JPH0720859B2 - Microcapsule manufacturing method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing sustained-release microcapsules of a water-soluble drug.

[Prior Art] Various dosage forms have been proposed for drugs that require long-term administration. Among them, JP-A-57-118512 discloses microencapsulation by a phase separation method using a coacervation agent such as mineral oil and vegetable oil.

[Problems to be Solved by the Invention] The microcapsules obtained by the above method have a drawback that particles are likely to stick to each other during the production process.

[Means for Solving the Problem] In view of such circumstances, the present inventors have conducted diligent research in order to develop a sustained-release preparation of a water-soluble drug, and found that a three-phase emulsion was formed and an in-water drying method was used. In the process of microencapsulating with W / O / W type three-phase emulsion, by adjusting the viscosity of W / O type emulsion to about 150 cp to 10000 cp The present invention was completed as a result of finding out that it was possible to obtain a microcapsule having a high uptake rate and excellent properties, and as a result of further research based on it.

The present invention, a solution containing a water-soluble drug as an inner aqueous phase, a solution containing a high molecular weight polymer as an oil phase to form a W / O type emulsion,
In a method for producing a sustained-release microcapsule of a water-soluble drug by dispersing the emulsion in a water phase to form a W / O / W emulsion and drying in water, a W / O / W emulsion is prepared. W / O when making
A method for producing microcapsules, characterized in that the viscosity of a mold emulsion is adjusted to about 150 cp to 10,000 cp.

Here, the viscosity was measured by an Ubbelohde viscometer according to the Japanese Pharmacopoeia. Moreover, the kinematic viscosity value is used for the viscosity.
cp indicates centi poise.

Examples of the water-soluble drug used in the present invention include those having a strong hydrophilicity and a small oil-water distribution ratio. The low oil-water distribution ratio means, for example, the oil-water distribution ratio between octanol and water of about 0.1 or less.

The water-soluble drug is not particularly limited, but a polypeptide having physiological activity, other antibiotics, antitumor agents,
Antipyretics, analgesics, antiphlogistics, antitussives, sedatives, muscle relaxants, antiepileptics, antiulcers, antidepressants, antiallergic agents, cardiotonics, antiarrhythmic agents, vasodilators, antihypertensive diuretics, Examples include antidiabetic agents, anticoagulants, hemostatic agents, antituberculous agents, hormonal agents, and opiate antagonists.

The physiologically active polypeptide used in the present invention preferably contains two or more amino acids and has a molecular weight of about 200 to 80,000.

Specific examples of the polypeptide include, for example, luteinizing hormone-releasing hormone (LH-RH), a derivative having the same action as that of the formula (I) (Pyr) Glu-R ₁ -Trp-Ser-R. _{2 -R 3 -R 4 -Arg-Pro} -R 5
(I) [R ₁ is His, Tyr, Trp or p-NH ₂ -Phe, R ₂ is Tyr or Phe, R ₃ is a Gly or D type amino acid residue, R ₄ is Leu,
Ile or Nle, R ₅ is Gly-NH-R ₆ (R ₆ is H or a lower alkyl group with or without a hydroxyl group) or NH-R
₆ (R ₆ is as defined above). ] The polypeptide or its salt represented by
3,853,837, same 4,008,209, same 3,972,859, British patent 1,
423,083, Proceedings of the National
Proceedings of the
National Academy of Sciences of the United
States of America) 78, 6509-6512 (1981
Year)].

In the above formula (I), the D-type amino acid residue represented by R ₃ is, for example, an α-D-amino acid having up to 9 carbon atoms (eg, D-Leu, Ile, Nle, Val, NVal, Abu, Phe, Phg, Ser, T
yr, Met, Ala, Trp, α-Aibu) and the like, which may optionally have a protecting group (eg, t-butyl, t-butoxy, t-butoxycarbonyl, naphthyl, etc.). Of course, an acid salt of peptide (I) or a metal complex compound can be used in the same manner as peptide (I).

An amino acid in the polypeptide of formula (I),
IUPA is used for abbreviations of peptides and protecting groups.
C-IUB Commission on Biochemical Nomenclature
Or an abbreviation commonly used in the art, and when an amino acid may have optical isomers, it indicates the L form unless otherwise specified.

