Solid preparation

Abstract

To provide a solid preparation that is less prone to wetting and / or dissolution due to interaction in concurrent blending of chlorpheniramine or a salt thereof dextromethorphan or a salt thereof and guaifenesin, and is also less prone to a deterioration of appearance quality.SOLUTION: A solid preparation contains (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, (c) guaifenesin, and (d) at least one selected from the group consisting of a silicate compound and magnesium stearate.SELECTED DRAWING: None

Description

Technical Field

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[0001] The present invention relates to a solid preparation containing chlorpheniramine.

Background Art

[0002] In pharmaceuticals, particularly in general pharmaceuticals such as general cold remedies and antipyretic analgesics, multiple medicinal components are formulated. For example, in general cold remedies, pharmaceuticals containing various medicinal components such as antipyretic analgesics, antihistamines, antitussives, expectorants, and nasal medications are widely distributed. In such preparations containing multiple medicinal components, interactions occur between the formulated medicinal components, and physicochemical changes such as changes in properties are likely to occur.

[0003] As agents used as active ingredients in general cold remedies, for example, chlorpheniramine as an antihistamine, dextromethorphan as an antitussive, and guaifenesin as an expectorant are known.

[0004] Patent Document 1 discloses a stable pharmaceutical composition containing a pharmaceutical active ingredient and silicic acid-treated crystalline cellulose (silicated crystalline cellulose), and examples of the pharmaceutical active ingredient include dextromethorphan, guaifenesin, chlorpheniramine, etc.

[0005] Also, Patent Document 2 discloses a pharmaceutical composition in which gastrointestinal disorders caused by loxoprofen or its salt are reduced or suppressed, and the reduction or suppression of the gastrointestinal disorders is achieved by combining loxoprofen or its salt with tranexamic acid or its salt and dextromethorphan or its salt and / or chlorpheniramine or its salt and / or guaifenesin.

[0006] Furthermore, Patent Documents 3 to 5 disclose pharmaceutical compositions in which the interaction between loxoprofen or its salts and its interacting components is suppressed, and components that interact with loxoprofen or its salts are listed as chlorpheniramine or its salts, guaifenesin, dextromethorphan or its salts, etc. Patent Document 3 also states that the pharmaceutical composition may further contain basic compounds such as magnesium aluminometasilicate and calcium silicate.

[0007] Furthermore, Patent Document 6 discloses a cold medicine containing naproxen or a salt thereof and a pharmaceutical ingredient selected from an anti-rhinitis component, an antitussive component, and an expectorant component, as a cold medicine that has improved therapeutic and alleviating effects on various cold symptoms. Examples of pharmaceutical ingredients listed include chlorpheniramine maleate, dextromethorphan, and guaifenesin. It is also stated that the cold medicine may contain silicates such as magnesium silicate, synthetic aluminum silicate, or magnesium aluminosilicate. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Special table number 2008-523044 [Patent Document 2] Japanese Patent Publication No. 2011-225529 [Patent Document 3] Japanese Patent Publication No. 2012-106973 [Patent Document 4] International Publication No. 2012 / 157752 [Patent Document 5] International Publication No. 2013 / 047869 [Patent Document 6] Japanese Patent Publication No. 2018-076306 [Overview of the project] [Problems that the invention aims to solve]

[0009] While all of the above literature indicates that multiple active ingredients can be combined in pharmaceuticals such as over-the-counter cold medicines, there is absolutely no mention or suggestion of the problem that when (a) chlorpheniramine or its salt, (b) dextromethorphan or its salt, and (c) guaifenesin are combined simultaneously, interactions between these drugs may cause wetting and / or dissolution, impairing the appearance and quality of the product. The object of the present invention is to provide a solid dosage form that suppresses wetting and / or dissolution due to interactions when the three components (a), (b), and (c) are formulated simultaneously, thereby suppressing deterioration of appearance quality. [Means for solving the problem]

