WO2006106799A1 - Microcapsule using polyvinyl alcohol copolymer - Google Patents

Microcapsule using polyvinyl alcohol copolymer Download PDF

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Publication number
WO2006106799A1
WO2006106799A1 PCT/JP2006/306615 JP2006306615W WO2006106799A1 WO 2006106799 A1 WO2006106799 A1 WO 2006106799A1 JP 2006306615 W JP2006306615 W JP 2006306615W WO 2006106799 A1 WO2006106799 A1 WO 2006106799A1
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WIPO (PCT)
Prior art keywords
copolymer
microcapsule
weight
microcapsule according
drug
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PCT/JP2006/306615
Other languages
French (fr)
Japanese (ja)
Inventor
Yoshihiro Furuya
Yuko Yamamoto
Original Assignee
Shionogi & Co., Ltd.
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Priority to JP2007512830A priority Critical patent/JPWO2006106799A1/en
Publication of WO2006106799A1 publication Critical patent/WO2006106799A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • B01J13/043—Drying and spraying

Definitions

  • the present invention relates to a microcapsule, and specifically to a microcapsule using a polybutyl alcohol copolymer.
  • a microcapsule is a particle having a particle diameter of usually several ⁇ m to several 100 ⁇ m, which is produced by coating fine particles or a liquid substance with a polymer substance.
  • a microcapsule made of acrylic Patent Document 1
  • a microcapsule made of polybulal alcohol Patent Documents 2 and 3
  • a microcapsule made of gelatin Patent Document 4
  • gelatin microcapsules are widely used, and are commercially available as capsules containing drugs such as vitamins.
  • a production method such as a spray chilling method in which a solution is sprayed and cooled instantaneously has been developed (Patent Document 5).
  • Patent Document 1 Japanese Unexamined Patent Publication No. 2000-33259
  • Patent Document 2 JP-A-3-114528
  • Patent Document 3 Japanese Patent Laid-Open No. 6-219924
  • Patent Document 4 Special Table 2003-517464
  • Patent Document 5 JP-A-6-254382
  • the gelatin raw material mainly has a problem of bovine spongiform encephalopathy (BSE) mainly in cow bones and cow skin, and the use of gelatin microcapsules has been partially reviewed.
  • Gelatin microcapsules cannot be produced by the spray drying method, which is the mainstream of capsule production methods.
  • gelatin does not necessarily have a high function of gas, the drug power contained in the capsule, for example, if it is unstable to oxygen, the contained drug may be decomposed. There is.
  • PVA copolymer a polyvinyl alcohol copolymer
  • International Publication Pamphlet WO02Z18494 International Publication Pamphlet WO02Z18494
  • microcapsules containing drugs must be described.
  • a polyvinyl alcohol copolymer can be unexpectedly included as long as it contains a polyvinyl alcohol copolymer, a drug, a surfactant and, if necessary, an excipient.
  • the following inventions have been completed.
  • a microcapsule comprising a polyvinyl alcohol copolymer, a surfactant and a drug.
  • the polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 100 to 2000 and at least one polymerizable vinyl monomer at a weight ratio of 6: 4 to 9: 1.
  • the polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 150 to 1000 and at least one polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1.
  • the polymerizable butyl monomer power Unsaturated carboxylic acids, esters of unsaturated carboxylic acids, and their salt power are also selected. Either one of (3) to (5) above is selected.
  • the polymerizable butyl monomer strength Acrylic acid or a salt thereof and methyl methacrylate, and the weight ratio of acrylic acid or a salt thereof to methyl methacrylate is 3: 7 to 0.5 in copolymerization. : The microcapsule according to (6), which is 9.5.
  • a microcapsule is produced, wherein the aqueous component of the water-in-oil type emulsion contains a polybulal alcohol copolymer, and the oily component contains a surfactant and a drug.
  • Method. (19) including the step of preparing an oil-in-water emulsion type by adding water to the water-in-oil type emulsion and the step of drying the oil-in-water type emulsion by solidifying it in a spray or liquid.
  • a microcapsule of a polyvinyl alcohol copolymer can be produced by containing a polyvinyl alcohol copolymer, a drug and a surfactant, and if necessary, an excipient.
  • the polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 100 to 2000 and at least one polymerizable bur monomer in a weight ratio of 6: 4 to 9: 1. If the viscosity of the obtained 2% by weight solution at 20 ° C. is 10 to 300 mPa ⁇ s, fine microcapsules can be produced.
  • FIG. 1 Microcapsules containing water-soluble excipients produced by spray drying
  • FIG. 2 Microcapsules containing water-insoluble excipients produced by spray drying method
  • FIG.3 Microcapsules produced by submerged coating method
  • microcapsules in the present invention include at least a polybulal alcohol copolymer.
  • PVA copolymer a drug and a surfactant.
  • excipients and other additives may be added.
  • a PVA copolymer is a copolymer of polybulal alcohol and a bully monomer.
  • polybulal alcohol specifically, polyvinyl alcohol having an average degree of polymerization of 100 to 2000, preferably polybutyl alcohol having an average degree of polymerization of 150 to 1000, more preferably a polybutyl alcohol having an average degree of polymerization of 200 to 800. Bull alcohol. If the average degree of polymerization is smaller than this, the oxygen permeability may be increased. If the degree of polymerization is larger, when the solution is sprayed by a spray drying method or the like, the yarn is sprinkled, that is, the spinnability is increased, and the particle diameter is increased. Variations may occur and the yield of microcapsules may be significantly reduced.
  • the polyvinyl alcohol in the PVA copolymer is completely saponified
  • Partially saponified partially saponified polybulal alcohol is preferred to saponified polyvinyl alcohol. This is because microcapsules are produced from oil-in-water emulsions. In this method, the polymer used as the capsule must be water-soluble, and the partially saponified polyvinyl alcohol can easily dissolve in water. .
  • Saponification is a reaction in which an acetic acid group of polyacetic acid butyl is substituted with a hydroxyl group using an alkali catalyst in a methanol solvent to form polybulu alcohol.
  • the degree of saponification, that is, the degree of saponification of this polybulal alcohol is 70 to 95%, preferably 75 to 92.5%, more preferably 80 to 90%.
  • the partially saponified polyvinyl alcohol as described above can be a commercially available product.
  • commercially available polyvinyl alcohols include Gohsenol E G05 and EG25 (manufactured by Enomoto Gosei Co., Ltd.). , PVA203, PVA204, PVA205 (manufactured by Kuraray Co., Ltd.), JP-04, JP-05 (manufactured by Nippon Vinegar Poval) and the like.
  • the vinyl monomer in the PVA copolymer is preferably a polymerizable vinyl monomer, specifically, unsaturated carboxylic acids, esters of unsaturated carboxylic acids, unsaturated nitriles, unsaturated amides. , Aromatic bulls, aliphatic bulls, unsaturated bond-containing heterocycles and salts thereof.
  • two or more polymerizable butyl monomers are copolymerized, at least one is an unsaturated carboxylic acid or a salt thereof, and at least one is an ester of an unsaturated carboxylic acid.
  • the unsaturated carboxylic acids or salts thereof are selected from the group consisting of acrylic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, itaconic acid and salts thereof.
  • Acrylic acid or a salt thereof is preferable.
  • unsaturated carboxylic acid esters include methyl methacrylate, methyl methacrylate, ethenore methacrylate, ethino rare acrylate, butino rare acrylate, isobutino methacrylate, isobutyl acrylate and cyclobutyl acrylate.
  • the group power is selected from the group consisting of an ester of polyethylene glycol and acrylic acid and an ester power of polypropylene glycol and acrylic acid.
  • the It is tilmetatalate.
  • the weight ratio of the methyl metatalylate to acrylic acid or a salt thereof in the copolymerization is preferably 7: 3 to 9.5: 0.5.
  • the PVA copolymer is obtained by copolymerizing the above-described partially saponified polybulal alcohol and a polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1, and the polymerizable property. Bull monomer strength methyl methacrylate and acrylic acid. The weight ratio of methyl methacrylate and acrylic acid of the polymerizable butyl monomer in the copolymerization is 7: 3 to 9.5: 0.5.
  • the weight ratio in the copolymerization of the above partially saponified polyvinyl alcohol, methyl methacrylate and acrylic acid is 60 to 90: 7 to 38: 0.5 to 12, particularly preferably ⁇ , the weight it force 80 : 17.5: 2.5 PVA copolymer.
  • weight ratios of polybutyl alcohol, methyl methacrylate and acrylic acid in copolymerization are the polymerization ratio of polyvinyl alcohol, methyl methacrylate and acrylic acid in the copolymer. The same, 60-90: 7-38: 0.5-12 respectively. This polymerization ratio can be measured by NMR.
  • the PVA copolymer described above can be produced based on International Publication Pamphlets WO02Z18494 and W02 005Z019286.
  • the viscosity of a 2% by weight solution at 20 ° C is 10 to 300 mPa's, preferably the viscosity of the solution is 20 -250 mPa's, more preferably the viscosity of the solution is 50-200 mPa's.
  • the weight ratio when copolymerizing partially saponified polyvinyl alcohol having an average degree of polymerization of 100 to 2000, methyl methacrylate and acrylic acid is 0 to 90: 7 to 38: 0.5 to is 12
  • PVA copolymers viscosity of 2 weight 0/0 solution at 20 ° C of the copolymer is 10-300's, preferably partially saponified poly Bulle alcohol having an average degree of polymerization of from 150 to 100 0, methyl methacrylate Tali rates and acrylic
  • the PVA copolymer has a weight ratio of 60 to 90: 7 to 38: 0.5 to 12 when the acid is copolymerized, and the viscosity of a 2% by weight solution of the copolymer at 20 ° C.
  • the amount of the PVA copolymer in the preparation of the present invention is 10 to 80% by weight, preferably 15 to 70% by weight, more preferably 18 to 65% by weight, based on the total amount of the preparation. If the amount is larger than this amount, the amount of the drug may be relatively small. If the amount is smaller, a micro force capsule may not be formed!
  • any surfactant that can be used physiologically can be used.
  • a non-one (nonionic) surfactant is preferred.
  • a tow type or span type surfactant is preferred.
  • polyhydric alcohol esters, polyhydric alcohol ester ethylene oxide adducts, polyethylene glycol monoesters, polyethylene glycol diesters, expensive alcohol ethylene oxide adducts, alkylphenolic ethylene oxide adducts, and the like can be used.
  • a polyhydric alcohol ester or a polyhydric alcohol ester ethylene oxide adduct is preferable.
  • polyhydric alcohol ester examples include sorbitan lauric acid monoester, sorbitan palmitic acid monoester, sorbitan stearic acid monoester, sorbitanoleic acid monoester, sorbitanoleic acid triester, etc. Sorbitan lauric acid monoester. These HLBs (Hydrophile-Lipophile Balance) are approximately 1-9.
  • polyhydric alcohol ester ethylene oxide adduct specifically, sorbitan lauric acid monoester ethylene oxide 4 mol adduct, sorbitan lauric acid monoester oxide 20 mol adduct, sorbitan palmitic acid monoester ethylene oxide 20 mol adduct Sorbitan palmitate monoester, 20 mol of ethylene oxide, sorbitan stearic acid monoester, ethylene oxide, 4 mol, sorbitan stearate monoester, 20 mol of ethylene oxide, sorbitanoleic acid monoester There are 5 mol of ethylene oxide, 20 mol of sorbitanoleic acid monoester ethylene oxide, 20 mol of sorbitanoleic acid triester, 20 mol adduct of ethylene oxide, preferably sorbitanoleic acid monoester ethylene oxide 2 0 mol. These HLB (Hydr ophile- Lipophile Balance) around 9-18 &.
  • HLB
  • a surfactant having an HLB of 5 to 20 is particularly preferable.
  • the amount of the surfactant of the present invention formulation based on the total amount of the formulation, 0.. 5 to: L0 by weight 0/0, preferably from 0.5 to 8 wt 0/0, more preferably 1 to 6% by weight. If the amount is larger than this amount, the amount of the drug may be relatively reduced. If the amount is smaller, the microcapsule may not be formed.
  • Examples of the medicine filled in the microcapsule of the present invention include nourishing tonicho, antipyretic analgesic, antipsychotic, anxiolytic, antidepressant, hypnotic sedative, antispasmodic, central Neuroactive agents, brain metabolism improving agents, cerebral circulation improving agents, antiepileptic agents, sympathomimetic agents, gastrointestinal agents, antacids, antiulcer agents, antitussive expectorants, antiemetics, respiratory stimulants, bronchodilators, Drugs for allergies, dental and oral drugs, antihistamines, cardiotonic drugs, arrhythmic drugs, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, antibacterial agents, Antibiotic, Chemotherapy, Diabetes, Osteoporosis, Antirheumatic, Skeletal muscle relaxant, Antispasmodic, Hormone, Alkaloid narcotic, Sulfur, G
  • Examples of nourishing tonic health agents include vitamins such as vitamin A, vitamin D, and vitamin E (acetic acid d-a-tocopherol).
  • Antipyretic analgesics and anti-inflammatory agents include, for example, aspirin, acetominophen, ethenzamid, ibuprofen, nospower pin, serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicinoleamide, aminovirin, ketoprofen, indomethacin, Examples include bucolome and pentazocine.
  • Examples of psychotropic drugs include chlorpromazine, reserpine and the like.
  • Examples of anti-anxiety drugs include alprazolam, chlordiazepoxide, diazepam and the like.
  • Examples of antidepressants include imibramin.
  • Examples of hypnotic sedatives include estazolam and perlapine.
  • Examples of central nervous system drugs include citicoline.
  • Examples of the cerebral circulation improving agent include vinpocetine.
  • Examples of the antiepileptic agent include fetoin and carbamazepine.
  • enteric agents examples include diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, healthy gastric antiseptics such as keihi oil, and intestinals such as resistant lactic acid bacteria and bifidobacteria.
  • Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like.
  • Examples of the anti-ulcer agent include lansoprazole, omebrazole, rabebrazol, famotidine, cimetidine, latidine hydrochloride and the like.
