Process for preparing ethylcellulose microcapsules

Pharmaceutically active compound-containing microcapsules the coating walls of which consist essentially of ethylcellulose and a water-insoluble, acid-soluble polymer material are disclosed. A method of preparing said microcapsules is also disclosed.

This invention relates to novel ethylcellulose microcapsules and a process 
for preparing same. 
It is known that ethylcellulose microcapsules are prepared by taking 
advantage of the liquid-liquid phase separation of ethylcellulose in 
cyclohexane. For example, Japanese Patent Publication (examined) Nos. 
528/1967, 11399/1969 and 30136/1975 disclose that said microcapsules are 
obtained by preparing a hot solution in cyclohexane of ethylcellulose and 
a phase-separation-inducing agent (e.g., butyl rubber, polybutadiene, 
polyethylene, polyisobutylene), dispersing particles of a core material in 
the solution, cooling the dispersion until the ethylcellulose separates 
out from the dispersion to form a liquid phase depositing on and around 
the particles of the core material, and then recovering the so formed 
microcapsules therefrom. Further, U.S. Pat. No. 3,531,418 discloses a 
method of preparing ethylcellulose microcapsules without using a 
phase-separation-inducing agent, i.e., direct flocculation of 
ethylcellulose by change of temperature. According to the known methods, 
however, it is difficult to obtain microcapsules which show rapid release 
of a pharmaceutically active compound in the stomach because the compact 
wall structure of ethylcellulose retards the release of the 
pharmaceutically active compound. 
The present invention provides for pharmaceutically active 
compound-containing ethylcellulose microcapsules which show rapid release 
of said pharmaceutically active compound in stomach or gastric juice. The 
present invention also provides for pharmaceutically active 
compound-containing microcapsules the coating walls of which consist 
essentially of ethylcellulose and a water-insoluble, acid-soluble polymer 
material. The present invention further provides a method for preparing 
such ethylcellulose microcapsules. 
According to the present invention, the pharmaceutically active 
compound-containing microcapsules whose coating walls consist essentially 
of ehylcellulose and a water-insoluble, acid-soluble polymer material can 
be prepared by the steps of: 
(i) dissolving ethylcellulose in a solvent, 
(ii) dispersing particles of a pharmaceutically active compound (core 
material) in the solution, 
(iii) cooling the dispersion in the presence of a water-insoluble, 
acid-soluble polymer material until the ethylcellulose separates out from 
the dispersion to form coating walls on and around the particles of said 
core material, and then, 
(iv) recovering the thus-formed microcapsules therefrom. 
A wide variety of polymer materials soluble in water at a pH of not higher 
than 5 can be used as the water-insoluble, acid-soluble polymer material 
of the present invention. Examples of such polymer material include 
dialkylaminoalkyl-cellulose (e.g., diethylaminomethylcellulose), 
benzylaminoalkyl-cellulose (e.g., benzylaminomethylcellulose), 
carboxyalkyl(benzylamino)cellulose (e.g., 
carboxymethyl(benzylamino)cellulose), 
dialkylaminoacetate.cellulose.acetate (e.g., 
diethylaminoacetate.cellulose.acetate), 
cellulose.acetate.dialkylamino.hydroxyalkyl ether (e.g., 
cellulose.acetate.N,N-di-n-butylamino.hydroxypropyl ether), 
piperidyl.alkyl.hydroxyalkylcellulose (e.g., 
piperidyl.ethyl.hydroxypropylcellulose, 
piperidyl.ethyl.hydroxyethylcellulose), carboxyalkyl.piperidyl.starch 