[0010] As a result of diligent research, the inventors have found that the above problem can be solved by adding (d) at least one selected from the group consisting of silicate compounds and magnesium stearate, in addition to the three components (a), (b), and (c) above, and have completed the present invention. In other words, the present invention includes the following embodiments. [1] A solid preparation containing at least one selected from the group consisting of (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin, and (d) a silicate compound and magnesium stearate. [2] The solid preparation according to [1], wherein (a) chlorpheniramine or a salt thereof is present in 1 part by mass, and (d) at least 0.05 parts by mass or more of at least one selected from the group consisting of silicate compounds and magnesium stearate. [3] The solid preparation according to [1] or [2], wherein (b) 0.01 parts by mass or more of at least one selected from the group consisting of (d) silicate compounds and magnesium stearate is present per 1 part by mass of dextromethorphan or a salt thereof. [4] A solid preparation according to any one of [1] to [3], wherein (c) guaifenesin is present in a quantity of 0.005 parts by mass or more of (d) at least one selected from the group consisting of silicate compounds and magnesium stearate. [5] A solid preparation according to any one of [1] to [4], wherein the content of at least one selected from the group consisting of (d) silicic acid compounds and magnesium stearate is 0.05 to 50% by mass of the whole composition. [6] (a) A solid dosage form according to any one of [1] to [5], wherein chlorpheniramine or a salt thereof is at least one selected from chlorpheniramine maleate and d-chlorpheniramine maleate. [7] (b) A solid preparation according to any one of [1] to [6], wherein the dextromethorphan or salt thereof is dextromethorphan hydrobromide hydrate. [8] (d) A solid preparation according to any one of [1] to [7], wherein the silicic acid compound is at least one selected from the group consisting of calcium silicate, light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, and silica. [9] A solid preparation used for treating the common cold, as described in any of [1] to [8].

[10] A solid preparation according to any of [1] to [9], wherein the dosage form is a tablet, capsule, granule, powder, or pill. [Effects of the Invention]

[0011] According to the present invention, in a solid formulation containing (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin, further incorporating (d) at least one selected from the group consisting of a silicate compound and magnesium stearate can suppress wetting and / or dissolution due to the interaction of these drugs, thereby suppressing deterioration of appearance quality. Therefore, according to the present invention, it is possible to provide a solid formulation containing the above three components in which deterioration of appearance quality is suppressed. [Modes for carrying out the invention]

[0012] The solid preparation of the present invention is characterized by containing at least one selected from the group consisting of (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin, and (d) a silicate compound and magnesium stearate.

[0013] In this invention, "chlorpheniramine or its salt" includes chlorpheniramine and its pharmaceutically acceptable salts, as well as solvates of chlorpheniramine and its pharmaceutically acceptable salts with water, alcohol, or the like. These can be produced by known methods, or commercially available products can be used. Chlorpheniramine has an asymmetric carbon, and therefore optical isomers exist. In the present invention, however, it may be a single optical isomer or a mixture of various optical isomers. For example, it may be the d-isomer or the dl-isomer. Examples of pharmaceutically acceptable salts of chlorpheniramine include organic acid salts such as maleate or fumarate, and inorganic acid salts such as hydrochloride or sulfate. "Chlorpheniramine or its salt" includes, for example, chlorpheniramine, chlorpheniramine maleate (dl-chlorpheniramine maleate), and d-chlorpheniramine maleate, and preferably chlorpheniramine maleate and d-chlorpheniramine maleate. These can be manufactured by known methods, or commercially available products can be used. For example, chlorpheniramine or its salts conforming to the Japanese Pharmacopoeia can be used. The content of "chlorpheniramine or its salt" contained in the solid formulation of the present invention is not particularly limited and may be determined by appropriate consideration based on the above dosage, but for example, it is 0.02 to 1.5% by mass of the total solid formulation, preferably 0.04 to 0.8% by mass.