In the present specification, in the above formula (I), R ₁ =
_{His, R 2 = Tyr, R} 3 = D-Leu, R 4 = Leu, the acetate of the polypeptide is R ₅ = NHCH ₂ -CH ₃ is referred to as "TAP-144". The common name of the polypeptide acetate is leuprolide.

Examples of the polypeptide include LH-RH antagonists (see US Pat. Nos. 4086219, 4124577, 4253997, and 4317815).

Further, as the peptide, for example, insulin, somatostatin, somatostatin derivative (US Patent Nos. 4087390, 4093574, 4100117 and 425).
3998), growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MS
H), thyroid hormone-releasing hormone (TRH) and its salts and derivatives (see JP-A-50-121273 and JP-A-52-116465), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle. Stimulating hormone (FSH), vasopressin, vasopressin derivative {see desmopressin [Journal of the Endocrine Society of Japan, Vol. 54, No. 5, pp. 676-691 (1978)]}, oxytocin, calcitonin, parathyroid hormone, glucagon, gastrin, secretin, Pancreozyme, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HC
G), enkephalins, enkephalin derivatives [see US Pat. No. 4277394, European Patent Application Publication No. 31567], endorphins, kyotorphins, interferons (alpha, beta, gamma), interleukins (I,
II, III), tuftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor (THF), blood thymus factor (FTS) and its derivatives (see US Pat. No. 4,229,438), and other thymic factors [medical history, 12th
5, Vol. 10, pp. 835-843 (1983)], tumor necrosis factor (TNF), colony inducing factor (CSF), motilin, deinorphin, bombesin, neurotensin, cerulein, bradykinin, urokinase, asparaginase, kallikrein. , Substance P, nerve growth factor, blood coagulation factor VIII, factor IX, lysozyme chloride, polymyxin B, colistin, gramicidin, bacitracin, protein synthesis stimulating peptide (UK patent 8232082)
No.), gastric acid secretion inhibitory polypeptide (GIP), vasoactive
intestinal polypeptide (VIP), platelet-derived
growth factor (PDGF), growth hormone secretory factor (GRF,
Somatoclinin), bone morphagenetic protein (BM
P), epidermal growth factor (EGF), etc.

Examples of the antitumor agent include bleomycin hydrochloride,
Methotrexate, actinomycin D, mitomycin
C, bisblastine sulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, crestin, picibanil, lentinan, levamisole, bestatin,
Azimexone, Glycyrrhizin, Poly I: C, Poly A: U, Poly
ICLC etc. are mentioned.

Examples of the above-mentioned antibiotics include gentamicin, dibekacin, canendomycin, ribidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline hydrochloride, oxytetracycline hydrochloride, lolitetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephalotin. Examples include lysine, cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazoline, cefotaxime, cefoperazone, ceftizoxime, moxolactam, thienamycin, sulfazecin, and aztreonam.

Examples of the above-mentioned antipyretic, analgesic and anti-inflammatory agents include sodium salicylate, sulpiline, sodium flufenamic acid, sodium diclofenac, indomethacin sodium, morphine hydrochloride, pethidine hydrochloride, levorphanol tartrate and oxymorphone. For example, efuedrine hydrochloride, methyl ehuedrin hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, alloclamide hydrochloride, clofedianol hydrochloride, picoperidamine hydrochloride, cloperastine hydrochloride, protoxylol hydrochloride, isoproterenol hydrochloride, salbutamol sulfate, terebutaline sulfate, etc. , As sedatives, for example, chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, atropine sulfate, methylscopolamine bromide, etc. For example, pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like, antiepileptics such as phenytoin sodium, ethosuximide, acetazolamide sodium, chlordiazepoxide hydrochloride and the like, and antiulcer agents such as metoclopromide and histidine hydrochloride. However, examples of antidepressants include imipramine, clomipramine, noxiptiline, and phenelzine sulfate.
Antiallergic agents include, for example, diphenhydramine hydrochloride, chlorpheniramine maleate, triperenamine hydrochloride, metzirazine hydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine hydrochloride, and cardiotonic agents such as transpioxocamphor,
Theophyllol, aminophylline, etilefrine hydrochloride, etc., include arrhythmia treatment agents such as propranolol hydrochloride, alprenolol hydrochloride, bufetrol hydrochloride, oxyprenolol hydrochloride, and vasodilators such as oxyfedrine hydrochloride, hydrochloric acid. Diltiazem, tolazoline hydrochloride, hexobenzine, bamethan sulfate and the like, and as hypotensive diuretics, for example, hexamethonium bromide, pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, clonidine hydrochloride, etc.
For example, glymidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like, anticoagulants such as heparin sodium and sodium citrate, and hemostatic agents such as thromboplastin, thrombin and menadione sodium bisulfite. , Acetomenaphthone, ε-aminocaproic acid, tranexamic acid, sodium carbazochrome sulfonate, adrenochrome monoaminoguanidine methanesulfonate, etc., antituberculous agents such as isoniazid, ethambutol, sodium paraaminosalicylate, etc. as hormone agents , Eg prednisolone succinate, sodium prednisolone phosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate, hex phosphate Strohl, acetate hexestrol, methimazole, etc. Examples of the narcotic antagonists, for example levallorphan tartrate, nalorphine hydrochloride and naloxone hydrochloride may be mentioned, respectively.

