WO2019009335A1 - Procédé de production de particules fines et particules fines - Google Patents

Procédé de production de particules fines et particules fines 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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English (en)
Japanese (ja)
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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/ja
Publication of WO2019009335A1 publication Critical patent/WO2019009335A1/fr

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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

La présente invention concerne un procédé de revêtement à sec de surfaces de substances nucléiques ayant des diamètres de particule inférieurs ou égaux à 100 µm, lesdites substances nucléiques étant utilisées en tant que particules primaires ; et des particules fines qui sont produites par ce procédé. La présente invention concerne un procédé de production de particules qui sont recouvertes d'une résine ou d'une graisse/huile, qui comprend une étape de mélange mécanique de premières particules qui contiennent un composant actif et ont des diamètres de particule inférieurs ou égaux à 100 µm et de secondes particules qui contiennent au moins l'une parmi une résine et une graisse/huile.
PCT/JP2018/025399 2017-07-04 2018-07-04 Procédé de production de particules fines et particules fines WO2019009335A1 (fr)

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003012504A (ja) * 2001-06-26 2003-01-15 Hosokawa Micron Corp 薬物含有複合粒子の製造方法
JP2003275281A (ja) * 2002-03-20 2003-09-30 Hosokawa Micron Corp 薬物含有複合粒子の製造方法
JP2004501183A (ja) * 2000-06-27 2004-01-15 ヴェクトゥラ　リミテッド 医薬組成物で使用するための粒子の製造法
JP2004035446A (ja) * 2002-07-02 2004-02-05 Tendou Seiyaku Kk 微小球体の製造方法およびその製造装置
JP2004143071A (ja) * 2002-10-23 2004-05-20 Hosokawa Funtai Gijutsu Kenkyusho:Kk 薬物含有複合粒子の製造方法および薬物含有複合粒子
US20100266703A1 (en) * 2007-06-26 2010-10-21 David Morton Novel powder and its method of manufacture
JP2012017326A (ja) * 2010-06-11 2012-01-26 Takashi Fujii 難溶物を含有するカプセルとその製造方法
JP2012524718A (ja) * 2009-04-24 2012-10-18 イシューティカ ピーティーワイ リミテッド 商業的規模での封入ナノ粒子の製造
JP2013512943A (ja) * 2009-12-08 2013-04-18 ベクトゥラ・リミテッド プロセスおよび生成物
JP2013155124A (ja) * 2012-01-30 2013-08-15 Moriroku Chemicals Co Ltd 医薬品の原末及びその製造方法
US20140050795A1 (en) * 2011-02-28 2014-02-20 Monash University Binder powders
JP2015533162A (ja) * 2012-10-15 2015-11-19 ニュー ジャージー インスティチュート オブ テクノロジー 医薬品成分を被覆するための無溶剤混合方法

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501183A (ja) * 2000-06-27 2004-01-15 ヴェクトゥラ　リミテッド 医薬組成物で使用するための粒子の製造法
JP2003012504A (ja) * 2001-06-26 2003-01-15 Hosokawa Micron Corp 薬物含有複合粒子の製造方法
JP2003275281A (ja) * 2002-03-20 2003-09-30 Hosokawa Micron Corp 薬物含有複合粒子の製造方法
JP2004035446A (ja) * 2002-07-02 2004-02-05 Tendou Seiyaku Kk 微小球体の製造方法およびその製造装置
JP2004143071A (ja) * 2002-10-23 2004-05-20 Hosokawa Funtai Gijutsu Kenkyusho:Kk 薬物含有複合粒子の製造方法および薬物含有複合粒子
US20100266703A1 (en) * 2007-06-26 2010-10-21 David Morton Novel powder and its method of manufacture
JP2012524718A (ja) * 2009-04-24 2012-10-18 イシューティカ ピーティーワイ リミテッド 商業的規模での封入ナノ粒子の製造
JP2013512943A (ja) * 2009-12-08 2013-04-18 ベクトゥラ・リミテッド プロセスおよび生成物
JP2012017326A (ja) * 2010-06-11 2012-01-26 Takashi Fujii 難溶物を含有するカプセルとその製造方法
US20140050795A1 (en) * 2011-02-28 2014-02-20 Monash University Binder powders
JP2013155124A (ja) * 2012-01-30 2013-08-15 Moriroku Chemicals Co Ltd 医薬品の原末及びその製造方法
JP2015533162A (ja) * 2012-10-15 2015-11-19 ニュー ジャージー インスティチュート オブ テクノロジー 医薬品成分を被覆するための無溶剤混合方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUMON, MICHIKO ET AL.: "Novel approach to DPI carrier lactose with mechanofusion process with additives and evaluation by IGC", CHEM. PHARM. BULL., vol. 54, no. 11, November 2006 (2006-11-01), pages 1508 - 1514, XP055561992, ISSN: 1347-5223, DOI: 10.1248/cpb.54.1508 *

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