KR0140209B1 - Sustained release microcapsule for water soluble drugs - Google Patents

Abstract

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Description

Sustained Release Microcapsules for Water Soluble Drugs

The present invention relates to sustained-release microcapsules containing water-soluble drugs.

Several drug types have been proposed for drugs that need to be administered for a long time. The microencapsulation specified in EP-A-0052510 is based on phase separation using coacervating agents such as mineral and vegetable oils. However, the microcapsules prepared according to the present method reduce redistribution or increase initial rupture due to the tendency to coalesce into particles or to form cleavage during the manufacturing process. In particular, early rupture is almost inevitable when the drug involved is water soluble.

EP-A-0145240 discloses a process for producing microcapsules by underwater drying; According to the method, the drug can be effectively introduced into the microcapsules by increasing the viscosity in the internal water phase, increasing the viscosity of the W / O emulsion by adding a carrier, or as a result of interaction with the added drug. have.

The requirements for microcapsules prepared for administering the drug to an organism vary when the effect of the microcapsules is highly dependent on the interaction with the original function of the organism. For the use of pharmaceuticals, microcapsules have been desired that can satisfy as many requirements as possible.

Under these circumstances it cannot be said that a satisfactory effect has always been obtained with known microcapsules.

For example, most of the water soluble low molecular weight drugs and some of the water soluble polymer drugs contained in the microcapsules are sometimes released in large quantities more than necessary immediately after administration, greatly deviating from release at a constant rate, causing problems in the practical application of medicines. You can also

Under these circumstances, the inventors found that, as a result of research for developing sustained-release preparations of various water-soluble drugs, it is possible to efficiently obtain microcapsules having excellent properties with almost no initial rupture by adding a basic drug-containing substance. After further research, the present invention was completed. That is, the present invention provides a sustained-release microcapsule of a water-soluble drug containing an organic basic material as a water-soluble drug and a drug-containing material, the wall of which is made of a polymer.

The water soluble drugs used in the present invention are those having high hydrophilicity and low oil-water molecular coefficient. Those having low oil-water partition coefficients are, for example, those having an octanol / water partition coefficient of 0.1 or less.

The above-mentioned water-soluble drugs include, for example, physiologically active polypeptides, other antibiotics, anticancer agents, antipyretics, analgesics, anti-inflammatory agents, antitussives and expectorants, sedatives, muscle relaxants, anti-interstitials, anti-ulcers, antidepressants, anti-allergic agents, cardiovascular drugs, Arrhythmia drugs, vasodilators, hypotensive diuretics, antidiabetic drugs, anticoagulants, hemostatic agents, tuberculin antibodies, hormonal agents and anesthetic antagonists.

The physiologically active polypeptide is preferably one composed of two or more amino acids having a powdery range of approximately 200 to 100,000.

The peptides described above are illustrated below. Progesterone free hormone (LH-RH), and derivatives thereof [US Pat. Nos. 3,853,837, 4,008,209, 3,972,859, 4,234,571, British Patent 1,423,083, Proc Natl. Acad Sci. US A Vol. 78, pages 6509-6512 (1981)], LH-RH antagonists (US Pat. Nos. 4,086,219, 4,124,577, 4,253,997, 4,317,815), insulin, somatostatin, somatostatin derivatives (US Pat. No. 4,087,390) , 4,093,574, 4,100,117, 4,253,998), growth hormone, somatomedin, prolactin, adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), tyrotropin free hormone (TRH) and Salts and derivatives thereof (Japanese Patent Application Publication Nos. 121273/1975, 116465/1977), thyroid stimulating hormone (TSH), progesterone (LH), follicle stimulating hormone (FSH), vasopressin, baropressin derivatives [Desmopressin Acta. Med. Scand., Vol. 192 21-27 (1972)], Oxytocin, Calcitonin, Parathyroid Hormone, Glucagon, Gastrin, Vasoactive Enteral Peptides (VIP), Lipocortin, Vasocortin, Atrial Natriuretic Excretion Hormones (ANP), secretin, pancregiomin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enke-pallins, enkephalin derivatives [European Patent Application Publication No. 31567 ], Endorphins, kyotopins, interferons (alpha, beta, and gamma), interleukins (I, II, III, IV, V, VI), tuftsin, thymopoietin, thymosin, timothymulin, Thymic humoral factor (THF), thymus thymique serique (FTS) and derivatives thereof [Proc. Natl. Acad. Sci. USA, Vol. 78, 1162-1166 (1981)], Tumor Necrosis Factor (TNF), Cell Induced Factors (CSF), Motiline, Dinotropin, Bombesin, Neurotensin, Cerulein, Bradykinin, Eurokinase, Aspa Laginase, kallikrein, substance p, nerve growth factor, blood coagulation factors VIII and IX, lysozyme chloride, polymyxin B, colistin, gramicidine and bacitracin.

