WO2019009335A1 - Method for producing fine particles, and fine particles - Google Patents

Method for producing fine particles, and fine particles Download PDF

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Publication number
WO2019009335A1
WO2019009335A1 PCT/JP2018/025399 JP2018025399W WO2019009335A1 WO 2019009335 A1 WO2019009335 A1 WO 2019009335A1 JP 2018025399 W JP2018025399 W JP 2018025399W WO 2019009335 A1 WO2019009335 A1 WO 2019009335A1
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Prior art keywords
particle
particles
resin
fat
coated
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PCT/JP2018/025399
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French (fr)
Japanese (ja)
Inventor
村上　正裕
昭博 松本
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村上　正裕
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Priority to JP2019527749A priority Critical patent/JPWO2019009335A1/en
Publication of WO2019009335A1 publication Critical patent/WO2019009335A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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

Definitions

  • the present invention relates to a method for simply dry-coating fine particles having a total particle size of 100 ⁇ m or less in a small amount of 10 g or less in total based on the mechanofusion method, and the fine particles produced by the above method.
  • the coating protects the unstable drug against moisture, oxygen, light, etc. and enhances the commercial value by giving a gloss to the appearance, so by adjusting the release characteristics of the drug, the drug It is done for the purpose of giving delayed or sustained function to
  • pan coating method a coating pan apparatus or a vented coating apparatus is used, and in the air suspension system, a fluidized bed type, a spouted bed type or a rolling fluidized bed type apparatus is used.
  • the mechanofusion method is known as a method of modifying / penetrating a coating material on the surface of core particles by using physical energy generated by collision of particles when mixing particles (Non-patent document 1) And Non-Patent Document 2).
  • the conventional method since the conventional method is wet, it is necessary to distill off the solvent or dispersant of the coating agent, so that a venting device for evaporation is required, and the apparatus used for coating is generally an open system.
  • the apparatus used for coating is generally an open system.
  • the high physiologically active substance may leak out of the apparatus, and the risk to health hazards of workers and environmental pollution increases.
  • An object of the present invention is to provide a method of coating a surface of a core material having a particle diameter of 100 ⁇ m or less as a primary particle in a containment vessel, and fine particles produced by the above method.
  • the present inventors found that by mixing the substances having different melting points, the low melting substance can coat the surface of the high melting substance by the heat generated upon collision of the particles (FIG. 1). ). Furthermore, the present inventors have found that the core material can be coated as a primary particle even at a particle size of 100 ⁇ m or less by this method, and this coating can control the elution of the drug. The present invention has been completed based on these findings.
  • a resin or oil-coated particle comprising a step of mechanically mixing a first particle having a particle diameter of 100 ⁇ m or less containing an active ingredient and a second particle containing at least one of a resin or oil.
  • Production method ⁇ 2> The method according to ⁇ 1>, wherein the particles coated with resin or fat are particles having an injectable particle diameter.
  • the mechanically mixing step is performed in the absence of a solvent and a liquid dispersion medium.
  • ⁇ 12> Any one of ⁇ 1> to ⁇ 11>, wherein the second particle is a solid dispersion or solid solution of an oil having a melting point of 15 ° C. to 100 ° C. and a polymer having a weight average molecular weight of 1000 or more The method described in. ⁇ 13> The method according to any one of ⁇ 1> to ⁇ 12>, wherein the second particle is a solid dispersion or solid solution of shellac and an enteric polymer. ⁇ 14> The method according to ⁇ 13>, wherein the enteric polymer is methacrylic acid copolymer L.
  • ⁇ 15> The method according to any one of ⁇ 1> to ⁇ 14>, wherein the step of mechanically mixing the first particle and the second particle is performed in a containment vessel.
  • the method as described in any one of ⁇ 1> to ⁇ 15> which performs the process of mechanically mixing a ⁇ 16> 1st particle
  • the containment vessel is a vessel having a major axis length and a height in the range of 1:10 to 10: 1.
  • a particle having having (i) core particles having a particle size of 100 ⁇ m or less containing an active ingredient, and (ii) a coating layer coated on the surface of the core particles and containing at least one of a resin or a fat and oil.
  • the core particle is a particle in which the porous particle includes the active ingredient.
  • the porous particles are particles consisting of ethyl cellulose.
  • grain as described in any one of ⁇ 21> to ⁇ 24> whose melting
  • the covering layer comprises shellac.
  • the covering layer comprises a biodegradable polymer and has an injectable particle size.
  • ⁇ 28> The particles according to any one of ⁇ 21> to ⁇ 25>, wherein the coating layer contains polylactic acid or a lactic acid / glycolic acid copolymer, and the 90% particle diameter (D90) of the particles is 150 ⁇ m or less.
  • ⁇ 31> The particle according to ⁇ 30>, wherein the enteric polymer is methacrylic acid copolymer L.
  • ⁇ 32> The particle according to any one of ⁇ 21> to ⁇ 31>, which is a sustained release particle.
  • ⁇ 33> The particles according to any one of ⁇ 21> to ⁇ 31>, which are enteric particles.
  • microparticles of the present invention are useful as enteric microparticles or sustained release microparticles.
  • the present invention is useful in the manufacture of functional pre-formulations of highly active pharmaceuticals (including biopharmaceuticals) contained in conventional preparations and in the manufacture of nosocomial preparations.
  • FIG. 1 shows a schematic view of the method of the present invention.
  • FIG. 2 shows the results of the dissolution test of core particle 1 and coated articles 1 to 3.
  • FIG. 3 shows electron microscope images of the core particle 1 and the coated article 1.
  • FIG. 4 shows the results of the dissolution test of the core particle 2 and the coated article 4.
  • FIG. 5 shows the results of the dissolution test of enteric coated articles 1 and 2.
  • FIG. 6 shows the electron microscopy of the core particle 3 and the enteric coating 2.
  • FIG. 7 shows an electron microscope image in Example 6.
  • Figure 8 shows the volume based particle size distribution of the particles of Example 6.
  • FIG. 9 shows the results of the dissolution test in Example 6.
  • FIG. 10 shows the results of the dissolution test for coated articles 6-8.
  • FIG. 11 shows the results of the dissolution tests of Coatings 7 and 9-11.
  • FIG. 12 shows an optical micrograph image of PLGA microspheres 2.
  • FIG. 13 shows the elution of vitamin B 12 from PLGA microspheres 2.
  • the method for producing particles according to the present invention comprises the step of mechanically mixing a first particle having a particle diameter of 100 ⁇ m or less containing an active ingredient and a second particle containing at least one of a resin or oil.
  • the particles of the present invention have (i) core particles having a particle size of 100 ⁇ m or less containing an active ingredient, and (ii) a coating layer coated on the surface of the core particles and containing at least one resin or fat. It is a particle.
  • the active ingredient is not particularly limited, but the following ingredients can be used.
  • Reserpine dihydroergotoxin mesilate, prazosin mesylate, metoprolol, propranolol, atenolol, candesartan lexetil, telmisartan, azirsartan, olmesartan, bisoprolol fumarate, calvegirol, valsartan, enalapril, imidapril, amlodipine besilate, diltiazem hydrochloride, Doxacin, trichlormethiazide etc (coronary vasodilator) Nitroglycerin, isosorbide dinitrate, diltiazem, nifedipine, dipyridamole etc (cough suppressant) Noscapine, salbutamol, procaterol, turopterol, tranilast, dextromethorphan hydrobromide, dihydrocodeine
  • Vitamin A Vitamin A, Vitamin B, Vitamin C (ascorbic acid etc.), Vitamin D, Vitamin E, Vitamin K, Folic Acid (vitamin M) etc.
  • Tannic acid Tannic acid, tannic acid albumin, berberine, memesalazine, dimethicone, vonoprazan, famotidine, ranitidine, cimetidine, nizatidine, metoclopramide, famotidine, omeprazole, domperidone, sulperido, trepibutone, sucralfate, active fungi agents (eg, lactamine, bifidobacteria etc.) ), Antacids (eg, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium aluminometasilicate, etc.), calcium polycarbophil, etc.
  • Antacids eg, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium aluminometasilicate, etc.
  • the particle diameter of the first particles is 100 ⁇ m or less, and may be 90 ⁇ m or less, 80 ⁇ m or less, 70 ⁇ m or less, 60 ⁇ m or less, 50 ⁇ m or less, 40 ⁇ m or less, or 30 ⁇ m or less.
  • the lower limit of the particle size of the first particles is not particularly limited, but may be 5 ⁇ m or more or 10 ⁇ m or more.
  • the particle size referred to in the present specification is a volume-based average particle size, and the volume-based average particle size can be measured by a laser diffraction particle size measurement apparatus (for example, SALD 2200 (Shimadzu Corporation)).
  • the first particles particles in which porous particles are loaded with an active ingredient by a method such as impregnation can be used.
  • the porous particles may be either porous organic particles or porous inorganic particles.
  • porous organic particles particles composed of a polypeptide or a derivative thereof, a protein or a derivative thereof, a polysaccharide or a derivative thereof, a synthetic polymer, or a mixture thereof can be used.
  • gelatin or a protein such as gelatin, collagen, atelocollagen, albumin, fibrin, protamine or derivatives thereof, ethylcellulose, duran gum, gum arabic, hyaluronic acid, alginic acid, chondroitin sulfate, heparin, chitin, chitosan, etc.
  • synthetic polymers such as ethyl cellulose, polylactic acid, lactic acid / glycolic acid copolymers, or derivatives thereof.
  • porous inorganic particles made of silicic acid or silicate can be used.
  • silicic acid or silicate include: silicic acid dioxide, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminosilicate, magnesium aluminometasilicate , Magnesium aluminum silicate and the like can be used.
  • the second particles contain at least one of a resin or a fat and oil.
  • the resin or fat which constitutes the second particle constitutes the coating layer in the particle of the present invention.
  • the resin constituting the second particle or the covering layer is not particularly limited, but, for example, polyester resin, acrylic resin, urethane resin, vinyl acetate resin, ethylene-vinyl acetate resin, epoxy resin, silicone resin, polystyrene resin, cellulose Resin etc. are mentioned.
  • grain or a coating layer For example, carnauba wax, avocado oil, horse mackerel oil, macadamia nut oil, olive oil, castor oil etc. are mentioned.
  • enteric polymer may be sufficient.
  • enteric polymers include methacrylic acid copolymers (eg, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, etc.), hydroxyalkyl alkyl cellulose phthalate esters (eg, hypromellose phthalate ester), hydroxyalkyl alkyl cellulose Acetic acid ester succinate (eg, hypromellose acetic acid ester succinate), carboxyalkylalkyl cellulose (eg, carboxymethyl ethyl cellulose), ethyl cellulose, cellulose acetate phthalate and the like can be used.
  • methacrylic acid copolymers eg, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, etc.
  • hydroxyalkyl alkyl cellulose phthalate esters eg, hypromel
  • shellac can be used as resin which comprises a 2nd particle
  • Shellac is a resin derived from a lacy scale bug, and is obtained by separating and purifying a resinous substance secreted by the lac scale insect in hot water.
  • the melting point of the resin or fat is preferably 15 ° C. or more and 100 ° C. or less, more preferably 25 ° C. or more and 90 ° C. or less.
  • the melting point of the second particle is preferably lower than the melting point of the first particle. That is, it is preferable that the melting point of the resin or fat which constitutes a coating layer is lower than the melting point of core particles.
  • the second particles are preferably solid dispersions or solid solutions of a fat having a melting point of 15 ° C. to 100 ° C. and a polymer having a weight average molecular weight of 1000 or more. That is, the coating layer in the particles of the present invention preferably contains a fat and oil having a melting point of 15 ° C. or more and 100 ° C. or less and a polymer having a weight average molecular weight of 1000 or more.
  • An example of the second particle is a solid dispersion or solid solution of shellac and an enteric polymer.
  • the coating layer in the particles of the present invention contains shellac and an enteric polymer.
  • the second particle and the covering layer may contain a biodegradable polymer.
  • biodegradable polymers include polylactic acid, lactic acid / glycolic acid copolymer, polyglycolic acid, polycapronolactone and the like.
  • the method of mixing the first particle and the second particle is not particularly limited as long as it is a method of mechanically mixing, but a ball mill, a dissolver, a high speed mixer, a homomixer, a kneader, a roll mill, an attritor, a sand mill And so on.
  • Mechanical mixing can preferably be carried out using a ball mill.
  • the step of mechanically mixing the first and second particles can preferably be performed in a containment vessel.
  • the containment vessel is preferably a vessel having a major axis length and a height in the range of 1:10 to 10: 1.
  • the step of mechanically mixing the first particles and the second particles is preferably performed in the absence of a solvent and a liquid dispersion medium.
  • the second particle may be divided and introduced.
  • the particles coated with the resin or the fat and oil in the present invention are preferably particles having an injectable particle diameter, and 90% particle diameter (up to 90% cumulative amount particle diameter: D90) is 150 ⁇ m or less Is more preferably 120 ⁇ m or less, still more preferably 100 ⁇ m or less, and particularly preferably 80 ⁇ m or less.
  • the 95% particle size (up to 95% particle size: D90) of the particles is preferably 150 ⁇ m or less, more preferably 120 ⁇ m or less, even more preferably 100 ⁇ m or less, and 80 ⁇ m or less Particularly preferred.
  • the resin- or fat-coated particles produced by the method of the present invention are preferably sustained release particles or enteric particles.
  • Sustained release is a property capable of gradually releasing the active ingredient to be contained. It is preferred that the active ingredient is gradually eluted from the solid preparation and the time required to elute 90% or more of the active ingredient is at least one hour or more. The time required to elute 90% or more of the active ingredient can be appropriately selected, for example, from 8 hours, 12 hours, and 24 hours after administration, depending on the type and purpose of the active ingredient.
  • the sustained release can be measured according to the dissolution test method described in the 17th revised Japanese Pharmacopoeia. Enteric refers to the property of dissolving in acid such as gastric acid and rapidly dissolving in the small intestine.
  • the step of coating with a resin or fat can be performed twice or more. That is, after producing particles coated with resin or fat by the step of mechanically mixing the first particle having a particle diameter of 100 ⁇ m or less containing the active ingredient and the second particle containing at least one of resin or fat. And producing a particle coated with a multilayer of resin or fat by performing a step of mechanically mixing the particle coated with the resin or fat with the third particle containing at least one of the resin or fat. can do.
  • the particles produced by the above have two or more coating layers containing at least one of resin and fat.
  • the fine particles of the present invention can be used as particulate agents (granules, fine granules or powders) as they are or mixed with other components, or used as tablets or tablets as tablets. May be
  • Example 1 Preparation of ethyl cellulose-porous fine particles 2 g of ethyl cellulose (Nisshin Kasei Co., Ltd., STD 7 cps) was taken in a 50 mL beaker, 16 g of acetone was added, and stirred with a stirrer to dissolve it (Liquid A). In a 50 mL beaker, 7 g of glycerin and 1 g of a 5% polyvinyl alcohol (Kuraray, KURARAY POVAL 220C or less, PVA) aqueous solution were taken and mixed by a three-one motor (Liquid B).
