MULTILAYER PHARMACEUTICAL COMPOSITION THAT CAN BE
DISPERSED IN WATER AND WHICH CONTAINS A COMBINATION
OF ANTIMALARIAL AGENTS
The present invention relates to a water-dispersible
multilayer pharmaceutical composition comprising an
antimalarial agent in combination with at least one other
antimalarial agent. The present invention also comprises a
method for producing such a pharmaceutical composition.
Each year, malaria causes 400 to 900 million cases of
fever, and between one and three million deaths, i.e., on
average, one death every 30 seconds. The vast majority of
victims are children under the age of 5 and pregnant women.
Despite the efforts undertaken to reduce transmission of
the disease and to improve its treatment, there has been
little change since the beginning of the 1990s. It is also
estimated that, if the prevalence of malaria continues at
its current rate, the mortality rate could double in the
next twenty years.
The strong upsurge in the disease observed over the last
few years is due to several factors, including:
-the vectors, namely anopheles mosquitoes, which
become resistant to conventional and inexpensive
insecticides, such as DDT (abbreviation for
1,1,l-trichloro-2,2-bis(p-chlorophenyl)ethane);
- the increase in the population in the areas at risk
and, mainly,
-the resistance of many strains of Plasmodium
falciparum, the parasite responsible for the deadly forms
of the disease, to the antimalarials conventionally used,
such as chloroquine, mefloquine, sulphadoxine-pyrimethamine
and amodiaquine.
Polychemoresistant P. falciparum malaria is very widespread
in south-east Asia and in South America. The African
continent, which bears the heaviest burden of morbidity and
mortality due to malaria, is now also affected. Resistance
to inexpensive monotherapies such as chloroquine and
sulphadoxine-pyrimethamine is gaining ground, hence the
increase in mortality. The current situation is partly due
to the fact that antimalarials were used badly over the
past century: antimalarials were used massively, always in
monotherapy, one after the other, and generally with
contempt for the regulations for the use of medicaments
since they were maintained despite unacceptable resistance
levels.
A new group of antimalarials - artemisinin derivatives, in
particular artesunate, artemether and dihydroartemisinin -
has been increasingly used over the past ten years. These
compounds have a very rapid therapeutic action (decrease in
parasite count and resolution of symptoms), they are
effective against polychemoresistant P. falciparum malaria,
they are well tolerated by patients and they reduce the
carrying of gametocytes (and can therefore reduce
transmission of malaria).
No resistance of the parasite to these compounds has been
observed to date, although a certain decrease in
sensitivity has been detected in vitro in China and in
Vietnam. Used alone, the artemisinin derivatives provide
recovery from P. falciparum malaria in seven days, but
several studies have shown that the artemisinin derivatives
combined with certain synthetic medicaments give high
recovery rates in only three days with greater treatment
compliance. According to some data, the use of these
combinations could also substantially defer the appearance
of resistance to the combined medicament in areas of low-
to-moderate transmission.
In response to the increase in resistance to antimalarials,
the WHO recommends, to countries which observe a resistance
to conventional monotherapies, such as chloroquine,
amodiaquine or sulphadoxine-pyrimethamine, the use of
therapeutic combinations, preferably those which contain
artemisinin derivatives, against P. falciparum malaria.
Artemisinin is a sesquiterpene lactone with two oxygen
atoms bonded by a peroxide bridge above a ring with seven
carbon atoms. It is mainly artemisinin derivatives which
are used in therapy, for instance artemether, artesunate,
arteether or dihydroartemisinin.
Artesunate corresponds to the following formula:

Among the antimalarials being developed is ferroquine, the
structural formula of which is represented below, and which
is described in application WO 96/35698

WO 2006/111647 also describes the combination of ferroquine
and an artemisinin derivative, and in particular
artesunate.
As a general rule, a combination of two active ingredients
is produced by mixing the powders containing the active
ingredients and the excipients, or else by granulating
them. The most conventional method consists in producing
the pharmaceutical composition corresponding to an active
ingredient, and in adding the second active ingredient
during the mixing or the granulation step.
However, artesunate and ferroquine are strongly
incompatible if the two active ingredients are combined
within one and the same tablet. In particular, the
combining of ferroquine and artesunate within the same
tablet inevitably causes a rapid increase in the level of
artesunate degradation products within the tablet
[characterized by changing the colour of the artesunate,
which goes from white to brown].
In the present application, the term "ferroquine" is
intended to mean ferroquine in the form of a base, a salt,
a hydrate or a solvate. Similarly, the term "artemisinin"
is intended to mean artemisinin or a derivative thereof,
for example artemether, artesunate, arteether or
dihydroartemisinin, it being possible for artemisinin or a
derivative thereof to be in the form of a base, a salt, a
hydrate or a solvate.
