Note: Descriptions are shown in the official language in which they were submitted.
CA 02286081 1999-10-14
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Pharmaceutical composition for gastric residence
The present invention relates to
pharmaceutical compositions for gastric residence,
comprising an active principle from the benzamides
family.
The benzamides are chemical compounds whose
structure comprises the following motif:
i
Certain benzamides are useful as active
principle of medicaments intended for the treatment,
especially, of disorders of the central nervous system.
Such benzamides can consist of amisulpride, tiapride,
sulpiride, their salts, if necessary, their enantiomers
and the salts of these enantiomers, as well as some of
their derivatives.
These benzamides can be administered by the
oral route. However, the Applicant has been able to
verify that administration by the oral route of these
benzamides can lead to a low and/or irregular
bioavailability. The term "bioavailability" is
understood here as meaning the fraction of active
principle which is absorbed from its pharmaceutical
form and which reaches the plasma.
A low or irregular bioavailability can be the
result of several factors among which it is possible to
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mention: a low solubility or a very slow dissolution of
the active principle or of the pharmaceutical form
which contains it; instability of the active principle,
either over the entire length of the gastrointestinal
tract, or in one part of it only; enzymatic degradation
in the mucous membrane or at the hepatic level of the
active principle; slow or incomplete absorption of the
active principle owing to a slow passive diffusion
through the intestine, or, in the case of an active
mechanism, a saturation of the transport system.
It is known that the bioavailability of
certain active principles can be modified by means of a
prolonged release formulation which releases the active
principle over the entire length of the gastro-
intestinal tract.
The Applicant, however, has been able to
establish that such a formulation is not suitable for
compounds of the benzamides family. In fact, the
Applicant has been able to determine that the
benzamides are generally poorly absorbed at the colonic
level in man, but that, on the other hand, they are
better absorbed in the small intestine. For certain of
these benzamides, absorption takes place quasi-
exclusively in the upper parts of the small intestine,
that is to say the jejunum, the duodenum or the
proximal ileum.
Continuing its research, the Applicant then
considered improving the bioavailability of the
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benzamides by formulating them in the form of a
pharmaceutical composition for gastric residence
favouring an absorption at the level of the small
intestine, or even, more specifically, the upper parts
of the small intestine.
The invention thus consists of a
pharmaceutical composition for gastric residence,
characterized in that it comprises:
(a) an active principle consisting of a benzamide or a
benzamide salt,
(b) a carbon dioxide generator system, and
(c) a means allowing the partial retention of the
carbon dioxide generated by the said carbon dioxide
generator system.
The figure represents the profile of plasma
release, in man, of tiapride hydrochloride, this
profile being obtained with a pharmaceutical
composition according to the invention.
When the active principle is a compound
comprising one or more centres of asymmetry, the term
"benzamide" in the sense of the present invention, and
unless stated otherwise, covers the different
enantiomers or diastereoisomers of these compounds,
including their mixtures, in particular their racemic
mixtures.
A pharmaceutical composition for gastric
residence is intended to reside for more than one hour
in the stomach with a view to prolonged and/or
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controlled release of the active principle.
A pharmaceutical composition for gastric
residence according to the invention has the advantage
of being able to float on the surface of liquids
contained in the stomach, and of being able to do this
very rapidly after having been absorbed. It has thus
been possible to verify that a composition according to
the invention is able to float less than two minutes
after having been contacted with an aqueous liquid.
It is very important that the flotation
occurs as rapidly as possible after absorption in order
to avoid the pharmaceutical composition being expelled
from the stomach. In fact, it is generally considered
that if the pharmaceutical composition for gastric
residence does not float within the three minutes
following absorption in a fasting subject, the
probability that it is evacuated from the stomach
becomes unacceptable.
The invention relates more particularly to
active principles consisting of sulpiride, amisulpride,
their salts, their enantiomers and the salts of these
enantiomers, as well as to tiapride, its oxide and its
salts.
