Method for producing coated solid preparation under solvent-free condition

Abstract

Provided is a method for producing a solid preparation in which only a powder containing HPMCAS is dispersed and which can be coated only by a single lamination step. A method for producing a coated solid preparation under solvent-free conditions, the method comprising at least: a preliminary mixing step in which a preliminary mixture is obtained by preliminary mixing of a powdery hydroxypropyl methyl cellulose acetate succinate, a powdery plasticizer, and a powdery wetting agent; a mixing step in which the preliminary mixture and a solid preparation are mixed to obtain a mixture; and a heating step for obtaining a coated solid preparation by heating the mixture.

Description

Technical Field

[0001] The present invention relates to a method for producing a solid preparation coated in the absence of a solvent. Background Art

[0002] Solid dosage form coatings are widely used to protect weakly acid-resistant drugs from gastric acid attack, achieve pH-dependent dissolution, and shield bitterness.

[0003] As coating agents, methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and carboxymethylethylcellulose (CMEC) are used in the cellulose system; polyvinyl alcohol (PVA) and polyvinyl acetate phthalate (PVAP) are used in the vinyl system; and copolymers of methacrylic acid and ethyl acrylate are used in the acrylic system. These coating agents can be used by dissolving the polymer in an organic solvent, or can be used as an aqueous latex or aqueous dispersion for coating. However, since an organic solvent or water is required as a solvent in either method, it takes a long time to spray these coating solutions, and the drying time of the solvent is also necessary. In addition, since some drugs are reluctant to come into contact with water or an organic solvent, it is expected that a coating method that does not use a solvent will be developed.

[0004] As an example of a coating method that does not use a solvent, an enteric coating method has been proposed in which a mixture of a liquid substance having a contact angle of 10° or less with respect to a polymer coating agent such as HPMCAS and a plasticizer is continuously sprayed onto a solid drug while a powdered polymer coating agent is spread and coated (Patent Document 1).

[0005] In addition, as an example of coating using only powder components, a coating method comprising the following three steps is proposed (Patent Document 2). The three steps are a step of mixing microparticles, core particles, and wax, and laminating the microparticles and wax on the core particles; a step of mixing the obtained laminated particles with a polymer such as HPMCAS, and coating the laminated particles with the polymer; and a step of solidifying the obtained polymer-coated laminated particles.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application Laid-Open No. 10-81620

[0009] Patent Document 2: Japanese Patent Application Publication No. 2021-84873 Summary of the invention

[0010] Problem that the invention aims to solve

[0011] However, in the method of Patent Document 1, since it is necessary to spray the liquid component and spread the powder component separately, the operation of this method becomes complicated. In addition, in the method of Patent Document 2, since the polymer lacks adhesion to the core particles, it is necessary to go through a two-step coating process of adding the polymer when coating the core particles with wax in advance and making the added polymer adhere to the core particles by utilizing the adhesive force of the wax, which requires operation time and effort.

[0012] In view of the above circumstances, an object of the present invention is to provide a method for producing a solid preparation that can be coated by only spreading a powder containing HPMCAS and performing a single layering step.

[0013] Solutions for solving problems

[0014] The present inventors have conducted intensive studies to solve the above problems and have found that by adding a powdered wetting agent to a mixture of powdered HPMCAS and a powdered plasticizer, the adhesion of HPMCAS to core particles can be greatly improved and coating can be achieved only by powder scattering and a single lamination step, thereby completing the present invention.

[0015] According to the present invention, the following method for producing a solid preparation can be provided. [1]

[0017] A method for producing a solid preparation coated in the absence of a solvent, wherein:

[0018] At least:

[0019] a preliminary mixing step of preliminarily mixing powdered hydroxypropyl methylcellulose acetate succinate, a powdered plasticizer, and a powdered wetting agent to obtain a preliminary mixture;

[0020] a mixing step of mixing the premix and the solid preparation to obtain a mixture; and

[0021] The heating step is to obtain a coated solid preparation by heating the mixture. [2]

[0023] The method for producing a solid preparation according to [1], wherein

[0024] The mixing step is performed while heating. [3]

