JPH08151322A - Oral sustained release agent - Google Patents

Abstract

PURPOSE: To obtain an oral sustained release agent comprising microcapsules enabling the sustained release and enteral absorption improvement of a physiologically active substance. CONSTITUTION: The microcapsules contain a physiologically active substance having water solubility (water solubility of >=0.1g/100ml, preferably >=1g/100ml, at 20 deg.C) at a pH of <=3, and a biodegradable polymer. The polymer is preferably a polyfatty acid ester, especially lactic acid/glycolic acid copolymer or hydroxybutyric acid/glycolic acid copolymer, which has preferably a weight- average mol.wt. of 2000-8000. The physiologically active substance is slightly soluble in water at a pH of 6-8, namely has a water solubility of <=0.01g/100ml, especially <=0.001g/100ml, at 20 deg.C, and is preferably imidazole, triazole, their condensed ring compound, etc. The microcapsules are obtained by dissolving the physiologically active substance and the polymer in an organic solvent, and subsequently subjecting the solution to a drying-in-water treatment or a spray-drying treatment.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a microcapsule obtained by using a biodegradable polymer.

[0002]

2. Description of the Related Art Drugs that are poorly water-soluble at pH 6-8 generally have poor digestive tract absorption after oral administration due to their slow dissolution rate, and are used as easily soluble salts to improve their solubility.
Alternatively, a solubilizing agent is added as a formulation additive to improve absorbency. However, for example, in the case of hydrochloride, hydrochloric acid is eliminated during storage, and in the case of adding a solubilizing agent, the tablet becomes large due to a large amount of compounding, which makes it difficult to take. In addition, since the acid added as a formulation additive immediately elutes and disappears, the effect of improving solubility disappears at the same time. Studies on nanocapsules containing indomethacin, which is a poorly water-soluble drug, have been reported (Pharmaceutical Research, Vol. 8, No. 1, page 101 (199).
1)), however, indomethacin is not readily soluble in water at a pH of 3 or less, and has not yet improved its absorbability.

[0003]

[Means for Solving the Problems] In view of such circumstances,
The present inventors designed and studied microcapsules containing a water-soluble physiologically active substance at a pH of about 3 or less using a biodegradable polymer as a base. As a result, pH
A microcapsule produced by adding a water-soluble physiologically active substance to a biodegradable polymer at a level of about 3 or less and dissolving it in an organic solvent is a microcapsule produced by dissolving the base substance in the digestive tract after oral administration. It has been found that the free acid is gradually released, and at the same time, the physiologically active substance is also released. Usually, the insoluble physiologically active substance is solubilized in the digestive tract below the duodenum to improve the absorbability. As a result of further intensive research based on these findings, the present invention has been completed.

That is, the present invention provides a microcapsule containing a water-soluble physiologically active substance having a pH of about 3 or less and a biodegradable polymer. The present invention also dissolves a water-soluble physiologically active substance at a pH of about 3 or less in an organic solvent together with a biodegradable polymer,
Microcapsules obtained by subsequent water-drying or spray-drying are also provided. Furthermore, the present invention provides p
Also provided is a method of producing microcapsules, characterized in that a water-soluble physiologically active substance is dissolved in an organic solvent together with a biodegradable high molecular weight polymer when H is about 3 or less and then dried in water or spray-dried. Furthermore, the present invention is characterized by dissolving a bioabsorbable bioactive substance in an organic solvent together with a biodegradable polymer, and then microencapsulating by drying in water or spray drying. A method of promoting absorption of a substance is also provided.

In the present invention, a biodegradable polymer having various decomposition rates can be used to microencapsulate a physiologically active substance which is water-soluble at a pH of about 3 or less,
Furthermore, by adding a suitable auxiliary agent, it becomes possible to control the decomposition rate of the polymer and the release rate and duration of the physiologically active substance. As used herein, "microcapsules" include microspheres, microcapsules, microparticles,
It means a generic term for nanoparticles, nanospheres, and nanocapsules.

The physiologically active substance used in the present invention is a drug which is water-soluble under acidic conditions, particularly at a pH of about 3 or less. Preferably, the physiologically active substance is near neutral, especially at pH 6-8.
It is poorly soluble in water. In the present specification, the term "water-soluble physiologically active substance" means that the water-soluble physiologically active substance is about 0.01 g or more, preferably about 1 g or more per 100 ml of water at 20 ° C. In addition, the fact that the physiologically active substance is poorly soluble in water means that the water solubility of the physiologically active substance is 1
About 0.01 g or less per 00 ml, preferably about 0.00
It means less than 1 g. Preferably, the physiologically active substance is poorly absorbed, particularly in the digestive tract below the duodenum.