(e.g., carboxymethyl.piperidyl.starch), poly-dialkylaminoalkylstyrene 
(e.g., poly-diethylaminomethylstyrene), 
poly-vinylacetacetal.dialkylaminoacetate (e.g., 
poly-vinylacetacetal.dimethylaminoacetate, 
poly-vinylacetacetal.diethylaminoacetate), 2-(p-vinylphenyl)glycine.vinyl 
acetate copolymer, N-vinylglycine.styrene copolymer, a copolymer of (A) 
dialkylaminoalkyl methacrylate and (B) one or two alkyl methacrylates 
(e.g., dimethylaminoethyl methacrylate.methyl methacrylate copolymer, 
butyl methacrylate.2-dimethylaminoethyl methacrylate-methyl methacrylate 
copolymer), a copolymer of (A) 2-alkyl-5-vinylpyridine, (B) alkyl acrylate 
or acrylonitrile and (C) methacrylic acid (e.g., 
2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid copolymer, 
2-methyl-5-vinylpyridine.acrylonitrile.methacrylic acid copolymer), a 
copolymer of 2-vinyl-5-alkylpyridine and styrene (e.g., 
2-vinyl-5-ethylpyridine.styrene copolymer), and a copolymer of 
2-vinylpyridine and alkyl methacrylate (e.g., 2-vinylpyridine.methyl 
methacrylate copolymer). Preferred examples of such polymer material 
include diethylaminomethylcellulose, benzylaminomethylcellulose, 
carboxymethyl(benzylamino)cellulose, 
diethylaminoacetate.cellulose.acetate, cellulose.acetate.N,N-di-n-butylami 
no.hydroxypropyl ether, piperidyl.ethyl.hydroxypropylcellulose, 
piperidyl.ethyl.hydroxyethylcellulose, carboxymethyl.piperidyl.starch, 
poly-diethylaminomethylstyrene, poly-vinylacetacetal.diethylaminoacetate, 
2-(p-vinylphenyl)glycine.vinyl acetate copolymer, N-vinylglycine.styrene 
copolymer, dimethylaminoethyl methacrylate.methyl methacrylate copolymer, 
butyl methacrylate-2-dimethyl-aminoethyl methacrylate.methyl methacrylate 
copolymer, 2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid 
copolymer, 2-methyl-5-vinylpyridine-acrylonitrile.methacrylic acid 
copolymer, 2-vinyl-5-ethylpyridine.styrene copolymer and 
2-vinylpyridine.methyl methacrylate copolymer. More preferred examples of 
the polymer material include 2-methyl-5-vinylpyridine.methyl 
acrylate.methacrylic acid copolymer, 
poly-vinylacetacetal.diethylaminoacetate, dimethylaminoethyl 
methacrylate.methyl acrylate copolymer and 
cellulose.acetate.N,N-di-n-butylamino.hydroxypropyl ether. 
In making the microcapsules of the present invention it is preferred that 
these polymer materials have a particle diameter of not more than 
one-tenth that of the core material, especially a particly size of not 
more than 50.mu., more especially of not more than 20.mu.. It is also 
preferred that these polymer materials are used in an amount of 0.1 to 20 
grams, especially 0.5 to 10 grams, per gram of ethylcellulose used. 
On the other hand, ethylcellulose having an ethoxy content of 47 to 55 W/W 
% is preferably used as the wall-forming material of the present 
invention. It is preferred that the viscosity of said ethylcellulose when 
measured at 25.degree. C. with respect to a 5 W/W % solution of it in 
toluene-ethanol (4:1) is within the range of 3 to 500 cP, especially 20 to 
200 cP. It is also preferred that said ethylcellulose is used in an amount 
of 0.05 to 5 grams, especially 0.1 to 1 gram, per gram of the core 
material used. 
Any solvents which dissolve ethylcellulose at a temperature of 70.degree. 
to 80.degree. C. and which does not dissolve the core material and the 
water-insoluble, acid-soluble polymer material can be used as the solvent 
of the invention. Examples of such solvent are cyclohexane, a mixture of 
cyclohexane and n-hexane, and the like. Especially, it is preferred to use 
cyclohexane as the solvent. 