[0026] The method for producing a solid preparation according to [1] or [2], wherein:

[0027] The mixing step is a mixing step of continuously spreading the preliminary mixture into the solid preparation to obtain a mixture. [4]

[0029] The method for producing a solid preparation according to any one of [1] to [3], wherein

[0030] The powdered hydroxypropylmethylcellulose acetate succinate has a volume-based average particle size of 1 to 10 μm as measured by dry laser diffraction. [5]

[0032] The method for producing a solid preparation according to any one of [1] to [4], wherein

[0033] The melting point of the powdered plasticizer is 50-69°C. [6]

[0035] The method for producing a solid preparation according to any one of [1] to [5], wherein

[0036] The powdered plasticizer is one or more selected from polyethylene glycol and stearic acid. [7]

[0038] The method for producing a solid preparation according to any one of [1] to [6], wherein

[0039] The melting point of the powdered wetting agent is at least 8° C. lower than the melting point of the powdered plasticizer. [8]

[0041] The method for producing a solid preparation according to any one of [1] to [7], wherein

[0042] The powdered wetting agent is propylene glycol monostearate, glycerol fatty acid ester, or a mixture containing propylene glycol monostearate and glycerol fatty acid ester as main components. [9]

[0044] The method for producing a solid preparation according to any one of [1] to [8], wherein

[0045] The powdered plasticizer and the powdered wetting agent have a volume-based average particle size of 1 to 500 μm as measured by dry laser diffraction.

[0046] Effects of the Invention

[0047] According to the present invention, a powdered coating component containing HPMCAS can be coated simply by scattering the powder and performing a single layering step, and the time required for the coating component preparation step and the coating step can be significantly reduced. DETAILED DESCRIPTION

[0048] Hereinafter, the present invention will be described in more detail.

[0049] The method for producing a solid preparation coated in the absence of a solvent of the present invention comprises the following steps (A) to (C).

[0050] Step (A): Preliminary mixing step of preliminarily mixing powdered HPMCAS, powdered plasticizer, and powdered wetting agent to obtain a preliminary mixture

[0051] Step (B): A mixing step of mixing the premix and the solid preparation to obtain a mixture

[0052] Step (C): a heating step of heating the mixture to obtain a coated solid preparation

[0053] Step (A) Preliminary mixing step

[0054] <Preparation of mixture>

[0055] [HPMCAS]

[0056] HPMCAS is a cellulose derivative having four substituents, namely, acetyl, succinyl, methoxy, and hydroxypropoxy groups, in cellulose, and a powdered substance is used in the production method of the present invention.

[0057] The methoxy group content of HPMCAS is preferably 12.0 to 28.0% by mass, more preferably 16.0 to 27.0% by mass, and even more preferably 20.0 to 26.0% by mass.

[0058] The content of the hydroxypropoxy group in HPMCAS is preferably 4.0 to 23.0% by mass, more preferably 4.5 to 17.0% by mass, and even more preferably 5.0 to 10.0% by mass.

[0059] The acetyl group content of HPMCAS is preferably 2.0 to 16.0% by mass, more preferably 3.0 to 15.0% by mass, and even more preferably 5.0 to 14.0% by mass.

[0060] The content of the succinyl group in HPMCAS is preferably 4.0 to 28.0% by mass, more preferably 4.0 to 23.0% by mass, and even more preferably 4.0 to 18.0% by mass.

[0061] In addition, as a suitable combination of the amounts of methoxyl groups, hydroxypropoxyl groups, acetyl groups, and succinyl groups in the HPMCAS, preferably, the methoxyl group content is 12.0 to 28.0 mass%, the hydroxypropoxyl group content is 4.0 to 23.0 mass%, the acetyl group content is 2.0 to 16.0 mass%, and the succinyl group content is 4.0 to 28.0 mass%. More preferably, the methoxyl group content is 16.0 to 27.0 mass%, the hydroxypropoxyl group content is 4.5 to 17.0 mass%, the acetyl group content is 3.0 to 15.0 mass%, and the succinyl group content is 4.0 to 23.0 mass%. Further preferably, the methoxyl group content is 20.0 to 26.0 mass%, the hydroxypropoxyl group content is 5.0 to 10.0 mass%, the acetyl group content is 5.0 to 14.0 mass%, and the succinyl group content is 4.0 to 18.0 mass%.

