Note: Descriptions are shown in the official language in which they were submitted.
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Coated Trimebutine Maleate Tablet
Field of the invention
The present invention relates to an improved and film-coated trimebutine
maleate tablet intended for oral administration, and to a process for
preparing it.
In particular, the invention relates to a new tablet which makes it possible
to administer a therapeutically effective amount of trimebutine maleate for a
rapid or
sustained bioavailability, but, in any case, without causing a persisting
bitter effect
which is eventually prejudicial to the patient's proper compliance with the
treatment.
Technological background of the invention
Trimebutine, or 2-dimethylamino-2-phenyl-n-butyl 3,4,5-
trimethoxybenzoate, is the first medicament known to act on the peripheral
encephalinergic receptors, in particular those associated with digestion. It
is a
regulator of digestive motor function. As it is, or salified with maleic acid,
trimebutine
is offered in tablet, injectable solution and suppository form and in powder
form for
the preparation of a suspension for oral administration.
Marketed internationally, these various pharmaceutical dosage forms are
indicated in the treatment of pain associated with functional disorders of the
alimen-
tary tract and the biliary tract, and in the treatment of pain and discomfort
associated
with functional intestinal disorders.
The orally administrable dosage forms are more especially suited to
ambulatory treatments. Tablets and also granules or powders are essentially
the forms
which can be intended for the preparation of suspensions for oral
administration.
Trimebutine maleate is the active principle commonly used for the
preparation of these oral dosage forms, with a daily indicative dosage of 300
to 600 mg
for an adult. This product, obtained by crystallization in water, melts at 105-
106 C. Its
solubility in water at 25 C is approximately I% (w/v), whereas trimebutine
base is
insoluble in water.
Trimebutine is, from a chemical standpoint, a benzoate type ester which is
sensitive to agents that promote hydrolysis reactions or related reactions.
These agents
comprise, in particular, water and reactive solvents such as lower alcohols,
temperature, light and various catalysts, especially both alkali metal-
containing and
alkaline-earth metal-containing catalysts. The hydrolysis of trimebutine
leads, among
other by-products, to the formation of 3,4,5-trimethoxybenzoic acid, the
quantitative
determination of which enables its chemical stability to be assessed under
various
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storage conditions.
In addition, maleic acid is temperature sensitive as a result of its
propensity to isomerize to fumaric acid, the acidity constant of which is
lower than that
of maleic acid. This acid, on salification with trimebutine, leads to a
trimebutine
fumarate of low water-solubility.
Moreover, like many compounds which are positively charged in aqueous
solution at pH values close to neutrality, trimebutine maleate administered
orally
induces, in the cavity and on the buccal mucosae, a strong bitterness and a
lasting
astringent sensation which can eventually cause poor compliance with the
treatments
in which the product is prescribed. This bitterness is especially
disadvantageous when
it is necessary to obtain a rapid therapeutic effect, which implies an almost
immediate
bioavailability as soon as the medicament has been swallowed. As an
illustration of the
truth of this problem, one of the two specialities in tablet form marketed in
France
states that "the tablets must be swallowed without being crunched, with a
glass of
water" ("Vidal" Dictionary of Pharmaceutical Specialities - 1996 ed.).
To date, the prior art reports only some imperfect attempts at overcoming
the problems described, namely both to provide for the stability of the
trimebutine
maleate during preparation and storage of the medicaments, and to mask or
eliminate
the persisting bitterness in the mouth caused by the product without retarding
its
therapeutic effect.
As regards the powder form, Patent FR 2,468,364 published on 8/5/1981
describes a process for preparing microcapsules containing a pharmaceutically
active
compound, the walls of which are ethylcellulose, a process carried out in
cyclohexane
and which involves a phase separation-inducing agent, preferably of the
phospholipid
class. As an example, microcapsules of trimebutine maleate are prepared, for
which
one of the quality criteria evaluated is the absence of bitter taste.
According to this same process carried out in cyclohexane, the patents
which follow are directed towards improving the quality of the microcapsules:
- FR 2,506,613 published on 3/12/1982 describes microcapsules, the walls of
which
consist of ethylcellulose and a polymer which is insoluble in water but
soluble in an
acid medium, which aim at a rapid release of the product in the gastric
medium. The
amount of trimebutine maleate incorporated does not exceed 15%, the release of
50%
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of the product in an artificial gastric medium being obtained after 17
minutes.
