CA1292913C - Sustained release pharmaceutical preparation comprising multilayer granules - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A multilayer granule is disclosed which comprises a core, a slow-release layer, a rapid-release layer provided outside the slow-release layer and a film layer containing a metal stearate and disposed between the slow-release layer and the rapid-release layer. A pharmacologically effective component can thereby be released over a prolonged period of time.

Description

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 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 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 Table 7 , Storage At roth temP-¦ 1 month ~l ~o~th 5 ~5 ~ 7 ~

10 T me 4 60 59 60 8.5 86 86 85 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 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

Claims (2)

1. 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 component 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 stearate and mixtures thereof.

2. A multilayer granule according to claim 1, wherein the film layer contains from 30 to 85 percent by weight of the film-forming component and from 15 to 70 percent by weight of the metal stearate.