  • Examples of antitussive expectorant include theophylline, potassium guaiacol sulfonate, and guaifenesin.
  • Examples of the antiemetic include metocloblamide.
  • Examples of bronchodilators include theophylline.
  • Examples of allergic drugs include amlexanotus and seratrodast.
  • Examples of the dental and oral medicine include oxytetracycline and triamcinolone acetonide.
  • Examples of the cardiotonic agent include digoxin.
  • Examples of the arrhythmia agent include pindolol.
  • Examples of the diuretic include furosemide and hydrochlorothiazide.
  • Examples of antihypertensive agents include candesartan cilexetil, methyldopa, and perindopril elpmin.
  • Examples of the coronary vasodilator include molsidomine.
  • Examples of peripheral vasodilators include cinnarizine.
  • An example of a bile agent is trepeptone.
  • Antibiotics include, for example, cephems such as cefadoxyl, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, naliditasic acid, enoxacin, and monobatamates such as carmonam natrium. , Penem and force ruba penem antibiotics
  • Examples of the chemotherapeutic agent include sulfamethizole.
  • Examples of the antidiabetic agent include tolptamide, voglibose, darribenclamide, troglidazone, and the like.
  • Examples of the osteoporosis agent include ibriflavone.
  • Examples of skeletal muscle relaxants include metcarbamol.
  • Examples of antispasmodic agents include dimenhydrinate.
  • Antirheumatic drugs include methotrexate and bucillamine. It is done.
  • hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
  • Alkaloid narcotics include opium and tocon.
  • sulfa drugs include sulfisomidine and sulfamethizole.
  • gout therapeutic agents include alopurinol and colchicine.
  • the blood coagulation inhibitor include dicumarol.
  • the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like.
  • These medicaments can be used alone or in combination with other medicaments.
  • these medicines are filled with a known appropriate amount appropriately determined according to the disease, age, etc. of the patient.
  • the amount of drug present invention formulation based on the total amount of the preparation, 5 to 60 wt%, is preferred properly 10 to 55 weight 0/0, more preferably 18 to 50 wt. If it is more than this amount, it may be impossible to form a mic mouth capsule, and if it is less, if it is not taken in a large amount, the drug will not be fully effective!
  • the drug in the preparation of the present invention may be a poorly water-soluble drug.
  • a drug having a water solubility (20 ° C) of 100 g / mL or less can be included in the preparation of the present application.
  • Health foods may be included in the preparation of the present invention instead of the drug.
  • Examples include Coenzyme Q10, EPA, DHA, ⁇ -carotene, flavonoids and carotenoids.
  • the preparation of the present invention may be a preparation containing the above-mentioned PVA copolymer, surfactant and drug, but an excipient can be added if necessary.
  • an excipient those that can be used physiologically can be used. Specifically, both water-soluble excipients and water-insoluble excipients can be used.
  • the amount of the excipient in the preparation of the present invention is 0 to 84.5% by weight, preferably 0 to 70% by weight, more preferably 0 to 40% by weight, based on the total amount of the preparation. If the amount is larger than this amount, the amount of the PVA copolymer or drug may be relatively decreased, and microcapsules may not be formed, or the intended stability may not be ensured.
  • a gelling agent and, if necessary, a gelling aid may be added.
  • the preparation can be solidified by adding a gelling agent or a gelling aid.
  • the gelling agent include kappa strenuous laginin, iota strenuous laginan, lambda struggle laginan, tamarind seed polysaccharide, locust bean gum, and dielan gum, preferably kappa strenuous laginan.
  • a water-soluble compound containing one or more of potassium ion, ammonium ion and calcium ion is used for kappa force laginan, and water-soluble compound containing calcium ion is used for iota force laginan.
  • a compound, preferably potassium salt is used for kappa force laginan.
  • the blending amount of each component of the PVA copolymer, the surfactant and the drug is 10 to 80% by weight of the PVA copolymer and 0.5 to 10% of the surfactant with respect to the total amount of the preparation. 5% to 60% by weight of drug.
  • the PVA copolymer is 15 to 70% by weight
  • the surfactant is 0.5 to 8% by weight
  • the drug is 10 to 55% by weight, based on the total amount of the preparation.
  • the PVA copolymer is 18 to 65% by weight
  • the surfactant is 1 to 6% by weight and the drug is 18 to 50% by weight, based on the total amount of the formulation.
  • the blending amount of each component of the PVA copolymer, surfactant, drug and excipient is 10 to 80% by weight of the PVA copolymer with respect to the total amount of the formulation.
  • the active agent is 0.5 to 10% by weight
  • the drug is 5 to 60% by weight and the excipient is 0 to 84.5% by weight.
  • the PVA copolymer is 15 to 70% by weight
  • the surfactant is 0.5 to 8% by weight
  • the drug is 10 to 55% by weight
  • the excipient is 0 to 70% by weight, based on the total amount of the formulation.
  • PVA copolymer is 18-65% by weight
  • surfactant is 1-6% by weight
  • drug is 18-50% by weight
  • excipient is 0-40% by weight of the total formulation.
  • a general method for producing microcapsules is used. Specific examples include a spray drying method, a fluidized bed granulation method, a submerged coating method, a polymerization coating method, a phase separation method, and an orifice method, preferably a spray drying method and a submerged curing coating method.
  • the spray drying method is a method in which a solution or dispersion is sprayed in a high-temperature air stream and dried immediately to obtain fine particles.
  • the submerged cured coating method is an oil-in-water type (oZw type) emulsion in oil. This is a method in which a microcapsule is obtained by dripping onto a glass and cooling to solidify, then collecting the solidified liquid droplets, washing, and drying.
  • oZw type oil-in-water type
  • a PVA copolymer, a drug and a surfactant, and if necessary, a solution obtained by dissolving or suspending an excipient in an organic solvent or the like is a spray drying method. If so, spray in a spray dryer.
  • a solution obtained by dissolving or suspending a PVA copolymer, a drug, a surfactant, and if necessary, a gelling agent, a gelling aid, and an excipient in an organic solvent or the like is used as a hydrophobic solvent. (Oil component) Some are dropped in alcohol or gelling aid solution, stirred and solidified, then collected, washed after surface washing and dried to obtain microcapsules.
  • spray dryer there is a spray dryer type
  • submerged coating method dryer there are a fluidized bed type and a drum type.
  • a hydrophobic drug in particular, in the case of a liquid hydrophobic drug, as another method described above, an emulsion is manufactured, and then the emulsion is cured in liquid with the force of spray drying.
  • This emulsion includes 1) an oil-in-water emulsion in which an oily component containing a drug, a surfactant, etc. is dispersed in an aqueous component in which a PVA copolymer is dissolved, and 2) a drug, a surfactant, etc.
  • phase inversion means that the type of emulsion changes from one force to the other. In this case, it is considered that the droplets gather to form a continuous phase, and another liquid confined in the droplets becomes a droplet.
  • microcapsules are manufactured using the emulsions 1) and 2) above, A larger amount of the drug is contained in the capsule when the emulsion prepared by the method is used.
  • the emulsion When a microcapsule is manufactured after the emulsion is manufactured by the method 2), about 80 to 90% of the drug can be included in the microcapsule. Therefore, after manufacturing the water-in-oil type (WZO type) emulsion of 2) above, the oil-in-water type (OZW type) emulsion prepared by phase inversion with water is microcapsuled by spray drying method or submerged cured coating method. The method of producing is preferred.
  • the amount of water to be added at the time of phase inversion is, as a weight ratio, aqueous component 3, preferably aqueous component 4, more preferably aqueous component 1 to oily component 1.
  • Aqueous component is added in the proportion of aqueous component 5.
  • an excipient can be added to the microcapsule, but when a hydrophobic drug is included in the microcapsule, a water-insoluble excipient is added as an excipient. Then, a microcapsule with few pores on the surface can be produced.
  • a water-insoluble excipient include anhydrous calcium hydrogen phosphate and crystalline cellulose.
  • the average particle size of the microcapsules of the preparation of the present invention is about 10 to 200 ⁇ m, and can be freely changed depending on the production method or the like. Further, the microcapsules of the preparation of the present invention can be filled into hard capsules, and can also be contained in granules and tablets.
  • an oxygen-labile drug having a low oxygen permeability of the PVA copolymer is included in the present invention, the drug can be stabilized.
  • the viscosity of the prepared polybutyl alcohol copolymer solution was 10 to 300 mPa ⁇ s.
  • Vitamin A palmitate (manufactured by Roche 'Vitamin' Japan) 10g of surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) PVA copolymer dissolved in lg and heated to 60 ° C (Daido Chemical Industries) Made by company, weight ratio of PVA with average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) Aqueous solution (aqueous solution concentration: 20wZv%) Manufacture type Emulsion (WZO type Emulsion) .
  • microcapsules could be obtained by drying this emulsion from the top of a spray dryer (Okawara Chemical Industries, Model L-8) using a rotary atomizer under the following conditions. The water content of the obtained microcapsules was 1.58%, and the yield of microcapsules was about 80%.
  • Vitamin A palmitate (manufactured by Roche 'Vitamin' Japan) 10g of surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) lg dissolved and heated to 60 ° C PVA copolymer with an average degree of polymerization of 500 Made by Daido Kasei Kogyo Co., Ltd.
  • the weight ratio of PVA with an average degree of polymerization of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) Calorie while stirring 100g of aqueous solution (water solution concentration: 20wZv%) It produces water-in-oil type emulsion (WZO type emulsion).
  • Microcapsules could be obtained by drying this emulsion from the top of a spray dryer (manufactured by Okawahara Koki Co., Ltd., type L-8) using a rotary atomizer under the spray dry production conditions of Example 1.
  • Fig. 1 shows an electron micrograph of the microcapsules prepared by this method.
  • Surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) lg was dissolved in 10 g of vitamin A palmitate (Roche 'Vitamin' Japan Co., Ltd.) and heated to 60 ° C PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) aqueous solution 100g (aqueous solution concentration: 20wZv% ) Is stirred and water-in-oil type emulsion (WZO type emulsion) is produced.
  • PVA copolymer with a polymerization degree of 500 manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5
  • Microcapsules could be obtained by drying this emulsion from the top of a spray dryer (manufactured by Okawara Chemical Co., Ltd., type L8) using a rotary atomizer under the conditions of Example 1.
  • Fig. 2 shows an electron micrograph of the microcapsules produced by this method.
  • Example 3 using anhydrous calcium hydrogen phosphate, which is a water-insoluble excipient, compared to the microcapsules of Example 2 using a water-soluble excipient.
  • the capsule had a dense surface. Since the surface of the microcapsule of Example 3 is dense, it is considered that the oxygen permeability is further reduced as compared with the microcapsule of Example 2.
  • PVA copolymer with a polymerization degree of 500 manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5
  • 40 g of aqueous solution concentration of aqueous solution: 20 wZv %)
  • Dissolve 50 g of water 1 g of the surfactant polyoxyethylene sorbitan monooleate and 4.8 g of sucrose.
  • Add 4 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) to the solution, coarsely emulsify with a homogenizer, and produce emulsion with a micronizer.
  • Microcapsules could be obtained from the top of a spray dryer (Okawara Chemical Industries, L8 type) using a rotary atomizer.
  • PVA copolymer having an average polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA having an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5)
  • Solution concentration: 20 wZv%) Dissolve 50 g of water, lg of surfactant polyoxyethylene sorbitan monooleate and 4.8 g of sucrose. Add 4 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) to the solution, coarsely emulsify with a homogenizer, and then produce emulsion with a micronizer.
  • PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) 20 g of aqueous solution (concentration of aqueous solution 20 wZv% ) And 200 g of water surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) 10 g of vitamin A palmitate (manufactured by Roche Vitamin Japan) 10 g together with lg and water-soluble excipient 5 g Let Dissolve 0.25 g of carrageenan (manufactured by Chuo Foods Materials Co., Ltd.) and 0.18 g of potassium salty salt (manufactured by Ishizu Pharmaceutical Co., Ltd.) at 80 ° C. in the emulsion. The emulsion was sprayed into ethanol to produce droplets
  • PVA copolymer with an average polymerization degree of 500 heated to 60 ° C (Daido Kasei Kogyo Co., Ltd., PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid have a weight ratio of 80: 17.5: 2.5 )
  • Dissolve sorbitan monolaurate sorbitan (manufactured by Wako Pure Chemical Industries, Ltd.) lg, 16 g of D-mannitol in 100 g of aqueous solution (concentration of aqueous solution: 20 wZv%) and 100 g of water.
  • Vitamin A palmitate (Roche 'Vitamin' Japan Co., Ltd.) is adsorbed to 3.5 g of light anhydrous caustic acid (Nippon Aerosil), and dispersed in the above aqueous solution to prepare an emulsion.
  • the mouthpiece can be obtained by drying this emulsion from the top of a spray dryer (Okawara Chemical Industries, L-8 type) with a rotary atomizer, under the spray-dry production conditions of Example 1. It was.
  • PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., PV with an average polymerization degree of 500 Weight ratio of A, methyl metatalylate and acrylic acid is 80: 17.5: 2.5) 250g aqueous solution (aqueous solution concentration: 8wZv%) and sorbitan monolaurate surfactant (manufactured by Wako Pure Chemical Industries, Ltd.) lg After dissolution, 10 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) is added with stirring to produce an oil-in-water emulsion (OZW emulsion).
  • OZW emulsion oil-in-water emulsion
  • the emulsion was dried under the conditions of Example 1 by using a rotary atomizer from the top of a spray dryer (manufactured by Okawara Chemical Co., Ltd., Model L-8), thereby obtaining microcapsules.
  • the yield of microcapsules was about 70%.
  • PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PV A, methyl methacrylate, and acrylic acid with an average polymerization degree of 500: 80: 17.5: 2.5) 20 g of aqueous solution (concentration of aqueous solution 20 wZv% ) And 200 g of water surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) 10 g of vitamin A palmitate (manufactured by Roche Vitamin Japan) with 5 g of lg and water-soluble excipients by phase inversion method Emulsify.
  • aqueous solution concentration of aqueous solution 20 wZv%
  • water surfactant sorbitan monolaurate manufactured by Wako Pure Chemical Industries, Ltd.