The amount of the water-soluble drug used varies depending on the type of drug, the desired pharmacological effect and the duration of the effect, but the concentration in the internal aqueous phase is about 0.001% to about 70% (W / W), and It is preferably selected from 0.01% to 50% (W / W).

The viscosity of the inner aqueous phase may be increased by further adding a drug holding substance to the inner aqueous phase in the method of the present invention.

The drug-holding substance, which is water-soluble, is difficult to dissolve in an organic solvent of an oil phase, in a state of being dissolved in water, has already become a highly viscous semi-solid state, or some external factor,
For example, temperature, pH, metal ion (eg Cu ⁺⁺ , Al ⁺⁺⁺ , Zn ⁺⁺ etc.), organic acid (eg tartaric acid, citric acid, tannic acid etc.) or its salt (eg calcium citrate etc.) ，
A substance having a property of becoming a semi-solid or solid matrix by virtue of the action of a chemical condensing agent (eg, glutaraldehyde, acetaldehyde, etc.) is more remarkably increased in viscosity.

Examples of the drug-holding substance include natural or synthetic gums and polymer compounds.

Examples of natural gums include acacia gum, Irish moss, karaya gum, tragacanth gum, guaiac gum, xanthan gum, and locus bean gum. Natural polymer compounds include casein, gelatin, collagen, albumin (eg, human serum albumin ), Proteins such as globulin and fibrin, and carbohydrates such as cellulose, dextrin, pectin, starch, agar and mannan. You can leave these as they are,
Alternatively, a partially chemically modified synthetic gum such as an ester or ether of the above natural gum (eg, methylcellulose, ethylcellulose, carboxymethylcellulose, gelatin succinate, etc.), or a hydrolyzed one (eg, Sodium alginate, sodium pectate, etc.) or salts thereof may be used.

Examples of synthetic polymer compounds include polyvinyl compounds (eg, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl ether, etc.), polycarboxylic acids [eg, polyacrylic acid, polymethacrylic acid, Carbopol (Goodrich)
Etc.], polyethylene compounds (eg, polyethylene glycol, etc.), polysaccharides (eg, polysucrose, polyglucose, polylactose, etc.) and salts thereof.

In addition, those which can be polymerized by the condensation and cross-linking caused by the aforementioned external factors are also included.

Among these drug-holding substances, gelatin, albumin, pectin, agar and the like are particularly preferable.
These drug holding substances may be used alone or as a mixture.

The high molecular weight polymer contained in the oil phase in the method of the present invention is a polymer which is hardly soluble or insoluble in water and has biocompatibility. Fatty acid ester (eg polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, etc.), poly-
α-cyanoacrylic acid ester, poly-β-hydroxybutyric acid, polyalkylene oxalate (eg, polytrimethylene oxalate, polytetramethylene oxalate, etc.), polyorthoester, polyorthocarbonate,
Alternatively, other polycarbonates (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acids (eg, poly-γ-benzyl-L-glutamic acid, poly-L-alanine, poly-γ-methyl-)
L-glutamic acid, etc.) and the like. Further, as other biocompatible high molecular weight polymers, polystyrene, polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, polyamino acids, silicone polymers, dextranstearate, ethyl cellulose, Acetyl cellulose, nitrocellulose, polyurethane, maleic anhydride type copolymer, ethylene vinyl acetate type copolymer, polyvinyl acetate,
Examples include polyvinyl alcohol and polyacrylamide. These polymers may be one kind, a copolymer of two or more kinds, or a simple mixture, or a salt thereof.