The physiologically active substance is not particularly limited by its medicinal effect, and examples thereof include antibiotics, antifungal agents,
Antihyperlipidemic agent, cardiovascular agent, antiplatelet agent (platelet aggregation inhibitor), antitumor agent, antipyretic agent, analgesic agent, antiphlogistic agent, antitussive antitussive agent, sedative agent, muscle relaxant, antiepileptic agent, Anti-ulcer agent,
Antidepressant, antiallergic, cardiotonic, antiarrhythmic agent,
Examples thereof include vasodilators, antihypertensive diuretics, antidiabetic agents, anticoagulants, hemostatic agents, antituberculous agents, hormone agents, opiate antagonists, bone resorption inhibitors, angiogenesis inhibitors, and the like. Examples of the antibiotic include gentamicin, dibekacin, canendomycin, lipidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline hydrochloride, oxytetracycline hydrochloride, loritetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine. , Cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazoline, cefotaxime, cefoperazone, ceftizoxime, moxolactam, thienamycin, sulfazecin, aztreonam and the like. Examples of the antifungal agent include 2-[(1R, 2
R) -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-triazolone, 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) and the like. Of these, 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-triazolone is preferred.

Examples of the antihyperlipidemic agent include pravastatin and simvastatin. Examples of the agents for circulatory organs include substituted alanylglycine compounds having angiotensin converting enzyme (ACE) inhibitory action, specifically 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, N- [N-[(S) -1
-Carboxy-3-phenylpropyl] -L-alanyl]
-N- (5-hydroxyindan-2-yl) glycine and the like can be mentioned. Among these, N- [N-[(S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N- (indan-2-yl) glycine is preferable. Examples of the antiplatelet drug include ticlopidine, cilostazol, alprostadil, limaprost, dipyridamole, eicosapentaate ethyl, beraprost, ozagrel, aspirin and the like.

Examples of the above 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, Azimexone, Glycyrrhizin, Poly I:
C, poly A: U, poly ICLC and the like. The above antipyretic, analgesic, anti-inflammatory agents, for example, sodium salicylate, sulpiline, sodium flufenamic acid, sodium diclofenac sodium, indomethacin sodium, morphine hydrochloride, pethidine hydrochloride, leporphanol tartrate,
Examples include oxymorphone.

Examples of the antitussive and antitussive agent include ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, alloclamide hydrochloride, clofedianol hydrochloride, picoperidamine hydrochloride, cloperastine, protoxyl chloride hydrochloride, isoprohydrochloride hydrochloride. Examples thereof include terenol, salbutamol sulfate and terbutaline sulfate. Examples of the sedative include chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, atropine sulfate, and methylscopolamine bromide. Examples of the muscle relaxant include pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like.

Examples of the above antiepileptic agents include phenytoin sodium, ethosuximide, acetazolamide sodium, chlordiazepoxide hydrochloride and the like. Examples of the anti-ulcer agent include benzimidazole compounds having a proton pump inhibitor action (eg, 2-[[[3-methyl-4- (2,2,3,3-tetrafluoropropoxy) -2-pyridyl]]. Methyl] thio] benzimidazole, 2-[[[3-methyl-4- (2,2,3,
3,3-pentafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole), metoclopromide, histidine hydrochloride and the like. Of these, 2-
[[[3-Methyl-4- (2,2,3,3-tetrafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole or 2-[[[3-Methyl-4- (2,2,2, 3,3,3-
Pentafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole is preferred. Examples of the antidepressant include imipramine, clomipramine, noxiptiline, phenelzine sulfate and the like.

Examples of the above-mentioned antiallergic agents include imidazopyridazine compounds having an antiasthmatic action (eg, 3-
(Imidazo [1,2-b] pyridazin-6-yl) oxy-
2,2-dimethylpropanesulfonamide, etc.), triazolopyridazine compounds having anti-asthma action (eg, 2-
Ethyl-2-[(7-methyl- [1,2,4] triazolo [1,
5-b] pyridazin-6-yl) -oxymethyl] butanesulfonamide, etc.), diphenhydramine hydrochloride, chlorpheniramine maleate, triperenamine hydrochloride, metzirazine hydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine hydrochloride and the like. . Of these, 3- (imidazo [1,2-b] pyridazin-6-yl) oxy-2,2-dimethylpropanesulfonamide or 2-ethyl-2-[(7-methyl- [1,2,4]] Triazolo
[1,5-b] Pyridazin-6-yl) -oxymethyl] butanesulfonamide is preferred. Examples of the cardiotonic agent include transbioxocamphor, theophyllol,
Examples include aminophylline and methoxyphenamine hydrochloride. Examples of the antiarrhythmic agent include propranolol hydrochloride, alprenolol hydrochloride, bufetrol hydrochloride,
Examples include oxyprenolol hydrochloride and the like.