- EP 0 076 515 published on 13/4/1983 also relates to microcapsules affording
rapid
release in the gastric medium, the walls of which consist of ethylcellulose
and a
polymer which is soluble in water and/or in an acid medium. The amount of
product
included is at best 12%, 50% of which is released in 10 to 20 minutes.
- EP 0 076 428 also published on 13/4/1983 is directed towards the same
objective as
the preceding patents; the walls consist of ethylcellulose and a polymer which
is
"expandable" in water. They contain approximately 10% of active principle, 50%
of
which is released in 4 to 25 minutes in an artificial gastric medium.
- EP 0 099 109 published on 25/1/1984 describes a process for preparing
microcapsules
which is declared to be advantageous, in which a particular phase separation-
inducing
agent participates.
It is clear that, through this succession of patents, their applicant is
aiming
at the preparation of a powder containing trimebutine maleate in the coated
state in
order to mask its bitterness while attempting to obtain a rapid release of the
active
principle from the microcapsules proposed. It is apparent that this objective
is
imperfectly achieved since, on the one hand this complex and economically
unsatisfactory process employs cyclohexane, which is an inflammable solvent,
difficult
to remove and subjected as a residual solvent to strict specification limits
by the health
authorities, and on the other hand it results in microcapsules which only
contain an
amount of trimebutine maleate of less than 20%, making it necessary for the
patients
to take an excessively large amount of medicament, bearing in mind the
recommended
daily dosage of 300 to 600 mg of trimebutine maleate, since it contains more
than four
times as much excipients as active principle.
In Application JP 80 40 885 published on 13/2/1996, a formulation
composed of a mixture of granules is described, in which, in the case of the
granules
containing trimebutine maleate, the bitter taste is practically eliminated by
granulation
of the active principle with a water-insoluble polymer and a hydrophobic salt.
As an
example, granules comprising trimebutine maleate contain 20% of the active
principle,
3% of insoluble polymer and 5% of a hydrophobic salt, namely magnesium
stearate or
calcium stearate. No result is mentioned regarding the rate of release and/or
the
stability of the trimebutine maleate in these granules.
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As regards tablets intended for the oral administration of trimebutine
maleate, in Patent FR 2,640,876 published on 29/06/1990, a pharmaceutical
composition in the form of a coating-free tablet comprising as active
principle 2-
dimethylamino-2-phenyl-l-butyl 3,4,5-trimethoxybenzoate maleate is described,
characterized in that this active principle, which represents 35 to 45% by
weight of the
composition, is dispersed homogeneously in a hydrophilic porous matrix of
hydroxypropylmethylcellulose representing 15 to 20% by weight of the
composition,
which comprises, in addition, 20 to 25% by weight of a water-soluble diluent
and 10 to
20% by weight of tartaric acid.
According to this invention, the kinetics of dissolution of the active
principle are, between thirty minutes and 8 hours, close to zero order,
approximately
50% of the product being released after 8 hours. It should be noted that these
tablets,
in particular those containing a high dose, can be swallowed only with
difficulty by
some patients, and that, under these conditions, the unintentionally prolonged
contact
time in the buccal cavity inevitably causes an unpleasant and persisting
bitterness.
Application JP No. 73574/1990 published on 6/12/1991 relates to a solid
preparation very similar to that of Patent FR 2 640 876 and to trimebutine
maleate
tablets intended for oral administration, in which an organic acid in the
proportion of
0.1 to 20 mg per 100 mg of maleate significantly inhibits the decomposition of
the
product, in which decomposition magnesium stearate is partially involved. It
is
specified that appropriate acids are tartaric acid or citric acid, and that
the
formulation comprises a metal (magnesium or calcium) stearate as lubricant for
the
compression.
