JP2012087073A - Method for producing coating particle, and the coating particle produced by the production method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a coating method capable of coating a drug stably and efficiently.SOLUTION: This method for producing coating particles which are coated with a coating compound includes processes: (A) a process of sticking a binder and a coating compound particle on each wax coating particle obtained by coating a core particle with wax; and (B) a process of heating particles obtained in the process (A) up to a melting point of wax or higher.

Description

  The present invention relates to a method for producing coating particles, and a coating particle produced by the production method.

  In order to impart various functions such as gastric solubility, enteric solubility, and sustained release to the preparation, a coating preparation in which the preparation is coated is used. The method of coating the preparation with the coating agent is classified into a wet method and a dry method, and the wet method is general.

  A typical wet method is a coating method in which a liquid in which a coating agent is dissolved or suspended is sprayed onto a preparation and then the liquid is evaporated. However, if the solvent of the coating agent is water, a lot of energy is required for evaporation after spraying, and if the core contains a component that deteriorates due to water, this will deteriorate. There was a problem that the use of various components was restricted. Further, when an organic solvent is used as a solvent for the coating agent, there is a problem that the organic solvent remains unless the organic solvent is completely removed.

  On the other hand, in the dry method, these problems do not occur because no solvent is used. However, it is difficult to coat a preparation with a coating agent without a solvent, and attempts have been made to use additives such as a dry binder. However, the current situation is that the efficiency of the coating is still not improved. For example, a fixed coating of the water-soluble drug sodium carbazochrome sulfonate using lauric acid as a wax binder is applied to the core SELPHYA particles, and this is further coated with a coating agent comprising a freeze-dried powder of ethylcellulose aqueous suspension. Has been published (see Non-Patent Document 1). However, this method has a problem in that the drug (sodium carbazochrome sulfonate is used in Non-Patent Document 1) is not sufficiently fixed, and a large amount of the drug is peeled off during or after the production. For this reason, the amount of drug that can be coated is limited, and the drug coating efficiency is also poor.

  Furthermore, when a secondary coating is further performed with a polymer or the like after the drug is coated, there is a problem that the coated drug is peeled off and mixed into the secondary coating layer. Since the drug mixed in the secondary coating layer is present near the surface of the coating particle, the time until elution is accelerated, so that the coating preparation obtained by this method has a drug dissolution rate. It was difficult to control. For this reason, the performance as a coating preparation was not sufficient.

Preparation of Controlled Release Microcapsules by a High-Speed Elliptical-Rotor Type Mixer (Abstract), Proceedings of the World Congress on Particle Technology 3, No. 121, Brighton, UK, July 7-9, 1998 )

  An object of the present invention is to provide a coating method (particularly dry coating method) capable of stably and efficiently coating a drug, and coated particles in which the drug is stably coated in a relatively large amount. .

  The present inventors surprisingly applied the binder and coating compound particles to the wax-coated particles in which the core particles are coated with wax, and further heated them to a temperature higher than the melting point of the wax. The present inventors have found that it is possible to stably (i.e., strongly) and efficiently coat the compound particles for use, and have made further improvements to complete the present invention.

That is, the present invention includes, for example, the following method for producing coating particles and coating particles.
Item 1.
(A) A step of attaching the binder and coating compound particles to the wax-coated particles obtained by coating the core particles with wax (B) A step of heating the particles obtained in the step (A) to a temperature equal to or higher than the melting point of the wax. , A method for producing coated particles coated with a coating compound.
Item 2.
Item 2. The method for producing coated particles according to Item 1, wherein the binder is at least one selected from the group consisting of triethyl citrate, triacetin, dibutyl sebacate, polyethylene glycol, propylene glycol, medium chain fatty acid, and triglyceride.
Item 3.
Item 3. The coating according to Item 1 or 2, wherein the wax is at least one selected from the group consisting of organic fatty acids, ester derivatives of organic fatty acids, higher alcohols, glycerin fatty acid esters, polyethylene glycol, oil hardened oils and natural waxes. Particle production method.
Item 4.
The manufacturing method of the coating particle in any one of claim | item 1 -3 whose average particle diameter of a core particle is 1-1000 micrometers.
Item 5.
Item 5. The method for producing coated particles according to any one of Items 1 to 4, wherein the coating compound is a drug.
Item 6.
Item 6. The method for producing coating particles according to any one of Items 1 to 5, wherein the coating compound particles have an average particle size of 1/5 or less of the average particle size of the core particles.
Item 7.
further,
(C) The manufacturing method of the coating particle in any one of claim | item 1-6 including the process of coating the particle | grains obtained through a process (B) with a coating polymer.
Item 8.
Item 8. The method for producing coated particles according to Item 7, wherein the coating polymer is at least one selected from the group consisting of a cellulosic polymer, an acrylic polymer, and a biodegradable polymer.
Item 9.
Item 9. A coated particle produced by the method for producing a coated particle according to any one of Items 1 to 8.
Item 10.
A compound coating particle for coating, comprising a coating compound particle coating layer on a core particle, wherein the coating compound particle coating layer contains a wax, a binder, and a coating compound particle.
Item 11-1.
The wax is at least one selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and monoesters of any of these fatty acids with glycerin, and polyethylene glycol Seeds,
Item 11. The coating compound-coated particles according to Item 10.
Item 11-2.
The binder is at least one selected from the group consisting of triethyl citrate, triacetin, dibutyl sebacate, and polyethylene glycol;
Item 10. The coating compound-coated particles according to Item 10 or 11-1.
Item 11-3.
The coating compound is a pharmacologically active substance,
Item 10. The coating compound-coated particles according to item 10, 11-1, or 11-2.
Item 12.
Item 10. The coating compound-coated particle according to any one of Items 10 to 11-3, further comprising a polymer coating layer on the coating compound particle coating layer.
Item 13.
Item 12. The polymer coating layer is a layer comprising at least one polymer selected from the group consisting of ethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, aminoalkyl methacrylate copolymer, and polylactic acid. The coating compound coated particles as described.

  According to the method for producing coating particles of the present invention, coating compound particles can be coated on core particles stably (that is, firmly) and efficiently. This improves the stability of the resulting coating particles. Also, the coating compound is not peeled off during coating, and the coating compound is not mixed into other coating layers (for example, a polymer coating layer when a polymer coating layer is laminated on a coating compound-containing layer). The sustained release property of the compound is also greatly improved (that is, it is possible to prevent the coating compound from eluting earlier than intended and to easily control the dissolution rate).