A subject of the present invention is a multilayer
pharmaceutical composition, characterised in that it
comprises at least two layers and a minimum of two active
ingredients per pharmaceutical composition, said
composition being water-dispersible and comprising:
ferroquine in the form of a base, a salt, a hydrate or
a solvate, as first active ingredient,
artemisinin or a derivative thereof, in the form of a
base, a salt, a hydrate or a solvate, as second active
ingredient,
pharmaceutically acceptable excipients.
According to one embodiment of the invention, the
pharmaceutical composition is in tablet form.
The pharmaceutical composition according to the invention
is a multilayer pharmaceutical composition comprising at
least two layers.
In particular, this pharmaceutical composition is a two-
layer pharmaceutical composition.
More particularly, this pharmaceutical composition is a
three-layer pharmaceutical composition.
Thus, such a pharmaceutical composition contains
therapeutically effective doses of ferroquine, or of a
pharmaceutically acceptable salt, of a hydrate or of a
solvate of ferroquine, and of at least one artemisinin
derivative or of a derivative thereof, or of a
pharmaceutically acceptable salt, of a hydrate or of a
solvate of artemisinin or of a derivative thereof, and also
at least one pharmaceutically acceptable excipient. Said
excipients are chosen, according to the pharmaceutical form
and the method of administration desired, from the usual
excipients which are known to those skilled in the art.
The ferroquine can in particular be in the form of an
L-tartrate salt, a dihydrochloride salt, a hydrochloride
salt or a base. An example of the salt/base ratio for the
L-tartrate salt of ferroquine is 1.69, and an example of
the salt/base ratio for the dihydrochloride salt of
ferroquine is 1.17.
The pharmaceutical composition also contains a
therapeutically effective dose of artemisinin or of a
derivative thereof, chosen from artemether, artesunate,
arteether and dihydroartemisinin. According to one
embodiment of the invention, the artemisinin derivative
used is artesunate.
It is important for it to be possible for the
pharmaceutical composition according to the invention to be
ingested as a conventional tablet and for it not to
dissolve in the oral cavity as it passes to the oesophagus,
even if the passage is facilitated by the simultaneous
swallowing of liquid. However, malaria also affects infants
and young children with immature swallowing, and it is also
important for these young patients to have access to the
antimalarial treatment. Thus, the pharmaceutical
composition according to the invention is available in the
form of tablets produced in different sizes according to
the dosage and specifically suitable for the age of the
patient. The size of the tablet or compression format
(width x length) is expressed in millimetres (1 x L mm) .
Since the thickness of the tablets obtained depends,
firstly, on the compression format used, secondly on the
amount of powder to be compressed and, finally, on the
compression force applied, it is therefore variable.
The pharmaceutical composition according to the invention
is also water-dispersible, making it suitable for
paediatric use.
The expression "water-dispersible pharmaceutical
composition" is intended to mean a pharmaceutical
composition with high hardness, limited friability and
rapid disintegration. The expression "water-dispersible"
does not limit the scope of the invention to a dispersion
of the pharmaceutical composition in water, but should be
understood to be the dispersion of the pharmaceutical
composition in an aqueous liquid vehicle, such as, for
example, water, fruit juice, milk or alternatively a fizzy
drink.
In particular, all the tests carried out on the 10 dosages
targeted a disintegration time of at most 120 ± 15 seconds
in purified water at ambient temperature.
Moreover, the hardness of the present composition is
dependent on the size of the tablet (compression format).
For tablets having a compression format of 5.50 x 9.60 mm,
the hardness of the present composition is between 50 and
16 ON, pref erably between 6 0 and 15 ON, and even more
preferably between 70 and 140N, for example 93.8N.
For tablets having a compression format of 6.95 x 12.17 mm,
the hardness of the present composition is between 100 and
17 5N, preferably between 110 and 16 5N, and even more
preferably between 115 and 160N, for example 132N.
For tablets having a compression format of 8.76 x 15.3 mm,
the hardness of the present composition is between 110 and
23 ON, preferably between 12 0 and 22 ON, and even more
preferably between 130 and 210N, for example 169N.
For tablets having a compression format of 10 x 17.5 mm,
the hardness of the present composition is between 140 and
260N, preferably between 160 and 240N, and even more
preferably between 170 and 230N, for example 198N.
The hardness is measured according to the method described
below: the tablet is placed against the fixed jaw of a
durometer. The other, mobile, j aw moves by means of a
motorized drive system and applies, to the tablet, a
pressure which constantly increases. The increase in
pressure is monitored electronically by the durometer and
continues to be applied to the sample until an equal or
greater value is measured. At the time of break, the
resistance of the tablet to the pressure applied decreases.
The measuring system detects this decrease and the highest
resistance value is then displayed and is validated as
being the breaking strength value for the tablet.
The friability of the pharmaceutical composition is also
dependent on the size of the tablet (compression format)
and on the compression strength applied, having an effect
on the disintegration time of the tablets obtained.
For tablets having a compression format of 5.50 x 9.60 mm,
the friability of the pharmaceutical composition after
4 minutes is, according to one of the aspects of the
invention, between 0 and 0.3%, preferably between 0 and
0.2%, even more preferably between 0 and 0.15%, for example
0.11%.