[0062] The contents of methoxy, hydroxypropoxy, acetyl and succinyl groups in HPMCAS can be measured according to the method described in the pharmaceutical article "Hydroxypropylmethylcellulose acetate succinate" of the 18th revised edition of the Japanese Pharmacopoeia.

[0063] The method for obtaining HPMCAS is not particularly limited, and it can be produced by a known production method or obtained as a commercial product. As a production method of HPMCAS, for example, the following method can be cited: in the presence of an aliphatic carboxylic acid, hydroxypropyl methylcellulose is subjected to an esterification reaction with an acetylating agent and a succinic acylating agent to obtain a reaction solution, and then the obtained reaction solution is mixed with water to precipitate, thereby preparing a suspension containing HPMCAS particles, and the HPMCAS in the above suspension is washed, recovered, dried, pulverized, etc., thereby preparing a method of HPMCAS.

[0064] From the viewpoint of forming a uniform coating film, the volume-based average particle size of HPMCAS measured by a dry laser diffraction method is preferably 1 to 10 μm.

[0065] [Plasticizer]

[0066] The plasticizer used in the production method of the present invention is in powder form.

[0067] The melting point of the plasticizer is preferably 50 to 69°C, more preferably 53 to 69°C, and even more preferably 53 to 60°C from the viewpoint of being able to efficiently form a coating film in the coating.

[0068] The volume-based average particle size of the plasticizer measured by dry laser diffraction is preferably 1 to 500 μm, more preferably 1 to 400 μm.

[0069] Specific examples of plasticizers include hydrocarbons such as paraffin wax, microcrystalline wax, and vaseline; beeswaxes such as beeswax and white beeswax; alcohols such as cetyl alcohol and stearyl alcohol; higher fatty acids such as stearic acid; higher fatty acid esters such as carnauba wax and rice wax; beef tallow, lard, cocoa butter, and beef tallow hardened oil; glycerol fatty acid esters such as hardened castor oil and glycerol monostearate; Lubri Wax-101 (hydrogenated vegetable oil), Polishing Wax-101 (a mixture of carnauba wax and paraffin), Precirol (glycerol-mono-, di-, and tri-mixed palmitate), sorbitan monostearate, acetylated glycerol monostearate, sucrose fatty acid esters, polyethylene glycol, and mixtures containing these components as main components (more than 50% by mass). Among them, polyethylene glycol and stearic acid, and a mixture containing polyethylene glycol and stearic acid as main components (more than 50% by mass) are preferred, and polyethylene glycol and stearic acid are more preferred.

[0070] The plasticizer may be used alone or in combination of two or more.

[0071] [Wetting agent]

[0072] The wetting agent used in the production method of the present invention is in powder form.

[0073] From the viewpoint of effectively laminating HPMCAS and a plasticizer on a solid preparation, the melting point of the wetting agent is preferably 8°C or more lower than the melting point of the plasticizer, and more preferably 10°C or more lower than the melting point of the plasticizer. The upper limit of the melting point of the wetting agent is not particularly limited, but from the viewpoint of easy availability, it is preferably lower than the melting point of the plasticizer and is 45°C or less. The lower limit of the melting point of the wetting agent is not particularly limited, but is preferably 30°C, and more preferably 35°C.

[0074] In this specification, powder means a substance that is solid and in a finely divided state under standard temperature (20°C).

[0075] The volume-based average particle size of the wetting agent measured by dry laser diffraction is preferably 1 to 500 μm, more preferably 1 to 300 μm.

[0076] Specific examples of wetting agents include poloxamer, propylene glycol stearate, glycerol fatty acid ester, etc. Among them, propylene glycol stearate, glycerol fatty acid ester, and a mixture containing propylene glycol stearate and glycerol fatty acid ester as main components (more than 50% by mass) are preferred, and propylene glycol stearate and glycerol fatty acid ester are more preferred.

