Note: Descriptions are shown in the official language in which they were submitted.
1~ 91;3
This invention relates to a multilayer granule
comprising a rapid-relase l`ayer formed around a slow-
release phase. Thus~ a moiety capable of slowly releasing
one or more ingredients and another moiety capable
of rapidly releasing the same ingredients are integrated
in the granule of the present invention, which makes
it possible to sustain the release of said ingredients
over a prolonged period of time. Some pharmaceuticals
require such sustained release. Thus the present invention
is useful in the pharmaceutical field.
In the pharmaceutical field, it is often
required to reduce the concentration of a medicine
in vivo as low as possible and to sustain the same
for a desired period of time. There have been attempts
to produce sustained release preparations of various
formulations which are intended to achieve the above
objeat. These formulations include a medicine wherein
a rapid-release moiety and a slow-release moiety are
separately formed and integrated for administration.
Particular examples thereof are a so-called double-
layer tablet produced by coating a slow-release core
with a rapid-release layer and molding the whole as
a single tablet; a hard capsule produced by separately
preparing slow-release granules and rapid-release granules
and encapsulating a mixture thereof; and a tablet produced
by compressing the above-mentioned granules together
with excipients. In these preparations, the release
of ingred~ents is performed in vivo repeatedly with a
proper time lag. Thus the concentration of the ingredients
~; : 30 in vivo is maintained substantially constant for a
prolonged period of time.
It is expected that sustained release preparations
of a type other than those described above can be devised.
A so-called multilayer granule is one of these expected
formulations.
The process for integratlng slow-release
granules and rapid-relea~e granules by mixing them,
" 129Zgl3
has a disadvantage that the compositional ratio of
the two components can not be constant but varies widely.
It is believed that this disadvantage is brought about
by difficulties in the mixing procedure in addition
to stochastic variance. Such a wide variation in
the compositional ratio significantly lowers the reliability
as well as usefulness of the sustained release preparation.
In contrast thereto, multilayer granules exhibit small
variation in the compositional ratio during administration
since they consist of single granules containing a
slow-release moiety and a rapid-release moiety in a
given ratio. Accordingly a multilayer granule can
be expected to be an excellent sustained release formulation
However the multilayer granule has a serious
disadvantage that the release-controlling mechanism
of the slow-release moiety may be damaged during the
formatlon of the rapid-release moiety thereon. Although
the reason therefor has not yet been sufficiently clarified,
it may be assumed that a solvent required for the formation
of the rapid-release moiety might moisten the slow-
rele~se moiety or that an external force required for
the formation of the rapid-release moiety might be
transmitted to the slow-release moiety, thereby to
damage a delicate release-controlling mechanism of
the latter. In any case, the destruction of the release-
controlling mechanism results in the loss of the slow-
release effect and thus the slow-release moiety is
` released at the same time as the rapid-release moiety,
as will be shown in the Experimental Examples hereinbelow.
In order to overcome this disadvantage, we
have attempted to form a blocking film layer at the
boundary between the slow-release iety and the rapid-
release moiety to protect the release-controlling mechanism
of the former therewith. Thus we have examined various
film-forming materials to determine whether they are
effective for this purpose or not. However no conventional
film can give the desired result as wi~ll be shown in
~' .
~ : .
iZ92~i3
the Experimental Example~ hereinbelow. Thus it has become
the object of an inven~ion to provide a film layer
composition capable of achieving the above-mentioned
purpose.
It has now been found that a film layer
containing a metal stearate can protect the release-
controlling mechanism of the slow-release moiety against
destruction and allow said moiety to fully exhibit the
desired function.
Accordingly, it is an object of the present
invention to protect the release-controlling mechanism of
a slow-release moiety of a multilayer granule consisting
of said slow-release moiety and a rapid-release moiety.
In order to achieve this object, the present
invention discloses a technique in which a layer
containing a metal stearate as an essential ingredient is
provided at the boundary between said slow-release moiety
and said rapid-release moiety.