  • Kuraray, KURARAY POVAL 220C or less, PVA polyvinyl alcohol
  • Solution D was added to solution C while stirring (600 rpm) with a three-one motor and emulsified for 1 minute. After emulsification, it was added to 500 mL of purified water while stirring (400 rpm) with a stirrer in a 500 mL beaker to precipitate porous fine particles.
  • the filtrate was filtered in the order of 75 ⁇ m eyelid sieve, 53 ⁇ m eyelid sieve, and the filtrate was obtained.
  • the obtained filtrate was suction filtered with a 20 ⁇ m eyelid sieve to obtain a filtered product.
  • the filtered product was re-dispersed with 200 mL of purified water, and suction filtered again with a 20 ⁇ m eyelid sieve to obtain a filtered product.
  • the filtered product was re-dispersed with 10 mL of purified water, again suction-filtered with a 20-well sieve, and the filtered product was obtained.
  • the filtrate was transferred to a 100 mL beaker, redispersed with a small amount of water and lyophilized.
  • Example 2 300 mg of core particles 1 and 150 mg of carnauba wax were weighed in a ball mill pot made of agate (inner diameter: 4 cm, height: 4 cm). Four 10 mm diameter agate balls were inserted. The mixture was mixed at a rotational speed of 500 rpm for 6 hours in a planetary ball mill (Floche, pulverisette 6) to obtain a coated product 2.
  • a planetary ball mill Floche, pulverisette 6
  • Example 3 300 mg of the core particle 1 and 30 mg of carnarowe were weighed out in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm). Four 10 mm diameter agate balls were inserted. The mixture was mixed at a rotational speed of 500 rpm for 6 hours in a planetary ball mill (Floche, pulverisette 6) to obtain a coated product 3.
  • a planetary ball mill Floche, pulverisette 6
  • Dissolution test 15 mg of core particles 1 or about 45 mg (equivalent to 15 mg as core particles 1) of coated articles 1 to 3 were weighed into a test tube and dissolved beforehand in a dissolution test solution (containing 0.05% Tween 80) warmed to 37 ° C. 5 mL each of purified water) was added. Tilt the test tube to 45 °, shake in a 37 ° C water bath and shake at 100 rpm, and sample 500 ⁇ L of the supernatant only so that the particles are not absorbed after 5, 10, 30, 45, 60, 90 and 120 minutes. The test tube was newly supplemented with 500 ⁇ L of the 37 ° C elution test solution. The results of the dissolution test are shown in FIG.
  • Example 4 300 mg of quinine hydrochloride dihydrate (Nacalai Tesque, Inc.) was placed in a ball mill pot made of agate (inner diameter: 4 cm, height: 4 cm) and ground with four agate balls of 10 mm in diameter at a rotational speed of 250 rpm for 30 minutes.
  • the powder at that time was designated as core particle 2 (melting point: 115 to 116 ° C.).
  • 150 mg of the core particle 2 and 150 mg of carnavar are placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and four agate balls of 10 mm in diameter with a planetary ball mill (Flucci, Pulverisette 6) rotation speed 250 rpm
  • the mixture was mixed for 6 hours to obtain a coated product 4.
  • the particle sizes of the core particle 2 and the coated product 4 were measured according to the above-mentioned particle size measuring method, and they were 11 ⁇ m and 18 ⁇ m, respectively.
  • the coated product 4 showed an extension of the dissolution as compared to the core particle 2 (FIG. 4).
  • Example 5 A solution of 10 mg of fluorescein-isothiocyanate-dextran (MW 3000-5000) (Sigma-Aldrich) in 4 mL of purified water is impregnated into 1 g of Florite (porous calcium silicate, Tomita Pharmaceutical) and frozen overnight After drying, core particles were prepared (core particles 3) (calcium silicate melting point: 1200 to 1500 ° C.). As a result of measuring the particle size of the core particle 3 according to the above-mentioned particle size measurement method, the average particle size was about 20 ⁇ m.
  • the obtained film was ground in an agate mortar, and a powder (shellac-Eudragit L100 powder) sieved with a wire mesh sieve with a 105 ⁇ m mesh was obtained.
  • 100 mg of the core particles 3 and 300 mg of shellac-Eudragit L100 powder are mixed and placed in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate having a diameter of 10 mm Pulverisette 6) was subjected to 12 cycles of 250 rpm for 30 min and 5 min for stop, and an enteric coated article 1 was obtained.
  • 100 mg of the coated enteric-coated product 1 and 50 mg of carnauba are put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, pulverisette 6)
  • the mixture was mixed for 6 hours at a rotational speed of 250 rpm to obtain an enteric coated article 2.
  • the enteric coatings 1 and 2 were subjected to a dissolution test for 30 minutes with 25 mL of Japanese Pharmacopoeia Dissolution Test 1 containing 0.05% Polysorbate 80 at 37 ° C. for 30 minutes, and then the dissolution test solution was 0.05% Polysorbate 80.
  • the dissolution test was continued by replacing it with 25 mL of the contained Japanese pharmacopoeia dissolution test second solution (pH 6.8) (FIG. 5).
  • the results of the above-mentioned electron microscopic observation of the core particle 3 and the enteric-coated product 2 are shown in FIG. In the core particle 3, while pores could be confirmed on the surface of the fine particles, no pores were observed in the enteric-coated product 2 (FIG. 6).
  • Example 6 Preparation of Coating Agent> Carnauba bulk powder of (Alfa Aesar TM) was ground in an agate mortar, the sieved product at 140 mesh (106 [mu] m mesh opening) wire mesh sieve was used as a coating agent.
  • ⁇ Particle evaluation> The surface state was evaluated by a scanning electron microscope (JSM-6510LA manufactured by JEOL). The particle size distribution was measured using a laser diffraction type particle sizer (SALD 2200 manufactured by Shimadzu).
  • ⁇ Dissolution test> The dissolution test was conducted according to Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). The eluted drug was measured using a fluorometer (Synergy H4 manufactured by BioTek Instruments Inc.). Test sample: Raw powder ground product, quinine coated product (equivalent to 5 mg of quinine hydrochloride dihydrate) Conditions: Dissolution test solution / 900 mL of 0.05% aqueous solution of Tween 80, agitation strength / 50 rpm, test temperature / 37 ⁇ 0.5 ° C
  • the particle size distribution determined by the laser diffraction method is shown in FIG. The average particle size was 10.34 ⁇ 0.35 ⁇ m for the raw powder and ground powder, and 10.16 ⁇ 0.44 ⁇ m for the coated product.
  • When core particles are coated as primary particles at a coating ratio of 50%, it is calculated from the volume ratio that the particle size is approximately 1.145 times, and the change in particle size due to the coating is expected to be small. In fact, in the actual measurement also, no significant difference was found between them until the cumulative relative frequency was about 70 to 80%. Therefore, it is assumed that many of the particles are coated as primary particles under these conditions.
  • Example 7 Using the powdered raw powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was poured into a 50 mL centrifuge tube made of glass and mixed 30 times, The mixture was sieved three times with a 100 mesh (149 ⁇ m mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with four agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at 100 rpm for 6 hours The coating 6 was obtained.
  • agate ball mill pot inner diameter 4 cm, height 4 cm
  • four agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at 100 rpm for 6 hours
  • the coating 6 was obtained.
  • Example 8 Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 ⁇ m mesh) wire mesh sieve. The obtained mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotational speed of 250 rpm for 6 hours The coating 7 was obtained. The same operation was performed 3 times to obtain 3 batches. The particle sizes of the three batches were 14.68 ⁇ 0.45 ⁇ m, 9.80 ⁇ 0.44 ⁇ m, and 11.02 ⁇ 0.46 ⁇ m, respectively.
  • Example 9 Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 ⁇ m mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at 500 rpm for 6 hours The coating 8 was obtained. The particle size was 13.00 ⁇ 0.40 ⁇ m.
  • coated articles 6 to 8 of Examples 7 to 9 were subjected to the dissolution test according to the method described in Example 6, and the dissolution behavior was as shown in FIG.
  • Example 10 Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 ⁇ m mesh) wire mesh sieve. The obtained mixture is put into a ball mill pot made of agate (inner diameter 4 cm, height 4 cm) and mixed with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) for 30 minutes at 250 rpm. The coating 9 was obtained.
  • Example 11 Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 ⁇ m mesh) wire mesh sieve. The obtained mixture is put into an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 alum balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotation speed of 250 rpm for 60 minutes The coating 10 was obtained.
  • agate ball mill pot inner diameter 4 cm, height 4 cm
  • 4 alum balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotation speed of 250 rpm for 60 minutes
  • the coating 10 was obtained.
  • Example 12 Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 ⁇ m mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotational speed of 250 rpm for 3 hours The coating 11 was obtained.
  • agate ball mill pot inner diameter 4 cm, height 4 cm
  • 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotational speed of 250 rpm for 3 hours
  • the coating 11 was obtained.
  • Example 8 The coated articles 7 of Example 8 and the coated articles 9 to 11 of Examples 10 to 12 were subjected to the elution test according to the method described in Example 6, and the elution behavior was as shown in FIG.
  • Example 13 ⁇ Preparation of PLGA Coating Agent> Lactic acid-glycolic acid (Sigma-Aldrich, Resomer TM RG502) a planetary ball mill (Furetche Co., Pulverisette6) [agate pot: inner diameter 40 mm, depth 40 mm, agate ball: diameter 10 mm (4 pieces) with, Grinding was performed at 250 rpm for 15 minutes to obtain PLGA coating agent 1. The particle diameter measured by the particle diameter measuring method described later was 21.86 ⁇ 0.45 ⁇ m.
  • PLGA Microsphere 1 25 mg of PLGA coating agent 2 is added, mixed with 31.25 mg of PLGA coating agent 2 and placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm), together with four agate balls made of a diameter of 10 mm A PLGA microsphere 2 was obtained by repeating a cycle of “rotation speed 250 rpm for 30 minutes ⁇ rest for 5 minutes” in Pulverisette 6) 12 times.
  • Example 14 ⁇ Preparation of PLGA Coating Agent> Using lactic acid / glycolic acid (PLGA 5020, Wako Pure Chemical Industries, Ltd.) with a planetary ball mill (Frece, Pulverisette 6) [pot made of agate: 40 mm in inner diameter, 40 mm in depth, ball made of agate: 10 mm in diameter (4 pieces)] 250 rpm 15 Grinding for a minute gave PLGA coating agent 2. The particle size measured by the particle size measuring method was 62.95 ⁇ 0.34 ⁇ m.
  • PLGA Microsphere Intermediate 25.75 mg of PLGA Coating Agent 1 and 31.25 mg of PLGA Coating Agent 2 are added to 68.75 mg of PLGA Microspheres, mixed, placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm), agate balls 10 mm in diameter PLGA microspheres 3 were obtained by repeating 12 cycles of 30 rpm ⁇ 5 minutes rest at a rotational speed of 250 rpm in a planetary ball mill (Frece, Pulverisette 6) together with 4 pieces.
  • agate ball mill pot inner diameter 4 cm, height 4 cm
  • agate balls 10 mm in diameter PLGA microspheres 3 were obtained by repeating 12 cycles of 30 rpm ⁇ 5 minutes rest at a rotational speed of 250 rpm in a planetary ball mill (Frece, Pulverisette 6) together with 4 pieces.
  • Example 15 25 mg of the crushed product of VB 12 obtained in Example 13, 50 mg of the coating agent 1 obtained in Example 13, and 62.5 mg of the coating agent 2 are added into a 50 mL centrifuge tube made of glass and mixed 30 times, then 100 mesh (149 [mu] m opening) The mixed sieve with a wire mesh sieve was performed once. The obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes ⁇ 5 minutes rest The cycle of was repeated 24 times to obtain PLGA microspheres 4.
  • Example 16 After adding 12.5 mg of the VB 12 ground product obtained in Example 13, 50 mg of the coating agent 1 obtained in Example 13, and 62.5 mg of the coating agent 2 and putting the mixture in a 50 mL glass centrifuge tube and mixing 30 times, 100 The mixture was sieved once with a mesh (149 ⁇ m mesh) wire mesh sieve.
  • the obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes ⁇ 5 minutes rest Of 1 cycle (to obtain PLGA microspheres 5), 2 times (to obtain PLGA microspheres 6), 6 times (to obtain PLGA microspheres 7) and 12 times (to obtain PLGA microspheres 8).
  • the PLGA microspheres obtained in Examples 14 and 15 were evaluated for particle size and initial burst by the particle size measurement method and the dissolution test method shown in Example 13, and the results are shown in Table 3.
  • the same amount of PLGA coating agent was charged at one time and processed, and was compared with two divided charges. As a result, although the initial burst does not have an effect, the addition of PLGA coating agent at one time promotes the aggregation of the particles, and the particle size is such that suspension injection can not be performed. Since the particle size was suppressed to 150% of the particle size or less to a cumulative amount of 95%, the particle size for suspension injection could be maintained.

Abstract

The present invention addresses the problem of providing: a method for dry-coating surfaces of nucleic substances having particle diameters of 100 μm or less, said nucleic substances being used as primary particles; and fine particles which are produced by this method. The present invention provides a method for producing particles that are covered with a resin or a fat/oil, which comprises a step for mechanically mixing first particles that contain an active component and have particle diameters of 100 μm or less and second particles that contain at least one of a resin and a fat/oil.

Description

微粒子の製造方法及び微粒子Method of producing fine particles and fine particles
　本発明は、メカノフュージョン法を基に、全量10ｇ以下の少量で、かつ、粒径100μｍ以下の微粒子を簡便に乾式コーティングするための方法、並びに上記方法により製造される微粒子に関する。 The present invention relates to a method for simply dry-coating fine particles having a total particle size of 100 μm or less in a small amount of 10 g or less in total based on the mechanofusion method, and the fine particles produced by the above method.
　医薬品製剤の分野において、コーティングは、水分、酸素、光などに対して不安定な薬物を保護するため、外観に光沢を与えることによって商品価値を高めるため、薬物の放出特性を調整することによって薬物に遅効性または持続性の機能を付与するためなどを目的として行われている。 In the field of pharmaceutical formulation, the coating protects the unstable drug against moisture, oxygen, light, etc. and enhances the commercial value by giving a gloss to the appearance, so by adjusting the release characteristics of the drug, the drug It is done for the purpose of giving delayed or sustained function to
　医薬品製剤におけるコーティングプロセスにおいては、湿式スプレーコーティング技術が主流となっている。上記したコーティング技術は、乾燥様式から、パンコーティング法と気中懸濁方式に大別されている。パンコーティング法ではコーティングパン装置又は通気式コーティング装置が使われ、気中懸濁方式では、流動層型、噴流層型、又は転動流動層型の装置が使われている。 In the coating process for pharmaceutical preparations, wet spray coating technology is in the mainstream. The above-mentioned coating techniques are roughly classified into pan coating method and air suspension method from drying mode. In the pan coating method, a coating pan apparatus or a vented coating apparatus is used, and in the air suspension system, a fluidized bed type, a spouted bed type or a rolling fluidized bed type apparatus is used.
