U.S. patent number 3,922,338 [Application Number 05/487,042] was granted by the patent office on 1975-11-25 for tablets containing in their mass controlled-release micro-capsules and process for manufacture of said tablets.
This patent grant is currently assigned to Choay S.A.. Invention is credited to Wladimir A. Coulon, Yvette Fr. M. J. Estevenel, Maurice H. Thely.
United States Patent |
3,922,338 |
Estevenel , et al. |
November 25, 1975 |
Tablets containing in their mass controlled-release micro-capsules
and process for manufacture of said tablets
Abstract
The present invention relates to new tablets for administration
of medicaments, which tablets contain in their mass,
controlled-release microcapsules, that is to say elemental
particles coated with a protective covering which contains an
encapsulated product which is gradually released in a controlled,
regular and time-dependent way. These new tablets are characterised
in that they are constituted by the association of a plurality of
superposed layers of which the medial layer is essentially
constituted by microcapsules containing an active substance, whilst
the exterior layers constitute means of protecting the
microcapsules of the medial layer, particularly against the shock
of compression when compressing them to tablets. The invention also
relates to a process for manufacturing said tablets.
Inventors: |
Estevenel; Yvette Fr. M. J.
(Paris, FR), Thely; Maurice H. (Paris, FR),
Coulon; Wladimir A. (Claye-Souilly, FR) |
Assignee: |
Choay S.A. (Paris,
FR)
|
Family
ID: |
9122459 |
Appl.
No.: |
05/487,042 |
Filed: |
July 10, 1974 |
Foreign Application Priority Data
|
|
|
|
|
Jul 12, 1973 [FR] |
|
|
73.25531 |
|
Current U.S.
Class: |
424/469; 264/113;
424/472; 424/474; 424/475; 424/479; 424/482 |
Current CPC
Class: |
A61K
9/209 (20130101); A61J 3/07 (20130101); A61J
3/10 (20130101); A61K 9/2081 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61J 3/10 (20060101); A61J
3/07 (20060101); A61K 9/24 (20060101); A61K
009/24 () |
Field of
Search: |
;424/19-22 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Browdy and Neimark
Claims
We claim:
1. Compressed layered tablets containing, in their mass,
controlled-release microcapsules, comprising the association of a
plurality of superposed layers, of which the medial layer
essentially comprises microcapsules containing an active substance,
while the exterior layers, which have a microcrystalline cellulose,
starch, alginate, or polyoxy ethylene glycol tablet excipient
composition, constitute means of protecting the microcapsules of
the medial layer, particularly against the shock of compression,
said tablet excipient composition being in the form of granules
having the same grain size as said microcapsules.
2. Tables according to claim 1, wherein said exterior layers also
contain active substances.
3. Tablets according to claim 2, wherein said active substances
contained in the exterior layers are identical substances.
4. Tablets according to claim 2, wherein said active substances
contained in each of the exterior layers are different from each
other.
5. Tablets according to claim 1, wherein said tablets have a
hardness of the order of 10 to 20 kg on their surface and of the
order of 8 to 16 kg on their periphery.
6. Tablets according to claim 1, wherein the ratio between the sum
of the thicknesses of the external layers and the thickness of the
medial layer containing the microcapsules, is between 0.8 and
4.
7. Tablets according to claim 1, wherein the ratio between the sum
of the thicknesses of the external layers and the thickness of the
medial layer containing the microcapsules is between 1 and 2.4.
Description
FIELD OF THE INVENTION
The present invention relates to new tablets containing in their
mass, controlled-release microcapsules and to the method of
manufacture of such tablets.
BACKGROUND OF THE INVENTION
The pharmaceutical industy has, for a long time, attempted to solve
the problem of prolonging the period of effective action of
medicaments. This problem is particularly important in the case
where the period of effective action is short and also if there is
a problem of conditioning two substances, or mixtures of
substances, which are incompatible with one another in the same
tablet especially when it would be advantageous to administer these
substances in association with one another.
It has been proposed to solve both of these problems by producing
"multi-layer" tablets in which a plurality of medicamental
substances are distributed in different layers, superposed on one
another by successive pressings.
