|Title of Invention||
"TABLET COMPRISING COMPRESSIBLE DILUENT"
|Abstract||A tablet comprising a low dose of active principle formed from microgranules comprising a directly compressible diluent, characterized in that the directly compressible diluent is composed solely of neutral microgranules and in that the active principle is attached as a coating to the neutral microgranules wherein the size of the neutral microgranules is between 100 and 2000 µm and hardness of the said tablet is between 0 and 20 daN and its friability is between 0 and 1%.|
|Full Text||The present invention relates to tablet comprising compressible diluents.
Dosing nonhomogeneity within tablets is one of the major problems encountered in the formulation of compositions comprising , a low dose of an active principle. For active principles with a low therapeutic margin, underdosing leads to therapeutic ineffectiveness and overdosing can result ±n toxic side effects.
Tablets are composed of one or more active principles and of tableting excipients, such as diluents, binders, lubricants and disintegrating agents. The active principle and the excipients are generally provided in the form of powders which are subjected to tableting, with or without preliminary treatment.
The various processes for the manufacture of tablets, namely dry granulation, direct compression and wet granulation, are presented in "Remington's Pharmaceutical Sciences, 16th Ed., 1980, Mack Publ. Co. of Easton, PA, USA, pp. 1553-1576".
Dry granulation is reserved for specific types of production, such as the manufacture of tablets comprising active principles which are soluble in water or sensitive to heat and to moisture. This technique is poorly suited to low doses of active principles because of the difficulty of obtaining homogeneous blends of dry powders.
Direction compression does not comprise a granulation stage prior to the compression and makes possible a considerable saving in time. Given that the majority of active principles have poor compressibility and/or are
used in a low amount per unit dose, they have to be
blended with excipients which are directly compressible
and which are compatible with the active principle in
order to be able to be subjected to direct compression.
Direct compression is carried out on high speed rotary
machines. The feed device, which generally operates by
gravity, is very sensitive to the agglomeration of the
powders or to the setting solid thereof. The rheology
of the blend of powders to be tableted is therefore a
determining factor in guaranteeing the uniformity in
weight of the tablets and the uniformity of their
Another major disadvantage of the direct compression
technique arises from the risk of separation of the
powders or "demixing". This demixing leads to tablets
which are nonhomogeneous in composition.
Thus, using the direct compression technique, it is
possible to observe a poor distribution of the active
principle in the excipients and a separation of the
active principle and the excipients during the blending
operation and in particular during all the transfer
operations, leading to a variation in weight and in the
content of active principle of the tablets. The poor
fluidity of the blend of powders generally is an
aggravating factor. The separation of the active
principle and excipients in the blend of powders before
tableting is observed in particular when the active
principle and excipients differ greatly in particle
Like dry granulation, direct compression is therefore
poorly suited to tablets comprising low doses of active
Furthermore, direct compression is not always
desirable, in particular when the active principle is
toxic: it is preferable to reduce the emission of dust
agglomerating the constituents by wet granulation.
Wet granulation consists in spraying a binder in
solution onto the powdered active
principle (s) /excipient (s) blend and in then granulating
the wet blend. Wet granulation has many advantages.
The formation of the grains limits the risks of
segregation of the powders composed of particles with
different sizes and shapes: there is therefore greater
assurance that the final tablet will be homogeneous
throughout its bulk. Furthermore, the conversion of a
powder into grains makes it possible to reduce the
problems of dust. The flow of the blend in the
tableting chamber is facilitated, which ensures that
the weight of the tablets will be uniform. Finally,
rendering the powder more dense makes possible easier
However, migration of the active principle inside the
granule can take place during the drying stage. This
phenomenon of migration is reinforced when the active
principle is soluble in the granulation excipient.
Another problem arises for crystalline active
principles exhibiting a degree of polymorphism.
Complete or partial dissolution of the active principle
during the granulation, followed by precipitation
during the drying, changes the particle sizes of the
active principle and optionally its crystallographic
state. Such modifications have a direct influence on
the dissolution and the bioavailability of the active
A number of approaches have been provided in the prior
art for solving the problem of the nonhomogeneity of
tablets comprising low doses of active principle, such
as combining, with a given active principle, a specific
blend of excipients which makes it possible to prevent
demixings, micronizing the active principle or
alternatively atomizing it or agglomerating it with the
direct compression excipient.
