addition of mepyramine
maleate to aspirin decreases its melting point, with a resulting effect on the
rate of
decomposition of the aspirin in this mixture. It has thus been observed that a
decrease
in the melting point leads to the degradation of the active principles in this
type of
combination.
All these drawbacks, which are well known to the person skilled in the art,
would, as a
result, not have prompted a combination of aspirin and a base salt such as
clopidogrel
hydrogenosulphate to be prepared in the same tablet or the same gelatin
capsule or in
the same sachet.
Entirely unexpectedly and surprisingly, it was possible, according to the
invention, to
prepare a pharmaceutical composition provided in a unit galenic form,
containing
aspirin in combination with another active principle which consists of a base
salt, more
specifically clopidogrel hydrogenosulphate, by using various manufacturing
methods
and various techniques, which are well known to the person skilled in the art.
Thus, the tablets according to the invention can be produced by various
manufacturing
methods, such as for example:
- the method by direct tabletting, in which the active principles and the
selected
excipients are mixed. The mixture obtained is sieved (calibrated) on a screen
of
predefined mesh size, to homogenize the particle sizes of the constituents.
Mixing is
carried out again to ensure good homogeneity of the active principles.
Specific
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excipients (example: a flow agent) and a lubricant are added and mixed. The
final
mixture obtained is then tabletted.
- the method with pregranulation, in which the granulation consists in
combining and
making dense the active principles and the selected excipients (internal phase
constituents), to obtain, after calibration on a given screen, a grain
consisting of
particles which are homogeneous in active principle content, which is suitable
for
compression, after adding the specific excipients (external phase
constituents). The
granulation makes it possible to improve the rheological properties of the
mixture to be
compressed, and the physical properties of the tablets, in particular in the
case of high
doses of active principles. When two active principles are combined in the
same tablet,
it is possible, depending on the case, to incorporate one of them into the
external
phase.
Three methods with granulation are currently used: wet granulation, dry
granulation
(compacting) and "hot melt" granulation.
Dry granulation (compacting) consists in making sure that the active
principles and the
selected excipients are mixed, calibrated and then mixed again. The mixture is
forced
between two mobile rollers, rotating in opposite directions, to obtain,
according to the
forces exerted, plaques of given mechanical strength. These plaques are
calibrated.
The specific excipients are added, and the final mixture is tabletted.
"Hot melt" granulation is a granulation method which can be used when an
active
principle degrades in the presence of water. The active principles and the
selected
excipients are calibrated and then mixed. The mixture is brought, under slow
stirring, to
a temperature which is slightly higher than the melting point of the
excipient, mixed
under rapid stirring, and then cooled to room temperature. The grain obtained
is
calibrated. The specific excipients are added and the final mixture is
tabletted. An
example of a "hot melt" method using a fluidized air bed granulator is
described below.
The active principles and the selected excipients, except for the fusible
excipient, are
calibrated and then transferred into a fluidized air bed granulator. The whole
is mixed
by fluidization with introduction of hot air, until a mixture temperature is
reached which
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is slightly lower than the melting point of the granulation excipient. The
molten
excipient is then sprayed onto the fluidized mixture. The fluidization air
temperature is
lowered. The grain obtained is calibrated. The specific excipients are added
and the
final mixture is tabletted.
The gelatin capsules and the single-dose sachets are prepared according to
techniques which are well known to a person skilled in the art.
The pharmaceutical compositions according to the invention are used for
treating a
pathology induced by platelet aggregation, including stable or unstable
angina,
disorders of the cardiovascular and cerebrovascular system such as
thromboembolic
disorders associated with atherosclerosis and with diabetes, such as unstable
angina,
stroke, restenosis after angioplasty, endarterectomy or installation of metal
endovascular prostheses, or thromboembolic disorders associated with
rethrombosis
after thrombolysis, with infarct, with dementia of ischaemic origin, with
peripheral
arterial diseases, with haemodialysis, with atrial fibrillation or during the
use of vascular
prostheses or of coronary artery bypasses, or during radiotherapy to reduce
the side-
effects thereof.