Examples of the vasodilators include oxyfedrine hydrochloride, diltiazem hydrochloride, tolazoline hydrochloride, hexobendine and bamethane sulfate. Examples of the antihypertensive diuretics include hexamethonium bromide,
Examples include pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, and clonidine hydrochloride. Examples of the antidiabetic agent include grimidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like. As the above anticoagulant,
For example, heparin sodium, sodium citrate and the like can be mentioned. Examples of the hemostatic agent include thromboplastin, thrombin, menadione sodium bisulfite, acetomenaphthone, ε-aminocaproic acid, tranexamic acid, sodium carbazochrome sulfonate, and adrenochrome monoaminoguanidine methanesulfonate.

Examples of the above-mentioned antituberculous agents include isoniazid, ethaneputol, sodium paraaminosalicylate and the like. Examples of the hormonal agents include prednisolone succinate, sodium prednisolone phosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate, hexestrol phosphate, hexestrol acetate, and methimazole. Examples of the narcotic antagonist include levallorphan tartrate, nalorphine hydrochloride, naloxane hydrochloride and the like. Examples of the bone resorption inhibitor include (sulfur-containing alkyl) aminomethylenebisphosphonic acid. Examples of the angiogenesis inhibitor include angiogenesis inhibitor steroids
[Science, Volume 221, 719 (1983)
Year)], Fumagillin (European Patent Publication No. 325,1)
19), fumagillol derivatives [eg, O-monochloroacetylcarbamoylfumagillol, O-dichloroacetylcarbamoylfumagillol and the like (European Patent Publication Nos. 357,061, 359,036 and 386, 386, No. 667, 415,294)] and the like.

Of the above physiologically active substances, basic compounds are preferred. In particular, imidazole or a condensed ring compound thereof, triazole or a condensed ring compound thereof, or a substituted alanylglycine compound is preferable. The imidazole or a fused ring compound thereof is preferably a benzimidazole compound {eg, 2-[[[3-methyl-4- (2,2,2,
3,3-Tetrafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole} or 3- (imidazo
[1,2-b] pyridazin-6-yl) oxy-2,2-dimethylpropanesulfonamide. The triazole or its fused ring compound is preferably 2-ethyl-2.
-[(7-Methyl- [1,2,4] triazolo [1,5-b] pyridazin-6-yl) oxymethyl] butanesulfonamide 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]-
It is 3- (2H, 4H) -1,2,4-triazolone. The substituted alanylglycine compound is preferably N- [N
-[(S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N- (indan-2-yl) glycine.

The amount of the above-mentioned drug used varies depending on the kind of the drug, the desired pharmacological effect, etc., but in the case of a w / o type emulsion, the concentration in the aqueous phase is from about 0.001% to about 90%. (W / W), more preferably about 0.01% to about 80% (W / W). The biodegradable polymer used in the present invention is a poorly soluble or insoluble in water, means a biocompatible biodegradable polymer, and specific examples thereof include polyfatty acid ester (eg, Polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polylactic acid caprolactone, etc.), poly-α-cyanoacrylic acid ester, poly-hydroxybutyric acid (eg, poly-β-hydroxybutyric acid, etc.), polyalkylene oxalate (eg. ,
Polytrimethylene oxalate, polytetramethylene oxalate, etc.), polyorthoester, polyorthocarbonate or other polycarbonate (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acid (eg, poly-γ-benzyl-L- Glutamic acid, poly-L-alanine, poly-γ-
Methyl-L-glutamic acid and the like), hyaluronic acid ester and the like. These high molecular polymers may be one kind, two or more kinds of copolymers, or simple mixtures, or salts thereof. Of these, polyfatty acid esters are preferred. More preferable examples are polylactic acid, lactic acid / glycolic acid copolymer, hydroxybutyric acid / glycolic acid copolymer (eg, β-hydroxybutyric acid / glycolic acid copolymer, etc.), butyric acid / glycolic acid copolymer or a mixture thereof. Is mentioned. Of these, especially lactic acid
Glycolic acid copolymers and hydroxybutyric acid / glycolic acid copolymers are preferred.

The weight average molecular weight of these high molecular weight polymers used in the present invention is preferably about 1,000 to 20,000, more preferably about 2,000 to 8.0.
00 range. In particular, fatty acid polyesters having a molecular weight in the above range are preferably used. The molecular weight in the present specification means gel permeation chromatography using polystyrene as a reference substance.
The molecular weight in terms of polystyrene measured by (GPC).
GPC column TSK gel (2000, 250
(0,3000, manufactured by Tosoh Corporation) was used, and chloroform was used as a moving layer. When a lactic acid / glycolic acid copolymer is used as the above polymer, the composition ratio (weight ratio) is about 100/0 to 25/75 (W / W, lactic acid /
(Glycolic acid) is preferable, and when a hydroxybutyric acid / glycolic acid copolymer is used, its composition ratio (weight ratio) is preferably about 100/0 to 25/75 (W / W, hydroxybutyric acid / glycolic acid). The amount of these high molecular weight polymers used depends on the strength of the pharmacological activity of the physiologically active substance, the release rate and the release period of the physiologically active substance, and is, for example, about 0.2 to 10,000 times that of the physiologically active substance.
It is prepared in an amount of (weight ratio), but preferably about 1 to about 100 times (weight ratio) of the high molecular weight polymer is used as the microcapsule base.