For tablets having a compression format of 6.95 x 12.17 mm,
the friability of the pharmaceutical composition after
4 minutes is, according to one of the aspects of the
invention, between 0 and 0.3%, and even more preferably
between 0 and 0.2%, for example 0.11%.
For tablets having a compression format of 8.76x15.3 mm,
the friability of the pharmaceutical composition after
4 minutes is, according to one of the aspects of the
invention, between 0 and 0.3%, and even more preferably
between 0 and 0.2%, for example 0.17%.
For tablets having a compression format of 10x17.5 mm,
the friability of the pharmaceutical composition after
4 minutes is, according to one of the aspects of the
invention, between 0 and 0.5%, preferably between 0 and
0.4%, even more preferably between 0 and 0.3%, for example
0.21%.
The friability of the tablets is measured after 100
rotations according to the method described in the European
Pharmacopoeia, 6th Edition, 2010, Chapter 2.9.7.
The disintegration is measured according to the method
described in the European Pharmacopoeia, 6th Edition, 2 010,
Chapter 2.9.1. The tablets obtained, irrespective of the
formats and the dosages, comply with the standard applied
with regard to "dispersible tablets".
The fineness of dispersion is also, in one embodiment,
consistent with the following definition; two tablets are
placed in 100 ml of purified water, which is stirred until
complete dispersion. The dispersion obtained is homogeneous
and passes through a screen with a nominal mesh size of
710 urn. The fineness of dispersion is measured according to
the method described in the European Pharmacopoeia, 6th
Edition, 2010, Chapter 7, relating to the definition of
dispersible tablets.
According to one embodiment, the tablet according to the
invention comprises two layers, one comprising ferroquine
in the form of a base, a salt, a hydrate or a solvate, and
the other comprising artesunate in the form of a base, a
salt, a hydrate or a solvate.
According to another embodiment, the tablet according to
the invention comprises three layers, one comprising
ferroquine in the form of a base, a salt, a hydrate or a
solvate, and a second comprising artesunate in the form of
a base, a salt, a hydrate or a solvate, these two layers
being separated by an isolating layer containing no active
ingredient (neutral).
The layers may be identical or different in terms of weight
or of volume, and they may or may not all be visible from
the exterior. For example, it is possible to have an upper
half of a tablet according to the invention comprising
ferroquine, and a lower half comprising artemisinin or a
derivative thereof, the two halves being the same colour
and having the same appearance, and therefore
indistinguishable by the patient. The two halves may
alternately be of different colour and/or have a different
appearance.
In the case of a tablet comprising three layers, the two
layers containing the 2 active ingredients will be
separated by an isolating layer which is the same colour
and has the same appearance as one of the two layers
comprising one of the active ingredients, said layers
therefore remaining indistinguishable by the patient. The
neutral isolating layer makes it possible to separate the
two layers containing the incompatible active ingredients.
It therefore limits the degradation of the active
ingredients within the tablet and therefore makes it
possible to obtain greater stability of the formulation.
The two halves and also the intermediate isolating layer
may alternatively be of different colour and/or have a
different appearance.
It is also envisaged that the tablet be a "sandwich" of
layers comprising different active ingredients, for example
a layer of artemisinin or of a derivative thereof, between
two layers of ferroquine, or vice versa.
Another aspect of the invention is that one of the layers
containing a first active ingredient is completely coated
with the other layer comprising the second active
ingredient.
According to another subject, the invention consists of a
water-dispersible multilayer pharmaceutical composition
comprising at most two active ingredients per
pharmaceutical composition, said composition comprising:
ferroquine as first active ingredient,
artemisinin or a derivative thereof as second active
ingredient, and
pharmaceutically acceptable excipients,
the level of disintegrating agent being less than 5% by
weight of the tablet, expressed relative to the total mass
of the tablet.
According to one embodiment of the invention, the level of
disintegrating agents of the pharmaceutical composition, in
particular of the tablet, is less than 5%, and in
particular less than 3.5%, relative to the total mass of
the tablet.
According to another embodiment of the invention, the level
of disintegrating agent in each of the layers is less than
2.5%, relative to the total mass of the tablet, for example
less than 2%.
The pharmaceutical composition according to the invention
has :
a disintegration time of 120 ± 15 seconds;
a friability of less than 0.5%;
a level of disintegrating agent of less than 5%
relative to the total mass of the tablet;
a level of disintegrating agent in each of the
layers of less than 2.5% relative to the mass;
a hardness of between:
¦ 50 and 160N when the pharmaceutical composition
has a compression format of 5.50 x 9.60 mm;
¦ 100 and 175N when the pharmaceutical composition
has a compression format of 6.95 x 12.17 mm;
¦ 110 and 2 3 ON when the pharmaceut ical compos it ion
has a compression format of 8.76 x 15.30 mm;
¦ 140 and 260N when the pharmaceutical composition
has a compression format of 10 x 17.50 mm.
