Substained release microcapsule of physiologically active compound which is slightly water soluble at pH 6 to 8

A pharmaceutical preparation is provided by a microcapsule containing a physiologically active substance which is water-soluble only at a pH of about 3 or below, and a polymer which is biodegradable upon oral administration. A process for producing the microcapsule is also provided.

TECHNICAL FIELD 
The present invention relates to a microcapsule using a biodegradable 
polymer to encapsulate a physiologically active substance. 
BACKGROUND OF THE INVENTION 
In general, drugs that are slightly water-soluble at pH 6 to 8 are slightly 
absorbed into the digestive tract after oral administration because of 
their low dissolution rates. In order to improve the solubility of the 
drugs, the slightly water-soluble drugs have been formulated as readily 
water-soluble salts, or a solution adjuvant is introduced as an additive. 
However, in the case of hydrochloric acid salts for example, hydrochloric 
acid sometimes separates from the hydrochloric acid salt during storage. 
When a solution adjuvant is added, the resulting tablets contain so many 
ingredients and sometimes become so large that it becomes difficult to 
take them. In addition, because the acid that is added as an additive 
readily dissolves and disappears, the effects of improving the solubility 
also disappear. 
Pharmaceutical Research, Vol. 8, No. 1, p. 101 (1991) reports studies on 
nanocapsules which contain the slightly water-soluble drug indomethacin. 
However, indomethacin is not readily soluble in water at a pH no higher 
than 3. In addition, no improvement in the absorption of the drug has been 
achieved in the study. 
DISCLOSURE OF THE INVENTION 
The present inventors have designed and studied a microcapsule containing a 
physiologically active substance that is soluble in water at a pH no 
higher than about 3 by using a biodegradable polymer as a base. As a 
result, it has been found that a microcapsule prepared by adding to a 
biodegradable polymer a physiologically active substance that is 
water-soluble at a pH no higher than about 3 and dissolving the mixture in 
an organic solvent gradually releases a water-soluble low molecular weight 
free acid and the physiologically active substance at the same time after 
degradation of the base occurs in the digestive tract after oral 
administration. It has also been found that the microcapsule solubilizes a 
physiologically active substance that is normally insoluble in the 
digestive tract from the duodenum to the rectum, thereby improving the 
absorption of the physiologically active substance. After further studies 
based on these findings, the present invention has been completed. 
The present invention provides a microcapsule comprising a physiologically 
active substance which is water-soluble at a pH no higher than about 3, 
and a biodegradable polymer. 
The present invention also provides a microcapsule which is obtainable by 
dissolving in an organic solvent a physiologically active substance which 
is water-soluble at a pH no higher than about 3 together with a 
biodegradable polymer, and then subjecting the resulting solution to 
in-water drying or spray drying. 
The present invention also relates to a process for producing a 
microcapsule which comprises dissolving in an organic solvent a 
physiologically active substance which is water-soluble at a pH no higher 
than about 3 together with a biodegradable polymer, and then subjecting 
the resulting solution to in-water drying or spray drying. 
The present invention further relates to a method of treating ulcer or 
hypertension in a mammal which comprises administering to such mammal in 
need thereof an effective therapeutic amount of the above microcapsule. 
The present invention still further relates a method of enhancing 
absorption of a slightly absorbable physiologically active substance, 
which comprises encapsulating the slightly absorbable physiologically 
active substance by dissolving in an organic solvent the slightly 
absorbable physiologically active substance together with a biodegradable 
polymer, and then subjecting the resulting solution to in-water drying or 
spray drying. 
The present invention also provides use of a slightly absorbable 
physiologically active substance and a biodegradable polymer for 
manufacture of a microcapsule. 
The present invention also provides use of the above microcapsule for 
enhancing absorption of a slightly absorbable physiologically active 
substance. 
The present invention makes it possible to encapsulate a physiologically 
active substance which is water-soluble at a pH no higher than about 3 
into microcapsules by using biodegradable polymers. Further, addition of 
an appropriate excipient can control the degradation rate of the polymer 
and the release rate or duration time of the physiologically active 
substance to be absorbed. 
The term "microcapsule" used herein is intended to collectively include 
microspheres, microcapsules, microparticles, nanoparticles, nanospheres, 
and nanocapsules. 
The physiologically active substance to be used in the present invention is 
a drug which is readily soluble in water under acidic conditions, in 
particular at a pH no higher than about 3. Preferably, the physiologically 
active substance is slightly soluble in water under neutral conditions, in 
particular at pH 6 to 8. The term "soluble in water" or "water-soluble" 
used herein regarding the physiologically active substance means that the 
water-solubility of the physiologically active substance is not less than 
about 0.01 g, preferably not less than about 1 g, per 100 ml of water at 
about 20.degree. C. The term "slightly soluble in water" or "slightly 
water-soluble" used herein regarding the physiologically active substance 
means that the water-solubility of the physiologically active substance is 
not more than about 0.01 g, preferably not more than about 0.001 g, per 
100 ml of water at about 20.degree. C. Preferably, the physiologically 
active substance is slightly absorbable, that is, slightly absorbed in the 
digestive tract from the duodenum to the rectum. 