Description of the invention
Overcoming the unresolved problems as described in the prior art, the
present invention is a technically simple and economically advantageous
approach
which is beneficial to the patient, the subject of which is a new improved
trimebutine
maleate tablet intended for oral administration, characterized in that it
comprises:
- a core comprising 30 to 60% of trimebutine maleate, and excipients suitable
for the
preparation of the said core and those appropriate to the stability and to the
release of
the active principle,
- a water-soluble film coating, of transient but sufficient efficacy to
protect from a
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disintegration of the core and from a premature release of the active
principle in the
buccal medium.
As described in this specification, in its main aspect, the invention relates
to a new tablet for the oral administration of a therapeutically effective
amount of
trimebutine maleate, the bioavailability of which can be rapid or sustained
but which,
in any case, does not cause in the buccal cavity any persisting bitterness
which, on use,
gives rise to an attitude of revulsion in the patient. These tablets display
resistance and
an exceptional physical stability which makes them amenable to the most
diverse kinds
of packaging (blister packs, in bulk in bottles, etc.) under adverse storage
conditions
(temperature, humidity, etc.).
In addition, an important aspect relates to the exceptional chemical
stability of the trimebutine maleate presented in this tablet form, even with
the tablets
stored under harsh conditions, thereby providing patients with a product which
is safe
and of definite therapeutic benefit.
In another aspect, the invention relates to the process for manufacturing
the tablets.
Another aspect of the invention relates to a composition which is suitable
for the preparation of the cores of the tablets, characterized in that
quantitative and
qualitative adaptation of its main constituents enables a rapid or sustained
release of
the active principle to be obtained.
Generally speaking, the film-coating of tablets brings about advantages
both for their industrial manufacture and for their use by the patient. Thus,
as regards
the manufacturing aspect, film-coated dosage forms are acknowledged to be less
sensitive to mechanical erosion, hence to generate less dust and, as a result,
to decrease
inter-drug contamination in the premises; in addition, it is acknowledged that
film-
coating favours the immediate packaging, in particular in blister packs, of
the tablets.
As regards the use by patients, the satiny or shiny texture provided by the
film-
forming mixture of the film coating prevents the naked tablet from adhering to
the
buccal mucosa and makes swallowing easier.
Besides these known advantages, the improvements provided by the
tablets of the invention are elaborated upon in the subsequent part of this
specification
and illustrated by tests of release of the active principle and of physical
and chemical
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stabilities in comparison with two commercially available specialities.
For the purposes of the invention in its broadest aspect, the tablets are
characterized in that their cores comprise, by weight, 30 to 60% of
trimebutine
maleate and, as excipients, 15 to 45% of one or more diluents, 2.5 to 25% of
one or
more binding agents, 0.5 to 25% of one or more acidifying agents, optionally 1
to 5%
of one or more disintegrating agents, and technical adjuvant agents, namely
0.5 to 5%
of a glidant and 0.25 to 2.5% of a lubricant, and characterized in that the
said cores are
coated with a film representing 1 to 5% by weight of the said tablet, the
composition of
which film comprises one or more water-soluble film-forming agents, one or
more
opacifying agents and, optionally, one or more plasticizers.
More specifically, the composition of a core comprises:
- in the proportion of 20 to 40%, one or more diluents chosen from cellulose
in
microcrystalline or powder form, mannitol, starch and, more especially,
lactose, in
particular hydrated, which is the preferred dilution agent;
- in the proportion of 2.5 to 25%, one or more binding agents chosen from
microcrystalline cellulose, gelatin of pharmaceutically acceptable quality,
methylcellulose and pregelatinized starch. Povidone, pregelatinized maize
starch and
hydroxypropylmethylcellulose of viscosity between 2.5 and 15,000 mPa.s are
preferred.
In particular, for cores for which a rapid disintegration is desired, a
mixture is used
representing 5 to 10% of the tablet and composed of 5 to 10 parts of maize
starch and
0.5 to 2 parts of hydroxypropylmethylcellulose whose viscosity is between 2.5
and 17.5
mPa.s, whereas for cores for which a sustained release of the active principle
is
desired, a mixture composed of 5 to 15 parts of hydroxypropylmethylcellulose
whose
viscosity is between 1,500 and 15,000 mPa.s and 0.5 to 1 part of povidone is
used in the
proportion of 15 to 20% of the tablet. It is especially preferable to use
hydroxypropylmethylcellulose of viscosity 5.2 to 7.0 mPa.s for the cores
affording
rapid disintegration, and hydroxypropylmethylcellulose of viscosity 4,000
mPa.s for
the cores affording sustained release;
- the acidifying agent is chosen from pharmaceutically acceptable organic
acids known
for their properties of sequestering metals and/or possessing a stabilizing
effect on the
active principle and/or enabling an acid environment, favourable to the
release of the
active principle from hydrophilic cores aimed at a sustained release, to be
created.