Accordingly, the invention provides a multilayer
granule comprising a core, a slow-release layer, a rapid-
release layer provided outside of said slow-release layer
and a film layer disposed between the slow-release layer
and the rapid-release layer, said film layer comprising
from 20 to 90 percent by weight of a film-forming
co mp o nent selected from ethyl cellulose,
hydroxypropylmethyl cellulose, shellac and wax and
mixtures thereof and from 80 to 10 percent by weight of a
metal stearate selected from calcium stearate, magnesium
st*arate and mixtures thereof. A pharmacologically
30~ effectlve component can thereby be released in sustained
anner over a long period of time;
The term "multilayer granule" is used herein as
a concept corresponding to a so-called multilayer tablet.
; By i'multilayer tablet" is generally meant a tablet wherein
35; a ~tablet core i8 coated with concentric layers different
from each other in properties or composition. In
particular, a double-layer tablet is called a cored
tablet. It i~noted that the multilayer structure denotes
:::
.
1~9Z~i3
3a
one wherein concentric layer different from each other in
properties or composition are laminated and integrated.
The same meaning i5 used in the present invention. Thus,
by the term "multilayer granule"
~, ~
: ~
: '
129Z9i3
is meant a granule wherein a number of layers different
from each other in properties or composition are laminiated
and integrated. In particular, the-core of the granule
is called a nuclear particle. A nuclear particle which
is merely a seed ~or producing granules is called a
nuclear seed.
In the present invention, a number of layers
different from each other in properties or composition
comprise in particular a slow-release moiety and a
rapid-release moiety. Thus the present invention is
concerned with a multilayer granule wherein a rapid-
release layer is formed around a slow-release phase.
The terms "slow" and "rapid" as used herein are determined
relatively. That is to say, when there are two moieties
showing different release initiation times from each
other, the one having a later release initiation time
is called "slow-release" while the other is called
"rapid-release". Therefore in the case of a structure
where an internal layer is enclosed in an intermediate
layer which, in turn, is enclosed in an external layer,
the i:nternal layer is slow-release in contrast to the
intermediate layer which is thus rapid-release, while
the same intermediate layer is, in turn, slow-release
in contrast to the external layer which is thus rapid-
release.
According to this definition, the rapid-
release moiety invariably serves as an enclosing
~`~ layer. Thus it will be merely called the rapid-release
layer in the present invention.
~ On the other hand, the slow-release moiety
~; ~ usually serves as an enclosing layer, but it sometimes
plays the role of a nuclear particle E~ se. Thus,
` ~ it will be generally called a slow-release phase hereinbelow.
~ Thus, the term "slow-release phase" includes both a
;~; 35 slow-release enclosing layer and a sIow-release nuclear
particle.
Since the slow-release phase and the rapid-
:::
12~2913
release layer are discrete, there exists a clear-cut
boundary between them. The present invention is
characteri~ed in that a film layer containing a metal
stearate as an essential ingredient is present at this
boundary. The term "film layer" means a layer which
comprises a film-forming material and is made into film
thereby. As indicated above, the film-forming material is
chosen from ethylcellulose, hydroxypropylmethylcellulose,
cellulose, shellac and wax.
Suitable metal stearates are calcium stearate
and magnesium stearate. The content of metal stearate in
the film layer may vary depending on other ingredients
therein, such as talc or wax. It is generally employed in
an amount of 10 to B0%, preferably 15 to 70%. The amount
of the metal stearate in the film layer may generally be
determined depending on the composition of the film layer.
The film layer may be formed in a conventional manner.
For example, a film-forming material, a metal ~tearate and
other ingredient~ are di~olved and disper~ed in ethyl
alcohol thereby to form a film layer ~olution. Then the
granules to be coated therewith are made to flow in a
fluidised bed or rotated in a tumbling granulator while
qpraying the above-mentioned film layer ~olution thereon.