Of these polymers, biodegradable high molecular weight polymers are particularly preferable when used as injections, and most preferable are polylactic acid, a copolymer of lactic acid and glycolic acid, or a mixture thereof. Can be mentioned. The ratio of lactic acid to glycolic acid in the copolymer is preferably about 100/0 to 50/50, and further, lactic acid is about 50 to 95 (w / w)% and glycolic acid is about 50 to 5 (w / w). w)% is good, preferably about 6 lactic acid
0 to 95 (w / w)%, glycolic acid about 40 to 5 (W / w)% are preferable, and more preferably lactic acid about 60 to 85 (w / w)% and glycolic acid about 40 to 15 ( w / w)% is good. Lactic acid is about 7
Copolymers of 5 ± 2 mol% and about 25 ± 2 mol% glycolic acid are preferred and often used.

The high molecular weight polymer used in the present invention preferably has an average molecular weight of about 1000 to 800,000, more preferably about 2000 to 100,000.

When the lactic acid-glycolic acid copolymer is used as the above polymer, the average molecular weight thereof is about 5,000 to 30,000.
Are preferred.

The amount of these high molecular weight polymers used depends on the strength of the pharmacological activity of the water-soluble drug and the rate and duration of drug release. For example, about 3 to 10,000 for the water-soluble drug.
The amount of the polymer is adjusted in an amount of 2 times (weight ratio), but preferably about 5 to 100 times (weight ratio) of the polymer is used as the microcapsule base.

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 120 ° C. or less and is not easily miscible with water, and may dissolve a high molecular weight polymer, for example, a halogenated alkane (eg, dichloromethane, chloroform, chloroethane). , Trichloroethane, carbon tetrachloride, 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.

In the method for producing microcapsules of the present invention, first, a water-soluble drug is added to water and dissolved to give an aqueous solution for the inner aqueous phase. Here, the above-mentioned drug holding substance may be further added. The aqueous solution may contain, as a pH adjusting agent for maintaining the stability or solubility of the water-soluble drug, for example, carbonic acid, acetic acid, oxalic acid, citric acid, tartar, succinic acid, phosphoric acid or their sodium salts. Or potassium salt, hydrochloric acid,
You may add sodium hydroxide etc. Further, as a stabilizer for water-soluble drugs, for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, or as a preservative, for example, paraoxybenzoic acid esters (eg, methylparaben, propyl). Paraben, etc.),
Benzyl alcohol, chlorobutanol, thimerosal, etc. may be added.

The aqueous solution for the inner aqueous phase thus obtained is added to a solution (oil phase) containing a polymer, and then an emulsification operation is performed to prepare 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-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.

Then, the W / O emulsion thus prepared is emulsified into three phases of W / O / W and subjected to an in-water drying method. That is,
The W / O type emulsion is further added to the aqueous phase of the third phase to form a W / O / W type emulsion, and then the solvent in the oil phase is removed to prepare microcapsules.

An emulsifier may be added to the aqueous phase of the outer phase, and examples thereof include any one that generally forms a stable O / W type emulsion, and examples thereof include anionic surfactants (eg, oleic acid). Sodium, sodium stearate, sodium lauryl sulfate, etc., nonionic surfactant [polyoxyethylene sorbitan fatty acid ester (Tween 80, Tween 60, manufactured by Atlas Powder Co., USA),
Polyoxyethylene castor oil derivative (HCO-60, HCO-50,
Nikko Chemicals Co., Ltd., etc.), or polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, etc., and one of these may be used, or some of them may be used in combination. The concentration at the time of use can be appropriately selected from the range of about 0.01% to 20%, and more preferably about 0.05% to 10%.

In the method of the present invention, when making a W / O / W type emulsion, W
The viscosity of the / O type emulsion is adjusted to about 150 cp to 10,000 cp, more preferably about 150 to 5000 cp. Examples of the method for adjusting the viscosity include increasing the concentration of the high molecular weight polymer in the oil phase, adjusting the amount ratio of the water phase and the oil phase, adjusting the temperature of the W / O emulsion, and the like. Methods such as adjusting the temperature of the water phase and adjusting the temperature of the W / O emulsion with a line heater or cooler when injecting the W / O type emulsion into the external water phase are available. These methods may be used alone or in combination.

In the above method, the point is that the viscosity of the W / O emulsion when the W / O emulsion becomes a W / O / W emulsion is about 150 cp to 10000 c.
All you have to do is p.