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These acids are citric acid and tartaric acid which are used in the proportion
0.5 to 2%
in the cores for which a rapid disintegration is desired, and are preferably
used in the
proportion of 10 to 20%, in particular with tartaric acid which is preferred,
in the
cores for which a sustained release of trimebutine maleate is desired;
- the glidant is silica, anhydrous or hydrated, which is used in the
proportion of 0.75 to
2.5%;
- the lubricant is chosen from the metal salts of stearic acid, to the
exclusion of the
other agents customarily proposed for this purpose. The lubricant is thus
chosen from
calcium and magnesium stearates. The latter is preferred, at concentrations of
0.5 to
1.5%, and more especially 1%;
- the disintegrating agent, which is optional, is chosen from crospovidone
(crosslinked
povidone), the sodium salt of crosslinked carboxymethylcellulose, also known
as
"croscarmellose sodium", and carboxymethyl starch which is preferred. The
optional
character of this agent corresponds to the need, where appropriate, to release
the
active principle rapidly, which is obtained by rapid disintegration of the
cores after
passage through the buccopharyngeal region. To this end, for the so-called
"immediate-release" tablets, sodium carboxymethyl starch is used in the
proportion of
1 to 5%, and preferably 2%, to obtain the requisite disintegration.
And as regards the coating film, the latter consists essentially of a water-
soluble film-forming agent chosen from acrylic polymers and cellulose polymers
such
as hydroxypropylmethylcellulose of viscosity between 2.5 and 17.5 mPa.s,
methylcellulose, ethylcellulose and hydroxypropylcellulose; and of a filler
substance
permitting better adhesion of the film to the core, such as lactose or
microcrystalline
cellulose. The opacifying agents and/or additive colorants are chosen from
iron oxides
and titanium dioxide. The plasticizers which can be used are chosen from
macrogols of
average molecular weight 3000 to 6000, propylene glycol, glycerol and polyoxyl
40
stearate. To carry out the film-coating of the cores, according to the
invention, the
compounds may be used mixed in solution or in suspension in water or in
pharmaceutically acceptable solvents such as ethanol, acetone or mixtures
thereof with
water. Preference is nevertheless given to a mixture comprising an aqueous
suspension
of hydroxypropylmethylcellulose whose viscosity is between 2.5 and 17.5 mPa.s
and
titanium dioxide, or alternatively a mixture comprising a hydroxypropyl-
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methylcellulose whose viscosity is between 2.5 and 17.5 mPa.s, lactose or
microcrystalline cellulose, polyethylene glycol of molecular weight 4000 or
polyoxyl 40
stearate and titanium dioxide in aqueous suspension. Special preference is
given to
mixtures in which the hydroxypropylmethylcellulose is of viscosity 5.2 to 7.0
mPa.s;
such especially suitable mixtures are marketed by the company Colorcon under
the
brand name OPADRY or by the company Seppic under the brand name
SEPIFILM ; they make it possible to obtain, in the proportion of 1.5 to 3% by
weight
relative to the weight of the core, and especially in the proportion of 2%, a
film of
transient resistance in the buccopharyngeal medium which enables the tablet to
be
administered without an effect of bitterness while preserving a
bioavailability of the
active principle under the conditions of release chosen for the latter.
Moreover, the
film coating produced by the film under the conditions of the invention is
fully
compatible with the imprinting, engraved or embossed, on the cores, such
imprinting
being indicative of the active principle and the dosage thereof and it being
possible,
during the coating operation with unsuitable compounds, for it to be filled in
or eroded
or erased, in any case, to become illegible.