The multilayer granule of the present invention
may be produced in the following manner. First a slow-
release nuclear particle or a granule seed 1~ prepared. A
generally available granule seed compri~ing a mixture of
white sugar and corn starch, which will be abbreviated as
an NPS hereinafter, may be employed. A nuclear particle
; 30 may be prepared by kneading a pharmaceutical ingredient to
be 810wly released with other ingredients such as wax with
the use of a binder and extruding the mixture to form a
pellet. However, the present invention is not restricted
to the particular manner of production of the nuclear
particle or seed. A ~low-
: ~
lZ9Z~13
release enclosing layer may be formed around the nuclear
seed in a conventional manner.
Then the particle coated with a slow-release
enclosing layer or a nuclear particle-containing pharmaceutical
ingredients is coated with a film layer which contains
a metal stearate as an essential ingredient. The coating
may be performed in the above-mentioned manner, i.e.,
by making the particle flow or tumble while spraying
the film layer solution thereon.
The intermediate particle thus obtained may
be further coated with a rapid-release layer in the
following manner. Firstly, ingredients of the rapid-
release moiety are dissolved and dispersed in water
to give a rapid-release layer solution. Then the intermediate
particle is made to flow or to tumble while gradually
adding the rapid-release layer solutiDn thereto, thereby
to laminate the latter an the former, followed by air-
drying.
The particle thus obtained may be further
coated with another rapid-release layer by repeating
the procedures for applying the film layer and the
rapid-release layer. Thus a multilayer granule consisting
of three or more layers may be produced.
The multilayer granule thus obtained may
be administered as a medicine as such. Alternately
it may be formulated into a capsule by enclosing the
same in a hard capsule or into a compressed tablet
by mixing with other ingredients and compressing the
mixture. These preparations comprising the multilayer
granule may be prepared by methods conventionally known
in the art. Thus no special description is required.
It is a function of the present invention
to sustain the release of medicinal compounds in a
multilayer granule, which has been considered difficult
35 ~in conventional multilayer granules. The reason for
this ~ifficulty is that laminating a number of layers
; ~ in a multilayer granule can physically and chemlcally
: :; "
iZ9Z913
damage the release-controlling mechanism of a slow-
release moiety. The present invention has solved this
problem and has made it possible to sustain the release
of a medicinal compound in a multilayer granule. In
particular, it provides a multilayer granule highly
resistant against filling and compression forces. Thus
the release of a medicinal compound can be sustained
even if the multilayer granule is enclosed in a hard
capsule or formulated into a compressed tablet. In
addition, this function of the present invention can
be consistèntly maintained even under various storage
conditions.
To further illustrate the present invention,
the following Examples will now be given.
Example 1
1.4 kg of 28- to 32-mesh white sugar-corn
starch granules INPS) were employed as nuclear seeds.
The seeds were tumbled in a small plate tumbling granulator
and a solution (prepared by dissolving and dispersing
400 g of dextromethorphan hydrobromide, 20 g of ethylcellulose,
20 g of purified shellac and 160 g of microcrystalline
wax in 1.9 kg of ethyl alc~holl was slowly added thereto,
thereby to laminate the latter on the former. The
particles where then air-dried at 50C for 12 hours
and the particles thus obtained and the layer thus
laminated thereon were referred to as R particles and
R layer respectively.
1.5 kg of the R particles were tumbled in
a~ small plate tumbling granulator and a solution (prepared
by dispersing 300 g of calcium stearate, 15 g of ethylcellu-
~;~ lose and 15 g of purified shellac in 2.2 kg of ethyl
alcohol) was gradually added thereto, thereby to laminate
the latter on the former. The particles were then :air-dried at 40~C for 12 hours and the particles thus
obtained and the layer thus laminated thereon were
referred to as C particles and C layer, respectively.