[0014] The "dextromethorphan or its salt" in the present invention includes dextromethorphan and its pharmaceutically acceptable salts, as well as solvates of dextromethorphan and its pharmaceutically acceptable salts with water, alcohol, etc. Examples of the dextromethorphan or its salt include dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, etc., and preferably dextromethorphan hydrobromide hydrate. These can be produced by known methods, and commercially available products can also be used. For example, dextromethorphan or its salt conforming to the Japanese Pharmacopoeia can be used. The content of the "dextromethorphan or its salt" contained in the solid preparation of the present invention is not particularly limited and may be appropriately determined by considering based on the above dosage. For example, it is 0.3 to 15% by mass, preferably 0.5 to 8% by mass, of the whole solid preparation.

[0015] The "guaifenesin" in the present invention can be produced by known methods, and commercially available products can also be used. For example, guaifenesin conforming to the Japanese Pharmacopoeia can be used. The content of guaifenesin contained in the solid preparation of the present invention is not particularly limited and may be appropriately determined by considering based on the above dosage. For example, it is 1 to 60% by mass, preferably 2.5 to 50% by mass, more preferably 3 to 30% by mass, of the whole solid preparation.

[0016] The "silicate compound" in the present invention is not particularly limited as long as the effects of the present invention are achieved. For example, known silicate compounds listed in the Japanese Pharmacopoeia, Pharmaceutical Additive Standards, Quasi-drug Raw Material Standards, etc. can be mentioned. Examples of the silicate compound include, for example, light anhydrous silicic acid, hydrous silicon dioxide, silica (e.g., wet silica, dry silica), metal silicate salts (e.g., aluminum silicate, calcium silicate, magnesium silicate), meta-metal silicate salts (e.g., magnesium aluminosilicate, magnesium metasilicate aluminate), compounds surface-treated with silicates (e.g., silicate-treated crystalline cellulose), etc. Preferably, it is at least one selected from calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium metasilicate aluminate, and silica. The content of the silicate compound contained in the solid preparation of the present invention is not particularly limited and may be appropriately determined in consideration of, for example, the content of chlorpheniramine or its salt, dextromethorphan or its salt, guaifenesin, and other medicinal components. For example, it is 0.01 to 70% by mass, preferably 0.05 to 50% by mass, more preferably 0.1 to 40% by mass of the whole solid preparation.

[0017] The "magnesium stearate" in the present invention can be produced by a known method, and commercially available products can also be used. For example, magnesium stearate conforming to the Japanese Pharmacopoeia can be used. The content of magnesium stearate contained in the solid preparation of the present invention is not particularly limited and may be appropriately determined in consideration of, for example, the content of chlorpheniramine or its salt, dextromethorphan or its salt, guaifenesin, and other medicinal components. For example, it is 0.01 to 70% by mass, preferably 0.05 to 50% by mass, more preferably 0.1 to 40% by mass of the whole solid preparation.

[0018] The mass ratio of (a) chlorpheniramine or a salt thereof and (d) a silicate compound and / or magnesium stearate contained in the solid formulation of the present invention is not particularly limited, but for example, per 1 part by mass of chlorpheniramine or a salt thereof, the silicate compound and / or magnesium stearate is, for example, 0.05 parts by mass or more, preferably 0.1 parts by mass or more, more preferably 0.2 parts by mass or more, particularly 0.5 parts by mass or more, and 100 parts by mass or less, preferably 50 parts by mass or less, of which the lower limit is 0.05 parts by mass or more, preferably 0.1 parts by mass or more, more preferably 0.2 parts by mass or more, and the upper limit is 100 parts by mass or less.

[0019] The mass ratio of (b) dextromethorphan or a salt thereof to (d) a silicate compound and / or magnesium stearate contained in the solid formulation of the present invention is not particularly limited, but for example, per 1 part by mass of dextromethorphan or a salt thereof, the silicate compound and / or magnesium stearate is, for example, 0.01 parts by mass or more, preferably 0.02 parts by mass or more, more preferably 0.03 parts by mass or more, and particularly 0.05 parts by mass or more, with an upper limit of 100 parts by mass or less, preferably 20 parts by mass or less.