　一方、メカノフュージョン法が、粒子を混合する際に粒子同士の衝突で発生する物理学的エネルギーを利用して核粒子表面にコーティング物質を修飾/浸透させる方法として知られている（非特許文献１及び非特許文献２）。 On the other hand, the mechanofusion method is known as a method of modifying / penetrating a coating material on the surface of core particles by using physical energy generated by collision of particles when mixing particles (Non-patent document 1) And Non-Patent Document 2).
　従来の湿式スプレーコーティング技術においては、対処が困難な領域も存在している。例えば、最少必要量による適用制限がその一つに挙げられる。現在利用されているコーティング技術で用いられている機器は、最少でも数百g程度の試料が必要となり、原薬量がmg単位程度しか得られない研究の初期段階で、コーティングを検討することは困難となっている。また、被コーティング物質（核粒子）の大きさの制限も問題の一つにあげられる。微粒子コーティングに特徴を持っているドラフトチューブ付噴流層コーティング（ワースター法）においても、最小でも100μｍ程度の粒子径の核粒子が必要となり、マイクロ・ナノテクノロジー分野での応用は困難となっている。上記の通り、従来のコーティング技術においては、100μm以下の核粒子に対するコーティングや数百g以下のスケールにおけるコーティングが困難であることが技術限界とされている。 There are also areas that are difficult to address in conventional wet spray coating techniques. For example, one of the application restrictions with the minimum requirement is one. The equipment used in the coating technology currently in use requires a sample of at least several hundreds of grams, and it is necessary to consider the coating in the early stages of research where only about mg of drug substance can be obtained. It is difficult. In addition, limitation of the size of the substance to be coated (core particles) is one of the problems. Also in the draft tube spouted bed coating (Wurster method) characterized by the fine particle coating, core particles with a particle diameter of at least about 100 μm are required, and its application in the field of micro / nano technology becomes difficult. As described above, in the conventional coating technology, it is considered as a technical limit that coating on core particles of 100 μm or less and coating on a scale of several hundred g or less are difficult.
　さらに、従来の方法は湿式であるためコーティング剤の溶媒または分散剤を留去が必要となるため、蒸発させるための通気設備が必要となり、一般にコーティングに用いる装置は開放系となっている。しかしながら、高生理活性を有する物質にコーティングを施す場合、開放系の装置では、高生理活性物質が装置外へ漏出のする危険があり、作業員の健康被害や環境汚染に対するリスクが大きくなる。 Furthermore, since the conventional method is wet, it is necessary to distill off the solvent or dispersant of the coating agent, so that a venting device for evaporation is required, and the apparatus used for coating is generally an open system. However, in the case of applying a coating to a substance having high physiological activity, in an open system, there is a risk that the high physiologically active substance may leak out of the apparatus, and the risk to health hazards of workers and environmental pollution increases.
　100μm以下の粒子径領域でのプロセッシングが可能になれば、機能性経口製剤のみならず吸入剤や機能性粉末注射剤などの非経口投与製剤の製造にも可能性が拡がり、また、mgオーダーでのコーティングが達成できれば、原末量が限られる研究開発初期の候補化合物の段階においてもコーティングによる製剤設計が可能となる。 If processing in the particle size range of 100 μm or less becomes possible, the possibilities extend not only to functional oral preparations but also to the production of parenteral administration preparations such as inhalants and functional powder injections, and also on the order of mg If coating can be achieved, formulation design by coating becomes possible even at the stage of candidate compounds in the early stage of research and development where the amount of raw powder is limited.
　本発明の課題は、100μm以下の粒子径を有する核物質を一次粒子として使用し、封じ込め容器中で、その表面をコーティングする方法、並びに上記方法により製造される微粒子を提供することである。 An object of the present invention is to provide a method of coating a surface of a core material having a particle diameter of 100 μm or less as a primary particle in a containment vessel, and fine particles produced by the above method.
　本発明者らは、ボールミルを使ってメカノフュージョンを行う場合、粉砕限界粒子径近傍　(数μm～10μm)の核粒子に対してコーティング剤に低融点物質を用いると、核粒子の粒子径は低下しない一方で、強い衝突エネルギーにより微粒子表面上でコーティング剤の溶融が起こって密なコーティングができるのではないかと考えた（図１）。そこで、本発明者らは、ボールミルを用いたメカノフュージョン法により、少量（数100mgオーダー）かつ平均粒子径約10μmの微粒子に対して溶出制御可能なコーティングが可能かどうかを調べた。その結果、本発明者らは、融点の差のある物質を混合することにより、粒子同士の衝突の際に発生する熱により低融点物質が、高融点物質表面をコーティングできることを見出した（図１）。さらに、本発明者らは、この方法により核物質が100μｍ以下の粒子径においても一次粒子としてコーティングでき、このコーティングにより医薬品の溶出を制御できることを見出した。本発明はこれらの知見に基づいて完成したものである。 When performing mechanofusion using a ball mill, when using a low melting material as a coating agent for core particles in the vicinity of the crushing limit particle diameter (several μm to 10 μm), the particle diameter of the core particles decreases. On the other hand, it was thought that strong collision energy would cause the coating agent to melt on the surface of the fine particles to form a dense coating (FIG. 1). Therefore, the present inventors investigated whether a coating capable of controlling the elution of a small amount (on the order of several hundred mg) and fine particles with an average particle diameter of about 10 μm can be obtained by the mechanofusion method using a ball mill. As a result, the present inventors found that by mixing the substances having different melting points, the low melting substance can coat the surface of the high melting substance by the heat generated upon collision of the particles (FIG. 1). ). Furthermore, the present inventors have found that the core material can be coated as a primary particle even at a particle size of 100 μm or less by this method, and this coating can control the elution of the drug. The present invention has been completed based on these findings.
　すなわち、本発明によれば以下の発明が提供される。
＜１＞　活性成分を含む粒径100μｍ以下の第一の粒子と、樹脂又は油脂の少なくとも一種を含む第二の粒子とを機械的に混合する工程を含む、樹脂又は油脂で被覆された粒子の製造方法。
＜２＞　樹脂又は油脂で被覆された粒子が、注射可能な粒子径を有する粒子である、＜１＞に記載の方法。
＜３＞　機械的に混合する工程を、溶媒及び液状分散媒の非存在下において行う、＜１＞又は＜２＞に記載の方法。
＜４＞　機械的に混合する工程において、第二の粒子を分割して投入する、＜１＞から＜３＞の何れか一に記載の方法。
＜５＞　第一の粒子の融点より第二の粒子の融点の方が低い、＜１＞から＜４＞の何れか一に記載の方法。
＜６＞　第一の粒子が、多孔性粒子に活性成分を包含させた粒子である、＜１＞から＜５＞の何れか一に記載の方法。
＜７＞　多孔性粒子が、エチルセルロースからなる粒子である、＜６＞に記載の方法。
＜８＞　第二の粒子が、15℃以上100℃以下の融点を有する樹脂又は油脂の少なくとも一種を含む、＜１＞から＜７＞の何れか一に記載の方法。
＜９＞　第二の粒子がシェラックを含む、＜１＞から＜８＞の何れか一に記載の方法。
＜１０＞　第二の粒子が生体内分解性高分子を含む、＜１＞から＜９＞の何れか一に記載の方法。
＜１１＞　生体内分解性高分子がポリ乳酸、ポリグリコール酸又は乳酸・グリコール酸コポリマーである、＜１０＞に記載の方法。
＜１２＞　 第二の粒子が、15℃以上100℃以下の融点を有する油脂と重量平均分子量１０００以上の高分子との固体分散体または固溶体である、＜１＞から＜１１＞の何れか一に記載の方法。
＜１３＞　第二の粒子が、シェラックと腸溶性ポリマーとの固体分散体または固溶体である、＜１＞から＜１２＞の何れか一に記載の方法。
＜１４＞　腸溶性ポリマーがメタクリル酸コポリマーＬである＜１３＞に記載の方法。
＜１５＞　第一の粒子と第二の粒子とを機械的に混合する工程を、封じ込め容器中において行う、＜１＞から＜１４＞の何れか一に記載の方法。
＜１６＞　第一の粒子と第二の粒子とを機械的に混合する工程を、ボールミルにより行う、＜１＞から＜１５＞の何れか一に記載の方法。
＜１７＞　封じ込め容器が、底面の長径と高さが1:10～10:1の範囲の容器である、＜１５＞に記載の方法。
＜１８＞　樹脂又は油脂で被覆された粒子が、徐放性粒子である、＜１＞から＜１７＞の何れか一に記載の方法。
＜１９＞　樹脂又は油脂で被覆された粒子が、腸溶性粒子である、＜１＞から＜１７＞の何れか一に記載の方法。
＜２０＞　＜１＞から＜１９＞の何れか一に記載の方法により、樹脂又は油脂で被覆された粒子を製造する工程、及び前記の樹脂又は油脂で被覆された粒子と、樹脂又は油脂の少なくとも一種を含む第三の粒子とを機械的に混合する工程を含む、樹脂又は油脂の多層で被覆された粒子の製造方法。 That is, according to the present invention, the following inventions are provided.
<1> A resin or oil-coated particle comprising a step of mechanically mixing a first particle having a particle diameter of 100 μm or less containing an active ingredient and a second particle containing at least one of a resin or oil. Production method.
<2> The method according to <1>, wherein the particles coated with resin or fat are particles having an injectable particle diameter.
<3> The method according to <1> or <2>, wherein the mechanically mixing step is performed in the absence of a solvent and a liquid dispersion medium.
The method as described in any one of <1> to <3> which divides | segments and injects | throws-in 2nd particle | grains in the process to mix <4> mechanically.
<5> The method according to any one of <1> to <4>, wherein the melting point of the second particle is lower than the melting point of the first particle.
<6> The method according to any one of <1> to <5>, wherein the first particle is a particle in which the porous particle includes the active ingredient.
The method as described in <6> whose <7> porous particle is a particle which consists of ethyl cellulose.
The method as described in any one of <1> to <7> in which <8> 2nd particle | grains contain at least 1 type of resin which has melting | fusing point 15 degreeC-100 degreeC or less, or fats and oils.
The method as described in any one of <1> to <8> in which <9> 2nd particle | grains contain shellac.
<10> The method according to any one of <1> to <9>, wherein the second particle comprises a biodegradable polymer.
<11> The method according to <10>, wherein the biodegradable polymer is polylactic acid, polyglycolic acid or lactic acid / glycolic acid copolymer.
<12> Any one of <1> to <11>, wherein the second particle is a solid dispersion or solid solution of an oil having a melting point of 15 ° C. to 100 ° C. and a polymer having a weight average molecular weight of 1000 or more The method described in.
<13> The method according to any one of <1> to <12>, wherein the second particle is a solid dispersion or solid solution of shellac and an enteric polymer.
<14> The method according to <13>, wherein the enteric polymer is methacrylic acid copolymer L.
<15> The method according to any one of <1> to <14>, wherein the step of mechanically mixing the first particle and the second particle is performed in a containment vessel.
The method as described in any one of <1> to <15> which performs the process of mechanically mixing a <16> 1st particle | grain and a 2nd particle | grain with a ball mill.
<17> The method according to <15>, wherein the containment vessel is a vessel having a major axis length and a height in the range of 1:10 to 10: 1.
The method as described in any one of <1> to <17> whose particle | grains covered with <18> resin or fats and oils are sustained-release particle | grains.
The method as described in any one of <1> to <17> whose particle | grains coat | covered with <19> resin or fats and oils are enteric particles.
<20> A step of producing particles coated with a resin or oil by the method according to any one of <1> to <19>, and particles coated with the resin or oil and a resin or oil A method for producing a multilayer resin- or oil-coated particle, which comprises the step of mechanically mixing with at least one third particle.
＜２１＞　（ｉ）活性成分を含む粒径100μｍ以下の核粒子と、（ｉｉ）前記核粒子の表面に被覆されており、樹脂又は油脂の少なくとも一種を含む被覆層、とを有する粒子。
＜２２＞　核粒子の融点より、被覆層を構成する樹脂又は油脂の融点の方が低い、＜２１＞に記載の粒子。
＜２３＞　核粒子が、多孔性粒子に活性成分を包含させた粒子である、＜２１＞又は＜２２＞に記載の粒子。
＜２４＞　多孔性粒子が、エチルセルロースからなる粒子である、＜２３＞に記載の粒子。
＜２５＞　被覆層を構成する樹脂又は油脂の融点が、15℃以上100℃以下である、＜２１＞から＜２４＞の何れか一に記載の粒子。
＜２６＞　被覆層がシェラックを含む、＜２１＞から＜２５＞の何れか一に記載の粒子。
＜２７＞　被覆層が生体内分解性高分子を含み、注射可能な粒子径を有する、＜２１＞から＜２５＞の何れか一に記載の粒子。
＜２８＞　被覆層がポリ乳酸または乳酸・グリコール酸コポリマーを含み、粒子の９０％粒径（Ｄ９０）が１５０μm以下である、＜２１＞から＜２５＞の何れか一に記載の粒子。
＜２９＞　被覆層が、15℃以上100℃以下の融点を有する油脂と重量平均分子量1000以上の高分子とを含む、＜２１＞から＜２８＞の何れか一に記載の粒子。
＜３０＞　被覆層が、シェラックと腸溶性ポリマーとを含む、＜２１＞から＜２９＞の何れか一に記載の粒子。
＜３１＞　腸溶性ポリマーがメタクリル酸コポリマーＬである＜３０＞に記載の粒子。
＜３２＞　徐放性粒子である、＜２１＞から＜３１＞の何れか一に記載の粒子。
＜３３＞　腸溶性粒子である、＜２１＞から＜３１＞の何れか一に記載の粒子。
＜３４＞　樹脂又は油脂の少なくとも一種を含む被覆層を２層以上有している、＜２１＞から＜３３＞の何れか一に記載の粒子。 <21> A particle having (i) core particles having a particle size of 100 μm or less containing an active ingredient, and (ii) a coating layer coated on the surface of the core particles and containing at least one of a resin or a fat and oil.
<22> The particle according to <21>, wherein the melting point of the resin or the fat or oil constituting the coating layer is lower than the melting point of the core particle.
<23> The particle according to <21> or <22>, wherein the core particle is a particle in which the porous particle includes the active ingredient.
<24> The particles according to <23>, wherein the porous particles are particles consisting of ethyl cellulose.
The particle | grain as described in any one of <21> to <24> whose melting | fusing point of resin or fats and oils which comprise a <25> coating layer is 15 degreeC or more and 100 degrees C or less.
<26> The particle according to any one of <21> to <25>, wherein the covering layer comprises shellac.
<27> The particle according to any one of <21> to <25>, wherein the covering layer comprises a biodegradable polymer and has an injectable particle size.
<28> The particles according to any one of <21> to <25>, wherein the coating layer contains polylactic acid or a lactic acid / glycolic acid copolymer, and the 90% particle diameter (D90) of the particles is 150 μm or less.