The pharmacological activity of the physiologically active substance is not 
specifically limited. Examples thereof include antibiotics, antifungal 
agents, antilipidemic agents, drugs for circulatory systems, anti-platelet 
aggregation drugs, antitumor agents, antipyretics, analgesics, 
anti-inflammatory agents, antitussiveexpectorants, sedatives, muscle 
relaxants, antiepileptic agents, antiulcer agents, antidepressants, 
antiallergic agents, cardiotonics, antiarrhythmic agents, vasodilators, 
hypotensive diuretics, antidiabetic agents, anticoagulants, hemostatics, 
antituberculous agents, hormone preparations, narcotic antagonists, bone 
resorption inhibitors, angiogenesis inhibitors, etc. 
Examples of the antibiotics include gentamicin, dibekacin, kanendomycin, 
lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline 
hydrochloride, oxytetracycline hydrochloride, rolitetracycline, 
doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, 
cefalotin, cefaloridine, cefotiam, cefsulodin, cefmenoxime, cefmetazole, 
cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxolactam, thienamycin, 
sulfazecin, azusleonam, etc. 
Examples of the antifungal agents include 
2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 
-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-3(2H,4H)-1,2,4-triazo 
lone, 
2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 
-yl)propyl]-4-[4-trifluoromethoxyphenyl]-3(2H,4H)-1,2,4-triazolone, 
2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 
-yl)propyl]-4-[4-(2,2,2-trifluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 
etc. In particular, 
2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 
-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazol 
one is preferred. 
Examples of the antilipidemic agents include pravastatin, simvastatin, etc. 
Examples of the drugs for circulatory systems include substituted 
alanylglycine compounds having angiotensin converting enzyme (ACE) 
inhibitory activity, such as 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, N-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine, and 
N-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-N-(5-hydroxyindan-2-yl)glyci 
ne. In particular, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
is preferred. 
Examples of the anti-platelet aggregation drugs include ticlopidine, 
cilostazol, alprostadil, limaprost, dipyridamole, ethyl icosapentaenoate, 
beraprost, ozagrel, aspirin, etc. 
Examples of the antitumor agents include bleomycin hydrochloride, 
methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine 
sulfate, daunorubicin hydrochloride, adriamycin, neocarzinostatin, 
cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, 
krestin, picibanil, lentinan, levamisole, bestatin, azimexon, 
glycyrrhizin, poly I:C, poly A:U, poly ICLC, etc. 
Examples of the antipyretics, analgesics and anti-inflammatory agents 
include sodium salicylate, sulpyrine, sodium flufenamate, diclofenac 
sodium, indomethacin sodium, morphine hydrochloride, pethidine 
hydrochloride, levorphanol tartarate, oxymorphone, etc. 
Examples of the antitussive expectorants include ephedrine hydrochloride, 
methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, 
dihydrocodeine phosphate, alloclamide hydrochloride, chlorphezianol 
hydrochloride, picoperidamine hydrochloride, cloperastine, protokylol 
hydrochloride, isoproterenol hydrochloride, salbutamol sulfate, 
terbutaline sulfate, etc. 
Examples of the sedatives include chlorpromazine hydrochloride, 
prochlorperazine, trifluoperazine, atropine sulfate, methylscopolamine 
bromide, etc. 
Examples of the muscle relaxants include pridinol methanesulfonate, 
tubocurarine chloride, pancuronium bromide, etc. 
Examples of the antiepileptic agents include phenytoin sodium, 
ethosuximide, acetazolamide sodium, chlordiazepoxide hydrochloride, etc. 
Examples of the antiulcer agents include benzimidazole compounds having 
proton pump inhibitory activity (e.g., 
2-[[[3-methyl-4-(2,2,3,3-tetrafluoropropoxy)-2-pyridyl]methyl]thio]benzimi 
dazole, 
2-[[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl]thio]benzi 
midazole, etc.), metoclopramide, histidine hydrochloride, etc. In 
particular, 
2-[[[3-methyl-4-(2,2,3,3-tetrafluoropropoxy)-2-pyridyl]methyl]thio]benzimi 
dazole, or 
2-[[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl]thio]-benz 
imidazole is preferred. 
Examples of the antidepressants include imipramine, clomipramine, 
noxiptilin, phenelzine sulfate, etc. 
Examples of the antiallergic agents include imidazopyridazine compounds 
having antiasthmatic activity (e.g., 
3-(imidazo[1,2-b]pyridazine-6-yl)oxy-2,2-dimethylpropane-sulfonamide, 
etc.), triazolopyridazine compounds having antiasthmatic activity (e.g., 
2-ethyl-2-[(7-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-oxymethyl]butan 
e-sulfonamide, etc), diphenhydramine hydrochloride, chlorpheniramine 
maleate, tripelennamine hydrochloride, methdilazine hydrochloride, 
clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine 
hydrochloride, etc. In particular, 
3-(imidazo[1,2-b]pyridazine-6-yl)oxy-2,2-dimethylpropane-sulfonamide, or 
2-ethyl-2-[(7-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-oxymethyl]butan 
esulfonamide is preferred. 