The outline of the manufacturing method of the coated particles of the present invention will be described. The schematic diagram of the isothermal mixer with a stirring blade which can be used for coating a core particle with a wax or attaching a binder and a coating compound particle to a wax coating particle is shown. The schematic diagram of the constant temperature cone type | mold rotary mixer which can be used for coating a primary polymer with a coating polymer, etc. is shown. The result of the elution test of the compound particles for coating (sodium carbazochrome sulfonate (CCSS) which is a model drug) using the secondary coating particles is shown.

  Hereinafter, the present invention will be described in more detail.

  The present invention relates to a method for producing coated particles coated with a coating compound. The production method includes (A): a step of attaching a binder and coating compound particles to wax-coated particles obtained by coating core particles with wax, and (B): particles obtained in step (A), Heating to a melting point or higher.

Wax coated particles The wax coated particles used in the present invention are obtained by coating the core particles with wax.

  The material of the core particles is not particularly limited, and can be appropriately selected according to the purpose of use of the coating particles produced by the production method of the present invention. For example, organic particles (for example, polymer particles), inorganic particles (for example, metal particles, oxide particles) and the like can be used.

As the polymer forming the polymer particles, a vinyl polymer is preferable, and as the vinyl monomer used for the production thereof, aromatic vinyl monomers such as styrene, α-methylstyrene, halogenated styrene, divinylbenzene, and vinyl acetate are used. , Vinyl esters such as vinyl propionate, unsaturated nitriles such as acrylonitrile, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, lauryl acrylate, lauryl methacrylate, ethylene Examples thereof include ethylenically unsaturated carboxylic acid alkyl esters such as glycol diacrylate and ethylene glycol dimethacrylate. These monomers can be used alone or in combination of two or more. In addition, conjugated diolefins such as butadiene and isoprene, acrylic acid, methacrylic acid, acrylamide, methacrylamide, glycidyl acrylate, glycidyl methacrylate, N-methylol acrylamide, N-methylol methacrylamide, 2-hydroxyethyl acrylate, 2 A copolymer with a copolymerizable monomer such as hydroxyethyl methacrylate, diallyl phthalate, allyl acrylate, and allyl methacrylate can also be used.
Further, for example, metal particles such as gold, silver, copper, and nickel, and magnetic particles such as magnetite can be used.
Also, for example, alumina, hydrous silicon dioxide, dry aluminum hydroxide, magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, titanium oxide, magnesium oxide, tricalcium phosphate, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, Core particles such as calcium lactate, magnesium aluminate metasilicate, medicinal charcoal, calcium sulfate, crystalline cellulose, flour, partially pregelatinized starch, corn starch (corn starch), rice starch, wheat starch, potato starch, soluble starch, tapioca starch It can also be used as particles. Moreover, the core particle material described in the case where the present invention is used in the following pharmaceutical field can also be used appropriately in fields other than the pharmaceutical field.

When the present invention is used in the pharmaceutical field (production of pharmaceutical coating particles), for example, the core particle may be a particle composed only of an active pharmacologically active ingredient (for example, a drug if it is a medicine). It may be a particle made of a mixture with an acceptable carrier, a particle having the surface of another carrier covered with a pharmacologically active ingredient, or a particle made of a carrier not containing any pharmacologically active ingredient. When the core particle contains a pharmacologically active component, the pharmacologically active component is preferably a component used as a medicine. The core particles may be controlled-release preparations such as immediate-release preparations and sustained-release preparations (sustained-release preparations). The core particles may contain appropriate additives. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a surfactant, a sustained release agent, a stabilizer, a sour agent, a fragrance, and a fluidizing agent. It can be illustrated. These additives can be used by appropriately setting an appropriate amount in the pharmaceutical formulation field. In particular, as core particles, pills, granules, powders, drug single crystals, drug powder aggregates, lactose particles, Hydroxyapatite particles, calcium carbonate particles, isomalt particles, and crystalline cellulose (grains), lactose / crystalline cellulose spherical particles, D-mannitol spherical particles, and the like that are commercially available as coating core particles in the pharmaceutical preparation region can be preferably used. A commercial item can also be used for these. For example, as the crystalline cellulose particles, SELFIA (registered trademark) manufactured by Asahi Kasei Kogyo Co., Ltd., non-parrel (registered trademark) manufactured by Freund Corporation can be used as sucrose spherical particles and mannitol spherical particles.

  Of these, polystyrene, polymethyl methacrylate, silver, alumina, crystalline cellulose particles, mannitol spherical particles, lactose crystals, drug crystal particles (eg, acetaminophen) and the like can be preferably used.

  The core particles are not particularly limited, but those having an average particle diameter of 1-1000 μm are preferable, those having 2-1000 μm are more preferable, those having 5-500 μm are more preferable, and those having 5-200 μm are even more preferable.

  The average particle diameter of the core particles is a weight average particle diameter determined by a sieving method. In more detail, the said average particle diameter is a weight average particle diameter calculated | required by the sieving method (Rotap shaker; Iida Seisakusho make). However, when the value obtained by the method is smaller than 30 μm, the median diameter (d50) is obtained by laser diffraction / scattering particle size distribution measurement, and the median diameter is defined as the average particle diameter. For the measurement, a commercially available laser diffraction / scattering particle size distribution measuring instrument (LDSA-2400A, Tohnichi Computer Application) can be used.

  Hereinafter, when referring to the average particle size of each particle, unless otherwise specified, the average particle size is determined by a sieving method (low tap shaker; manufactured by Iida Seisakusho), unless otherwise specified. The weight average particle size. Specifically, it is a 50% by weight diameter obtained by sieving using a standard sieve (low tap shaker; manufactured by Iida Seisakusho). The average particle diameter of the coating compound particles is the median diameter (d50), and is determined by laser diffraction / scattering particle size distribution measurement. For this measurement, a commercially available laser diffraction / scattering particle size distribution measuring instrument (LDSA-2400A, : Tohnichi Computer Application).

  The core particles are coated with wax and used as wax coating particles in the present invention. Examples of the wax used in the present invention include organic fatty acids, ester derivatives of organic fatty acids, higher alcohols, glycerin fatty acid esters, polyethylene glycol, and natural waxes.

  As the organic fatty acid, a higher fatty acid is preferable, a fatty acid having 8 to 20 carbon atoms is more preferable, and a fatty acid having 10 to 18 carbon atoms is more preferable. In addition, the fatty acid preferably has 0, 1, or 2 carbon-carbon double bonds (C = C), and more preferably has 0 (ie, saturated fatty acid). Moreover, it can be a fatty acid having a straight chain or branched chain, and is preferably a straight chain fatty acid. Specific examples of preferable organic fatty acids include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and the like, and lauric acid, myristic acid, palmitic acid, and stearic acid are particularly preferable. .

  Examples of the organic fatty acid ester derivatives include the above organic fatty acid ester derivatives.