  • vitamin A palmitate manufactured by Roche Vitamin Japan
  • Carrageenan (manufactured by Chuo Foods Co., Ltd.) 0.25 g
  • potassium salty salt (manufactured by Ishizu Pharmaceutical Co., Ltd.) 0.18 g is dissolved at 80 ° C, and this liquid is sesame oil (manufactured by Hoei Pharmaceutical Co., Ltd.) Drops were generated by pouring force into oil such as oil. The droplets were cooled and solidified at 4 ° C or lower, collected, washed with a solvent, and dried to obtain microcapsules.
  • Fig. 3 shows an electron micrograph of the microcapsules prepared by this method.
  • the drug when a drug having poor stability to oxygen is encapsulated in the microcapsule, the drug can be stabilized. It can be used not only for pharmaceuticals but also for health foods and foods.

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Abstract

A microcapsule comprising a copolymer of polyvinyl alcohol with a vinyl monomer ('polyvinyl alcohol copolymer') and a compound included therein. In the case where the compound is hydrophilic, the microcapsule can be produced efficiently by drying a mixed solution of the compound, a surfactant and a polyvinyl alcohol copolymer by spray drying method or drying-in-liquid method. In the case where the compound is hydrophobic, the microcapsule can be produced efficiently by preparing a water-in-oil emulsion (W/O emulsion) with the compound and a surfactant, causing the phase-inversion of the emulsion into an oil-in-water emulsion (O/W emulsion) by addition of water and drying the emulsion by spray drying method or drying-in-liquid method.

Description

明 細 書  Specification
ポリビュルアルコール共重合体を用レ、たマイクロカプセル  A microcapsule using polybulal alcohol copolymer
技術分野  Technical field
[0001] 本発明は、マイクロカプセルに関するもので、具体的には、ポリビュルアルコール共 重合体を用いたマイクロカプセルに関するものである。  [0001] The present invention relates to a microcapsule, and specifically to a microcapsule using a polybutyl alcohol copolymer.
背景技術  Background art
[0002] 現在、種々のマイクロカプセルが研究開発されて!/、る。マイクロカプセルとは、微小 な粒子や液状物質を高分子物質などで被覆することによって製造される通常数 μ m 〜数 100 μ mの粒子径をもつ粒子である。例えば、アクリルを素材としたマイクロカプ セル (特許文献 1)、ポリビュルアルコールを素材としたマイクロカプセル (特許文献 2 、 3)、ゼラチンを素材としたマイクロカプセル (特許文献 4)等がある。この中で、ゼラ チンマイクロカプセルが汎用されており、ビタミン等の薬物を包含するカプセルとして 市販されている。また、ゼラチンマイクロカプセルの製造方法としては、溶液をスプレ 一し、瞬時に冷却するスプレーチリング法のような製造方法が開発されている（特許 文献 5)。  [0002] Currently, various microcapsules are being researched and developed! A microcapsule is a particle having a particle diameter of usually several μm to several 100 μm, which is produced by coating fine particles or a liquid substance with a polymer substance. For example, there are a microcapsule made of acrylic (Patent Document 1), a microcapsule made of polybulal alcohol (Patent Documents 2 and 3), a microcapsule made of gelatin (Patent Document 4), and the like. Of these, gelatin microcapsules are widely used, and are commercially available as capsules containing drugs such as vitamins. As a method for producing gelatin microcapsules, a production method such as a spray chilling method in which a solution is sprayed and cooled instantaneously has been developed (Patent Document 5).
特許文献 1：特開 2000— 33259号公報  Patent Document 1: Japanese Unexamined Patent Publication No. 2000-33259
特許文献 2：特開平 3 - 114528号公報  Patent Document 2: JP-A-3-114528
特許文献 3：特開平 6 - 219924号公報  Patent Document 3: Japanese Patent Laid-Open No. 6-219924
特許文献 4：特表 2003 - 517464号公報  Patent Document 4: Special Table 2003-517464
特許文献 5：特開平 6 - 254382号公報  Patent Document 5: JP-A-6-254382
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0003] し力しながら、ゼラチンの原料は、主として牛骨および牛皮で牛海綿状脳症 (BSE) の問題があり、一部ゼラチンマイクロカプセルの使用が見直されている。また、ゼラチ ンマイクロカプセルは、現在カプセル製造法の主流である噴霧乾燥法によって、製造 することができない。さらに、ゼラチンは、必ずしもガスノ リア一機能が高くないため、 カプセルに内包する薬物力 例えば酸素に不安定ならば、内包薬物が分解する恐 れがある。 [0003] However, the gelatin raw material mainly has a problem of bovine spongiform encephalopathy (BSE) mainly in cow bones and cow skin, and the use of gelatin microcapsules has been partially reviewed. Gelatin microcapsules cannot be produced by the spray drying method, which is the mainstream of capsule production methods. Furthermore, since gelatin does not necessarily have a high function of gas, the drug power contained in the capsule, for example, if it is unstable to oxygen, the contained drug may be decomposed. There is.
[0004] 近年、酸素透過性の低 、素材が種々開発されて!、る。この中で、ポリビュルアルコ ールとビニル基の共重合体であるポリビニルアルコール共重合体（以下、「PVAコポ リマー」と 、う）がある（国際公開パンフレット WO02Z18494号公報)。しかしながら、 薬物を内包したマイクロカプセルにつ 、ては記載されて ヽな 、。  [0004] In recent years, various materials with low oxygen permeability have been developed! Among them, there is a polyvinyl alcohol copolymer (hereinafter referred to as “PVA copolymer”), which is a copolymer of polybulal alcohol and vinyl group (International Publication Pamphlet WO02Z18494). However, microcapsules containing drugs must be described.
課題を解決するための手段  Means for solving the problem
[0005] そこで、本発明者らが鋭意検討した結果、今回意外にも、ポリビニルアルコール共 重合体、薬物、界面活性剤および要すれば賦形剤を含有すれば、ポリビニルアルコ ール共重合体のマイクロカプセル剤を製造できることを見出し、以下の発明を完成し た。 [0005] Thus, as a result of intensive studies by the present inventors, a polyvinyl alcohol copolymer can be unexpectedly included as long as it contains a polyvinyl alcohol copolymer, a drug, a surfactant and, if necessary, an excipient. The following inventions have been completed.
(1)ポリビニルアルコール共重合体、界面活性剤および薬物を含有することを特徴と するマイクロカプセル剤。  (1) A microcapsule comprising a polyvinyl alcohol copolymer, a surfactant and a drug.
(2)賦形剤を含有する上記（1)記載のマイクロカプセル剤。  (2) The microcapsule according to the above (1), which contains an excipient.
( 3)当該ポリビュルアルコール共重合体が平均重合度 100〜 2000のポリビュルアル コールと少なくとも 1以上の重合性ビニル単量体とを重量比 6： 4〜9： 1の割合で共重 合させて得られる共重合体であり、溶液の粘度が 10〜300mPa'sである当該共重 合体の溶液を用いて製造したものである上記（1)または（2)記載のマイクロカプセル 剤。  (3) The polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 100 to 2000 and at least one polymerizable vinyl monomer at a weight ratio of 6: 4 to 9: 1. The microcapsule according to (1) or (2) above, which is a copolymer obtained and produced using a solution of the copolymer having a viscosity of 10 to 300 mPa's.
(4)当該ポリビュルアルコール共重合体が平均重合度 150〜1000のポリビュルアル コールと少なくとも 1以上の重合性ビニル単量体とを重量比 6： 4〜9： 1の割合で共重 合させて得られる共重合体であり、溶液の粘度が 50〜200mPa'sである当該共重 合体の溶液を用いて製造したものである上記（1)または（2)記載のマイクロカプセル 剤。  (4) The polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 150 to 1000 and at least one polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1. The microcapsule according to (1) or (2) above, which is a copolymer obtained and produced using a solution of the copolymer having a solution viscosity of 50 to 200 mPa's.
(5)当該ポリビュルアルコールが部分けん化ポリビュルアルコールである上記（3)ま たは (4)記載のマイクロカプセル剤。  (5) The microcapsule according to the above (3) or (4), wherein the polybulal alcohol is a partially saponified polybulal alcohol.
(6)当該重合性ビュル単量体力 不飽和カルボン酸類、不飽和カルボン酸類のエス テル類及びそれらの塩力も選択される 1または 2以上である上記（3)から（5)の 、ず れかに記載のマイクロカプセル剤。 (7)当該重合性ビュル単量体力 アクリル酸又はその塩及びメチルメタタリレートであ り、共重合する際におけるアクリル酸又はその塩とメチルメタタリレートの重量比が 3 : 7〜0. 5 : 9. 5である上記（6)記載のマイクロカプセル剤。 (6) The polymerizable butyl monomer power Unsaturated carboxylic acids, esters of unsaturated carboxylic acids, and their salt power are also selected. Either one of (3) to (5) above is selected. The microcapsule described in 1. (7) The polymerizable butyl monomer strength Acrylic acid or a salt thereof and methyl methacrylate, and the weight ratio of acrylic acid or a salt thereof to methyl methacrylate is 3: 7 to 0.5 in copolymerization. : The microcapsule according to (6), which is 9.5.
(8)平均重合度 100〜2000の部分けん化ポリビュルアルコール、メチルメタクリレー トぉょびァクリル酸を共重合する際にぉける重量比が60〜90: 7〜38 :0. 5〜12で あり、溶液の粘度が 10〜300mPa'sである当該共重合体の溶液を用いて製造したも のである上記 (3)から（7)の!、ずれかに記載のマイクロカプセル剤。  (8) Weight ratio of 60-90: 7-38: 0.5-12 in the copolymerization of partially saponified polybulal alcohol having an average degree of polymerization of 100-2000 and methyl methacrylate and acrylic acid. The microcapsule according to any one of (3) to (7) above, which is produced using a solution of the copolymer having a solution viscosity of 10 to 300 mPa's.
(9)当該界面活性剤が非イオン系である上記（1)記載のマイクロカプセル剤。  (9) The microcapsule according to (1) above, wherein the surfactant is nonionic.
(10)当該界面活性剤がトウイン系またはスパン系である上記（9)記載のマイクロカブ セル剤。  (10) The microcapsule agent according to (9) above, wherein the surfactant is a tow type or a span type.
(11)当該界面活性剤の HLBが 5〜20である上記（9)または（10)記載のマイクロ力 プセル剤。  (11) The micropower capsule agent according to (9) or (10) above, wherein the surfactant has an HLB of 5 to 20.
(12)当該薬物の水溶解度が 100 gZmL以下である上記（1)記載のマイクロカブ セル剤。  (12) The microcapsule agent according to (1) above, wherein the drug has a water solubility of 100 gZmL or less.
(13)当該薬物が酸素に分解されやすい薬物である上記（1)記載のマイクロカプセ ル剤。  (13) The microcapsule according to (1) above, wherein the drug is a drug that is easily decomposed into oxygen.
(14)当該賦形剤が水不溶性賦形剤である上記（2)記載のマイクロカプセル剤。 (14) The microcapsule according to (2) above, wherein the excipient is a water-insoluble excipient.
(15) 10〜80重量％のポリビュルアルコール共重合体、 0. 5〜10重量％の界面活 性剤、 5〜60重量％の薬物および 0〜84. 5重量％の賦形剤を含有する上記（2)か ら（14)のいずれかに記載のマイクロカプセル剤。 (15) Contains 10-80% by weight polybulal alcohol copolymer, 0.5-10% by weight surfactant, 5-60% by weight drug and 0-84.5% by weight excipient The microcapsule according to any one of (2) to (14) above.
(16) 15〜70重量％のポリビュルアルコール共重合体、 0. 5〜8重量％の界面活性 剤、 10〜55重量％の薬物および 0〜70重量％の賦形剤を含有する上記（15)記載 のマイクロカプセル剤。  (16) The above containing 15-70% by weight polybulal alcohol copolymer, 0.5-8% by weight surfactant, 10-55% by weight drug and 0-70% by weight excipient ( 15) The microcapsule described in the above.
(17)上記（1)〜（16)のいずれかのマイクロカプセル剤を含有する顆粒剤、錠剤また は硬カプセル剤。  (17) A granule, tablet or hard capsule containing the microcapsule of any one of (1) to (16) above.
(18)油中水滴型ェマルジヨンの水性成分がポリビュルアルコール共重合体を含有 するものであり、油性成分が界面活性剤および薬物を含有するものであることを特徴 とするマイクロカプセル剤を製造する方法。 ( 19 )油中水滴型ェマルジヨンに水を添カ卩して水中油滴型ェマルジヨンを調製するェ 程、及び該水中油滴型ェマルジヨンを噴霧乾燥または液中で固化させた後乾燥する 工程を含むことを特徴とする上記（18)記載のマイクロカプセル剤を製造する方法。(18) A microcapsule is produced, wherein the aqueous component of the water-in-oil type emulsion contains a polybulal alcohol copolymer, and the oily component contains a surfactant and a drug. Method. (19) including the step of preparing an oil-in-water emulsion type by adding water to the water-in-oil type emulsion and the step of drying the oil-in-water type emulsion by solidifying it in a spray or liquid. A method for producing a microcapsule as described in (18) above.
(20)上記（18)または（19)記載の方法により製造されたマイクロカプセル剤。 (20) A microcapsule produced by the method described in (18) or (19) above.
(21)マイクロカプセルを製造するためのポリビュルアルコール共重合体の使用。 発明の効果  (21) Use of polybulal alcohol copolymer for producing microcapsules. The invention's effect
[0006] ポリビニルアルコール共重合体、薬物および界面活性剤、さらに要すれば、賦形剤 を含有すれば、ポリビニルアルコール共重合体のマイクロカプセル剤を製造すること ができる。特に、ポリビュルアルコール共重合体としては、平均重合度 100〜2000 のポリビュルアルコールと少なくとも 1以上の重合性ビュル単量体とを重量比 6 :4〜9 ： 1の割合で共重合させて得られ、 20°Cにおける 2重量％溶液の粘度が 10〜300m Pa · sであれば、微粒子のマイクロカプセルを製造することができる。  [0006] A microcapsule of a polyvinyl alcohol copolymer can be produced by containing a polyvinyl alcohol copolymer, a drug and a surfactant, and if necessary, an excipient. In particular, the polybulal alcohol copolymer is obtained by copolymerizing polybulal alcohol having an average degree of polymerization of 100 to 2000 and at least one polymerizable bur monomer in a weight ratio of 6: 4 to 9: 1. If the viscosity of the obtained 2% by weight solution at 20 ° C. is 10 to 300 mPa · s, fine microcapsules can be produced.
