Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 336326
The present invention relates to a sustained-
release form of diltiazem, a calcium antagonist used in
the treatment of angina and hypertension for several
years.
It is known that the half-life of this active
ingredient is short, of the order of four hours, and the
drug is presently administered in the form of tablets
three or four times per day, which is all the more
exacting for the patient because his treatment must be
10 continued for prolonged periods. Furthermore, in the case
of the administration of this pharmaceutical form, the
plasma concentration varies widely between the two doses
so that the therapeutic efficacy is not continuous and
there exists an increased risk of side effects at peak
15 concentrations.
Consequently, it is desirable to have a
pharmaceutical form which gives rise to sustained-release
of an approximately constant concentration of this active
ingredient so that it is possible to administer the drug
20 only once or twice a day.
Different means are known for the obtention of
sustained-release pharmaceutical forms which can be
administered orally either in the form of tablets or in
the form of microgranules, such as those described in
25 EP-A-0 076 428, EP-A-0 061 217 and EP-A-0 216 743.
Such means must be adapted to each drug since
the rate and duration of release of the active ingredient
as well as its plasma concentration depend on its physico-
chemical properties, including its solubility and
30 stability in the gastro-intestinal tract, and on its
pharmacokinetic parameters.
Such a form is particularly difficult to prepare
for compounds of short half-life, less than 4-5 hours,
such as diltiazem, since the duration of its release in
35 vivo from the pharmaceutical form does not exceed the
residence time of the drug in the gastro-intestinal tract,
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i.e., maximally 8 to 10 hours, and then only if release
commences immediately on arrival in the stomach.
Furthermore, during this period release is
required to be more or less constant although the pH of
5 the surrounding medium changes from 1.5 in the stomach to
6.9 in the jejunum.
One of the objects of the present invention is
a sustained-release pharmaceutical composition of
diltiazem which, depending on the type of treatment,
10 requires only one or two daily administrations by the oral
route. It consists of a capsule of gelatin, starch or
other polymer which can be rapidly degraded in the gastric
environment, containing a large number of microbeads
composed of a core containing the active ingredient
15 surrounded by a microporous membrane, this membrane being
composed of a non-water-soluble film-forming polymer, a
plasticizer and a filling material; the thickness of the
membrane of the microbeads as well as the amount of active
ingredient in the core and its size are chosen such that
20 diltiazem is liberated from the microbeads in vitro in
artificial dissolution media in which the pH varies from
1.5 to 7, at a substantially constant rate for at least 6
hours, after a latent period of less than one hour.
The core may be constituted of small spheres,
25 produced by extrusion/sphere-formation from a plastic mass
based on a polyol such as mannitol or a polymer such as
polyglycol, and a water-soluble salt of diltiazem, but a
core is preferred which consists of a inert grain composed
of excipients, this inert grain being coated with the
30 active ingredient.
The inert grain may be constituted by a sugar,
with a hydrocolloid, such as gum arabic, gelatin or starch
or a biocompatible polymer such as the micro-crystalline
celluloses, alkylcelluloses, carboxymethylcelluloses as
35 well as mixtures of them or other excipients well known to
the specialist skilled in the art. A mineral filling
1 336326
material such as talc may be added if required. The inert
grain can be prepared in a standard manner in a turbine,
or by extrusion/sphere-formation from polymers or by
granulation of a molten mass passing through a vibrating
5 nozzle before cooling.
The active ingredient is then bound to the inert
grain in one or several successive layers in a turbine or
~ in a fluidized bed either by the spraying of a solution or
suspension of the diltiazem salt and a polymeric binder
lo with evaporation of the solvent, or by the spraying of an
alcoholic solution of the binder onto the substrate
followed by spraying of the diltiazem salt as a powder
onto the viscous layer just deposited; the second
solution is preferred since the cores thus obtained form
15 less aggregates and are more regular.