The multi-layer tablets which have been produced with the object of
constituting controlled-release types of medicament, comprise a
plurality of superposed layers, the most common number of layers
being three. Each of these layers has such a composition that the
medicaments are liberated at intervals of time which are spaced
apart. When the multi-layer tablets are intended to separate active
constituents which are incompatible with one another, three layers
are again usually provided, which comprise a thin central layer of
an inert substance which separates two layers of much greater
thickness, which contain the incompatible medicaments.
Nevertheless, the multi-layer tablets already known which are of
the controlled-release type, that is to say, tablets which release
the active ingredients in a controlled manner over a period of
time, suffer from the disadvantage that it cannot be ensured that
the active constituent is liberated in a programmed manner at
sufficiently regular intervals.
It is for this reason that attempts have been made to find other
forms which produce a controlled-release effect over a period of
time. It is for this reason that microcapsules have been
proposed.
The microcapsules comprise elemental particles of small dimensions,
that is to say, having dimensions from a few microns to several
millimeters. These microcapsules may be in a solid or liquid state
and may be coated with a protective covering to form a
"micro-package." This micro-package is capable of being destroyed
by mechanical or any bio-chemical action, at the time when it is
desired to use the micro-packaged substance. Alternatively, the
structure thereof may be such that it constitutes a coating through
which the active constituent is progressively liberated.
The protective coating covering the elemental particles is obtained
either by chemical or mechanical methods of encapsulation. The
coatings of microcapsules, which are intended to act in a
controlled-release manner over a period of time, are prepared by
methods known per se. In particular, it is possible to regulate the
rate of external diffusion of the encapsulated product by different
methods. It is particularly possible to vary the thickness, to a
greater or lesser extent, of the coating and, above all, by
providing the coating with a predetermined micro-porosity.
Nevertheless, these microcapsules are relatively fragile
structures. Until now, it has proved impossible to put them into
the form of tablets. A tablet is, of course, a very convenient form
of administration since it reduces the volume to be swallowed by a
patient. In fact, in the course of the process of mixing with
pressing with adjuvants or other associated substances, an abrasive
effect is noticed. This affects the external layer of the
microcapsules and leads to at least a partial destruction of the
microcapsule. This, accordingly, affects the quality of the
controlled-release effect desired. Moreover, the direct pressing of
the microcapsule, irrespective of whether or not the microcapsule
is of the double core coating type, has the effect of destroying
its external and internal structure and the tablet obtained loses
all its effectiveness.
This impossibility of pressing microcapsules under satisfactory
conditions whilst preserving the wholeness of the microcapsules,
has necessitated the microcapsules to be hitherto used in the form
of gelules. This pharmaceutical form whilst it enables the
microcapsules to retain their effectiveness, nevertheless suffers
from a disadvantage which is of some consequence, that is to say,
it is difficult to swallow. Moreover, this format is unsuitable
when one attempts to associate microcapsules with one or more other
active substances. In fact, not only does this entail extremely
large gelules, but additionally, the operation of mixing the
microcapsules with other granulated active agents has an abrasive
effect due to the contact of the microcapsules with one another.
The resultant erosion of the microcapsules has the effect of
annoyingly affecting the controlled-release.
SUMMARY OF THE INVENTION
The object of the present invention is to provide new tablets which
contain controlled-release microcapsules in their mass, which
respond better to the necessities of the art than
controlled-release agents previously known. In particular, it is an
object of the invention to provide new tablets which permit the use
of microcapsules which allow the controlled-release of the active
constituent in a regular and time-dependent manner, whilst at the
same time permitting an important reduction in the dimensions of
the pharmaceutical preparations including microcapsules.
According to the present invention, there are provided new tablets
containing, in their mass, controlled-release microcapsules,
characterised in that they are constituted by the association of a
plurality of superposed layers, of which the medial layer is
essentially constituted by microcapsules containing an active
substance, whilst the exterior layers -- which may possibly also
contain identical or different active substances and which have a
composition usual for the making of tablets -- constitute means of
protecting the microcapsules of the medial layer, particularly
against the shock of compression.