The pharmaceutical compositions according to the invention are used for
preparing a
medicinal product intended for treating the abovementioned pathologies, and
enable
the treatment of these pathologies.
In the pharmaceutical compositions according to the invention, the clopidogrel
hydrogenosulphate and the aspirin are present in a clopidogrel
hydrogenosulphate/aspirin molar ratio of between 2.5 and 11.5, preferably of
between
5 and 9.
In humans, 1 to 500 mg per day of clopidogrel hydrogenosulphate and 1 to 500
mg per
day of aspirin are administered, the doses being expressed in equivalent
amount of
clopidogrel in the free form.
97.875 mg of clopidogrel hydrogenosulphate and 75 to 325 mg of aspirin are
preferably administered.
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Compositions containing 97.875 mg of clopidogrel hydrogenosulphate and 75 mg
of
aspirin are particularly preferred.
Compositions containing 97.875 mg of clopidogrel hydrogenosulphate and 375 mg
of
aspirin are also preferred.
5 EXAMPLE 1
Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method for granulation by compacting
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 75
Pregelatinized corn starch 30
Anhydrous colloidal silica 2
Anhydrous (3-lactose 324.625
Microcrystalline cellulose (90 p,m) 30
Hydroxypropylcellulose with low degree 30
of substitution
Hydrogenated castor oil 10.5
Total 600
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2 g of anhydrous
colloidal
silica
b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are
added to a)
and mixed
c) the mixture b) is calibrated and then mixed again
d) the mixture is compacted and then calibrated on 1000 mm mesh size
e) 75 g of aspirin, 250 g of anhydrous lactose, 30 g of microcrystalline
cellulose and
30 g of hydroxypropylcellulose with a low degree of substitution are mixed
with the
calibrated grain
f) 10.5 g of hydrogenated castor oil are added before final mixing
g) the final mixture is tabletted at the theoretical unit mass of 600 mg
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~ The anhydrous [3-lactose can be replaced with an equivalent amount of
mannitol.
EXAMPLE 2
Tablet containing 75 mg of clopidogrel base and 200 mg of aspirin
Example: method for granulation by compacting
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 200
Pregelatinized corn starch 30
Anhydrous colloidal silica
Anhydrous ~-lactose 199.625
Microcrystalline cellulose (90 Vim) 30
Hydroxypropylcellulose with low degree 30
of substitution
Hydrogenated castor oil 10.5
Total 600
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2 g of anhydrous
colloidal
silica
b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are
added to a)
and mixed
c) the mixture b) is calibrated and then mixed again
d) the mixture is compacted and then calibrated on 1000 mm mesh size
e) 200 g of aspirin, 125 g of anhydrous lactose, 30 g of microcrystalline
cellulose and
30 g of hydroxypropylcellulose with a low degree of substitution are mixed
with the
calibrated grain
f) 10.5 g of hydrogenated castor oil are added before final mixing
g) the final mixture is tabletted at the theoretical unit mass of 600 mg
~ The anhydrous ~i-lactose can be replaced with an equivalent amount of
mannitol.
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EXAMPLE 3
Tablet containing 75 mg of clopidogrel base and 325 mg of aspirin
Example: method for granulation by compacting
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 325
Pregelatinized corn starch 30
Anhydrous colloidal silica 2
Anhydrous (3-lactose 74.625
Microcrystalline cellulose (90 wm) 30
Hydroxypropylcellulose with low degree 30
of substitution
Hydrogenated castor oil 10.5
Total 600
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2 g of anhydrous
colloidal
silica
b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are
added to a)
and mixed
c) the mixture b) is calibrated and then mixed again
d) the mixture is compacted and then calibrated on 1000 mm mesh size
e) 325 g of aspirin, 30 g of microcrystalline cellulose and 30 g of
hydroxypropyl-
cellulose with a low degree of substitution are mixed with the calibrated
grain
f) 10.5 g of hydrogenated castor oil are added before final mixing
g) the final mixture is tabletted at the theoretical unit mass of 600 mg
~ The anhydrous (3-lactose can be replaced with an equivalent amount of
mannitol.