In the method for adjusting the viscosity of the above W / O type emulsion, the concentration in the case of adjusting the concentration of the high molecular weight polymer in the oil phase varies depending on the type of high molecular weight polymer, the type of solvent, etc. Approximately 10 to 80, although not uniquely determined
% (W / W) is preferred.

In the method for adjusting the viscosity of the W / O type emulsion described above, the amount ratio in the case of adjusting the amount ratio of the water phase and the oil phase is unique depending on the type and amount of the water-soluble drug and the property of the oil phase. Although it is not decided on, about W / O = about 1% to 50% (V
/ V) is preferable.

In the method for adjusting the viscosity of the above W / O type emulsion, W / O
The temperature for adjusting the temperature of the emulsified product is, for example, in the range of about -20 ° C to the boiling point of the organic solvent, but it is usually preferable to emulsify in the range of about 0 ° C to 30 ° C.

When adjusting the viscosity of the W / O type emulsion, the W / O type emulsion should be used when adjusting the concentration of the high molecular weight polymer in the oil phase and when adjusting the amount ratio of the water phase and the oil phase. It can be done at the time of creation.

When adjusting the viscosity of the W / O emulsion by adjusting the temperature of the W / O emulsion, for example, W / O in the external water phase
By adjusting the temperature of the W / O type emulsion when adding the O-type emulsion, by adjusting the temperature of the external water phase when adding the W / O-type emulsion to the external water phase in advance It can also be carried out by adjusting the temperature of the W / O type emulsion when producing the W / O / W type emulsion.

For the removal of the solvent of the oil phase in the in-water drying method, a commonly used method is adopted. As the method, for example, simply W /
Depending on whether the O / W emulsion is left under stirring, heated, or blown with nitrogen gas, etc., gradually reduce the pressure while stirring with a propeller-type stirrer or a magnetic stirrer. Or remove it while adjusting the degree of vacuum using a rotary evaporator.
In the step of removing the solvent, when the solidification of the high molecular weight polymer has progressed to some extent, the time required to gradually warm the W / O / W type emulsion for the purpose of more complete removal of the solvent can be obtained. It can be shortened.

The microcapsules thus obtained are separated by centrifugation or filtration, and the free water-soluble drug or the like adhering to the surface of the microcapsules is repeatedly washed with distilled water several times. For example, the water in the microcapsules and the solvent in the microcapsule film are removed more completely by heating and under reduced pressure.

The microcapsules obtained above are sieved if necessary to remove microcapsule portions that are too large. The particle size of the microcapsules depends on the degree of sustained release, and when used as a suspension agent, it may be in a range that satisfies the dispersibility and needle penetration, for example, an average diameter of about 0.
The range is 5 to 400 μm, preferably about 2 to 200 μm.
m, more preferably about 2 to 100 μm.

As described above, according to the method of the present invention, it is possible to increase the uptake rate of the water-soluble drug, which is the main drug, into the microcapsules. Furthermore, since the amount of the organic solvent used during the production is smaller than that in the oil-in-dry method, the method of the present invention is advantageous in industrial production.

Further, the microcapsules produced by the method of the present invention have less aggregation of microcapsules in the production process, and it is possible to obtain microcapsules with a well-ordered spherical shape, and in the step of removing the solvent in the oil phase. It has many advantages such as being easy to control and thereby controlling the surface structure of the microcapsules (for example, the number and size of pores that are the main drug release routes) that influence the drug release rate. Have

The microcapsules produced by the method of the present invention can be directly administered to a living body as an implant. Further, it can be molded into various preparations for administration, and can be used as a raw material for producing such preparations.

The above-mentioned preparation is more preferably in the form of injection.

For example, in order to use the microcapsules of the present invention as an injection, the microcapsules of the present invention can be used as a dispersant [eg, Tween80,
HCO-60, carboxymethylcellulose, sodium alginate, etc.], preservative (eg, methylparaben, propylparaben, etc.), isotonicity agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) , Sustained-release injection.

Furthermore, the sustained-release injection of the microcapsules described above may be used as a suspension in addition to the above composition by adding an excipient (eg, mannitol, sorbitol, lactose, glucose, etc.), redispersing, and then freezing. If it is dried or spray-dried to be solidified and distilled water for injection or an appropriate dispersion medium is added at the time of use, a more stable sustained-release injection can be obtained.