Sulpiride or 5-(aminosulphonyl)-N-[(1-ethyl-
2-pyrrolidinyl)methyl]-2-methoxybenzamide and its
preparation process are described in the special French
Medicine Patent No. 4879M, the teaching of which is
incorporated in full in the present description.
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Sulpiride is a useful neuroleptic in the treatment of
acute and chronic psychoses (i) for disinhibitory
dosage: psychoses or predominant withdrawal states,
apragmatism, abulia or (ii) for antiproductive dosage:
5 delirious or confusional psychoses, schizophrenia.
Tiapride or N-[2-(diethylamino)ethyl]-
2-methoxy-5-(methylsulphonyl)benzamide, its salts, its
oxide and processes for their preparation are described
in French Patent No. 75 09808, the teaching of which is
incorporated in full in the present description.
Tiapride, in particular in hydrochloride form, is a
useful neuroleptic in the treatment of restlessness and
aggressivity of insane subjects, behavioural disorders
when they are manifested by hyperactivity, aggressivity
or irritability phenomena, especially in alcoholics and
the old, motor behavioural disorders such as, for
example, tremors, spontaneous or iatrogenic
neuromuscular dyskinesias, abnormal movements such as
chorea, tics, hemiballism, sensitive behavioural
disorders such as, for example, cephalalgias,
migraines, various pains, especially intense and
stubborn pains. The present invention is more
particularly suited to tiapride hydrochloride.
Amisulpride or 4-amino-N-[(1-ethyl-
2-pyrrolidinyl)methyl]5-(ethylsulphonyl)-2-methoxy-
benzamide, its enantiomers and some of its derivatives
are described in French Patent No. 78 01632, the
teaching of which is incorporated in full in the
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present description. The invention is very particularly
suitable for amisulpride per se, that is to say
4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-
5-(ethylsulphonyl)-2-methoxybenzamide, its
S laevorotatory ((S)-(-)-amisulpride) and dextrorotatory
((R)-(+)-amisulpride) enantiomers, mixtures of these
enantiomers, the tartrates of amisulpride per se and of
its enantiomers, as well as mixtures of these
tartrates. A preferred tartrate consists of the
compound described in Example IV of the Patent
FR 78 01632, that is to say the (D) tartrate of
(S)-(-)-amisulpride, in other words the [S-(R*,R*)]-
2,3-dihydroxybutanedioate of (S)-(-)-4-amino-
N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulphonyl)-
2-methoxybenzamide.
Amisulpride is a neuroleptic used in the treatment of
psychoses, more particularly in the treatment of
paranoid and productive schizophrenias, of acute
delirious psychoses, as well as in the treatment of
deficient schizophrenic states, residual psychotic
developments and inhibition states with slowing.
Amisulpride is also useful in the treatment of
dysthymia.
Besides the benzamides mentioned above, other
benzamides can be employed within the context of the
present invention, such as metoclopramide, veralipride,
alizapride or clebopride.
The carbon dioxide generator system has the
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principal function of forming carbon dioxide in the
form of bubbles. These bubbles contribute to rapidly
introducing, and then to maintaining, the
pharmaceutical composition of the invention at the
surface of the liquids contained in the stomach.
A suitable carbon dioxide generator system in
a pharmaceutical composition according to the invention
generally comprises at least one carbon dioxide
generator agent. The carbon dioxide generator agent is
usually a carbonate of an alkali or alkaline earth
metal, such as calcium carbonate, or a bicarbonate of
an alkali metal, preferably sodium bicarbonate.
Such a carbon dioxide generator system,
formed solely of a carbon dioxide generator agent, only
commences to form bubbles of carbon dioxide after
having been contacted with a medium of acidic pH,
generally that of the stomach.