[0077] The wetting agents may be used alone or in combination of two or more.

[0078] It should be noted that, in addition to the premix containing the above powdered ingredients, drugs, colorants, pigments, lubricants, anti-adhesive agents, etc. that are generally recognized in pharmaceutical sciences may also be added to the coating.

[0079] The drug is not particularly limited as long as it is an orally administrable drug. Examples of the drug include central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussive expectorants, antihistamines, antipyretic analgesics and anti-inflammatory agents, diuretics, sympathetic nerve stimulants, antimalarials, antidiarrheals, antipsychotic drugs, vitamins and their derivatives.

[0080] Examples of the central nervous system drug include diazepam, idebenone, aspirin, ibuprofen, acetaminophen, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethsalamide, ketoprofen, and chlordiazepoxide.

[0081] Examples of the circulatory system drug include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, propranolol hydrochloride, and alprenolol hydrochloride.

[0082] As the respiratory system drugs, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin and the like can be exemplified.

[0083] As digestive system drugs, for example, benzimidazole drugs having anti-ulcer effects such as 2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]benzimidazole and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl)benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl and 5-aminosalicylic acid can be cited.

[0084] Examples of the antibiotic include thalampicillin hydrochloride, baampicillin hydrochloride, cefaclor and erythromycin.

[0085] Examples of the antitussive and expectorant include narcotine hydrochloride, pentoxyverine citrate, dextromethorphan hydrobromide, isominier citrate, and dimethorphan phosphate.

[0086] Examples of the antihistamine include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride.

[0087] Examples of the antipyretic, analgesic and anti-inflammatory agent include ibuprofen, diclofenac sodium, flufenamic acid, sulbinine, aspirin and ketoprofen.

[0088] Examples of diuretics include caffeine and the like.

[0089] Examples of the sympathetic nerve stimulant include dihydrocodeine phosphate and racemic (dl)-methylephedrine hydrochloride.

[0090] Examples of the antimalarial agent include quinine hydrochloride and the like.

[0091] Examples of the antidiarrheal agent include loperamide hydrochloride.

[0092] Examples of antipsychotic drugs include chlorpromazine and the like.

[0093] Examples of vitamins and their derivatives include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

[0094] Examples of colorants include yellow iron oxide, ferric oxide (red), orange flavor, brown iron oxide, caramel, light silicic anhydride, food blue No. 5, food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, food blue No. 2, talc, sodium fluorescein, green tea powder, vitamin C, food lake pigments, carotenoid pigments, flavonoid pigments, and quinone pigments.

[0095] Examples of the pigment include carbon black, edible red No. 2 aluminum lake, edible red No. 3 aluminum lake, edible red No. 40 aluminum lake, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, edible blue No. 1 aluminum lake, edible blue No. 2 aluminum lake, ferric oxide, yellow ferric oxide, and black iron oxide.

[0096] As the lubricant, magnesium stearate, calcium stearate, colloidal silicon dioxide and stearic acid can be exemplified.

[0097] Examples of the anti-adhesive include talc and the like.

[0098] <Preliminary Mixing Process>

[0099] The preliminary mixing method is preferably a method that can uniformly disperse the above components, and examples thereof include a method of mixing the above components by hand in a plastic bag or the like, or a method of batch mixing using a device such as a V-type mixer.

[0100] The time and number of preparatory mixing are not limited as long as they can be performed uniformly.

[0101] In the preliminary mixing step, the mixing ratio of each component is not particularly limited. For example, the amount of the powdered plasticizer is preferably 1 to 200 parts by mass, more preferably 1 to 100 parts by mass, relative to 100 parts by mass of the powdered HPMCAS. In addition, the amount of the powdered wetting agent is preferably 1 to 50 parts by mass, more preferably 1 to 30 parts by mass, relative to 100 parts by mass of the powdered HPMCAS.

[0102] Process (B) Mixing process

[0103] <Solid preparation>

[0104] Examples of solid preparations include granules, fine granules, tablets, powders, pills, pouches, capsules, and pharmacological substances. In addition, from the viewpoint of uniformly forming a coating film, the shape of the solid preparation is preferably close to a spherical shape.