1.22 kg of the C particles were tumbled in
-` lZ9Z913
a small plate tumb~ing granuIator and a solution (prepared
by dissolving and dispersing l~0 g of dextromethorphan
hydrobromide, 1 kg of diprophylline, 140 g of light
silica, 140 g of talc and 20 g of corn starch in 3.2
kg of ethyl alcohol) was gradually added thereto, thereby
to laminate the latter on the former. The particles
were then air-dried at 40C for 12 hours and the particles
thus obtained and the layer thus laminiated thereon
were referred to as I particles and I layer, respectively.
The I particles comprise multilayer granules within
the present invention.
For reference, the overall weight ratio of
the ingredients of the nuclear seed and each layer
will be shown:
nuclear seed: NPS 70;
R layer: dextromethorphan hydrobromide 20;
ethylcellulose l;
purified shellac l;
microcrystalline wax 8;
C layer: calcium stearate 20;
ethylcellulose l;
purified shellac l;
I layer: dextromethorphan hydrobromide 10;
diprophylline I00;
light silica 14;
talc 14;
corn starch 2.
Example 2
The procedure of Example 1 was followed except
that the amount of NPS in the formulation was 60 parts
~`~ by weight instead of 70 parts by weight and that the
C layer had the following three compositions thereby
to give three types of multilayer granules (1), (2)
:::
and l3), each comprising multilayer granules withln
the present invention:
:~:
:
12gZ913
(l) (2) (3)
C layer: magnesium stearate 25 22.5 20;
vinyl acetate 2 2 2;
methylcellulose 2.5 5 7.5.
5 Example 3
The procedure of Example l was followed except
that the C and I layers had the following compositions
thereby to give four types of multilayer granules (4),
15), (6) and 17), each comprising a multilayer granules
within the present invention;
(4)(5) (6) (7~
C layer: calcium stearate 20 15 lO 5;
talc 5 lO 15 20;
ethylcellulose l l l l;
purified shellac l l l l;
I layer: dextromethorphan hydrobromide lO;
diprophylline lO0;
light silica 5;
talc lO;
corn starch 5;
polyethylene glycol 5.
Every granule had the same I layer.
Example 4
The procédure of Example l was followed to
~ 25 give multilayer granules of the following formulation
: which comprise multilayer granules within the present
` invention:
nuclear seed: NPS 80;
: R layer: dextromethorphan hydrobromide 20;
octyl decyl triglyceride5;
C layer: calcium stearate 16;
talc g;
ethylcellulose l;
purified shellac l;
35 I layer: dextromethorphan hydrobromide lO;
diprophylline lO0;
talc lO;
:~
~ .
: : : ~
12~Z9i3
light silica 5;
corn starch 5;
polyethylene glycol 5.
Example 5
192 g of bunazosin hydrochloride, 1.22 kg
of a sucrose fatty acid ester, 200 g of a micropowder
of ethylcellulose and 200 g of a vegetable oil were
mixed together. Then a solution obtained by dissolving
20 g of ethylcellulose and 20 g of purified shellac
in 200 ml of ethyl alcohol was added thereto. The
obtained mixture was extruded to give particles of
5 mm in diameter. These particles were air-dried at
40C for 12 hours and dressed through 16-mesh and 42-
mesh sieves. The particles thus obtained were called
R particles.
976 g of the R particles were tumbled in
a small plate tumbling granulator and a solution lobtained
by dlssolving and dispersing 20 g of ethylcellulose,
20 g of purified shellac, 300 g of calcium stearate
and 160 g of talc in 1.6 kg of ethyl alcohol) was gradually
added thereto thereby to laminate the latter on the
former. The particles were then air-dried at 40C
for 12 hours,and the particles thus obtained and the
layer thus laminated thereon were referred to as C
particles and C layer, respectively.
1.107 kg of the C particles were tumbled
in a small plate tumbling granulator and a solution
(obtained by dissolving and dispersing 18 g of bunazosin
;hydrochloride, 22.5 g of talc, 966 g of lactose, 45
; 30 g of light silica, 45 g of sodium croscarmellose and
22.5 g of hydroxypropylcellulose in 3.5 kg of ethyl
alcohol) was gradually added thereto, thereby to laminate
the latter on the former. The particles were thereafter
air-dried at 40C for 12 hours and the particles thus
-:
; 35 obtained and the layer thus laminated thereon were
referred to as I particles and I layer, respectively.