According to an advantageous embodiment of the invention, the
tablets in accordance with the invention have a hardness of the
order of 10 to 20 kg on their surface and of the order of 8 to 16
kg on their periphery.
According to a preferable embodiment of the invention, the ratio
between the sum of the thicknesses of the external layers and the
thickness of the medial layer containing the microcapsules, is
advantageously between 0.8 and 4 and preferably between 1 and
2.4.
According to the present invention there is also provided a method
of making tablets containing, within their mass, controlled-release
microcapsules characterised in that they are prepared in a
tablet-making machine, a first external layer -- which essentially
comprises excipients, and possibly therapeutically active
substances -- which is subjected to a light compression, by simple
levelling, for example, in that an internal layer superposed on the
first external layer is prepared, the internal layer essentially
comprising microcapsules containing an active substance, which
internal layer is subjected to a light compression, by simple
levelling, for example, in that a second external layer is
prepared, of which the composition is identical to or different
from, that of the first external layer, which is superposed on the
internal layer of microcapsules, after which the superposed layers
are subjected to compression in a machine for making tablets, which
exerts a pressure force capable of giving rise to tablets of which
the cohesion is sufficient to ensure the disintegration of the
tablet in accordance with the conditions required by the French
Pharmacopoeia.
According to an advantageous embodiment of the process according to
the present invention, the microcapsules containing an active
substance, are associated, in the medial layer, with an excipient
which favors the disintegration of the microcapsules. By putting
the process in accordance with the present invention into effect,
there are obtained tablets in which the microcapsules contained in
the medial layer are not damaged during the compression process due
to the presence of external layers of a sufficient thickness which
protects the medial layer on each side.
Tests carried out by the applicant have shown that for a medial
layer thickness of between 0.6 and 3 millimeters, and preferably
between 1 to 2 millimeters, the thickness of each of the external
layers must be between 0.8 and 2 millimeters and preferably between
1 and 1.2 millimeters. The tablets obtained in accordance with the
present invention have associated therewith the advantage inherent
in their presentation in the form of tablets, that is to say, the
administration of active substances in a small volume together with
the advantage of microcapsules, that is to say, a
controlled-release of one or more active substances in a programmed
manner with respect to time.
DESCRIPTION OF PREFERRED EMBODIMENTS
The carrying out of the process in accordance with the present
invention will now be described in greater detail.
A composition adapted to form the external layers of the final
tablet is prepared. This composition essentially comprises
excipients to which may possibly be added active substances; the
excipients advantageously comprise an excipient of appropriate
charge, for example, a microcrystalline .alpha.-cellulose such as
that which is known under the trade name of "AVICEL PH 102" (sold
particularly by the firm "SEPIC"), associated with a corn starch
and with a lubricant such as for example, a mixture of mono- di-
and tri-palmitostearic esters of glycerol such as those which are
sold (by Etablissements GATTEFOSSE) under the trade name of
"PRECIROL". Into such a composition can be introduced active
substances which are incompatible with those contained in the
microcapsules, or active substances which are immediate-acting
compared with the active substances contained in the microcapsules
which act progressively over a period of time. Alternatively, the
composition may contain active substances which act at a level of
gastro-intestinal transit different from that of the substance
contained in the microcapsules.
This composition is put into the form of granules whichh have a
grain size identical to that of the microcapsules, so that the free
flow in the tablet machine can be identical in the two
compositions.
A composition adapted to form the medial layer of the final tablet
is then prepared by association of the microcapsules containing the
active substance, with an excipient which improves the free flow
and which facilitates the disintegration and, in so doing, the
splitting of the tablets. Half of the quantity of the external
layer composition is introduced into the matrix of a tablet-making
machine, in which it is subjected to a light compression with a
punch which is just sufficient to level this first external layer.
After levelling of the first external layer, the medial layer
composition prepared is superposed thereon. This is then subjected
to a light compression with a punch, which is, again, just
sufficient to level it. A second external layer constituted by the
other half of the external layer composition is then superposed on
the medial layer containing the microcapsules. The assembly of the
three superposed layers is then subjected, in a tablet-making
machine, to a compressive force which is a function, in particular,
of the nature of the products being made into tablets, and which
produces tablets having a hardness, when measured on a Stokes
apparatus, lying within the range of 10 to 20 kg on its surface and
of 8 to 16 kg around its periphery. Such a hardness value is
sufficient, in the pharmaceutical condition art, to ensure the
wholeness of the microcapsules is preserved.