Any pharmaceutically active compounds (or medicaments) can be used as the 
core material to be microencapsulated in the present invention. Such 
pharmaceutically active compound or medicament to be microencapsulated may 
be either solid, gel or semi-solid. In order to prepare a homogenous 
dispersion at the microencapsulation step, it is preferred that said 
pharmaceutically active compound or medicament has a particle size of 30 
to 1000.mu., especially 50 to 500.mu.. Eligible for microencapsulation as 
solids are particles of materials such as, for example, vitamines (e.g., 
ascorbic acid), amino acids (e.g., potassium aspartate, magnesium 
aspartate), minerals (e.g., potassium chloride), anti-microbial agents 
(e.g., benzylpenicillin potassium salt, sulfomethizole), anti-tumor agents 
(e.g., 5-fluorouracil, bleomycin hydrochloride), metabolic agents (e.g., 
glutathion), cardiovascular agents (e.g., dilthiazem hydrochloride), 
analgesics (e.g., acetylsalicylic acid), anti-histaminics (e.g., 
diphenhydramine hydrochloride), neuro-psycotropic agents (e.g., calcium 
N-(.gamma.,.gamma.-dihydroxy-.beta.,.beta.-dimethylbutyryl)-.gamma.-aminob 
utyrate), agents affecting digestive organs (e.g., methylmethionine 
sulfonium chloride, 
1,1-dimethyl-5-methoxy-3-(dithien-2-yl-methylene)-piperidinium bromide, 
precipitated calcium carbonate, 
1-(3,4,5-trimethoxybenzoyloxy)-2-dimethylamino-2-phenylbutane maleate), 
agents affecting respiratory organs (e.g., tri-methoquinol hydrochloride), 
and so forth. Also eligible for microencapsulation as semi-solids are, for 
example, slurries such as a slurry composed of 30 W/W % of sodium 
polyacrylate, 40 W/W % of water and 30 W/W % of 5-fluorouracil And 
pharmaceutically active compounds in the form of "gel" which can be 
microencapsulated include, for example, dextran gel having a medicament 
(e.g., methylmethionine sulfonium chloride) adsorbed therein, 
formalin-treated gelatin gel having a medicament (e.g., sulfamethomidine) 
dispersed therein, and so forth. 
Further, the core material to be microencapsulated may contain a 
water-soluble organic acid. Said organic acid serves to accelerate the 
release of the pharmaceutically active compound from microcapsules. 
Examples of such organic acid include hydroxy-lower alkane-dicarboxylic 
acid (e.g., malic acid, tartaric acid), hydroxy-lower alkane-tricarboxylic 
acid (e.g., citric acid), lower alkane-dicarboxylic acid (e.g., malonic 
acid, succinic acid) and lower alkene-dicarboxylic acid(e.g., maleic acid, 
fumaric acid). It is preferred that said acid has a particle size of not 
more than 30.mu.. It is also preferred that the amount of said acid in the 
core material is within the range of one to 90 W/W %, especially 10 to 80 
W/W %. The organic acid-containing core material may be prepared by 
granulating a mixture of the core material and the organic acid by 
conventional means (e.g., wet-granulation method, dry-granulation method), 
and the particle size of the organic acid-containing core material should 
be preferably within a range of 30 to 1,000.mu.. 
In making the microcapsules of a pharmaceutically active compounds 
according to the present invention, it is preferred to dissolve 
ethylcellulose in a solvent such as those mentioned above, and then 
dispersing the particles of a pharmaceuticcally active compound (core 
material) to the solution under stirring. In this case, it is preferred to 
dissolve ethylcellulose at a temperature of 70.degree. to 80.degree. C. 
Further, it is also preferred to dissolve ethylcellulose at a 
concentration of 0.5 to 10 W/W %, especially one to 5 W/W %. 
When the above-mentioned dispersion is cooled in the presence of the 
water-insoluble, acid-soluble polymer material, ethylcellulose separates 
out in the form of "gel" from the dispersion by flocculation thereof to 
form coating walls of and around particles of the core material and at the 
same time said water-insoluble, acid-soluble polymer material is 
incorporated into the coating walls of the embryonic microcapsules. It is 
preferred to cool the dispersion at a rate of 0.05.degree. to 4.degree. 
C., especially 0.1.degree. to 2.degree. C., per minute. 