1.48 kg of the I particles were mixed together
'
- lZ92913
with 1 g of calcium stearate and 15 g of light silicae
and compressed into tablets each weighing 75 mg. Thus
tablets containing multilayer granules of the present
invention were produced.
In order to illustrate the effects of the
present invention, the following Experimental Examples
will now be given.
Experimental Example 1: Control test
The following C and I particles were prepared
as control samples.
1.4 kg of granule seeds comprising a mixture
of white sugar and corn starch (NPS), which were employed
as nuclear seeds, were tumbled in a small plate tumbling
granulator and a solution (obtained by dissolving and
dispersing 400 g of phenylpropanolamine hydrochloride,
550 g of talc, 80 g of light silica, 240 g of stearic
acid and 30 g of hydroxypropylcellulose in 3 kg of
ethyl alcohol) was gradually added thereto, thereby
to laminate the latter on the former. Then the particles
were air-dried at 50C for 12 hours. The particles
thus obtained and the layer thus laminated thereon
were referred to as R particles and R layer, respectively.
1350 g of the R particles were tumbled in
a small fluidized bed apparatus and a solution (obtained
b~ dissolving and dispersing 66.5 g of ethylcellulose
and 66.5 g of talc in l.9 kg of ethyl alcohol) was
sprayed thereon thereby to laminate the latter on the
former and result in a weight gain of 130 g per 1350
g of the R particles. The particles were then air-
dried at 50C for 12 hours and the partlcles thusobtained and the layer thus laminated thereon were
referred to as C particles and C layer, respectively.
1 kg of the C particles were tumbled in a
small fluidized bed apparatus and a solutlon ~obtained
by dissolving and dispersing 32 g of gum arabic and
1.4 g of light silica in 95 g of water) was sprayed
~;~ thereon, thereby to laminate the latter on the former.
:::
:::
~;
1~929i3
The particles were then air-dried at 50C for 12 hours
and then particles thus obtained and the layer thus
laminated thereon were referred to as I particles
and I layer, respectively.
Each sample was introduced into a rotatory
basket as specified in the Dissolution Test of the
Japanese Pharmacopoeia, 10th ed., and subjected to
the dissolution test with the use of the 1st l~quid
as specified thereln. The amount of the eluate was
determined by absorbance at 256 nm with the elapse
of time and the dissolution ratio (%~ being determined
therefrom. Table 1 shows the results.
Table 1
Time (hr)
Sample
0.5 1 2 3 5
C partlcles 1.5 8.8 26.0 41.6 70.1
I particles 6.3 24.4 54.7 71.5 85.6
~ 9 shown in Table 1, the dissolution pattern
of the C particles is different from that of the I
particles, although the two patterns would be expected
to be the same. This fact 5uggests that the barrier
effect of the C layer was lost by laminating the I
layer thereon. Thus, it was revealed that the release-
controlling mechanlsm of the slow-release phase could
not be protected by using a conventional film layer
obtained according to the prior art.
Experimental Example 2: Control test
C and I particles were prepared in the same
manner as described in Experimental Example 1, except
that the nuclear seeds and each layer had the following
composition by weight:
nuclear seed: NPS 70;
R layer: dextromethorphan hydrobromide 20;
sucrose fatty acid ester 8;
:: ~
' '
lZ9Z913
corn starch l;
hydrooxypropylcellulose l;
C layer: ethylcellulose 3.34;
purified shellac 3.33;
methylcellulose- 3.33;
I layer: gum arabic 4.8;
light silica 0.2.
The same dissolution test was performed as
that described in Experimental Example 1. The amount
of the eluate was determined by the absorbance at 275
nm with the elapse of time and the dissolution ratio
(%) being determined therefrom. Table 2 shows the
results. The same conclusion could be drawn from Table
2 as the one described in Experimental Example 1.