  Examples of the higher alcohol include alcohols having 8 to 18 carbon atoms. Moreover, what has a carbon-carbon double bond (C = C) 0, 1, or 2 is preferable, and what has 0 (namely, what does not have the said double bond) is more preferable. The alcohol may be a straight chain or branched chain, and is preferably a straight chain alcohol. Specific examples of preferred higher alcohols include capryl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, etc. Among them, cetyl alcohol and stearyl alcohol are preferred.

  Examples of the glycerin fatty acid ester include monoesters, diesters, and triesters of the above organic fatty acid and glycerin. Specific examples of preferable glycerin fatty acid esters include glyceryl monostearate.

  The polyethylene glycol (PEG) preferably has a weight average molecular weight of about 1500 to 10000, more preferably about 4000 to 8000. For example, commercially available product Macrogol 6000 (PEG having a weight average molecular weight of about 6000) can be preferably used.

  Examples of the oil and fat hardened oil include those produced by hydrogenating vegetable oil or fish oil.

  Examples of natural waxes include carnauba wax and rice wax.

  In addition, a wax can be used 1 type or in combination of 2 or more types.

  The wax is preferably wax particles, which are preferably used for coating the core particles. The wax particles can be produced by a known method. For example, wax particles can be produced by pulverizing and granulating wax using a jet mill, hammer mill, pin mill or the like. Further, when the wax is liquid at room temperature, it may be cooled and pulverized as appropriate. Lauric acid, myristic acid, stearic acid, macrogol 6000, and the like have a melting point of about 44 to 69 ° C., and thus are preferable in terms of easy temperature control during production.

The average particle size of the wax particles is preferably about 2 to 100 μm, more preferably about 3 to 50 μm, and still more preferably about 3 to 30 μm.

  Examples of the method of coating the core particles with the wax include a method of mixing the core particles and the wax particles. Specifically, for example, a method in which core particles and wax particles are charged in a constant temperature mixer equipped with stirring blades and stirred while heating and mixed may be mentioned. The heating may be performed, for example, to a degree higher than the melting point of the wax particles by several degrees C (for example 1 to 5 degrees C) (for example, about 60 to 75 degrees C). Moreover, after heating, it is preferable to cool with stirring. The amount of core particles and wax particles used is not particularly limited. An excessive amount of wax particles may be used with respect to the core particles. Moreover, you may perform mixing using another well-known kneading machine.

  The wax-coated particles thus obtained are particles having a wax layer on the core particle surface. In the particles, the wax content is preferably about 3 to 40% by mass, more preferably about 5 to 30% by mass. The average particle size of the wax coating particles is preferably about 7 when the average particle size of the core particles is 5. Specifically, it is about 12-1020 micrometers, for example, Preferably it is about 15-1000 micrometers.

Binder and Coating Compound Particles In the method for producing coating particles of the present invention, binder and coating compound particles are adhered to wax coating particles.

  As the binder, a pharmaceutically acceptable liquid binder can be used. Such binders are known and are described, for example, in Pharmaceutical Additives 2000 (edited by Japan Pharmaceutical Additives Association: Yakuji Nippo). Oily oils are preferred at normal temperature, specifically, triethyl citrate, triacetin, dibutyl sebacate, polyethylene glycol (weight average molecular weight of about 100 to 1000, particularly about 200 to 800 (eg, Macrogol 400)), propylene Examples include glycols, medium chain fatty acids (for example, fatty acids having 4 to 8 carbon atoms) triglycerides (for example, miglycol; capric acid triglycerides), and the like. Of these, triethyl citrate, triacetin, polyethylene glycol and the like are particularly preferable.

  A binder can be used 1 type or in combination of 2 or more types.

  The coating compound particles are particles of a compound for which the core particles are desired to be coated. The average particle size of the particles is preferably 1/5 or less, more preferably 1/10 or less, of the average particle size of the core particles. Specifically, for example, about 0.005 to 50 μm is preferable, about 0.01 to 50 μm is more preferable, and about 0.1 to 10 μm is more preferable.

  The compound particles for coating are not particularly limited, and examples thereof include particles such as pharmacologically active substances (for example, pharmaceuticals and agricultural chemicals), foods, fragrances, dyes, pigments, metals, and toners. Among these, drug particles are preferable. That is, it is preferably a particle comprising a compound used as a medicine or agrochemical. The pharmacologically active substance is not particularly limited. For example, drugs for central nervous system (aspirin, indomethacin, ibuprofen, naproxen, diclofenac sodium, meclofenoxate hydrochloride, chlorpromazine, tolmethine sodium, milnacipran hydrochloride, phenobarbital, etc.) , Peripheral nervous system drugs (etomidrine, tolperisone hydrochloride, ethyl pipetanate bromide, methylbenactidium bromide, furopropion, etc.) Respiratory drugs (ephedrine hydrochloride, chlorprenalin hydrochloride, oxerazine citrate, cloperastine, cromoglycate sodium, etc.), digestive drugs (berberine chloride, loperamide hydrochloride, cimetidine, ranitidine hydrochloride) Famotidine, etc.), coronary vasodilators (nifedipine, nicardipine, verapamil, etc.), vitamins (ascorbic acid, thiamine hydrochloride, calcium pantothenate, riboflavin, etc.), metabolic preparations (camostat mesylate, mizoribine, lysozyme chloride, etc.), Allergic drugs (cyproheptadine hydrochloride, diphenhydramine hydrochloride, alimemazine tartrate, suplatast tosilate, diphenhydramine maleate, etc.), chemotherapeutic agents (acyclovir, enoxacin, ofloxacin, pipemidic acid trihydrate, levofloxacin, etc.), antibiotics (erythromycin, hydrochloric acid) Cefcapene pivoxil, cefteram pivoxil, cefpodoxime proxetyl, cefaclor, cephalexin, clarithromycin, rokitamycin and the like.

  The particle diameter of the coating compound can be adjusted by pulverization and granulation by a known method. For example, the coating compound can be pulverized by a known method to obtain a powder having a desired average particle diameter, and the coating compound powder can be used in the present invention. The pulverization can be performed using a jet mill, a hammer mill, a pin mill, a ball mill, a planetary ball mill, or the like. Also, a drug powder obtained by a method such as pulse jet or spray drying can be used. Alternatively, a nanocrystal obtained by miniaturizing a drug using a microfluidizer can be powdered and used. It may be a drug powder obtained by freeze grinding.

  The coating compound can be used alone or in combination of two or more. That is, the coating compound particle may be a particle comprising one or more coating compounds.

  Furthermore, the coating compound particles may contain an optional component other than the coating compound. Examples of such optional components include pharmaceutically acceptable additives, such as excipients, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, sustained-release agents. , Stabilizers, acidulants, fragrances, fluidizing agents, and the like. The amount of these optional components added to the coating compound particles can be appropriately set. Moreover, mixing and granulation of the coating compound and optional components can be performed by known methods.