The tablets thus obtained are advantageously flat and bevelled
having a diameter of the order of 11 mm, a final weight of between
0.360 and 0.660 grams, and a final total thickness of between 3.3
and 5.65 mm, the thickness of each of the external layers being
between 0.8 and 2 mm if the thickness of the medial layer is of the
order of 0.6 to 3 mm and preferably between 1 and 2 mm. Besides the
embodiments described herein before, the invention also comprises
other embodiments, which will be apparent from the following
description.
The invention will be further described, purely by way of example,
with reference to the following nonlimitative examples which show
methods of preparing new tablets in accordance with the
invention.
EXAMPLE 1
1. A composition adapted to form the external layers of the final
tablet is prepared by mixing the following constituents in the
proportions stated:
Active constituents: Hesperidine methyl-chalcone 0.065 g Aspirin
0.100 g 4-chloro-1-dehydro-methyl-testosterone 0.00165 g Excipients
Lubricants such as, for example, a mixture of mono-, di - and tri-
palmitostearic esters of glycerol (known in particular, under the
trade name of "PRECIROL") 0.00175 g Corn Starch 0.050 g Filler
excipient such as for example, microcrystalline .alpha.-cellulose
(known under the trade name of "AVICEL PH 102") Q.s.p. 0.260 g
This mixture is put into the form of granules of a grain size
identical to that of the microcapsules, in such a manner that the
dispersion in the tablet making machine of this composition is
identical to that of the microcapsules. In practice, the granules
obtained have a grain size less than 1000 .mu..
2. A composition adapted to form the medial layer of the final
tablet is prepared, by mixing the following constituents in the
proportions stated:
Active constituent: Microcapsules enclosing papaverine chlorhydrate
of the order of 0.097 g Filler excipient favoring free flow such as
"AVICEL PH 102" for example Q.s.p. 0.140 g
3. a. 0.130 g of the composition described in (1) is placed into
the matrix of a tablet machine, and is subjected to a pressing, by
levelling for example, with the aid of the suitable means such as
the punch of the machine, without, however, supplying a compressive
force to this latter.
b. On the external layer thus produced, the composition described
in (2) is superposed and this is also subjected to a pressing, by
levelling for example, with the aid of suitable means such as the
punch of the machine, in such a manner that the punch only exerts
the compressive force exercised by its own weight.
c. On the microcapsule layer is then superposed 0.130 g of the
composition described in (1).
d. The multi-layer composition thus obtained, comprising a medial
layer of microcapsules protected by two external layers, is
submitted to a suitable compressive force in a tablet machine in
such a manner as to obtain tablets having a hardness sufficient to
be pharmaceutically satisfactory whilst nevertheless permitting a
disintegration conforming to the standards laid down in the French
Pharmacopoeia and preserving the programmed controlled-release of
the active constituents.
The tablet obtained by using the method which has just been
described is a flat tablet, chamfered, having a diameter of 11 mm,
a final thickness of 3.8 mm and a final weight of 0.400 g. This
disinegrates in a period of 35 minutes. The thickness of each of
the external layers is 1.07 mm whilst the thickness of the
microcapsule layer is 1.65 mm.
The hardness of this tablet measured on Strokes apparatus is 10 kg
on its surface and 5 kg on its periphery.
The tablets in accordance with the present invention which have
just been described cause the immediate liberation of the
therapeutic agents contained in their external layers and the
controlled-release, over a prolonged period of time, up to 8 hours,
of the papaverine contained in the microcapsules of the medial
layer. One practical application shows a particular interest in the
case of medicaments of which the therapeutic action is transient,
such as is the case with papaverine, because it allows a
progressive controlled-release of the papaverine in the patient,
and thus maintains a constant amount of medicament. The application
of the new pharmaceutical form in accordance with the present
invention, to the administration of other medicaments of which the
therapeutic action is fleeting, such as adrenaline, and trinitrine,
is of major interest.
