Coated solid pharmaceutical preparations

Abstract

To provide a coated solid pharmaceutical preparation which prevents a user from feeling an unpleasant taste and / or odor of a pharmacologically active substance when taking it, and also prevents discoloration over time.SOLUTION: In a coated solid pharmaceutical preparation, a solid pharmaceutical preparation containing a pharmacologically active substance is coated with a film containing a film-forming polymer and a flaky substance.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a coated solid pharmaceutical formulation. [Background technology]

[0002] Conventionally, solid pharmaceutical preparations such as tablets, capsules, and granules have been coated with a polymer or sugar coating to reduce unpleasant tastes and odors when taken, improve stability (for example, to prevent discoloration and odor generation over time, and to prevent whiskers and clouding of packaging containers due to sublimation), or to prevent direct contact with pharmacologically active substances. In particular, the method of coating solid pharmaceutical preparations such as tablets, capsules, and granules with film-forming polymers is widely used, because the production time required is much shorter and the production operation is easier than with sugar coating, and various functions such as water solubility, gastric solubility, enteric properties, and sustained release properties can be added depending on the type of polymer.

[0003] However, because the density of the film-forming polymer coating is less than that of sugar coating, various efforts have been made to improve it. For example, in order to block oxygen and the odor of tablets, it has been proposed to coat tablets with a film coating composition containing polyvinyl alcohol and talc (50 to 86% by mass of the solid content) (Patent Document 1: JP 2006-188490 A). Also, in order to reduce the odor of cysteine, it has been proposed to apply a coating film containing a partially saponified product of polyvinyl alcohol to a solid preparation containing L-cysteine ​​or a salt thereof (Patent Document 2: JP 2008-201711 A). Furthermore, in order to prevent discoloration and odor generation, it has been proposed to apply a coating film containing a polyvinyl alcohol copolymer and having a thickness of 60 μm or more to uncoated tablets containing tranexamic acid, ascorbic acid, and L-cysteine ​​(Patent Document 3: International Publication No. 2011 / 049093). In addition to the above, a coating composition for a solid preparation containing a water-unstable drug, which contains hydroxypropyl cellulose, talc, propylene glycol, and polyethylene glycol in a specific blending ratio (Patent Document 4: JP 2007-001873 A), and a coating agent for a solid preparation containing polyvinyl alcohol and bentonite or magnesium aluminum silicate (Patent Document 5: WO 2010 / 074223 A) have also been reported.

[0004] However, these coatings have not been able to sufficiently reduce the unpleasant taste and / or odor of pharmacologically active substances, and the amount of coating required is often large, making production time consuming. Furthermore, there are problems such as the fact that it can only be applied to tablets of a specific shape, the need for complex and advanced technology and special spray nozzles, etc., high costs, and the difficulty of producing with stable quality. Furthermore, the dissolution or disintegration characteristics of the coated solid pharmaceutical preparation may change due to excessively fast or slow dissolution or disintegration, and defects in the manufacturing process may affect the stability or appearance of the pharmacologically active substance, which may result in the pharmacologically active substance not being able to fully exert its effects. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2006-188490 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-201711 [Patent Document 3] International Publication No. 2011 / 049093 Brochure [Patent Document 4] Japanese Patent Application Laid-Open No. 2007-001873 [Patent Document 5] International Publication No. 2010 / 074223 Brochure Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a coated solid pharmaceutical preparation which not only reduces the unpleasant taste and / or odor of a pharmacologically active substance when taken, but also reduces discoloration over time. [Means for solving the problem]

[0007] As a result of extensive research to solve the above problems, the present inventors have discovered that by applying a coating containing a film-forming polymer and a scale-like substance to a solid pharmaceutical preparation containing a pharmacologically active substance, not only is the unpleasant taste and / or odor of the pharmacologically active substance less likely to be felt when taken, but discoloration over time during storage of the preparation is also less likely to occur, thereby completing the present invention.

[0008] That is, the present invention provides a coated solid pharmaceutical preparation in which a coating containing a film-forming polymer and a scale-like substance is applied to a solid pharmaceutical preparation containing a pharmacologically active substance. The present invention also provides a method for suppressing unpleasant taste and / or odor caused by a pharmacologically active substance when taking a solid pharmaceutical preparation containing the pharmacologically active substance, which method comprises applying a coating containing a film-forming polymer and a scale-like substance to the solid pharmaceutical preparation. Furthermore, the present invention provides a method for suppressing discoloration over time during storage of a solid pharmaceutical preparation containing a pharmacologically active substance, which method comprises applying a coating containing a film-forming polymer and a scale-like substance to the solid pharmaceutical preparation. [Effects of the Invention]

[0009] The coated solid pharmaceutical preparation of the present invention not only makes it difficult to sense the unpleasant taste and / or odor of the pharmacologically active substance when taken, but also makes it difficult for discoloration to occur over time during storage of the preparation. DETAILED DESCRIPTION OF THE INVENTION

[0010] <Coated solid pharmaceutical preparations> The coated solid pharmaceutical preparation of the present invention is a solid pharmaceutical preparation containing a pharmacologically active substance, to which a coating containing a film-forming polymer and a scale-like substance (hereinafter, this coating will also be referred to as a "specific coating") has been applied. The pharmacologically active substance used in the coated solid pharmaceutical preparation of the present invention is not particularly limited, but is preferably one that generally has an unpleasant taste and / or odor, such as bitterness or strong irritation, when made into a solid preparation, or one that generally has stability problems, such as the generation of an unpleasant odor over time, discoloration, etc., when made into a solid preparation. According to the present invention, even when such a pharmacologically active substance is used, it is possible to suppress the occurrence of stability problems, such as an unpleasant taste and / or odor when taking the pharmacologically active substance, or the generation of an unpleasant odor over time, discoloration, etc.