  The coating compound particles can be used alone or in combination of two or more. That is, the coating particle of the present invention is a particle comprising one or more kinds of coating compound particles.

  Examples of the method for attaching the binder and coating compound particles to the wax coating particles include a method of mixing these (wax coating particles, binder, and coating compound particles). These may be mixed at one time, or after first mixing the wax coating particles and the binder, the coating compound particles may be further added and mixed. That is, the binder and the coating compound particles may be attached to the wax coating particles at one time, or after the binder is attached to the wax coating particles, the coating compound particles may be further attached.

  These mixing can be performed using a known mixer capable of applying a compressive force or a shearing force. For example, mortar; tilting cylindrical tumbler, V-shaped tumbler, double-cone tumbler, etc. rotating container type solid mixer; ribbon-type mixer, rotating disk-type mixer, etc. mechanical stirring mixer; V with internal blades -Type tumblers, double cone tumblers with internal blades, universal mixers, bra blender type mixers, high-speed stirring granulators, high-speed elliptical rotor type mixers, etc .; kneader mixers, internal mixers, muellers Examples thereof include mixers such as mixers, Henschel mixers and roll mills; mechanical stirrers such as turbine-type stirrers and pullage-type stirrers; stirrers such as mechano-mills and hybridizers that use impact force due to high-speed air current or mechanical stirring. More specifically, for example, mixing can be performed using a constant temperature mixer with a stirring blade. For example, the stirring blade can be mixed by rotating at about 100 to 300 rpm. The mixing may be performed for about 1 to 60 minutes, for example.

  The ratio of mixing these is, for example, preferably 3 to 60 parts by mass, more preferably 4 to 50 parts by mass, and further preferably 5 to 40 parts by mass with respect to 100 parts by mass of the wax coating particles. Moreover, 30-200 mass parts of coating compound particles are preferable with respect to 100 mass parts of wax coating particles, and 40-150 mass parts is more preferable.

Heating of the wax coating particles to which the binder and coating compound particles are attached After the binder and coating compound particles are attached to the wax coating particles, the particles (ie, the wax coating particles to which the binder and coating compound particles are attached) are heated. To do.

  The heating may be performed simultaneously with the operation of attaching the binder and coating compound particles. That is, for example, heating may be performed while mixing the wax coating particles, the binder, and the coating compound particles. Moreover, you may heat, mixing a wax coating particle and a binder, and also adding and mixing a coating compound particle.

  Heating is performed up to the melting point of the wax. When the wax is heated to the melting point or higher, the wax is dissolved. Subsequent cooling (below the melting point of the wax) sets the wax again. The coating compound particles are firmly fixed by the heating and cooling operation. That is, the coating compound particles are firmly coated. Although it is considered that the coating compound particles are firmly fixed by dissolving and re-solidifying the wax, this effect cannot be obtained by melting and re-solidifying only the wax. In other words, the coating compound particles are not firmly fixed with the wax alone, but rather are easily peeled off. Although not intended to be limited, it is considered that the dissolved wax mixes with the binder and is filled between the coating compound particles and hardens, thereby fixing the coating compound particles more firmly. As is clear from these explanations, after heating, it is necessary to cool to about the melting point or less (preferably a temperature lower by 5 to 10 ° C. than the melting point) and harden the wax again.

  As described above, since the heating temperature is based on the melting point of the wax, the heating temperature can be appropriately set according to the type of wax used. For example, about 35-85 degreeC, Preferably about 45-75 degreeC can be illustrated. The heating time can also be set as appropriate. For example, about 10 minutes to 2 hours can be exemplified.

  The average particle size of the coating compound coating particles thus obtained is preferably about 2 to 1000 μm, more preferably about 5 to 1000 μm.

  In addition, since the coating compound particles obtained in this way are strongly coated with the coating compound particles, the coating compound particles are not peeled off during the production, and thus contamination does not occur. For example, when the coating compound affects the human body such as a physiologically active substance, it is not preferable that it is peeled off and taken into the human body via the skin or breathing. Further, when the coating compound is colored such as toner, it is not preferable that it is peeled off and contaminates the surroundings. With the coating compound coating particles of the present invention, since the coating compound particles are firmly coated, the problem that the coating compound is peeled off and contaminates the surroundings at the time of production and after completion is solved. In this respect, the present invention is excellent.

Further Coating with Coating Polymer In the method for producing the coated particles of the present invention, the coating compound particles can be coated on the core particles as described above, and then coating can be performed with the coating polymer. That is, the method can further include (C): a step of coating the particles obtained through the step (B) with a coating polymer.

  If the layer containing the coating compound particles (coating compound particle coating layer) is a primary coating layer, the polymer coating layer can be said to be a secondary coating layer coated on the primary coating layer. Hereinafter, such notation (“primary coating layer” and “secondary coating layer”) may be used. Further, the coating particles having only the primary coating layer may be hereinafter referred to as primary coating particles. In addition, the coating particles having the primary coating layer and the secondary coating layer may be referred to as secondary coating particles. The primary coating layer contains a wax, a binder, and coating compound particles. The secondary coating layer contains a coating polymer. In the method for producing coated particles of the present invention, when coating with a coating polymer is also performed, the resulting coated particles are secondary coating particles, and the particles are composed of a core particle, a primary coating layer, and a secondary coating layer. . The particles before coating with the coating polymer are primary coating particles, and the particles are composed of a core particle and a primary coating layer. Furthermore, the particles obtained by the method described above are primary coating particles. That is, as described above, primary coating particles can be produced by heating and cooling the wax coating particles to which the binder and coating compound particles are adhered.

  Examples of the coating polymer include a cellulose polymer, an acrylic polymer, a biodegradable polymer, and the like.

  Specific examples of the cellulose polymer include ethyl cellulose (for example, EC N-10F manufactured by Shin-Etsu Chemical Co., Ltd., Surerease manufactured by Nippon Colorcon Co., Ltd.), hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (for example, AQOAT manufactured by Shin-Etsu Chemical Co., Ltd.). ), Polyvinyl acetal diethylaminoacetate, carboxymethylethyl cellulose, cellulose acetate phthalate and the like. Preferred are ethyl cellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.

  Specific examples of the acrylic polymer include an aminoalkyl methacrylate copolymer (E100, EPO), a methacrylic acid-methyl methacrylate copolymer (L100, L100-55), and a methacrylic acid-methyl methacrylate copolymer (S-100). Aminoalkyl methacrylate copolymer (RL100, RLPO) aminoalkyl methacrylate copolymer (RS100, RSPO), ethyl acrylate / methyl methacrylate copolymer (FS30), and the like. For example, the Eudragit series can be preferably used as a commercial product. The description in parentheses after these polymer names is the Eudragit series name. Eudragit EPO, L100, L100-55, S-100, RLPO and RSPO are preferable.