The antibiotic described above is as follows; Gentamicin, dibecacin, cannedomycin, libidomycin, tobramycin, amikacin, pradiomycin, tetracycline hydrochloride, oxytetracycline hydrochloride, lolitetracycline, doxycycline hydrochloride, Ampicillin, piperacillin, ticarcillin, cephalotin, cephaolidine, cephtyma, ceftsulodine, ceftenoxime, ceftazol, cefazoline, cefotaxime, cephaperazone, ceftizone, moxalactam, Thienamycin, sulfazecin and aztec leonam.

The anticancer agent mentioned above is as follows; Bleomycin hydrochloride, methoxtrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin, neo carcinostatin, cytosine arabinoside, 5- Fluorouracil, Tetrahydrofuryl-5-Fluorouracil, Crestine, Fishvanyl, Lentinan, Levamisol, Vestatin, Azimexone, Licorice, Poly I: C, Poly A: U and Poly ICLC.

The antipyretics, analgesics, and anti-inflammatory agents mentioned above are as follows; Sodium salicylate, sulfinine, sodium fulfenamate, sodium diclofenac, sodium indomethacin, morphine hydrochloride, petidine hydrochloride, levorpanol tartarate, and oxymorphone; The above-mentioned antitussive expectorant is as follows; Ephedrine hydrochloride, methyl ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, alloclamide hydrochloride, clopedanol hydrochloride, picoperidin amine hydrochloride, cloperastine, protokilol hydrochloride, Isproperolol hydrochloride, salbutamol sulfate, and terbutalin sulfate; The above-mentioned sedatives include chloropromazine hydrochloride, prochlorperazine, trifluoroperazine, atropine sulfate and scopolamine methyl bromide; Muscle relaxants mentioned above include pridinol methane sulfonate, tubocurin chloride and pancuronium bromide; Examples of the above-described anti-interfering agents include phenytoin sodium, ethoxysimid, acetazolamide sodium, and chlor diazepoxide hydrochloride; Anti-ulcer agents mentioned above include metoclopramide and histidine hydrochloride; The antidepressants mentioned above include imipramine, clomipramine, oxycitiline and phenelzin sulfate; The anti-allergic drugs described above include diphenhydramine hydrochloride, chloropheniramine malate, tripyleneamine hydrochloride, metordylazine hydrochloride, clemizolhydrochloride, diphenylpyralline hydrochloride and methoxyphenamine hydrochloride There is; The cardiac agents described above include trans-π-oxo campo, theophylrol, aminophylline and ethylephrine hydrochloride; The antiarrhythmic agents described above include propranolol hydrochloride, allotriol hydrochloride, bufetolol hydrochloride and oxypriol hydrochloride; The vasodilators mentioned above include oxyphedrine hydrochloride, diltiazem hydrochloride, tolazoline hydrochloride, hexobendine, and methane sulfate; The above-mentioned hypotensive diuretics include hexamethonium bromide, phentornium, mecamylamine hydrochloride, ecarazine hydrochloride, and clonidine hydrochloride; The antidiabetic agents described above include glymidine sodium, glybizide, phenformin hydrochloride, buformin hydrochloride and metoformin; The blood coagulants mentioned above include heparin sodium and sodium citrate; The hemostatic agents mentioned above include thromboplastin, thrombin, menadione bisulfite sodium, acetomenaftone, ε-aminocaproic acid, tranexamic acid, sodium carbazochrome sulfonic acid and adreno chromonoaminoguanidine metasulfonate ; Anti-tuberculosis therapeutics mentioned above include isoniazid, ethanebutol and sodium p-aminosalicylate; The above-mentioned hormones include prednisolone succinate, prednisolone sodium phosphate, dexamethasone sodium sulfate, betamethasone sulfate, hexoestrol phosphate, hexoestrol acetate, and metiazole; Anesthetic antagonists mentioned above include levalolpan tartarate, nallopine hydrochloride and naloxone hydrochloride.