[0011] Examples of pharmacologically active substances that are likely to produce an unpleasant taste include ascorbic acid, aspirin, acetaminophen, allylisopropylacetylurea, alprenolol, isoaminil, ibuprofen, etilefrine, ethenzamide, epinastine, ephedrines (pseudoephedrine, methylephedrine, etc.), erythromycin, caffeine, carbetapentane, quinine, chlordiazepoxide, chlorpheniramine, chlorpromazine, codeine, diazepam, digitoxin, diazepam, phenytoin ... Examples of antihistamines include hydrocodeine, diphenhydramine, cimetidine, dimemorfan, dextromethorphan hydrobromide, diltiazem, cefaclor, celecoxib, talampicillin, thiamine, theophylline, delapril, tranexamic acid, noscapine, bacampicillin, calcium pantothenate, pirenzepine, pirenzepine hydrochloride, fexofenadine, pheniramine, fursultiamine, propranolol, promethazine, meclofenoxate, meloxicam, loxoprofen, and loperamide. Of these, ascorbic acid, aspirin, acetaminophen, ibuprofen, ethenzamide, epinastine, ephedrines, caffeine, chlorpheniramine, diphenhydramine, thiamine, theophylline, tranexamic acid, noscapine, calcium pantothenate, pirenzepine hydrochloride, fexofenadine, and meloxicam are preferred.

[0012] Examples of pharmacologically active substances that are likely to produce an unpleasant odor when taken or over time include Chinese herbal extracts such as Kakkonto, Kakufugedokuto, Kyoseihafuganryo, Shosaikoto, Shoseiryuto, Sanzaoninto, Jumihaidokuto, and Shikokeishito; herbal medicines and biological extracts such as aloe, fennel, turmeric, valerian, licorice, chrysanthemum, cinnamon bark, bezoar, peony, ginger, earth dragon, taiso, passionflower, ginseng, garlic, hops, and ephedra; amino acids such as isoleucine, cysteine, valine, methionine, and leucine; vitamin B1 and its derivatives; vitamin C group such as ascorbic acid and erythorbic acid; vitamin E, as well as ibuprofen, glucosamine, chondroitin sulfate, sodium chondroitin sulfate, hyaluronic acid, and methylmethionine sulfonium chloride. Among these, ascorbic acid, vitamin B1 and its derivatives, ibuprofen, herbal extracts, chondroitin sulfate, sodium chondroitin sulfate, cysteine, methionine, herbal extracts, and vitamin C are preferred.

[0013] Among the above-mentioned pharmacologically active substances that are likely to produce an unpleasant taste or an unpleasant odor when taken or over time, ascorbic acid, aspirin, acetaminophen, ibuprofen, ethenzamide, epinastine, ephedrines, caffeine, Chinese herbal extracts, chlorpheniramine, chondroitin sulfate, sodium chondroitin sulfate, cysteine, methionine, diphenhydramine, herbal extracts, theophylline, tranexamic acid, noscapine, calcium pantothenate, vitamin B1 and its derivatives, vitamin C, pirenzepine hydrochloride, fexofenadine, and meloxicam are preferred.

[0014] In the present invention, it is also preferred to contain at least one or more pharmacologically active substances selected from aspirin, acetaminophen, ibuprofen, ethenzamide, epinastine, ephedrines, caffeine, herbal extracts, chlorpheniramine, chondroitin sulfate, sodium chondroitin sulfate, cysteine, diphenhydramine, herbal extracts, theophylline, tranexamic acid, noscapine, calcium pantothenate, vitamin C, and pirenzepine hydrochloride. It is more preferable that the composition contains at least one or more pharmacologically active substances selected from the group consisting of ibuprofen, ephedrines, epinastine, chondroitin sulfate, sodium chondroitin sulfate, cysteine, diphenhydramine, tranexamic acid, calcium pantothenate, vitamin C, and pirenzepine hydrochloride, it is even more preferable that the composition contains at least one or more pharmacologically active substances selected from ibuprofen and cysteine, and it is particularly preferable that the composition contains at least cysteine. These pharmacologically active substances generally have problems not only with respect to unpleasant taste and / or odor, but also with respect to stability, such as discoloration over time. However, according to the present invention, a coated solid pharmaceutical preparation can be produced that is not only less likely to have the unpleasant taste and / or odor of the pharmacologically active substance when taken, but is also less likely to discolor over time as described above.

[0015] In addition, pharmacologically active substances other than those mentioned above that may cause stability problems include, for example, azulene, ethyl aminobenzoate, benzoic acids, ambroxol, camphor, salicylic acids, magnesium oxide, sodium bicarbonate, magnesium hydroxide, tipepidine, neucillin, vitamin B6, vitamin B12, vitamin D, vitamin E, menthol, and Scopolia extract.

[0016] In addition to the above, other pharmacologically active substances include pharmacologically active substances (hereinafter also referred to as "other pharmacologically active substances") that are usually incorporated into gastric preparations, enteric preparations, or sustained-release preparations. The coated solid pharmaceutical preparation of the present invention is likely to exhibit gastric, enteric, and sustained-release properties. In particular, even when the amount of coating is small, gastric, enteric, and sustained-release properties are likely to be exhibited, and it is expected that the production time will be shortened and energy consumption and the amount of raw materials used will be reduced.

[0017] Other pharmacologically active substances include, for example, isosorbide, isoprenaline, isopropamide, ibudilast, indomethacin, urapidil, esomeprazole, ethinylestradiol, emedastine, potassium chloride, oxycodone, omeprazole, captopril, carteolol, quetiapine, chlormadinone, salazosulfapyridine, salicylamide, dioctyl sodium sulfosuccinate, diclofenac, disopyramide, dipyridamole, diprophylline, scopolamine, cephalexin, tacrolimus, tapentadol, tamsulosin, and tolterodione. Examples of such antihistamines include benzodiazepine, nicardipine, nifedipine, barnidipine, sodium valproate, paroxetine, bisacodyl, hydromorphone, pyridoxal, pyridoxine or a salt thereof, pindolol, faniramine, fesoterodine, bunazosin, ferrous fumarate, flavin adenine dinucleotide, pramipexole, furosemide, bezafibrate, belladonna total alkaloids, beraprost, vonoprazan, mesalazine, methylphenidate, metoprolol, morphine, soluble ferric pyrophosphate, rabeprazole, lansoprazole, ferrous sulfate, and roxatidine.