[0020] The mass ratio of (c) guaifenesin and (d) silicic acid compound and / or magnesium stearate contained in the solid formulation of the present invention is not particularly limited, but for example, per 1 part by mass of guaifenesin, the amount of silicic acid compound and / or magnesium stearate is, for example, 0.005 parts by mass or more, preferably 0.01 parts by mass or more, particularly 0.02 parts by mass or more, and 50 parts by mass or less, preferably 10 parts by mass or less, of silicic acid compound and / or magnesium stearate, with a lower limit of 0.005 parts by mass or more, and an upper limit of 50 parts by mass or less.

[0021] The mass ratio of the combination of (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin contained in the solid formulation of the present invention to (d) a silicate compound and / or magnesium stearate is not particularly limited, but for example, per 1 part by mass of the above combination, the silicate compound and / or magnesium stearate is, for example, 0.0001 parts by mass or more, preferably 0.001 parts by mass or more, more preferably 0.002 parts by mass or more, even more preferably 0.005 parts by mass or more, particularly 0.01 parts by mass or more, and the upper limit is 50 parts by mass or less, preferably 10 parts by mass or less.

[0022] The problem of the present invention, which is the wetting and / or dissolution of (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin when they are combined, and the resulting deterioration of appearance quality, is thought to be caused by the physical contact of the three components. Therefore, as a solid preparation of the present invention, a solid preparation in which the three components are not physically separated and are contained in a state in which they can come into contact is particularly mentioned. Examples of such solid preparations include granules obtained by mixing and granulating these components in the same group, or tablets obtained by tableting these granulated powders, or granules obtained by granulating these components in a different group and then mixing the granulated powders, or tablets obtained by tableting these mixed powders.

[0023] The solid dosage form of the present invention may contain active ingredients other than chlorpheniramine or its salts, dextromethorphan or its salts, and guaifenesin, as long as they do not inhibit the effects of the present invention. For example, antipyretic analgesics, antirheumatic drugs, antihistamines, antitussives, expectorants, bronchodilators, gastric mucosal protectants, caffeines, vitamins, hypnotics and sedatives, masticatory dissolving agents, anti-inflammatory agents, anticholinergics, herbal medicines, and traditional Chinese medicine prescriptions.

[0024] Examples of antipyretic and analgesic drugs include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, ibuprofen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium. Examples of medications used for rhinitis include pseudoephedrine hydrochloride, total belladonna alkaloids, isopropamide iodide, and dipotassium glycyrrhizinate. Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimazine tartrate, isotipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, isotipendyl hydrochloride, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, diphenyldisulfonic acid carbinoxamine, mebhydroline napadisylate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimazine tartrate, phenetazine tannate, clemastine fumarate, and mequitazine. Examples of narcotic antitussives include codeine phosphate hydrate and dihydrocodeine phosphate. Examples of non-narcotic antitussives include alloclamide, isoaminyl, eprazinon, oxerazine, clofedanol, clobutinol, cloperastine, dibnate, dimemorphan, tipepidine, noscapine, hydrocotarnin, pentoxyverine, benproperine, and hominoben, as well as their salts and hydrates. Examples of their salts and hydrates include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibnate sodium, dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, pentoxyverine citrate, and their hydrates. Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia / fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methyl ephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosal protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation products of aluminum hydroxide and sodium bicarbonate, coprecipitation products of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitation products of magnesium hydroxide and aluminum potassium sulfate, and magnesium carbonate. Examples of caffeine-containing substances include sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine. Examples of vitamins include vitamin B1 or its derivatives or salts, such as thiamine nitrate; vitamin B2 or its derivatives or salts, such as riboflavin; vitamin C or its derivatives or salts, such as ascorbic acid; and vitamin P (hesperidin) or its derivatives or salts. Examples of hypnotic and sedative drugs include allyl isopropylacetylurea and bromovalerylurea. Examples of mucolytic agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, seraptase, and glycyrrhizic acid and its salts. Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide. Examples of crude drugs include ephedra, nandina fruit, parsley, galangal, licorice, balloon flower, plantago-aquatica, plantago-aquatica, citrine, senega, fritillary, fennel, phellodendron bark, cow's ren, turmeric, chamomile, cinnamon, gentian, ox gall, animal bile (including bear bile), adenophora, ginger, lanceolata, clove, citrus peel, atractylodes, zinnia, bamboo shoot ginseng, and ginseng. Examples of traditional Chinese medicine prescriptions include Kakkonto, Kakkonto-ka-kikyo, Keihito, Kososan, Saikokeihito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekobokuto, and Maoto.