Since the water-soluble drug solution in the present invention may be acidic, neutral or basic, it can be advantageously applied for the purpose of slowing down the acidic or neutral drug and for using the basic drug at low concentration.

The present invention is particularly useful for the preparation of sustained release preparations of neutral or basic polypeptides, such as LH-RH, TRH or derivatives thereof. The amount of water-soluble drug to be used depends on the nature of the drug, the desired pharmacological effect, and the duration of the effect. Microcapsules of water-soluble drugs are generally prepared by drying in water or by phase separation, wherein the concentration of the drug in the inner or water phase is from about 0.01% to about 90% (W / W), preferably from 0.1% to 80%. (W / W).

The drug-retaining material of the present invention does not have to be highly viscous or solid or semisolid in the inner water phase, and may be any organic material as long as it has a positively charged basic residue, and exhibits no pharmacological effect in the amount of use, and interacts with the polymer. Can work.

Such organic basic materials have a pKa of basic residues of at least 8.0, preferably of 8.5 to 13.0, and the pH of their aqueous solutions (1.0 W / V%) is at least 7.0, preferably of 7.6 to 13.0.

The drug-bearing substance described above includes basic amino acids, polypeptides containing basic amino acids, other organic bases such as basic derivatives of sugars, and natural or synthetic basic macromolecules.

The basic amino acids mentioned above include arginine (pK ₃ = 12.48; pH 10.8), lysine (pK ₃ = 10.53; pH 10.0), histidine (pK ₃ = 9.17; pH 7.8) and their derivatives.

The above-described polypeptides containing basic amino acids include L-Ala-L-His-L-Lys, L-Arg-L-Phe, Gly-L-His, Gly-L-His-Gly, Gly-L-His -L-Lys, L-His-Gly, L-His-Leu, L-His-L-Val, L-Lys-L- Tyr-L-Lys, L-His-L-Val, and L-Lys- L-Lys-L-Lys. Amino acids (residues) are expressed according to the IUPAC nomenclature.

Organic bases mentioned above include N-methyl glucamine and diethanol amines.

The above-mentioned natural or synthetic basic macromolecules include chitosan, poly-L-lysine and protamine.

Among these compounds, basic derivatives of basic amino acids such as arginine, lysine, histidine and monosaccharides such as N-methyl glucamine are particularly preferred.

These compounds may be used alone or in combination, and depending on the nature of the compound, the amount used is 0.1% to 90% (W / W), preferably approximately 0.5% to 75% (W / W) in the (internal) water phase. Select from the range of W).

The polymers described above are those having acidic moieties in their molecules and are poorly soluble or insoluble in water and suitable for organisms, for example poly-fatty acid esters (polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polylactic acid). In vivo degradation types such as lactones), poly-α-cyanoacrylic acid esters, poly-β-hydroxybutyric acid and polyamino acids (poly-γ-benzyl-L-glutamate, poly-γ-methyl-L-glutamate, etc.) And polymers. Other macromolecules suitable for the organism include polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid and maleic anhydride copolymers. Such polymers may be used alone or as two or more copolymers or simple mixtures.

Among these polymers, particular preference is given to using biodegradable polymers as injections; Most preferred polymers are polylactic acid, copolymers of lactic acid and glycolic acid and mixtures thereof.

The average molecular weight of the polymer used in the present invention is preferably about 1,000 to 800,000, preferably about 2,000 to 200,000.

When polylactic acid-glycolic acid is used as the high molecular polymer, a molar ratio of about 100/0 to 40/60 is required.