[0018] Among the above-mentioned pharmacologically active substances, ascorbic acid, aspirin, acetaminophen, ibuprofen, ethenzamide, epinastine, ephedrines, caffeine, Chinese herbal extracts, chlorpheniramine, chondroitin sulfate, sodium chondroitin sulfate, cysteine, methionine, diphenhydramine, herbal extracts, theophylline, tranexamic acid, noscapine, calcium pantothenate, vitamin B1 and its derivatives, vitamin C, pyridoxine or a salt thereof, pirenzepine hydrochloride, fexofenadine, and meloxicam are preferred, and ascorbic acid, ibuprofen, cysteine, pyridoxine or a salt thereof are particularly preferred.

[0019] The pharmacologically active substance may be used alone or in combination of two or more. The content of the pharmacologically active substance in the coated solid pharmaceutical preparation of the present invention is preferably 1% by mass to 99% by mass, more preferably 5% by mass to 95% by mass, even more preferably 20% by mass to 90% by mass, and even more preferably 30% by mass to 85% by mass. When the dosage form is a tablet or capsule, it is more preferably 40% by mass to 85% by mass, even more preferably 50% by mass to 80% by mass, and particularly preferably 60% by mass to 80% by mass. On the other hand, when the dosage form is a granule, it is more preferably 30% by mass to 70% by mass, even more preferably 30% by mass to 60% by mass, and particularly preferably 30% by mass to 50% by mass.

[0020] In addition to the pharmacologically active substances, the solid pharmaceutical preparation may contain pharmaceutical additives as needed. Examples of pharmaceutical additives include stabilizers, surfactants (e.g., sodium lauryl sulfate, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, etc.), plasticizers, lubricants (e.g., talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerin fatty acid esters, etc.), solubilizers, buffers, sweeteners, bases, adsorbents, flavoring agents, binders (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, etc.), suspending agents, antioxidants, glossing agents, flavorings, sustaining agents, wetting agents, wetting adjusters, and antifoaming agents. , refreshing agents, antistatic agents, coloring agents, flavoring agents, fragrances, isotonicity agents, softeners, emulsifiers, thickeners, foaming agents, excipients (e.g., lactose, lactose hydrate, sucrose, glucose, mannitol, sorbitol, xylitol, corn starch, crystalline cellulose, etc.), pH adjusters, dispersants, disintegrants (e.g., croscarmellose sodium, carmellose, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, etc.), disintegration aids, preservatives, solubilizers, solubilizers, solvents, and fluidizing agents (e.g., light anhydrous silicic acid, hydrated silicon dioxide, etc.). Specific examples of these pharmaceutical additives include those listed in the Pharmaceutical Additives Encyclopedia 2016 (edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha), Yakushoku-Hatsu No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), and the Japan Pharmaceutical Additives Association website (http: / / www.jpec.gr.jp / ).

[0021] Furthermore, the mass ratio of the pharmacologically active substance in the solid pharmaceutical formulation to the pharmaceutical additives in the solid pharmaceutical formulation [(pharmacologically active substance) / (pharmaceutical additive)] is, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, preferably 0.01 or more, more preferably 0.05 or more, even more preferably 0.1 or more, and particularly preferably 0.3 or more, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, preferably 20 or less, more preferably 16 or less, even more preferably 8 or less, and particularly preferably 4 or less. As a specific range, 0.01 or more and 20 or less is preferred, 0.05 or more and 16 or less is more preferred, 0.1 or more and 8 or less is even more preferred, and 0.3 or more and 4 or less is particularly preferred.

[0022] From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the content of the solid pharmaceutical preparation in the coated solid pharmaceutical preparation of the present invention is preferably 70% by mass or more and 99.9% by mass or less, more preferably 80% by mass or more and 99.9% by mass or less, even more preferably 85% by mass or more and 99.9% by mass or less, still more preferably 90% by mass or more and 99.5% by mass or less, and particularly preferably 95% by mass or more and 98% by mass or less.

[0023] The film-forming polymer in the specific coating is not particularly limited as long as it is a polymer used to form a coating on a solid pharmaceutical preparation by spray coating or the like, and may be one or more selected from water-soluble polymers, water-insoluble polymers, gastrosoluble polymers, and enteric polymers. Among these, water-soluble polymers and water-insoluble polymers are preferred from the viewpoint of their effect of suppressing unpleasant taste and / or unpleasant odor and discoloration.

[0024] Examples of water-soluble polymers include cellulose-based water-soluble polymers, polyalkylene glycol-based water-soluble polymers, polyvinyl alcohol-based water-soluble polymers, and polyvinylpyrrolidone-based water-soluble polymers. Among these, cellulose-based water-soluble polymers and polyvinyl alcohol-based water-soluble polymers are preferred from the viewpoint of suppressing unpleasant taste and / or odor and discoloration, and cellulose-based water-soluble polymers and polyvinyl alcohol-(meth)acrylic acid-alkyl(meth)acrylate copolymer-based water-soluble polymers are more preferred. Examples of water-soluble cellulose polymers include methylcellulose (e.g., Methocel Premium A, METOLOSE, etc.), hypromellose (also known as hydroxypropyl methylcellulose (e.g., Methocel Premium K, Methocel Premium F, Methocel Premium E, METOLOSE SR, TC-5, Benecel, etc.)), and hydroxypropyl cellulose (e.g., Kulcel, etc.). Examples of the polyalkylene glycol-based water-soluble polymer include macrogol (also known as polyethylene glycol). Examples of polyvinyl alcohol-based water-soluble polymers include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers (e.g., POVACOAT, etc.), partially saponified polyvinyl alcohols (e.g., Gohsenol, Kuraray Poval, J Poval, etc.), fully saponified polyvinyl alcohols (also known as Poval), and polyvinyl alcohol-polyethylene glycol graft copolymers (e.g., Kollicoat IR, etc.). Examples of polyvinylpyrrolidone-based water-soluble polymers include povidone (also known as polyvidone, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, etc.)), copolyvidone (e.g., Kollidon VA64, Plasdone S-630, etc.), and the like.