US 3 568 828 provides the dissolution of a blend of
estrogen and progesterone in chloroform using wet
granulation. The process consists subsequently in
spraying the solution onto microcrystalline cellulose,
in drying the blend, in adding lactose and a lubricant
to the blend, and in then tableting the combined
mixture. The use of volatile solvents represents a
major disadvantage, for reasons of safety of
manufacture and of residual amounts in the tablets.
US 4 489 026 provides tablets comprising less than 10
micrograms of active principle per tablet. These
tablets are obtained by very slowly spraying the
solution of active principle in a volatile solvent onto
a very finely divided powder of a highly absorbent
excipient which is insoluble in the solvent. The
excipient is chosen from lactose, starch, calcium
carbonate, TiC>2 and microcrystalline cellulose. The
process disclosed in this document is slow and employs
Thiel et al. (J. Pharm. Pharmacol. , 1986, 38, 335-343)
have provided the use of the fluidized air bed
granulation technique. The active principle is
micronized and blended with the powdered excipients.
The blend is subjected, in the fluidized air bed
device, to spraying with a solution of binder.
Michael et al. (Pharmaceutical Technology, June 1988,
pp. 68-84) have disclosed a process which consists in
spraying an aqueous solution of PVP onto an excipient
with a relatively large particle size, for example
lactose. The active principle, with a low particle
size, is subsequently sprayed and adheres to the
surface of the moistened particles of excipient.
Problems related to the drying and to the poor fluidity
of the active principle remain.
WO 97/04750 discloses a process which consists in
adding, in a granulator, a 1% aqueous solution of
active principle to a directly compressible excipient
which is preferably soluble in the solution. The water
evaporates without heating under the effect of a stream
of air. The granules are subsequently tableted. This
process is limited to water-soluble active principles.
Few documents of the prior art disclose the preparation
by direct compression of low dose tablets.
EP 503 521 provides the blending of very fine particles
of active principle with a small amount of excipients
and then the gradual addition of the remainder of the
excipients. This method is based on the electrostatic
adhesion of the fine particles of active principle to
the larger particles of excipients. This very lengthy
method only applies to certain active principles and is
highly dependent on the surface condition of the
particles of active principle and of the excipients.
The tablets disclosed in EP 503 521 comprise a
micronized steroid and an atomized polyol, such as
lactose, mannitol, sorbitol, cellulose, xylitol,
dextrose, fructose or sucrose, preferably lactose. Each
60 mg tablet comprises 180 micrograms of active
principle. The variation in the content of active
principle is less than 0.5%.
Greaves F.C. et al. (Pharmaceutical Technology, January
1995, pp. 60-63) and WO 95/17169 disclose tablets
obtained by direct compression which comprise less than
10 mg of micronized estradiol. The estradiol is
combined with agglomerated (and nonatomized) mannitol,
with microcrystalline cellulose and with croscarmellose
In the context of the present invention, the Applicant
Company has succeeded in developing a tablet obtained
by direct compression of neutral microgranules.
This is because the Applicant Company has discovered
that neutral microgranules were directly compressible.
An excipient, in order to be used in direct
compression, must have good flowability, must not
spontaneously agglomerate, must form a tablet with good
mechanical or cohesive strength under the effect of a
reasonable compression force and must make possible
disintegration in an appropriate time. Numerous
directly compressible diluents and binders have been
developed. Excipients for direct compression remain
expensive as they require elaborate preparation
processes or the addition of numerous additives.
Sugars and carbohydrates are commonly used as binders
and disintegrating agents in the formulation of tablets
because of their pleasant taste. However, they are in a
crystalline form and do not always exhibit good direct
compression properties, and the powders which result
therefrom are not very fluid, with the result that they
have to be subjected to a surface treatment or be used
in combination with specific additives in order to be
Directly compressible lactose is one of the most widely
used excipients in direct compression: however, it is
incompatible with some active principles.
Directly compressible starch (or pregelatinized starch)
is subjected to a chemical and mechanical treatment in
order to prevent aggregation of the starch grains. It
is composed of 5% amylose, 15% amylopectin and 80%
unmodified starch. It is used as binder (in the form of
a solution), as diluent or as disintegrating agent.
Directly compressible sucrose comprises between 95 and
98% of sucrose and an additive such as starch,
maltodextrin, inverted sugar or a lubricant. It is used
as binder and in particular as diluent.