The dose of the sustained-release preparation of the present invention is determined by the type and content of the main drug, a water-soluble drug, the dosage form, the duration of drug release, the target animal [eg, warm-blooded mammals (eg, mouse, rat, horse). , Bovine, human)], and variously depending on the purpose of administration, but an effective amount of the main drug. For example, the weight of the microcapsule as a single dose for the warm-blooded mammal is about
0.01 to 200 mg / kg body weight, preferably about 0.2 to 40 mg /
kg body weight, more preferably about 0.2 mg to 20 mg / kg body weight,
More preferably from the range of about 0.2 mg to 6 mg / kg body weight,
It can be appropriately selected. The volume of the suspension solution when administered as the above injection can be appropriately selected from the range of about 0.1 to 10 ml, preferably about 0.1 to 5 ml, more preferably about 0.5 to 3 ml.

In this way, a microcapsule comprising an effective amount of a water-soluble drug, which is larger than a usual single dose, and a biocompatible high molecular weight polymer, and capable of sustained drug release over a long period of time is prepared. The obtained pharmaceutical composition is obtained.

The sustained-release preparation of the present invention has the following features, for example.

(1) Sustained release of a water-soluble drug can be obtained in various dosage forms, and when long-term administration is required to perform the expected treatment especially for injections, instead of daily administration,
The desired pharmacological effect can be stably obtained by injection once a week, once a month, or once a year, and the sustained release for a longer period of time can be achieved as compared with conventional sustained release preparations. Sex is obtained.

(2) When the biodegradable polymer is administered as an injection, no surgical operation such as implantation is required.
It can be easily administered subcutaneously and intramuscularly or intraperitoneally just like a general suspension injection. Further, since the biodegradable polymer is used, it is not necessary to take out the administered substance again.

In addition, it can be directly administered to tumors, inflammatory sites or local areas where receptors are present, systemic side effects can be reduced, and drugs can be efficiently acted on their target organs over a long period of time, which is expected to enhance the action. . Furthermore, vascular embolization therapy proposed by Kato et al. For renal cancer, lung cancer, etc. [Lancet, Volume II, pp. 479-480, (19
It can also be used for intra-arterial administration in (1979)].

(3) The release of the main drug is continuous, and in the case of hormone antagonists, selecter antagonists, etc., a stronger pharmacological effect can be obtained than the frequent daily administration.

(4) Create a conventional W / O / W three-phase emulsion,
A water-soluble drug which is the main drug can be efficiently incorporated into the microcapsules and a fine, spherical microcapsule can be obtained, as compared with the production method in which the microcapsules are dried in water.

[Examples] Hereinafter, the present invention will be described more specifically with reference to Examples. In the following examples, the weight average molecular weight is based on polystyrene standards.

Example 1 500 mg of α-type interferon was dissolved in 300 mg of water at 50 ° C,
Add 3,500 mg of polylactic acid (weight average molecular weight: 21,000) to 4 ml of methylene chloride and mix for 20 seconds with a small homogenizer (Polytron, Kinematica, Switzerland).
A W / O type emulsion was obtained. This emulsion was cooled to 15 ° C in a closed container, and defoaming and liquid temperature were adjusted. 15 ° C
The viscosity of the emulsion cooled at 4500 was 4500 cp with an Ubbelohde viscometer. Next, this emulsion was made into a (W / O) / W type emulsion by using a homogenizer in 500 ml of a 0.5% polyvinyl alcohol (PVA) aqueous solution. At this time, the homogenizer was operated at 4,000 rpm for 1 minute. After that, the (W / O) / W emulsion liquid is slowly stirred with a normal stirrer for 2 hours, and the (W / O) type microcapsules are waited for solidification as methylene chloride evaporates, and then collected with a centrifuge. They were collected and simultaneously washed with purified water. The collected microcapsules were obtained as a powder by freeze-drying.

The content of α-type interferon captured in the microcapsules was 11.5%, and the recovery rate (intake rate was 92.0%).

Example 2 450 mg of leuprolide and 50 mg of sodium carboxymethyl cellulose (Na-CMC) were added to 500 mg of water.
Dissolve at 60 ° C in water and add 4000 mg of a copolymer of lactic acid and glycolic acid (lactic acid / glycolic acid = 75 mol% / 25 mol%, weight average molecular weight: 12000) to 4.5 ml of methylene chloride. And mixed for 20 seconds to obtain a W / O emulsion. The viscosity of this emulsion at 15 ° C. was 3300 cp. The subsequent steps were carried out in exactly the same manner as in Example 1 to produce microcapsules. The content of Ryuprolide in the microcapsules was 9.8% and the recovery rate (uptake rate) was 98.
%Met.