The particle | grain as described in any one of <21> to <28> in which a <29> coating layer contains the fats and oils which have melting | fusing point 15 degreeC-100 degreeC, and the polymer of weight average molecular weight 1000 or more.
The particle | grain as described in any one of <21> to <29> in which a <30> coating layer contains shellac and an enteric polymer.
<31> The particle according to <30>, wherein the enteric polymer is methacrylic acid copolymer L.
<32> The particle according to any one of <21> to <31>, which is a sustained release particle.
<33> The particles according to any one of <21> to <31>, which are enteric particles.
The particle | grain as described in any one of <21> to <33> which has a coating layer which contains at least 1 type of <34> resin or fats and oils in two or more layers.
　本発明の微粒子は、腸溶性微粒子、又は徐放性微粒子として有用である。本発明は、従来製剤に含有させる高活性医薬品（バイオ医薬品を含む）の機能性原製剤の製造及び院内製剤の製造において有用である。 The microparticles of the present invention are useful as enteric microparticles or sustained release microparticles. The present invention is useful in the manufacture of functional pre-formulations of highly active pharmaceuticals (including biopharmaceuticals) contained in conventional preparations and in the manufacture of nosocomial preparations.
図１は、本発明の方法の模式図を示す。FIG. 1 shows a schematic view of the method of the present invention. 図２は、核粒子１とコーティング品１～３の溶出試験の結果を示す。FIG. 2 shows the results of the dissolution test of core particle 1 and coated articles 1 to 3. 図３は、核粒子１とコーティング品１の電子顕微鏡像を示す。FIG. 3 shows electron microscope images of the core particle 1 and the coated article 1. 図４は、核粒子２とコーティング品４の溶出試験の結果を示す。FIG. 4 shows the results of the dissolution test of the core particle 2 and the coated article 4. 図５は、腸溶性コーティング品１及び２の溶出試験の結果を示す。FIG. 5 shows the results of the dissolution test of enteric coated articles 1 and 2. 図６は、核粒子３と腸溶性コーティング品２の電子顕微鏡増を示す。FIG. 6 shows the electron microscopy of the core particle 3 and the enteric coating 2. 図７は、実施例６における電子顕微鏡像を示す。FIG. 7 shows an electron microscope image in Example 6. 図８は、実施例６の粒子の体積基準粒度分布を示す。Figure 8 shows the volume based particle size distribution of the particles of Example 6. 図９は、実施例６における溶出試験の結果を示す。FIG. 9 shows the results of the dissolution test in Example 6. 図１０は、コーティング品６～８の溶出試験の結果を示す。FIG. 10 shows the results of the dissolution test for coated articles 6-8. 図１１は、コーティング品７及び９～１１の溶出試験の結果を示す。FIG. 11 shows the results of the dissolution tests of Coatings 7 and 9-11. 図１２は、PLGAマイクロスフェア2の光学顕微鏡写真像を示す。FIG. 12 shows an optical micrograph image of PLGA microspheres 2. 図１３は、PLGAマイクロスフェア2からのビタミンＢ１２の溶出を示す。FIG. 13 shows the elution of vitamin B 12 from PLGA microspheres 2.
　本発明の実施の形態について説明する。
　本発明による粒子の製造方法は、活性成分を含む粒径100μｍ以下の第一の粒子と、樹脂又は油脂の少なくとも一種を含む第二の粒子とを機械的に混合する工程を含む、樹脂又は油脂で被覆された粒子の製造方法である。
　本発明の粒子は、（ｉ）活性成分を含む粒径100μｍ以下の核粒子と、（ｉｉ）前記核粒子の表面に被覆されており、樹脂又は油脂の少なくとも一種を含む被覆層、とを有する粒子である。 An embodiment of the present invention will be described.
The method for producing particles according to the present invention comprises the step of mechanically mixing a first particle having a particle diameter of 100 μm or less containing an active ingredient and a second particle containing at least one of a resin or oil. Is a method of producing coated particles.
The particles of the present invention have (i) core particles having a particle size of 100 μm or less containing an active ingredient, and (ii) a coating layer coated on the surface of the core particles and containing at least one resin or fat. It is a particle.
　活性成分としては、特に限定されないが、以下の成分を使用することができる。
（抗炎症剤）
　アスピリン、アセトアミノフェン、エトドラック、メフェナミック、メクロフェナミック、ピロキシカム、イソプロピルアンチピリン、トラネキサム酸、イブプロフェン等
（催眠・鎮静剤）
　ニトラゼパム、トリアゾラム、フェノバルビタール、アミバルビタ－ル、アリルイソプロピルアセチル尿素、ブロムワレニル尿素、フルニトラゼパム、ゾルピデム酒石酸塩、アルプラゾラム、エチゾラム、パロキセチン塩酸塩水和物、ロラゼパム、ロフラゼプ酸エチル、エスシロプラムシュウ酸塩等
（抗てんかん剤）
　フェニトイン、メタルビタール、プリミドン、クロナゼパム、カルバマゼピン、バルプロ酸等
（鎮うん剤）
　塩酸メクリジン、ジメンヒドリナート等
（抗うつ剤）
　イミプラニン、ノキシプチリン、フェネルジン等
（精神神経用剤）
　ハロペリドール、メプロバメート、クロルジアゼポキシド、ジアゼバム、オキサゼバム、スルピリド、リスペリドン、アリピプラゾール、オランザピン、クエチアピンフマル酸塩、パリペリドン、ペロスピロン塩酸塩水和物、デュロキセチン塩酸塩、パロキセチン、塩酸セルトラリン、アモキサピン等
（鎮けい剤）
　パパベリン、アトロピン、エトミドリン等
（強心剤）
　ジゴキシン、ジギトキシン、メチルジゴキシン、ユビデカレノン等
（不整脈剤）
　ピンドロール、アジマリン、ジソピラミド等
（利尿剤）
　ヒドロクロロチアジド、スピロノラクトン、トリアムテレン、フロセミド、ブメタニド等 The active ingredient is not particularly limited, but the following ingredients can be used.
(Anti-inflammatory agent)
Aspirin, acetaminophen, etodolac, mefenamic, meclofenamic, piroxicam, isopropylantipyrine, tranexamic acid, ibuprofen etc (hypnosis / sedatives)
Nitrazepam, triazolam, phenobarbital, amibarbital, allylisopropylacetylurea, bromvalenylurea, flunitrazepam, zolpidem tartrate, alprazolam, etizolam, paroxetine hydrochloride hydrate, lorazepam, ethyl loflazepate, escilopalm oxalate etc Epilepsy agent)
Phenytoin, metal bital, primidone, clonazepam, carbamazepine, valproic acid etc.
Meclidine hydrochloride, dimenhydrinate etc (antidepressant)
Imiplanin, noxiptyline, phenelzine etc (psychiatric agents)
Haloperidol, meprobamate, chlordiazepoxide, diazepam, oxazebam, sulpiride, risperidone, aripiprazole, olanzapine, quetiapine fumarate, paliperidone, perospirone hydrochloride hydrate, duloxetine hydrochloride, paroxetine, sertraline hydrochloride, amoxapine etc (antiseptics)
Papaverine, atropine, etmidolin etc. (cardiac)
Digoxin, digitoxin, methyl digoxin, ubidecarenone etc (arrhythmic agent)
Pindolol, azimarin, disopyramide etc (diuretic)
Hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide etc.
（抗高血圧剤）
　レセルピン、メシル酸ジヒドロエルゴトキシン、塩酸プラゾシン、メトプロロール、プロプラノロール、アテノロール、カンデサルタンレキセチル、テルミサルタン、アジルサルタン、オルメサルタン、ビソプロロールフマル酸塩、カルベジロール、バルサルタン、エナラプリル、イミダプリル、アムロジピンベシル酸塩、ジルチアゼム塩酸塩、ドキサシン、トリクロルメチアジド等
（冠血管拡張剤）
　ニトログリセリン、硝酸イソソルビド、ジルチアゼム、ニフェジピン、ジピリダモール等
（鎮咳剤）
　ノスカピン、サルブタモール、プロカテロール、ツロプテロール、トラニラスト、臭化水素酸デキストロメトルファン、リン酸ジヒドロコデイン、リン酸コデイン等
（去痰剤）
　ブロムヘキシン塩酸塩、アンブロキソール塩酸塩、グアイフェネシン等
（脳循環改善剤）
　ニカルジピン、ピンポセチン等
（交感神経興奮剤）
　塩酸メチルエフェドリン等
（糖尿病治療薬）
　グリメピリド、ボグリボース、メトホルミン、ミチグリニドカルシウム水和物、ピオグリタゾン、ビルダグリプチン、シダグリプチンリン酸塩水和物、トレラグリプチンコハク酸塩等
（抗病原微生物剤）
　エリスロマイシン、ジョサマイシン、クロラムフェニコール、テトラサイクリン、リファンピシン、グリセオフルビン、レボフロキサシ、セフジトレンピボキシル、セフカペンピボキシル、トスフロキサシントシル酸塩水和物、セフジニル、アジスロマイシン水和物、アモキシシリン、バンコマイシン、オフロキサシン、メトロニダゾール、アシクロビル、バラシクロビル、ミコナゾー、イトラコナゾール等
（抗ヒスタミン剤）
　ジフェンヒドラミン、プロメタジン、メキタジン、クレマスチンフマル酸塩、ベボタスチンベシル酸塩、フェキソフェナジン、オロパタジン、セチリジン塩酸塩、ロラタジン等
（ステロイド剤）
　トリアムシノロン、デキサメタゾン、ベタメタゾン、プレドニソロン、ダナゾール、メチルテストステロン、酢酸クロルマジノン等 (Antihypertensive agent)
Reserpine, dihydroergotoxin mesilate, prazosin mesylate, metoprolol, propranolol, atenolol, candesartan lexetil, telmisartan, azirsartan, olmesartan, bisoprolol fumarate, calvegirol, valsartan, enalapril, imidapril, amlodipine besilate, diltiazem hydrochloride, Doxacin, trichlormethiazide etc (coronary vasodilator)
Nitroglycerin, isosorbide dinitrate, diltiazem, nifedipine, dipyridamole etc (cough suppressant)
Noscapine, salbutamol, procaterol, turopterol, tranilast, dextromethorphan hydrobromide, dihydrocodeine phosphate, codeine phosphate etc (excipient agent)
Bromhexine hydrochloride, ambroxol hydrochloride, guaifenesin etc (brain circulation improving agent)
Nicardipine, pinpocetin, etc. (sympathomimetic agents)
Methyl ephedrine hydrochloride etc (diabetes treatment)
Glimepiride, voglibose, metformin, mitiglinide calcium hydrate, pioglitazone, vildagliptin, shedagliptin phosphate hydrate, trelagliptin succinate etc (antipathogenic agent)
Erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin, levofloxacin, cefditoren pivoxil, cefdopenpivoxil, tosufoxacin tosylate hydrate, cefdinir, azithromycin hydrate, amoxicillin, vancomycin, ofloxacin, metronidazole, acyclovir , Valacyclovir, miconazo, itraconazole etc (antihistamines)
Diphenhydramine, promethazine, mequitazine, clemastine fumarate, bebotastine besilate, fexofenadine, olopatadine, cetirizine hydrochloride, loratadine etc (steroids)
Triamcinolone, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate, etc.
（ビタミン剤）
　ビタミンＡ類、ビタミンＢ類、ビタミンＣ類（アスコルビン酸等）、ビタミンＤ類、ビタミンＥ類、ビタミンＫ類、葉酸（ビタミンＭ類）等
（消化器系疾患治療剤）
　タンニン酸、タンニン酸アルブミン、ベルベリン、メサラジン、ジメチコン、ボノプラザン、ファモチジン、ラニチジン、シメチジン、ニザチジン、メトクロプラミド、ファモチジン、オメプラゾール、ドンペリドン、スルピリド、トレピブトン、スクラルファート、活性生菌剤（例えば、ラクトミン、ビフィズス菌等）、制酸剤（例えば、水酸化アルミニウム、合成ヒドロタルサイト、酸化マグネシウム、メタケイ酸アルミン酸マグネシウム等）、ポリカルボフィルカルシウム等
（その他）
　アレンドロン酸ナトリウム水和物、ラロキシフェン、カフェイン、ジクマロール、シンナリジン、クロフィブラート、ゲファルナート、ブロベネシド、メルカプトプリン、メトトレキサート、ウルソデスオキシコール酸、メシル酸ジヒドロエルゴタミン、グルクロノラクトン、γ－アミノ酪酸、コンドロイチン、コンドロイチン硫酸ナトリウム、ラクトフェリン、乳性タンパク、システイン、コラーゲン、核酸（DNA、si-RNA、RNAデコイ、cDNA、アンチセンスRNAなど）、生理活性ペプチド(インスリン、カルシトニンなど)、生理活性タンパク質(ポリクローナル抗体、モノクローナル抗体、ガンマグロブリン、成長ホルモン、インターフェロンなど)等 (Vitamin)
Vitamin A, Vitamin B, Vitamin C (ascorbic acid etc.), Vitamin D, Vitamin E, Vitamin K, Folic Acid (vitamin M) etc. (Digestive system disease treatment agent)
Tannic acid, tannic acid albumin, berberine, memesalazine, dimethicone, vonoprazan, famotidine, ranitidine, cimetidine, nizatidine, metoclopramide, famotidine, omeprazole, domperidone, sulperido, trepibutone, sucralfate, active fungi agents (eg, lactamine, bifidobacteria etc.) ), Antacids (eg, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, magnesium aluminometasilicate, etc.), calcium polycarbophil, etc. (others)
Sodium alendronate hydrate, raloxifene, caffeine, dicoumarol, cinnarizine, clofibrate, gefarnate, bloveneside, mercaptopurine, methotrexate, ursodes oxycholate, dihydroergotamine mesylate, glucuronolactone, γ-aminobutyric acid, chondroitin, Chondroitin sulfate sodium, lactoferrin, milk protein, cysteine, collagen, nucleic acid (DNA, si-RNA, RNA decoy, cDNA, antisense RNA etc.), physiologically active peptide (insulin, calcitonin etc.), physiologically active protein (polyclonal antibody, Monoclonal antibody, gamma globulin, growth hormone, interferon etc) etc
　第一の粒子（核粒子とも言う）の粒径は100μｍ以下であり、90μｍ以下、80μｍ以下、70μｍ以下、60μｍ以下、50μｍ以下、40μｍ以下、又は30μｍ以下でもよい。第一の粒子（核粒子とも言う）の粒径の下限は特に限定されないが、5μｍ以上または10μｍ以上でもよい。本明細書で言う粒径とは体積基準平均粒子径であり、体積基準平均粒子径は、レーザー回折粒子径測定装置（例えば、SALD2200(島津製作所)）により測定することができる。 The particle diameter of the first particles (also referred to as core particles) is 100 μm or less, and may be 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less, or 30 μm or less. The lower limit of the particle size of the first particles (also referred to as core particles) is not particularly limited, but may be 5 μm or more or 10 μm or more. The particle size referred to in the present specification is a volume-based average particle size, and the volume-based average particle size can be measured by a laser diffraction particle size measurement apparatus (for example, SALD 2200 (Shimadzu Corporation)).