図面の簡単な説明  Brief Description of Drawings
[0007] [図 1]噴霧乾燥法によって製造した水溶性賦形剤を配合したマイクロカプセル [0007] [Fig. 1] Microcapsules containing water-soluble excipients produced by spray drying
[図 2]噴霧乾燥法によって製造した水不溶性賦形剤を配合したマイクロカプセル [図 3]液中硬化被膜法によって製造したマイクロカプセル  [Fig. 2] Microcapsules containing water-insoluble excipients produced by spray drying method [Fig.3] Microcapsules produced by submerged coating method
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0008] 本発明におけるマイクロカプセル剤には、少なくともポリビュルアルコール共重合体  [0008] The microcapsules in the present invention include at least a polybulal alcohol copolymer.
(以下、「PVAコポリマー」という）、薬物および界面活性剤を含有する。また、これらと ともに賦形剤やその他の添加剤を添加してもよ 、。  (Hereinafter referred to as “PVA copolymer”), a drug and a surfactant. In addition to these, excipients and other additives may be added.
PVAコポリマーとは、ポリビュルアルコールとビュル単量体の共重合体である。この 中でポリビュルアルコールとして、具体的には、平均重合度 100〜2000のポリビ- ルアルコール、好ましくは平均重合度 150〜1000のポリビュルアルコール、より好ま しくは平均重合度 200〜800のポリビュルアルコールである。この平均重合度よりも 小さければ、酸素透過性が高くなる可能性があり、大きければ噴霧乾燥法等で当該 溶液を噴霧する際、糸を曳く状態、すなわち曳糸性が増大し、粒子径にばらつきが 生じたり、マイクロカプセルの収率が著しく低下する恐れがある。  A PVA copolymer is a copolymer of polybulal alcohol and a bully monomer. Among these, as polybulal alcohol, specifically, polyvinyl alcohol having an average degree of polymerization of 100 to 2000, preferably polybutyl alcohol having an average degree of polymerization of 150 to 1000, more preferably a polybutyl alcohol having an average degree of polymerization of 200 to 800. Bull alcohol. If the average degree of polymerization is smaller than this, the oxygen permeability may be increased. If the degree of polymerization is larger, when the solution is sprayed by a spray drying method or the like, the yarn is sprinkled, that is, the spinnability is increased, and the particle diameter is increased. Variations may occur and the yield of microcapsules may be significantly reduced.
[0009] さらに、 PVAコポリマー中のポリビニルアルコールとしては、完全にけん化した完全 けん化ポリビニルアルコールよりも、部分的にけん化した部分けん化ポリビュルアルコ ールが好ましい。これは、水中油滴型ェマルジヨンからマイクロカプセルを製造する 本法において、カプセル剤となるポリマーは水溶性でなければならず、部分ケン化し たポリビニルアルコールが容易に水に溶ける恐れがある力もである。けん化とは、メタ ノール溶媒中でアルカリ触媒を用いてポリ酢酸ビュルの酢酸基を水酸基に置換し、 ポリビュルアルコールにする反応を 、う。このポリビュルアルコールがけん化した度合 い、すなわちけん化度は、 70〜95%、好ましくは 75〜92. 5%、より好ましくは 80〜 90%である。 [0009] Furthermore, the polyvinyl alcohol in the PVA copolymer is completely saponified Partially saponified partially saponified polybulal alcohol is preferred to saponified polyvinyl alcohol. This is because microcapsules are produced from oil-in-water emulsions. In this method, the polymer used as the capsule must be water-soluble, and the partially saponified polyvinyl alcohol can easily dissolve in water. . Saponification is a reaction in which an acetic acid group of polyacetic acid butyl is substituted with a hydroxyl group using an alkali catalyst in a methanol solvent to form polybulu alcohol. The degree of saponification, that is, the degree of saponification of this polybulal alcohol is 70 to 95%, preferably 75 to 92.5%, more preferably 80 to 90%.
[0010] なお、上記のような部分けん化ポリビニルアルコールは、市販品を使用できることも 可能であり、好ましいポリビニルアルコールの市販品としては、例えばゴーセノール E G05、 EG25 (曰本合成ィ匕学社製）、 PVA203, PVA204, PVA205 (クラレ社製）、 JP— 04、 JP— 05 (日本酢ビ ·ポバール製)等が挙げられる。  [0010] The partially saponified polyvinyl alcohol as described above can be a commercially available product. Examples of commercially available polyvinyl alcohols include Gohsenol E G05 and EG25 (manufactured by Enomoto Gosei Co., Ltd.). , PVA203, PVA204, PVA205 (manufactured by Kuraray Co., Ltd.), JP-04, JP-05 (manufactured by Nippon Vinegar Poval) and the like.
[0011] PVAコポリマー中のビニル単量体としては、重合性ビニル単量体が好ましぐ具体 的には不飽和カルボン酸類、不飽和カルボン酸のエステル類、不飽和二トリル類、 不飽和アミド類、芳香族ビュル類、脂肪族ビュル類、不飽和結合含有複素環類およ びそれらの塩である。好ましくは 2以上の重合性ビュル単量体を共重合させたもので あり、少なくとも 1つが不飽和カルボン酸類又はそれらの塩であり、少なくとも 1つが不 飽和カルボン酸のエステル類である。  [0011] The vinyl monomer in the PVA copolymer is preferably a polymerizable vinyl monomer, specifically, unsaturated carboxylic acids, esters of unsaturated carboxylic acids, unsaturated nitriles, unsaturated amides. , Aromatic bulls, aliphatic bulls, unsaturated bond-containing heterocycles and salts thereof. Preferably, two or more polymerizable butyl monomers are copolymerized, at least one is an unsaturated carboxylic acid or a salt thereof, and at least one is an ester of an unsaturated carboxylic acid.
[0012] 不飽和カルボン酸類又はそれらの塩類として、具体的には、アクリル酸、メタクリル 酸、クロトン酸、フマル酸、マレイン酸、ィタコン酸及びそれらの塩からなる群力 選ば れるものである。好ましくは、アクリル酸又はその塩である。  [0012] Specifically, the unsaturated carboxylic acids or salts thereof are selected from the group consisting of acrylic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, itaconic acid and salts thereof. Acrylic acid or a salt thereof is preferable.
[0013] 不飽和カルボン酸のエステル類として、具体的には、メチルメタタリレート、メチルァ タリレート、ェチノレメタタリレート、ェチノレアタリレート、ブチノレアタリレート、イソブチノレメ タクリレート、イソブチルアタリレート、シクロへキシルメタタリレート、シクロへキシルァク リレート、 2—ェチルへキシルメタタリレート、 2—ェチルへキシルアタリレート、ヒドロキ シェチルメタタリレート、ヒドロキシェチルアタリレート、ポリエチレングリコールとメタタリ ル酸とのエステル、ポリエチレングリコールとアクリル酸とのエステル、ポリプロピレング リコールとアクリル酸とのエステル力もなる群力 選ばれるものである。好ましくは、メ チルメタタリレートである。 [0013] Specific examples of the unsaturated carboxylic acid esters include methyl methacrylate, methyl methacrylate, ethenore methacrylate, ethino rare acrylate, butino rare acrylate, isobutino methacrylate, isobutyl acrylate and cyclobutyl acrylate. Hexyl methacrylate, cyclohexyl methacrylate, 2-ethyl hexyl methacrylate, 2-ethyl hexyl acrylate, hydroxy cetyl methacrylate, hydroxyethyl acrylate, esters of polyethylene glycol and methacrylate The group power is selected from the group consisting of an ester of polyethylene glycol and acrylic acid and an ester power of polypropylene glycol and acrylic acid. Preferably, the It is tilmetatalate.
[0014] 共重合する際における上記メチルメタタリレートとアクリル酸又はその塩の重量比と しては、 7:3〜9.5:0.5であることが好ましい。  [0014] The weight ratio of the methyl metatalylate to acrylic acid or a salt thereof in the copolymerization is preferably 7: 3 to 9.5: 0.5.
[0015] PVAコポリマーとして、好ましくは上述した部分けん化ポリビュルアルコールと、重 合性ビニル単量体が重量比で 6: 4〜9： 1の割合で共重合させて得られ、かつ当該 重合性ビュル単量体力メチルメタタリレートおよびアクリル酸である。共重合する際に おける当該重合性ビュル単量体のメチルメタタリレートおよびアクリル酸の重量比が 7 :3〜9.5:0.5である。より好ましくは、上述した部分けん化ポリビニルアルコールと、 メチルメタタリレートおよびアクリル酸の共重合する際における重量比が 60〜90： 7〜 38:0.5〜12、特に好ましく ίま、当該重量 it力 80: 17.5:2.5である PVAコポリマ 一である。  [0015] Preferably, the PVA copolymer is obtained by copolymerizing the above-described partially saponified polybulal alcohol and a polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1, and the polymerizable property. Bull monomer strength methyl methacrylate and acrylic acid. The weight ratio of methyl methacrylate and acrylic acid of the polymerizable butyl monomer in the copolymerization is 7: 3 to 9.5: 0.5. More preferably, the weight ratio in the copolymerization of the above partially saponified polyvinyl alcohol, methyl methacrylate and acrylic acid is 60 to 90: 7 to 38: 0.5 to 12, particularly preferably ί, the weight it force 80 : 17.5: 2.5 PVA copolymer.
[0016] なお、共重合する際におけるポリビュルアルコール、メチルメタタリレートおよびァク リル酸のそれぞれの重量比は、共重合体中のポリビニルアルコール、メチルメタクリレ ートおよびアクリル酸の重合比と同じであり、それぞれ60〜90:7〜38:0.5〜12で ある。この重合比は、 NMRで測定可能である。  [0016] It should be noted that the weight ratios of polybutyl alcohol, methyl methacrylate and acrylic acid in copolymerization are the polymerization ratio of polyvinyl alcohol, methyl methacrylate and acrylic acid in the copolymer. The same, 60-90: 7-38: 0.5-12 respectively. This polymerization ratio can be measured by NMR.
[0017] 上述した PVAコポリマーは、国際公開パンフレット WO02Z18494号公報、 W02 005Z019286号公報に基づき、製造することが可能である。  [0017] The PVA copolymer described above can be produced based on International Publication Pamphlets WO02Z18494 and W02 005Z019286.
[0018] 上記 PVAコポリマーにおいて、 20°Cにおける 2重量％溶液の粘度（B型粘度計で 測定、以下粘度は B型粘度計の測定値）が 10〜300mPa's、好ましくは当該溶液の 粘度が 20〜250mPa's、より好ましくは当該溶液の粘度が 50〜200mPa'sである。  [0018] In the above PVA copolymer, the viscosity of a 2% by weight solution at 20 ° C (measured with a B-type viscometer, hereinafter the viscosity is a measured value of a B-type viscometer) is 10 to 300 mPa's, preferably the viscosity of the solution is 20 -250 mPa's, more preferably the viscosity of the solution is 50-200 mPa's.
[0019] 従って、 PVAコポリマーとしては、平均重合度 100〜2000の部分けん化ポリビ- ルアルコール、メチルメタタリレートおよびアクリル酸を共重合する際における重量比 カ 0〜90:7〜38:0.5〜12であり、当該コポリマーの 20°Cにおける 2重量0 /0溶液 の粘度が 10〜300mPa'sである PVAコポリマー、好ましくは平均重合度 150〜100 0の部分けん化ポリビュルアルコール、メチルメタタリレートおよびアクリル酸を共重合 する際にぉける重量比が60〜90:7〜38:0.5〜12であり、当該コポリマーの 20°C における 2重量％溶液の粘度が 20〜250mPa'sである PVAコポリマー、より好ましく は平均重合度 200〜800の部分けん化ポリビュルアルコール、メチルメタタリレートお ょびァクリル酸を共重合する際にぉける重量比が60〜90 : 7〜38 : 0. 5〜12であり、 当該コポリマーの 20°Cにおける 2重量％溶液の粘度が 50〜200mPa' sである PVA コポリマーである。 Accordingly, as the PVA copolymer, the weight ratio when copolymerizing partially saponified polyvinyl alcohol having an average degree of polymerization of 100 to 2000, methyl methacrylate and acrylic acid is 0 to 90: 7 to 38: 0.5 to is 12, PVA copolymers viscosity of 2 weight 0/0 solution at 20 ° C of the copolymer is 10-300's, preferably partially saponified poly Bulle alcohol having an average degree of polymerization of from 150 to 100 0, methyl methacrylate Tali rates and acrylic More preferably, the PVA copolymer has a weight ratio of 60 to 90: 7 to 38: 0.5 to 12 when the acid is copolymerized, and the viscosity of a 2% by weight solution of the copolymer at 20 ° C. is 20 to 250 mPa's. Is a partially saponified polybutyl alcohol with an average degree of polymerization of 200-800, methyl methacrylate The weight ratio obtained when copolymerizing benzoic acid is 60 to 90: 7 to 38: 0.5 to 12, and the viscosity of a 2% by weight solution of the copolymer at 20 ° C. is 50 to 200 mPa's. Is a PVA copolymer.
[0020] 本発明製剤中の PVAコポリマーの配合量としては、製剤の全量に対し、 10〜80重 量％、好ましくは 15〜70重量％、より好ましくは 18〜65重量％である。この量よりも 多ければ、相対的に薬物の配合量が少なくなる可能性があり、少なければマイクロ力 プセルを形成しな!、恐れがある。  [0020] The amount of the PVA copolymer in the preparation of the present invention is 10 to 80% by weight, preferably 15 to 70% by weight, more preferably 18 to 65% by weight, based on the total amount of the preparation. If the amount is larger than this amount, the amount of the drug may be relatively small. If the amount is smaller, a micro force capsule may not be formed!