The amount of polymer to be used depends on the pharmacological activity of the water soluble drug to be used, the rate and duration of drug release; For example, polymers in an amount of 1/5 to 10,000 times (parts by weight) of the water-soluble drug are used for preparation, and preferably 1 to 1000 times (parts by weight) of the polymer are used as the base of the microcapsules.

The concentration of the oily polymer is approximately 0.5% to 90% (W / W), preferably approximately 2% to 60% (W / W).

The solution (oil phase) containing the above-mentioned polymer is a solution in which the polymer is dissolved in the oil phase.

The above-mentioned solvents are solvents having a boiling point of about 120 ° C. or less, are immiscible with water, dissolve the polymer, and use halogenated alkanes (eg, dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride, etc.) and ethyl. Acetate, ethyl ether, cyclohexane, benzene, n-hexane and toluene, and may be used as a mixture of two or more.

Coacervates are high molecular compounds, such as mineral oils and vegetable oils, which are miscible with the solvent of the polymer, and do not dissolve the encapsulating polymer, for example silicone oil, sesame oil, soy milk, corn oil, cottonseed oil, coconut oil, linseed oil and Mineral oil, and two or more of these may be used in combination.

The sustained-release microcapsules of the present invention are prepared, for example, by the following method (water drying method). That is, first, the water-soluble drug is dissolved in water at the above-mentioned concentration, and the drug-retaining substance is added thereto to dissolve or suspend at the above-mentioned concentration to obtain an internal water phase.

Carbonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid or its sodium or potassium salt, hydrochloric acid or sodium hydroxide are added as pH adjusters to maintain stability and solubility of the water-soluble drug. Else albumin, gelatin, citric acid, ethylenediamine sodium tetraacetate, dextrin or sodium bisulfite as stabilizer for water-soluble drugs, or p-hydroxybenzoic acid esters (methylparaben, propyl paraben, etc.), benzyl alcohol, chlorobutanol or Thimerosal may be added.

The obtained internal aqueous phase is added to a polymer-containing solution (oil phase), and then emulsified to obtain a W / O emulsion.

Emulsification is carried out according to known dispersion methods. This method includes an intermittent vibration method, a method using a mixer such as a propeller mixer or a turbine mixer, a colloid milling method, a homogenizer method and an ultrasonic irradiation method.

The W / O emulsion thus prepared is then used to prepare microcapsules by drying in water or by phase separation. In order to prepare microcapsules by an underwater drying method, a W / O emulsion is added to a third aqueous phase to form a W / O / W / three phase emulsion, and then the solvent in the oil phase is desorbed.

Emulsifiers may be added to the outer aqueous layer; As the emulsifier, generally, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (poly (oxyethylene) sorbitan fatty acid esters [Twin 80, Tween 60, Atlas Powder Co., Ltd.], Polyoxyethylene castor oil derivatives [HCO-60, HCO-50, Nikko Chemical Co., Ltd.], polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin and gelatin. It can be any and can be used individually or in combination. The amount to be used is appropriately selected in the range of about 0.01% to 20%, preferably about 0.05% to 10%.

Desorption of the solvent in the oil phase is carried out by the usual method; Desorption is carried out by gradually reducing the pressure by stirring with a propeller type stirrer or a magnetic stirrer, or by adjusting the degree of vacuum using a rotary evaporator. When the solidification of the polymer to some extent reduces the loss of drug due to release from the internal water phase, the time required for this method can be shortened by starting the heating of the W / O / W emulsion, which facilitates the desorption of the solvent. have.

The microcapsules thus obtained are collected by centrifugation or filtration, and then washed repeatedly with distilled water to remove free water-soluble and drug and drug-retaining substances adsorbed on the surface of the capsule, and if necessary, desorption of water in the microcapsules by heating under reduced pressure. Desorption of the solvent in the film of the microcapsules is carried out completely.

When the microcapsules are prepared by the phase separation method, the above-described coacervate agent is added to the above-mentioned W / O emulsion with gentle stirring to precipitate and solidify the polymer.