The water-insoluble, acid-soluble polymer material may be added to the 
dispersion either before cooling said dispersion or during the cooling 
step. Especially, it is preferred that the polymer material is added to 
the dispersion at the stage where coating walls of ethylcellulose in the 
form of "gel" is formed on and around the particles of the 
pharmaceutically active compound (core material) and the thus-formed 
coating walls have a viscosity of 0.1 to 50 P, especially 1 to 10 P. More 
specifically, since the coating walls having a viscosity of the 
above-mentioned range is formed on and around the core material by cooling 
the dispersion to 55.degree. to 75.degree. C., especially 60.degree. to 
70.degree. C., it is preferred that the polymer material is added to the 
dispersion when cooled to said temperature. When the dispersion is further 
cooled to a temperature not higher than 40.degree. C. (e.g., 30.degree. to 
20.degree. C.), the thus-formed embryonic microcapsules are shrunken and 
become solid by solvent loss from the coating walls, thus giving stable 
ethylcellulose microcapsules. 
The microcapsules thus obtained may be recovered by conventional manners 
such as, for example, decantation, centrifugation, filtration and so 
forth. Further, if required, the ethylcellulose microcapsules may be 
washed with a suitable solvent (e.g., cyclohexane, petroleum-ether, 
n-hexane) and then dried by conventional manners (e.g., hot-air drying 
method). 
Further, in carrying out the phase-separation of ethylcellulose, a 
phase-separation-inducing agent, an organopolysiloxane and a surfactant 
may be used in combination with ethylcellulose. Suitable examples of the 
phase-separation-inducing agent include polyethylene, butyl rubber, 
polyisobutylene and polybutadiene. Dimethylpolysiloxane and 
methylphenylpolysiloxane are suitable as the organopolysiloxane. Further, 
the surfactants which can be used in the present invention include, for 
example, an ester of C.sub.12-18, fatty acid with sorbitan (e.g., sorbitan 
monolaurate, sorbitan sesquilaurate, sorbitan trilaurate, sorbitan 
monooleate), an ester of C.sub.6-18 fatty acid with glycerin (e.g., 
glycerin monocaprylate, glycerin monolaurate, glycerin monooleate), a 
phospholipid (e.g., soybean phospholipid) and calcium 
stearoyl-2-lactylate. It is preferred that said phase-separation-inducing 
agent, organopolysiloxane and surfactant are added to the ethylcellulose 
solution prior to dispersing the core material in said solution. Suitable 
concentration of the phase-separation-inducing agent, the 
organopolysiloxane and the surfactant in the ethylcellulose solution is 
0.1 to 10 W/V %, 0.01 to 10 W/V % and 0.003 to 10 W/V %, respectively. 
Pharmaceutically active compound-containing microcapsules the capsule walls 
of which are composed of ethylcellulose and a water-insoluble, 
acid-soluble polymer material are obtained by any one of the 
above-mentioned operations. Preferred amount of the polymer material which 
is contained or incorporated in the coating walls of ethylcellulose is 0.2 
to 20 grams, especially 1 to 10 grams, per gram of ethylcellulose. 
The pharmaceutically active compound-containing microcapsules of the 
present invention thus obtained show rapid release of said 
pharmaceutically active compound (core material) in stomach or other 
gastric organs because the water-insoluble, acid-soluble polymer material 
incorporated or contained in the coating walls of ethylcellulose dissolve 
swiftly in the presence of hydronium ion, for example, in an acidic 
solution such as gastric juice. Namely, the coating walls of the 
microcapsules of the invention when contacted with hydronium ion become 
porous and permeable to water, and water thus permeated or penetrated into 
the microcapsules serves to dissolve the core material and release it 
rapidly from the microcapsules. Moreover, when an organic acid-containing 
core material is used in the invention, said acid further accelerates the 
release of a pharmaceutically active compound from the microcapsules 
because the hydronium ion which said organic acid releases in water 
induces the dissolution of the polymer material from the interior side of 
the coating walls and serves to increase the porosity of said coating 
walls. In the microcapsules of the present invention the release velocity 
of a pharmaceutically active compound can be controlled by suitable choice 
of the amount of the polymer material and/or organic acid used. Further, 
as mentioned above, hydronium ion which the organic acid releases in water 
makes the coating walls porous enough to release the pharmaceutically 
active compound in stomach from the microcapsules and, therefore, the 
microcapsules which are obtained by using an organic acid-containing core 
material show no substantial retardation in release of a pharmaceutically 
active compound in stomach even when administered orally to patients 
suffering from hypoacidity or anacidity. 