The hydrolysis of the high molecular weight polymer is low pH or high pH.
Accelerated with H, acidic or basic auxiliaries can be used to control the erosion rate of high molecular weight polymers. The solid auxiliary agent may be mixed with the physiologically active substance, or may be dissolved in an organic solvent containing a polymer. The amount of the auxiliary agent used is 0.1% to 30% (W
/ W). Specific examples of the auxiliary agents include inorganic acids such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, heparin and ascorbic acid, sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide. Inorganic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, organic bases such as triethanolamine, Tween, Pluronic,
And a surfactant such as (registered trademark).

The concentration of the high molecular weight polymer in the oil phase is about 0.5.
To about 90% (W / W), more preferably about 2 to about 60% (W / W). As the solution (oil phase) containing the high molecular polymer, a solution obtained by dissolving the high molecular polymer in an organic solvent is used. The organic solvent has a boiling point of about 12
It is a substance that is not miscible with water at 0 ° C or less and can dissolve a high molecular weight polymer. Specific examples thereof include halogenated alkanes (eg, dichloromethane, chloroform, chloroethane, trichloroethane, tetrachloride). Carbon, etc.), ethyl acetate, ethyl ether, cyclohexane, benzene, n-hexane, toluene and the like, and these may be used as a mixture of two or more kinds.

Examples of the method for producing the microcapsules of the present invention include a method in which an organic solvent solution of the physiologically active substance and the high molecular weight polymer is subjected to underwater drying, spray drying (ie, spray drying method) or phase separation. is there. First, a physiologically active substance and a polymer are dissolved in an organic solvent. Also,
The oil phase solution contains, as a pH adjusting agent for controlling the in vivo decomposition rate of the polymer, for example, carbonic acid, acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid, phosphoric acid or their sodium salts or potassium. It is also possible to add a salt, hydrochloric acid, sodium hydroxide or the like as an aqueous solution and then perform an emulsification operation to obtain a w / o type emulsion. A known dispersion method is used for the emulsification operation. Examples of the method include an intermittent shaking method, a method using a mixer such as a propeller stirrer or a turbine stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method. When the physiologically active substance is insoluble, an atomization operation is performed to prepare an s / o type emulsion.

Then, the w / o prepared in this way
Type emulsion, oil phase solution or s / o type emulsion is microencapsulated by an in-water drying method. When the microcapsules are produced by the in-water drying method, the w / o type emulsion, the oil phase solution or the s / o type emulsion is further added to the aqueous phase of the third phase to prepare the w / o / w type emulsion. , O / w type or s /
After forming the o / w type emulsion, the solvent in the oil phase is removed to prepare microcapsules. An emulsifier may be added to the outer aqueous phase, examples of which are generally stable o /
Any one that forms a w-type emulsion may be used, and examples thereof include anionic surfactants (eg, sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (eg, polyoxyethylene). Sorbitan fatty acid ester [eg Tween (Twe
en) 80, Tween 60, Atlas Powder Co., Ltd., polyoxyethylene castor oil derivative [eg, HCO-60, HC
O-50, Nikko Chemicals, etc.), or polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, etc.,
You may use it in combination of 1 type or 2 types or more of these. The concentration at the time of use can be appropriately selected from the range of about 0.01% to about 20% (W / W), and more preferably about 0.05% to about 10% (W / W). To be

The solvent in the oil phase is removed by a conventional method. As the method, the pressure is gradually reduced while stirring with a propeller stirrer, a magnetic stirrer, or the like, or a rotary evaporator or the like is used.
Remove while adjusting vacuum. In this case, when the solidification of the high molecular weight polymer progresses to a certain extent and the loss due to the release of the physiologically active substance from the inner aqueous phase is reduced, the w / o / w type, o / W type or s /
The time required can be shortened by gradually heating the o / w emulsion. The microcapsules thus obtained are collected by centrifugation or filtration, and then the free bioactive substance and bioactive substance-retaining substance adhering to the surface of the microcapsules are repeated several times with distilled water. To wash. If necessary, heating is performed and the water content in the microcapsules and the solvent in the microcapsule membrane are removed more completely under reduced pressure.

When microcapsules are produced by the phase separation method, the following coacervation agent is gradually added to the w / o type, s / o type emulsion or oil phase with stirring to give a high molecular weight polymer. Let it stick out and solidify. As the coacervation agent, a polymer system miscible with a solvent of a polymer, a mineral oil system or a vegetable oil system compound, as long as it does not dissolve the encapsulating polymer, for example, silicon oil, Sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil,
Examples include linseed oil and mineral oil. You may use these in mixture of 2 or more types.