  Specific examples of biodegradable polymers include polylactic acid (poly-L-lactic acid, poly-D-lactic acid, poly-DL-lactic acid), glycolic acid, ε-caprolactone, and N-methylpyrrolidone. Homopolymers, copolymers or mixtures of these polymers, polycaprolactam, chitin, chitosan and the like.

In addition, “vinyl polymer” described as “polymer forming polymer particles” in the description of the core particle can also be used as the coating polymer.
In addition, a coating polymer can be used 1 type or in combination of 2 or more types. In dry coating, it is easy to use a wide variety of polymers as a coating polymer in combination, and various effects can be imparted to the coating particles using this property. For example, by using an aminoalkyl methacrylate copolymer and a water-soluble polymer as a coating polymer, when the core particle or the coating compound particle is a substance having bitterness, it is effective for controlling the elution rate of the bitter substance. In this case, examples of the water-soluble polymer include hydroxypropylmethylcellulose, hydroxypropylcellulose, PVA (polyvinyl alcohol) copolymer, pullulan, and polyethylene oxide. As the PVA copolymer, for example, a PVA copolymer used as a main component of a hard capsule described in WO02 / 017848 can be preferably used.

  When the coating polymer is coated on the coating compound particle coating layer, it is preferably used as coating polymer particles. In order to obtain the coating polymer particles, specifically, for example, a commercially available polymer may be pulverized, or a liquid polymer may be dried and pulverized. Further, for example, emulsion particles such as polylactic acid may be dried and then processed by a jet mill or the like.

  The method for granulating the coating polymer is not particularly limited, and a known method can be used. For example, the coating polymer can be granulated in the same manner as exemplified for the pulverization and granulation of the coating compound. The coating polymer particles are not particularly limited, but the average particle diameter is preferably about 0.05 to 10 μm, more preferably about 0.1 to 10 μm.

  Coating with the coating polymer is performed by adhering the coating polymer particles to the primary coating particles and dissolving them to form a film.

  The method for coating the coating polymer on the primary coating particles is not particularly limited. For example, using a mixer, coating can be performed by mixing primary coating particles and coating polymer particles. As the mixer, for example, a rotating container type solid mixer such as an inclined cylindrical tumbler, a V-shaped tumbler, or a double-conical outer tumbler can be suitably used. Heating is performed during mixing. Heating is performed at a temperature equal to or higher than the melting point of the polymer to be used (in the case of a polymer in which glass transition occurs, glass transition temperature) or higher (preferably, the temperature is +1 to 10 ° C.). Therefore, the heating temperature can be appropriately set according to the type of polymer used. Although it does not restrict | limit in particular, For example, about 50-90 degreeC can be illustrated.

  As a result, the coating polymer adheres to the primary coating particles and forms a film. Although a limited interpretation is not desired, it is considered that the wax of the primary coating particles is slightly dissolved by heating, and the adhesion efficiency of the coating polymer particles is enhanced by the dissolved wax. And it is thought that the adhering coating polymer particles themselves are melted by heating to form a film. For this reason, after depositing the coating polymer at a heating temperature equal to or higher than the melting point of the wax, film formation is performed at a temperature higher than the melting point (or glass transition temperature) of the coating polymer by further increasing the heating temperature (that is, adhesion and It is also possible to form the film in two stages.

  In the coating treatment, an anti-aggregation agent (preventing the aggregation of the coating polymer particles) may be used. For example, when the primary coating particles and the coating polymer particles are mixed, it is possible to prevent the coating polymer particles from aggregating by adding an agglomeration inhibitor and mixing them. Examples of such an aggregation inhibitor include light anhydrous silicic acid, talc, titanium oxide, magnesium stearate and the like.

  As a preferred embodiment in which the coating is performed by mixing, specifically, for example, primary coating particles, coating polymer particles, and an anti-aggregation agent are placed in a constant temperature conical rotary mixer, and heat of about 60 to 80 ° C. is applied. However, the method of mixing for about 0.5 to 6 hours is mentioned.

  The amount of the coating polymer used is, for example, preferably about 5 to 250 parts by mass, more preferably about 10 to 200 parts by mass when 100 parts by mass of the primary coating particles are used.

  The average particle size of the coating particles (secondary coating particles) thus obtained is usually about 5 to 1000 μm, preferably about 10 to 500 μm.

Primary coating particle and secondary coating particle The present invention includes the primary coating particle and the secondary coating particle.

  The primary coating particles are composed of core particles and a primary coating layer, and the primary coating layer contains a wax, a binder, and coating compound particles. The secondary coating particles are composed of core particles, a primary coating layer, and a secondary coating layer, and the secondary coating layer is a polymer coating layer and contains a coating polymer. The particles obtained through the steps (A) and (B) can be regarded as primary coating particles, and the particles obtained through the step (C) can be regarded as secondary coating particles.

  Various conditions such as each constituent component and average particle diameter of the primary coating particles and the secondary coating particles are as described above.

The thickness of the primary coating layer is not particularly limited, but it is usually thicker than the average particle diameter of the coating compound particles. For example, it is preferably about 1 to 30 μm, more preferably about 1 to 25 μm. Further, the thickness of the secondary coating layer is not particularly limited. For example, it is preferably about 3 to 200 μm, more preferably about 5 to 150 μm. The thickness of each coating layer can be calculated by dividing the difference in the average particle diameter of the coating particles by 2. That is, for example, the thickness of the primary coating layer can be calculated by the following equation.
(Primary coating particle average particle size-core particle average particle size) / 2
Further, the thickness of the secondary coating layer can be calculated by the following formula.
(Secondary coating particle average particle size minus primary coating particle average particle size) / 2

  Further, in the primary coating particles, the wax coating particles, the binder, and the coating compound particles, and each mass part ratio is preferably about 0.1 to 30 when the wax coating particles are 100, and the coating compound The particles are preferably about 0.5 to 200. In particular, when the purpose of coating is surface modification or the like, the coating film becomes thin, so the binder is preferably about 0.1 to 5, and the coating compound particles are preferably about 0.5 to 40. Further, when a pharmacologically active substance is used as the coating compound particle (particularly when the coating particle is used as a medicine), the binder 5 to 30 and the coating compound particle 30 to 200 are preferable.