Other direct compression excipients include mannitol,
microcrystalline cellulose and dicalcium phosphate.
Direct compression granules exhibiting good fluidity
based on fructose, lactitol or xylitol have also been
developed; they are prepared by atomization or by
In the prior art, neutral microgranules are used for
attaching a coating of active principle and are
generally coated with a polymer film intended to modify
the release of the active principle.
The United States Pharmacopoeia (USP XVII, 1990)
describes neutral microgranules as essentially
spherical granules comprising between 62.5 and 91.5% of
sucrose, the remainder being composed essentially of
starch. The United States Pharmacopoeia also requires a
distribution in the size of the particles such that the
variation with respect to the indicated range (for
example 425-500, 500-600, 710-850 or 1000-1400 microns)
is low and such that the diameter of the neutral
microgranules is therefore uniform. The solubility of
the neutral microgranules varies according to their
sucrose content. They are prepared by coating
crystalline sucrose with a suspension of starch in
sugar syrup. Generally, the greater the diameter of the
neutral microgranules, the greater the proportion of
starch. Neutral microgranules with a size of between
200 nm and 2000 /im can be obtained commercially.
In the prior art, numerous tableting studies have been
carried out on uncoated inert granules but no study has
been carried out on neutral microgranules.
The study of the tableting of nuclei prepared by
extrusion/spheronization starting from microcrystalline
cellulose, lactose or dicalcium phosphate reveals that
microcrystalline cellulose is a plastic material, that
lactose knits together by fragmentation and then by
plastic deformation, and that dicalcium phosphate
dihydrate knits together essentially by fragmentation.
Microcrystalline cellulose powder is known as being
highly compressible but this study shows that
microcrystalline cellulose nuclei obtained by
extrusion/spheronization are not compressible and give
soft tablets. Nuclei comprising a blend of
microcrystalline cellulose and lactose are more
compressible and more brittle than microcrystalline
cellulose nuclei. Finally, nuclei comprising a blend of
dicalcium phosphate dihydrate and microcrystalline
cellulose are more easily subjected to plastic
deformations than the two other types of nuclei; they
have a higher level of cohesion and are more
compressible (Schwartz JB. , Nguyen NH. and Schnaare
RL., Compaction Studies on Beads: Compression and
Consolidation Parameters, Drug Dev. Ind. Pharm., 1994,
20 (20), 3105-3129).
Similar results have been obtained with
lactose/microcrystalline cellulose nuclei (Wang C. et
al., Drug Dev. Ind. Pharm., 1995, 21(7), 753-779). This
is because these nuclei have different compression and
consolidation properties from those of powders with the
same composition. The low compressibility of nuclei
rich in microcrystalline cellulose has been attributed
to the loss in plasticity of the cellulose during the
The properties of granules comprising a dicalcium
phosphate/microcrystalline cellulose (80/20) blend have
also been studied (Johannson B., Nicklasson F. and
Alderborn G., Tabletting properties of pellets of
varying porosity consisting of dicalcium phosphate and
microcrystalline cellulose, Pharm. Res., 1995, 12 (9),
The mechanism of compression of nuclei comprising
microcrystalline cellulose, alone or as a mixture with
10% of lactose, of propanolol or of dicalcium
phosphate, has been compared with that of the
corresponding powders. At equal porosities, the nuclei
require a lower compression pressure than the
corresponding powders. The compressibility of
microcrystalline cellulose decreases by addition of
lactose, of dicalcium phosphate or of propanolol
(Maganti L. and Celik M. , Compaction studies on
pellets, I. Uncoated pellets, Int. J. Pharm., 1993, 95,
29-42; Celik M. , Compaction of multiparticulate oral
dosage forms, in Multiparticulate Oral Drug Delivery,
New York, Marcel Dekker, 1994, 181-215).
Microcrystalline cellulose nuclei comprising
theophylline have been prepared by
extrusion/spheronization using a variable proportion of
a water/ethanol mixture. The water results in harder
and less porous grains which are therefore less
compressible. The grains prepared with ethanol are more
brittle, break during tableting and form new surfaces
for bonding (Millili GP. and Schwartz JB., The strength
of microcrystalline cellulose pellets, The effects of
granulating with water ethanol mixtures, Drug Dev. Ind.
Pharm., 1990, 16(8), 1411-1426).