The microcapsules thus obtained are collected by filtration and then repeatedly washed with heptane or the like to remove the coacervation agent. Further, the free physiologically active substance and the solvent are removed by a method similar to the in-water drying method. An anti-agglomeration agent may be added to prevent the particles from aggregating during washing. The microcapsules obtained above are lightly crushed, if necessary, and then sieved to remove the microcapsule portions that are too large. When using the spray dry method as a method for producing the microcapsules of the present invention,
As the organic solvent used in the oil phase, a solvent having a property of being easily miscible with water is used in addition to the above-mentioned ones. For example, acetone,
Examples thereof include acetonitrile, tetrahydrofuran, dioxane, pyridine, alcohols (eg, methanol, ethanol, etc.), and these may be used as a mixture of two or more kinds. Alternatively, a mixed solution of the above organic solvent capable of uniformly dissolving the drug and the high molecular weight polymer and water may be used.

Then, the w / o type emulsion or the s / o type suspension or solution thus prepared is sprayed into the drying chamber of the spray dryer by using a nozzle, and atomized droplets are formed in an extremely short time. Volatilize the organic solvent and water in
Prepare powder-shaped microcapsules. As the nozzle, there are a two-liquid nozzle type, a pressure nozzle type, a rotating disk type, and the like. At the same time, for the purpose of preventing aggregation of the microcapsules, an aqueous solution of aggregation inhibitor is sprayed from another nozzle. That is, two nozzles are installed, and a w / o type emulsion, an s / o type suspension or a physiologically active substance / high molecular polymer solution is sprayed from one side, and an appropriate coagulation inhibitor aqueous solution is sprayed from the other side. A quantity is sprayed to coat the microcapsule surface. When using a two-fluid nozzle or a pressure nozzle as the nozzle, two nozzles may be installed in the central part of the spray dryer, but a physiologically active substance / high molecular polymer solution and an anticoagulant solution are mixed in the nozzle. It is advisable to use various nozzles having a structure for spraying two liquids so that they can be sprayed separately without doing so.

The water-soluble inorganic salts, organic acids and organic acid salts used as anti-agglomeration agents can be administered to the human body.
There is no particular limitation as long as it is a non-adhesive substance that is solid at room temperature. Examples of inorganic salts include alkali metal halides (eg, sodium chloride, potassium chloride, sodium bromide, potassium bromide, etc.), alkaline earth metal halides (eg, calcium chloride, magnesium chloride, etc.), ammonium halides. (Eg, ammonium chloride, ammonium bromide, etc.), alkali metal carbonates or hydrogen carbonates (eg, sodium carbonate, potassium carbonate,
Sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkaline earth metal carbonates (eg, calcium carbonate, magnesium carbonate, etc.), ammonium carbonate, ammonium hydrogen carbonate, alkali metal phosphates (eg, trisodium phosphate, phosphorus) Acid 3 potassium, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid 2
Potassium hydrogen), diammonium hydrogen phosphate, ammonium dihydrogen phosphate, alkaline earth metal oxides (eg magnesium oxide, calcium oxide, etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, Calcium hydroxide, etc.) and the like. Examples of the water-soluble organic acid include citric acid, tartaric acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, dextran sulfate, carboxymethyl cellulose, alginic acid and pectic acid. Examples of the water-soluble organic acid salt include acetic acid, citric acid, tartaric acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, dextran sulfate, carboxymethyl cellulose, alginic acid, pectic acid, carbonic acid, bicarbonate and alkali metal (eg. , Sodium, potassium etc.), ammonia, basic amino acids or salts with alkaline earth metals (eg calcium, magnesium etc.).

Of these, water-soluble inorganic salts are particularly preferable. These water-soluble inorganic salts, organic acids and organic acid salts can be used alone or in combination of two or more kinds at an appropriate ratio. The compounding ratio of the water-soluble inorganic salt, organic acid or organic acid salt with respect to the high molecular weight polymer may be within the range in which the aggregation preventing effect is recognized. Specifically, the weight ratio is about 0.001 to about 100 times, more preferably about 0.00.
It is selected from 01 to about 50 times. More preferably about 0.
1 to about 10 times is selected. Further, in the present invention, a surfactant may be mixed with the above anticoagulant or sprayed simultaneously with the physiologically active substance / polymeric polymer solution using a nozzle separate from the anticoagulant, whereby The surfactant is dispersed or coated on the surface of the fine particle preparation, and exhibits extremely excellent dispersibility when the fine particle preparation is dispersed in the dispersion medium. Preferable specific examples of the surfactant include, for example, alkylene glycols (eg, propylene glycol etc.), polysorbates (eg, polysorbate 40, polysorbate 6).
0, polysorbate 80, etc., macrogoles (eg,
Macro Goal 300, Macro Goal 400, Macro Goal 600, Macro Goal 1500, Macro Goal 400
0, macrogol 6000), polyoxyethylene hydrogenated castor oils (eg, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.), etc. An agent is mentioned, and these 1 type, or 2 or more types can be used in combination at an appropriate ratio.
The compounding ratio of the above-mentioned surfactant to the high molecular weight polymer may be in the range in which improvement in dispersibility is recognized. In particular,
The weight ratio is selected from about 0.000001 to about 10 times, more preferably about 0.000005 to about 5 times. More preferably, it is selected from about 0.0001 to about 0.01 times. The microcapsules thus obtained are heated, if necessary, to more completely remove the water in the microcapsules and the solvent in the microcapsule membrane under reduced pressure.