Examples of the cardiotonics include transbioxo-camphor, theophyllol, 
aminophylline, methoxyphenamine hydrochloride, etc. 
Examples of the antiarrhythmic agents include propranolol hydrochloride, 
alprenolol hydrochloride, bufetolol hydrochloride, oxyprenolol 
hydrochloride, etc. 
Examples of the vasodilators include oxyephedrine hydrochloride, diltiazem 
hydrochloride, tolazoline hydrochloride, hexobendine, bamethan sulfate, 
etc. 
Examples of the hypotensive diuretics include hexamethonium bromide, 
pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, 
clonidine hydrochloride, etc. 
Examples of the antidiabetic agents include glymidine sodium, glipizide, 
phenformin hydrochloride, buformin hydrochloride, metformin, etc. 
Examples of the anticoagulants include heparin sodium, sodium citrate, etc. 
Examples of the hemostatics include thromboplastin, thrombin, menadione 
sodium bisulfite, acetomenaphthone, .epsilon.-aminocaproic acid, 
tranexamic acid, carbazochrome sodium sulfonate, adrenochrome 
monoaminoguanidine methanesulfonate, etc. 
Examples of the antituberculous agents include isoniazid, ethambutol, 
sodium para-aminosalicylate, etc. 
Examples of the hormone preparations include prednisolone succinate, 
prednisolone sodium phosphate, dexamethasone sodium sulfate, betamethasone 
sodium phosphate, hexoestrol phosphate, hexoestrol acetate, methymazole, 
etc. 
Examples of the narcotic antagonists include levallorphan tartarate, 
nalorphine hydrochloride, naloxone hydrochloride, etc. 
Examples of the bone resorption inhibitors include (sulfur-containing 
alkyl)aminomethylenebisphosphonic acid, etc. 
Examples of the angiogenesis inhibitors include angiostatic steroids, 
disclosed in Science, 221, 719 (1983), fumagillin, disclosed in 
EP-A-325,119, fumagillol derivatives (e.g., 
O-monochloroacetylcarbamoylfumagillol, 
O-dichloroacetyl-carbamoylfumagillol, etc., (EP-A-357,061, EP-A-359,036, 
EP-A-386,667, EP-A-415,294), etc. 
Of the above physiologically active substances, basic compounds are 
preferred. In particular, an imidazole or its condensed ring compound, a 
triazole or its condensed ring compound, or a substituted alanylglycine 
compound is most preferred. The imidazole or its condensed ring compound 
is preferably a benzimidazole compound {e.g., 
2-[[[3-methyl-4-(2,2,3,3-tetra-fluoropropoxy)-2-pyridyl]methyl]thio]-benzi 
midazole} or 
3-(imidazo[1,2-b]pyridazin-6-yl)oxy-2,2-dimethylpropanesulfonamide. The 
triazole or its condensed ring compound is preferably 
2-ethyl-2-[(7-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)oxymethyl]-butan 
esulfonamide, or 
2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1 
-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3-(2H,4H)-1,2,4-triazo 
lone. The substituted alanylglycine compound is preferably 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
. 
The amount of the physiologically active substance to be used varies 
depending upon such factors as a particular kind of substance, desired 
pharmacological activity, etc. When water/oil (w/o) type emulsions are 
prepared, the concentration of the physiologically active substance in the 
aqueous phase is about 0.001% to about 90% (W/W), preferably about 0.01% 
to about 80% (W/W). 
The biodegradable polymer to be used in the present invention is a 
biocompatible polymer which is degradable in living bodies and slightly 
soluble or insoluble in water. 
Examples of the biodegradable polymers include poly fatty acid esters 
(e.g., polylactic acid, polyglycollic acid, polycitric acid, polymalic 
acid, polylactic acid caprolactone), poly-.alpha.-cyanoacrylic acid 
esters, polyhydroxybutyric acid (e.g., poly-.beta.-hydroxybutyric acid), 
polyalkylene oxalates (e.g., polytrimethylene oxalate, polytetramethylene 
oxalate), poly ortho esters, poly ortho carbonates and other 
polycarbonates (e.g., polyethylene carbonate, polyethylenepropylene 
carbonate), polyamino acids (e.g., poly-.gamma.-benzyl-L-glutamic acid, 
poly-L-alanine, poly-.gamma.-methyl-L-glutamic acid), hyaluronic acid 
esters, etc. These polymers may be used alone or in combination thereof. 
They may be used in the form of a copolymer or a mixture of two or more 
polymers. They may also be in the form of salts thereof. 