More particularly, the pharmaceutical composition according
to the invention has:
a disintegration time of 120 ± 15 seconds;
a friability of less than 0.4%;
a level of disintegrating agent of less than 3.5%
relative to the total mass of the tablet;
a level of disintegrating agent in each of the
layers of less than 2% relative to the mass;
a hardness of between:
¦ 70 and 140N when the pharmaceutical composition
has a compression format of 5.50 x 9.60 mm;
¦ 115 and 160N when the pharmaceutical composition
has a compression format of 6.95 x 12.17 mm;
¦ 13 0 and 210N when the pharmaceutical composition
has a compression format of 8.76 x 15.30 mm;
¦ 170 and 230N when the pharmaceutical composition
has a compression format of 10 x 17.50 mm.
The applicant has found, surprisingly, that the
pharmaceutical compositions according to the invention,
despite high tablet hardnesses, very low friabilities, and
a level of disintegrating agent of less than 5%, or even
less than 3.5%, relative to the total mass of the tablet,
are nevertheless hydrodispersible. The term
"hydrodispersible" or "water-dispersible" is intended to
mean the definition in the European Pharmacopoeia, which
stipulates that dispersible tablets are uncoated tablets or
film-coated tablets intended to be dispersed in water
before administration, giving a homogeneous dispersion.
According to .another embodiment of the invention, the
pharmaceutical composition comprises:
compounds of the internal phase for the ferroquine
layer:
o between 5% and 3 0% of ferroquine,
o between 0.2% and 1.0% of disintegrating agent,
o between 10% and 40% of diluent,
- optionally, compounds of the external phase for the
ferroquine layer:
o between 0.1% and 1% of lubricant,
o between 0 and 4.0% of sweetener,
- compounds of the internal phase for the layer of
artemisinin or a derivative thereof:
o between 5% and 20% of artemisinin or a derivative
thereof,
o between 0 and 10% of diluent,
o between 8% and 16% of codiluent,
o between 0.5% and 2% of binder,
o between 0 and 2% of disintegrating agent,
optionally, compounds of the external phase for the
layer of artemisinin or a derivative thereof:
o between 0 and 1% of lubricant,
o between 0 and 0.3% of flow agent,
compounds for the neutral isolating layer:
o between 10% and 30% of diluent,
o between 0 and 10% of codiluent,
o between 0 and 0.5% of lubricant,
o between 0 and 2% of disintegrating agent,
it being understood that, if the pharmaceutical composition
does not comprise an external phase, it should contain from
0.5% to 2% of lubricant.
The pharmaceutically acceptable excipients comprise a
disintegrating agent which can be chosen from sodium
carboxymethyl starch, sodium croscarmellose, calcium
carboxymethylcellulose or sodium carboxymethylcellulose,
pregelatinized starch, crospovidone or alginic acid or one
of its derivatives.
Examples of binders which can be used in the invention are
polyethylene glycol, pregelatinized starch, copovidone,
maltodextrins, hydroxypropylcellulose, guar gum, alginates,
for example sodium alginates, povidone (polyvinyl-
pyrrolidone PVP K30), carbomers, methylcellulose, dextrins,
hydroxyethylmethylcellulose, hydroxypropylcellulose,
hypromellose, ethylcellulose, polydextrose, gelatin,
propylene glycol or else polymethacrylates.
The diluent can be chosen from microcrystalline cellulose
PH 112, starch (maize, rice, potato, in particular),
pregelatinized starch, maltose, mannitol, maltitol,
xylitol, lactitol, sorbitol, fructose, lactose (whether it
is anhydrous, monohydrate or atomized), dextrin or a
derivative thereof, calcium carbonate, calcium lactate,
calcium phosphate, calcium sulphate or sucrose, for
example.
Examples of lubricants which can be used in the context of
the invention are magnesium stearate, hydrogenated castor
oil, glyceryl palmitostearate, polyoxyethylene stearates,
glyceryl behenate, sodium lauryl sulphate, calcium
stearate, leucine, sodium stearyl fumarate, poloxamer,
glyceryl monostearate or else polyethylene glycol.
Sweetener can be chosen from potassium acesulfame, sucrose,
sucralose, aspartame, neohesperidin dihydrochalcone,
thaumatin, neotame, tagatose, sodium saccharin, sodium
cyclamate, maltose, mannitol, maltitol, xylitol, lactitol,
sorbitol, fructose, lactose (whether it is anhydrous,
monohydrate or atomized) or else trehalose.
The flow agent can be chosen from colloidal silica, talc,
magnesium silicate, calcium stearate or calcium phosphate,
for example.