[0025] Examples of water-insoluble polymers include water-insoluble alkyl (meth)acrylate polymers and water-insoluble cellulose polymers. Among these, water-insoluble alkyl (meth)acrylate polymers are preferred, and water-insoluble alkyl (meth)acrylate polymers containing ammonium salt-type cationic functional groups are more preferred, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration. Examples of water-insoluble alkyl (meth)acrylate polymers include ethyl acrylate-methyl methacrylate copolymers (e.g., Eudragit NE30D, etc.), ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymers (also known as aminoalkyl methacrylate copolymer RS ​​(e.g., Eudragit RS100, Eudragit RSPO, Eudragit RL, Eudragit RLPO, Eudragit RS30D, Eudragit RL30D, etc.)). Examples of the water-insoluble cellulose polymer include ethyl cellulose (for example, Ethocel, Aquacoat, Cerioscoat, Surerease, etc.).

[0026] Examples of the gastrosoluble polymer include polyvinyl acetal-based gastrosoluble polymers such as polyvinyl acetal diethylaminoacetate (e.g., AEA); and (meth)acrylic acid-based gastrosoluble polymers such as methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (also known as aminoalkyl methacrylate copolymer E (e.g., Eudragit EPO, Eudragit E100)) and methyl methacrylate-diethylaminoethyl methacrylate copolymer (e.g., Kollicoat Smartseal 30D).

[0027] Examples of enteric polymers include methacrylic acid-ethyl acrylate copolymers (also known as methacrylic acid copolymer LD (e.g., Eudragit L30D-55, Eudragit L100-55, etc.)), methacrylic acid-methyl methacrylate copolymers (also known as methacrylic acid copolymer L (e.g., Eudragit L100), methacrylic acid copolymer S (e.g., Eudragit S100)), and methyl acrylate-methyl methacrylate-methacrylic acid copolymers (e.g., Eudragit FS30D). In addition to (meth)acrylic acid-based enteric polymers such as those mentioned above, examples include ceracephate (also known as cellulose acetate phthalate (e.g., CAP, Aquateric, etc.)), hypromellose phthalate (also known as hydroxypropyl methylcellulose phthalate (e.g., HP-55, HP-50, etc.)), hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT, etc.)), and carboxymethylethylcellulose (e.g., CMEC, etc.).

[0028] The film-forming polymers may be used alone or in combination of two or more.

[0029] From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the content of the film-forming polymer in the coated solid pharmaceutical formulation of the present invention is preferably from 0.01 to 15% by mass, more preferably from 0.05 to 12.5% ​​by mass, even more preferably from 0.1 to 10% by mass, still more preferably from 0.3 to 7.5% by mass, even more preferably from 0.5 to 5% by mass, and particularly preferably from 1 to 3% by mass. From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the content of the film-forming polymer in the specific film is preferably 30% by mass or more and 99.9% by mass or less, more preferably 50% by mass or more and 99.9% by mass or less, even more preferably 60% by mass or more and 99.9% by mass or less, and particularly preferably 70% by mass or more and 99.9% by mass or less.

[0030] The mass ratio of the film-forming polymer in the specific coating to the pharmacologically active substance in the solid pharmaceutical formulation [(film-forming polymer) / (pharmacologically active substance)] is preferably 0.001 or more, more preferably 0.003 or more, even more preferably 0.01 or more, and particularly preferably 0.015 or more, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, and is preferably 0.2 or less, more preferably 0.1 or less, even more preferably 0.075 or less, and particularly preferably 0.05 or less, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, etc. Specifically, the range is preferably 0.001 or more and 0.2 or less, more preferably 0.003 or more and 0.1 or less, even more preferably 0.01 or more and 0.075 or less, and particularly preferably 0.015 or more and 0.05 or less.

[0031] In the present invention, the term "scaly substance" refers to a flake-like substance having a scale-like shape with a particle diameter greater than its thickness. The scaly substance is preferably a silicon atom-containing scaly substance. Examples include potassium aluminum silicate (mica, sericite), fine silicon dioxide (scaly silica), aluminum silicate (colloidal hydrated aluminum silicate (bentonite), hydrated aluminum silicate (kaolin)), magnesium aluminum silicate, etc. The scaly substance may also be coated with a coloring pigment such as iron oxide or titanium oxide. The amount of the coloring pigment coated is preferably 10 to 150 parts by mass per 100 parts by mass of the scaly substance. One type of scaly substance may be used alone, or two or more types may be used in combination.

[0032] Among these scaly substances, aluminum potassium silicate and fine silicon dioxide are preferred from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration.

[0033] The average particle size of the scale-like substance is usually in the range of 0.2 to 500 μm, preferably in the range of 0.5 to 300 μm, and more preferably in the range of 1 to 150 μm. The thickness of the scale-like substance is usually in the range of 10 to 5000 nm, preferably in the range of 50 to 2000 nm, and more preferably in the range of 100 to 1200 nm. The aspect ratio of the scale-like substance is usually in the range of 5-500, preferably in the range of 10-300, and more preferably in the range of 15-150. The average particle size of the scaly substance is the average particle size equivalent to a sphere measured by a laser diffraction scattering method, and the average particle size, thickness and aspect ratio can be measured by a dynamic image analysis method.

[0034] From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the content of the scaly substance in the coated solid pharmaceutical formulation of the present invention is preferably 0.0001% by mass or more and 20% by mass or less, more preferably 0.0005% by mass or more and 10% by mass or less, even more preferably 0.001% by mass or more and 5% by mass or less, even more preferably 0.01% by mass or more and 3% by mass or less, and particularly preferably 0.1% by mass or more and 1% by mass or less. From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the content of the scaly substance in the specific coating is preferably 0.001% by mass or more and 70% by mass or less, more preferably 0.01% by mass or more and 50% by mass or less, even more preferably 0.1% by mass or more and 40% by mass or less, and particularly preferably 10% by mass or more and 30% by mass or less.