As a special preference, the invention relates to the tablets whose
percentage compositions are as follows:
Tablets A for rapid disintegration, termed immediate-release forms: "IRF"
i) composition for cores weighing 200 & 400 mg
- trimebutine maleate 50.00%
- lactose monohydrate 36.00%
- maize starch 7.00%
- hydroxypropylmethylcellulose (6 mPa.s) 1.00%
- sodium carboxymethyl starch 2.00%
- tartaric acid 1.000/,
- silica gel 2.00%
- magnesium stearate 1.00%
ii) coatin 2.00% of the weight of the core of a composition comprising
hydroxypropylmethylcellulose (6 mPa.s), lactose, polyethylene glycol 4000 and
titanium dioxide, or alternatively hydroxypropylmethylcellulose (6 mPa.s),
microcrystalline cellulose, polyoxyl 40 stearate and titanium dioxide.
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Tablets B termed sustained-release: "SRF"
i) composition for cores wei2hin2 747.00 & 508.00 m2
- trimebutine maleate 40.16%
- lactose monohydrate 24.07%,
- hydroxypropylmethylcellulose (4000 mPa.s) 16.06%
- tartaric acid 16.06%
- povidone 1.61%
- silica gel 1.02%
- magnesium stearate 1.02%
ii) coatin 2.00% of the weight of the core of a composition comprising
hydroxypropylmethylcellose (6 mPa.s) and titanium dioxide, or alternatively
hydroxypropylmethylcellulose (6 mPa.s), lactose, polyethylene glycol 4000 and
titanium dioxide.
As regards the process for manufacturing the tablets according to the
invention, this process consists, in a first stage, in preparing a suitable
composition,
and then in subjecting it to compression in order to obtain the cores which
are
thereafter film-coated.
Thus, the implementation of the process for preparing the tablets termed
"IRF", the preferred constituents of which have been described above for the
tablets
A, consists in:
i) preparing the composition
- in a powder mixer or a fluidized bed apparatus, mixing the trimebutine
maleate,
lactose monohydrate, pregelatinized maize starch, hydroxypropylmethylcellulose
and
half of the carboxymethyl starch, then granulating the homogeneous mixture
with
tartaric acid in aqueous solution and sizing the wet granules,
- drying the granules in a fluidized bed or in a ventilated oven at 60 C, then
sizing
them on a screen of aperture 1 to 1.5 mm, then mixing them in a powder mixer
with
the second half of the carboxymethyl starch, the silica gel and the magnesium
stearate,
ii) preparing the cores by compression of the granules on a rotary pelleting
machine
with punches of suitable size for obtaining cores of mass equivalent to 200 or
400 mg,
containing doses of 100 and 200 mg of trimebutine maleate, respectively, and
the
hardness of which is 50 to 70 N,
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iii) film-coating the cores in a coating pan with the film-coating suspension
at a
temperature of between 35 and 45 C and under conditions such that this film
coating
coats the cores uniformly in the proportion of an amount of 4 mg for the cores
weighing 200 mg and 8 mg for the cores weighing 400 mg.
The implementation of the process for preparing the tablets B termed
"SRF", differing little from the one described above, consists in:
i) preparing the composition
- in a powder mixer or a fluidized bed apparatus, mixing the trimebutine
maleate,
lactose monohydrate and tartaric acid, then granulating the homogeneous
mixture
with an aqueous or ethanolic solution of povidone and sizing the wet granules,
- drying the granules in a fluidized bed or in a ventilated oven at a
temperature of 45 to
60 C, sizing them on a screen of aperture 1 to 1.5 mm, then mixing them in a
powder
mixer with the hydroxypropylmethylcellulose, the silica gel and the magnesium
stearate,
ii) preparing the cores by compression of the granules on a rotary pelleting
machine
with punches of suitable size for obtaining cores of mass equivalent to 747 or
508 mg,
containing doses of 300 and 200 mg of trimebutine maleate, respectively, and
the
hardness of which is 80 to 200 N,
iii) film-coating the cores in a coating pan with the film-coating suspension
at a
temperature of between 35 and 45 C and under conditions such that this film
coating
coats the cores uniformly in the proportion of an amount of 15 mg for the
cores
weighing 747 mg and 10 mg for the cores weighing 508 mg.