It emerges from all the studies carried out on granules
formed from inert excipients that the tableting
properties of the nuclei are very different from those
of the powders and that it is therefore impossible to
predict the behavior of the nuclei in tableting from
the mechanical properties of the powders used for their
In the context of the present invention, the Applicant
Company has developed a pharmaceutical tablet
comprising a low dose of active principle comprising a
directly compressible diluent, characterized in that
the directly compressible diluent is composed solely of
neutral microgranules and in that the active principle
is attached as a coating to the neutral microgranules.
In the context of the present invention, the term
"neutral microgranules" is understood to mean
essentially spherical granules comprising sucrose and
starch. Neutral microgranules particularly valued in
the context of the invention comprise less than 91.5%
The present invention advantageously employs spherical
particles, guaranteeing good flowability and good
homogeneity of the blend to be tableted.
The excellent rheological properties of the neutral
microgranules make them good candidates as direct
compression excipient. The flow time of the neutral
microgranules under the conditions of the test
described in the Pharmacopoeia is much less than 10
seconds. This property makes possible very efficient
feeding of the tablet presses. In addition, the neutral
microgranules have a very low compaction volume.
The neutral microgranules have the advantage of
constituting a direct compression excipient which does
not generate dust.
Finally, the neutral microgranules have a
disintegration time much less than 15 minutes.
In addition, the present invention makes it possible to
avoid the problems of demixing generally observed in
direct compression as all the particles to be tableted
have the same size.
The dimension or the mass of the tablets can be
adjusted as desired for low dosages since the demixing
problems (which limit these parameters in conventional
processes) are eliminated. Furthermore, the shape, the
ability to be scored and the engraving of the tablets
are retained when such systems are used.
Finally, the tablet according to the invention can
advantageously be used as placebo tablet, in particular
during technical trials, such as the operational
qualification of tableting equipment, performance
qualification, machine trials after format change and
machine adjustment validation.
The neutral microgranules have a size of between 100
and 2000 Mm, preferably between 200 and 600 /mi, or
preferably between 200 and 400 nm.
The tablets of the present invention exhibit a
uniformity in mass of much less than 5% and of the
order of 1% for tablets with a mass of the order of 300
to 500 mg, a friability of less than 1%, a
disintegration time at 37°C of less than 15 minutes,
and a hardness of the order of 0 to 20 daN. These
parameters can be adjusted by the interplay of the
The tablet can additionally comprise a lubricant in an
amount of less than 1% by mass, preferably of between
0.125 and 0.75% by mass, more preferably of the order
of 0.25% to 0.5% by mass.
The lubricant makes it possible to reduce friction
between particles and between particles and the press
mold. It also makes it possible to reduce adhesion of
the grains to the punches and to obtain a degree of
gloss. The lubricant is chosen, for example, from
magnesium, zinc or calcium stearate, talc, Aerosil®,
stearic acid and PEGs.
The active principle is advantageously chosen from
steroids, neuroleptics and other active principles
which act on the central nervous system, agents for
protecting the cardiovascular system, hormones or
homeopathic active principles.
The amount of active principle is preferably less than
40 mg/g of system to be tableted, to be adjusted
according to the type of active principle, the method
of attaching the coating and its effect after attaching
the coating on the mechanical properties of the system
which is ready to be tableted.
The attaching of the coating of the active principle to
the neutral microgranules is carried out according to
conventional methods, such as the attaching of a
coating starting from solutions or suspensions, in a
pan or in a fluidized air bed, optionally in the
presence of binding agents in the spraying solvent. The
amount of binder will be adjusted according to the
nature and the amount of active principle to be
attached as a coating.
The solvent used for the attaching of the coating will
generally be water or any other authorized solvent with
an appropriate drying stage.
The tablets according to the invention can be film
coated, either to improve their appearance or to mask
the color or to protect the active principle from
light, moisture or oxygen in the air.
The tablets according to the invention can also be
coated with a gastroresistant film or a film intended
for the modified release of the active principle.
Another subject matter of the present invention is a
tableting premix which consists of a composition
containing between 99 and 100% by mass of neutral
microgranules coated with active principle and between
0 and 1% by mass of a lubricant,, which composition is
intended to be subjected to direct compression.
The active principle preferably represents less than 4%
by mass of the neutral microgranules.
Finally, the present invention relates to a process for
the preparation of the tablets of the invention.