In particular, poly fatty acid esters are preferred. More preferred 
polymers are polylactic acid, lactic acid/glycolic acid copolymers, 
hydroxybutyric acid/glycolic acid copolymers (e.g., .beta.-hydroxybutyric 
acid/glycolic acid copolymers), butyric acid/glycolic copolymers or 
mixtures thereof of the above, lactic acid/glycollic acid copolymers, and 
hydroxybutyric acid/glycolic acid copolymers are particularly preferred. 
The weight-average molecular weight of the biodegradable polymer is 
preferably selected from the range of about 1,000 to about 20,000, more 
preferably about 2,000 to about 8,000. In particular, fatty acid 
polyesters having a weight-average molecular weight selected from the 
above range are preferred. 
The molecular weight used herein is a molecular weight indicated as the 
molecular weight of polystyrene which is determined by gel permeation 
chromatography (GPC) using polystyrene as a standard material. The 
determination was carried out using GPC column TSK gel (2000, 2500, 3000; 
manufactured by Tosoh, Japan) and chloroform as the mobile phase. 
The composition ratio of the copolymer, e.g., lactic acid/glycollic acid 
copolymer or hydroxybutyric acid/glycollic acid copolymer is preferably 
about 100/0 to 25/75 (W/W; lactic acid or hydroxybutyric acid/glycolic 
acid), is more preferably about 75/25 to 25/75 (W/W). 
The amount of the biodegradable polymer to be used depends upon various 
factors such as the degree of the pharmacological activity, release rate, 
and duration time of the physiologically active substance. For example, 
the polymer is used as the microcapsule base in an amount of about 0.2 to 
10,000 times (by weight), preferably about 1 to 100 times (by weight), of 
the weight of the physiologically active substance. 
The hydrolysis of the biodegradable polymer can be accelerated at a low or 
high pH. Therefore, acidic or basic excipients can be used in order to 
modulate the polymer erosion rate. The excipients can be mixed in a solid 
form with the physiologically active substance or dissolved in an organic 
solvent containing the polymer. The amount of the excipients should be 
between 0.1% and 30% (weight relative to the polymer weight). Examples of 
the excipients include inorganic acids such as ammonium sulfate and 
ammonium chloride, organic acids such as citric acid, benzoic acid, 
heparin and ascorbic acid, inorganic bases such as sodium carbonate, 
potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide, 
organic bases such as protamine sulfate, spermine, choline, ethanolamine, 
diethanolamine and triethanolamine, and surfactants such as TWEEN.TM. 
(polyoxyethylenesorbitan fatty acid ester) and PLURONIC.TM. 
(polyoxyethylene-polyoxypropylene copolymer). 
The concentration of the biodegradable polymer in the oil phase is selected 
from the range of about 0.5 to about 90% (W/W), preferably between about 2 
to about 60% (W/W). 
The above polymer-containing solution (oil phase) is a solution of a 
polymer in an organic solvent. 
The organic solvent is not specifically limited so long as it has a boiling 
point no higher than about 120.degree. C. and is slightly miscible with 
water and dissolves the biodegradable polymer. Examples of the organic 
solvents include halogenated alkanes (e.g., dichloromethane, chloroform, 
chloroethane, trichloroethane, carbon tetrachloride, etc.), ethyl acetate, 
ethyl ether, cyclohexane, benzene, n-hexane, toluene, etc. These solvents 
can be mixtures of two or more solvents. 
The microcapsule of the present invention can be prepared, for example, by 
subjecting a solution of the above physiologically active substance and 
the above biodegradable polymer in an organic solvent to in-water drying, 
spray drying or phase separation. Initially, the physiologically active 
substance and the polymer are dissolved in an organic solvent. In order to 
adjust the biodegradation rate of the polymer, an aqueous solution of a pH 
adjustor may be added, followed by emulsification to prepare a w/o type 
emulsion. The pH adjustors include carbonic acid, acetic acid, oxalic 
acid, citric acid, tartaric acid, succinic acid, phosphoric acid or their 
sodium or potassium salts, hydrochloric acid, sodium hydroxide, etc. 
The emulsification can be carried out by conventional dispersion techniques 
such as intermittent shaking, mixing by means of a mixer (e.g., propeller 
agitator, turbine agitator, etc.), colloid mill operation, mechanical 
homogenization, ultrasonication, etc. 
When the physiologically active substance is insoluble, it is subjected to 
fine-granulation to prepare a solid/oil (s/o) type emulsion. 
Then, the w/o type emulsion, oil phase solution, or s/o type emulsion thus 
obtained is subjected to in-water drying to prepare microcapsules. When 
the microcapsules are prepared by an in-water drying process, the w/o type 
emulsion, oil phase solution, or s/o type emulsion is further added to the 
third phase (aqueous phase) to form a w/o/w type, o/w type or s/o/w type 
emulsion, followed by removal of the solvent in the oil phase to prepare 
microcapsules. 