As prepared, the film-coated tablets are then packaged in blister packs, in
polypropylene or high density polyethylene bottles and the like.
The invention is illustrated without implied limitation by the examples
which follow.
Example 1: Film-coated tablets for rapid disintegration, containing a 100 mi!
dose of
trimebutine maleate - so-called "IRF" form
The following are introduced into a vortexing centrifugal powder mixer:
- 10.400 kg of trimebutine maleate,
- 7.488 kg of lactose monohydrate,
- 1.450 kg of pregelatinized maize starch,
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- 0.208 kg of sodium carboxymethyl starch,
- 0.208 kg of hydroxypropylmethylcellulose (6 mPa.s).
Homogeneous mixing of the constituents is achieved by stirring for 3
minutes, and then, in the same apparatus, using the tool suitable for
granulation, the
mixture is wetted with a solution of 0.208 kg of tartaric acid dissolved in
2.7 1 of water.
The granules are sized wet on a rotary size grader, then dried in a
fluidized bed at 50 C until the residual moisture content is less than 1%.
The granules are then sized on a rapid screen of mesh aperture 1.5 mm
and thereafter introduced into a powder mixer of the container type. The
following are
then added:
- 0.208 kg of carboxymethyl starch,
- 0.416 kg of silica gel,
- 0.208 kg of magnesium stearate.
The whole is mixed for 20 minutes at slow speed (5 to 10 rpm), then
subjected to compression on a rotary tableting press equipped with punches 8
mm in
diameter.
The cores obtained have the following properties:
- mean mass 200 mg 15 mg
- mean hardness 60 N f 10 N
- friability < 1%
- disintegration time in water at 37 C: not more than 8 minutes.
The cores are then film-coated in a coating pan (for example in an
apparatus of the "Ultra Coater Aeromatic S2" type) by spraying with an aqueous
suspension containing methylhydroxypropylcellulose (6 mPa.s), lactose hydrate,
titanium dioxide and polyethylene glycol 4000. In the abovementioned type of
apparatus, the working conditions are as follows:
- air inflow temperature: 50 C,
- rate of introduction of the film-coating suspension: 30 g/minute,
- spraying pressure: 2 bars,
to obtain at a temperature of 35 to 45 C a homogeneous film coating of 4 mg
per
tablet, the mean final mass of which is 204 mg 15.3 mg and the unit
composition of
which is as follows:
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- trimebutine maleate 100.0 mg
lactose monohydrate 72.0 mg
- pregelatinized maize starch 14.0 mg
- hydroxypropylmethylcellulose 2.0 mg
- sodium carboxymethyl starch 4.0 mg
- tartaric acid 2.0 mg
- silica gel 4.0 mg
- magnesium stearate 2.0 mg
- mixture of film-coating agents 4.0 mg
including hydroxypropylmethylcellulose 6 mPa.s 0.93 mg, lactose hydrate 1.4
mg,
titanium dioxide 0.87 mg and polyethylene glycol 4000 0.80 mg.
The immediate packaging of these tablets is performed in blister packs
(aluminium/polyvinyl chloride).
An identical procedure is used to prepare "IRF" tablets containing a 200
mg dose of trimebutine maleate. The modification made consists in equipping
the
rotary tableting press with suitable punches for obtaining cores with a mean
mass of
400 mg, which, under the conditions of the example, is carried out with
punches whose
diameter is 11 mm. These cores are then film-coated with the mixture of film-
coating
agents in the proportion of 8 mg per core so as to obtain finished tablets
with a mean
mass of 408 mg.
Example 2: Film-coated sustained-release tablets containin2 a 300 mg dose of
trimebutine maleate - so-called "SRF" form
The following are introduced into an "Aeromatic" type fluidized bed
apparatus:
- 10.500 kg of trimebutine maleate,
- 2.100 kg of lactose monohydrate,
- 4.200 kg of tartaric acid,
after homogenization, 2.000 kg of a 21% (w/v) aqueous solution of povidone are
added
gradually and mixing is continued for 16 minutes. The granule obtained is
dried at
60 C until the residual solvation, determined with a thermobalance, is less
than 0.6%.