In order to accelerate the formation of the
bubbles of carbon dioxide, and thus to improve the
flotation of the pharmaceutical composition for gastric
residence of the invention, it is preferred to employ a
carbon dioxide generator system which is independent of
the pH. Such a system can comprise a carbon dioxide
generator agent such as those mentioned further above,
as well as at least one acidic compound chosen from the
group formed by monocarboxylic acids such as lactic
acid, polycarboxylic acids and partial salts of
polycarboxylic acids. As acidic compounds, it is more
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particularly possible to mention tartaric, malefic,
malonic, malic, fumaric, succinic, adipic and citric
acids and their partial salts, such as monosodium
citrate.
In such a carbon dioxide generator system,
the content of acidic compound is generally chosen such
that the number of moles in the said acidic compound
with respect to the number of moles in the said carbon
dioxide generator agent is between 0.7 and 1.4 times
the stoichiometric amount. However, if the active
principle or any other component entering into the
formulation of the composition according to the
invention has a basic character, it can be necessary as
a consequence to increase the content of acidic
compound.
The means allowing the partial retention of
the carbon dioxide generated by the carbon dioxide
generator system must allow diffusion of the carbon
dioxide in a controlled manner. It must prevent the
too-rapid diffusion of carbon dioxide which would lead
to a too-short flotation in time of the pharmaceutical
composition according to the present invention.
Conversely, it must allow a sufficient diffusion of the
carbon dioxide to ensure a determined flotation time of
the said composition in the stomach, as well as the
sufficient diffusion of water or of an aqueous compound
in the composition according to the invention.
This means can consist of a porous mineral
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matrix, especially of matrices based on silicates or
calcium fluoride, or, preferably, of a polymer.
According to a particularly advantageous aspect of the
invention, the said polymer consists of at least one
hydrophilic polymer.
The hydrophilic polymers suitable for a
pharmaceutical composition according to the invention
are those able to form a hydrocolloid gel in contact
with an aqueous liquid, in particular aqueous liquids
contained in the stomach. By way of such hydrophilic
polymers, it is possible to mention (i) the natural
polysaccharides such as alginates, xanthan gum, guar
gum or carob gum, (ii) the semisynthetic
polysaccharides, in particular cellulose derivatives
such as methylcellulose, ethylcellulose,
methylhydroxyethylcellulose, carboxymethylcellulose and
its salts such as sodium carboxymethylcellulose or
calcium carboxymethylcellulose and, preferentially,
hydroxypropylcellulose, hydroxypropylmethylcellulose
and mixtures of hydroxypropylcellulose and
hydroxypropylmethylcellulose or (iii) vinyl polymers,
synthetic hydrophilic polymers such as polymers derived
from acrylic and methacrylic acids and their salts,
such as polyacrylates, especially those marketed under
the trade name Carbopol~, amino acid polymers such as
polylysines and (iv) certain proteins or their
derivatives such as gelatins. The cellulose derivatives
are particularly preferred.
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The contents of the different constitutive
compounds of a pharmaceutical composition according to
the invention are generally chosen such that the
relative density of this composition in the stomach is
5 less than 1.00.
Usually, a pharmaceutical composition
according to the invention comprises from 5 to 70~,
preferably from 10 to 60~, by weight of active
principle, from 10 to 75~, preferably from 15 to 50~,
10 by weight of at least one hydrophilic polymer and from
5 to 50$, preferably 10 to 40~, by weight of carbon
dioxide generator agent, the percentages being
expressed with respect to the total weight of the said
composition.
A pharmaceutical composition for gastric
residence according to the invention can be present in
the form of gelatin capsules, granules or, preferably,
tablets. The latter are floating tablets, that is to
say they can float on the liquids of the stomach.
Such a pharmaceutical composition can be
prepared by simple mixing of its components, followed
by conversion to pharmaceutical form carried out in a
conventional manner. Prior to the conversion to
pharmaceutical form, in particular with a view to
obtaining a floating tablet, the mixture comprising all
or part of the constitutive components of the
composition according to the invention can be
granulated or agglomerated.