[0021] 界面活性剤としては、生理学的に使用することができるものであれば、用いることが できる。特に、ノ-オン (非イオン)界面活性剤が好ましい。たとえば、トウイン系または スパン系の界面活性剤が好ましい。より具体的には多価アルコールエステル、多価ァ ルコールエステル酸化エチレン付加物、ポリエチレングリコールモノエステル、ポリエ チレングリコールジエステル、高価アルコール酸化エチレン付加物およびアルキルフ ェノール酸化エチレン付加物等を用いることができる。好ましくは多価アルコールエス テルまたは多価アルコールエステル酸化エチレン付加物である。  [0021] As the surfactant, any surfactant that can be used physiologically can be used. In particular, a non-one (nonionic) surfactant is preferred. For example, a tow type or span type surfactant is preferred. More specifically, polyhydric alcohol esters, polyhydric alcohol ester ethylene oxide adducts, polyethylene glycol monoesters, polyethylene glycol diesters, expensive alcohol ethylene oxide adducts, alkylphenolic ethylene oxide adducts, and the like can be used. A polyhydric alcohol ester or a polyhydric alcohol ester ethylene oxide adduct is preferable.
[0022] 多価アルコールエステルとして、具体的にはソルビタンラウリン酸モノエステル、ソル ビタンパルミチン酸モノエステル、ソルビタンステアリン酸モノエステル、ソルビタンォ レイン酸モノエステル、ソルビタンォレイン酸トリエステル等があり、好ましくはソルビタ ンラウリン酸モノエステルである。これらの HLB (Hydrophile- Lipophile Balance)は、 およそ 1〜9である。 [0022] Specific examples of the polyhydric alcohol ester include sorbitan lauric acid monoester, sorbitan palmitic acid monoester, sorbitan stearic acid monoester, sorbitanoleic acid monoester, sorbitanoleic acid triester, etc. Sorbitan lauric acid monoester. These HLBs (Hydrophile-Lipophile Balance) are approximately 1-9.
多価アルコールエステル酸化エチレン付加物として、具体的にはソルビタンラウリン 酸モノエステル酸化エチレン 4モル付加物、ソルビタンラウリン酸モノエステル酸化工 チレン 20モル付加物、ソルビタンパルミチン酸モノエステル酸化エチレン 20モル付 加物、ソルビタンパルミチン酸モノエステル酸化エチレン 20モル付カ卩物、ソルビタン ステアリン酸モノエステル酸化エチレン 4モル付カ卩物、ソルビタンステアリン酸モノエス テル酸化エチレン 20モル付カ卩物、ソルビタンォレイン酸モノエステル酸化エチレン 5 モル付カ卩物、ソルビタンォレイン酸モノエステル酸化エチレン 20モル付カ卩物、ソルビ タンォレイン酸トリエステル酸化エチレン 20モル付加物等があり、好ましくは、ソルビ タンォレイン酸モノエステル酸化エチレン 20モル付カ卩物である。これらの HLB (Hydr ophile- Lipophile Balance)およそ 9〜18で & 。 As polyhydric alcohol ester ethylene oxide adduct, specifically, sorbitan lauric acid monoester ethylene oxide 4 mol adduct, sorbitan lauric acid monoester oxide 20 mol adduct, sorbitan palmitic acid monoester ethylene oxide 20 mol adduct Sorbitan palmitate monoester, 20 mol of ethylene oxide, sorbitan stearic acid monoester, ethylene oxide, 4 mol, sorbitan stearate monoester, 20 mol of ethylene oxide, sorbitanoleic acid monoester There are 5 mol of ethylene oxide, 20 mol of sorbitanoleic acid monoester ethylene oxide, 20 mol of sorbitanoleic acid triester, 20 mol adduct of ethylene oxide, preferably sorbitanoleic acid monoester ethylene oxide 2 0 mol. These HLB (Hydr ophile- Lipophile Balance) around 9-18 &.
本発明において用いる界面活性剤としては、特に、 HLBが 5〜20である界面活性 剤が好ましい。  As the surfactant used in the present invention, a surfactant having an HLB of 5 to 20 is particularly preferable.
[0023] 本発明製剤中の界面活性剤の配合量としては、製剤の全量に対し、 0. 5〜： L0重 量0 /0、好ましくは 0. 5〜8重量0 /0、より好ましくは 1〜6重量％である。この量よりも多 ければ、相対的に薬物の配合量が少なくなる可能性があり、少なければマイクロカブ セルを形成しな 、恐れがある。 [0023] As the amount of the surfactant of the present invention formulation, based on the total amount of the formulation, 0.. 5 to: L0 by weight 0/0, preferably from 0.5 to 8 wt 0/0, more preferably 1 to 6% by weight. If the amount is larger than this amount, the amount of the drug may be relatively reduced. If the amount is smaller, the microcapsule may not be formed.
[0024] 本願発明のマイクロカプセル中に充填される医薬品としては、例えば滋養強壮保 健薬、解熱鎮痛消炎薬、向精神薬、抗不安薬、抗うつ薬、催眠鎮静薬、鎮痙薬、中 枢神経作用薬、脳代謝改善剤、脳循環改善剤、抗てんかん剤、交感神経興奮剤、 胃腸薬、制酸剤、抗潰瘍剤、鎮咳去痰剤、鎮吐剤、呼吸促進剤、気管支拡張剤、ァ レルギ一用薬、歯科口腔用薬、抗ヒスタミン剤、強心剤、不整脈用剤、利尿薬、血圧 降下剤、血管収縮薬、冠血管拡張薬、末梢血管拡張薬、高脂血症用剤、利胆剤、 抗生物質、化学療法剤、糖尿病用剤、骨粗しょう症用剤、抗リウマチ薬、骨格筋弛緩 薬、鎮痙剤、ホルモン剤、アルカロイド系麻薬、サルファ剤、痛風治療薬、血液凝固 阻止剤、抗悪性腫瘍剤など力 選ばれた 1種または 2種以上の成分が用いられる。  [0024] Examples of the medicine filled in the microcapsule of the present invention include nourishing tonicho, antipyretic analgesic, antipsychotic, anxiolytic, antidepressant, hypnotic sedative, antispasmodic, central Neuroactive agents, brain metabolism improving agents, cerebral circulation improving agents, antiepileptic agents, sympathomimetic agents, gastrointestinal agents, antacids, antiulcer agents, antitussive expectorants, antiemetics, respiratory stimulants, bronchodilators, Drugs for allergies, dental and oral drugs, antihistamines, cardiotonic drugs, arrhythmic drugs, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, antibacterial agents, Antibiotic, Chemotherapy, Diabetes, Osteoporosis, Antirheumatic, Skeletal muscle relaxant, Antispasmodic, Hormone, Alkaloid narcotic, Sulfur, Gout, Anticoagulant, Anti-neoplastic Use one or more selected ingredients It is.
[0025] 滋養強壮保健薬には、例えばビタミン A、ビタミン D、ビタミン E (酢酸 d— a -トコフエ ロール)などのビタミンが挙げられる。解熱鎮痛消炎薬としては、例えばアスピリン、ァ セトァミノフェン、ェテンザミド、イブプロフェン、ノス力ピン、セラぺプターゼ、塩化リゾ チーム、トルフエナム酸、メフエナム酸、ジクロフェナクナトリウム、フルフエナム酸、サリ チノレアミド、アミノビリン、ケトプロフェン、インドメタシン、ブコローム、ペンタゾシンなど が挙げられる。  [0025] Examples of nourishing tonic health agents include vitamins such as vitamin A, vitamin D, and vitamin E (acetic acid d-a-tocopherol). Antipyretic analgesics and anti-inflammatory agents include, for example, aspirin, acetominophen, ethenzamid, ibuprofen, nospower pin, serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicinoleamide, aminovirin, ketoprofen, indomethacin, Examples include bucolome and pentazocine.
[0026] 向精神薬としては、例えばクロルプロマジン、レセルピンなどが挙げられる。抗不安薬 としては、例えばアルプラゾラム、クロルジァゼポキシド、ジァゼパムなどが挙げられる 。抗うつ薬としては、例えばイミブラミンなどが挙げられる。催眠鎮静薬としては、例え ばエスタゾラム、ペルラピンなどが挙げられる。中枢神経作用薬としては、例えばシチ コリンなどが挙げられる。脳循環改善剤としては、例えばビンポセチンなどが挙げられ る。抗てんかん剤としては、例えばフエ-トイン、カルバマゼピンなどが挙げられる。胃 腸薬には、例えばジアスターゼ、含糖ペプシン、ロートエキス、セルラーゼ AP3、リパ ーゼ AP、ケィヒ油などの健胃消ィ匕剤、耐性乳酸菌、ビフィズス菌などの整腸剤などが 挙げられる。 [0026] Examples of psychotropic drugs include chlorpromazine, reserpine and the like. Examples of anti-anxiety drugs include alprazolam, chlordiazepoxide, diazepam and the like. Examples of antidepressants include imibramin. Examples of hypnotic sedatives include estazolam and perlapine. Examples of central nervous system drugs include citicoline. Examples of the cerebral circulation improving agent include vinpocetine. Examples of the antiepileptic agent include fetoin and carbamazepine. stomach Examples of enteric agents include diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, healthy gastric antiseptics such as keihi oil, and intestinals such as resistant lactic acid bacteria and bifidobacteria.
[0027] 制酸剤としては、例えば炭酸マグネシウム、炭酸水素ナトリウム、メタケイ酸アルミン酸 マグネシウム、合成ヒドロタルサイト、沈降炭酸カルシウム、酸化マグネシウムなどが挙 げられる。抗潰瘍剤としては、例えばランソプラゾール、オメブラゾール、ラベブラゾー ル、ファモチジン、シメチジン、塩酸ラ-チジンなどが挙げられる。鎮咳去痰剤として は、例えばテオフィリン、グアヤコールスルホン酸カリウム、グァイフェネシンなどが挙 げられる。鎮吐剤としては、例えばメトクロブラミドなどが挙げられる。気管支拡張剤と しては、例えばテオフィリンなどが挙げられる。アレルギー用薬としては、アンレキサノ タス、セラトロダストなどが挙げられる。歯科口腔用薬としては、例えばォキシテトラサ イクリン、トリァムシノロンァセトニドなどが挙げられる。  [0027] Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include lansoprazole, omebrazole, rabebrazol, famotidine, cimetidine, latidine hydrochloride and the like. Examples of antitussive expectorant include theophylline, potassium guaiacol sulfonate, and guaifenesin. Examples of the antiemetic include metocloblamide. Examples of bronchodilators include theophylline. Examples of allergic drugs include amlexanotus and seratrodast. Examples of the dental and oral medicine include oxytetracycline and triamcinolone acetonide.
[0028] 強心剤としては、例えばジゴキシンなどが挙げられる。不整脈用剤としては、例えば ピンドロールなどが挙げられる。利尿薬としては、例えばフロセミド、ヒドロクロロチアジ ドなどが挙げられる。血圧降下剤としては、例えばカンデサルタンシレキセチル、メチ ルドパ、ぺリンドプリルエルプミンなどが挙げられる。  [0028] Examples of the cardiotonic agent include digoxin. Examples of the arrhythmia agent include pindolol. Examples of the diuretic include furosemide and hydrochlorothiazide. Examples of antihypertensive agents include candesartan cilexetil, methyldopa, and perindopril elpmin.
[0029] 冠血管拡張剤としては、例えばモルシドミンなどが挙げられる。末梢血管拡張薬とし ては、例えばシンナリジンなどが挙げられる。利胆剤としては、例えばトレピプトンなど が挙げられる。抗生物質には、例えばセフアドロキシル、セフィキシム、セフジトレンピ ボキシル、セフテラムピボキシル、セフポドキシミプロキセチルなどのセフエム系、アン ピシリン、シクラシン、ナリジタス酸、エノキサシンなどの合成抗菌剤、カルモナムナトリ ゥムなどのモノバタタム系、ぺネム系及び力ルバぺネム系抗生物質などが挙げられる  [0029] Examples of the coronary vasodilator include molsidomine. Examples of peripheral vasodilators include cinnarizine. An example of a bile agent is trepeptone. Antibiotics include, for example, cephems such as cefadoxyl, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, naliditasic acid, enoxacin, and monobatamates such as carmonam natrium. , Penem and force ruba penem antibiotics
[0030] 化学療法剤としては、例えばスルファメチゾールなどが挙げられる。糖尿病用剤とし ては、例えばトルプタミド、ボグリボース、ダリベンクラミド、トログリダゾンなどが挙げら れる。骨粗しょう症用剤としては、例えばイブリフラボンなどが挙げられる。骨格筋弛 緩薬としては、メトカルバモールなどが挙げられる。鎮けい剤としては、ジメンヒドリナ ートなどが挙げられる。抗リウマチ薬としては、メソトレキセート、ブシラミンなどが挙げ られる。ホルモン剤としては、例えばリオチロニンナトリウム、リン酸デキメタゾンナトリウ ム、プレドニゾロン、ォキセンドロン、酢酸リュープロレリンなどが挙げられる。アルカロ イド系麻薬として、ァヘン、トコンなどが挙げられる。サルファ剤としては、例えばスル フイソミジン、スルファメチゾールなどが挙げられる。痛風治療薬としては、例えばァロ プリノール、コルヒチンなどが挙げられる。血液凝固阻止剤としては、例えばジクマロ ールが挙げられる。抗悪性腫瘍剤としては、例えば 5—フルォロウラシル、ゥラシル、 マイトマイシンなどが挙げられる。 [0030] Examples of the chemotherapeutic agent include sulfamethizole. Examples of the antidiabetic agent include tolptamide, voglibose, darribenclamide, troglidazone, and the like. Examples of the osteoporosis agent include ibriflavone. Examples of skeletal muscle relaxants include metcarbamol. Examples of antispasmodic agents include dimenhydrinate. Antirheumatic drugs include methotrexate and bucillamine. It is done. Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like. Alkaloid narcotics include opium and tocon. Examples of sulfa drugs include sulfisomidine and sulfamethizole. Examples of gout therapeutic agents include alopurinol and colchicine. Examples of the blood coagulation inhibitor include dicumarol. Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin and the like.