The granule is then sized on a rapid screen of mesh aperture 1.5 mm and
thereafter introduced into a vortexing centrifugal powder mixer. 4.200 kg of
lactose
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atomisate, 4.200 kg of hydroxypropylmethylcellulose 4000 mPa.s, 262.5 g of
silica gel
and 262.5 g of magnesium stearate are then introduced.
The whole is then mixed for 2 minutes and thereafter subjected to
compression on a rotary tableting press. The cores obtained have the following
properties:
- mean mass 747 mg 30 mg
- mean hardness 180 N t 20 N
- friability < 1 %
The cores are then film-coated in a coating pan as described in Example 1,
with an aqueous suspension containing hydroxypropylmethylcellulose (6 mPa.s),
and
titanium dioxide, to obtain a homogeneous film coating of 15 mg per tablet,
the mean
final mass of which is 762 mg 30 mg and the composition of which is as
follows:
- trimebutine maleate 300.0 mg
- lactose monohydrate 180.0 mg
- tartaric acid 120.0 mg
- povidone 12.0 mg
- hydroxypropylmethylcellulose 120.0 mg
- silica gel 7.5 mg
- magnesium stearate 7.5 mg
- mixture of film-coating agents 15.0 mg
including hydroxypropylmethylcellulose 6 mPa.s 11.5 mg and titanium dioxide
3.5 mg.
The tablets are packaged in blister packs or in bottles according to their
use and the storage conditions.
A variant of this procedure consists in equipping the rotary tableting press
with punches suitable for obtaining cores whose mean mass is 508.0 mg
containing a
200.0 mg dose of trimebutine maleate. These cores are film-coated with the
mixture of
film-coating agents, in the proportion of 10.0 mg per core in order to obtain
finished
tablets whose mean mass is 518.0 mg.
Tests
The tests carried out comprise:
- study of the physical and chemical stability of the film-coated rapid- or
sustained-
release tablets of the invention,
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- comparative study of the tilm-coated rapid-release tablets of the invention
with
commercially available tablets.
Except for the assessment of appearance, the tests relating to the physical
criteria were carried out according to protocols adapted from the European
Pharma-
copoeia, which are:
- the disintegration test (Ph. Eur. V.5.1.1),
- the dissolution test (Ph. Eur. V 5.4.1),
- the friability test (Ph. Eur. V.5.8.2.-1),
- the hardness test (Ph. Eur. V.5.8.3.-1).
As regards the studies of chemical stability of the trimebutine maleate,
these were determined by assaying the 3,4,5-trimethoxybenzoic acid, which is
repre-
sentative of the hydrolysis of the active principle. This assay is carried out
by high
pressure liquid chromatography (HPLC - Ph. Eur. V.6.20.4) with a 125-mm column
of
a Merck Lichrospher 60 RP select B support and performing the elution with a
pH 3.6
phosphate buffer/acetonitrile mixture, spectrophotometric detection being
performed
at 220 nm.
- stability studies
In packagings in blister packs (PVC/aluminium) or in polypropylene
bottles, the film-coated "IRF" and "SRF" tablets studied were stored for 6
months in
ovens at 40 C 4 C, in an anhydrous atmosphere or an atmosphere of relative
humidity (RH) 75% 5%. The results of these tests are recorded in the tables
which
follow.
1) Stability of IRF tablets
The studies were carried out after 6 months of storage of the tablets at
40 C 4 C in an atmosphere of relative humidity 75% 5%.
The criteria adopted for the study are:
- appearance, disintegration time, hardness, crumbling and the test of
dissolution of
the active principle as regards physical stability,
- the assay of TMBA as regards the chemical stability of the active principle.
To T 6 months
40 C + 75% RH
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Physical stab.
- appearance white off-white
- hardness 79 N 82 N
- crumbling 1.27% 0.69%
- disintegration time 7 to 9 min 10 to 12 min
- dissolution test 10 min 25% 20.7%
- dissolution test 20 min 100.3% 96.9%
- dissolution test 30 min 100.9% 101.8%
Chemical stab.
- % TMBA 0.01% 0.10%
2) Stability of SRF tablets
The studies were carried out after 6 months of storage of the tablets at
40 C 4 C in an anhydrous medium and in an atmosphere of relative humidity
75% f
5%.