[0105] <Mixing process>

[0106] There is no particular restriction on the mixing method of the premix and the solid preparation, as long as it is a method that can uniformly mix the premix and the solid preparation. Specifically, the same as the above-mentioned premix method, it is also possible to mix by hand mixing or batch mixing, or it is also possible to mix by stirring the solid preparation and the premix in a coating device. As a mixing method, it is preferably a method in which the premix is ​​continuously spread on the solid preparation. As a coating device used in the mixing process, a centrifugal rotary coating device, a drum coating device, a fluidized bed coating device, etc. can be cited. From the viewpoint of stirring, a centrifugal rotary coating device is preferably used.

[0107] In addition, the mixing step may be performed under heating conditions, that is, may be performed simultaneously with the heating step described later. The heating conditions when the mixing step is performed under heating are as shown in the heating step described later.

[0108] In the mixing step, the mixing ratio of the preliminary mixture and the solid preparation is not particularly limited. For example, the amount of the preliminary mixture is preferably 0.01 to 500 parts by mass, more preferably 0.1 to 300 parts by mass, based on 100 parts by mass of the solid preparation.

[0109] Process (C) Heating process

[0110] <Heating process>

[0111] By performing the heating step, the preliminary mixture present adjacent to the solid preparation is dissolved and further covers the solid preparation to form a film, thereby forming a coating layer on at least a portion of the surface of the solid preparation.

[0112] From the viewpoint of forming a coating film, the product temperature of the solid preparation during the heating step is preferably set to be equal to or higher than the melting point of the plasticizer, more preferably 53 to 80°C, and even more preferably 53 to 73°C.

[0113] From the viewpoint of forming a coating film, the heating time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours, and even more preferably 20 minutes to 120 minutes.

[0114] In the present heating step, the apparatus used in the mixing step and the heating step may be used, or another apparatus may be used. Examples of apparatuses that can be used other than the above apparatuses include an oven-type dryer and the like.

[0115] The heating step may also be performed simultaneously with the mixing step. That is, the solid preparation and the premix may be heated while being mixed. In addition, the heating may be continued while the mixing step is stopped after the heating step.

[0116] In addition, in order to prevent the particles from sticking together during the heating process, silicon dioxide (SiO 2 ), dispersion of magnesium stearate, corn starch, etc.

[0117] As described above, in the present invention, a coating preparation (solid preparation) can be obtained by preparing a solvent-free preliminary mixture without using any solvent.

[0118] Alternatively, a multi-layer coating film can be formed by changing the composition of the preliminary mixture and repeating steps (A) to (C).

[0119] Furthermore, as described above, the solid preparation obtained by the production method of the present invention as described above may be coated with other polymer compounds thereafter.

[0120] Example

[0121] Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

[0122] Unless otherwise specified, each physical property was measured or calculated according to the above-mentioned method. In the following description, "%" indicating the amount of a substituent means "mass %".

[0123] Example 1

[0124] <Experiment 1: Preparation of granules containing theophylline (solid preparation)>

[0125] 450 g of D-mannitol / low-substituted hydroxypropyl cellulose / polyvinyl alcohol (completely saponified) granules (SmartEx (registered trademark), QD-100, manufactured by Shin-Etsu Chemical Co., Ltd.), 25 g of theophylline, 10 g of low-substituted hydroxypropyl cellulose (hydroxypropoxy group content: 11.1%, average particle size: 20.2 μm), and 15 g of polyvinyl alcohol (PE-05JPS, manufactured by JAPAN VAM & POVAL CO., LTD.) were charged into a wet granulation apparatus (GRANUMEIST (registered trademark), manufactured by Freund Corporation), and granulation was performed while stirring for 5 minutes while adding 140 g of water. The granules were charged into an extrusion granulator (Dome Granulator, manufactured by DALTON CORPORATION), and the granules were granulated by a hole diameter of 1.5 mm. The extrudate was put into a spherical granulator (Marumerizer, manufactured by DALTON CORPORATION) to shape the particles from cylindrical to spherical, and the obtained particles were dried in a forced air oven at 50°C for 24 hours to obtain a solid preparation of spherical core particles.