According to one embodiment, the pharmaceutical composition
comprises:
in the compounds of the internal phase for the
ferroquine layer, sodium carboxymethyl starch as
disintegrating agent, microcrystalline cellulose as
diluent;
in the compounds of the external phase for the
ferroquine layer, magnesium stearate as lubricant,
potassium acesulfame as sweetener,-
in the compounds of the internal phase for the
artesunate layer, calcium carbonate as diluent,
microcrystalline cellulose as codiluent, sodium
croscarmellose as disintegrating agent, povidone as binder;
in the compounds of the external phase for the
artesunate layer, colloidal silica as flow agent, magnesium
stearate as lubricant;
in the compounds of the neutral isolating layer,
calcium carbonate as diluent, microcrystalline cellulose as
codiluent, magnesium stearate as lubricant and sodium
carboxymethyl starch as disintegrating agent.
The daily doses of each of the two active ingredients of
the combination according to the invention can be the
following:
-ferroquine: between 1 and 10 mg/kg/day, for example 2,
4 or 6 mg/kg/day;
-artemisinin derivative: between 1 and 10 mg/kg/day,
for example between 2 and 6 mg/kg/day, or else
approximately 4 mg/kg/day.
There may be specific cases where higher or lower dosages
are appropriate; such dosages do not depart from the
context of the invention. According to customary practice,
the appropriate dosage for each patient is determined by
the physician according to the method of administration and
the weight and response of said patient.
The pharmaceutical composition according to the invention
is intended to be administered for 3 consecutive days, in
one or more daily intakes of each of the two active
ingredients, preferably a single intake per day. This
treatment time limited to 3 days is particularly
advantageous, in comparison with the 7 days recommended for
a monotherapy with the artemisinin derivatives, in that it
enables better treatment compliance by the patients, thus
avoiding premature interruptions of the treatment which
induce, in the long term, resistance of the parasite.
By way of examples of a pharmaceutical composition
according to the invention, the following tablets can be
envisaged:
Such a tablet is, for example, compressed while adhering to
the following parameters:
compacting pressure for the internal phase of the
ferroquine layer: 4 5 bar;
compression format: 17.5 x 10 mm;
compression force applied to the first layer
(artesunate layer): 0 kN;
- compression force applied to the second layer
(neutral layer): 2 kN;
final compression force for the second layer
(ferroquine layer): 24 kN.
Such a tablet is, for example, compressed while adhering to
the following parameters:
compacting pressure for the internal phase of the
ferroquine layer: 4 5 bar;
- compression format: 8.76 x 15.30 mm;
compression force applied to the first layer
(artesunate layer): 0.2 kN;
- compression force applied to the second layer
(neutral layer): 0.4 kN;
- final compression force for the third layer
Such a tablet is, for example, compressed while adhering to
the following parameters:
compacting pressure for the internal phase of the
ferroquine layer: 4 5 bar;
compression format: 6.95 x 12.17 mm;
compression force applied to the first layer
(artesunate layer): 0.2 Re-
compression force applied to the second layer
(neutral layer): 0.2 kN;
final compression force for the third layer
(ferroquine layer): 13.4 kN.
Such a tablet is, for example, compressed while adhering to
the following parameters:
compacting pressure for the internal phase of the
ferroquine layer: 45 bar;
- compression format: 5.5 x 9.6 mm;
- compression force applied to the first layer
(artesunate layer): 0.2 kN;
- compression force applied to the second layer
(neutral layer): 0.2 kN;
- final compression force for the third layer
(ferroquine layer): 8.75 kN.
According to another subject, the invention consists of a
method for producing the pharmaceutical composition.
The grains for compression of the ferroquine layer are
prepared separately from the grains for compression of the
layer of artemisinin or derivatives thereof and from the
grains of the neutral layer.
The grain for compression of the ferroquine layer is
prepared by
- premixing the internal phase compounds,
compacting the internal phase, and
mixing the compacted grain with the external phase
excipients.
The grain for compression of the layer of artemisinin or
derivatives thereof is prepared by mixing the active
ingredient and the excipients of the internal and external
phase. The grain of the neutral layer is, for its part,
prepared by simple mixing of all its constituents.
The compression step is then carried out on a multilayer
tableting machine, for example of the Fette P102i or Hata
HT45 type.
More particularly, the grain for compression of the
ferroquine layer is prepared according to the following
steps:
- weighing out of the internal phase compounds,
screening of these compounds,
- premixing of these compounds in order to obtain a
homogeneous distribution of the active ingredient
and of the excipients,
compacting of the internal phase using a roller
compactor,
- weighing out of the external phase excipients,
- mixing of the internal phase compacted grain and of
the external phase excipients so as to obtain a
grain ready for compression,
and the grain for compression of the layer of artemisinin
or derivatives thereof is prepared according to the
following procedure:
weighing out of the internal phase compounds,
- premixing of the internal phase compounds,
we ighing out of the magne s ium stearat e and the
colloidal silica and then screening thereof,
final mixing of the magnesium stearate and colloidal
silica compounds so as to obtain a mixture ready for
compression.
The grain for compression of the neutral layer is prepared
according to the following procedure:
weighing out of all the constituents,
screening of these constituents,
- mixing of all the constituents.