An emulsifying agent may be added to the outer phase (aqueous phase). In 
general, any emulsifying agent can be used so long as it forms a stable 
o/w type emulsion. Examples of the emulsifying agents include anionic 
surfactants (e.g., sodium oleate, sodium stearate, sodium laurate); 
nonionic surfactants such as polyoxyethylenesorbitan aliphatic acid esters 
(e.g., TWEEN 80, TWEEN 60 (Atlas Powder Co.)), polyoxyethylene castor oil 
derivatives (e.g., HCO-60, HCO-50 (Nikko Chemicals)), polyvinyl 
pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, 
gelatin, etc. These emulsifying agents can be used alone or in combination 
thereof. The concentration of the emulsifying agent to be used is selected 
from the range of about 0.01% to about 20% (W/W), preferably about 0.05% 
to 10% (W/W). 
The solvent in the oil phase can be removed by. conventional methods, for 
example, by stirring with a propeller-type stirrer, magnetic stirrer, 
etc., under atmospheric pressure or gradually reduced pressure, or by 
evaporating the solvent while controlling degree of vacuum by using a 
rotary evaporator, etc. In this case, when solidification of the polymer 
proceeds to some degree and the loss of the physiologically active 
substance caused by its release from the internal phase is decreased, a 
w/o/w type, o/w type or s/o/w type emulsion may be warmed gradually to 
remove the solvent completely. This warming operation shortens the time 
for removing the solvent. 
The microcapsules thus obtained are collected by centrifugation or 
filtration. Then, the free physiologically active substance, carriers for 
the substance, etc., attached onto the surface of the microcapsules are 
washed off with distilled water repeatedly several times. Water in the 
microcapsules and the solvent in the microcapsules are completely dried 
under reduced pressure, if necessary, with warming. 
When the microcapsules are prepared by the phase separation process, the 
coacervation agent below is gradually added with stirring to the w/o type 
or s/o type emulsion or the oil phase to precipitate and solidify the 
polymer. 
Any coacervation agent can be used so long as it is a polymeric, 
mineral-oil or vegetable-oil compound which is miscible with a solvent for 
the polymer and which does not dissolve a polymer for encapsulation. The 
coacervation agents include, for example, silicone oil, sesame oil, 
soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral 
oil, etc. These coacervation agents can be used as mixtures thereof. 
The microcapsules thus obtained are collected by filtration, and then 
repeatedly washed with heptane, etc., to remove the coacervation agent. 
The free physiologically active substance and solvent are removed in a 
similar manner to that in the in-water drying process. In order to prevent 
aggregation of the particles during the washing, an aggregation preventing 
agent may be added. 
The microcapsules thus obtained are screened, if necessary after light 
pulverization, to remove microcapsules that are too large. 
When the microcapsule of the present invention is produced by a spray 
drying process, the organic solvents to be used for the oil phase may be 
the above-mentioned solvent or a solvent that is readily miscible with 
water, such as acetone, acetonitrile, tetrahydrofuran, dioxane, pyridine, 
alcohols (e.g., methanol, ethanol), etc. These solvents can be used as 
mixtures thereof. An appropriate mixing ratio of a mixture of water with 
the above organic solvent which homogeneously dissolves the 
physiologically active substance and the polymer may be used. 
Then, the w/o type emulsion or s/o type suspension or solution thus 
obtained is sprayed into a drying chamber of a spray dryer through a 
nozzle, and the organic solvent and water in the atomized droplets are 
volatilized in a very short time to prepare powdery microcapsules. The 
nozzle may be a two-liquid type nozzle, pressure type nozzle, rotary disc 
type nozzle, etc. At the same time, in order to prevent aggregation of the 
microcapsules, an aqueous solution of an aggregation-preventing agent is 
sprayed from another nozzle. That is, the spray dryer is provided with two 
nozzles, and the w/o type emulsion, s/o type suspension or physiologically 
active substance/polymer solution is sprayed from one nozzle, while a 
suitable amount of an aqueous solution of an aggregation-preventing agent 
is sprayed from the other nozzle to form coating on the surface of the 
microparticles. When a two-liquid nozzle or pressure nozzle is used as the 
nozzle, the two nozzles may be provided in the center of the spray dryer. 
Preferably, a nozzle having the structure for two-liquid spraying are used 
so that the physiologically active substance/polymer solution and the 
aqueous solution of the aggregation-preventing agent can be sprayed 
separately without mixing them in the nozzles. 
The aggregation-preventing agents include water-soluble inorganic salts, 
organic acids and organic acid salts. They are not specifically limited so 
long as they can be administered to human bodies and are solid 
non-adherent substance at room temperature. The inorganic salts include, 
for example, alkaline metal halides (e.g., sodium chloride, potassium 
chloride, sodium bromide, potassium bromide, etc.), alkaline earth metal 
halides (e.g., calcium chloride, magnesium chloride, etc.), ammonium 
halides (e.g., ammonium chloride, ammonium bromide, etc.), alkaline metal 
carbonates or bicarbonates (e.g., sodium carbonate, potassium carbonate, 
sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal 
carbonates (e.g., calcium carbonate, magnesium carbonate, etc.), ammonium 
carbonate, ammonium bicarbonate, alkaline metal phosphates (e.g., sodium 
phosphate, potassium phosphate, disodium hydrogenphosphate, dipotassium 
hydrogenphosphate, sodium dihydrogenphosphate, potassium 
dihydrogenphosphate, etc.), diammonium hydrogenphosphate, ammonium 
dihydrogenphosphate, alkaline earth metal oxides (e.g., magnesium oxide, 
calcium oxide, etc.), alkaline earth metal hydroxides (e.g., magnesium 
hydroxide, calcium hydroxide, etc.), etc. 