Practical and presently-preferred embodiments of the present invention are 
illustratively shown in the following lines. Throughout the specification 
and claims, the terms "alkyl", "lower alkane" and "lower alkene" should be 
interpreted as referring to alkyl of one to 4 carbon atoms, lowr alkane of 
one to 4 carbon atoms and lower alkene of 2 to 4 carbon atoms, 
respectively. 
EXPERIMENT I 
Microcapsules containing trimebutine maleate(chemical name: 
1-(3,4,5-trimethoxybenzoyloxy)-2-dimethylamino-2-phenylbutane maleate) 
were prepared according to the following method. Then, the yield of 
microcapsules thus obtained, the amount of the active ingredient contained 
in the microcapsules and the 50% release time (i.e., a period of time 
which was necessary to release 50% of the active ingredient from the 
microcapsules) were examined, respectively. 
(Method) 
(i) Core material: 
20 parts (by weight) of an aqueous 15 W/V % methylcellulose solution were 
added to a mixture of 23 parts (by weight) of trimebutine maleate and 74 
parts (by weight) of lactose, and the mixture was granulated and dried in 
a conventional manner. The granules (particle size: 105-210.mu.) thus 
obtained were used as the core material. 
(ii) Preparation of microcapsules: 
27 g of silicone resin which met the requirements specified in JAPANESE 
STANDARDS OF FOOD ADDITIVE 4th-Edition [said silicone resin being prepared 
by dispersing silicon dioxide at a concentration of 3-15 W/W % in 
dimethylpolysiloxane (viscosity: 100-1,100 cSt at 25.degree. C.)] and 20 g 
of ethylcellulose (ethoxy content: 48.5 W/W %, viscosity: 100 cP) were 
dissolved at 80.degree. C. in 700 ml of cyclohexane under stirring. 100 g 
of the core material were dispersed in the solution, and the dispersion 
was cooled to about 70.degree. C. under stirring at 400 r.p.m.. Then, a 
suspension of 2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid 
copolymer (molar ratio=2.4:1.9:1; average particle size: 7.mu.) in 200 ml 
of cyclohexane containing soybean phospholipid (0.8 g/200 ml) was added 
to the dispersion, and said dispersion was cooled to room temperature. The 
microcapsules thus obtained were recovered by filtration, washed with 
n-hexane and then dried. Said microcapsules were passed through JIS 
standard sieve (350.mu. aperture). Trimebutine maleate-containing 
microcapsules which met the requirements of "Pulvers" specified in THE 
PHARMACOPOEIA OF JAPAN 9th-Edition were obtained. 
(iii) Estimation of release time: 
The microcapsules obtained in paragraph (ii) were added to water or a 
simulated gastric fluid specified in THE PHARMACOPOEIA OF JAPAN 
9th-Edition, and the mixture was stirred at 37.degree. C. The amount of 
the active ingredient released from the microcapsules was examined with 
the lapse of time, and the 50% release time of the active ingredient was 
estimated therefrom. 
(Results) 
The results are shown in the following Table 1. 
TABLE 1 
______________________________________ 
Amount of 
active 
ingredient 
50% release 
Amount of Yield of contained time (minutes) 
Experi- 
copolymer micro- in micro- simulated 
ment used capsules capsules gastric 
Nos. (g) (g) (%) water fluid 
______________________________________ 
(The methods of the present invention) 
1. 30 144 15.5 80 17 
2. 100 209 10.7 87 8 
3. 150 265 8.5 76 5 
(Control) 
4. 0 114 19.3 78 37 
______________________________________ 
EXPERIMENT II 
Microcapsules containing timepidium bromide (chemical name: 
1,1-dimethyl-5-methoxy-3-(dithien-2-ylmethylene)-piperidinium bromide) and 
citric acid were prepared according to the following method. Then, the 
yield of microcapsules thus obtained, the amount of the active ingredient 
contained in the microcapsules and the 50% release time (i.e., a period of 
time which was necessary to release 50% of the active ingredient from the 
microcapsules) were examined, respectively. 