[0035] The mass ratio of the scaly substance in the specific coating to the pharmacologically active substance in the solid pharmaceutical preparation [(scaly substance) / (pharmacologically active substance)] is preferably 0.00001 or more, more preferably 0.0001 or more, even more preferably 0.001 or more, and particularly preferably 0.005 or more, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, and is preferably 1 or less, more preferably 0.5 or less, even more preferably 0.1 or less, and particularly preferably 0.05 or less, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, etc. Specifically, the range is preferably 0.00001 or more and 1 or less, more preferably 0.0001 or more and 0.5 or less, even more preferably 0.001 or more and 0.1 or less, and particularly preferably 0.005 or more and 0.05 or less. Furthermore, the mass ratio of the scaly substance in the specific coating to the film-forming polymer in the specific coating [(scaly substance) / (film-forming polymer)] is preferably 0.0002 or more, more preferably 0.002 or more, even more preferably 0.02 or more, and particularly preferably 0.1 or more, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, and is preferably 20 or less, more preferably 10 or less, even more preferably 5 or less, and particularly preferably 1 or less. A specific range is preferably 0.0002 or more and 20 or less, more preferably 0.002 or more and 10 or less, even more preferably 0.02 or more and 5 or less, and particularly preferably 0.1 or more and 1 or less.

[0036] The specific coating may contain pharmaceutical additives as required in addition to the coating-forming polymer and the scale-like substance. Examples of pharmaceutical additives include plasticizers, coating agents, dispersants, colorants, and antifoaming agents. Specific examples of these pharmaceutical additives include those listed in the Pharmaceutical Additives Encyclopedia 2016 (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nipposha), Yakushoku-hatsu No. 1204-1 (Pharmaceutical Affairs Administration Law), and the Japan Pharmaceutical Additives Association website (http: / / www.jpec.gr.jp / ). Pharmaceutical additives may be used singly or in combination of two or more.

[0037] Specific examples of plasticizers include Karion 83, triethyl citrate, glycerin, glycerin fatty acid esters, sesame oil, dimethylpolysiloxane-silicon dioxide mixtures, D-sorbitol, medium-chain triglycerides, corn starch-derived sugar alcohol liquid, triacetin, concentrated glycerin, castor oil, diethyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, polyoxyethylene (105) polyoxypropylene (5) glycol, propylene glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, cottonseed oil-soybean oil mixtures, and glycerin monostearate. These may be used alone or in combination. The content of the plasticizer in the specific coating is usually 30% by mass or less, and preferably 25% by mass or less.

[0038] Specific examples of coating agents include olive oil, cacao butter, kagoso, castor wax, caramel, carnauba wax, carboxyvinyl polymer, carboxymethylethyl cellulose, carboxymethyl starch sodium, carmellose calcium, carmellose sodium, dried aluminum hydroxide gel, dried milky white lac, winter plum powder, fish scale leaf, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropyl cellulose, light liquid paraffin, spermaceti, Crystalline cellulose, hydrogenated oil, synthetic wax, high glucose starch syrup, hard wax, succinated gelatin, wheat flour, wheat starch, rice starch, white beeswax, titanium oxide, magnesium oxide, dimethylpolysiloxane (for internal use), dimethylpolysiloxane-silicon dioxide mixture, calcined gypsum, sucrose fatty acid ester, zinc powder, aluminum hydroxide gel, hydrogenated rosin glycerin ester, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, refined gel Ingredients: gelatin, refined shellac, refined white sugar, zein, sorbitan sesquioleate, cetanol, gypsum, gelatin, shellac, sorbitan fatty acid ester, D-sorbitol, D-sorbitol liquid, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, simple syrup, medium gold leaf, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, terpene resin, starch (soluble), corn syrup, corn oil, triacetin, calcium lactate, lactose, concentrated glycerin, white shellac, white sugar, honey, paraffin, pearl powder, potato Starch, castor oil, diethyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, glucose, pullulan, propylene glycol, povidone, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 80, macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000,Examples of such additives include macrogol 6000, macrogol 20000, macrogol 35000, D-mannitol, starch syrup, beeswax, myristyl alcohol, phthalic anhydride, anhydrous calcium hydrogen phosphate, Japan wax, aluminum monostearate, glycerin monostearate, sorbitan monolaurate, montan acid ester wax, medicinal charcoal, lauromacrogol, calcium sulfate, liquid paraffin, DL-malic acid, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, calcium dihydrogen phosphate, and rosin. These may be used alone or in combination of two or more. The content of the coating agent in the specific film is usually 30% by mass or less, and preferably 20% by mass or less.

[0039] Specific examples of dispersants include gum arabic, gum arabic powder, propylene glycol alginate, ethanol, oleic acid, carboxyvinyl polymer, carmellose sodium, agar powder, citric acid, sodium citrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, choline phosphate, safflower oil, white beeswax, titanium oxide, dioctyl sodium sulfosuccinate, sucrose fatty acid ester, sodium hydroxide, stearic acid, magnesium stearate, purified oleic acid, purified soybean lecithin, sorbitan sesquioleate, sorbitan fatty acid ester, D-sorbitol, soybean oil, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, tragacanth powder, sorbitan trioleate, lactose, concentrated glycerin, potato starch, propylene glycol, and polysorbate 80. Examples of suitable surfactants include pyrene glycol fatty acid esters, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polysorbate 20, polysorbate 60, polysorbate 80, sodium polyphosphate, macrogol 300, macrogol 4000, macrogol 6000, anhydrous sodium citrate, anhydrous sodium pyrophosphate, magnesium aluminometasilicate, sodium metaphosphate, methylcellulose, Japan wax, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, lauromacrogol, liquid paraffin, and calcium hydrogen phosphate. These may be used alone or in combination of two or more. The content of the dispersant in the specific coating is usually 25% by mass or less, and preferably 15% by mass or less.

[0040] Specific examples of colorants include acacia tannin powder, turmeric extract, yellow ferric oxide, Opaspray K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, β-carotene, licorice extract, gold leaf, black iron oxide, light anhydrous silicic acid, titanium oxide, ferric oxide, Food Blue No. 1, 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, sodium hydroxide, talc, copper chlorophine sodium, copper chlorophyll, naked barley leaf extract, d-borneolol, octyldodecyl myristate, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, riboflavin sodium phosphate, rose oil, etc. These may be used alone or in combination of two or more. The content of the colorant in the specific film is usually 10% by mass or less, and preferably 5% by mass or less.

[0041] Specific examples of antifoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for internal use), dimethylpolysiloxane-silicon dioxide mixtures, sucrose fatty acid esters, silicone resin emulsions, silicone antifoaming agents, polyoxyl 40 stearate, sorbitan fatty acid esters, sorbitan trioleate, and polysorbate 80. These may be used alone or in combination of two or more. The content of the antifoaming agent in the specific coating is usually 5% by mass or less, and preferably 1% by mass or less.