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EXAMPLE 4
Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method by direct tabletting
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 75
Corn starch 30
Anhydrous colloidal silica 2
Mannitol 300 DC 324.625
Microcrystalline cellulose (90 pm) 60
Hydrogenated castor oil 10.5 '
Total 600
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2 g of anhydrous
colloidal
silica
b) 75 g of aspirin, 30 g of corn starch, 324.6 g of mannitol and 60 g of
microcrystalline
cellulose are added to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) 10.5 g of hydrogenated castor oil are added to c) before the final mixing
e) the final mixture is tabletted at the theoretical unit mass of 600 mg
~ The mannitol can be replaced with an equivalent amount of anhydrous ~-
lactose.
EXAMPLE 5
Tablet containing 75 mg of clopidogrel base and 325 mg of aspirin
Example: method by direct tabletting
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 325
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Constituents Amount in mg
Corn starch 30
Anhydrous colloidal silica _ 2
Mannitol 300 DC 124.625
Microcrystalline cellulose (90 pm) 60
Hydrogenated castor oil 10.5
Total 600
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2 g of anhydrous
colloidal
silica
b) 325 g of aspirin, 30 g of corn starch, 124.6 g of mannitol and 60 g of
microcrystalline
cellulose are added to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) 10.5 g of hydrogenated castor oil are added to c) before the final mixing
e) the final mixture is tabletted at the theoretical unit mass of 650 mg
~ The mannitol can be replaced with an equivalent amount of anhydrous ~-
lactose.
EXAMPLE 6
Gelatin capsule containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method by simple mixing
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 75
Pregelatinized corn starch ~50
Anhydrous colloidal silica 2.5
Mannitol 300 DC 265.875
Hydrogenated castor oil 8,75
Total 500
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2.5 g of anhydrous
colloidal silica
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b) 75 g of aspirin, 50 g of pregelatinized corn starch and 265.9 g of mannitol
are added
to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) 8.75 g of hydrogenated castor oil are added to c) before the final mixing
5 e) the final mixture is divided up into gelatin capsules at the theoretical
unit mass of
500 mg
~ The mannitol can be replaced with an equivalent amount of anhydrous (3-
lactose.
EXAMPLE 7
Gelatin capsule containing 75 mg of clopidogrel base and 325 mg of aspirin
10 Example: method by simple mixing
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 325
Pregelatinized corn starch 50
Anhydrous colloidal silica 2.5
Mannitol 300 DC 15.875
Hydrogenated castor oil 8.75
Total 500
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2.5 g of anhydrous
colloidal silica
b) 325 g of aspirin, 50 g of pregelatinized corn starch and 15.9 g of mannitol
are added
to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) 8.75 g of hydrogenated castor oil are added to c) before the final mixing
e) the final mixture is divided up into gelatin capsules at the theoretical
unit mass of
500 mg
~ The mannitol can be replaced with an equivalent amount of anhydrous ~-
lactose.
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EXAMPLE 8
Sachet containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method by simple mixing
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg base)
Aspirin 75
Anhydrous colloidal silica 2.5
Mannitol 300 DC 824.625
Total 1000
a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2.5 g of anhydrous
colloidal silica
b) 75 g of aspirin and 824.6 g of mannitol are added to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) the mixture is divided up into sachets at the theoretical mass of 1 g
~ A pulverulent flavouring can be added to the mixture.
EXAMPLE 9
Sachet containing 75 mg of clopidogrel base and 325 mg of aspirin
Example: method by simple mixing
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg base)
Aspirin 325
Anhydrous colloidal silica 2.5
Man nitol 574.625
Total 1000
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a) 97.875 g of clopidogrel hydrogenosulphate are mixed with 2.5 g of anhydrous
colloidal silica
b) 325 g of aspirin and 574.6 g of mannitol are added to a) and mixed
c) the mixture b) is calibrated and then mixed again
d) the mixture is divided up into sachets at the theoretical mass of 1 g
~ A pulverulent flavouring can be added to the mixture.