According to this process, the compression force is
advantageously between 5 and 50 kN when the compression
surface area is 1 cm2 (i.e. 50 to 500 MPa) , preferably
between 10 and 30 kN.
The present invention is illustrated without implied
limitation by the following examples.
Example 1; Properties on tableting on an alternating
press of the neutral microgranules without the
attachment of a coating.
The neutral microgranules are obtained from NP-Pharm.
The properties are studied on three batches A
(500-600 Aim), B (200-250 Mm) and C (250-300 /im) . Batch
A is studied at two lubrication levels: 0.25% (Al) and
0.5% (A2) of magnesium stearate. Batches B and C are
studied at a degree of lubrication of 0.25%. 100 g of
neutral microgranules of each batch are weighed out
and, depending upon the level of magnesium stearate,
0.25 g or 0.50 g of lubricant is added. Blending is
carried out on a Turbula (48 rpm) for one minute.
Each batch is tested at 3 different levels of
compression forces of the order of: 10, 15 and 20 kN,
on an alternating tablet press (Frogerais OA; punches
1 cm2; mold height standardized at 1 cm, i.e. a working
volume of 1 cm3) .
These various systems are tested on an alternating
tablet press equipped with force sensors (strain
gauges) and inductive displacement sensors on the upper
and lower punches. The tablets obtained are subjected
to a test of hardness by diametrical compression with a
maximum force of 20 daN (Schleuniger type) .
During tableting, the forces are measured at the two
punches. The upper punch force (UPF) is converted into
pressure (MPa) by taking into account the surface area
of the punch. The ratio of the lower punch force/upper
punch force gives the percentage of transmission.
During the decompression phase, the compact passes
through a sudden stage of expansion related to the
elastic recovery, possibly followed by viscoelastic
behavior during ejection. This stage can be studied by
virtue of two parameters : the residual force and the
ejection force. The monitoring of this stage also makes
it possible to describe the problems of adhesion to the
The residual force is measured at the lower punch when
the stress exerted at the upper punch has ceased and
when ejection has not yet been carried out. An optimum
for good conditions for tableting of the neutral
microgranules is obtained for a value of less than
The ejection force corresponds to the force necessary
for the ejection of the tablet out of the mold by the
lower punch. In order not to have problems during the
tableting operation, it is commonly accepted that this
force must be less than or of the order of 50 daN.
Likewise, the cohesion index, equal to:
important to evaluate as it can affect the dissolution
and the release of the active principle (hydrophobic
characteristics of the lubricant) .
For 500-600 ^m neutral microgranules, the difference in
the hardnesses, when 0.25% or 0.5% of magnesium
stearate is used, is very slight.
The percentage of transmission, also known as
"lubricating index", remains very high for both
systems, in the vicinity of 93%.
Finally, the ratio of upper punch force (UPF) to
ejection force changes linearly with a coefficient of
correlation of 0.99 and therefore allows it to be
estimated (by extrapolation) that the acceptable limit
for the ejection force of 50 daN will be reached for
the two batches Al and A2 between 230-260 MPa.
On the basis of these results, it appears that a level
of magnesium stearate of 0.25% is sufficient.
Comparison between the neutral microgranules of
different sizes (batches Al, B and C) with lubrication
with 0.25% of magnesium stearate.
The hardness decreases very substantially when the size
of the microgranules increases. At identical levels of
increasing force, the hardness increases faster with
the smaller systems.
The ejection force is lowest for batch C. The two other
batches Al and B are virtually identical, with a
slightly higher ejection force. The limit of
acceptability of 50 daN would be reached in the
vicinity of an applied pressure of 250 MPa for Al and B
and would exceed 300 MPa for C (evaluation by
It is clearly seen that the cohesion index decreases
with the increase in the size of the microgranules. The
optimum cohesion index of an excipient for direct
compression is in the vicinity of 1 000; this value is
achieved or virtually achieved for the small neutral
microgranules tested (batch B).
For the system of the 500-600 /xm neutral microgranules,
the degree of lubrication of 0.25% appears sufficient
to produce sufficient tabletability with a satisfactory
range of hardness. The limit of tabletability relating
to the ejection force would be reached in the vicinity
of a compression pressure of 230-260 MPa. The
transmission ratio, always greater than 90%, is
excellent in all these scenarios.