Preferably, an appreciable quantity of active
ingredient should not be left in the microbeads when, in
vivo, they leave the duodenal resorption zone, which
corresponds in vitro to the release of at least 60% of the
20 active ingredient from the core within 8 hours, and the
concentration of active ingredient in the core is
calculated as a function of this.
Usually, for technical reasons, it is preferable
that the concentration of active ingredient in the core is
25 30 to 50% by weight, but in particular in the case of the
higher dosage pharmaceutical compositions according to the
invention, there may be up to 85~ of active ingredient in
the core.
It is desirable to have microbeads of a diameter
30 varying between 0.4 and 1.4 mm, so that the number of
microbeads introduced into a capsule of acceptable
dimensions which can be swallowed by the patient without
difficulty, is more than loO and preferably lies between
200 and 600; thus the dose of the active ingredient and
35 the kinetics of its release will be of an acceptable
reproducibility from one capsule to another in spite of
1 33-63`26
the unavoidable heterogeneity of the microbeads due to the
manufacturing techniques. Under these conditions the
cores will preferably have diameters varying between 0.4
mm and 1.3 mm. In the case in which the active ingredient
5 is bound by a binder to the inert grain from 5 to 20% by
weight of binder is used in relation to the weight of the
diltiazem salt. Binders which can be used are water-
soluble binders well known to the technique, and which are
compatible with the diltiazem salt, such as methylcellu-
10 loses, water-soluble polyacrylates and polyvinylpyrroli-
dones. A polyvinylpyrrolidone of molecular mass of
approximately 50,000, marketed by GAF (FGR) under the
trade name Plasdone, is preferably used.
As diltiazem salt, the standard salt, namely the
15 hydrochloride is usually used but other more or less
water-soluble salts may be used, either salts of mineral
acids such as the sulfate, or salts of organic acids such
as fumarate, oxalate, succinate and similar compounds;
the amount of active ingredient in the core and the
20 thickness of the membrane will be defined as a function of
the solubility of the salt in aqueous medium.
A fundamental feature of the invention resides
in the choice of the properties of the microporous
membrane which surrounds the core.
In fact, it has been observed that, in order to
obtain a sustained-release pharmaceutical form, having
acceptable in vivo kinetics, it is necessary that the in
vitro diffusion kinetics of the diltiazem salt from the
microbeads in standard artificial dissolution media in
30 which the pH varies from 1.5 to 7 is approximately
constant for at least 6 hours and preferably up to 8
hours, and the time necessary to obtain a constant rate of
diffusion, i.e. the latent period, is less than one hour.
Under these conditions, capsules containing 120
35 mg of active ingredient included in microbeads of the
invention, administered twice a day to human subjects
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gives rise, at equilibrium, to a plasma concentration
which is always higher than 80 ng/ml, with a peak close to
130 ng/ml which is reached within 6 hours, whereas a
standard pharmaceutical composition administered twice a
5 day at the same doses rapidly gives rise to a peak
concentration of up to 180 ng/ml with a rapid decrease to
50 ng/ml after 6 hours.
of the non-water-soluble biocompatible polymers
which are stable in vivo and capable of constituting the
10 microporous membrane, mention may be made of the
polyacrylates and polymethacrylates of the Eudragit type,
the alkylcelluloses including the methylcelluloses of the
Tylose type (Hoechst) and the ethylcelluloses such as
those marketed by Hercules and the lacquers of natural
15 origin such as the shellac gums. The properties of the
last-mentioned are poorly reproducible from one batch to
another and ethylcellulose, the viscosity of which, when
measured according to the method of the US National
~ormulary, lies between lo and 50 mPa.s. is preferred
20 since it is of reproducible quality and chemically inert.
The polymers must be combined with a plas-
ticizing agent so that the membrane is not brittle, and
with a finely divided filling material which may amount to
between 35 and 75~ by weight of the membrane.
Of the plasticizing agents which may be used, in
particular phthalic esters, polyethylenglycols, castor oil
and glycerol, castor oil is preferred.