[0031] これらの医薬は単独または他の医薬との合剤として使用することができる。また、これ らの医薬は、患者の疾患、年齢等に応じて適宜、定められた公知の適量が充填され る。 [0031] These medicaments can be used alone or in combination with other medicaments. In addition, these medicines are filled with a known appropriate amount appropriately determined according to the disease, age, etc. of the patient.
[0032] 本発明製剤中の薬物の配合量としては、製剤の全量に対し、 5〜60重量％、好ま しくは 10〜55重量0 /0、より好ましくは 18〜50重量である。この量よりも多ければ、マ イク口カプセルが形成できなく可能性があり、少なければ大量服用しないと、十分に 薬効が発揮できな!、恐れがある。 [0032] As the amount of drug present invention formulation, based on the total amount of the preparation, 5 to 60 wt%, is preferred properly 10 to 55 weight 0/0, more preferably 18 to 50 wt. If it is more than this amount, it may be impossible to form a mic mouth capsule, and if it is less, if it is not taken in a large amount, the drug will not be fully effective!
[0033] 本発明製剤中の薬物としては、難水溶性薬物でもよい。特に、水溶解度（20°C)が 100 g/mL以下の薬物でも本願製剤中に包含することができる。  [0033] The drug in the preparation of the present invention may be a poorly water-soluble drug. In particular, a drug having a water solubility (20 ° C) of 100 g / mL or less can be included in the preparation of the present application.
[0034] 本発明製剤中に酸素で分解されやす！ヽ薬物を含有した場合、酸素に対する安定 性を増大させることができる。例えば、ビタミン A、ビタミン B2、ビタミン B12、ビタミン C 、ビタミン D、ビタミン E等が挙げられる。  [0034] Easily decomposed with oxygen in the preparation of the present invention!ヽ When a drug is contained, stability against oxygen can be increased. Examples include vitamin A, vitamin B2, vitamin B12, vitamin C, vitamin D, vitamin E, and the like.
[0035] 上記薬物の代わりに本発明製剤中に健康食品を含有させてもよい。例えば、コェン ザィム Q10、 EPA、 DHA、 βカロチン、フラボノイド、カロチノイド等がある。  [0035] Health foods may be included in the preparation of the present invention instead of the drug. Examples include Coenzyme Q10, EPA, DHA, β-carotene, flavonoids and carotenoids.
[0036] 本発明製剤は、上述した PVAコポリマー、界面活性剤および薬物を含む製剤であれ ばよいが、要すれば賦形剤を添加することもできる。賦形剤としては、生理学的に使 用することができるものを用いることができる。具体的には水溶性賦形剤、水不溶性 賦形剤をいずれも使用することができる。より具体的にはぶどう糖、果糖、乳糖、蔗糖 、 D—マン-トーノレ、エリスリトーノレ、マノレチトーノレ、トレノヽロース、ソノレビトーノレ、トウモ ロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン、結晶セルロース（mi crocrvstalline cellulose)、無水ケィ酸、無水リン酸カルシウム、無水リン酸水素カルシ ゥム、沈降炭酸カルシウム、ケィ酸カルシウム、含水二酸ィ匕ケィ素等がある。好ましく は、白糖、結晶セルロース，無水リン酸水素カルシウムである。 [0036] The preparation of the present invention may be a preparation containing the above-mentioned PVA copolymer, surfactant and drug, but an excipient can be added if necessary. As the excipient, those that can be used physiologically can be used. Specifically, both water-soluble excipients and water-insoluble excipients can be used. More specifically, glucose, fructose, lactose, sucrose, D-mann-tonore, erythritole, manoletitre, trenosose, sonorebitonore, corn starch, potato starch, wheat starch, rice starch, crystalline cellulose (mi crocrvstalline cellulose), Caustic anhydride, anhydrous calcium phosphate, anhydrous calcium phosphate Lum, precipitated calcium carbonate, calcium silicate, hydrous diacid, etc. Sucrose, crystalline cellulose, and anhydrous calcium hydrogen phosphate are preferred.
[0037] 本発明製剤中の賦形剤の配合量としては、製剤の全量に対し、 0〜84. 5重量％、 好ましくは 0〜70重量％、より好ましくは 0〜40重量％である。この量よりも多ければ 、相対的に PVAコポリマーまたは薬物の量が減少し、マイクロカプセルが形成しない 、あるいは目的とする安定性を確保できない恐れがある。  [0037] The amount of the excipient in the preparation of the present invention is 0 to 84.5% by weight, preferably 0 to 70% by weight, more preferably 0 to 40% by weight, based on the total amount of the preparation. If the amount is larger than this amount, the amount of the PVA copolymer or drug may be relatively decreased, and microcapsules may not be formed, or the intended stability may not be ensured.
[0038] 本発明製剤において、ゲル化剤や必要に応じてゲル化補助剤を添加することもで きる。特に、後述する液中硬化被膜法の場合、ゲル化剤ゃゲルイ匕補助剤の添カ卩によ つて、製剤を固化することができる。ゲル化剤としては、カッパ一力ラギーナン、ィオタ 一力ラギーナン,ラムダ一力ラギーナン、タマリンド種子多糖、ローカストビーンガム、 ジエランガムがあり、好ましくは、カッパ一力ラギーナンである。ゲル化補助剤としては 、カッパ一力ラギーナンについてはカリウムイオン、アンモ-ゥムイオン及びカルシゥ ムイオンの 1種または 2種以上を含む水溶性ィ匕合物、ィオタ一力ラギーナンについて はカルシウムイオンを含む水溶性ィ匕合物があり、好ましくは、塩ィ匕カリウムである。  [0038] In the preparation of the present invention, a gelling agent and, if necessary, a gelling aid may be added. In particular, in the case of the in-liquid cured coating method described later, the preparation can be solidified by adding a gelling agent or a gelling aid. Examples of the gelling agent include kappa strenuous laginin, iota strenuous laginan, lambda struggle laginan, tamarind seed polysaccharide, locust bean gum, and dielan gum, preferably kappa strenuous laginan. As a gelling aid, a water-soluble compound containing one or more of potassium ion, ammonium ion and calcium ion is used for kappa force laginan, and water-soluble compound containing calcium ion is used for iota force laginan. There is a compound, preferably potassium salt.
[0039] 本発明製剤において、 PVAコポリマー、界面活性剤および薬物のそれぞれの成分 について配合量は、製剤の全量に対し、 PVAコポリマーが 10〜80重量％、界面活 性剤が 0. 5〜10重量％ぉょび薬物が5〜60重量％でぁる。好ましくは、製剤の全量 に対し、 PVAコポリマーが 15〜70重量％、界面活性剤が 0. 5〜8重量％ぉよび薬 物が 10〜55重量％である。より好ましくは、製剤の全量に対し、 PVAコポリマーが 1 8〜65重量％、界面活性剤が 1〜6重量％および薬物が 18〜50重量％である。  [0039] In the preparation of the present invention, the blending amount of each component of the PVA copolymer, the surfactant and the drug is 10 to 80% by weight of the PVA copolymer and 0.5 to 10% of the surfactant with respect to the total amount of the preparation. 5% to 60% by weight of drug. Preferably, the PVA copolymer is 15 to 70% by weight, the surfactant is 0.5 to 8% by weight and the drug is 10 to 55% by weight, based on the total amount of the preparation. More preferably, the PVA copolymer is 18 to 65% by weight, the surfactant is 1 to 6% by weight and the drug is 18 to 50% by weight, based on the total amount of the formulation.
[0040] 本発明製剤にぉ 、て、 PVAコポリマー、界面活性剤、薬物および賦形剤のそれぞ れの成分について配合量は、製剤の全量に対し、 PVAコポリマーが 10〜80重量％ 、界面活性剤が 0. 5〜10重量％、薬物が 5〜60重量％および賦形剤が 0〜84. 5 重量％である。好ましくは、製剤の全量に対し、 PVAコポリマーが 15〜70重量％、 界面活性剤が 0. 5〜8重量％、薬物が 10〜55重量％および賦形剤が 0〜70重量 %である。より好ましくは、製剤の全量に対し、 PVAコポリマーが 18〜65重量％、界 面活性剤が 1〜6重量％、薬物が 18〜50重量％および賦形剤が 0〜40重量％であ る。 [0041] 本発明製剤の製造方法としては、マイクロカプセルを製造する一般的な方法が用 いられる。具体的には、噴霧乾燥法、流動層造粒法、液中硬化被膜法、重合被覆法 、相分離法、オリフィス法があるが、好ましくは噴霧乾燥法、液中硬化被膜法である。 噴霧乾燥法とは、高温気流中に溶液や分散液を噴霧し、瞬時に乾燥させて微粒子 を得る方法であり、液中硬化被膜法とは、水中油滴型 (oZw型)ェマルジヨンを油 中に滴下し冷却固化した後、固化した液滴を捕集し洗浄後、乾燥させマイクロカプセ ルを得る方法である。 [0040] In the preparation of the present invention, the blending amount of each component of the PVA copolymer, surfactant, drug and excipient is 10 to 80% by weight of the PVA copolymer with respect to the total amount of the formulation. The active agent is 0.5 to 10% by weight, the drug is 5 to 60% by weight and the excipient is 0 to 84.5% by weight. Preferably, the PVA copolymer is 15 to 70% by weight, the surfactant is 0.5 to 8% by weight, the drug is 10 to 55% by weight and the excipient is 0 to 70% by weight, based on the total amount of the formulation. More preferably, PVA copolymer is 18-65% by weight, surfactant is 1-6% by weight, drug is 18-50% by weight and excipient is 0-40% by weight of the total formulation. . [0041] As a method for producing the preparation of the present invention, a general method for producing microcapsules is used. Specific examples include a spray drying method, a fluidized bed granulation method, a submerged coating method, a polymerization coating method, a phase separation method, and an orifice method, preferably a spray drying method and a submerged curing coating method. The spray drying method is a method in which a solution or dispersion is sprayed in a high-temperature air stream and dried immediately to obtain fine particles. The submerged cured coating method is an oil-in-water type (oZw type) emulsion in oil. This is a method in which a microcapsule is obtained by dripping onto a glass and cooling to solidify, then collecting the solidified liquid droplets, washing, and drying.
[0042] 本発明製剤の製造方法として疎水性薬物の場合、 PVAコポリマー、薬物および界 面活性剤を、要すれば賦形剤を有機溶媒等に溶解または懸濁した液を噴霧乾燥法 であるならば、噴霧乾燥機内で噴霧する。または、液中硬化被膜法であれば、 PVA コポリマー、薬物、界面活性剤、要すればゲル化剤およびゲル化補助剤、賦形剤を 有機溶媒等に溶解または懸濁した液を疎水性溶媒 (油性成分)ある 、はアルコール 、ゲル化補助剤溶解液に滴下、攪拌し、固化させた後、捕集、表面洗浄後乾燥を行 い、マイクロカプセルを得る。  [0042] In the case of a hydrophobic drug as a method for producing the preparation of the present invention, a PVA copolymer, a drug and a surfactant, and if necessary, a solution obtained by dissolving or suspending an excipient in an organic solvent or the like is a spray drying method. If so, spray in a spray dryer. Alternatively, in the case of a submerged cured coating method, a solution obtained by dissolving or suspending a PVA copolymer, a drug, a surfactant, and if necessary, a gelling agent, a gelling aid, and an excipient in an organic solvent or the like is used as a hydrophobic solvent. (Oil component) Some are dropped in alcohol or gelling aid solution, stirred and solidified, then collected, washed after surface washing and dried to obtain microcapsules.
[0043] 噴霧乾燥機としては、スプレードライヤー型のものがあり、液中硬化被膜法の乾燥 機としては、流動層型やドラム型のものがある。  [0043] As the spray dryer, there is a spray dryer type, and as the submerged coating method dryer, there are a fluidized bed type and a drum type.
[0044] 疎水性薬物の場合、特に液状の疎水性薬物の場合、上記の別法として、ェマルジ ヨンを製造した後、このェマルジヨンを噴霧乾燥する力、液中硬化させる。このエマル ジョンとしては、 1) PVAコポリマーを溶解した水性成分の中に、薬物、界面活性剤等 を含有した油性成分を分散させた水中油滴型ェマルジヨン、 2)薬物、界面活性剤等 を含有した油性成分の中に PVAコポリマーを溶解した水性成分を分散させた油中 水滴型 (WZO型)ェマルジヨンを製造後、当該ェマルジヨンに水を添加して転相さ せ、製造した水中油滴型 (OZW型)ェマルジヨンを製造することができる。その後、 それぞれのェマルジヨンを噴霧乾燥法、液中硬化被膜法にてマイクロカプセルを製 造する。ここで、転相とは、ェマルジヨンの型が一方力 他方の型へと変化することで ある。この場合、液滴が集まって連続相となり、その中に閉じ込められた別の液が液 滴になるものと考えられる。  [0044] In the case of a hydrophobic drug, in particular, in the case of a liquid hydrophobic drug, as another method described above, an emulsion is manufactured, and then the emulsion is cured in liquid with the force of spray drying. This emulsion includes 1) an oil-in-water emulsion in which an oily component containing a drug, a surfactant, etc. is dispersed in an aqueous component in which a PVA copolymer is dissolved, and 2) a drug, a surfactant, etc. After producing a water-in-oil type (WZO type) emulsion in which an aqueous component in which a PVA copolymer is dissolved is dispersed in the oily component, water is added to the emulsion to invert the phase, and the resulting oil-in-water type ( OZW type) emulsion can be manufactured. Then, microcapsules are manufactured by spray drying method and submerged curing coating method for each emulsion. Here, phase inversion means that the type of emulsion changes from one force to the other. In this case, it is considered that the droplets gather to form a continuous phase, and another liquid confined in the droplets becomes a droplet.