　第一の粒子（核粒子）としては多孔性粒子に活性成分を含侵などの方法により担持させた粒子を使用することができる。
　多孔性粒子は、多孔性有機粒子又は多孔性無機粒子の何れでもよい。 As the first particles (core particles), particles in which porous particles are loaded with an active ingredient by a method such as impregnation can be used.
The porous particles may be either porous organic particles or porous inorganic particles.
　多孔性有機粒子としては、ポリペプチド又はその誘導体、タンパク質又はその誘導体、多糖類又はその誘導体、合成高分子、あるいはそれらの混合物からなる粒子を使用することができる。具体的には、ゼラチン、コラーゲン、アテロコラーゲン、アルブミン、フィブリン、プロタミンなどの蛋白質またはポリペプチド又はそれらの誘導体、エチルセルロース、ジュランガム、アラビアゴム、ヒアルロン酸、アルギン酸、コンドロイチン硫酸、ヘパリン、キチン、キトサンなどの多糖又はそれらの誘導体、エチルセルロース、ポリ乳酸、乳酸・グリコール酸コポリマーなどの合成高分子又はそれらの誘導体などを挙げることができる。 As porous organic particles, particles composed of a polypeptide or a derivative thereof, a protein or a derivative thereof, a polysaccharide or a derivative thereof, a synthetic polymer, or a mixture thereof can be used. Specifically, gelatin or a protein such as gelatin, collagen, atelocollagen, albumin, fibrin, protamine or derivatives thereof, ethylcellulose, duran gum, gum arabic, hyaluronic acid, alginic acid, chondroitin sulfate, heparin, chitin, chitosan, etc. Or derivatives thereof, synthetic polymers such as ethyl cellulose, polylactic acid, lactic acid / glycolic acid copolymers, or derivatives thereof.
　多孔性無機粒子としては、ケイ酸またはケイ酸塩などからなる多孔性無機粒子を使用することができる。ケイ酸またはケイ酸塩としては、具体的には、二酸化ケイ酸、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミニウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸マグネシウムアルミニウムなどを使用することができる。 As the porous inorganic particles, porous inorganic particles made of silicic acid or silicate can be used. Specific examples of the silicic acid or silicate include: silicic acid dioxide, hydrous silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminosilicate, magnesium aluminometasilicate , Magnesium aluminum silicate and the like can be used.
　第二の粒子は、樹脂又は油脂の少なくとも一種を含む。第二の粒子を構成する樹脂又は油脂は、本発明の粒子において被覆層を構成する。
　第二の粒子又は被覆層を構成する樹脂としては、特に限定されないが、例えば、ポリエステル樹脂、アクリル樹脂、ウレタン樹脂、酢酸ビニル樹脂、エチレン－酢酸ビニル樹脂、エポキシ樹脂、シリコーン樹脂、ポリスチレン樹脂、セルロース樹脂などが挙げられる。
　第二の粒子又は被覆層を構成する油脂としては、特に限定されないが、例えば、カルナバロウ、アボガド油、つばき油、マカデミアナッツ油、オリーブ油、ヒマシ油などが挙げられる。 The second particles contain at least one of a resin or a fat and oil. The resin or fat which constitutes the second particle constitutes the coating layer in the particle of the present invention.
The resin constituting the second particle or the covering layer is not particularly limited, but, for example, polyester resin, acrylic resin, urethane resin, vinyl acetate resin, ethylene-vinyl acetate resin, epoxy resin, silicone resin, polystyrene resin, cellulose Resin etc. are mentioned.
Although it does not specifically limit as fats and oils which comprise a 2nd particle | grain or a coating layer, For example, carnauba wax, avocado oil, horse mackerel oil, macadamia nut oil, olive oil, castor oil etc. are mentioned.
　第二の粒子を構成する樹脂又は油脂としては、腸溶性ポリマーでもよい。
　腸溶性ポリマーとしては、メタクリル酸コポリマー（例えばメタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＳ等）、ヒドロキシアルキルアルキルセルロースフタル酸エステル（例えば、ヒプロメロースフタル酸エステル）、ヒドロキシアルキルアルキルセルロース酢酸エステルコハク酸エステル（例えば、ヒプロメロース酢酸エステルコハク酸エステル）、カルボキシアルキルアルキルセルロース（例えばカルボキシメチルエチルセルロース）、エチルセルロース、セルロースアセテートフタレート等を使用することができる。 As resin or fats and oils which comprise 2nd particle | grains, enteric polymer may be sufficient.
Examples of enteric polymers include methacrylic acid copolymers (eg, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, etc.), hydroxyalkyl alkyl cellulose phthalate esters (eg, hypromellose phthalate ester), hydroxyalkyl alkyl cellulose Acetic acid ester succinate (eg, hypromellose acetic acid ester succinate), carboxyalkylalkyl cellulose (eg, carboxymethyl ethyl cellulose), ethyl cellulose, cellulose acetate phthalate and the like can be used.
　また、第二の粒子又は被覆層を構成する樹脂としては、シェラックを使用することができる。シェラックとは、ラックカイガラムシ由来の樹脂であり、ラックカイガラムシが分泌する樹脂状物質を熱湯中で分離、精製することにより得られる。 Moreover, shellac can be used as resin which comprises a 2nd particle | grain or a coating layer. Shellac is a resin derived from a lacy scale bug, and is obtained by separating and purifying a resinous substance secreted by the lac scale insect in hot water.
　樹脂又は油脂の融点は、好ましくは15℃以上100℃以下であり、より好ましくは25℃以上90℃以下である。 The melting point of the resin or fat is preferably 15 ° C. or more and 100 ° C. or less, more preferably 25 ° C. or more and 90 ° C. or less.
　本発明においては、第一の粒子の融点より第二の粒子の融点の方が低いことが好ましい。即ち、核粒子の融点より、被覆層を構成する樹脂又は油脂の融点の方が低いことが好ましい。 In the present invention, the melting point of the second particle is preferably lower than the melting point of the first particle. That is, it is preferable that the melting point of the resin or fat which constitutes a coating layer is lower than the melting point of core particles.
　第二の粒子は好ましくは、15℃以上100℃以下の融点を有する油脂と重量平均分子量1000以上の高分子との固体分散体または固溶体である。即ち、本発明の粒子における被覆層は、好ましくは、15℃以上100℃以下の融点を有する油脂と重量平均分子量1000以上の高分子とを含む。 The second particles are preferably solid dispersions or solid solutions of a fat having a melting point of 15 ° C. to 100 ° C. and a polymer having a weight average molecular weight of 1000 or more. That is, the coating layer in the particles of the present invention preferably contains a fat and oil having a melting point of 15 ° C. or more and 100 ° C. or less and a polymer having a weight average molecular weight of 1000 or more.
　第二の粒子の一例としては、シェラックと腸溶性ポリマーとの固体分散体または固溶体である。この場合、本発明の粒子における被覆層は、シェラックと腸溶性ポリマーとを含むものとなる。 An example of the second particle is a solid dispersion or solid solution of shellac and an enteric polymer. In this case, the coating layer in the particles of the present invention contains shellac and an enteric polymer.
　第二の粒子および被覆層は、生体内分解性高分子を含むものでもよい。生体内分解性高分子としてはポリ乳酸または乳酸・グリコール酸コポリマー、ポリグリコール酸、ポリカプロノラクトンなどを挙げることができる。 The second particle and the covering layer may contain a biodegradable polymer. Examples of biodegradable polymers include polylactic acid, lactic acid / glycolic acid copolymer, polyglycolic acid, polycapronolactone and the like.
　第一の粒子と第二の粒子とを混合する方法は、機械的に混合する方法であれば特に限定されないが、ボールミル、ディソルバー、ハイスピードミキサー、ホモミキサー、ニーダー、ロールミル、アトライター、サンドミル等を用いて実施することができる。機械的な混合は、好ましくはボールミルを用いて実施することができる。 The method of mixing the first particle and the second particle is not particularly limited as long as it is a method of mechanically mixing, but a ball mill, a dissolver, a high speed mixer, a homomixer, a kneader, a roll mill, an attritor, a sand mill And so on. Mechanical mixing can preferably be carried out using a ball mill.
　第一の粒子と第二の粒子とを機械的に混合する工程は、好ましくは封じ込め容器中において行うことができる。封じ込め容器は、好ましくは、底面の長径と高さが1:10～10:1の範囲の容器である。 The step of mechanically mixing the first and second particles can preferably be performed in a containment vessel. The containment vessel is preferably a vessel having a major axis length and a height in the range of 1:10 to 10: 1.
　第一の粒子と第二の粒子とを機械的に混合する工程は、溶媒及び液状分散媒の非存在下において行うことが好ましい。
　第一の粒子と第二の粒子とを機械的に混合する工程において、第二の粒子を分割して投入してもよい。 The step of mechanically mixing the first particles and the second particles is preferably performed in the absence of a solvent and a liquid dispersion medium.
In the step of mechanically mixing the first particle and the second particle, the second particle may be divided and introduced.
　本発明における樹脂又は油脂で被覆された粒子は、注射可能な粒子径を有する粒子であることが好ましく、粒子の９０％粒径（累積量９０％まで粒子径：Ｄ９０）が１５０μm以下であることが好ましく、１２０μm以下であることがより好ましく、１００μm以下であることがさらに好ましく、８０μm以下であることが特に好ましい。粒子の９５％粒径（累積量９５％まで粒子径：Ｄ９０）が１５０μm以下であることが好ましく、１２０μm以下であることがより好ましく、１００μm以下であることがさらに好ましく、８０μm以下であることが特に好ましい。 The particles coated with the resin or the fat and oil in the present invention are preferably particles having an injectable particle diameter, and 90% particle diameter (up to 90% cumulative amount particle diameter: D90) is 150 μm or less Is more preferably 120 μm or less, still more preferably 100 μm or less, and particularly preferably 80 μm or less. The 95% particle size (up to 95% particle size: D90) of the particles is preferably 150 μm or less, more preferably 120 μm or less, even more preferably 100 μm or less, and 80 μm or less Particularly preferred.
　本発明の方法により製造される樹脂又は油脂で被覆された粒子は、好ましくは徐放性粒子、又は腸溶性粒子である。 The resin- or fat-coated particles produced by the method of the present invention are preferably sustained release particles or enteric particles.
　徐放性とは、内包する活性成分物を徐々に放出できる性質である。活性成分が、徐々に固形製剤から溶出され、活性成分の90％以上を溶出するのに要する時間が少なくとも１時間以上であることが好ましい。活性成分の90％以上を溶出するのに要する時間は、活性成分の種類と目的により、例えば、投与から8時間、12時間、24時間と適時選択することができる。徐放性は、第17改正日本薬局方に記載の溶出試験法に準じて測定することができる。
　腸溶性とは、胃酸などの酸に溶けず小腸で急速に溶解する性質をいう。 Sustained release is a property capable of gradually releasing the active ingredient to be contained. It is preferred that the active ingredient is gradually eluted from the solid preparation and the time required to elute 90% or more of the active ingredient is at least one hour or more. The time required to elute 90% or more of the active ingredient can be appropriately selected, for example, from 8 hours, 12 hours, and 24 hours after administration, depending on the type and purpose of the active ingredient. The sustained release can be measured according to the dissolution test method described in the 17th revised Japanese Pharmacopoeia.
Enteric refers to the property of dissolving in acid such as gastric acid and rapidly dissolving in the small intestine.
　本発明においては、樹脂又は油脂で被覆する工程を2回以上行うことができる。即ち、活性成分を含む粒径100μｍ以下の第一の粒子と、樹脂又は油脂の少なくとも一種を含む第二の粒子とを機械的に混合する工程により樹脂又は油脂で被覆された粒子を製造した後に、前記の樹脂又は油脂で被覆された粒子と、樹脂又は油脂の少なくとも一種を含む第三の粒子とを機械的に混合する工程を行うことにより、樹脂又は油脂の多層で被覆された粒子を製造することができる。上記により製造される粒子は、樹脂又は油脂の少なくとも一種を含む被覆層を2層以上有している。 In the present invention, the step of coating with a resin or fat can be performed twice or more. That is, after producing particles coated with resin or fat by the step of mechanically mixing the first particle having a particle diameter of 100 μm or less containing the active ingredient and the second particle containing at least one of resin or fat. And producing a particle coated with a multilayer of resin or fat by performing a step of mechanically mixing the particle coated with the resin or fat with the third particle containing at least one of the resin or fat. can do. The particles produced by the above have two or more coating layers containing at least one of resin and fat.
　本発明の微粒子は、そのまま又は他の成分と混合し、粒状剤（顆粒剤、細粒剤又は散剤）として使用することができ、又は打錠して錠剤として使用したり、カプセル剤として使用してもよい。 The fine particles of the present invention can be used as particulate agents (granules, fine granules or powders) as they are or mixed with other components, or used as tablets or tablets as tablets. May be
　以下の実施例により本発明を具体的に説明するか、本発明の範囲は実施例により限定されるものではない。 The present invention will be specifically described by the following examples, but the scope of the present invention is not limited by the examples.
実施例１
（１）エチルセルロース―多孔性微粒子の調製
　50mLビーカーにエチルセルロース（日新化成株式会社、STD　7cps）2gを取り、アセトン16gを加え、スターラーで攪拌して溶解した(A液)。
　50mLビーカーにグリセリン7gと5%ポリビニルアルコール(クラレ、クラレポバール220C)以下、PVA)水溶液1gを取り、スリーワンモーターにて混和した(B液)。
　100mLビーカーにグリセリン45gと5%PVA水溶液5gを取り、スリーワンモーターにて混和した(C液)。
　A液にB液を乳化機(ヒスコトロン　マイクロテック・ニチオン)にて用い、60目盛で1分間乳化した(D液)。 Example 1
(1) Preparation of ethyl cellulose-porous fine particles 2 g of ethyl cellulose (Nisshin Kasei Co., Ltd., STD 7 cps) was taken in a 50 mL beaker, 16 g of acetone was added, and stirred with a stirrer to dissolve it (Liquid A).
In a 50 mL beaker, 7 g of glycerin and 1 g of a 5% polyvinyl alcohol (Kuraray, KURARAY POVAL 220C or less, PVA) aqueous solution were taken and mixed by a three-one motor (Liquid B).
In a 100 mL beaker, 45 g of glycerin and 5 g of a 5% PVA aqueous solution were taken and mixed by a three-one motor (Liquid C).
The solution A was used to elute the solution A for 1 minute on a 60 scale using an emulsifying machine (Hiscotron Microtech Nichion) (solution D).