The method for producing the multilayer tablets, and in
particular three-layer, ferroquine-neutral-artemisinin or a
derivative thereof, tablets can thus be exemplified as
described below:
a) preparation of the ferroquine layer:
al) weighing out of the ferroquine, a diluent and a
disintegrating agent,
a2) premixing for 15 minutes at 7 rpm,
a3) optionally, calibrating on a rotary calibrating device
with a 1.5 mm screen,
a4) mixing for 3 0 minutes at 7 rpm,
a5) compacting on a roller compactor, for example an
Alexanderwerk WP 50 roller compactor with screens of 2.5
and 1.25 mm,
a6) optionally, mixing of a lubricant and secondarily of a
sweetener, then calibration of this ingredient or these two
ingredients on a rotary calibration of device with a 1 mm
screen,
a7) if step a6) has been carried out, mixing of the
compounds resulting from step a6) and of the compounds
resulting from step a5),
a8) optionally, mixing in a Robotainer mixer, for
3 0 minutes at 7 rpm;
b) preparation of the layer of artemisinin or a derivative
thereof:
bl) weighing out of the active ingredient (artemisinin or a
derivative thereof), a diluent, a disintegrating agent, a
binder and a codiluent,
b2) optionally, mixing in an inverting mixer, or a CMA
rotary mixer, for 15 minutes at 7 rpm,
b3) optionally, calibrating on a CMA rotary calibrating
device with a screen of, for example, 1 mm,
b4) mixing of a lubricant and of a flow agent, then
optionally calibration of these two ingredients with a
1.0 mm screen,
b5) optionally, mixing in a Robotainer mixer for 15 minutes
at 7 rpm,
b6) mixing in a Robotainer mixer for 3 0 minutes at 7 rpm,
c) preparation of the neutral layer:
cl) weighing out of the two diluents, the disintegrating
agent and the lubricant,
c2) optionally, calibrating on a rotary calibrating device
with a 1.0 mm screen,
c3) optionally, mixing in an inverting mixer, or a CMA
rotary mixer, for 30 minutes at 7 rpm,
d) compression of the mixtures obtained:
- in a9) if this step has been carried out, or, where
appropriate, in the final step carried out in a), and
- in b6), and
- in c3),
for example in a multilayer tableting machine, for example
of the Fette P102i or Hata HT45 type.
According to one embodiment of the invention, the agents
mentioned in the steps hereinafter are, respectively:
- step al) : microcrystalline cellulose PHI12, sodium
carboxymethyl starch,
- step a6) or, where appropriate, in the last step carried
out in a): magnesium stearate and potassium acesulfame,
- step bl) : calcium carbonate, sodium croscarmellose,
povidone (PVP K30) and microcrystalline cellulose PH112,
- step b4): magnesium stearate and anhydrous colloidal
silica,
- step cl) : microcrystalline cellulose, calcium carbonate,
sodium carboxymethyl starch, magnesium stearate.
By way of example, a pharmaceutical composition according
to the invention which has the composition mentioned in the
table and which is produced according to the abovementioned
method has the following characteristics:
- compression format: 17.5 x 10 mm,
- average tablet hardness (n=10): 198N,
- friability after 4 minutes (%) according to the
European Pharmacopoeia (n=10): 0.21%
- disintegration time according to the European
Pharmacopoeia (n=6) in purified water at ambient
temperature: 123 seconds,
- conformity with respect to fineness of dispersion
according to the European Pharmacopoeia: conforms.
NEW SET OF CLAIMS
1. Multilayer tablet, characterized in that it comprises
at least two layers and a minimum of two active
ingredients per tablet, said tablet being water-
dispersible and comprising:
- a layer comprising ferroquine in the form of a base,
a salt, a hydrate or a solvate,
another layer comprising artesunate in the form of a
base, a salt, a hydrate or a solvate,
- pharmaceutically acceptable excipients.
2. Tablet according to Claim 1, characterized in that the
tablet is a two-layer tablet.
3. Tablet according to Claim 1, characterized in that the
tablet is a three-layer tablet.
4. Tablet according to either one of Claims 1 and 3,
characterized in that the two layers are separated by
an isolating layer containing not active ingredient
(neutral).
5. Tablet according to any one of Claims 1 to 4,
characterized in that the tablet has a disintegration
time of at most 120 ± 15 seconds.
6. Tablet according to any one of Claims 1 to 5,
characterized in that the tablet has a compression
format of 5.50 x 9.60 mm and a hardness of between 50
and 160N.
7. Tablet according to Claim 6, characterized in that the
tablet has a compression format of 5.50 x 9.60 mm and
a hardness of between 60 and 150N.
8. Tablet according to Claim 7, characterized in that the
tablet has a compression format of 5.50 x 9.60 mm and
a hardness of between 70 and 14ON.
9. Tablet according to any one of Claims 1 to 5,
characterized in that the tablet has a compression
format of 6.95 x 12.17 mm and a hardness of between
100 and 175N.