The water-soluble organic acids include, for example, citric acid, tartaric 
acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, 
dextran sulfate, carboxymethylcellulose, alginic acid, pectic acid, etc. 
The water-soluble organic acid salts include, for example, salts of acetic 
acid, citric acid, tartaric acid, malic acid, succinic acid, benzoic acid, 
chondroitin sulfate, dextran sulfate, carboxymethylcellulose, alginic 
acid, pectic acid, carbonic acid, bicarbonic acid, etc., with an alkaline 
metal (e.g., sodium, potassium, etc.), ammonium, basic amino acid or 
alkaline earth metal salt (e.g., calcium, magnesium, etc.). 
In particular, water-soluble inorganic salts are preferred. These 
water-soluble inorganic salts, organic acids and organic acid salts can be 
used alone or in combination thereof in an appropriate ratio. 
The formulation ratio of the above water-soluble inorganic salt, organic 
acid or organic acid salt based on the polymer may be in the range in 
which aggregation-preventing effect is observed. For example, the ratio by 
weight is about 0.001 to about 100, preferably about 0.01 to about 50, 
more preferably about 0.1 to about 10 
In the present invention, a surfactant may be contained in the 
aggregation-preventing agent solution and may be sprayed with the 
physiologically active substance/polymer solution. Alternatively, it may 
be sprayed with the physiologically active substance/polymer solution 
through a nozzle other than that for the aggregation-preventing agent. 
Thus, the surfactant is dispersed on the surface of the microcapsule 
preparation, or the surface of the microcapsule preparation is coated with 
the surf actant. This provides very high dispersibility when the 
microparticle preparation is dispersed in a dispersive medium. 
Preferred examples of the surfactants include nonionic surfactants such as 
alkylene glycols (e.g., propylene glycol, etc.), polysorbates (e.g., 
polysorbate 40, polysorbate 60, polysorbate 80, etc.), macrogols (e.g., 
macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, 
macrogol 6000, etc.), polyoxyethylene hardened castor oil (e.g., 
polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor 
oil 50, polyoxyethylene hardened castor oil 60,), etc. These surfactants 
can be used alone or in combination thereof in an appropriate mixing 
ratio. 
The formulation ratio of the above surfactant based on the polymer is not 
specifically limited so long as it is in the range in which improved 
dispersibility is observed. For example, the ratio by weight is about 
0.0000001 to about 10, preferably about 0.000005 to about 5, more 
preferably about 0.00001 to about 0.01. 
Water in the microcapsules and the solvent in the microcapsule membrane are 
completely removed under reduced pressure, if necessary, with warming. 
The microcapsules of the present invention can be administered as they are 
or after processing them into various preparations orally, intrarectally, 
or directly into organs. 
The above preparations include oral preparations (e.g., powders, granules, 
capsules, tablets), suppositories (e.g., rectal suppositories, vaginal 
suppositories), injections, etc. In particular, oral preparations are 
preferred. 
The microcapsules of the present invention can be processed into tablets 
according to conventional methods. For example, to the microcapsules are 
added an excipient (e.g., lactose, crystalline cellulose, sucrose, starch 
such as corn starch, etc.), a disintegrating agent (e.g., starch such as 
corn starch, croscarmellose sodium, carboxymethylstarch sodium, calcium 
carbonate, etc.), a binder (e.g., crystalline cellulose, acacia, dextrin, 
carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropylcellulose, 
etc.) or a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 
6000, etc.), etc. Then the mixture is compressed for shaping. 
The microcapsules of the present invention can be processed into oily or 
aqueous solid suppositories, semi-solid or liquid suppositories by per se 
known methods. The oleaginous bases for the above composition are not 
specifically limited so long as they do not dissolve the microcapsules. 
Examples thereof include higher fatty acid glycerides [e.g., cacao butter, 
Witepsol (Dynamit-Nobel, Germany), etc.], intermediate fatty acids [e.g., 
Miglyol (Dynamit-Nobel), etc.], vegetable oils (e.g., sesame oil, soybean 
oil, cottonseed oil, etc.), etc. The aqueous bases include, for example, 
polyethylene glycol and propylene glycol. The aqueous gels include, for 
example, natural gum, cellulose derivatives, vinyl polymers, 
polyacrylates, etc. 