Example 3 Cefotiam dihydrochloride 50 mg, gelatin 20 mg and water 250 mg
Dissolve in 40 ℃, polylactic acid (weight average molecular weight: 30000) 4g
Was mixed with a solution dissolved in 6.3 ml of chloroform and stirred to obtain a W / O type emulsion. This W / O emulsion was put in a glass syringe and adjusted to 16 ° C. Then of 0.1% (W / W)
7000r while injecting into 1000ml of 16 ℃ water layer containing Tween80
After stirring and emulsifying at pm for 1 minute and then waiting for the evaporation of chloroform at 2000 rpm for 3 hours, 5 to 80 μm microcapsules were obtained by a filtration method. The viscosity of the W / O emulsion at this time was about 180 cp. The uptake rate of cefotiam into microcapsules was 85%.

Example 4 450 mg of Ryuprolide and 90 mg of gelatin were dissolved in 1 ml of distilled water to obtain an aqueous phase. 4 g of a copolymer of lactic acid and glycolic acid (lactic acid / glycolic acid = 75 mol% / 25 mol%, weight average molecular weight: 14000) was added to 6 ml of methylene chloride and n-pentane.
A liquid dissolved in a mixed liquid with 1.5 ml was used as an oil phase. While gradually adding the water phase to the oil phase while stirring with a turbine type mixer at room temperature
I made a W / O emulsion. At this time, the viscosity was 70 cp at 24 ° C.

On the other hand, 500 ml of 0.5% polyvinyl alcohol aqueous solution was cooled to 15 ° C, and the W / O emulsion was gradually injected with stirring with a homogenizer to prepare a (W / O) / W emulsion. Thereafter, the (W / O) / W emulsion was volatilized with a propeller stirrer at room temperature for about 4 hours while volatilizing methylene chloride and n-pentane to solidify the oil phase. The solidified phase was collected by centrifugation to obtain a leuprolide-containing microcapsule. It was further washed with water, freeze-dried and powdered. At this time, the uptake rate of Ryuprolide into the microcapsules was 89%.

Example 5 Ryuprolide 495 mg and gelatin 80 mg were dissolved in 0.5 ml of distilled water to obtain an aqueous phase. A liquid prepared by dissolving 3970 mg of a copolymer of lactic acid and glycolic acid (lactic acid / glycolic acid = 75 mol% / 25 mol%, weight average molecular weight: 14000) in 5.5 ml of methylene chloride was used as an oil phase. A W / O emulsion was prepared by gradually adding an aqueous phase to an oil phase while stirring with a turbine mixer at room temperature, and cooled to 18 ° C. At this time, the viscosity was 310 cp.

On the other hand, 1000 ml of 0.1% polyvinyl alcohol aqueous solution at 18 ° C
After cooling, the W / O emulsion was gradually injected with stirring with a homogenizer to prepare a (W / O) / W emulsion.
Then, the (W / O) / W emulsion was slowly stirred at room temperature for about 3 hours with a propeller stirrer while volatilizing methylene chloride to solidify the oil phase. The solidified phase was collected by centrifugation to obtain a leuprolide-containing microcapsule. It was further washed with water, freeze-dried and powdered. The uptake rate of Ryuprolide into the microcapsules at this time was
It was 94%.

[Effect of the Invention] According to the method of the present invention, by adjusting the viscosity of the W / O type emulsion to a value higher than that in the conventional method, the uptake rate of the water-soluble drug into the microcapsules is remarkably increased. Can be increased to Therefore, sustained-release microcapsules of a water-soluble drug can be advantageously produced.

Claims (1)

[Claims] 1. A W / O type emulsion is prepared by using a solution containing a water-soluble drug as an inner aqueous phase and a solution containing a polymer as an oil phase to disperse the emulsion in the aqueous phase. In the method for producing a sustained-release microcapsule of a water-soluble drug by producing a / W-type emulsion and drying in water, the viscosity of the W / O-type emulsion when the W / O / W-type emulsion is produced is about A method for producing microcapsules, which is characterized by adjusting to 150 cp to 10000 cp.