[0042] The thickness and coating amount of the specific coating may be adjusted depending on the type of film-forming polymer, the type of solid pharmaceutical preparation, and the dosage form, but the thickness of the specific coating is usually 0.1 μm or more, preferably 1 μm or more, and particularly preferably 2 μm or more. For example, in the case of a tablet with a diameter of about 9 mm and a mass of about 200 mg, a coating thickness of 5 μm corresponds to a mass of about 1 to 2 mg per tablet.

[0043] Furthermore, the mass ratio of the coating amount of the specific coating to the solid pharmaceutical formulation [(specific coating) / (solid pharmaceutical formulation)] is preferably 0.0001 or more, more preferably 0.001 or more, even more preferably 0.005 or more, and particularly preferably 0.01 or more, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, etc., and is preferably 1 or less, more preferably 0.75 or less, even more preferably 0.5 or less, and particularly preferably 0.1 or less, from the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, etc. Specific ranges are preferably 0.0001 or more and 1 or less, more preferably 0.001 or more and 0.75 or less, more preferably 0.005 or more and 0.5 or less, and particularly preferably 0.01 or more and 0.1 or less. Even in the case of a small coating amount as described above, the coated solid pharmaceutical formulation of the present invention is unlikely to produce an unpleasant taste and / or unpleasant odor of the pharmacologically active substance upon administration and is unlikely to discolor over time.

[0044] From the viewpoint of the effect of suppressing unpleasant taste and / or unpleasant odor and discoloration, the total content of the solid pharmaceutical formulation and the specific coating in the coated solid pharmaceutical formulation of the present invention is preferably 75% by mass or more and 100% by mass or less, more preferably 80% by mass or more and 100% by mass or less, even more preferably 85% by mass or more and 100% by mass or less, and particularly preferably 90% by mass or more and 100% by mass or less.

[0045] The coated solid pharmaceutical preparation of the present invention may have a coating other than the specific coating (hereinafter, this coating may also be referred to as "another coating"). The other coating is similar to the specific coating except that it does not contain a scale-like substance. In addition, the other coating may be applied between the solid pharmaceutical preparation and the specific coating, or may be applied outside the specific coating.

[0046] In the present invention, the term "coated solid pharmaceutical preparation" refers to a pharmaceutical preparation in which a coating is applied to a solid pharmaceutical preparation. The coating may be applied directly to the solid pharmaceutical preparation or via another coating. The coated solid pharmaceutical formulation is preferably for oral use. Dosage forms of solid pharmaceutical preparations and coated solid pharmaceutical preparations include those described in the General Provisions for Preparations for Oral Administration and Preparations for Oral Application in the Seventeenth Edition of the Japanese Pharmacopoeia. Specific examples include tablets, capsules, granules, powders, solid syrups, oral jellies, and oral tablets. Tablets include regular tablets as well as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. Oral tablets include lozenges, sublingual tablets, buccal tablets, adhesive tablets, and gums. Capsules include hard capsules as well as soft capsules. Granules include fine granules and effervescent granules. Among these dosage forms, tablets, capsules, granules, and powders are preferred.

[0047] The coated solid pharmaceutical formulation of the present invention can be produced by appropriately combining conventional methods. A solid pharmaceutical formulation containing a pharmacologically active substance may be formulated by a conventional method and then coated with a specific coating. Furthermore, other coatings may be applied as needed before and / or after coating with the specific coating. When preparing solid pharmaceutical preparations such as tablets, capsules, granules, and powders, if it is necessary to prepare a granulated powder, the granulated powder can be produced by a commonly used granulation method (e.g., wet granulation methods such as spray granulation using a solution or dispersion containing water or an organic solvent, agitation granulation, fluidized bed granulation, tumbling granulation, and tumbling fluidized bed granulation, and dry granulation methods such as compaction granulation using a granular binder). Tablets can be produced by mixing the granulated powder with pharmaceutical additives as needed and compressing the mixture. Capsules can be produced by mixing the granulated powder or tablets with pharmaceutical additives as needed and filling hard or soft capsules.

[0048] The specific coating can be formed by coating the solid pharmaceutical preparation obtained as described above with a film-forming polymer, a scaly substance, and, if necessary, a pharmaceutical additive. The coating method is not particularly limited, and examples thereof include pan coating, fluidized bed coating, rolling coating, dry coating, and combinations thereof. More specifically, examples include a method of coating using a solution or suspension in which a composition containing a film-forming polymer, a scaly substance, and, if necessary, a pharmaceutical additive is added to a solvent such as purified water or ethanol.

[0049] The coated solid pharmaceutical preparation of the present invention not only prevents the unpleasant taste and / or odor of the pharmacologically active substance from being felt when taken, but also is less likely to discolor over time.The coated solid pharmaceutical preparation of the present invention also has excellent dissolution and disintegration properties. Furthermore, the sealability (shielding properties) is improved without compromising the functionality of the film-forming polymer, such as water-soluble, gastrosoluble, enteric, and sustained-release properties. This can be expected to suppress the generation of unpleasant odors over time, prevent sublimation, improve stability, and suppress formulation changes. The same effects are also achieved even with a small amount of film coverage. This shortens production time and reduces energy consumption, CO2 emissions, and raw material usage, enabling low-cost, low-environmental-impact production.