10. Tablet according to Claim 9, characterized in that the
tablet has a compression format of 6.95 x 12.17 mm and
a hardness of between 110 and 165N.
11.Tablet according to Claim 10, characterized in that
the tablet has a compression format of 6.95 x 12.17 mm
and a hardness of between 115 and 160N.
12. Tablet according to any one of Claims 1 to 5,
characterized in that the tablet has a compression
format of 8.76 x 15.3 mm and a hardness of between 110
and 230N.
13. Tablet according to Claim 12, characterized in that
the tablet has a compression format of 8.76 x 15.3 mm
and a hardness of between 120 and. 220N.
14.Tablet according to Claim 13, characterized in that
the tablet has a compression format of 8.76 x 15.3 mm
and a hardness of between 130 and 210N.
15. Tablet according to any one of Claims 1 to 5,
characterized in that the tablet has a compression
format of 10 x 17.5 mm and a hardness of between 140
and 260N.
16. Tablet according to Claim 15, characterized in that
the tablet has a compression format of 10 x 17.5 mm
and a hardness of between 160 and 240N.
17.Tablet according to Claim 16, characterized in that
the tablet has a compression format of 10 x 17.5 mm
and a hardness of between 170 and 230N.
18.Tablet according to any one of Claims 1 to 8,
characterized in that the tablet has a compression
format of 5.50 x 9.6 0 mm and a friability after
4 minutes of between 0 and 0.3 0%.
19.Tablet according to Claim 18, characterized in that
the tablet has a compression format of 5.50 x 9.60 mm
and a friability of between 0 and 0.20%.
20.Tablet according to Claim 19, characterized in that
the tablet has a compression format of 5.50 x 9.60 mm
and a friability of between 0 and 0.15%.
21.Tablet according to any one of Claims 1 to 5 and 9 to
11, characterized in that the tablet has a compression
format of 6 . 95 x 12.17 mm and a friability after
4 minutes of between 0 and 0.30%.
22.Tablet according to Claim 21, characterized in that
the tablet has a compression format of 6.95 x 12.17 mm
and a friability of between 0 and 0.20%.
23. Tablet according to any one of Claims 1 to 6 and 12 to
14, characterized in that the tablet has a compression
format of .8.76 x 15.3 mm and a friability after
4 minutes of between 0 and 0.30%.
24.Tablet according to Claim 23, characterized in that
the tablet has a compression format of 8.76 x 15.3 mm
and a friability of between 0 and 0.20%.
25. Tablet according to any one of Claims 1 to 6 and 15 to
17, characterized in that the tablet has a compression
format of 10 x 17.5 mm and a friability after
4 minutes of between 0 and 0.5%.
26. Tablet according to Claim 25, characterized in that
the tablet has a compression format of 10x17.5 mm
and a friability of between 0 and 0.4%.
27. Tablet according to Claim 26, characterized in that
the tablet has a compression format of 10 x 17.5 mm
and a friability of between 0 and 0.3%.
28. Tablet according to any one of Claims 1 to 27,
characterized in that the tablet comprises a level of
disintegrating agent of less than 5%, relative to the
total mass of the pharmaceutical composition.
29. Tablet according to Claim 28, characterized in that
the tablet comprises a level of disintegrating agent
of less than 3.5%, relative to the total mass of the
pharmaceutical composition.
30. Tablet according to Claim 28, characterized in that
the tablet comprises a level of disintegrating agent
of less than 2% in each of the layers.
31. Tablet according to any one of Claims 1 to 34,
characterized in that the tablet has:
a disintegration time of 120 ± 15 seconds;
a friability of less than 0.5%;
a level of disintegrating agent of less than 5%
relative to the total mass of the tablet;
a level of disintegrating agent in each of the
layers of less than 2.5% relative to the total mass;
a hardness of between:
¦ 50 and 160N when the tablet has a compression
format of 5.50 x 9.60 mm
or
¦ 10 0 and 17 5N when the tablet has a compression
format of 6.95 x 12.17 mm
or
¦ 110 and 2 3 ON when the tablet has a compression
format of 8.76 x 15.30 mm
or
¦ 14 0 and 2 6 ON when the tablet has a compression
format of 10 x 17.50 mm.
32. Tablet according to Claim 31, characterized in that
the tablet has:
a disintegration time of 120 ± 15 seconds;
a friability of less than 0.4%;
a level of disintegrating agent of less than 3.5%
relative to the total mass of the tablet;
a level of disintegrating agent in each of the
layers of less than 2% relative to the total mass;
a hardness of between:
¦ 70 and 140N when the tablet has a compression
format of 5,50 x 9.60 mm
or
¦ 115 and 160N when the tablet has a compression
format of 6.95 x 12.17 mm
or
¦ 130 and 210N when the tablet has a compression
format of 8.76 x 15.30 mm
or
¦ 170 and 230N when the tablet has a compression
format of 10 x 17.5 0 mm.