  Further, in the secondary coating particles, the wax coating particles, the binder, the coating compound particles, and the coating polymer, respectively, when the weight part ratio is 100, the binder and the coating compound particles are the primary coating. As in the case of particles, the coating polymer is preferably about 0.5 to 500. In particular, when the purpose of coating is surface modification or the like, the coating film becomes thin, and therefore the coating polymer is preferably about 0.5 to 70. When a pharmacologically active substance is used as the coating compound particle (particularly when the coating particle is used as a medicine), the coating polymer is preferably about 20 to 500.

  Such primary coating particles and secondary coating particles can be preferably used as, for example, pharmaceuticals, agricultural chemicals, cosmetics, toners, paints, sanitary products (toiletries), catalysts, and the like. Particularly in the pharmaceutical field, it can be preferably used as a bitterness mask preparation, a sustained-release preparation, an enteric preparation, and the like.

  Hereinafter, the present invention will be specifically described, but the present invention is not limited to the following examples. In addition, in FIG. 1, the outline | summary of the manufacturing method of the coating particle of this invention is shown. Further, hereinafter, “recovery rate” indicates the ratio (%) of the mass of the recovered product when the mass of the charged raw material is 100%. Hereinafter, the average particle diameter of the particles is 0, 32, 44, 53, 63, 74, 90, 106, 125, 149, 177, 210, 250 unless otherwise specified, except for the coating compound particles. Screening was performed using a low-tap shaker (manufactured by Iida Seisakusho) equipped with meshes of 297, 355, and 420 (μm), and from the results, the relationship between the cumulative weight% under the sieve and the particle diameter was determined, and the 50 weight% diameter Is a weight average particle diameter obtained by calculating.

The average particle size of the coating compound particles is median (d50), and was determined using a laser scattering particle size measuring device (LDSA-2400A, Tohnichi Computer Application).

Production Example 1: Production of wax-coated particles 1
〔material〕
[Core particles]
Crystalline cellulose spherical granules (Selfia SCP-100; manufactured by Asahi Kasei Co., Ltd.) were classified into 53 to 90 μm (low tap shaker) as core particles. The average particle diameter of the core particles was 79.5 μm. Hereinafter, the SELPHY SCP-100 may be referred to as SCP.

[wax]
Stearic acid (manufactured by NOF Chemical Co., Ltd.) was treated with a fluidized bed jet mill (pocket jet; manufactured by Kurimoto Steel Works) installed in a classification rotor under the conditions of a classification rotor rotational speed of 15000 rpm and an operating pressure of 0.6 MPa. The obtained particles having an average particle size of 5.5 μm (laser scattering type particle size measuring apparatus; measured by LDSA-2400A, Tohnichi Computer Application) were used as wax particles. Hereinafter, the stearic acid may be referred to as SA.

〔Production method〕
Charge 17g of SCP and 3g of SA into a constant temperature mixer with stirring blades (schematic diagram is shown in Fig. 2. The mixing machine may be referred to as AMT hereinafter), mix for 10 minutes at a stirring blade speed of 200rpm, and then rise to 65 ° C. Further mixing was performed at a constant temperature of 200 rpm for 1 hour with a stirring blade rotating at a temperature. Thereafter, the rotation continued and the system was cooled (to about 30 ° C.). The cooling time was 1 hour 45 minutes. By this operation, wax-coated particles were obtained. The wax-coated particles (SCP dry-coated with SA) may hereinafter be referred to as SCP / SA. The recovery rate from AMT was 96.4%.

[Evaluation of wax coating particles]
When SCP / SA obtained using a microscope (manufactured by Keyence Corporation) was observed, the surface of SCP / SA had a gloss of SA. Also, it had a shape similar to the shape of the core particle SCP. From these facts, it was confirmed that SA uniformly coated the surface of SCP. Furthermore, when SCP and SCP / SA were dispersed in water, SCP immediately settled, but SCP / SA did not sink. This also showed that the SCP surface was coated with SA.

Further, it is preferable that the SCP / SA has an average particle diameter of 82.3 μm, and that the ratio of particles agglomerating or almost uncoated is small. Therefore, the ratio (yield) at which good coating particles were obtained in the coating operation was calculated.
Specifically, the yield (hereinafter sometimes referred to as microencapsulation rate) was determined by the following calculation formula.

Microencapsulation rate (%) = 100− (aggregation rate + SA single aggregate particle rate)

Here, the agglomeration rate (%) was defined as the fraction of particles having a particle size of 106 μm or more when classified using a low-tap shaker. The SA single aggregate particle ratio (%) was the ratio of SA single aggregate particles not containing SCP core particles inside, specifically, the fraction of particles of 53 μm or less by low tap shaker classification. As a result, the aggregation rate was 4.2%, the SA single aggregation rate was 0%, and the microencapsulation rate was calculated to be 95.8%. From this, it was found that the wax operation particles can be obtained with very high efficiency by the coating operation.

Production Example 2: Production of wax-coated particles 2
Production Example 1 except that crystalline cellulose spherical granules (Selfia SCP-100; manufactured by Asahi Kasei Co., Ltd.) are classified into 32-74 μm (low tap shaker) (average particle size 57.6 μm) as core particles. Wax coated particles were produced in the same manner.

  The recovery rate of the wax-coated particles (SCP / SA) thus obtained from AMT was 97.5%. The average particle size of the SCP / SA was 67.4 μm. Furthermore, the fractionation of particles of 90 μm or more after classification with a low-tap shaker is defined as the aggregation rate (%), and the classification fraction of particles of 32 μm or less is defined as the SA single aggregation particle rate (%). The rate was 3.0%, the SA single aggregation rate was 0%, and the microencapsulation rate was calculated to be 97.0%.

  Furthermore, about 3 g of the SCP / SA is dispersed in 50 mL of ethanol, SA is extracted, dried, and then the amount of SA is measured to determine the SA coating rate (the amount of SA coated relative to the amount of SA used). Was 96.9%.

From the above, it was found that good wax coating particles can be obtained with high efficiency by the production method, and that the coating efficiency of the wax on the core particles is also good.

Example 1: Production of primary coating particles 1
〔material〕
[Wax coated particles]
The SCP / SA obtained in Production Example 1 (classified to a particle size of 53 to 106 μm and an average particle size of about 81.8 μm) was used as wax coating particles.

[binder]
Triethyl citrate (Nacalai Tesque; reagent special grade) (hereinafter sometimes referred to as TEC) was used as it was.

[Coating compound particles]
Sodium carbazochrome sulfonate (manufactured by Sanwa Chemical Co., Ltd.), which is a water-soluble drug (hereinafter, sometimes referred to as CCSS), was treated with the same jet mill used in Production Example 1 and pulverized and granulated. The average particle diameter of the obtained particles was 5.0 μm. This was used as coating compound particles.