The present invention also shows a great interest in the case where
it is desired to administer one substance which it is desired to
maintain at a regular level in the patient for a long period of
time, without having to greatly increase the number of doses or by
giving extremely large doses; this being the case, for example,
with hypnotic or tranquilizing substances.
The form of administration in accordance with the present invention
is also particularly interesting in that it allows the association
of microcapsules with other therapeutic substances, notably in that
it allows association of two or more substances of which the
actions are complementary or potentialise one another, such as is
the case with the association of a delaying product and a
non-delaying product, or with the association of a hypnotic agent
having immediate action with a hypnotic agent having a delayed
action.
EXAMPLE 2
Other excipients besides "AVICEL PH 102" described in Example 1
have been tested in association with the microcapsules of the
medial layer containing the active constituent, such as papaverine
chlorhydrate as described in Example 1. The efficiency of those
excipients has been studied. The efficiency criterion chosen in the
tests which will be described hereinafter, is the time release in
vitro of micro-encapsulated papaverine chlorhydrate. This is a
function of the excipient associated with the microcapsules. This
test has made it clear, in the first place of the role of the
excipient, which plays a complementary role in the protection of
the microcapsules, preventing these latter from sticking together
and from being damaged during the preparation of the tablets, which
have the result of affecting the controlled-release effect.
The process also makes clear, in the second place, the importance
of the choice of the excipient, which must not have too great an
adhesiveness, which raises the risk of conferring a too strong
cohesion on the microcapsules before compression, thus preventing
them from satisfactorily disintegrating. The choice of the
excipient must, on the contrary, favor the disintegration of the
microcapsules. The studies which will be described hereinafter
compare the release times in vitro of micro-encapsulated papaverine
chlorhydrate associated with different excipients as follows:
1. "AVICEL" plus corn starch
2. Maize starch
3. Alginate
4. Polyoxyethyleneglycol (POEG) + "AVICEL"
The test on the liberation of papaverine chlorhydrate consists in
placing the sample in a disintegration apparatus of the type
described in the American Pharmacopoeia, Edition XVIII, and to
simulate the progressive passage from the gastric medium to the
intestinal medium at 37.degree.C .+-. 1.degree. C.
The compositions of the gastric and intestinal medias are those
described on pages 1026 and 1027 respectively of the American
Pharmacopoeia. The pH of the gastric medium is adjusted to 1.6 and
the pH of the intestinal medium is adjusted to 5.0. However, this
latter does not contain any pancreatin, which is inactive at this
pH. The sample is immersed for an hour in a bath containing only
the gastric medium at 37.degree.C. Every hour thereafter, half the
volume of the bath is removed and replaced by an equal volume of
intestinal medium.
The results obtained with these different excipients are, in other
respects, compared with the time of liberation of the
micro-encapsulated papaverine chlorhydrate associated with "AVICEL"
in the standard tablets (that is to say, made according to
conventional pharmacotechnical methods for the obtaining of
classical non-multilayer tablets; in the description which follows,
the expression "standard tablets", is always used in this manner).
The results of this study are shown in Table I below, as well as in
the accompanying drawing.
TABLE I
Time of liberation in vitro of micro-encapsulated papaverine
chlorhydrate.
Comparison with standard tablets and with microcapsules alone.
Incidence of the nature of the excipients.
__________________________________________________________________________
Multilayered tablets in accordan- ce with the invention Micro-
Standard "AVICEL" Maize Alginate POEG % of capsules tablet + starch
Starch +AVICEL papaverine alone "AVICEL" Curve Curve Curve Curve
Curve S I II III IV
__________________________________________________________________________
25 2 h25 0 h30 0h40 1 h15 1 h35 2 h00 50 6 h00 1 h00 2h00 2 h25 1
h45 3 h15 75 >10 h 1 h40 3h00 3 h50 4 h05 4 h30 90 " 2 h15 5h00
5 h15 5 h30 7 h00 100 " 2 h30 8h00 8 h00 >8 h >8 h
__________________________________________________________________________
The accompanying drawing shows the curves obtained corresponding to
Table I, to wit: The curve S corresponds to standard type tablets,
that is to say, to tablets comprising microcapsules containing
papaverine chlorhydrate, made, as indicated above, according to
usual pharmacotechnical methods for obtaining of non-multilayer
classical tablets.