33 . Tablet according to any one of Claims 1 to 32,
characterized in that the tablet comprises:
compounds of the internal phase for the ferroquine
layer which are the following:
¦ between 5% and 3 0% of ferroquine,
¦ between 0.2% and 1.0% of disintegrating agent.,
¦ between 10% and 40% of diluent,
optionally, compounds of the external phase for the
ferroquine layer which are the following:
¦ between 0.1% and 1% of lubricant,
¦ between 0 and 4.0% of sweetener,
compounds of the internal phase for the layer of
artemisinin or a derivative thereof, said compounds
being the following:
¦ between 5% and 20% of artemisinin or a
derivative thereof,
¦ between 0 and 10% of diluent,
¦ between 8% and 16% of codiluent,
¦ between 0.5% and 2% of binder,
¦ between 0 and 2% of disintegrating agent,
optionally, compounds of the external phase for the
layer of artemisinin or a derivative thereof, said
compounds being the following:
¦ between 0 and 1% of lubricant,
¦ between 0 and 0.3% of flow agent,
compounds for the neutral isolating layer which are
the following:
¦ between 10% and 30% of diluent,
¦ between 0 and 10% of codiluent,
¦ between 0 and 0.5% of lubricant,
¦ between 0 and 2% of disintegrating agent,
it being understood that, if the tablet does not
comprise an external phase, it should contain from
0.5% to 2% of lubricant.
34. Tablet according to Claim 33, characterized in that it
comprises:
- in the compounds of the internal phase for the
ferroquine layer, sodium carboxymethyl starch as
disintegrating agent, microcrystalline cellulose as
diluent,
in the compounds of the external phase for the
ferroquine layer, magnesium stearate as lubricant,
potassium acesulfame as sweetener,
in the compounds of the internal phase for the
artesunate layer, calcium carbonate as diluent,
microcrystalline cellulose as codiluent, sodium
croscarmellose as disintegrating agent of the layer
of artemisinin or a derivative thereof, povidone as
binder of the layer of artemisinin or a derivative
thereof,
in the compounds of the external phase for the
artesunate layer, colloidal silica as flow agent,
magnesium stearate as lubricant,
in the compounds of the neutral isolating layer,
calcium carbonate as diluent, microcrystalline
cellulose as codiluent, magnesium stearate as
lubricant and sodium carboxymethyl starch as
disintegrating agent.
35. Method for producing a tablet according to any one of
the preceding claims, characterized by the following
steps:
e. preparation of the ferroquine layer:
i. al) weighing out of the ferroquine, a diluent
and a disintegrating agent,
ii. a2) premixing for 15 minutes at 7 rpm,
iii a3) optionally, calibrating on a rotary
calibrating device with a 1.5 mm screen,
iv. a4) mixing for 30 minutes at 7 rpm,
v. a5) compacting on a roller compactor, for
example an Alexanderwerk WP 50 roller compactor
with screens of 2.5 and 1.25 mm,
vi. a6) optionally, mixing of a lubricant and
secondarily of a sweetener, then calibration of
this ingredient or these two ingredients on a
rotary calibrating device with a 1 mm screen,
vii. a7) if step a6) has been carried out, mixing of
the compounds resulting from step a6) and of
the compounds resulting from step a5),
viii. a8) optionally, mixing in a Robotainer mixer
for 30 minutes at 7 rpm,
f. preparation of the layer of artemisinin or a
derivative thereof:
i. bl) weighing out of the active ingredient
(artemisinin or a derivative thereof), a
diluent, a disintegrating agent, a binder and a
codiluent,
ii. b2) optionally, mixing in an inverting mixer,
or a CMA rotary mixer, for 15 minutes at 7 rpm,
iii. b3) optionally, calibrating on a CMA rotary
calibrating device with a screen of, for
example, 1 mm,
iv. b4) mixing of a lubricant and of a flow agent,
then optionally calibration of these two
ingredients with a 1.0 mm screen,
v. b5) optionally, mixing in a Robotainer mixer
for 15 minutes at 7 rpm,
vi. b6) mixing in a Robotainer mixer for 30 minutes
at 7 rpm,
g. preparation of the neutral layer:
i. cl) weighing out of the two diluents, the
disintegrating agent and the lubricant,
ii. c2) optionally, calibrating on a rotary
calibrating device with a 1.0 mm screen,
iii. c3) optionally, mixing in an inverting mixer, or
a CMA rotary mixer, for 3 0 minutes at 7 rpm,
h. compression of the mixtures obtained
i. in a9) if this step has been carried out, or,
where appropriate, in the final step carried
out in a),
and
ii . in b6) , and
iii . in c3) .
h. compression of the mixtures obtained
i. in a9) if this step has been carried out, or,
where appropriate, in the final step carried
out in a),
and
ii . in b6), and
iii . in c3) .

ABSTRACT

The present invention relates to a multilayer pharmaceutical composition that can be dispersed in water,
containing one antimalarial agent in combination with at least one other antimalarial agent. The present invention also relates to a
method for producing such a pharmaceutical composition.