When the microcapsules of the present invention are processed into, for 
example, injections, the microcapsules are dispersed in an aqueous vehicle 
together with a dispersing agent (e.g., TWEEN 80, HCO-60 (manufactured by 
Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.), a 
preservative (e.g., methylparaben, propylparaben, benzyl alcohol, 
chlorobutanol, etc.), a tonicity agent (e.g., sodium chloride, glycerin, 
sorbitol, glucose, etc.), etc., to prepare aqueous suspensions. They may 
also be dispersed in a vegetable oil (e.g., olive oil, sesame oil, peanut 
oil, cottonseed oil, corn oil, etc.), propylene glycol, etc., to prepare 
oily suspensions. In this manner, sustained release injections can be 
prepared. 
The microcapsules of the present invention can be used for treating various 
diseases such as ulcer, hypertension, asthma, hyperlipemia, bacterial or 
fungal infections, tumor, inflammatory diseases, epilepsy, depression, 
allergic diseases, arrhythmia, diabetes, tuberculosis, osteoporosis, etc., 
in mammals such as mice, rats, horses, cattle, humans, etc., depending 
upon. pharmacological activity of the physiologically active substance. 
Preferably, the microparticules of the present invention are used for 
treating ulcer or hypertension. 
The effective therapeutic dose of the microcapsules or their preparations 
of the present invention varies depending upon such factors as the kind 
and content of physiologically active substance as an active ingredient, 
dosage forms, duration of the release, recipient animals and purposes of 
treatment. It is important to ensure that the effective dose of the active 
ingredient will be administered. For example, the unit dose for a human 
may be selected from the range of about 1 mg to 10 g, preferably about 10 
mg to 2 g, calculated as the weight of the microcapsules. Preferably, the 
microcapsules of the present invention are used in a sustained-release 
preparation. 
The microcapsules of the present invention have, for example, the following 
advantages: 
(1) The microcapsules can improves absorption of a physiologically active 
substance which is slightly soluble and slightly absorbable into the 
digestive tract from the duodenum to the rectum. That is, the 
biodegradable polymer contained in the microparticles as a base degrades 
in the digestive tract after administration of the microcapsules to 
gradually release a free acid of a water-soluble low molecular weight 
molecule (monomer to oligomer) together with a physiologically active 
substance. Thus, the physiologically active substance which does not 
normally dissolve in the digestive tract is solubilized by the released 
acid, and thus its absorption can be improved. 
(2) Sustained release microcapsules particularly for oral administration 
can be prepared from a slightly water-soluble physiologically active 
substance by using a biodegradable polymer having varying biodegradation 
rates. Further, addition of an appropriate additive can control the 
degradation rate of the biodegradable polymer and the release rate and 
duration time of the physiologically active substance. 
(3) When a readily soluble salt such as hydrochloric acid salt is used to 
improve the solubility of physiologically active substances as in prior 
art techniques, hydrochloric acid separates from the hydrochloric acid 
salt during storage. However, the biodegradable polymers in the present 
invention do not cause such a problem. 
(4) When additives such as acids are added as solution adjuvants, the acids 
readily dissolve and disappear and solubilization effects are not 
obtained. On the other hand, the solubility of the biodegradable polymers 
in the present invention can be controlled. 
(5) The microcapsules can be produced by an in-water drying process, phase 
separation process, spray drying process, etc. These processes can be 
controlled to provide homogeneously spherical microcapsules having a 
particle size of 0.1 to 1000 .mu.m. 
(6) In a spray drying process, microcapsules having a high drug content of 
10 to 50% can be prepared in a short period of time. 
The following examples further illustrate the present invention in detail 
but are not to be construed to limit the scope thereof. In the examples, 
all the percents (%) are indicated as weight/weight percents.

EXAMPLE 1 
The antiulcer drug 
2-[[[3-methyl-4-(2,2,3,3,-tetrafluoropropoxy)-2-pyridyl]methyl]thio]benzim 
idazole (hereinafter sometimes referred to as Compound A) (400 mg) and 
lactic acid/glycollic acid copolymer (lactic acid/glycollic acid=50/50, 
average molecular weight calculated as polystyrene=5400) (3.6 g) were 
dissolved in dichloromethane (5 ml) to prepare an o/w type emulsion using 
a homogenizer in an aqueous solution (800 ml) of 0.1% polyvinyl alcohol 
(PVA). Then, the emulsion was slowly stirred with a conventional propeller 
stirrer. After dichloromethane vaporized and the microcapsules hardened, 
the microcapsules were collected by centrifugation and at the same time 
washed with purified water. The collected microcapsules were freeze-dried 
for a day to obtain powdery microcapsules. 
The drug content in the total amount of the microcapsules was 10.0%, and 
the entrapment was 100%. The microcapsules were suspended in 0.5% 
methylcellulose, and orally administered to SD-strain male rats (body 
weight: 250 g) in a dose of 20 mg/kg. A suspension of the drug alone in 
0.5% methylcellulose was also administered for comparison. In both cases, 
the plasma concentration of the drug and the absorption ratio were 
determined. The results are shown in Table 1. 