__. ~....._ _ _..._~ ._.~__.. _ . .
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With a view to the preparation of a floating
. tablet according to the invention, it is possible to
compress the mixture of constitutive components of the
composition according to the invention. It is possible
to add to the mixture to be compressed lubricating
agents such as polyethylene glycols of molecular weight
of between 1500 and 10,000, magnesium stearate or
sodium stearyl fumarate, as well as conventional
excipients such as flow agents or compression agents.
A pharmaceutical composition according to the
invention, comprising a given benzamide, can be used
for the treatment of illnesses already treated by the
same benzamide in its conventional form. Thus, if the
benzamide consists of amisulpride, sulpiride, one of
their enantiomers, tiapride, or one of their salts, the
pharmaceutical composition according to the invention
can be used in the treatment of one of the pathologies
mentioned further above, respectively, for each of
these benzamides.
The examples which follow are intended to
illustrate the present invention.
Example 1: floating tablets containing tiapride
hydrochloride
The following compounds (~ by mass) were
mixed in a lemniscate mixer (Turbula~):
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tiapride hydrochloride 37.0
hydroxypropylmethylcellulosel 30.0
polyethylene glycol 6000 3.0~
anhydrous monosodium citrate 16.8
sodium bicarbonate 13.2
hydroxypropylmethylcellulose 90 SH4000SR marketed by Shin-Etsu
The homogeneous mixture thus formed was
compressed on an alternating compressing machine to
obtain round, flat tablets of diameter 15 mm and
comprising 300 mg of tiapride hydrochloride.
The dissolution of the tablets was tested
according to the following method, using the paddle
dissolution apparatus described in the European
Pharmacopoeia:
the tablets were arranged in baskets revolving at
75 rpm and submerged in 1000 ml of 0.01 M hydrochloric
acid at a temperature of 37 ~ 0.5°C. A sample of the
medium, of volume 3 ml, was taken every hour up to four
hours, then every two hours up to 12 hours. The
quantity of tiapride was determined for each sample by
U.V. spectrophotometry, in comparison with the
absorbance of a standard solution containing 300 ~.g/ml
of tiapride hydrochloride, in 0.01 M hydrochloric acid.
It was thus possible to determine the
dissolution profile below:
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hour 1 2 3 4 6 8 10 12
dissolved 12 18 19 27 35 42 44 51
Example 2: floating tablets containing tiapride
hydrochloride
The following compounds (~ by mass) were
mixed in a lemniscate mixer (Turbula~):
tiapride hydrochloride 44.17
hydroxypropylmethylcellulosel 28.68
magnesium stearate 0.50
sodium stearylfumarate 2,g7~
anhydrous monosodium citrate 13.26
anhydrous monosodium carbonate 10.42
Aerosil silica 2002 0.10
1 hydroxypropylmethylcellulose 90 SH4000SR marketed by Shin-Etsu
z marketed by Degussa
The homogeneous mixture thus formed was
compressed on an alternating compressing machine to
obtain round, convex tablets of diameter 10 mm and
comprising 200 mg of tiapride expressed as tiapride
base.
The dissolution of the tablets was tested
using the paddle dissolution apparatus described in the
European Pharmacopoeia according to the following
method:
the tablets were arranged in baskets of cylindrical
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shape, length 35 mm and diameter 19 mm, with
perforations of diameter 5 mm. They were immersed in
1000 ml of 0.01 M hydrochloric acid at a temperature of
37 ~ 0.5°C. The dissolution medium was stirred by
paddles revolving at 100 rpm. The medium was sampled
every 15 minutes in a closed circuit by a peristaltic
pump, and the quantity of tiapride determined by W
spectrophotometry in comparison with the absorbance of
a standard solution containing 200 ~g/ml of tiapride
base, in 0.01 M hydrochloric acid.