Curves I to IV relate to multi-layer tablets in accordance with the
invention, in which:
Curve I: the active constituent of the medial layer is associated
with "AVICEL" and corn starch;
Curve II: the active constituent of the medial layer is associated
with maize starch;
Curve III: the active constituent of the medial layer is associated
with alginates;
Curve IV: the active constituent of the medial layer is associated
with "AVICEL PH 102" and polyoxyethyleneglycol.
Table I above, as well as the curves shown in the accompanying
drawing show very clearly the extended and progressive
controlled-release with respect to time of tablets containing
microcapsules; moreover, the superiority of certain excipients
(notably AVICEL PH 102 + polyoxyethyleneglycol) is also clearly
shown.
EXAMPLE 3
The compositions described in Example 1 are prepared, and by
putting into operation the process described in that example,
tablets of different weights having various thicknesses of layers
are prepared, in particular: Tablets B. Diameter 11 mm Weight 0.660
grams Total thickness 6.20 mm Medial layer (microcapsules) 1.67 mm
External layers (each) 2.25 mm Tablets C. Diameter 11 mm Weight
0.270 grams Total thickness 2.90 mm Medial layer (microcapsules)
1.68 mm External layers (each) 0.61 mm
The time of liberation in vitro of micro-encapsulated papaverine
chlorhydrate is then studied as a function of the respective
thicknesses of the two external layers and the medial layer. Table
II below shows clearly the liberation times: in the case of tablets
such as those described in Example 1 (column 6); in the case of
tablets B above (column 7); in the case of tablets C above (column
5); and comparing them with the time of liberation of the
papaverine chlorhydrate obtained: in the one case with
microcapsules alone, containing papaverine chlorhydrate (column 2);
in the second case with tablets of standard type, that is to say
tablets constituted by microcapsules containing papaverine
chlorhydrate, manufactured in accordance with usual methods for the
obtaining of classical tablets of non-multilayer type (column 3);
and in the third case with an association of constituents mentioned
in Example 1, in the form of a simple mixture and not in the form
of multilayer tablets in accordance with the present invention
(column 4).
TABLE II
Time of liberation in vitro of micro-encapsulated papaverine
chlorhydrate. Incidence of the thickness of the layers.
__________________________________________________________________________
Multilayer tablets in accordance with the % of pa- invention
paverine Micro- Standard Mixture external external external chlor-
capsules tablets not layer layer layer hydrate only tablet-
liberated ted 0.6 mm 1.07 mm 2.25 mm
__________________________________________________________________________
(1) (2) (3) (4) (5) (6) (7) 25 2 h25 0 h30 1 h00 0 h35 0 h40 0 h50
50 6 h00 1 h00 2 h20 1 h15 2 h00 2 h00 75 >10h 1 h40 5 h00 2 h15
3 h00 3 h00 90 " 2 h15 8 h00 3 h30 5 h00 5 h00 100 " 2 h30 10 h00 4
h00 8 h00 8 h00
__________________________________________________________________________
1. Column relating to microcapsules alone:
This relates to the study of the liberation time in vitro of
papaverine chlorhydrate for the microcapsules per se. It is to be
noted that after 10 hours, the liberation of the papaverine is
extremely slow.
2. Column relating to standard tablets:
This relates to tablets having been subjected to a classical
compression. In this case, during the course of the compression,
the microcapsules of the superficial layer have suffered a
deterioration which gives them a type of "paraffin" appearance,
which prevents the damping necessary for disintegration.
To permit the testing of the liberation of the papaverine
chlorhydrate, the tablets had to be broken by hand to allow the
disintegration and the dosage in vitro: the results obtained
indicate that there is no improvement in the controlled-release and
that the encapsulated microgranules have been damaged by the
compression.
3. Column relating to the non-tabletted association:
This study shows the incidence of excipients and of the other
possibly associated substances on the time of release of the
papaverine.