The microcapsules thus obtained are collected by filtration and then washed repeatedly with heptane or the like to remove the coacervate. Removal of the free chemicals and desorption of the solvent are carried out in a similar manner as in water drying. Agglomeration inhibitors may be added for the purpose of preventing agglomeration of the particles during washing.

Sustained release formulations of the present invention are used for the preparation of injections, oral, transdermal, nasal, rectal, urethral and vaginal suppositories.

The microcapsules prepared as described above may be roughly ground and sieved to remove very large microcapsules if necessary. The particle size of the microcapsules depends on the desired degree of sustained release, that is, the extent to which the microcapsules can be sufficiently dispersed and pass through the syringe needle; For example, the average particle radius is about 0.5 to 400 μm, preferably about 2 to 200 μm.

Thus, the present invention increases the trapping rate of the water soluble drug into the microcapsules and enables the production of microcapsules with a rigid wall with little initial mass release.

In addition, the microcapsules of the present invention have several advantages. For example, it is possible to obtain a uniform spherical microcapsules having an arbitrary particle size by hardly forming aggregates together during the manufacturing process, and the surface structure of the microcapsule which determines the release rate of the drug by facilitating the removal of the solvent in the oil phase. (Eg, the number and size of the holes through which the drug is released) can be modified.

The microcapsules produced according to the present invention can be administered in the form of injections or pellets without any further steps in muscles, subcutaneous tissues, blood vessels, organs, joint cavities, tumor lesions and the like. They can also be administered after shaping into various formulations, that is to say used as starting materials for producing such formulations.

For example, the microcapsules of the present invention may be formulated with dispersants (e.g. Tween 80, HCO-60, carboxymethylcellulose, sodium alginate), preservatives (e.g. methylparabens, propyl parabens) and tonicity agents (e.g. For example, an aqueous suspension is prepared with sodium chloride, mannitol, sorbitol, glucose), or dispersed together with vegetable oils such as sesame oil or corn oil to prepare an oily suspension, which is a practically useful sustained release injection.

Sustained-release injectables containing microcapsules are redispersed as an additional suspending agent (e.g., mannitol, sorbitol, lactose, glucose), followed by redispersion, lyophilization or spray drying, and distilled water for injection or suitable dispersion medium before use. Treatment can be used to obtain more stable sustained release injections.

The dosage of the sustained-release preparation of the present invention is based on the type and content of the water-soluble drug, the drug form, the duration of the drug release, the object to be administered [for example, warm-blooded mammals (for example, rats, mice, horses, cattle, Human)), and the purpose of administration and the effective amount of the water-soluble drug. For example, a single dose in the above-mentioned warm-blooded animals requires approximately 0.1 mg to 100 mg (microcapsules) / kg (body weight), preferably approximately 0.2 mg to 50 mg / kg body weight.

As described above, pharmaceutical compositions prepared as microcapsules typically consist of an effective amount of water-soluble drugs and polymers suitable for the organism in excess of one dose, and are capable of sustained release of the drug for a long time with little initial rupture. Can be obtained.

In the present invention, a solid membrane of the microcapsules is formed by the reaction between the acidic residues of the polymer and the basic residues of the drug-bearing substance, and the trapping rate is increased by lowering the diffusion rate near the surface of the microcapsules. It is assumed that release is suppressed. Therefore, the higher the basicity and the greater the number of residues of the drug bearer, the more effectively the drug bearer can prevent the initial mass release. When the water-soluble drug included has a basic moiety or when the basic moiety reacts and adds to the water-soluble drug as a prodrug, the water-soluble drug itself acts as a drug bearing material to obtain the excellent microcapsules described above.

Sustained release formulations prepared according to the invention are characterized as follows;

(1) excellent sustained release of water-soluble drugs can be obtained in various drug types; Especially for injections that need to be administered over a long period of time for the expected therapeutic effect, they are injected once a week, once a month or once a year instead of daily to obtain the desired pharmacological effect; Thus, more stable sustained release over a long period of time is obtained compared to conventional sustained release formulations.

(2) Injections made using biodegradable polymers do not require surgical procedures such as transplantation, and can be easily administered to subcutaneous, intramuscular, organ and lesions and re-extracted from the organism like ordinary suspension injections. none.