[0126] <Example 1>

[0127] 500 g of HPMCAS (methoxy group content: 22.3%, hydroxypropoxy group content: 6.9%, acetyl group content: 7.7%, succinyl group content: 15.1%, average particle size: 4.6 μm), 250 g of polyethylene glycol (MACROGOL 4000PS, manufactured by NOF CORPORATION, described as PEG4000 in Table 1. The same shall apply hereinafter), 100 g of propylene glycol monostearate (KAOHOMOTEX PS-200V, manufactured by Kao Corporation of Japan), and 300 g of talc were placed in a plastic bag and preliminarily mixed by hand mixing 100 times to prepare a premix.

[0128] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating device (CFgranulator CF-360, manufactured by Freund Corporation), and the pre-mixture was continuously added at a rate of 11.5 g / min from the powder supply portion at the top of the device while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the pre-mixture. After the mixing step, 2.5 g of silicon dioxide (Adsolider101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued by centrifugal flow for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. The coating yield (hereinafter referred to as the yield) was 96.40%. It should be noted that the yield was calculated according to the following formula.

[0129] Yield (%) = (weight of recovered coated solid preparation - weight of solid preparation before coating) / weight of coating composition supplied × 100

[0130] <Example 2>

[0131] 350 g of HPMCAS (methoxy group: 22.3%, hydroxypropoxy group: 6.9%, acetyl group: 7.7%, succinyl group: 15.1%, average particle size: 4.6 μm), 175 g of stearic acid (Kolliwax (registered trademark), manufactured by S Fine BASF), 70 g of propylene glycol monostearate (KAOHOMOTEX PS-200V, manufactured by Kao Corporation of Japan), and 210 g of talc were put into a plastic bag and preliminarily mixed by mixing by hand 100 times to prepare a premix.

[0132] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.5 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued while centrifugal flow was performed for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. When the yield was calculated in the same manner as in Example 1, the yield was 94.45%.

[0133] <Example 3>

[0134] 350 g of HPMCAS (methoxy group: 22.3%, hydroxypropoxy group: 6.9%, acetyl group: 7.7%, succinyl group: 15.1%, average particle size: 4.6 μm), 157.5 g of polyethylene glycol (MACROGOL 4000PS, manufactured by NOF CORPORATION), 87.5 g of stearic acid (Kolliwax (registered trademark), manufactured by S Fine BASF), 70 g of propylene glycol monostearate (KAOHOMOTEX PS-200V, manufactured by Kao Corporation of Japan), and 210 g of talc were put into a plastic bag and preliminarily mixed by mixing by hand 100 times to prepare a premix.

[0135] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.5 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued by centrifugal flow for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. When the yield was calculated in the same manner as in Example 1, the yield was 96.36%.

[0136] <Example 4>

[0137] 350 g of HPMCAS (methoxy group content: 22.3%, hydroxypropoxy group content: 6.9%, acetyl group content: 7.7%, succinyl group content: 15.1%, average particle size: 4.6 μm), 157.5 g of polyethylene glycol (MACROGOL 6000SP, manufactured by Sanyo Chemical Industries, Ltd., Japan, described as PEG6000 in Table 1. The same shall apply hereinafter), 87.5 g of stearic acid (Kolliwax (registered trademark), manufactured by SFine BASF), 70 g of propylene glycol monostearate (KAOHOMOTEX PS-200V, manufactured by Kao Corporation, Japan), and 210 g of talc were placed in a plastic bag and preliminarily mixed by hand mixing 100 times to prepare a premix.

[0138] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.5 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued while centrifugal flow was performed for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. When the yield was calculated in the same manner as in Example 1, the yield was 96.35%.