(Method) 
(i) Core material: 
28 parkts (by weight) of a 25 W/V % solution of poly-vinyl acetate in 
ethanol were added to a mixture of 23 parts (by weight) of timepidium 
bromide, 37 parts (by weight) of citric acid and 33 parts (by weight) of 
lactose, and the mixture was granulated and dried in a conventional 
manner. The granules (particle size: 105-210.mu.) thus obtained were used 
as the core material. 
(ii) Preparation of microcapsules: 
22.5 g of dimethylpolysiloxane (viscosity: 10,000 cSt at 25.degree. C.) and 
25 g of ethylcellulose (ethoxy content: 48.5 W/W %, viscosity: 100 cP) 
were dissolved at 80.degree. C. in 700 ml of cyclohexane under stirring. 
100 g of the core material were dispersed in the solution, and the 
dispersion was cooled to about 75.degree. C. under stirring at 400 r.p.m.. 
To the dispersion was added a suspension of 
2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid copolymer (molar 
ratio=2.4:1.9:1) in 150 ml of cyclohexane containing soybean phospholipid 
(0.085 g/150 ml). Then, said dispersion was treated in the same manner as 
described in Experiment I. Timepidium bromide-containing microcapsules 
which met the requirements of "Pulvers" specified in THE PHARMACOPOEIA OF 
JAPAN 9th-Edition were thereby obtained as shown in the following Table 2. 
TABLE 2 
______________________________________ 
Amount of Yield of Amount of 
copolymer micro- active ingredient 
Experiment 
used capsules contained in 
Nos. (g) (g) microcapsules (%) 
______________________________________ 
(The method of the present invention) 
1. 125 243 9.3 
(Control) 
2. 0 122 18.2 
______________________________________ 
(iii) Estimation of release time: 
The microcapsules obtained in paragraph (ii) were added to water, and the 
mixture was stirred at 37.degree. C. The amount (%) of the active 
ingredient released from the microcapsules was examined with the lapse of 
time, and the 50% release time of the active ingredient were estimated 
therefrom. 
(Results) 
The results are shown in the following Table 3. 
TABLE 3 
______________________________________ 
The amount (%) of the active in- 
gredient released from the microcapsules 
Microcapsules of 
Period of the present inven- 
Control (the 
time tion (the amount of 
amount of co- 
(minutes) copolymer: 125 g) 
polymer: 0 g) 
______________________________________ 
10 15 2 
15 28 3 
20 41 7 
30 60 12 
45 76 20 
60 86 28 
90 94 43 
120 98 56 
50% release 
24 minutes 106 minutes 
time 
______________________________________

EXAMPLE 1 
30 g of polyethylene (molecular weight: 7,000) and 25 g of ethylcellulose 
(ethoxy content: 48.0 W/W %; viscosity: 45 cP) were dissolved at 
80.degree. C. in 850 ml of cyclohexane, and 100 g of glutathion having a 
particle size of 105-210.mu. were dispersed in the solution. The 
dispersion was cooled to about 65.degree. C. under stirring at 350 r.p.m.. 
150 g of polyvinylacetal diethylaminoacetate (nitrogen content: 2.0 W/W %; 
average particle size: 10.mu.) were added gradually to the dispersion, and 
said dispersion was cooled to room temperature. The microcapsules thus 
obtained were recovered by filtration, washed with n-hexane, and then 
dried. Then, said microcapsules were passed through JIS standard sieve 
(350.mu. aperture). 265 g of glutathion-containing microcapsules which met 
the requirements of "Pulvers" specified in THE JAPANESE PHARMACOPOEIA OF 
JAPAN 9th-Edition were obtained. 
______________________________________ 
Amount of glutathion contained in 
36.4 W/W % 
the microcapsules: 
50% release time of glutathion in 
106 minutes 
water (estimated in the same manner 
as described in Experiment I): 
50% release time of glutathion in 
17 minutes 
a simulated gastric fluid (estima- 
ted in the same manner as described 
in Experiment I): 
______________________________________ 
EXAMPLE 2 
Microcapsules were prepared in the same manner as described in Example 1 
except that 30 g of polyisobutylene (molecular weight: 700,000) and 150 g 
of dimethylaminoethyl methacrylate.methyl methacrylate copolymer (molar 
ratio=1:1) (average particle size: 9.6.mu.) were used instead of 
polyethylene and polyvinylacetal.diethylaminoacetate. 268 g of 
glutathion-containing microcapsules which met the requirements of 
"Pulvers" specified above were obtained. 