It was thus possible to determine the
dissolution profile below:
hour 1 2 3 4 6 8 10 12 14
dissolved 24 33 42 49 63 76 86 93 98
To measure the flotation of the tablets, the
tablet disintegration apparatus described in the
European Pharmacopoeia was used under the following
experimental conditions:
- volume of water at 37°C ~ 1°C, 800 ml
- stirring mechanism stopped in the low position
- ends of the tubes open.
The tablets to be tested were introduced into
6 tubes. The tiapride hydrochloride tablets of
Example 2 started to float at 2 min, and they continued
to float for at least 120 min.
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Pharmacokinetic study of the tablets of Example 2.
The tablets of Example 2 were administered to
12 volunteers. Plasma samples were taken every 30 min
from 0 to 3 h, every 2 h from 4 to 12 h, then at 16,
5 20, 24, 36 and 48 h after administration. The results
are presented in the figure, which shows the mean
plasma levels of tiapride base for the tablets of
Example 2.
Example 3: floating tablets containing amisulpride
10 The following compounds were mixed in a
granulator/ mixer type mixer:
amisulpride 39.4
hydroxypropylmethylcellulosel 29.8
succinic acid 15.9$
1 5 1 hydroxypropylmethylcellulose 90 SH4000SR marketed by Shin-Etsu
The mixture was then granulated with 10~ of
water, and the granules dried in vacuo. After
calibration, the granules were mixed with 13.7 sodium
bicarbonate, then lubricated with 1~ magnesium stearate
and 0.2$ Aerosil silica 200 (marketed by Degussa).
The homogeneous mixture thus formed was
compressed on an alternating compressing machine to
obtain round, convex tablets of diameter 10 mm and
comprising 200 mg of amisulpride.
The dissolution method of Example 2 was used
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to determine the dissolution profile of the tablets
thus prepared. The standard used was 200 ~tg/ml of
amisulpride base. The following results were obtained:
hour 1 2 3 4 6 8 10 12 14
~ dissolved 22 34 43 51 65 76 84 91 96
Their ability to float was tested by the
method of Example 2. They started to float after 2 min,
and they continued to float for at least 120 min.
Example 4: floating tablets containing
(S)-(-)-amisulpride (D)-tartrate
Floating tablets of amisulpride were prepared
according to the procedure described in Example 3. The
tablets obtained comprised (~ by mass) and were
measured out to give a dose of 50 mg of
(S)-(-)-amisulpride (D)-tartrate.
(S)-(-)-amisulpride (D)-tartrate 15.0
150 mesh lactose 30.0
hydroxypropylmethylcellulosel 32.6
magnesium stearate 1.0~
tartaric acid 10.0$
sodium bicarbonate 11.2
Aerosil silica 2002 0.2~
1 hydroxypropylmethylcellulose 90 SH4000SR marketed by Shin-Etsu
z marketed by Degussa
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The dissolution method of Example 2 was used
to determine the dissolution profile of the tablets
thus prepared. The standard used was 50 ~g/ml of
amisulpride base. The following results were obtained:
hour 1 2 3 4 6 8 10 12 14
dissolved 24 34 41 46 56 67 77 84 90
Their ability to float was tested by the
method of Example 1. They started to float after 2 min,
and they continued to float for at least 120 min.
Example 5: controlled-release floating tablets
containing amisulpride
Floating amisulpride tablets were prepared
according to the procedure described in Example 1.
The tablets obtained comprised (~ by mass):
amisulpride 41.9
hydroxypropylmethylcellulosel 20.0
sodium stearyl fumarate 2.0~
magnesium stearate 1.0~
anhydrous monosodium citrate 20.0
sodium bicarbonate 15.0
Aerosil silica 2002 0.1~
1 hydroxypropylmethylcellulose 90 SH4000SR marketed by Shin-Etsu
z marketed by Degussa
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The dissolution method of Example 1 was used,
modifying the times of taking samples to determine the
dissolution profile of the tablets thus prepared. The
following results were obtained:
hour 0.5 1 1.5 2 2.5 3 4
dissolved 40 35 63 70 78 88 100