[0050] <Method for suppressing unpleasant taste and / or odor, and method for suppressing discoloration> The method of the present invention for suppressing unpleasant taste and / or unpleasant odor caused by a pharmacologically active substance when taking a solid pharmaceutical preparation containing the pharmacologically active substance is characterized by applying a coating containing a film-forming polymer and a scale-like substance to the solid pharmaceutical preparation. The method of the present invention for suppressing discoloration over time during storage of a solid pharmaceutical preparation containing a pharmacologically active substance is characterized by applying a coating containing a film-forming polymer and a scale-like substance to the solid pharmaceutical preparation. The meanings of various terms, the contents and ratios of each component, etc. in the method for suppressing an unpleasant taste and / or an unpleasant odor and the method for suppressing discoloration of the present invention are the same as the meanings of various terms, the contents and ratios of each component, etc. explained for the coated solid pharmaceutical preparation of the present invention. [Example]

[0051] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0052] (Examples 1-1 to 1-4) (1) Manufacturing of solid pharmaceutical preparations (uncoated tablets) L-cysteine ​​(manufactured by Nippon Rika Yakuhin) 1920 g, ascorbic acid (manufactured by Fuso Chemical Co., Ltd.) 4000 g, pyridoxine hydrochloride (manufactured by BASF) 400 g, crystalline cellulose (Ceolas (manufactured by Asahi Kasei)) 1580 g, low-substituted hydroxypropyl cellulose (L-HPC (manufactured by Shin-Etsu Chemical Co., Ltd.)) 320 g, light anhydrous silicic acid (manufactured by Freund Corporation) 24 g, calcium stearate (manufactured by Merck) 112 g were used to prepare powder for tableting by conventional methods. The resulting mixed powder was compressed into tablets using a rotary tablet press (VIRGO-0512 tablet press: manufactured by Kikusui Seisakusho) with an 8.5 mm diameter mortar and pestle to a mass of 265 mg per tablet and a thickness of 4.7 mm, yielding approximately 8.2 kg of uncoated tablets.

[0053] (2) Production of the coated solid pharmaceutical preparation (film-coated tablet) of the present invention A film-coating solution was prepared by dissolving and suspending 60 g of a film-forming polymer (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer: POVACOAT (Nisshin Chemical Industry)) and 20 g of a scaly substance (titanium oxide (41.2%) coated potassium aluminum silicate (58.8%): average particle size 6.2 μm (laser diffraction scattering method), Merck) in 1500 g of purified water. The uncoated tablets (350 g) obtained in (1) above were coated with the film coating solution in a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight gain per uncoated tablet was 1 mg (Example 1-1), 2 mg (Example 1-2), 5 mg (Example 1-3), or 10 mg (Example 1-4), respectively, to obtain coated solid pharmaceutical preparations of the present invention as film-coated tablets.

[0054] (Comparative Examples 1-1 to 1-4) A film-coating solution was prepared by dissolving and suspending 60 g of a film-forming polymer (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer: POVACOAT (Nisshin Chemical Industry Co., Ltd.)) and 20 g of titanium oxide (Ishihara Sangyo Kaisha, Ltd.) in 1500 g of purified water. 350 g of uncoated tablets obtained in the same manner as in Example 1(1) were coated with the above film coating solution in a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight increase per uncoated tablet was 1 mg (Comparative Example 1-1), 2 mg (Comparative Example 1-2), 5 mg (Comparative Example 1-3), or 10 mg (Comparative Example 1-4), respectively, to obtain comparative coated solid pharmaceutical preparations as film-coated tablets.

[0055] (Test Example 1: Deodorizing Effect Test) The coated solid pharmaceutical formulations prepared in Examples 1-1 to 1-4 and Comparative Examples 1-1 to 1-4, and 30 plain tablets obtained in Example 1(1), were each placed in a No. 5 standard glass bottle, which was then stoppered and sealed. After storage at 25°C for 24 hours, the bottle was opened, and the cysteine ​​odor at that time was evaluated by 12 subjects according to the following evaluation criteria, and an average score was calculated. The results are shown in Table 1.

[0056] <Evaluation criteria for unpleasant odor suppression effect> 0 points: No cysteine ​​odor 1 point: Slight cysteine ​​odor 2 points: Cysteine ​​smell 3 points: Strong cysteine ​​odor

[0057] [Table 1]

[0058] As shown in Table 1, the coated solid pharmaceutical preparations (Examples 1-1 to 1-4) provided with a coating containing a scale-like substance in addition to a film-forming polymer had a less noticeable unpleasant odor originating from the pharmacologically active substance. Furthermore, the coated solid pharmaceutical preparation of the present invention had little unpleasant odor even when the coating amount was as low as 1 mg / tablet, and the coated solid pharmaceutical preparation of the present invention had such a suppressed unpleasant odor that it was barely noticeable when the coating amount was 2 mg / tablet or more.

[0059] (Test Example 2: Discoloration prevention effect test) Thirty tablets each of the coated solid pharmaceutical formulations of Examples 1-4 and Comparative Examples 1-4 were placed in a No. 5 standard glass bottle and sealed with a stopper. The bottles were stored in a constant temperature room at 60°C for 22 days, and the color change from before storage (initial) was measured using a spectrophotometer (SE 7700: manufactured by Nippon Denshoku Industries Co., Ltd.) to calculate ΔE (relative to initial). The results are shown in Table 2.

[0060] [Table 2]

[0061] As shown in Table 2, the coated solid pharmaceutical formulations (Examples 1-4) in which a coating containing a scale-like substance in addition to a film-forming polymer was applied to a solid pharmaceutical formulation containing a pharmacologically active substance were found to be less likely to discolor over time and to have excellent stability.

[0062] Example 2 (1) Manufacturing of undercoated tablets A talc-containing film coating solution was prepared by dissolving and suspending 48 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT, manufactured by Nisshin Chemical Industry Co., Ltd.), 10 g of titanium oxide (manufactured by Ishihara Sangyo Kaisha, Ltd.), and 22 g of talc (manufactured by Nippon Talc Co., Ltd.) in 320 g of purified water. 400 g of the uncoated tablets produced in Example 1(1) were coated with the above-mentioned talc-containing film coating solution using a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight increase per uncoated tablet was 20 mg, thereby obtaining undercoated tablets. (2) Production of the coated solid pharmaceutical preparation (film-coated tablet) of the present invention A film-coating solution containing a scale-like substance was prepared by dissolving and suspending 39 g of a film-forming polymer (hypromellose: TC-5 (Shin-Etsu Chemical Co., Ltd.)) and 1 g of a scale-like substance (titanium oxide (25.3%) coated fine silicon dioxide (74.7%): average particle size 19.1 μm (laser diffraction scattering method), Merck) in 1500 g of purified water. 350 g of the undercoated tablets were coated with the above-mentioned scaly substance-containing film coating solution using a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight gain per tablet was 1 mg, thereby obtaining film-coated tablets of the present invention. 1 mg / tablet of the outermost coating of this formulation contains 0.975 mg / tablet of film-forming polymer and 0.025 mg / tablet of scaly substance. The coated solid pharmaceutical preparation of Example 2 was subjected to a deodorizing effect test in the same manner as in Test Example 1, and the average score was 0.08, indicating an excellent deodorizing effect.