The microcapsules produced by the method of the present invention can be administered orally, rectally, or into organs as they are or after being molded into various preparations by a conventional method.
Examples of the above-mentioned preparations include oral agents (eg powders, granules, capsules, tablets), suppositories (eg rectal suppositories, vaginal suppositories), injections and the like. Of these, oral preparations are preferred.

The microcapsules of the present invention can be formed into tablets, for example, according to a generally known production method. For example, excipients (eg, lactose, crystalline cellulose, sucrose,
Starch such as corn starch), disintegrant
(Eg, starches such as corn starch, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, etc.), binders (eg, crystalline cellulose, gum arabic, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.) Or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000)
Etc.) is added and compression molding is performed.

In order to use the microcapsules of the present invention as suppositories, oily or aqueous solid, semisolid or liquid products can be produced by a method known per se. The oily base used in the above composition may be one that does not dissolve the microcapsules, and examples thereof include glycerides of higher fatty acids [eg, cacao butter, Witepsols (Dynamite Nobel), etc.], intermediate fatty acids [eg, migliols. (Dynamite Nobel Co., etc.)], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers and acrylic acid polymers.

For example, in order to use the microcapsules of the present invention as an injection, the microcapsules of the present invention are dispersed.
(Eg, Tween 80, HCO 60 (manufactured by Nikko Chemicals), carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, bezyl alcohol, chlorobutanol, etc.), isotonicity agent (eg. , Sodium chloride, glycerin, sorbitol, glucose, etc.) into an aqueous suspension together with olive oil, sesame oil, peanut oil, cottonseed oil, vegetable oil such as corn oil, propylene glycol or the like to form an oil suspension. It shall be a sustained-release injection.

The microcapsules of the present invention are ulcers, hypertension, asthma, hyperlipidemia, bacterial or fungal infections in mammals such as mice, rats, horses, cows and humans, depending on the pharmacological effect of the physiologically active substance. It can be used for the treatment of various diseases such as tumors, inflammatory diseases, epilepsy, depression, allergic diseases, arrhythmias, diabetes, tuberculosis, osteoporosis and the like. The microcapsules of the invention are preferably used for the treatment of ulcers or hypertension. The dosage of the microcapsules of the present invention or a formulation thereof varies depending on the type and content of the physiologically active substance as a medicinal ingredient, the dosage form, the duration of release of the physiologically active substance, the animal to be administered, the purpose of administration, etc. Any effective amount of active substance may be used. For example, the dose for a human is about 1 mg to 10 g, preferably about 10 mg to 2 g of microcapsules.
Can be appropriately selected from the range.

[0033]

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. % Indicates W / W% unless otherwise specified. Example 1 Anti-ulcer drug 2-[[[3-Methyl-4- (2,2,3,3-tetrafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole (hereinafter may be referred to as Compound A 400 mg) and lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 50/50, polystyrene-converted average molecular weight 5400) 3.6 g are dissolved in 5 ml of dichloromethane and dissolved.
800 ml of 1% polyvinyl alcohol (PVA) aqueous solution
A homogenizer was used to prepare an o / w emulsion. Then, the mixture was slowly stirred for 3 hours with an ordinary propeller stirrer, waited for the microcapsules to solidify as the dichloromethane volatilized, was collected by a centrifuge, and was simultaneously washed with purified water. The collected microcapsules were obtained as a powder by freeze-drying overnight. The drug content in the total amount of the microcapsules was 10.0%, and the trap rate was 100%. The microcapsules were suspended in 0.5% methylcellulose, and SD male rats (body weight: 2
50 g) was orally administered at a dose of 20 mg / kg, and the plasma concentration was measured. Table 1 shows the results of comparison with oral administration of a liquid in which only the drug was suspended in 0.5% methylcellulose.