EXAMPLE 10
Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method for "hot melt' granulation
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 75
Macrogol 6000 97.5
Corn starch 32.5
Anhydrous colloidal silica 2
Mannitol 273.625
Microcrystalline cellulose (50 Vim) 65
Hydrogenated castor oil 6.5
Total 650
a) 97.875 g of clopidogrel hydrogenosulphate, 97.5 g of macrogol 6000, 32.5 g
of corn
starch and 273.6 g of mannitol are mixed after calibration
b) the mixture temperature is brought to 65°C, in a thermostatted
incubator, under slow
stirring
c) the mixture is granulated under rapid stirring, cooled to room temperature
and then
calibrated
d) 75 g of aspirin, 2 g of anhydrous colloidal silica and 65 g of
microcrystalline cellulose
are added to the calibrated grain, and mixed
e) 6.5 g of hydrogenated castor oil are added to d) before final mixing
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f) the final mixture is tabletted at the theoretical unit mass of 650 mg
EXAMPLE 11
Table containing 75 mg of clopidogrel base and 325 mg of aspirin
Example: method for "hot melt' granulation
Unit formula
Constituents Amount in mg
Clopidogrel hydrogenosulphate 97.875
(corresponding to 75 mg of base)
Aspirin 325
Macrogol 6000 97.5
Corn starch 32.5
Anhydrous colloidal silica 2
Mannitol 23.625
Microcrystalline cellulose (50 pm) 65
Hydrogenated castor oil 6.5
Total 650
a) 97.875 g of clopidogrel hydrogenosulphate, 97.5 g of macrogol 6000, 32.5 g
of corn
starch and 23.6 g of mannitol are mixed after calibration
b) the mixture temperature is brought to 65°C, in a thermostatted
incubator, under slow
stirring
c) the mixture is granulated under rapid stirring, cooled to room temperature
and then
calibrated
d) 325 g of aspirin, 2 g of anhydrous colloidal silica and 65 g of
microcrystalline
cellulose are added to the calibrated grain, and mixed
e) 6.5 g of hydrogenated castor oil are added to d) before final mixing
f) the final mixture is tabletted at the theoretical unit mass of 650 mg
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EXAMPLE 12
Tablets containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method by direct tabletting
Unit formula
Constituents Amount in mg
Clopidogrel Form 2 (corresponding to 97.875
75 mg of base)
Aspirin 75,00
Emdex~ 136.605
Hydrogenated castor oil 5.520
Total 315
EXAMPLE 13
Constituents Amount in mg
Clopidogrel Form 2 (corresponding to 97.875
75 mg of base)
Aspirin 75.00
Cellactose 80 121.875
Hydrogenated castor oil 5.25
Total 300
Procedure for EXAMPLES 12 and 13
The mixing of the active principles and the diluents is carried out with a
mini-rhon
machine for 10 minutes.
Lubricant (hydrogenated castor oil) is added, and then mixing is carried out
with a
mini-rhon machine for 5 minutes.
EXAMPLE 14
Tablets containing 75 mg of clopidogrel base and 75 mg of aspirin
Example: method by direct tabletting
Unit formula
Constituents Amount in mg
Clopidogrel Form 2 (corresponding to 97.875
75 mg of base)
Aspirin 75.00
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Constituents Amount in mg
Emdex~
10.00
Avicel PH 112 21.125
Pearlitol SD 200 24.00
Anhydrous colloidal silica 2.00
Hydrogenated castor oil 4.20
Total 240
Procedure:
The active principles are mixed with the diluents for 10 minutes with a mini-
rhon
machine.
5 Anhydrous colloidal silica is added to the mixture above, and then sieving
is carried out
through a screen of mesh size 0.315 mm.
Mixing is carried out with a mini-rhon machine for 5 minutes.
Lubricant (hydrogenated castor oil) is added, and mixing is carried out with a
mini-rhon
machine for 5 minutes.