The compressibility increases as the size of the
microgranules decreases. The cohesion index of
approximately 1000 (regarded as value of excellence) is
virtually achieved with microgranules of approximately
200-300 fjim. The cohesive properties of the small- to
intermediate-sized systems without the attachment of a
coating are nevertheless very good.
Example 2; Properties on tableting of the neutral
microgranules which have attached a coating of
molsidomine on an instrument-controlled alternating
The following batches of neutral microgranules with an
attached coating are prepared by using neutral
microgranules with a particle size of between 200 and
300 Mm. The degree of lubrication is set at 0.25%.
The active principle is molsidomine, attached as a
coating to the neutral microgranules starting from an
aqueous solution or in the presence of a binder in
solution, Pharmacoat 603, according to the quantitative
ratios given in the following table:
The operation is carried out as in Example 1 and the
batches are listed at three levels of compression force
between 7.5 and 26 kN (i.e. between 75 and 260 MPa,
expressed as stress).
The tablets are subjected to a hardness test as in
Example 1; their mass is also measured. The results are
presented in Table 2.
The tablets obtained from neutral microgranules with an
attached coating of AP are compared with the tablets
obtained from the same neutral microgranules (same
size) but not with an attached coating of active
principle. These tests therefore make it possible to
study the influence of the attaching to the neutral
microgranules of a coating of molsidomine on their
properties on tableting.
The neutral microgranules without the attachment of a
coating give the same results as described in example 1
for the systems with a similar particle size.
The hardnesses obtained are satisfactory for relatively
weak compression forces (75 MPa) and they increase
rapidly when the compression force increases. High
hardnesses of 17 daN are obtained for compression
forces which are still relatively weak, of the order of
18 kN, i.e. 180 MPa. The cohesion indices tend towards
excellence at values of the order of 900.
For the systems with the attachment of a coating, the
levels of hardness are lower at an identical
compression force. However, these levels of hardness
are highly satisfactory for compression forces of the
order of 15 to 25 kN. The cohesion indices are lower
than for the neutral microgranules without the
attachment of a coating but remain at highly acceptable
values of the order of 400 to 500. The influence of the
amount of active principle attached as a coating is not
very noticeable with regard to these systems. On the
other hand, it is possible to see the influence of the
process for the attachment of the coating, since the
systems in which the coating is attached in the
presence of a binder prove to be more cohesive than the
systems in which the coating is attached starting from
a simple solution.
In all cases, the residual forces after compression are
very weak and always less than 15 daN for the
compression forces tested.
The ejection forces are generally acceptable but tend
toward the limit values of 50 to 60 daN when the
compression forces increase to 25 kN.
No phenomenon of sticking, jamming or capping of the
tablets formed is seen, however. A very slightly
greater lubrication makes it possible to reduce the
ejection forces at the highest pressures. The margin of
maneuver, in the conventional formulation/manufacture
interplay (product/press pair), remains very large
The transmission ratios are excellent in all cases, of
the order of 93 to 95%.
The mass of the tablet is very stable, with a random
variation about the mean of less than 1.5% in the worst
of the cases.
The systems of neutral microgranules with an attached
coating of active principle exhibit highly advantageous
compression properties. The cohesion of these systems
is very good, even if it is influenced by the presence
of the active principle attached as a coating at the
surface of the neutral microgranules.
The force transmission and the uniformity of the masses
are two major advantages of these systems.
Example 3; Properties of the neutral microgranules
without an attached coating on a rotary press as a
function of the degree of lubricant.
This test consists of the tableting on a rotary tablet
press of neutral microgranules without an attached
coating comprising different levels of magnesium
stearate, in order to determine the minimum degree of
lubricant necessary in order to obtain tablets with
The levels of magnesium stearate studied are 0.125,
0.25, 0.5 and 0.75%.
The size of the neutral microgranules is between 315
and 400 Mm.
Preblending is carried out between half the mass of the
microgranules and half the mass of stearate using a
Turbula mixer for 1 minutes.
The preblended part and the remainder of the
microgranules and of the stearate are subsequently
blended in an Erweka cube mixer for 5 minutes.
The volume of the mold is adjusted in order to obtain
tablets of the order of 350 mg. The compression is
adjusted in order for the hardness of the compacts to
have an acceptable value for each content of stearate.
The adjustment of the precompression is indexed at 4
and is unmodified.