　スリーワンモーターで攪拌中(600rpm)のC液にD液を加え、一分間乳化した。乳化後、500mLビーカーにてスターラーで攪拌中(400rpm)の精製水500mL中へ加え、多孔性微粒子を析出させた。75μm眼開きふるいフルイ、53μm眼開きふるいフルイの順で濾過し、濾液を得た。得た濾液を20μm眼開きフルイにて吸引ろ過し、濾取物を得た。濾取物を200mLの精製水で再分散し、再度20μm眼開きフルイにて吸引ろ過、濾取物を得た。濾取物を10mLの精製水で再分散し再度20眼開きフルイにて吸引ろ過、濾取物を得た。濾取物を100mLビーカーへ移し、少量の水で再分散し、凍結乾燥した。 Solution D was added to solution C while stirring (600 rpm) with a three-one motor and emulsified for 1 minute. After emulsification, it was added to 500 mL of purified water while stirring (400 rpm) with a stirrer in a 500 mL beaker to precipitate porous fine particles. The filtrate was filtered in the order of 75 μm eyelid sieve, 53 μm eyelid sieve, and the filtrate was obtained. The obtained filtrate was suction filtered with a 20 μm eyelid sieve to obtain a filtered product. The filtered product was re-dispersed with 200 mL of purified water, and suction filtered again with a 20 μm eyelid sieve to obtain a filtered product. The filtered product was re-dispersed with 10 mL of purified water, again suction-filtered with a 20-well sieve, and the filtered product was obtained. The filtrate was transferred to a 100 mL beaker, redispersed with a small amount of water and lyophilized.
（２）エチルセルロース多孔性微粒子へのビタミンB12の充填 
　充てんは含浸法にて行った。すなわち、50mLのチューブにエチルセルロース多孔性微粒子0.5gを秤量し、12.5mg/mLのVB12（ALEXIS　BIOCEMICALS）溶液1 mLを加えた。チューブミキサーで攪拌後、真空-0.09Mpaにて30分間減圧を行った。その後一晩凍結乾燥を行った。翌日、均一にかき混ぜ、核粒子１を得た。エチルセルロース多孔性微粒子の融点は165～173℃である。 (2) Filling of vitamin B12 into ethyl cellulose porous fine particles
The filling was carried out by the impregnation method. That is, 0.5 g of ethyl cellulose porous microparticles were weighed into a 50 mL tube, and 1 mL of a 12.5 mg / mL solution of VB 12 (ALEXIS BIOCHEMICALS) was added. After stirring with a tube mixer, a vacuum was applied for 30 minutes under a vacuum of -0.09 Mpa. After that, freeze drying was performed overnight. The next day, the mixture was uniformly mixed to obtain core particles 1. The melting point of the ethyl cellulose porous fine particles is 165 to 173.degree.
（３）コーティング
　メノウ製ボールミルポット(内径4cm、高さ4cm)に核粒子1を300mg、カルバナロウ（Alfa　AesarTM）（融点は　82～86　℃）を600mg秤取した。直径10mmのメノウ製ボールを4個入れた。遊星ボールミル（フレッチェ社、pulverisette6)にて、回転速度500rpmで6時間混合し、コーティング品1を得た。 (3) coating agate ball mill pot (inner diameter 4 cm, height 4 cm) core particles 1 300 mg, the Karubanarou a (Alfa Aesar TM) (melting point 82 ~ 86 ° C.) was weighed 600 mg. Four 10 mm diameter agate balls were inserted. The mixture was mixed at a rotational speed of 500 rpm for 6 hours in a planetary ball mill (Floche, pulverisette 6) to obtain a coated product 1.
実施例２
　メノウ製ボールミルポット(内径4cm、高さ4cm)に核粒子1を300mg、カルバナロウを150mg秤取した。直径10mmのメノウ製ボールを4個入れた。遊星ボールミル（フレッチェ社、pulverisette6)にて、回転速度500rpmで6時間混合し、コーティング品2を得た。 Example 2
300 mg of core particles 1 and 150 mg of carnauba wax were weighed in a ball mill pot made of agate (inner diameter: 4 cm, height: 4 cm). Four 10 mm diameter agate balls were inserted. The mixture was mixed at a rotational speed of 500 rpm for 6 hours in a planetary ball mill (Floche, pulverisette 6) to obtain a coated product 2.
実施例３
　メノウ製ボールミルポット(内径4cm、高さ4cm)に核粒子1を300mg、カルバナロウを30mg秤取した。直径10mmのメノウ製ボールを4個入れた。遊星ボールミル（フレッチェ社、pulverisette6)にて、回転速度500rpmで6時間混合し、コーティング品３を得た。 Example 3
300 mg of the core particle 1 and 30 mg of carnarowe were weighed out in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm). Four 10 mm diameter agate balls were inserted. The mixture was mixed at a rotational speed of 500 rpm for 6 hours in a planetary ball mill (Floche, pulverisette 6) to obtain a coated product 3.
＜微粒子の特性の評価＞
　実施例１～３のサンプルにつき、以下に示す方法により電子顕微鏡観察、粒子径測定、溶出試験を行って、微粒子の特性を評価した。 <Evaluation of properties of fine particles>
The samples of Examples 1 to 3 were subjected to electron microscope observation, particle diameter measurement, and elution test by the methods described below to evaluate the characteristics of the microparticles.
（１）電子顕微鏡観察
　走査型電子顕微鏡（JEOL、JSM-6510LA）を用いて、微粒子表面の観察を行った。観察結果を図３に示す。 (1) Electron Microscope Observation The surface of the fine particles was observed using a scanning electron microscope (JEOL, JSM-6510LA). The observation results are shown in FIG.
（２）粒子径測定
　核粒子１およびコーティング品１～３を数mgとり、0.05%tween80水溶液0.5～1mLにバスソニケーターを用いて分散させた。その液につき、レーザー回折粒子径測定装置SALD2200(島津製作所)で体積平均粒子径を測定した。 (2) Particle Size Measurement Several mg of the core particles 1 and the coated products 1 to 3 were taken and dispersed in 0.5 to 1 mL of a 0.05% tween 80 aqueous solution using a bath sonicator. The volume average particle size of the solution was measured by a laser diffraction particle size measuring device SALD 2200 (Shimadzu Corporation).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
（３）溶出試験
核粒子1　15mgまたはコーティング品１～３を約45mg（核粒子1として15mg相当）を試験管に秤取し、あらかじめ37℃に温めておいた溶出試験液（0.05％Tween80含有精製水）5ｍLずつ加えた。試験管をななめ45°に傾け37℃の恒温水槽にいれ100rpmで振盪し、5、10、30、45、60、90、120分後に微粒子を吸い取らないように、上清のみを500μLをサンプリングし、新たに37℃の溶出試験液500μLを試験管に補充を行った。
　溶出試験の結果を図２に示す。 (3) Dissolution test 15 mg of core particles 1 or about 45 mg (equivalent to 15 mg as core particles 1) of coated articles 1 to 3 were weighed into a test tube and dissolved beforehand in a dissolution test solution (containing 0.05% Tween 80) warmed to 37 ° C. 5 mL each of purified water) was added. Tilt the test tube to 45 °, shake in a 37 ° C water bath and shake at 100 rpm, and sample 500 μL of the supernatant only so that the particles are not absorbed after 5, 10, 30, 45, 60, 90 and 120 minutes. The test tube was newly supplemented with 500 μL of the 37 ° C elution test solution.
The results of the dissolution test are shown in FIG.
＜微粒子の特性評価の結果＞
　コーティング品1～３のVB12溶出は、いずれも、核粒子１からの溶出に比べて、溶出時間の延長が認められた(図２)。コーティング品1については、核粒子1表面で観察できた細孔が認められなかった(図３)。体積平均粒子径を測定したところ、配合比率に基づき核粒子1表面にカルバナロウが一次粒子としてコーティングされたとしたときの理論の体積平均粒子径の値とほぼ一致した(表１)。そのことから、本特許の方法により、20μmの核粒子上を一次粒子の形態のまま、溶出制御可能なコーティングが施すことができることがわかった。 <Result of characterization of fine particles>
Elution of the VB 12 of the coated articles 1 to 3 was prolonged as compared with the elution from the core particle 1 (FIG. 2). In the case of the coated product 1, no pores were observed on the surface of the core particle 1 (FIG. 3). When the volume average particle size was measured, it was almost the same as the value of the volume average particle size of theory when carbanaro was coated as primary particles on the surface of the core particle 1 based on the compounding ratio (Table 1). From the fact, it was found that the method of the present patent can apply an elution-controllable coating in the form of primary particles on core particles of 20 μm.
実施例４
　キニーネ塩酸塩二水和物(ナカライテスク株式会社)300mgをメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに回転数250rpmで30分粉砕した。そのときの粉末を核粒子2（融点は115～116℃）とした。核粒子2を150mgとカルバナロウを150mgとをメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、6時間混合し、コーティング品4を得た。核粒子2とコーティング品4につき、前述の粒子径測定方法に準じて粒子径を測定したところ、それぞれ11μm、18μm であった。0.05% ポリソルベート80水溶液900mL中で日本薬局方の溶出試験法に従い、溶出試験を行ったところ、コーティング品４は核粒子２に比べて溶出の延長が認められた（図４）。 Example 4
300 mg of quinine hydrochloride dihydrate (Nacalai Tesque, Inc.) was placed in a ball mill pot made of agate (inner diameter: 4 cm, height: 4 cm) and ground with four agate balls of 10 mm in diameter at a rotational speed of 250 rpm for 30 minutes. The powder at that time was designated as core particle 2 (melting point: 115 to 116 ° C.). 150 mg of the core particle 2 and 150 mg of carnavar are placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and four agate balls of 10 mm in diameter with a planetary ball mill (Flucci, Pulverisette 6) rotation speed 250 rpm The mixture was mixed for 6 hours to obtain a coated product 4. The particle sizes of the core particle 2 and the coated product 4 were measured according to the above-mentioned particle size measuring method, and they were 11 μm and 18 μm, respectively. According to the dissolution test in 900 mL of 0.05% polysorbate 80 aqueous solution according to the dissolution test method of the Japanese Pharmacopoeia, the coated product 4 showed an extension of the dissolution as compared to the core particle 2 (FIG. 4).
実施例５
　フルオレセイン-イソチオシアネート-デキストラン(MW 3000-5000)（Sigma-Aldrich）10mgを4ｍLの精製水に溶解した液をフローライト（多孔性の特殊ケイ酸カルシウム、富田薬品）1gに含浸させ、1晩凍結乾燥し、核粒子を調製した（核粒子３）（ケイ酸カルシウム融点は1200～1500℃）。核粒子3の粒子径を前述の粒子径測定法に従い粒子径を測定した結果、平均粒子径は約20μｍであった。シェラックとEudragit L100 (= 80:20) （融点は59℃）をエタノールに溶解して、テフロンシート上に広げ、一週間風乾して、フィルムを形成させた。得られたフィルムをメノウ乳鉢で粉砕し、105μｍ目開きの金網ふるいで篩過した粉末（シェラック―Eudragit L100 粉末）を得た。核粒子３を100mgとシェラック―Eudragit L100 粉末を300mgとを混合し、メノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて、250 rpm 30min、停止5 minを１サイクルとし、それを12 サイクル行い、腸溶性コーティング品1を得た。コーティング腸溶性コーティング品1を100mgとカルバナロウを50mgとをメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、6時間混合し、腸溶性コーティング品２を得た。腸溶性コーティング品１と２につき、37℃下、0.05% ポリソルベート80含有日本薬局方溶出試験第一液（ｐH1.2）25ｍLで30分間溶出試験を行った後、溶出試験液を0.05% ポリソルベート80含有日本薬局方溶出試験第二液（ｐH6.8）25ｍLに入れ替えて溶出試験を継続した（図５）。核粒子３および腸溶性コーティング品２を前述の電子顕微鏡観察を行った結果を図７に示す。核粒子３では微粒子表面に細孔が確認できた一方、腸溶性コーティング品２では細孔は認められなかった（図６）。 Example 5
A solution of 10 mg of fluorescein-isothiocyanate-dextran (MW 3000-5000) (Sigma-Aldrich) in 4 mL of purified water is impregnated into 1 g of Florite (porous calcium silicate, Tomita Pharmaceutical) and frozen overnight After drying, core particles were prepared (core particles 3) (calcium silicate melting point: 1200 to 1500 ° C.). As a result of measuring the particle size of the core particle 3 according to the above-mentioned particle size measurement method, the average particle size was about 20 μm. Shellac and Eudragit L100 (= 80:20) (melting point 59 ° C) were dissolved in ethanol, spread on a Teflon sheet and air dried for one week to form a film. The obtained film was ground in an agate mortar, and a powder (shellac-Eudragit L100 powder) sieved with a wire mesh sieve with a 105 μm mesh was obtained. 100 mg of the core particles 3 and 300 mg of shellac-Eudragit L100 powder are mixed and placed in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate having a diameter of 10 mm Pulverisette 6) was subjected to 12 cycles of 250 rpm for 30 min and 5 min for stop, and an enteric coated article 1 was obtained. 100 mg of the coated enteric-coated product 1 and 50 mg of carnauba are put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, pulverisette 6) The mixture was mixed for 6 hours at a rotational speed of 250 rpm to obtain an enteric coated article 2. The enteric coatings 1 and 2 were subjected to a dissolution test for 30 minutes with 25 mL of Japanese Pharmacopoeia Dissolution Test 1 containing 0.05% Polysorbate 80 at 37 ° C. for 30 minutes, and then the dissolution test solution was 0.05% Polysorbate 80. The dissolution test was continued by replacing it with 25 mL of the contained Japanese pharmacopoeia dissolution test second solution (pH 6.8) (FIG. 5). The results of the above-mentioned electron microscopic observation of the core particle 3 and the enteric-coated product 2 are shown in FIG. In the core particle 3, while pores could be confirmed on the surface of the fine particles, no pores were observed in the enteric-coated product 2 (FIG. 6).
実施例６
＜コーティング剤の調製＞
　カルナバロウ原末（Alfa　AesarTM）をメノウ乳鉢にて粉砕し、140メッシュ（106μm目開き）金網ふるいでの篩過品を、コーティング剤として用いた。 Example 6
<Preparation of Coating Agent>
Carnauba bulk powder of (Alfa Aesar TM) was ground in an agate mortar, the sieved product at 140 mesh (106 [mu] m mesh opening) wire mesh sieve was used as a coating agent.
＜キニーネコーティング品の調製＞
　キニーネ塩酸塩二水和物（ナカライテスク株式会社）原末を粉砕した後、（図１）に示す方法にてコーティングを行った。
　すなわち、キニーネ塩酸塩二水和物300mgを、遊星ボールミル（フレッチェ社、pulverisette6）［メノウ製ポット:内径40mm,深さ40mm, メノウ製ボール:径10mm(４個)］を用いて、250rpmで２時間粉砕し、原末粉砕品を得た。コーティング剤を所定量加え、引き続き、250rpmで６時間処理し、コーティング品を得た。 <Preparation of quinine-coated products>
After crushing the raw powder of quinine hydrochloride dihydrate (Nacalai Tesque, Inc.), coating was performed according to the method shown in FIG.