[0034]

[Table 1] Oral administration solution Cmax Tmax Absorption rate (μg / ml) (hr) (%) 0.5% suspension of Compound A in methylcellulose 0.218 0.25 5.4 Microcapsule suspension 0.423 1.5 27.0 Cmax (maximum blood concentration), Tmax ( Both the maximum blood concentration reaching time and the absorption rate were significantly improved with the microcapsule type oral preparation. That is, by oral administration of a 0.5% suspension of Compound A in methylcellulose,
After passage through the stomach, the pH of the small intestine was so low that it gave a low absorption rate of 5.4%. On the other hand,
In the lactic acid / glycolic acid copolymer microcapsules, lactic acid or glycolic acid was released together with the drug in the small intestine, and the absorption rate increased because the drug existed in a solubilized state. In addition, Tmax was extended 6 times and sustainability was also obtained.

Example 2 500 mg of Compound A and 4.5 g of a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 50/50, polystyrene-converted average molecular weight 5400) were dissolved in 7 ml of dichloromethane, and the citric acid buffer solution ( 0.5 ml of pH3) was added and mixed with a small homogenizer (Polytron, Kinematica, Switzerland) for about 30 seconds to obtain a w / o type emulsion. This emulsion is treated with a 0.5% PVA aqueous solution 1000 m
A homogenizer was used in 1 to make a w / o / w emulsion. Then, the mixture is gently stirred for 3 hours with an ordinary propeller stirrer, and after the volatilization of dichloromethane, the w / o type microcapsules are solidified and collected by a centrifuge.
At the same time, it was washed with purified water. The collected microcapsules were obtained as a powder by freeze-drying overnight. The drug content in the microcapsules was 9.9%, and the trap rate was 99%. This microcapsule
The suspension was suspended in 5% methylcellulose and orally administered to SD male rats (body weight: 250 g) at a dose of 20 mg / kg.
Similarly, a liquid prepared by suspending only the drug in 0.5% methylcellulose was orally administered. The plasma concentration of drug in these cases was measured. Table 2 shows the results.

[Table 2] Orally administered liquid Cmax Tmax Absorption rate (μg / ml) (hr) (%) 0.5% methylcellulose suspension of Compound A 0.218 0.25 5.4 Microcapsule suspension 0.713 3.0 42.1 Microscopic in both Cmax, Tmax and absorption rate A remarkable improvement was observed in the capsule type oral preparation. That is,
Compared to oral administration of a 0.5% suspension of Compound A in methylcellulose, the lactic acid / glycolic acid copolymer microcapsules showed a marked increase in absorption rate and durability.

Example 3 Anti-ulcer drug 2-[[[3-Methyl-4- (2,2,3,3,3-pentafluoropropoxy) -2-pyridyl] methyl] thio]
1 g of benzimidazole and 9 g of polylactic acid (molecular weight 6000)
Were dissolved in 30 ml of acetonitrile, sprayed from one two-fluid nozzle installed in a spray dryer, and a 5% mannitol aqueous solution was simultaneously sprayed from the other two-fluid nozzle to obtain powder microcapsules. At this time, the inlet temperature of the drying chamber was 100 ° C., the outlet temperature was 50 ° C., and the spray rate was 10 ml / min.

Example 4 3 g of anti-asthma drug 2-ethyl-2-[(7-methyl- [1,2,4] triazolo [1,5-b] pyridazin-6-yl) oxymethyl] butanesulfonamide, Polyhydroxybutyric acid / glycolic acid copolymer (hydroxybutyric acid / glycolic acid =
60/40, polystyrene equivalent average molecular weight 7,000) 5 g
And polylactic acid (molecular weight 6000) 4g ethanol 10m
It was dissolved in a mixed solution of 1 and 30 ml of acetonitrile and sprayed from a rotary disk atomizer installed in a spray dryer to obtain powder microcapsules. At this time, the inlet temperature of the drying chamber was 100 ° C., the outlet temperature was 50 ° C., and the spray rate was 10 ml / min.

Example 5 N- [N-[(S) which is an angiotensin converting enzyme inhibitor
-1-Ethoxycarbonyl-3-phenylpropyl]-
L-alanyl] -N- (indan-2-yl) glycine 1 g
And 5 g of polyhydroxybutyric acid / glycolic acid copolymer (hydroxybutyric acid / glycolic acid = 40/60, polystyrene-converted average molecular weight 7,000) are dissolved in 6 ml of dichloromethane, and a homogenizer is used with 500 ml of 0.1% PVA aqueous solution. / W type emulsion. Then, the mixture was slowly stirred for 3 hours with an ordinary propeller stirrer, waited for the microcapsules to solidify as the dichloromethane volatilized, was collected by a centrifuge, and was simultaneously washed with purified water. The collected microcapsules were obtained as a powder by freeze-drying overnight.