[0063] (Examples 3-1 to 3-4) A film-coating solution containing the scale-like substance was prepared by dissolving and suspending 39.9 g of a film-forming polymer (hypromellose: TC-5 (Shin-Etsu Chemical Co., Ltd.)) and 0.1 g of a scale-like substance (titanium oxide (41.2%) coated potassium aluminum silicate (58.8%): average particle size 6.2 μm (laser diffraction scattering method), Merck) in 1500 g of purified water. 350 g of the undercoated tablets produced in Example 2(1) were coated with the above-mentioned scale-like substance-containing film coating solution in a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight gain per uncoated tablet reached 1 mg (Example 3-1), 2 mg (Example 3-2), 3 mg (Example 3-3), and 4 mg (Example 3-4), respectively, to obtain coated solid pharmaceutical formulations of the present invention as film-coated tablets. The coated solid pharmaceutical preparations of Examples 3-1 to 3-4 and the undercoated tablets produced in Example 2(1) were subjected to a deodorizing effect test in the same manner as in Test Example 1. The results are shown in Table 3.

[0064] [Table 3]

[0065] When hypromellose was used as the film-forming polymer and aluminum potassium silicate was used as the scaly substance in combination (Examples 3-1 to 3-4), the unpleasant odor originating from the pharmacologically active substance could also be suppressed.

[0066] Example 4 (1) Manufacturing of granular materials A kneaded solution of 40 g of polyoxyl stearate 40 (NOF Corp.) in 500 g of purified water was added to a mixture of 1800 g of ibuprofen (BASF Corp.), 2240 g of refined white sugar (Toyo Sugar Refining Co., Ltd.), 288 g of crystalline cellulose (Asahi Kasei Corp.), 320 g of cornstarch (Nippon Cornstarch Co., Ltd.), and 112 g of hydroxypropyl cellulose (Nippon Soda Corp.). This composition was extruded and granulated in a conventional manner, then dried and sieved through 30 mesh and 42 mesh sieves to obtain granules. (2) Manufacturing of granules (coated granules) A coating solution was prepared by mixing 26.3 parts by mass of a film-forming polymer dispersion (ammonioalkyl methacrylate copolymer dispersion (solids content 30% by mass, manufactured by Evonik)), 1.0 part by mass of a scaly substance (titanium oxide (12.3%) coated potassium aluminum silicate (87.7%): average particle size 77.2 μm (laser diffraction scattering method): manufactured by Merck), 3.5 parts by mass of talc (manufactured by Muramatsu Sangyo), 2.6 parts by mass of triethyl citrate (manufactured by San-Ei Gen F.F.I.), and 66.6 parts by mass of purified water. 500 g of the granules obtained in (1) above were coated with the above coating solution in a fluidized bed coating apparatus (SFP-01, manufactured by Powrex) at a concentration of 2.5% by mass based on the granules. These granules were divided into 546.7 mg packets using aluminum heat seals to obtain divided granules containing 200 mg of ibuprofen. The granules of Example 4 contain 7.0 mg of film-forming polymer and 0.89 mg of scale-like substance in 13.3 mg of film per packet.

[0067] (Comparative Example 2) A coating solution was prepared by mixing 26.3 parts by mass of ammonioalkyl methacrylate copolymer dispersion (solid content 30% by mass, manufactured by Evonik), 4.5 parts by mass of talc (manufactured by Muramatsu Sangyo), 2.6 parts by mass of triethyl citrate (manufactured by San-Ei Gen F.F.I.), and 66.6 parts by mass of purified water. 500 g of the granules produced in Example 4(1) were coated with the above coating solution in a fluidized bed coating apparatus (SFP-01, manufactured by Powrex) at a concentration of 2.5% by mass based on the granules. These granules were divided into 546.7 mg packets using aluminum heat seals to obtain divided granules containing 200 mg of ibuprofen. The granules of Comparative Example 2 contained 7.0 mg of film-forming polymer in 13.3 mg of film per packet, but did not contain any scaly substance.

[0068] (Test Example 3: Unpleasant taste masking test) For the divided granules of Example 4 and Comparative Example 2, five subjects were asked to hold one packet in their mouths for 15 seconds and evaluate the unpleasant taste according to the following evaluation criteria, and the average score was calculated. The results are shown in Table 4.

[0069] <Unpleasant taste masking evaluation criteria> 0 points: No bitterness or astringency 1 point: Slight bitterness and astringency 2 points: Bitter and astringent 3 points: Strong bitterness and astringency

[0070] [Table 4]

[0071] As shown in Table 4, the coated solid pharmaceutical preparation (Example 4) provided with a coating containing a scale-like substance in addition to a film-forming polymer was less likely to produce an unpleasant taste derived from the pharmacologically active substance.

[0072] (Examples 5-1 to 5-14) A film-coating solution was prepared by dissolving and suspending 15 g of a film-forming polymer (polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer: POVACOAT (Nisshin Chemical Industry)) and 5 g of the scale-like substance shown in Table 5 in 375 g of purified water. The uncoated tablets (350 g) produced in Example 1(1) were coated with the above film coating solution using a coating machine (HiCoater HC-LABO, manufactured by Freund Corporation) until the weight increase per uncoated tablet was 5 mg, thereby obtaining the coated solid pharmaceutical formulation of the present invention as film-coated tablets.

[0073] [Table 5]

[0074] The coated solid pharmaceutical preparations of Examples 5-1 to 5-14 were subjected to a deodorizing effect test in the same manner as in Test Example 1, and all of them had an average score of 0, indicating an excellent deodorizing effect.

Claims

[Claim 1] A method for suppressing discoloration over time during storage of a solid pharmaceutical preparation containing a pharmacologically active substance, comprising applying to the solid pharmaceutical preparation a coating containing a film-forming polymer and one or more scale-like substances selected from potassium aluminum silicate coated with iron oxide and / or titanium oxide and fine silicon dioxide.

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