[0139] <Example 5>

[0140] 350 g of HPMCAS (methoxy group content: 22.3%, hydroxypropoxy group content: 6.9%, acetyl group content: 7.7%, succinyl group content: 15.1%, average particle size: 4.6 μm), 157.5 g of polyethylene glycol (MACROGOL 4000PS, manufactured by NOF CORPORATION), 87.5 g of stearic acid (Kolliwax (registered trademark), manufactured by S Fine BASF), 70 g of glycerol fatty acid ester (POEM W-90VP, manufactured by Riken Vitamin Co., Ltd.), and 210 g of talc were put into a plastic bag and preliminarily mixed by mixing by hand 100 times to prepare a premix.

[0141] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.5 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued while centrifugal flow was performed for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. When the yield was calculated in the same manner as in Example 1, the yield was 94.50%.

[0142] <Example 6>

[0143] 500 g of HPMCAS (methoxy group content: 22.3%, hydroxypropoxy group content: 6.9%, acetyl group content: 7.7%, succinyl group content: 15.1%, average particle size: 4.6 μm), 250 g of polyethylene glycol (MACROGOL 4000PS, manufactured by NOF CORPORATION, described as PEG4000 in Table 1. The same shall apply hereinafter), 75 g of propylene glycol monostearate (KAOHOMOTEX PS-200V, manufactured by Kao Corporation of Japan), and 300 g of talc were placed in a plastic bag and preliminarily mixed by hand mixing 100 times to prepare a premix.

[0144] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.3 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued by centrifugal flow for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. The coating yield (hereinafter referred to as the yield) was 76.40%.

[0145] <Comparative Example 1>

[0146] 500 g of HPMCAS (methoxy group: 22.3%, hydroxypropoxy group: 6.9%, acetyl group: 7.7%, succinyl group: 15.1%, average particle size: 4.6 μm), 250 g of polyethylene glycol (MACROGOL 4000PS, manufactured by NOF CORPORATION) and 300 g of talc were put into a plastic bag and preliminarily mixed by mixing by hand 100 times to prepare a preliminary mixture.

[0147] Next, 500 g of the solid preparation prepared in Experiment 1 was placed in a centrifugal rotary coating apparatus (CFgranulator CF-360, manufactured by Freund Corporation), and the premix was continuously added at a rate of 11.5 g / min from the powder supply portion at the upper part of the apparatus while centrifugal flow was performed under the conditions of a supply air temperature of 90°C and a product temperature of 68°C, thereby mixing the solid preparation and the premix. After the mixing step, 2.5 g of silicon dioxide (Adsolider 101 (registered trademark), manufactured by Freund Corporation) was added to the granules, and the heating step was continued while centrifugal flow was performed for 30 minutes without changing the supply air temperature, thereby obtaining a solid preparation coated under solvent-free conditions. When the yield was calculated in the same manner as in Example 1, the yield was 8.2%.

[0148] [Table 1]

[0149]

[0150] [Table 2]

[0151]

Claims

1. A method for producing a solid preparation coated in the absence of a solvent, wherein: At least: a preliminary mixing step of preliminarily mixing powdered hydroxypropyl methylcellulose acetate succinate, a powdered plasticizer, and a powdered wetting agent to obtain a preliminary mixture; a mixing step of mixing the premix and the solid preparation to obtain a mixture; and The heating step is to obtain a coated solid preparation by heating the mixture.

2. The method for producing a solid preparation according to claim 1, wherein: The mixing step is performed while heating.

3. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The mixing step is a mixing step of continuously spreading the preliminary mixture into the solid preparation to obtain a mixture.

4. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The powdered hydroxypropylmethylcellulose acetate succinate has a volume-based average particle size of 1 to 10 μm as measured by dry laser diffraction.

5. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The melting point of the powdered plasticizer is 50-69°C.

6. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The powdered plasticizer is one or more selected from polyethylene glycol and stearic acid.

7. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The melting point of the powdered wetting agent is at least 8° C. lower than the melting point of the powdered plasticizer.

8. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The powdered wetting agent is propylene glycol monostearate, glycerol fatty acid ester, or a mixture containing propylene glycol monostearate and glycerol fatty acid ester as main components.

9. The method for producing a solid preparation according to claim 1 or claim 2, wherein: The powdered plasticizer and the powdered wetting agent have a volume-based average particle size of 1 to 500 μm as measured by dry laser diffraction.

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