That is, 300 mg of quinine hydrochloride dihydrate was added to 250 rpm using a planetary ball mill (Fletsche company, pulverisette 6) [pot made from agate: inner diameter 40 mm, depth 40 mm, agate made balls: diameter 10 mm (four)]. It was ground for time to obtain a ground powder product. The coating agent was added in a predetermined amount, and subsequently treated at 250 rpm for 6 hours to obtain a coated product.
＜粒子評価＞
　表面状態は走査型電子顕微鏡（JEOL製 JSM-6510LA）にて評価した。粒度分布はレーザー回折型粒度測定機（島津製SALD2200）を用いて測定した。 <Particle evaluation>
The surface state was evaluated by a scanning electron microscope (JSM-6510LA manufactured by JEOL). The particle size distribution was measured using a laser diffraction type particle sizer (SALD 2200 manufactured by Shimadzu).
＜溶出試験＞
　溶出試験は、日本薬局方溶出試験法第二法（パドル法）に準じて行った。溶出した薬物は蛍光光度計(BioTek Instruments Inc.製 SynergyH4)を用いて測定した。  
試験サンプル: 原末粉砕品、キニーネコーティング品 (キニーネ塩酸塩二水和物として5mg相当)
条件：溶出試験液/0.05% Tween 80 水溶液 900 mL, 攪拌強度/ 50 rpm ,試験温度 / 37±0.5℃ <Dissolution test>
The dissolution test was conducted according to Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). The eluted drug was measured using a fluorometer (Synergy H4 manufactured by BioTek Instruments Inc.).
Test sample: Raw powder ground product, quinine coated product (equivalent to 5 mg of quinine hydrochloride dihydrate)
Conditions: Dissolution test solution / 900 mL of 0.05% aqueous solution of Tween 80, agitation strength / 50 rpm, test temperature / 37 ± 0.5 ° C
　核粒子に用いた原末粉砕品と得られたコーティング品（カルバナロウ/原末粉砕品＝1：2）の表面状態を走査型電子顕微鏡（SEM）により観察した（図７）。原末粉砕品の表面は鱗片状であるのに対して、コーティング品は比較的平滑な表面状態を示した。レーザー回折法より求めた粒度分布を図８に示す。平均粒子径は、原末粉砕末が 10.34±0.35μm、コーティング品は 10.16±0.44μmであった。核粒子が一次粒子としてコーティングされる場合、コーティング率50％では体積比から粒子径は約1.145倍になると計算され、コーティングによる粒子径の変化は小さいものと予想される。実際、実測においても累積相対頻度約70～80％のところまで両者に大きな差が認められなかった。従って、この条件では粒子の多くが一次粒子としてコーティングされているものと推察される。 The surface condition of the raw powder crushed product used for the core particles and the obtained coated product (Carbanaro / raw powder crushed product = 1: 2) was observed by a scanning electron microscope (SEM) (FIG. 7). While the surface of the ground powder product was scaly, the coated product exhibited a relatively smooth surface condition. The particle size distribution determined by the laser diffraction method is shown in FIG. The average particle size was 10.34 ± 0.35 μm for the raw powder and ground powder, and 10.16 ± 0.44 μm for the coated product. When core particles are coated as primary particles, at a coating ratio of 50%, it is calculated from the volume ratio that the particle size is approximately 1.145 times, and the change in particle size due to the coating is expected to be small. In fact, in the actual measurement also, no significant difference was found between them until the cumulative relative frequency was about 70 to 80%. Therefore, it is assumed that many of the particles are coated as primary particles under these conditions.
　原末粉砕品とコーティング品からの薬物溶出挙動を比較したところ、コーティングにより溶出の延長が認められた（図９）。この薬物溶出の延長は、カルバナロウと原末粉砕品の比が1:2で最も大きく、2時間にわたり溶出が持続した。一方、2:1と1:10では30分で約90％が溶出する放出挙動を示した（図９）。 When the drug elution behavior from the ground powder product and the coated product was compared, extension of the elution was recognized by the coating (FIG. 9). The prolongation of the drug elution was the largest at a ratio of carnarowe to that of the pulverized powder of 1: 2, and the elution lasted for 2 hours. On the other hand, in 2: 1 and 1:10, about 90% eluted the release behavior in 30 minutes (FIG. 9).
実施例７
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgを、ガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を3回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数100rpmで、6時間混合し、コーティング品６を得た。 Example 7
Using the powdered raw powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was poured into a 50 mL centrifuge tube made of glass and mixed 30 times, The mixture was sieved three times with a 100 mesh (149 μm mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with four agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at 100 rpm for 6 hours The coating 6 was obtained.
実施例８
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgをガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を3回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、6時間混合し、コーティング品７を得た。同操作を3回行い、3バッチを得た。3バッチの粒子径は、それぞれ、14.68±0.45μｍ、9.80±0.44μｍ、11.02±0.46μｍとなった。 Example 8
Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 μm mesh) wire mesh sieve. The obtained mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotational speed of 250 rpm for 6 hours The coating 7 was obtained. The same operation was performed 3 times to obtain 3 batches. The particle sizes of the three batches were 14.68 ± 0.45 μm, 9.80 ± 0.44 μm, and 11.02 ± 0.46 μm, respectively.
実施例９
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgをガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を3回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数500rpmで、6時間混合し、コーティング品８を得た。粒子径は、13.00±0.40μｍとなった。 Example 9
Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 μm mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at 500 rpm for 6 hours The coating 8 was obtained. The particle size was 13.00 ± 0.40 μm.
　実施例７～９のコーティング品６～８について、実施例６記載の方法に従って溶出試験を行ったところ、溶出挙動は図１０に示す通りとなった。 The coated articles 6 to 8 of Examples 7 to 9 were subjected to the dissolution test according to the method described in Example 6, and the dissolution behavior was as shown in FIG.
実施例１０
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgをガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を3回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、30分混合し、コーティング品９を得た。 Example 10
Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 μm mesh) wire mesh sieve. The obtained mixture is put into a ball mill pot made of agate (inner diameter 4 cm, height 4 cm) and mixed with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) for 30 minutes at 250 rpm. The coating 9 was obtained.
実施例１１
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgをガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を3回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、60分混合し、コーティング品１０を得た。 Example 11
Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 μm mesh) wire mesh sieve. The obtained mixture is put into an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 alum balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotation speed of 250 rpm for 60 minutes The coating 10 was obtained.
実施例１２
　実施例６に示した原末粉砕品（キニーネ塩酸塩二水和物）とコーティング剤（カルナバロウ）を用い、各150 mgをガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を３回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpmで、3時間混合し、コーティング品１１を得た。 Example 12
Using the powdered powder (quinine hydrochloride dihydrate) shown in Example 6 and a coating agent (Carnauba wax), 150 mg of each was put into a 50 mL centrifuge tube made of glass and mixed 30 times, and then 100 The mixture was sieved three times with a mesh (149 μm mesh) wire mesh sieve. The resulting mixture is placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm) and mixed with 4 agate balls with a diameter of 10 mm in a planetary ball mill (Flucci, Pulverisette 6) at a rotational speed of 250 rpm for 3 hours The coating 11 was obtained.
　実施例８のコーティング品７および実施例１０～１２のコーティング品９～１１について、実施例６記載の方法に従って溶出試験を行ったところ、溶出挙動は図１１に示す通りとなった。 The coated articles 7 of Example 8 and the coated articles 9 to 11 of Examples 10 to 12 were subjected to the elution test according to the method described in Example 6, and the elution behavior was as shown in FIG.
実施例１３
＜PLGAコーティング剤の調製＞
　乳酸・グリコール酸（シグマ・アルドリッチ社、ResomerTMRG502）を遊星ボールミル（フレッチェ社、pulverisette6）［メノウ製ポット:内径40mm,深さ40mm, メノウ製ボール:径10mm(4個)］を用いて、250rpm　15分間粉砕して、PLGAコーティング剤１を得た。後述する粒子径測定方法にて測定した粒子径は、21.86±0.45μmであった。 Example 13
<Preparation of PLGA Coating Agent>
Lactic acid-glycolic acid (Sigma-Aldrich, Resomer TM RG502) a planetary ball mill (Furetche Co., Pulverisette6) [agate pot: inner diameter 40 mm, depth 40 mm, agate ball: diameter 10 mm (4 pieces) with, Grinding was performed at 250 rpm for 15 minutes to obtain PLGA coating agent 1. The particle diameter measured by the particle diameter measuring method described later was 21.86 ± 0.45 μm.
＜ＰＬＧＡマイクロスフェアの調製＞
　シアノコバラミン100mgを、遊星ボールミル（フレッチェ社、pulverisette6）［メノウ製ポット:内径40mm,深さ40mm, メノウ製ボール:径10mm(4個)］を用いて、250rpm　2時間粉砕して、VB12粉砕品を得た。後述する粒子径測定方法で、分散媒に塩化メチレンを用いて測定したVB12粉砕品の粒子径は、粒子径9.07±0.47μmであった。VB12粉砕品15mgとPLGAコーティング剤１　60mgを加え、ガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を３回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpm30分→5分間休止のサイクルを12回繰り返し、PLGAマイクロスフェア1を得た。PLGAマイクロスフェア1 25mgにPLGAコーティング剤２　31.25 mgを加えて、混合し、メノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて「回転数250rpm　30分→5分間休止」のサイクルを12回繰り返し、PLGAマイクロスフェア2を得た。 <Preparation of PLGA Microspheres>
Cyanocobalamin 100mg, planetary ball mill (Furetche Co., Pulverisette6) [agate pot: inner diameter 40 mm, depth 40 mm, agate ball: diameter 10 mm (4 pieces) with, by pulverizing 250 rpm 2 hours, VB 12 pulverized product I got The particle diameter of the crushed product of VB 12 measured using methylene chloride as the dispersion medium by the particle diameter measurement method described later was the particle diameter of 9.07 ± 0.47 μm. 15 mg of VB 12 ground product and 60 mg of PLGA coating agent 1 were added and placed in a 50 mL glass centrifuge tube and mixed 30 times, and then mixed and sieved three times with 100 mesh (149 μm mesh) wire mesh sieve . The obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes → 5 minutes rest The cycle of was repeated 12 times to obtain PLGA microspheres 1. PLGA Microsphere 1 25 mg of PLGA coating agent 2 is added, mixed with 31.25 mg of PLGA coating agent 2 and placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm), together with four agate balls made of a diameter of 10 mm A PLGA microsphere 2 was obtained by repeating a cycle of “rotation speed 250 rpm for 30 minutes → rest for 5 minutes” in Pulverisette 6) 12 times.
（１）光学顕微鏡観察
　光学顕微鏡を用いて、PLGAマイクロスフェア２の微粒子の観察を行った。
（２）粒子径測定方法
　ＰＬＧＡマイクロスフェア2，4，5を数mgとり、0.05%tween80水溶液0.5～1mLにバスソニケーターを用いて分散させた。その液につき、レーザー回折粒子径測定装置SALD2200(島津製作所)で体積平均粒子径を測定した。
（３）溶出試験方法
　PLGAマイクロスフェア１～７を約2～5mgを試験管に秤取し、あらかじめ37℃に温めておいた溶出試験液（9.6mM　リン酸緩衝液-生理食塩水　pH7.4）10ｍL加えた。37℃の空気恒温槽にいれ100rpmで水平振盪し、あらかじめ決めた時間に、上清を1000μLサンプリングし、新たに37℃の溶出試験液1000μLを試験管に補充を行い、溶出試験を継続した。なお、1hr溶出率を初期バーストとして評価した (1) Optical microscope observation The microparticles of PLGA microspheres 2 were observed using an optical microscope.
(2) Particle Size Measurement Method Several mg of PLGA microspheres 2, 4 and 5 were taken, and dispersed in 0.5 to 1 mL of a 0.05% tween 80 aqueous solution using a bath sonicator. The volume average particle size of the solution was measured by a laser diffraction particle size measuring device SALD 2200 (Shimadzu Corporation).
(3) Dissolution test method About 2-5 mg of PLGA microspheres 1 to 7 are weighed into a test tube, and the dissolution test solution (9.6 mM phosphate buffer-saline pH 7.4) previously warmed to 37 ° C. ) 10 mL was added. In a 37 ° C. air thermostat, horizontally shake at 100 rpm, and at a predetermined time, 1000 μL of the supernatant was sampled, and 1000 μL of the 37 ° C. elution test solution was newly replenished in the test tube, and the elution test was continued. In addition, 1 hr elution rate was evaluated as initial burst
　図１２に示す光学顕微鏡写真像より、本方法により、球形に近い不定形のマイクロスフェアが得られることが分かった。また、この写真に示すPLGAマイクロスフェア２は、PLGAのコーティング剤1を2分割して投入したが、得られた微粒子一つ一つにVB12の赤色が確認でき、VB12を含有していない微粒子は確認できなかった。このことより、本方法により、マイクロスフェア内に薬物を均一に包含させることができることが分かった。 From the optical micrograph image shown in FIG. 12, it was found that the near spherical spherical shaped amorphous microspheres can be obtained by this method. In addition, PLGA microspheres 2 shown in this photograph were divided into two portions of PLGA coating agent 1 and charged, but the red particles of VB 12 can be confirmed in each of the obtained microparticles, and VB 12 is not contained. No particulates could be confirmed. From this, it was found that the method makes it possible to uniformly incorporate the drug in the microspheres.
　さらに、表２に示す通り、遊星ボールミルでの処理中に、PLGAコーティング剤を追加することにより、初期バーストが抑制できること分かった。得られたPLGAマイクロアスフェア２は、図１３に示す通り初期バーストの後、長期にわたりVB12を持続放出することが確認できた。 Furthermore, as shown in Table 2, it was found that the initial burst can be suppressed by adding the PLGA coating agent during the processing with the planetary ball mill. It was confirmed that the obtained PLGA microsphere 2 sustained-released VB 12 for a long period after the initial burst as shown in FIG.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
実施例１４
＜PLGAコーティング剤の調製＞
　乳酸・グリコール酸（PLGA5020、和光純薬社）を遊星ボールミル（フレッチェ社、pulverisette6）［メノウ製ポット:内径40mm,深さ40mm, メノウ製ボール:径10mm(４個)］を用いて、250rpm 15分間粉砕して、PLGAコーティング剤２を得た。粒子径測定方法にて測定した粒子径は、62.95±0.34μmであった。 Example 14
<Preparation of PLGA Coating Agent>
Using lactic acid / glycolic acid (PLGA 5020, Wako Pure Chemical Industries, Ltd.) with a planetary ball mill (Frece, Pulverisette 6) [pot made of agate: 40 mm in inner diameter, 40 mm in depth, ball made of agate: 10 mm in diameter (4 pieces)] 250 rpm 15 Grinding for a minute gave PLGA coating agent 2. The particle size measured by the particle size measuring method was 62.95 ± 0.34 μm.