It can be stated that the other substances which are put into the
preferred composition diminish the liberation time of the
papaverine (compare columns 2 and 4). It is also necessary to
compare the results obtained with multilayer tablets in accordance
with the invention to those obtained by the association of
microcapsules and other excipients (compare columns 5, 6 and 7 with
column 4). The study of the above details leads to the conclusion
that the thickness of the external layers must not be less than 0.8
mm; it must be between 0.8 and 2 mm, and preferably between 1 and
1.2 mm.
For the pressure forces such as those utilised, that is to say,
leading to a disintegration of the tablet in accordance with the
conditions laid down in the French Pharmacopoeia, the superficial
part of the medial layer, that is to say about 0.2 mm on either
side of this middle layer, are found to be damaged at the moment of
compression, for external layers which, as stated hereinbefore, are
of a thickness of 0.8 to 1.07 mm. The medial layer can therefore
have a thickness advantageously lying between 0.6 and 3 mm, and
preferably between 1 and 2 mm.
EXAMPLE 4
The principle characteristics of the compressed tablets according
to this invention have been verified and more particularly:
their hardness
their speed of disintegration
the times required for liberating the active principal of the
compressed tablet, on tablets made on industrial machines of the
Layer-Press type made by Manesty the composition of these tablets
being as follows: exterior layers Starx 1500 corn starch 0.06g
colorant: Coccine 0.0005 g "Avicel PH102" Q.S.P. 0.600g medial
layer Microcapsules of papaverine chlorhydrate 0.112g
polyoxyethyleneglycol 4000 0.06g "Avicel PH102"/starch (granules)
Q.S.P. 0.400g
while varying:
the speed of rotation of the machine from 600 tablets/min. to 1400
tablets/minute,
the pressure of compression, that is the pressure which
counterbalances the pressure exerted on the upper punches from 2.8
tons to 4 tons.
The tests have been carried out using four portions -- or sub lots
-- numbered from I to IV, of the same fabrication lot, Lot 74056
PP, each of these parts corresponding to one of the parameters that
were varied, and which have been mentioned above.
The results obtained are tabulated in Table III, which follows,
from which it is evident that the tablets conforming to the present
invention present a great hardness and a great cohesion, while
disintegrating rapidly.
TABLE III
__________________________________________________________________________
MULTILAYERED TABLETS CONTAINING CONTROLLED-RELEASE MICROCAPSULES
ACCORDING TO THE INVENTION Frac- Weight Thickness Speed Compensa-
Hardness Hard- Disin- 25% of P.A. 50% of P.A. 75% of PA tions per
in MM Rpm tory on edges ness on tegro- liberated liberated
liberated Unit pressure faces tion in: in: in:
__________________________________________________________________________
I 1,05 g 5,8 600 3 t --k 14,5 k 30" 2 H 45 5 H 7 H 15 II 1,12 g 5,8
800 4 t 15 k 19 k 1'7" 2 H 30 4 H 30 >8 H III 1,09 g 5,7 1000 4
t 16 k 19,5 k 46" 2 H 30 3 H 45 5 H IV 1,09 5,6 1400 2,8 t 14 k 17
k 1' 2 H 5 H 45 >8
__________________________________________________________________________
H Compression accomplished on a "Manesty" type Layer-press Punches
16 mm chamfered plates P.A. = Microencapsulated papaverine
chlorohydrate
It will be seen from the preceding description that the present
invention allows the obtaining of new tablets containing, in their
mass, controlled-release microcapsules, which show important
advantages with respect to the prior art, and in particular, that
of permitting administration in a small volume, of one or more
active substances, of which the liberation in the patient is
programmed.
Various minor modifications can be made to the present invention
without departing from the scope thereof. Thus, it will be readily
appreciated that the preceding examples refer to the
controlled-release, with respect to time, of papaverine. It will be
readily apparent that the present invention gives the optimum
results and it will be understood that other microencapsulated
medicaments can be put into a form which conform to the present
invention and which will give equally satisfactory results.
Moreover, utilization of multi-layer compounds containing
microcapsules in their mass can extend to fields other than
therapeutics (for example, the progressive liberation of
insecticides, disinfectants and coloring materials).
* * * * *