The amount of plasticizing agent introduced
depends on the type used. It usually represents from lo
30 to 30% by weight of the film-forming agent.
The presence of a filling material in sufficient
amount is fundamental; it reduces the swelling time of the
membrane in vivo, hence the latent period, without
simultaneously increasing excessively the rate of
35 diffusion of the active ingredient; a low diffusion rate,
necessary for a sustained release form, can be obtained by
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increasing the thickness of a membrane of conventional
composition, but the latent period is simultaneously
increased.
It is known that in the case of diltiazem, it is
5 of fundamental importance to have a short latent period,
in order to avoid bioavailability losses and release of
the active ingredient during too short a period before the
microbeads leave the gastro-intestinal tract.
Nonetheless, in order to reduce this latent period, it is
10 not possible to reduce the thickness of the membrane
excessively as this would make it difficult to reproduce
its diffusion properties during manufacture; the
heterogeneity which would result in the case of the beads
thus obtained in the same batch or in successive batches
15 would make it practically impossible to manufacture
pharmaceutical compositions, the rate of release of the
active ingredient from which is defined and reproducible.
of the finely divided filling materials which
can be used, and which are insoluble in the solvent in
20 which the membrane is applied, mention may be made of
talc, silica, metal silicates such as A1 and Mg silicates,
kaolin, powdered lactose and sucrose, metal oxides such as
titanium oxides, or their mixtures. Neutral filling
materials such as talc are preferred.
In a preferred embodiment of the invention, the
membrane is constituted of 25 to 40% by weight of
ethylcellulose, from 5 to 10% by weight of castor oil and
from 50 to 70% by weight of talc.
The microporous membrane can be applied by
30 spraying an alcoholic or aqueous-alcoholic dispersion of
the film-forming polymer, plasticizing agent and filling
material into a turbine or into an air-operated fluidized
bed.
In the case of an ethylcellulose-based membrane,
35 its thickness will vary between 15 micrometers and 60
micrometers.
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The amount of the composition to be deposited in
order to form a membrane of suitable thickness is
determined by preliminary tests during which the rate of
diffusion of diltiazem in vitro is measured under the
5 standard conditions of the United States Pharmacopea (USP
Z1. Chap. 711, page 1243; apparatus N 1) using artificial
dissolution media of different pHs varying from 1.5 to 7
and being, for example, 1.5, 4.5 and 7, starting from
microbeads containing the selected core and membranes of
lo different thicknesses deposited in successive layers. The
thickness of the membrane is then chosen so that an
approximately constant rate of diffusion is established
within less than one hour and from the measured value of
the diffusion rate from the microbeads with this membrane
15 thickness are deduced what must be the dimensional
characteristics of the core in order to insure the in
vitro release per hour of about 10~ of the amount of
active ingredient present.
It has in fact been observed that this in vitro
20 rate of release gives plasma concentrations in vivo which
are satisfactory for the intended thereapeutic use.
The microbeads of the invention are stable; the
kinetics of in vitro dissolution do not change during
storage as has frequently been observed with this type of
25 pharmaceutical form.
The pharmaceutical compositions according to the
invention can be made available in the form of capsules of
conventional composition and size containing from loo to
600, and preferably from 200 to 350, microbeads of the
30 invention such that a unit dose contains from 90 mg to 350
mf of diltiazem. The required number of microbeads are
introduced into each capsule; the same microbeads can be
used irrespective of the unit dose to be made up but, for
extreme doses, it is preferable in particular to select
35 the composition and size of the microbeads such that the
number of microbeads per capsule lies between 300 and 350.
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These microbeads can be introduced into other
pharmaceutical forms : cachets, divisible or indivisible
tablets, suppositories and liquid or gelled suspensions.