＜PLGAマイクロスフェアの調製＞
　実施例１３で得たVB12粉砕品25mg、実施例１３で得たコーティング剤1　50mg、コーティング剤2　62.5mgを加え、ガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を1回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpm30分→5分間休止のサイクルを12回繰り返し、PLGAマイクロスフェア中間体を得た。PLGAマイクロスフェア中間体　68.75 mgにＰＬＧＡコーティング剤1　25mgとＰＬＧＡコーティング剤2　31.25mgを加えて、混合し、メノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpm 30分→5分間休止のサイクルを12回繰り返し、PLGAマイクロスフェア3を得た。 <Preparation of PLGA Microspheres>
25 mg of the crushed product of VB 12 obtained in Example 13, 50 mg of the coating agent 1 obtained in Example 13, and 62.5 mg of the coating agent 2 are added into a 50 mL centrifuge tube made of glass and mixed 30 times, then 100 mesh (149 [mu] m opening) The mixed sieve with a wire mesh sieve was performed once. The obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes → 5 minutes rest The cycle of was repeated 12 times to obtain PLGA microsphere intermediate. PLGA Microsphere Intermediate 25.75 mg of PLGA Coating Agent 1 and 31.25 mg of PLGA Coating Agent 2 are added to 68.75 mg of PLGA Microspheres, mixed, placed in an agate ball mill pot (inner diameter 4 cm, height 4 cm), agate balls 10 mm in diameter PLGA microspheres 3 were obtained by repeating 12 cycles of 30 rpm → 5 minutes rest at a rotational speed of 250 rpm in a planetary ball mill (Frece, Pulverisette 6) together with 4 pieces.
実施例１５
　実施例１３で得たVB12粉砕品25mg、実施例１３で得たコーティング剤1　50mg、コーティング剤2　62.5mgを加え、ガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を1回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpm30分→5分間休止のサイクルを24回繰り返し、PLGAマイクロスフェア4を得た。 Example 15
25 mg of the crushed product of VB 12 obtained in Example 13, 50 mg of the coating agent 1 obtained in Example 13, and 62.5 mg of the coating agent 2 are added into a 50 mL centrifuge tube made of glass and mixed 30 times, then 100 mesh (149 [mu] m opening) The mixed sieve with a wire mesh sieve was performed once. The obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes → 5 minutes rest The cycle of was repeated 24 times to obtain PLGA microspheres 4.
実施例１６
　実施例１３で得たVB12粉砕品12.5 mg、実施例１３で得たコーティング剤1　50mg、コーティング剤2　62.5mgを加え、ガラス製50ｍＬ容遠沈管の中に入れ30回降り混ぜた後、100メッシュ（149μm目開き）金網ふるいでの混合篩過を1回行った。得られた混合品をメノウ製ボールミルポット(内径4cm、高さ4cm)に入れて、直径10mmのメノウ製ボールを4個とともに遊星ボールミル（フレッチェ社、pulverisette6)にて回転数250rpm30分→5分間休止のサイクルを1回（PLGAマイクロスフェア5を得る）、2回（PLGAマイクロスフェア6を得る）、6回（PLGAマイクロスフェア7を得る）、12回（PLGAマイクロスフェア8を得る）を行った。 Example 16
After adding 12.5 mg of the VB 12 ground product obtained in Example 13, 50 mg of the coating agent 1 obtained in Example 13, and 62.5 mg of the coating agent 2 and putting the mixture in a 50 mL glass centrifuge tube and mixing 30 times, 100 The mixture was sieved once with a mesh (149 μm mesh) wire mesh sieve. The obtained mixture is put in a ball mill pot made of agate (inner diameter 4 cm, height 4 cm), together with 4 balls made of agate with a diameter of 10 mm in a planetary ball mill (Flucci company, Pulverisette 6) rotation speed 250 rpm 30 minutes → 5 minutes rest Of 1 cycle (to obtain PLGA microspheres 5), 2 times (to obtain PLGA microspheres 6), 6 times (to obtain PLGA microspheres 7) and 12 times (to obtain PLGA microspheres 8).
　実施例１４及び１５にて得られたPLGAマイクロスフェアについて、実施例１３に示す粒子径測定方法と溶出試験方法により、粒子径と初期バーストを評価した結果を表３に示す。同じ量のPLGAコーティング剤を１度に投入し処理したときと、2分割投入し処理したときとを比べた。その結果、初期バーストに影響はないものの、PLGAコーティング剤を１度に投入し処理すると粒子同士の凝集が促進され、懸濁注射が出来ない粒子径となった一方で、分割投入すると、凝集が抑えられ、累積量95%まで粒子径150μm以下に分布したことから、懸濁注射可能な粒子径を保つことができた。 The PLGA microspheres obtained in Examples 14 and 15 were evaluated for particle size and initial burst by the particle size measurement method and the dissolution test method shown in Example 13, and the results are shown in Table 3. The same amount of PLGA coating agent was charged at one time and processed, and was compared with two divided charges. As a result, although the initial burst does not have an effect, the addition of PLGA coating agent at one time promotes the aggregation of the particles, and the particle size is such that suspension injection can not be performed. Since the particle size was suppressed to 150% of the particle size or less to a cumulative amount of 95%, the particle size for suspension injection could be maintained.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　実施例１５及び１６にて得られたPLGAマイクロスフェアについて、実施例１３に示す溶出試験方法により、初期バーストを評価した結果を表４に示す。
　遊星ボールミルの「回転数250rpm　30分→5分間休止」とのサイクル数、1回（PLGAマイクロスフェア5）、2回（PLGAマイクロスフェア6）、6回（PLGAマイクロスフェア7）、12回（PLGAマイクロスフェア8）、24回（PLGAマイクロスフェア4）と、サイクル数を増やすことにより、初期バーストを抑制することができることが分かった。 The results of evaluating the initial burst of the PLGA microspheres obtained in Examples 15 and 16 by the dissolution test method shown in Example 13 are shown in Table 4.
Number of cycles of “rotation speed 250 rpm 30 minutes → 5 minutes rest” of the planetary ball mill, once (PLGA microspheres 5), twice (PLGA microspheres 6), 6 times (PLGA microspheres 7), 12 times (PLGA) By increasing the cycle number to 24 times (PLGA microspheres 4), it was found that the initial burst can be suppressed.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004

Claims (34)

  1. 活性成分を含む粒径100μｍ以下の第一の粒子と、樹脂又は油脂の少なくとも一種を含む第二の粒子とを機械的に混合する工程を含む、樹脂又は油脂で被覆された粒子の製造方法。 A method of producing particles coated with resin or fat comprising mechanically mixing a first particle having a particle size of 100 μm or less containing an active ingredient and a second particle containing at least one of a resin or fat.
  2. 樹脂又は油脂で被覆された粒子が、注射可能な粒子径を有する粒子である、請求項１に記載の方法。 The method according to claim 1, wherein the resin or fat-coated particles are particles having an injectable particle size.
  3. 機械的に混合する工程を、溶媒及び液状分散媒の非存在下において行う、請求項１又は２に記載の方法。 The method according to claim 1 or 2, wherein the step of mechanically mixing is performed in the absence of a solvent and a liquid dispersion medium.
  4. 機械的に混合する工程において、第二の粒子を分割して投入する、請求項１から３の何れか一項に記載の方法。 The method according to any one of claims 1 to 3, wherein in the step of mechanically mixing, the second particles are divided and introduced.
  5. 第一の粒子の融点より第二の粒子の融点の方が低い、請求項１から４の何れか一項に記載の方法。 The method according to any one of claims 1 to 4, wherein the melting point of the second particle is lower than the melting point of the first particle.
  6. 第一の粒子が、多孔性粒子に活性成分を包含させた粒子である、請求項１から５の何れか一項に記載の方法。 The method according to any one of claims 1 to 5, wherein the first particle is a particle in which the porous particle incorporates the active ingredient.
  7. 多孔性粒子が、エチルセルロースからなる粒子である、請求項６に記載の方法。 The method according to claim 6, wherein the porous particles are particles consisting of ethyl cellulose.
  8. 第二の粒子が、15℃以上100℃以下の融点を有する樹脂又は油脂の少なくとも一種を含む、請求項１から７の何れか一項に記載の方法。 The method according to any one of claims 1 to 7, wherein the second particles contain at least one of a resin or a fat having a melting point of 15 ° C to 100 ° C.
  9. 第二の粒子がシェラックを含む、請求項１から８の何れか一項に記載の方法。 9. A method according to any one of the preceding claims, wherein the second particle comprises shellac.
  10. 第二の粒子が生体内分解性高分子を含む、請求項１から９の何れか一項に記載の方法。 10. The method according to any one of the preceding claims, wherein the second particle comprises a biodegradable polymer.
  11. 生体内分解性高分子がポリ乳酸、ポリグリコール酸又は乳酸・グリコール酸コポリマーである、請求項１０に記載の方法。 The method according to claim 10, wherein the biodegradable polymer is polylactic acid, polyglycolic acid or lactic acid / glycolic acid copolymer.
  12. 第二の粒子が、15℃以上100℃以下の融点を有する油脂と重量平均分子量１０００以上の高分子との固体分散体または固溶体である、請求項１から１１の何れか一項に記載の方法。 The method according to any one of claims 1 to 11, wherein the second particle is a solid dispersion or solid solution of a fat and oil having a melting point of 15 ° C to 100 ° C and a polymer having a weight average molecular weight of 1000 or more. .
  13. 第二の粒子が、シェラックと腸溶性ポリマーとの固体分散体または固溶体である、請求項１から１２の何れか一項に記載の方法。 13. A method according to any one of the preceding claims, wherein the second particles are a solid dispersion or solid solution of shellac and an enteric polymer.
  14. 腸溶性ポリマーがメタクリル酸コポリマーＬである請求項１３に記載の方法。 The method according to claim 13, wherein the enteric polymer is methacrylic acid copolymer L.
  15. 第一の粒子と第二の粒子とを機械的に混合する工程を、封じ込め容器により行う、請求項１から１４の何れか一項に記載の方法。 The method according to any one of the preceding claims, wherein the step of mechanically mixing the first and second particles is performed by means of a containment vessel.
  16. 第一の粒子と第二の粒子とを機械的に混合する工程を、ボールミル中において行う、請求項１から１５の何れか一項に記載の方法。 The method according to any one of claims 1 to 15, wherein the step of mechanically mixing the first particles and the second particles is performed in a ball mill.
  17. 封じ込め容器が、底面の長径と高さが1:10～10:1の範囲の容器である、請求項１５に記載の方法。 The method according to claim 15, wherein the containment vessel is a vessel having a major axis length and a height in the range of 1:10 to 10: 1.
  18. 樹脂又は油脂で被覆された粒子が、徐放性粒子である、請求項１から１７の何れか一項に記載の方法。 The method according to any one of claims 1 to 17, wherein the resin or fat-coated particles are sustained release particles.
  19. 樹脂又は油脂で被覆された粒子が、腸溶性粒子である、請求項１から１７の何れか一項に記載の方法。 18. The method according to any one of the preceding claims, wherein the resin or oil-coated particles are enteric particles.
  20. 請求項１から１９の何れか一項に記載の方法により、樹脂又は油脂で被覆された粒子を製造する工程、及び前記の樹脂又は油脂で被覆された粒子と、樹脂又は油脂の少なくとも一種を含む第三の粒子とを機械的に混合する工程を含む、樹脂又は油脂の多層で被覆された粒子の製造方法。 A process for producing particles coated with a resin or oil according to the method of any one of claims 1 to 19, and particles coated with the resin or oil described above, and at least one of resin or oil. A method for producing a multi-layer resin- or oil-coated particle, comprising the step of mechanically mixing with a third particle.
  21. （ｉ）活性成分を含む粒径100μｍ以下の核粒子と、（ｉｉ）前記核粒子の表面に被覆されており、樹脂又は油脂の少なくとも一種を含む被覆層、とを有する粒子。 (I) particles having a core particle having a particle diameter of 100 μm or less containing an active ingredient, and (ii) a coating layer coated on the surface of the core particle and containing at least one of a resin or a fat and oil.
  22. 核粒子の融点より、被覆層を構成する樹脂又は油脂の融点の方が低い、請求項２１に記載の粒子。 The particles according to claim 21, wherein the melting point of the resin or fat constituting the coating layer is lower than the melting point of the core particles.
  23. 核粒子が、多孔性粒子に活性成分を包含させた粒子である、請求項２１又は２２に記載の粒子。 The particle according to claim 21 or 22, wherein the core particle is a particle having a porous particle incorporated with an active ingredient.
  24. 多孔性粒子が、エチルセルロースからなる粒子である、請求項２３に記載の粒子。 The particles according to claim 23, wherein the porous particles are particles consisting of ethyl cellulose.
  25. 被覆層を構成する樹脂又は油脂の融点が、15℃以上100℃以下である、請求項２１から２４の何れか一項に記載の粒子。 The particles according to any one of claims 21 to 24, wherein the melting point of the resin or fat constituting the covering layer is 15 ° C or more and 100 ° C or less.
  26. 被覆層がシェラックを含む、請求項２１から２５の何れか一項に記載の粒子。 26. The particle according to any one of claims 21-25, wherein the covering layer comprises shellac.
  27. 被覆層が生体内分解性高分子を含み、注射可能な粒子径を有する、請求項２１から２５の何れか一項に記載の粒子。 26. A particle according to any one of claims 21 to 25, wherein the covering layer comprises a biodegradable polymer and has an injectable particle size.
  28. 被覆層がポリ乳酸または乳酸・グリコール酸コポリマーを含み、粒子の９０％粒径（Ｄ９０）が１５０μm以下である、請求項２１から２５の何れか一項に記載の粒子。 The particles according to any one of claims 21 to 25, wherein the covering layer comprises polylactic acid or lactic acid / glycolic acid copolymer and the 90% particle diameter (D90) of the particles is 150 μm or less.
  29. 被覆層が、15℃以上100℃以下の融点を有する油脂と重量平均分子量1000以上の高分子とを含む、請求項２１から２８の何れか一項に記載の粒子。 The particles according to any one of claims 21 to 28, wherein the coating layer comprises a fat having a melting point of 15 ° C to 100 ° C and a polymer having a weight average molecular weight of 1000 or more.
  30. 被覆層が、シェラックと腸溶性ポリマーとを含む、請求項２１から２９の何れか一項に記載の粒子。 30. The particle according to any one of claims 21 to 29, wherein the covering layer comprises shellac and an enteric polymer.
  31. 腸溶性ポリマーがメタクリル酸コポリマーＬである請求項３０に記載の粒子。 31. A particle according to claim 30, wherein the enteric polymer is methacrylic acid copolymer L.
  32. 徐放性粒子である、請求項２１から３１の何れか一項に記載の粒子。 32. A particle according to any one of claims 21 to 31, which is a sustained release particle.
  33. 腸溶性粒子である、請求項２１から３１の何れか一項に記載の粒子。 32. A particle according to any one of claims 21 to 31, which is an enteric particle.
  34. 樹脂又は油脂の少なくとも一種を含む被覆層を２層以上有している、請求項２１から３３の何れか一項に記載の粒子。 The particles according to any one of claims 21 to 33, which have two or more coating layers containing at least one resin or fat.
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