〔Production method〕
6 g of SCP / SA (53-106 μm) obtained in Production Example 1 and 1.2 g of TEC were mixed by AMT (rotation speed: 200 rpm, 1 minute). The system becomes wet by the mixing, and 7.2 g of CCSS was added thereto, and mixing was further performed under conditions of 66 ° C., rotation speed 200 rpm, and 40 minutes. Thereafter, the system was cooled (to about 30 ° C.) while mixing was continued. The cooling time was about 30 minutes. By this operation, primary coating particles were obtained. The primary coating particles (SCP / SA coated with TEC and CCSS) may be hereinafter referred to as TEC-CCSS particles. The recovery rate from AMT was 98.0%. The average particle size of the TEC-CCSS particles was 99.5 μm.

[Evaluation of primary coating particles]
The obtained TEC-CCSS particles were observed with a microscope. CCSS is a very strong yellow substance. The TEC-CCSS particles were colored yellow and there was no uneven color. This indicates that SCP / SA particles are uniformly coated with CCSS particles.
The average particle diameter of the obtained TEC-CCSS particles was 99.5 μm.
In addition, the classification fraction of particles of 149 μm or more when classified by a low-tap shaker is the aggregation rate (%), and the classification fraction of particles of 32 μm or less is the CCSS single aggregate particle rate (%). The rate was calculated. As a result, the aggregation rate was 5.1%, the CCSS single aggregation rate was 3.5%, and the microencapsulation rate was calculated to be 91.4%.
In addition, the CCSS coating rate (the ratio of coated CCSS to the used CCSS) is calculated from the CCSS content of TEC-CCSS particles (calculated by extracting CCSS with water and measuring the extract with a spectrophotometer (wavelength 363 nm)). The calculated value was 90.4%.
The procedure is specifically as follows. That is, about 30 mg of TEC-CCSS was precisely weighed, added to 500 mL of distilled water, stirred for 20 minutes, 10 mL of distilled water was added to 5 mL of the supernatant, and the absorbance was measured at 363 nm. The CCSS concentration was calculated from a separately prepared calibration curve, and the CCSS content of the TEC-CCSS particles was determined.

Furthermore, the strength of CCSS immobilization in TEC-CCSS particles was examined by the following method. That is, with respect to 53-149 μm TEC-CCSS particles obtained by classification, an air jet sieve (manufactured by ALPINE) equipped with a sieve having an opening of 20 μm was used, and a reduced pressure treatment (2.5 kPa, 3 minutes) was performed. went. No weight loss was observed before and after the treatment. From this, it was found that CCSS is firmly fixed.

Example 2: Production of primary coating particles 2
〔material〕
Triacetin (Nacalai Tesque; reagent special grade) (hereinafter sometimes referred to as TA) was used as a binder. The same wax coating particles and coating compound particles as in Example 1 were used.

〔Production method〕
3.9 g of SCP / SA obtained in Production Example 1 and 1.2 g of TA were mixed with AMT (rotation speed: 200 rpm, 1 minute). The system becomes wet by the mixing, and 4.7 g of CCSS was added thereto, and further mixing was performed under conditions of 66 ° C., rotation speed 200 rpm, and 35 minutes. Thereafter, the system was cooled (to about 30 ° C.) while mixing was continued. The cooling time was about 30 minutes. By this operation, primary coating particles were obtained. Hereinafter, the primary coating particles (SCP / SA coated with TA and CCSS) may be referred to as TA-CCSS particles. The recovery rate from AMT was 97.9%. Moreover, the average particle diameter of the said TA-CCSS particle | grains was 97.5 micrometers.

[Evaluation of primary coating particles]
The microencapsulation rate was examined in the same manner as in Example 1. As a result, the aggregation rate was 1.4%, the CCSS single aggregation rate was 2.5%, and the microencapsulation rate was calculated to be 94.2%.

Example 3: Production of primary coating particles 3
〔material〕
Polyethylene glycol (manufactured by Nacalai Tesque: weight average molecular weight 400) (sometimes referred to as PEG400) was used as a binder. As the wax coating particles, the particles (SCP / SA) obtained in Production Example 2 were used. The same compound particles (CCSS) as in Example 1 were used as the coating compound particles.

〔Production method〕
4 g of SCP / SA obtained in Production Example 2 (32-90 μm was used. The average particle size is 67.3 μm) and 0.8 g of PEG were mixed in AMT (rotation speed: 200 rpm, 1 minute). By this mixing, the system is in a wet state. 4.8 g of CCSS was added thereto, and further mixing was performed at 67 ° C., rotation speed 200 rpm, and 30 minutes. Thereafter, the system was cooled (to about 30 ° C.) while mixing was continued. The cooling time was about 30 minutes. By this operation, primary coating particles were obtained. The primary coating particles (SCP / SA coated with PEG and CCSS) may be hereinafter referred to as PEG-CCSS particles. The recovery rate from AMT was 95.0%. The average particle size of the PEG-CCSS particles was 74.4 μm.

[Evaluation of primary coating particles]
The microencapsulation rate was examined in the same manner as in Example 1. As a result, the aggregation rate (particle weight fraction of 125 μ or more) was 4.3%, the CCSS single aggregation rate was 1.7%, and the microencapsulation rate was calculated to be 94.0%.

Comparative Example 1: Production of primary coating particles without using a binder 1
Primary coating particles were produced in the same manner as in Example 1 except that the binder (triethyl citrate) was not used. Hereinafter, the primary coating particles may be referred to as No-CCSS particles. When the strength of CCSS immobilization of No-CCSS particles was examined by the same method as in Example 1 (depressurization treatment using an air jet sieve), 86.4% of CCSS was peeled off. The value was calculated from the weight before and after the sheave treatment.

Example 4: Production of secondary coating particles 1
〔material〕
[Primary coating particles]
TEC-CCSS particles (classified to 53-125 μm, average particle size 96.9 μm) obtained in the same manner as in Example 1 were used.

[Coating polymer]
An aminoalkyl methacrylate copolymer (RSPO; manufactured by Evonik) (hereinafter sometimes referred to as RSPO) was used as a coating polymer. Specifically, RSPO was processed by a fluidized bed jet mill (classifying rotor rotational speed: 6000 rpm, operating pressure: 0.6 MPa) installed in a classifying rotor, and an average particle size of 5.0 μm (laser scattering type particle size measuring device; LDSA- 2400A, Tohnichi Computer Application), which was used for coating. In order to prevent aggregation of the polymer particles, light anhydrous silicic acid (Aerosil # 200; manufactured by Nippon Aerosil Co., Ltd.) was used as an aggregation inhibitor.