In what follows, particular embodiments of the
5 invention are described as examples of the microbeads, the
process for their preparation and novel sustained-release
pharmaceutical compositions of the invention. The curves
of dissolution in artificial media of various pH prepared
as described in the U.s.P. have been plotted with an
lo apparatus into which the quantity of microbeads
corresponding to the dose of active ingredient have been
introduced per liter of medium. The diltiazem
hydrochloride released as a function of time is measured
by spectrophotometry.
EXAMPLE:
In order to prepare about lo kg of granular
substrate, about 2 kg of "seed" obtained by sieving
crystallized sucrose through a 0.500 mm mesh sieve and
20 freed of dust by sieving through a 0,200 mm mesh sieve are
introduced into a turbine.
An aqueous-alcoholic solution containing sucrose
(6 parts) and polyvidone K30 (one part) in a water-ethyl
alcohol mixture (50/50 -V/V), i.e. about 5 liters for 2.5
25 kg of sucrose/polyvidone mixture, are sprayed several
times.
Between each spraying, dusting is done with a
mixture of talc (one part), maize starch (one part) and
sucrose (2 parts) until microspheres of about 0.5 to
30 0.6 mm diameter are obtained. After drying in an
incubator at 40C, the fraction with diameters included
between 0.600 mm and 0.300 mm is isolated; it will
subsequently be used as the granular substrate.
About 1.5 kg of granular substrate are then
35 introduced into a turbine and its weight is approximately
doubled by spraying with a 10% (wt/v) alcoholic solution
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of polyvidone and dusting between each spraying with
diltiazem hydrochloride previously passed through a 0.5 mm
mesh sieve until about 2.5 kg of cores are obtained.
Drying is performed in an incubator at 40C.
The content of active ingredient is of the order
of 40% by weight. The small cores are removed by means of
a 0.6 mm mesh sieve and the cores are reintroduced into a
turbine equipped with a spraying device. An alcoholic
solution containing about 12% by weight of a mixture of
10 ethyl cellulose (5 parts) and castor oil (one part) is
spraying onto the cores which are dusted with talc between
sprayings; the ethylcellulose has a viscosity of from 18
to 24 mPa.s.
When the mass of the beads has increased by 10%
15 a first sample A is taken, then the deposition of the
membrane is continued to give a sample B taken after a
weight increase of 30%, and a sample C taken after a
weight increase of 55%; these three batches are dried in
an incubator at 40OC. The kinetics of dissolution for
20 each of them are determined in vitro at pH 1.5, and hence
the release per hour at constant rate (the percentage of
active ingredient released by the microbeads in one hour)
and the latent period can be deduced.
The results obtained are shown in the table
25 below:
Test sample : : Rate of
corresponding to 120 mg : Latent period : release
of active ingredient : : per hour
Sample A : o :25 %
Sample B : 2 hours :13,75%
Sample C : 4 hours : 9 %
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In this case, it is observed that the microbeads
B and C did not comply with the characteristics of the
invention tlatent period too long) and that the membrane
was required to be thicker than that of the microbeads A
5 (too rapid dissolution) and consequently the operating
conditions have been modified in order to give rise to the
microbeads according to the invention.
Microbeads have thus been prepared to give a
dose of 120 mg of active ingredient in a capsule N 1 with
lo 250 microbeads per capsule; these microbeads contain 48%
by weight of active ingredient, the inert grain represents
31% by weight of the microbead whereas the membrane
represents 17.5% by weight of the microbead.
Starting from a representing 11% of the final
15 weight of the microbead, microbeads have also been
prepared to give a dose of 300 mg of active ingredient in
a capsule N 0, which contained 75~ by weight of active
ingredient; the membrane represents 11% by weight of the
microbead.
In vitro, these microbeads show practically no
latent period, the rate of release is constant and the
amount of diltiazem released at the end of 4 hours is
about 40% of the total quantity whereas it is about 60% at
the end of 6 hours.
These properties are not altered after at least
lB months storage at ambient temperature and after 3
months storage at 40C or at 55C.