[0039]

The microcapsules of the present invention have the following advantages, for example. (1) Orally or rectally administrated by producing a bioactive substance that does not dissolve in the digestive tract below the duodenum and has low absorbability into a microcapsule based on a biodegradable polymer After that, the base decomposes in the digestive tract to gradually release water-soluble low-molecular (monomer-oligomer) free acids, and at the same time release physiologically active substances, simultaneously releasing drugs that are not normally dissolved in the digestive tract. It can be solubilized to improve absorption. (2) It is possible to make poorly water-soluble physiologically active substances into oral sustained-release microcapsule type preparations by using biodegradable high molecular weight polymers with various decomposition rates, and further biodegradable by appropriate additives. It is possible to control the decomposition rate of the functional polymer and the release rate and duration of the physiologically active substance. (3) When an easily soluble salt is used to improve the solubility of a physiologically active substance, for example, hydrochloric acid is eliminated from the hydrochloride during storage, which causes a problem. It has no shortcomings. (4) Formulation additives added as solubilizers, such as acids, elute and disappear immediately, so the solubilizing effect disappears.
The biodegradable polymer can control the elution. (5) As a method for producing the microcapsules, a submerged drying method, a phase separation method, a spray drying method, or the like is used, and microcapsules having a uniform spherical shape whose particle diameter can be controlled in a range of 0.1 to 1000 μm can be obtained. can get. (6) By the spray-drying method, microcapsules containing a physiologically active substance at a high content of 10 to 50% can be prepared in a short time.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/44 ACJ 31/50 ABF ACF 38/00 ABU AEQ 45/00 47/34 D B01J 13/12 13 / 04 C08L 67/04 LPM 9342-4D B01J 13/02 J 9342-4D A

Claims (26)

[Claims] 1. Microcapsules comprising a water-soluble physiologically active substance having a pH of about 3 or less and a biodegradable polymer. 2. The microcapsule according to claim 1, wherein the biodegradable polymer is a polyfatty acid ester. 3. The microcapsule according to claim 1, wherein the biodegradable polymer is a lactic acid / glycolic acid copolymer. 4. A weight ratio of lactic acid / glycolic acid of 100 /
The microcapsule according to claim 3, which is 0 to 25/75. 5. The microcapsule according to claim 1, wherein the biodegradable polymer is a hydroxybutyric acid / glycolic acid copolymer. 6. The microcapsule according to claim 5, wherein the weight ratio of hydroxybutyric acid / glycolic acid is 100/0 to 25/75. 7. The microcapsule according to claim 1, wherein the biodegradable polymer has a weight average molecular weight of about 2000 to about 8000. 8. The water solubility of the physiologically active substance is about 0.
The microcapsule according to claim 1, which has an amount of 01 g / 100 ml or more. 9. The water solubility of the physiologically active substance is about 1 g at 20 ° C.
The microcapsule according to claim 1, which has a volume of at least 100 ml. 10. The microcapsule according to claim 1, wherein the physiologically active substance is sparingly water-soluble at a pH of 6-8. 11. The physiologically active substance is basic.
The described microcapsules. 12. The microcapsule according to claim 11, wherein the physiologically active substance is imidazole or a condensed ring compound thereof, triazole or a condensed ring compound thereof, or a substituted alanylglycine compound. 13. The microcapsule according to claim 12, wherein the imidazole or a condensed ring compound thereof is a benzimidazole compound. 14. The benzimidazole compound is 2-
The microcapsule according to claim 13, which is [[[3-methyl-4- (2,2,3,3-tetrafluoropropoxy) -2-pyridyl] methyl] thio] benzimidazole. 15. The microcapsule according to claim 12, wherein the imidazole or a condensed ring compound thereof is 3- (imidazo [1,2-b] pyridazin-6-yl) oxy-2,2-dimethyl-propanesulfonamide. 16. The triazole or a condensed ring compound thereof is 2-ethyl-2-[(7-methyl- [1,2,4] triazolo [1,5-b] pyridazin-6-yl) -oxymethyl] butane. The microcapsule according to claim 12, which is a sulfonamide. 17. The triazole or a fused ring compound thereof is 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]-
The microcapsule according to claim 12, which is 3- (2H, 4H) -1,2,4-triazolone. 18. The substituted alanylglycine compound is N-
The microcapsule according to claim 12, which is [N-[(S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N- (indan-2-yl) glycine. 19. The microcapsule according to claim 1, which is sustained-release. 20. The microcapsule according to claim 1, which is an oral preparation. 21. The microcapsule according to claim 20, wherein the physiologically active substance is a poorly absorbable physiologically active substance. 22. The microcapsule according to claim 1, which is used for treating ulcer. 23. The microcapsule according to claim 1, which is used for treating hypertension. 24. A water-soluble physiologically active substance having a pH of about 3 or less is dissolved in an organic solvent together with a biodegradable polymer,
Then, microcapsules obtained by drying in water or spray drying. 25. A water-soluble physiologically active substance having a pH of about 3 or less is dissolved in an organic solvent together with a biodegradable polymer,
Then, a method for producing microcapsules, which comprises drying in water or spray drying. 26. A non-absorbable physiologically active substance characterized by being dissolved in an organic solvent together with a biodegradable high molecular weight polymer, and then microencapsulated by drying in water or spray drying. Absorption promotion method.