Table 2
Sample I Time (hr)
C particlés ¦ 2.5 5.0 11.3 17.5 30.0 45.0
I particles 15.0 23.1 40.0 55.6 68.8 _
Experimental Example 3: Control test
Cl, C2, Il and I2 particles were prepared
in the followlng manner.
The Cl, C2 and Il particles were prepared
in the same manner as described in Experimental Example
1, except that the nuclear seeds and each layer had
the following compositions by welght:
nuclear seed: NPS 70;
R layer: dextromethorphan hydrobromide 20;
sucrose fatty acid ester 8;
corn starch l;
hydroxypropylstarch l;
Cl layer: ethylcellulose 2.25;
purified shellac 2.25;
methylcellulose 2.25;
; triacetylgIyceride 0.75;
~ 2913
C2 layer: hydroxypropyl methyl phthalate 2.25;
microcrystalline wax 0.75;
I2 layer: gum arabic 4.8;
light silica 0.2.
1.155 kg of the Il particles were then tumbled
in a small plate tumbling granulator and a solution
~obtained by dissolving and dispersing 100 g of dex~x~thorphan~
1 kg of diprophylline, 140 g of talc, 140 g of light
silica and 40 g of polyethylene glycol in 10 Q of ethyl
alcohol) was gradually added thereto, thereby to laminate
the latter on the former. The particles were then
air-dried at 50C for 12 hours and the particles thus
obtained and the layer thus laminated thereon were
referred to as I2 particles and I2 layer, respectively.
The same dissolution test as that described
in Experimental Example 1 was performed. The dissolution
ratio (%) of the dextromethorphan in each of the C2,
Il and I2 particles was determined with elapse of time
while that ~%) of the diprophylline in the I2 particles
was similarly determined Table 3 shows the results.
Table 3
25 Sample ¦ Object compound 0.5 Time ~ Ir) 3 5
2 particlesdextromethorphan 1.54.2 9.5 15.6 30.6
~; hydrobromide
~;~ Il particles¦ do. 4.25.8 8.3 14.4 24.4
: :
30 I2 particlesdo. 51.9 61.975.0 83.1 92.5
(18.6) (28.6) (41.1) ~50.3) (59.2)
diprophylline 95.0 98.2 99.3 103.5 98.7
_ _
35Since the diprophylline in the I2 layer was
rapidly dissolved, it is assumed that the dextromethorphan
hydrobromide (33.3%) in the same layer (I2) might similarly
-
lZ92913
be rapidly dissolved. Thus the-dissolution of the
slow-release moiety in the I2 particles can be expressed
by the values in parentheses which are determined by
æubtracting the dissolution of said rapid-release moiety.
~ comparison among the dissolution ratios of the slow-
release moieties in the C2, Il and I2 particles indicates
that the dissolution pattern of the C2 particles is
similar to that of the Il particles but significantly
different from that of the I2 particles, which suggests
that the slow-release characteristic of the I2 particles
was significantly damaged. Therefore the following
conclusion may be drawn. Namely, that strengthening
of the C layer by dividing the same into two layers,
i.e., Cl and C2, is somewhat effective. Thus, it is
possible to protect the release-controlling mechanism
to such an extent as to allow laminating of the Il
layer thereon. However, this effect is as yet insufficient,
so that any protective effect is no longer observed
when the I2 layer was further laminated thereon. This
result suggests that it is impossible to protect the
release-controlling mechanism of the slow-release phase
with the use of a conventional film layer obtained
according to the prior art even if the layer is strengthened
by dividing the same into two layers.
Experimental Example 4
The multilayer granules of the present invention
as produced in Example 1 were employed as a test sample.
Further multilayer granules, which were produced according
to the procedure of Example 1 except that microcrystalline
wax was used instead of calcium stearate, were employed
as a control sample.