上記 1)、 2)のェマルジヨンを用いてマイクロカプセルを製造した場合、上記 2)の方 法で調製したェマルジヨンを用いたほうが、カプセル内に多量の薬物が包含される。When microcapsules are manufactured using the emulsions 1) and 2) above, A larger amount of the drug is contained in the capsule when the emulsion prepared by the method is used.
2)の方法でェマルジヨンを製造後、マイクロカプセルを製造した場合、当該マイクロ カプセル中には、約 80〜90%の薬物を包含することができる。よって、上記 2)の油 中水滴型 (WZO型)ェマルジヨンを製造後、水によって転相させて調製した水中油 滴型 (OZW型)ェマルジヨンを噴霧乾燥法、液中硬化被膜法にてマイクロカプセル を製造する方法が好ましい。 When a microcapsule is manufactured after the emulsion is manufactured by the method 2), about 80 to 90% of the drug can be included in the microcapsule. Therefore, after manufacturing the water-in-oil type (WZO type) emulsion of 2) above, the oil-in-water type (OZW type) emulsion prepared by phase inversion with water is microcapsuled by spray drying method or submerged cured coating method. The method of producing is preferred.
[0045] 上記 2)の転相法でェマルジヨンを製造する場合、転相時添加する水の量としては、 重量比で油性成分 1に対して水性成分 3、好ましくは水性成分 4、より好ましくは水性 成分 5の割合で、水性成分を添加する。  [0045] When producing emulsion by the phase inversion method of 2) above, the amount of water to be added at the time of phase inversion is, as a weight ratio, aqueous component 3, preferably aqueous component 4, more preferably aqueous component 1 to oily component 1. Aqueous component is added in the proportion of aqueous component 5.
[0046] さらに、上述した様に、マイクロカプセル中に賦形剤を添加することが可能であるが 、疎水性薬物をマイクロカプセル中の包含する場合、賦形剤として水不溶性賦形剤 を添加すれば、表面上にポアが少ないマイクロカプセルを製造することができる。水 不溶性賦形剤として好ましくは無水リン酸水素カルシウム、結晶セルロースがある。  [0046] Further, as described above, an excipient can be added to the microcapsule, but when a hydrophobic drug is included in the microcapsule, a water-insoluble excipient is added as an excipient. Then, a microcapsule with few pores on the surface can be produced. Preferred examples of the water-insoluble excipient include anhydrous calcium hydrogen phosphate and crystalline cellulose.
[0047] 本発明製剤のマイクロカプセルの平均粒子径は、約 10〜200 μ mであり、製造法 等によって自由に変更することができる。また、本発明製剤のマイクロカプセルは、硬 カプセルに充填でき、また顆粒剤や錠剤にも含有することができる。  [0047] The average particle size of the microcapsules of the preparation of the present invention is about 10 to 200 µm, and can be freely changed depending on the production method or the like. Further, the microcapsules of the preparation of the present invention can be filled into hard capsules, and can also be contained in granules and tablets.
[0048] 前述したように PVAコポリマーの酸素透過性が低ぐ酸素に不安定な薬物を本発 明製剤に包含させた場合、当該薬物を安定ィ匕することができる。  [0048] As described above, when an oxygen-labile drug having a low oxygen permeability of the PVA copolymer is included in the present invention, the drug can be stabilized.
実施例  Example
[0049] 以下に実施例および試験例を記載し、本願発明を具体的に説明するが、本願発明 はこれらに限定されるものではない。なお、以下の実施例において、調製されたポリ ビュルアルコール共重合体の溶液の粘度は、 10〜300mPa · sであった。  Examples and test examples will be described below to specifically describe the present invention, but the present invention is not limited to these. In the following examples, the viscosity of the prepared polybutyl alcohol copolymer solution was 10 to 300 mPa · s.
(実施例 1)  (Example 1)
ビタミン Aパルミテート（ロッシュ 'ビタミン 'ジャパン株式会社製） 10gに界面活性剤 モノラウリン酸ソルビタン (和光純薬工業株式会社製） lgを溶解し、 60°Cに加温した P VAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA、メチルメタタリ レート、アクリル酸の重量比が 80: 17. 5 : 2. 5)水溶液 (水溶液濃度： 20wZv%) 10 Ogを攪拌しながらカ卩え、油中水滴型ェマルジヨン (WZO型ェマルジヨン)を製造する 。その後、このェマルジヨンに水 150gを攪拌しながら徐々に加え 40°Cまで冷却し、 水中油滴型ェマルジヨン（OZW型ェマルジヨン）を製造する。このェマルジヨンをス プレードライヤ一（大川原化工機製、 L— 8型)の塔頂より回転式アトマイザ一によつ て、下記の条件で乾燥することによってマイクロカプセルを得ることができた。得られ たマイクロカプセルの水分量は 1. 58%、マイクロカプセルの収率は約 80%であった Vitamin A palmitate (manufactured by Roche 'Vitamin' Japan) 10g of surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) PVA copolymer dissolved in lg and heated to 60 ° C (Daido Chemical Industries) Made by company, weight ratio of PVA with average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) Aqueous solution (aqueous solution concentration: 20wZv%) Manufacture type Emulsion (WZO type Emulsion) . Thereafter, 150 g of water is gradually added to the emulsion while stirring and cooled to 40 ° C to produce an oil-in-water emulsion (OZW emulsion). Microcapsules could be obtained by drying this emulsion from the top of a spray dryer (Okawara Chemical Industries, Model L-8) using a rotary atomizer under the following conditions. The water content of the obtained microcapsules was 1.58%, and the yield of microcapsules was about 80%.
(スプレードライヤー製造条件） (Spray dryer manufacturing conditions)
アトマイザ一回転数： 25000rpm  Atomizer speed: 25000rpm
スプレー液の流量 ：20 gZ分  Spray flow rate: 20 gZ min
乾燥温度： 110°C  Drying temperature: 110 ° C
[0050] (実施例 2) [0050] (Example 2)
ビタミン Aパルミテート（ロッシュ 'ビタミン 'ジャパン株式会社製） 10gに界面活性剤 モノラウリン酸ソルビタン (和光純薬工業株式会社製） lgを溶解し、 60°Cに加温した 平均重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 100g (水 溶液濃度： 20wZv%)を攪拌しながらカロえ、油中水滴型ェマルジヨン (WZO型エマ ルジョン）を製造する。その後、このェマルジヨンに水 150gを攪拌しながら徐々にカロ え冷却し、 D—マン-トール 16gを溶解し、水中油滴型ェマルジヨン（OZW型ェマル ジョン）を製造する。このェマルジヨンをスプレードライヤー（大川原化工機製、 L— 8 型）の塔頂より回転式アトマイザ一によつて、実施例 1のスプレードライ製造条件で乾 燥することによってマイクロカプセルを得ることができた。  Vitamin A palmitate (manufactured by Roche 'Vitamin' Japan) 10g of surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) lg dissolved and heated to 60 ° C PVA copolymer with an average degree of polymerization of 500 Made by Daido Kasei Kogyo Co., Ltd. The weight ratio of PVA with an average degree of polymerization of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) Calorie while stirring 100g of aqueous solution (water solution concentration: 20wZv%) It produces water-in-oil type emulsion (WZO type emulsion). Thereafter, 150 g of water is gradually stirred and cooled in this emulsion, and 16 g of D-mannitol is dissolved to produce an oil-in-water emulsion (OZW emulsion). Microcapsules could be obtained by drying this emulsion from the top of a spray dryer (manufactured by Okawahara Koki Co., Ltd., type L-8) using a rotary atomizer under the spray dry production conditions of Example 1.
得られたマイクロカプセルの水分量は、 1. 57%、マイクロカプセルの収率は 90% 以上であり、水溶性賦形剤である D—マンニトールを添加することで収率を向上する ことはできたが、スプレードライ機内で若干べたつきが認められた。なお、本法で調製 したマイクロカプセルの電子顕微鏡写真を図 1にしめす。  The water content of the obtained microcapsules is 1.57%, the yield of microcapsules is 90% or more, and the yield can be improved by adding D-mannitol, which is a water-soluble excipient. However, slight stickiness was observed in the spray dryer. Fig. 1 shows an electron micrograph of the microcapsules prepared by this method.
[0051] (実施例 3)  [0051] (Example 3)
ビタミン Aパルミテート（ロッシュ 'ビタミン 'ジャパン株式会社製） 10gに界面活性剤 モノラウリン酸ソルビタン (和光純薬工業株式会社製） lgを溶解し、 60°Cに加温した 重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA 、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 100g (水溶液 濃度： 20wZv%)を攪拌しながらカ卩え、油中水滴型ェマルジヨン (WZO型ェマルジ ヨン)を製造する。その後、このェマルジヨンに水 150gを攪拌しながら徐々に加え冷 却し、無水リン酸水素カルシウム 16gを溶解し、水中油滴型ェマルジヨン（OZW型ェ マルジヨン)を製造する。このェマルジヨンをスプレードライヤー（大川原化工機製、 L 8型）の塔頂より回転式アトマイザ一によって、実施例 1の条件で乾燥することによ つてマイクロカプセルを得ることができた。 Surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) lg was dissolved in 10 g of vitamin A palmitate (Roche 'Vitamin' Japan Co., Ltd.) and heated to 60 ° C PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) aqueous solution 100g (aqueous solution concentration: 20wZv% ) Is stirred and water-in-oil type emulsion (WZO type emulsion) is produced. Thereafter, 150 g of water is gradually added to the emulsion while stirring and cooled, and 16 g of anhydrous calcium hydrogen phosphate is dissolved to produce an oil-in-water emulsion (OZW emulsion). Microcapsules could be obtained by drying this emulsion from the top of a spray dryer (manufactured by Okawara Chemical Co., Ltd., type L8) using a rotary atomizer under the conditions of Example 1.
得られたマイクロカプセルの水分量は、 0. 70%、マイクロカプセルの収率は 85% 程度であり、水不溶性賦形剤を添加することによって、乾燥効率が向上し、非常に密 なマイクロカプセルを得ることができた。本法で製造したマイクロカプセルの電子顕微 鏡写真を図 2にしめす。  The water content of the obtained microcapsules is 0.70%, and the yield of microcapsules is about 85%. By adding a water-insoluble excipient, the drying efficiency is improved and very dense microcapsules are obtained. Could get. Fig. 2 shows an electron micrograph of the microcapsules produced by this method.
図 1、 2の写真から明らかなように、水溶性賦形剤を用いた実施例 2のマイクロカブ セルにくらべ、水不溶性賦形剤である無水リン酸水素カルシウムを用いた実施例 3の マイクロカプセルは、表面が緻密であった。実施例 3のマイクロカプセルの表面が緻 密であることから、実施例 2のマイクロカプセルにくらべ酸素透過能はさらに低減され ると考免られる。  As is clear from the photographs in FIGS. 1 and 2, the microcapsules of Example 3 using anhydrous calcium hydrogen phosphate, which is a water-insoluble excipient, compared to the microcapsules of Example 2 using a water-soluble excipient. The capsule had a dense surface. Since the surface of the microcapsule of Example 3 is dense, it is considered that the oxygen permeability is further reduced as compared with the microcapsule of Example 2.
[0052] (実施例 4) [0052] (Example 4)
重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA 、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 40g (水溶液濃 度： 20wZv%)に水 50g,界面活性剤モノォレイン酸ポリオキシエチレンソルビタン 1 g及び白糖 4. 8gを溶解する。その溶解液にビタミン Aパルミテート（ロッシュ 'ビタミン' ジャパン株式会社製) 4gを加え、ホモジナイザーで粗乳化した後、微粒化装置でェ マルジヨンを製造する。このェマルジヨンをスプレードライヤー（大川原化工機製、 L 8型）の塔頂より回転式アトマイザ一によつてマイクロカプセルを得ることができた。  PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) 40 g of aqueous solution (concentration of aqueous solution: 20 wZv %), Dissolve 50 g of water, 1 g of the surfactant polyoxyethylene sorbitan monooleate and 4.8 g of sucrose. Add 4 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) to the solution, coarsely emulsify with a homogenizer, and produce emulsion with a micronizer. Microcapsules could be obtained from the top of a spray dryer (Okawara Chemical Industries, L8 type) using a rotary atomizer.
[0053] (実施例 5) [0053] (Example 5)
平均重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 40g (水 溶液濃度： 20wZv%)に水 50g、界面活性剤モノォレイン酸ポリオキシエチレンソル ビタン lg及び白糖 4. 8gを溶解する。その溶解液にビタミン Aパルミテート（ロッシュ' ビタミン 'ジャパン株式会社製) 4gを加え、ホモジナイザーで粗乳化した後、微粒化装 置でェマルジヨンを製造する。このェマルジヨンにアルギン酸ナトリウム 1. 8gを溶解し 、この液を 1%塩ィ匕カルシウム水溶液に攪拌しながら注下し液滴を生成した。この液 滴を捕集し，乾燥することによってマイクロカプセルを得ることができた。 PVA copolymer having an average polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA having an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) Solution concentration: 20 wZv%) Dissolve 50 g of water, lg of surfactant polyoxyethylene sorbitan monooleate and 4.8 g of sucrose. Add 4 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) to the solution, coarsely emulsify with a homogenizer, and then produce emulsion with a micronizer. In this emulsion, 1.8 g of sodium alginate was dissolved, and this liquid was poured into a 1% aqueous solution of calcium chloride and stirred to form droplets. The microcapsules could be obtained by collecting these droplets and drying them.
[0054] (実施例 6) [Example 6]
重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PVA 、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 20g (水溶液濃 度 20wZv%)および水 200gに界面活性剤モノラウリン酸ソルビタン (和光純薬工業 株式会社製） lgおよび水溶性賦形剤 5gと共にビタミン Aパルミテート（ロッシュ'ビタミ ン 'ジャパン株式会社製） 10gを転相法により乳化させる。乳化液にカラギーナン（中 央フーズマテリアル株式会社製) 0. 25g、塩ィ匕カリウム (石津製薬株式会社製) 0. 1 8gを 80° Cで溶解する。このェマルジヨンをエタノール中に噴霧することにより液滴 を生成した。この液滴を捕集し、乾燥することによってマイクロカプセルを得ることがで きた。  PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid is 80: 17.5: 2.5) 20 g of aqueous solution (concentration of aqueous solution 20 wZv% ) And 200 g of water surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) 10 g of vitamin A palmitate (manufactured by Roche Vitamin Japan) 10 g together with lg and water-soluble excipient 5 g Let Dissolve 0.25 g of carrageenan (manufactured by Chuo Foods Materials Co., Ltd.) and 0.18 g of potassium salty salt (manufactured by Ishizu Pharmaceutical Co., Ltd.) at 80 ° C. in the emulsion. The emulsion was sprayed into ethanol to produce droplets. It was possible to obtain microcapsules by collecting these droplets and drying them.