〔Production method〕
1 g of TEC-CCSS particles and 1.5 g of RSPO are mixed with a constant-temperature conical rotary mixer (with a Teflon (registered trademark) sheet baffle inside) (a schematic diagram is shown in FIG. 3. Hereinafter, the mixer may be referred to as RMT). ), And mixed for 5 minutes at an RMT rotation speed of 60 rpm and 30 ° C. Thereafter, when the temperature was raised to 45 ° C. at a rotation speed of 60 rpm (total time 15 minutes from the start), the rotation was stopped, 25 mg of Aerosil was added, and the temperature was raised again at a rotation speed of 60 rpm. RSPO was fixed for 30 minutes at the time when the temperature reached 66 ° C. (total time 45 minutes from the start of charging). Thereafter, the temperature was raised again to form a film at 72 ° C. for 30 minutes, and then cooled for 10 minutes to obtain secondary coating particles (primary coating particles coated with RSPO). The total process time was 125 minutes. The secondary coating particles obtained below may be referred to as RSPO microcapsules (abbreviated as RSPO-MC). The yield of the obtained RSPO-MC was 97.0%.

[Evaluation of secondary coating particles]
The obtained RSPO-MC was observed with a microscope. The color of RSPO-MC was yellow derived from CCSS of the primary coating particles, and there was no color unevenness. From this, it was found that RSPO was uniformly formed and coated.

  The average particle size of RSPO-MC was 121.8 μm.

  In addition, the classification fraction of particles of 177 μm or more when classified by a low-tap shaker is the aggregation rate (%), and the classification fraction of particles of 53 μm or less is the RSPO single aggregate particle rate (%). The rate was calculated. As a result, the aggregation rate was 4.1%, the RSPO single aggregation rate was 0%, and the microencapsulation rate was calculated to be 95.9%.

Test Example 1: Secondary coating particle dissolution test
In order to verify the pharmaceutical usefulness of RSPO-MC, the following dissolution test was performed.

  Wax-coated particles obtained in the same manner as in Example 1 using crystalline cellulose granules (hereinafter sometimes referred to as CP) (Selfia CP-203; manufactured by Asahi Kasei Co., Ltd., average particle size 238.0 μm) as core particles (CP / SA). Then, using the CP / SA, primary coating particles (TEC-CCSS particles) were obtained in the same manner as in Example 3. Furthermore, RSPO was coated using the TEC-CCSS particles in the same manner as in Example 5 to obtain the following secondary coating particles (CP-RSPO-MC).

CP-RSPO-MC (20) (RSPO coating film amount is 20wt%)
CP-RSPO-MC (24) (RSPO coating film amount is 24wt%)
CP-RSPO-MC (30) (RSPO coating film amount is 30wt%)

  Further, in the same manner as in Example 1 and Example 4, the following secondary coating particles (SCP-RSPO-MC) were obtained.

SCP-RSPO-MC (51) (RSPO coating film amount is 51wt%)
SCP-RSPO-MC (53) (RSPO coating film amount is 53wt%)
SCP-RSPO-MC (59) (RSPO coating film amount is 59 wt%: obtained in Example 3 above)

  In addition, the RSPO coating film amount of each secondary coating particle was determined as follows. That is, the CCSS content of TEC-CCSS particles, which are the core particles used for RSPO coating, and the CCSS content of each secondary coating particle were measured (spectroscopic measurement method; determined using absorbance at 363 nm) The amount of RSPO coating film of each secondary coating particle was determined from the CCSS concentration ratio.

  Each of the secondary coating particles described above was used in the dissolution test. The dissolution test was performed according to dissolution test method method 2 (paddle, 100 rpm) described in the 15th revised Japanese Pharmacopoeia. As a dissolution test solution, 900 mL of distilled water and 37 ° C. were used. The amount of CCSS eluted in the dissolution test solution injection was determined from the absorbance (363 nm). The results are shown in FIG. In addition, the lower figure of FIG. 4 is the figure which expanded the part to the elution time 1 hour of the upper figure of FIG.

  From FIG. 4, it was confirmed that any of the secondary coating particles has a good sustained release property. Moreover, it has confirmed that the elution rate differed with the particle size and kind of core particle. It was confirmed that the dissolution rate of CCSS decreased as the RSPO coating amount increased. Furthermore, even each SCP-RSPO-MC obtained using small-sized core particles (SCP: average particle size; 79.5 μm) is gradually elution from the start of the test (bottom of Fig. 4). It was found that a film having no burst of elution was obtained.

  Based on the above, it is possible to produce coated particles with various elution rates and excellent quality without elution bursts by changing the size and type of the core particles or adjusting the polymer coating amount. I understand that I can do it.

Claims (13)

(A) A step of attaching the binder and coating compound particles to the wax-coated particles obtained by coating the core particles with wax (B) A step of heating the particles obtained in the step (A) to a temperature equal to or higher than the melting point of the wax. , A method for producing coated particles coated with a coating compound. The method for producing coated particles according to claim 1, wherein the binder is at least one selected from the group consisting of triethyl citrate, triacetin, dibutyl sebacate, polyethylene glycol, propylene glycol, medium chain fatty acid, and triglyceride. . The wax according to claim 1 or 2, wherein the wax is at least one selected from the group consisting of an organic fatty acid, an ester derivative of an organic fatty acid, a higher alcohol, a glycerin fatty acid ester, a polyethylene glycol, a hardened oil and a natural wax. A method for producing coating particles. The manufacturing method of the coating particle in any one of Claims 1-3 whose average particle diameter of a core particle is 1-1000 micrometers. The method for producing coated particles according to claim 1, wherein the coating compound is a drug. The manufacturing method of the coating particle in any one of Claims 1-5 whose average particle diameter of the compound particle for coating | cover is 1/5 or less of the average particle diameter of a core particle. further,
(C) The manufacturing method of the coating particle in any one of Claims 1-6 including the process of coating the particle | grains obtained through a process (B) with a coating polymer. The method for producing coated particles according to claim 7, wherein the coating polymer is at least one selected from the group consisting of a cellulosic polymer, an acrylic polymer, and a biodegradable polymer. The coating particle manufactured by the manufacturing method of the coating particle in any one of Claims 1-8. A compound coating particle for coating, comprising a coating compound particle coating layer on a core particle, wherein the coating compound particle coating layer contains a wax, a binder, and a coating compound particle. The wax is at least selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid, and monoesters of any of these fatty acids with glycerin, and polyethylene glycol One kind,
The binder is at least one selected from the group consisting of triethyl citrate, triacetin, dibutyl sebacate, and polyethylene glycol;
The coating compound is a pharmacologically active substance,
The coating compound-coated particle according to claim 10. The coating compound-coated particles according to claim 10 or 11, further comprising a polymer coating layer on the coating compound particle coating layer. The polymer coating layer is a layer comprising at least one polymer selected from the group consisting of ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, aminoalkyl methacrylate copolymer, and polylactic acid. Compound coating particles for coating according to 1.

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