Dissolution ratios (~) were determined with
elapse of time in the same manner as that described
in Example 2. Table 4 shows the results.
:
-
lZ9Z913
16
Table 4
Time Ihr)
Sample 0.5 1 2 3 4 5 6 910.5
Control ¦ 10298 100 100 101 97 100 10198 ll
Test sample ¦ 35 45 63 78 90 96 100 99 99 ¦
Table 4 suggests that the multilayer granules
obtained by prior arts lost the release-controlling
mechanism while that of the multilayer granules of
the present invention is maintained owing to the protective
effect of the film layer according to the present invention.
Experimental Example 5
The multilayer granules of the present invention
~1), (2) and ~3) as produced in Example 2 were employed
as samples. Each sample was immersed in the 1st liquid
as specified in the Japanese Pharmacopoeia for two
hours to determine the dissolution ratio. Then it
was removed therefrom and introduced into the 2nd liquid
as speclfied in the same Pharmacopoela and the dissolution
ratio was determined again.
The following Table 5 shows the results.
The dissolution ratio after two hours was shown by
~- adding thereto the dissolution ratio with the 1st liquid
for two hours.
Table 5
; Sample Time (hr)
0.5~ 1 2 4 5 6 7 8.5 10
(1) 40 42 42 45 46 47 47 49 51
30~ ~ (2) 44~ 50 52 60 62 65 68 73 78
(3) 45 53 64 78 83 87 90 95 100
Table 5 suggests that the releaslng period
would be proIonged with an increase in the content of
35~ the magneslum stearate in the film layer according to the
present invention and that a preferable content thereof is
80% or below.
Experimental Example 6
: ~ ,
.
lZ9Z913
17
The multilayer granules of the present invention
(4), l5), (6) and 7 as produced in Example 3 were used
as samples. The dissolution ratios were determined
in the same manner as that described in Experimental
Example 5.
, The following Table 6 shows the results.
The description with regard to Table 5 is similarly
applied thereto.
Table 6
_ Time (hr)
Sample 0 5 l 2 3 4 5 6 7 8.5 10
~4) 15 16 16 - - 17 - - - 20
15 (5) 20 20 21 25 26 30 35 40 52 62
(6) 28 31 39 43 51 66 71 85 90 96
(7) 32 35 45 63 85 99 96 98 102 99
Table 6 suggests that a preferable content
of the calcium stearate in the film layer according
to the present invention is 15 to 70~.
Experimental Example 7
The multiIayer granules of the present invention
25 as produced in Example 4 were employed as a sample
;~ and stored at room temperature for a month, at 45C
for a month and at 55C for a month. Then the dissolution
ratios were determined in the same manner as that described
in Experimental Example 5.
The following Table 7 shows the results.
The description with regard to Table 5 is similarly
applied thereto.
Table 7 suggests that the ilm layer according
to the present invention would not lose its protective
35 efect on the release-controlling mechanism under various
` ~ storage conditions.
: ~ :
` 1292913
18
Table 7
,
Storage At roth temP-¦ 1 month ~l ~o~th
5 ~5 ~ 7 ~
10 T me 4 60 59 60
68 66 66
7 78 76 78
8.5 86 86 85
91 89 90
11.5 95 94 95
: 13 100 97 99
:
:~ Experimental Example 8
2S The R particles and tablets as produced in
Example 5 were employed as samples. The R particles
and tablets were subjected to a dlssolution test by
the rotatory basket method and by the paddle method,
respectively, thereby to determine dissolution ratios.
: 30 Water was used a-~ the eluent.
The following Table 8 shows the resu.lts.
Table 8
Time (hr)
35Sample 1 2 3 4 6 8 10 22
R particles 34 37 40 44 50 61 69 98
Tablets 29 33 38 40 48 58 76 94
lZ9Z913
19
Table 8 suggests that the film layer according
to the present invention would not lose its protective
ffect on the release-controlling mechanism after applying
a compression force thereto.
s
::
~ 25
~ ~ :
: 30