[0055] (実施例 7) [Example 7]
60°Cに加温した平均重合度 500の PVAコポリマー（大同化成工業株式会社製、平 均重合度 500の PVA、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5) 水溶液 100g (水溶液濃度： 20wZv%)と水 100gに界面活性剤モノラウリン酸ソルビ タン (和光純薬工業株式会社製） lg、 D—マン-トール 16gを溶解する。そこに、軽 質無水ケィ酸（日本ァエロジル) 3. 5gにビタミン Aパルミテート（ロッシュ 'ビタミン'ジャ パン株式会社製)を吸着させ、上記の水溶液に分散させェマルジヨンを調製する。こ のェマルジヨンをスプレードライヤー（大川原化工機製、 L— 8型）の塔頂より回転式 アトマイザ一によつて、実施例 1のスプレードライ製造条件で乾燥することによってマ イク口カプセルを得ることができた。  PVA copolymer with an average polymerization degree of 500 heated to 60 ° C (Daido Kasei Kogyo Co., Ltd., PVA with an average polymerization degree of 500, methyl methacrylate and acrylic acid have a weight ratio of 80: 17.5: 2.5 ) Dissolve sorbitan monolaurate sorbitan (manufactured by Wako Pure Chemical Industries, Ltd.) lg, 16 g of D-mannitol in 100 g of aqueous solution (concentration of aqueous solution: 20 wZv%) and 100 g of water. Vitamin A palmitate (Roche 'Vitamin' Japan Co., Ltd.) is adsorbed to 3.5 g of light anhydrous caustic acid (Nippon Aerosil), and dispersed in the above aqueous solution to prepare an emulsion. The mouthpiece can be obtained by drying this emulsion from the top of a spray dryer (Okawara Chemical Industries, L-8 type) with a rotary atomizer, under the spray-dry production conditions of Example 1. It was.
[0056] (実施例 8) [Example 8]
重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PV A、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 250g (水溶 液濃度： 8wZv%)に界面活性剤モノラウリン酸ソルビタン (和光純薬工業株式会社 製） lgを溶解した後、ビタミン Aパルミテート（ロッシュ 'ビタミン 'ジャパン株式会社製） 10gを攪拌しながら加え、水中油滴型ェマルジヨン (OZW型ェマルジヨン)を製造す る。このェマルジヨンをスプレードライヤー（大川原化工機製、 L— 8型）の塔頂より回 転式アトマイザ一によつて、実施例 1の条件で乾燥することによってマイクロカプセル を得ることができた。マイクロカプセルの収率は、約 70%であった。 PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., PV with an average polymerization degree of 500 Weight ratio of A, methyl metatalylate and acrylic acid is 80: 17.5: 2.5) 250g aqueous solution (aqueous solution concentration: 8wZv%) and sorbitan monolaurate surfactant (manufactured by Wako Pure Chemical Industries, Ltd.) lg After dissolution, 10 g of vitamin A palmitate (Roche “Vitamin” Japan Co., Ltd.) is added with stirring to produce an oil-in-water emulsion (OZW emulsion). The emulsion was dried under the conditions of Example 1 by using a rotary atomizer from the top of a spray dryer (manufactured by Okawara Chemical Co., Ltd., Model L-8), thereby obtaining microcapsules. The yield of microcapsules was about 70%.
[0057] (実施例 9) [Example 9]
重合度 500の PVAコポリマー（大同化成工業株式会社製、平均重合度 500の PV A、メチルメタタリレート、アクリル酸の重量比が 80 : 17. 5 : 2. 5)水溶液 20g (水溶液 濃度 20wZv%)および水 200gに界面活性剤モノラウリン酸ソルビタン (和光純薬ェ 業株式会社製） lgおよび水溶性賦形剤 5gと共にビタミン Aパルミテート（ロッシュ'ビ タミン 'ジャパン株式会社製） 10gを転相法により乳化させる。乳化液にカラギーナン ( 中央フーズマテリアル株式会社製) 0. 25g、塩ィ匕カリウム (石津製薬株式会社製) 0. 18gを 80° Cで溶解し、この液をゴマ油 （保栄薬工株式会社製)等の油に攪拌しな 力 注下し液滴を生成した。この液滴を 4°C以下で冷却固化した後、捕集し、溶媒で 洗浄後、乾燥することによってマイクロカプセルを得ることができた。  PVA copolymer with a polymerization degree of 500 (manufactured by Daido Kasei Kogyo Co., Ltd., weight ratio of PV A, methyl methacrylate, and acrylic acid with an average polymerization degree of 500: 80: 17.5: 2.5) 20 g of aqueous solution (concentration of aqueous solution 20 wZv% ) And 200 g of water surfactant sorbitan monolaurate (manufactured by Wako Pure Chemical Industries, Ltd.) 10 g of vitamin A palmitate (manufactured by Roche Vitamin Japan) with 5 g of lg and water-soluble excipients by phase inversion method Emulsify. Carrageenan (manufactured by Chuo Foods Co., Ltd.) 0.25 g, potassium salty salt (manufactured by Ishizu Pharmaceutical Co., Ltd.) 0.18 g is dissolved at 80 ° C, and this liquid is sesame oil (manufactured by Hoei Pharmaceutical Co., Ltd.) Drops were generated by pouring force into oil such as oil. The droplets were cooled and solidified at 4 ° C or lower, collected, washed with a solvent, and dried to obtain microcapsules.
本法で調製したマイクロカプセルの電子顕微鏡写真を図 3にしめす。  Fig. 3 shows an electron micrograph of the microcapsules prepared by this method.
産業上の利用可能性  Industrial applicability
[0058] 酸素に対する安定性が悪い医薬品を本マイクロカプセルに内包した場合、当該医 薬品を安定ィ匕することができる。また、医薬品のみならず、健康食品、食品にも用い ることがでさる。 [0058] When a drug having poor stability to oxygen is encapsulated in the microcapsule, the drug can be stabilized. It can be used not only for pharmaceuticals but also for health foods and foods.

Claims

請求の範囲  The scope of the claims
[I] ポリビニルアルコール共重合体、界面活性剤および薬物を含有することを特徴とす るマイクロカプセル剤。  [I] A microcapsule comprising a polyvinyl alcohol copolymer, a surfactant and a drug.
[2] 賦形剤を含有する請求項 1記載のマイクロカプセル剤。  [2] The microcapsule according to claim 1, further comprising an excipient.
[3] 当該ポリビュルアルコール共重合体が平均重合度 100〜2000のポリビュルアルコ ールと少なくとも 1以上の重合性ビニル単量体とを重量比 6 :4〜9： 1の割合で共重合 させて得られる共重合体であり、溶液の粘度が 10〜300mPa' sである当該共重合 体の溶液を用いて製造したものである請求項 1または 2記載のマイクロカプセル剤。  [3] The polybulal alcohol copolymer is a copolymer of polybulal alcohol having an average degree of polymerization of 100 to 2000 and at least one polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1. 3. The microcapsule according to claim 1 or 2, which is a copolymer obtained by using a solution of the copolymer having a viscosity of 10 to 300 mPa's.
[4] 当該ポリビュルアルコール共重合体が平均重合度 150〜1000のポリビュルアルコ ールと少なくとも 1以上の重合性ビニル単量体とを重量比 6 :4〜9： 1の割合で共重合 させて得られる共重合体であり、溶液の粘度が 50〜200mPa' sである当該共重合 体の溶液を用いて製造したものである請求項 1または 2記載のマイクロカプセル剤。  [4] The polybulal alcohol copolymer is a copolymer of polybulal alcohol having an average degree of polymerization of 150 to 1000 and at least one polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1. 3. The microcapsule according to claim 1 or 2, which is a copolymer obtained by using a solution of the copolymer having a viscosity of 50 to 200 mPa's.
[5] 当該ポリビュルアルコールが部分けん化ポリビュルアルコールである請求項 3または 4記載のマイクロカプセル剤。  5. The microcapsule according to claim 3 or 4, wherein the polybulal alcohol is a partially saponified polybulal alcohol.
[6] 当該重合性ビュル単量体力 不飽和カルボン酸類、不飽和カルボン酸類のエステル 類及びそれらの塩力 選択される 1または 2以上である請求項 3〜5のいずれかに記 載のマイクロカプセル剤。  [6] The polymerizable bur monomer power Unsaturated carboxylic acid, ester of unsaturated carboxylic acid and salt power thereof are selected 1 or 2 or more The microcapsule according to any one of claims 3 to 5 Agent.
[7] 当該重合性ビュル単量体力 アクリル酸又はその塩及びメチルメタタリレートであり、 共重合する際におけるアクリル酸又はその塩とメチルメタタリレートの重量比が 3： 7〜 0. 5 : 9. 5である請求項 6記載のマイクロカプセル剤。  [7] The polymerizable butyl monomer power is acrylic acid or a salt thereof and methyl methacrylate, and the weight ratio of acrylic acid or a salt thereof to methyl methacrylate is 3: 7 to 0.5: The microcapsule according to claim 6, which is 9.5.
[8] 平均重合度 100〜2000の部分けん化ポリビュルアルコール、メチルメタタリレートお ょびァクリル酸を共重合する際にぉける重量比が60〜90 : 7〜38 : 0. 5〜12であり、 溶液の粘度が 10〜300mPa' sである当該共重合体の溶液を用いて製造したもので ある請求項 3〜7のいずれかに記載のマイクロカプセル剤。  [8] Weight ratio when copolymerizing partially saponified polybulal alcohol having an average degree of polymerization of 100 to 2000, methyl methacrylate and acrylic acid is 60 to 90: 7 to 38: 0.5 to 12 The microcapsule according to any one of claims 3 to 7, which is produced using a solution of the copolymer having a viscosity of 10 to 300 mPa's.
[9] 当該界面活性剤が非イオン系である請求項 1記載のマイクロカプセル剤。  9. The microcapsule according to claim 1, wherein the surfactant is nonionic.
[10] 当該界面活性剤がトウイン系またはスパン系である請求項 9記載のマイクロカプセル 剤。  10. The microcapsule according to claim 9, wherein the surfactant is a tow type or a span type.
[II] 当該界面活性剤の HLBが 5〜20である請求項 9または 10記載のマイクロカプセル 剤。 [II] The microcapsule according to claim 9 or 10, wherein the surfactant has an HLB of 5 to 20. Agent.
[12] 当該薬物の水溶解度が 100 μ gZmL以下である請求項 1記載のマイクロカプセル剤  12. The microcapsule according to claim 1, wherein the drug has a water solubility of 100 μgZmL or less.
[13] 当該薬物が酸素に分解されやすい薬物である請求項 1記載のマイクロカプセル剤。 13. The microcapsule according to claim 1, wherein the drug is a drug that is easily decomposed into oxygen.
[14] 当該賦形剤が水不溶性賦形剤である請求項 2記載のマイクロカプセル剤。 14. The microcapsule according to claim 2, wherein the excipient is a water-insoluble excipient.
[15] 10〜80重量％のポリビュルアルコール共重合体、 0. 5〜10重量％の界面活性剤、 [15] 10-80% by weight of polybulal alcohol copolymer, 0.5-10% by weight of surfactant,
5〜60重量％の薬物および 0〜84. 5重量％の賦形剤を含有する請求項 2〜 14の 15 to 60% by weight of drug and 0 to 84.5% by weight of excipients.
V、ずれかに記載のマイクロカプセル剤。 V, the microcapsule according to any one of the above.
[16] 15〜70重量％のポリビュルアルコール共重合体、 0. 5〜8重量％の界面活性剤、 1[16] 15-70% by weight polybulal alcohol copolymer, 0.5-8% by weight surfactant, 1
0〜55重量％の薬物および 0〜70重量％の賦形剤を含有する請求項 15記載のマイ クロカプセル剤。 16. The microcapsule according to claim 15, comprising 0 to 55% by weight of drug and 0 to 70% by weight of excipient.
[17] 請求項 1〜16のいずれかに記載のマイクロカプセル剤を含有する顆粒剤、錠剤また は硬カプセル剤。  [17] A granule, tablet or hard capsule containing the microcapsule according to any one of claims 1 to 16.
[18] 油中水滴型ェマルジヨンの水性成分がポリビュルアルコール共重合体を含有するも のであり、油性成分が界面活性剤および薬物を含有するものであることを特徴とする マイクロカプセル剤を製造する方法。  [18] A microcapsule is produced, characterized in that the aqueous component of the water-in-oil type emulsion contains a polybulal alcohol copolymer, and the oily component contains a surfactant and a drug. Method.
[19] 油中水滴型ェマルジヨンに水を添加して水中油滴型ェマルジヨンを調製する工程、 及び該水中油滴型ェマルジヨンを噴霧乾燥または液中で固化させた後乾燥するェ 程を含むことを特徴とする請求項 18記載のマイクロカプセル剤を製造する方法。  [19] including a step of adding water to an oil-in-water emulsion to prepare an oil-in-water emulsion, and a step of drying the oil-in-water emulsion by solidification in a spray or liquid. 19. A method for producing a microcapsule according to claim 18.
[20] 上記請求項 18または 19記載の方法により製造されたマイクロカプセル剤。 [20] A microcapsule produced by the method according to claim 18 or 19.
[21] マイクロカプセルを製造するためのポリビュルアルコール共重合体の使用。 [21] Use of polybulal alcohol copolymer to produce microcapsules.
PCT/JP2006/306615 2005-03-31 2006-03-30 Microcapsule using polyvinyl alcohol copolymer WO2006106799A1 (en)

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