______________________________________ 
Amount of glutathion contained in 
36.3 W/W % 
the microcapsules: 
50% release time of glutathion in 
98 minutes 
water (estimated in the same manner 
as described in Experiment I): 
50% release time of glutathion in 
20 minutes 
a simulated gastric fluid (estima- 
ted in the same manner as described 
in Experiment I): 
______________________________________ 
EXAMPLE 3 
30 g of polyethylene (molecular weight: 7,000) and 25 g of ethylcellulose 
(ethoxy content: 48.0 W/W %; viscosity: 45 cP) were dissolved at 
80.degree. C. in 850 ml of cyclohexane, and 100 g of trimethoquinol 
hydrochloride (chemical name: 
l-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline 
hydrochloride monohydrate) having a particle size of 149-297.mu. were 
dispersed in the solution. The dispersion was cooled to about 65.degree. 
C. under stirring at 350 r.p.m.. 150 g of 2-vinyl-5-ethylpyridine.styrene 
copolymer (molar ratio=1:1) (average article size: 13.mu.) were added 
gradually to the dispersion, and said dispersion was cooled to room 
temperature. The microcapsules thus obtained are treated in the same 
manner as described in Example 1, whereby 265 g of trimethoquinol 
hydrochloride-containing microcapsules which met the requirements of 
"Pulvers" specified above were obtained. 
______________________________________ 
Amount of trimethoquinol hydrochloride 
36.3 W/W % 
contained in the microcapsules: 
50% release time of trimethoquinol 
158 minutes 
hydrochloride in water (estimated in 
the same manner as described in 
Experiment I): 
50% release time of trimethoquinol 
21 minutes 
hydrochloride in a simulated gastric 
fluid (estimated in the same manner 
as described in Experiment I): 
______________________________________ 
EXAMPLES 4-17 
Microcapsules were prepared in the same manner as described in Experiment I 
except that 100 g of a polymer shown in the following Table 4 were used 
instead of 2-methyl-5-vinylpyridine.methyl acrylate.methacrylic acid 
copolymer. Trimebutine maleate-containing microcapsules which met the 
requirements of "Pulvers" specified above were thereby obtained as shown 
in Table 4. 
TABLE 4 
______________________________________ 
Yield of 
Example microcapsules 
Nos. Polymers (g) (%)*.sup.1 
______________________________________ 
4. diethylaminomethyl- 213 97 
cellulose 
5. benzylaminomethyl- 202 92 
cellulose 
6. carboxymethyl(benzyl- 
209 95 
amino)cellulose 
7. diethylaminoacetate. 205 93 
cellulose.acetate 
8. cellulose.acetate.N,N-- 
200 91 
di-n-butylamino.hydroxy- 
propyl ether 
9. piperidyl.ethyl. 202 92 
hydroxypropylcellulose 
10. piperidyl.ethyl.hydroxyethyl- 
205 93 
cellulose 
11. carboxymethyl.piperidyl- 
216 98 
starch 
12. poly-diethylaminomethyl- 
207 94 
styrene 
13. 2-methyl-5-vinylpyridine. 
194 88 
acrylonitrile.methacrylic 
acid copolymer 
14. 2-vinylpyridine.methyl 
200 91 
methacrylate copolymer 
15. 2-(p-vinylphenyl)glycine. 
209 95 
vinyl acetate copolymer 
16. N--vinylglycine.styrene 
202 92 
copolymer 
17. butyl methacrylate.2-dimethyl- 
203 92 
aminoethyl methacrylate.methyl 
methacrylate copolymer 
______________________________________ 
Note: 
*.sup.1 The yield (%) of microcapsules was calculated to the following 
formula: 
##STR1## 
a: amount (%) of active ingredient contained in microcapsules 
b: amount (grams) of active ingredient used 
Yobs: yield (grams) of microcapsules which met the requirements of 
"Pulvers" specified in THE PHARMACOPOEIA OF JAPAN 9thEdition.