(3) W / O / W emulsions are prepared, and water-soluble drugs as main components can be more effectively included in microcapsules as a main component, and at the same time, fine and uniform spherical microcapsules are prepared. To obtain.

(4) Compared with the conventional production method of preparing W / O / W emulsions and consisting of a phase separation method or a drying method in water, it is possible to obtain microcapsules which reduce unnecessary initial release and further stabilize the release rate. Safe formulations can be prepared.

EXAMPLE

The following examples will illustrate the invention in more detail.

EXAMPLE 1

2 mg of TRG (free form) is dissolved in 0.05 ml of water, at which point 30 or 50 mg of N -methylglucamine is dissolved or suspended as drug retention material.

This solution or suspension is added to a solution of 1 g of lactic acid-glycolic acid copolymer (lactic acid / glycolic acid: 75/25 weight-average molecular weight 14,000, hereafter abbreviated as PLGA) in 1.6 g of dichloromethane, and a small homogenizer [Chinematica of Switzerland Co. Polytron, a product, for 30 to 60 seconds, to obtain a W / O emulsion. This emulsion is poured into 100 ml of 0.1% polyvinyl alcohol (PVA) aqueous solution and mixed in a small homogenizer to give a W / O / W emulsion. The dichloromethane is then evaporated from the W / O / W emulsion with stirring to solidify the internal W / O emulsion and collected by centrifugation. The pellet is again dispersed in distilled water and centrifuged again to remove the free drug and free drug retention material by washing.

The collected microcapsules are lyophilized to more completely remove the solvent and water, thus obtaining the microcapsules as a powder.

Agents of TRH-containing microcapsules prepared as above and N-methylglucamine-free microcapsules prepared for comparison-trapping rate (% substantially incorporated relative to amount used) and at 37 ° C. In vitro dissolution tests conducted in phosphate buffer at pH 7.0, the percent remaining in microcapsules after 1 day are shown in Table 1.

TABLE 1

a) weight percentage of N-methylglucamine relative to the weight of PLGA

b) 1 / 30M of phosphate buffer at pH 7.0 at 37 ° C

If N-methylglucamine is not used, the drug-trapping rate is high enough because basic TRH was chosen as the drug, but after 1 day the percent remaining was 32.7%, indicating that 67.3% of TRH was released.

On the other hand, when 3 or 5% of N-methylglucamine is added, the release (initial release) after 1 day is reduced with increasing concentration, so that better microcapsules can be prepared.

EXAMPLE 2

Instead of water-soluble drugs, phenol red, which is commonly used as a marker, is used.

2 mg of phenol red is dissolved in 0.05 ml of water, at which time 30 or 50 mg of arginine is dissolved or suspended as drug retention material. The solution or suspension was then treated similarly to Example 1 to obtain a microcapsule containing phenol red.

Tables 2 and 3 show the trapping rate, initial rupture, and% remaining after 1, 2 and 4 weeks.

TABLE 2

a) weight% of arginine to weight of PLGA

TABLE 3

Microcapsules containing arginine show an increase in trapping rate, which increase depends on the concentration of arginine added, and also a significant increase in residual rate after 1 day. Microcapsules of phenol reds prepared by adding arginine to a concentration of 3-5% exhibit almost zero order of release over 4 weeks or more after some initial release.

EXAMPLE 3

2 mg of TRH is dissolved in 0.05 ml of water, where 10, 50, 90 or 150 mg of histidine is dissolved or suspended as drug-bearing material. The suspension was then treated similarly to that described in Example 1 to obtain microcapsules containing TRH.

Initial rupture of the obtained microcapsules is shown in Table 4.

TABLE 4

a) percentage of histidine weight to PLGA weight (%)

Initial rupture after 1 day is significantly reduced by histidine addition, and microcapsules with the desired release are obtained by histidine addition up to a concentration of 5-15%.

EXAMPLE 4

2 mg of methotrexate is dissolved in 0.1 ml of water, where 20 or 30 mg of lysine is dissolved as drug-bearing material.

The solution was treated similarly to that described in Example 1 to obtain microcapsules containing methotrexate.

Initial rupture of the obtained microcapsules is shown in Table 5.