TABLE 1 
______________________________________ 
Orally administered 
C.sub.max T.sub.max 
Absorption 
suspension (.mu.g/ml) 
(hr) ratio (%) 
______________________________________ 
Suspension of Compound A in 
0.218 0.25 5.4 
0.5% methylcellulose 
Suspension of microcapsules 
0.423 1.5 27.0 
______________________________________ 
The results show that the oral microcapsule preparation significantly 
improved C.sub.max (peak blood level), T.sub.max (time required to obtain 
the peak blood level) and the absorption ratio. In other words, the oral 
administration of the suspension of Compound A in 0.5% methylcellulose 
provided a low administration ratio of 5.4% because Compound A has a very 
low solubility at the pH in the small intestine, whereas the lactic 
acid/glycollic acid copolymer microcapsules increased the absorption ratio 
because they released lactic acid or glycollic acid together with the drug 
in the small intestine and the drug was, therefore, present in solubilized 
form. In addition, T.sub.max was prolonged six times, and the prolonged 
release was achieved. 
EXAMPLE 2 
Compound A (500 mg) and lactic acid/glycollic acid copolymer (lactic 
acid/glycollic acid=50/50, average molecular weight calculated as 
polystyrene=5400) (4.5 g) were dissolved in dichloromethane (7 ml), and 
citric acid buffer (pH 3) (0.5 ml) was added and mixed for about 30 
seconds with a small homogenizer (Polytron, manufactured by Kinematica, 
Switzerland) to give a w/o type emulsion. From this emulsion, a w/o/w type 
emulsion was prepared using a homogenizer in 0.5% PVA aqueous solution 
(1000 ml). Then, the emulsion was slowly stirred with a conventional 
propeller stirrer for 3 hours. After dichloromethane vaporized while w/o 
type microcapsules hardened, the microcapsules were centrifuged and 
collected and at the same time washed with purified water. The collected 
microcapsules were freeze-dried for a day to obtain powdery microcapsules. 
The drug content in the microcapsules was 9.9%, and the entrapment was 99%. 
The microcapsules were suspended in 0.5% methylcellulose, and orally 
administered to SD-strain male rats (body weight: 250 g) in a dose of 20 
mg/kg. For comparative purposes, a suspension of the drug alone in 0.5% 
methylcellulose was also administered. In both cases, the plasma 
concentration of the drug and the absorption ratio were determined. The 
results are shown in Table 2. 
TABLE 2 
______________________________________ 
Orally administered 
C.sub.max T.sub.max 
Absorption 
suspension (.mu.g/ml) 
(hr) ratio (%) 
______________________________________ 
Suspension of Compound A in 
0.218 0.25 5.4 
0.5% methylcellulose 
Suspension of microcapsules 
0.713 3.0 42.1 
______________________________________ 
The results show that the oral microcapsule preparation significantly 
improved C.sub.max, T.sub.max and the absorption ratio. In other words, 
the oral administration of the lactic acid/glycollic acid copolymer 
microcapsules provided a significantly improved absorption ratio and 
prolonged release of the drug compared to the suspension of Compound A in 
0.5% methylcellulose. 
EXAMPLE 3 
The antiulcer drug 
2-[[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl]thio]benzi 
midazole(1 g) and polylactic acid (molecular weight: 6000) (9 g) were 
dissolved in acetonitrile (30 ml). The solution was sprayed from one 
two-fluid nozzle which was provided in a spray dryer, and at the same time 
5% mannitol aqueous solution was sprayed from another two-fluid nozzle. 
Thus, powdery microcapsules were obtained. The temperature at the entrance 
of the drying chamber was 100.degree. C., the temperature at the outlet 
was 50.degree. C., and the flow rate was 10 ml/min. 
EXAMPLE 4 
The antiasthmatic drug 
2-ethyl-2-[(7-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)oxymethyl]-butan 
esulfonamide (3 g), polyhydroxybutyric acid/glycollic acid copolymer 
(hydroxybutyric acid/glycollic acid=60/40, average molecular weight 
calculated as polystyrene=7000) (5 g) and polylactic acid (molecular 
weight: 6000) (4 g) were dissolved in a mixture of ethanol (10 ml) and 
acetonitrile (30 ml). The solution was sprayed from a rotary disc atomizer 
provided in a spray dryer to obtain powdery microcapsules. The temperature 
at the entrance of the drying chamber was 100.degree. C., the temperature 
at the outlet was 50.degree. C., and the flow rate was 10 ml/min. 
EXAMPLE 5 
The angiotensin converting enzyme inhibitor 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
(1 g) and polyhydroxybutyric acid/glycollic acid copolymer (hydroxybutyric 
acid/glycollic acid=40/60, average molecular weight calculated as 
polystyrene=7000) (5 g) were dissolved in dichloromethane (6 ml). From 
this solution, an o/w type emulsion was prepared using a homogenizer in 
0.1% PVA aqueous solution (500 ml). Then, the emulsion was slowly stirred 
with a conventional propeller stirrer for 3 hours. After dichloromethane 
vaporized and the microcapsules hardened, the microcapsules were collected 
by centrifugation and at the same time washed with purified water. The 
collected microcapsules were freeze-dried for a day to obtain powdery 
microcapsules.