After optimization of the adjustments of mass and of
hardness, and after operating for 30 to 60 seconds, 20
tablets are removed every 30 seconds for 5 minutes.
The four parameters of hardness, mass, reliability and
disintegration time are subsequently measured.
Hardness: this test is intended to determine,
under defined conditions, the resistance to
breaking of the tablets, measured by the force
necessary to bring about their breakage by
It is measured using an Erweka device and is
carried out on 10 tablets.
Mass: it is measured using a Sartorius balance and
is carried out on 10 tablets.
Friability: this test is intended to determine,
under defined conditions, the friability of the
uncoated tablets, that is to say the phenomenon by
which the surface of the tablets is damaged or
exhibits signs of abrasion or of breakage under
the effect of mechanical impacts or of attrition.
It is measured using an Erweka device and is
carried out on 10 tablets.
Disintegration time: it is intended to determine
the greater or lesser ability of the tablets to
dissolve over time in a liquid medium. It is
measured using an Erweka device and is carried out
in water at 37°C on 6 tablets.
The results obtained are presented in Tables 3 and
Mass: The French Pharmacopoeia recommends a limit
deviation as percentage of the mean mass of 5% for
tablets corresponding to the mass involved. For
the various levels of magnesium stearate, the
values fluctuate on both sides of the mean and
thus the distribution is random. All the batches
are in accordance as the values found are much
less than the limits set by the Pharmacopoeia.
Friability: according to the French Pharmacopoeia,
the maximum loss in mass regarded as acceptable is
1% of the mass of the tablets subjected to the
test. For the various levels of magnesium stearate
used, we are aware that the results are much less
than the standard of the Pharmacopoeia and thus
the various batches are in accordance.
Hardness: the French Pharmacopoeia does not lay
down a limit. For all the levels of magnesium
stearate, the results show that we are always
within the adjustment limits and therefore the
various batches are in accordance.
Disintegration time: the French Pharmacopoeia sets
disintegration conditions according to the type of
tablet. For bare or uncoated tablets, the time
must be less than 15 minutes. Our results are
therefore in accordance with the standard of the
Pharmacopoeia, except with 0.75% of magnesium
stearate and with the compression force used,
where the time is 22 minutes.
The tabletability of the neutral microgranules on a
rotary tablet press is therefore demonstrated, with
excellent results. It should be noted that the
production yields are excellent: the hopper empties
without external help down to the last grains. The
absence of production of dust in the press and the
atmosphere throughout the operation is also very
1. A tablet comprising a low dose of active principle formed from microgranules comprising a directly compressible diluent, characterized in that the directly compressible diluent is composed solely of neutral microgranules and in that the active principle is attached as a coating to the neutral microgranules wherein the size of the neutral microgranules is between 100 and 2000 ]im and hardness of the said tablet is between 0 and 20 daN and its friability is between 0 and 1%.
2. The tablet as claimed in claim 1, wherein the size of neutral microgranules is preferably between 200 and 600 µm.
3. The tablet as claimed in claim 1, wherein the size of the neutral microgranules is between 200 and 400 µm.
4. The tablet as claimed in one of the preceding claims, wherein its disintegration time is less than 15 minutes.
5. The tablet as claimed in one of the preceding claims, wherein it is composed of an active principle attached as a coating to neutral microgranules and of compression excipients in an amount of less than 1% by weight with respect to the weight of the tablet.
6. The tablet as claimed in claim 5, wherein it optionally comprises a lubricant in an amount of less than 1% by mass of the tablet.
7. The tablet as claimed in claim 6, wherein the content of lubricant is between 0.125 and 0.75% by mass, preferably of the order of 0.25% by mass.
8. The tablet as claimed in one of the preceding claims, wherein the amount of active principle is less than 40 mg/g of system to be tableted, preferably less than 10 mg/g.
|Indian Patent Application Number||IN/PCT/2002/00098/DEL|
|PG Journal Number||09/2009|
|Date of Filing||25-Jan-2002|
|Name of Patentee||LABORATOIRES DES PRODUITS ETHIQUES ETHYPHARM|
|Applicant Address||21 RUE SAINT-MATHEIU, 78550 HOUDAN, FRANCE.|
|PCT International Classification Number||A61K 9/50|
|PCT International Application Number||PCT/FR00/02132|
|PCT International Filing date||2000-07-25|