TABLE 5

a) percentage of lysine weight to PLGA weight

After 1 day, the initial rupture was significantly reduced by lysine addition, and microcapsules with the desired release were obtained by adding lysine up to 2-3% concentration.

[Example 5]

2 mg of 5-fluorouracil are dissolved in 0.1 ml of water, where 20 or 30 mg of lysine is dissolved as drug-bearing material. The solution is treated similarly to that described in Example 1 to obtain microcapsules containing 5-fluorouracil.

Initial rupture of the obtained microcapsules is shown in Table 6.

TABLE 6

a) percentage of lysine weight to PLGA weight

Initial rupture after 1 day was significantly reduced by lysine addition, and microcapsules with the desired release were obtained by lysine addition up to 2 or 3% concentration.

EXAMPLE 6

2 mg of bleomycin hydrochloride is dissolved in 0.1 ml of water, where 20 or 30 mg of lysine is dissolved as drug retentate. The solution is then treated similarly to that described in Example 1 to obtain microcapsules containing bleomycin hydrochloride.

Initial rupture of the obtained microcapsules is shown in Table 7.

TABLE 7

a) percentage of lysine weight to PLGA weight

After 1 day, the initial rupture was markedly reduced by the addition of lysine and a capsule with the desired release was obtained by adding lysine up to 2 or 3% concentration.

EXAMPLE 7

10 mg of methotrexate is dissolved in 0.1 ml of water with 20 or 30 mg of L-Lys-L-Lys-L-Lys warmed as drug retention material. The solution was then treated similarly to that described in Example 1 to obtain microcapsules containing methotrexate.

Initial rupture of the obtained microcapsules is shown in Table 8.

TABLE 8

a) Percentage of L-Lys-L-Lys-L-Lys weight to PLGA weight

Claims (13)

A sustained-release microcapsule of a water-soluble drug containing a water-soluble drug and a drug-retaining material of an organic basic material having a pKa of 8.0 or more, wherein the biocompatible polymer polymer is a wall material. The microcapsule according to claim 1, wherein the organic basic substance is an organic base, a basic amino acid, a polypeptide containing a basic amino acid, a basic derivative of a saccharide, a natural basic macromolecule or a synthetic basic macromolecule. The microcapsule according to claim 2, wherein the organic base is N-methylglucamine or diethanolamine. The microcapsule according to claim 2, wherein the basic amino acid is arginine, lysine or histidine. 3. The microcapsule of claim 2, wherein the natural basic macromolecule is chitosan, poly-L-lysine or protamine. The microcapsule of claim 1, wherein the water soluble drug is a physiologically active polypeptide, antibiotic or anti-tumor agent. 7. The microcapsule according to claim 6, wherein the physiologically active polypeptide is progesterone-free hormone, progesterone-free hormone derivative, tyrotropin-free hormone or tyrotropin-free hormone derivative. 7. The microcapsule of claim 6, wherein the antitumor agent is bleomycin or methotrexate. The microorganism of claim 1, wherein the biocompatible polymer is an acidic moiety and is a component selected from the group consisting of poly-fatty acid esters, poly-α-cyanoacrylic acid esters, poly-β-hydroxybutyric acid esters, and polyamino acids. capsule. The microcapsule of claim 1, wherein the biocompatible polymer is a homopolymer of lactic acid or a copolymer of lactic acid and glycolic acid. The microcapsule according to claim 1, wherein the concentration of the organic basic substance is 0.1 to 90 (W / W)% in the inner water phase. A water-soluble drug is dissolved in water, and an organic basic material having a pKa of 8.0 or more is dissolved or suspended therein to form an internal water phase, which is added to an oil phase containing a biocompatible polymer and then emulsified to perform W / O emulsion. Then create i) add W / O emulsion to the third water phase to form a three-phase emulsion of type W / O / W, and then dry the W / O / W emulsion, ii) A method for producing a microcapsule according to claim 1, wherein a coacervate is added to the W / O emulsion under stirring to precipitate and solidify the W / O emulsion, followed by filtration, washing, and drying. A sustained release preparation consisting of the microcapsules according to claim 1.