The criteria adopted for the study are:
- appearance and dissolution test for physical stability,
- the assay of TMBA for the chemical stability of the active principle.
To T 6 months
40 C 40 C + 75% RH
Physical stab.
- appearance white off-white off-white
- dissolution 1 h 7.6% 7.3%
4 h 25.8% 27.7%
8 h 49.0% 54.8%
Chemical stab. 0.09% 0.10% 0.15%
- % TMBA
These tests, performed under harsh storage conditions, bear out the
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excellent stability of the tablets of the invention.
As regards the "IRF" tablets:
- the physical stability proves exceptional, in particular bearing in mind the
significant
criterion of the objective towards which the invention is directed, which is
to avoid the
premature disintegration of the tablet and consequently the dissolution of the
active
principle. In effect, regarding these points, a slight increase in the
disintegration time
(approximately 3 minutes) is observed after 6 months, which corresponds to a
slight
decline in the rate of dissolution of the trimebutine maleate,
- the chemical stability is also considered satisfactory. The formation
of 0.09% of TMBA corresponds, on the ratio of the molecular weights, to the
0. 09 x 503.5
degradation of 212.2 = 0. 21 % 1 of trimebutine maleate
(TMBA - MW = 212.2; trimebutine maleate - MW = 503.5)
As regards the "SRF" tablets:
- the physical stability is exceptional bearing in mind the criterion of
dissolution which
is essential for sustained-release forms,
- the chemical stability is also good, considering that the formation of 0.06%
of TMBA
corresponds to the degradation of 0.14% of trimebutine maleate.
- comparative tests
To demonstrate the noteworthy improvements provided by the film-
coated dosage form according to the invention, comparative tests were carried
out
between the tablets obtained in Example 1 and commercially available tablets
containing a 100.0 mg dose of trimebutine maleate.
As regards the latter, the qualitative information on the excipients of the
two specialities appears in the "Vidal" Dictionary of Pharmaceutical
Specialities:
- tablets "D": lactose, mannitol, sucrose, polyethylene glycol 6000, magnesium
stearate,
gelatin, wheat starch, silica gel.
- tablets "T": lactose, hypromellose, croscarmellose, magnesium stearate.
The tablets of Example 1 were compared with the tablets "D" and/or the
tables "T" as regards, on the one hand the release of the active principle,
and on the
other hand their chemical stability after storage at 40 C - 75% relative
humidity for 6
months as regards the hydrolysis of the trimebutine maleate, determined by
assaying
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3,4,5-trimethoxybenzoic acid (TMBA).
The results are presented in the tables which follow:
Ex. 1 Tab. "D" Tab. "T"
% dissolution
- 10 min 23.0% 26.0% 83.3%
- 20 min 101.2% 50.4% 98.7%
- 30 min 101.7% 69.2% 98.6%
- 45 min - 92.9%
- 60 min - 98.0%
Comparative dissolution study
Studies at 6 months 40 C - 75% RH
Ex. 1 Tab. "D" Tab. "T"
- % TMBA 0.10% 0.45% 0.70%
- % degrad. active principle 0.23% 1.06% 1.66%
()
Comparative stability study
() Relative % of degradation, calculated on the ratio of the MWs of TMBA
(212.2) and
of trimebutine maleate (503.5) and subtracting the TMBA present at To.
These tests bear out the improvements provided by the film-coated tablet
according to the invention:
- the dissolution study proves the transient efficacy of the film coating,
which enables
virtually all of the active principle to be released in between 10 and 20
minutes,
whereas, for the tablets "D", the whole of the release is obtained only after
60 minutes,
and for the tablets "T", this release is almost complete before 10 minutes.
These results
show that the tablets "D", in order to avoid buccal bitterness, release the
active
principle only slowly and in an excessively retarded manner whereas, on the
contrary,
the tablets "T" release the trimebutine maleate excessively rapidly with a
consequent
appearance of persisting buccal bitterness;
- the study of chemical stability shows that, overall, the degradation of
trimebutine
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maleate is 4 and 6 times greater, respectively, in the tablets "D" and "T"
than in the
tablets of the invention according to Example 1.