[0025] The solid dosage form of the present invention may be formulated in a form containing the above-mentioned active ingredient and a conventionally pharmaceutically acceptable carrier or additive in the pharmaceutical technology. Examples of the carriers or additives mentioned above include excipients, disintegrants, binders, fluidizers, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, and fragrances. These additives are used in amounts that are conventional in the field of pharmaceutical formulation technology.

[0026] Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose monohydrate, refined sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; and anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, and calcium carbonate. Examples of disintegrants include carmellose, carmellose calcium, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (L-HPC), and hydroxypropyl starch, with croscarmellose sodium and L-HPC being preferred. Examples of binders used include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, acacia powder, methylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, acacia gum, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropylcellulose and hydroxypropylmethylcellulose being preferred. Examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, kaolin, and talc. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and sucrose fatty acid esters. Examples of colorants include yellow iron(III) oxide, iron(III) oxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2, food red No. 3, food red No. 102, food red No. 104, food red No. 105, food red No. 106, food lake pigment, riboflavin, sodium riboflavin phosphate, and titanium dioxide. Examples of pH adjusting agents include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and their salts. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (160) polyoxypropylene (30) glycol. Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of flavoring agents include ascorbic acid, citric acid, tartaric acid, malic acid, sucralose, and stevia extract. Examples of fragrances include L-menthol, peppermint oil, lemon oil, and vanillin. The carrier or additive described above may be used as a single type, or two or more types may be used in appropriate mixed form.

[0027] The formulation of the solid dosage form of the present invention can be carried out using general methods described in publications such as the Granulation Handbook (edited by the Japan Powder Technology Association, Ohmsha), Formulation Design for Orally Administered Formulations (edited by Professor Mitsuru Hashida, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Compression Molding Technology of Powders (edited by the Powder Engineering, Formulation and Particle Design Subcommittee, Nikkan Kogyo Shimbun), and the Handbook of Pharmaceutical Machinery Technology (2nd edition, edited by the Pharmaceutical Machinery Technology Research Association 20th Anniversary Publication Editorial Committee, Pharmaceutical Machinery Technology Research Association), and there are no special restrictions.

[0028] For example, when formulating the solid dosage form of the present invention into tablets, the active ingredient and a conventionally pharmaceutically acceptable carrier or additive are mixed and granulated, and then compressed into tablets using various tablet presses commonly used in pharmaceutical formulation (e.g., rotary tablet presses). Furthermore, when formulating the solid dosage form of the present invention into capsules, the active ingredient and a conventionally pharmaceutically acceptable carrier or additive are mixed and granulated, and then the granulated material is filled into capsules to form capsules. The granulation method is not particularly limited, and known methods (extrusion granulation, rolling granulation, agitation granulation, fluidized bed granulation, spray drying granulation, crushing granulation, melt granulation, etc.) may be used.

[0029] Examples of solid formulations of the present invention include tablets (including uncoated tablets, coated tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc.), capsules (including soft capsules, hard capsules, etc.), granules, powders, and pills, with tablets being preferred.

[0030] The above-mentioned solid dosage forms may be coated by conventional methods using commonly formulated coating bases. For example, tablets may be coated with a coating base to form film-coated tablets. Examples of coating bases include water-soluble bases such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolividone, polyvinyl alcohol, polyvinyl alcohol copolymer, and macrogol; water-insoluble bases such as ethylcellulose; enteric-coated bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, acrylic acid copolymer, and carboxyvinyl polymer; gastric-soluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and polyvinyl acetate diethylaminoacetate; and gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. Furthermore, in the present invention, the coating base may be one type or two or more types. Furthermore, coating additives may be used in the coating. Examples of coating additives include light-shielding agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate.

[0031] Furthermore, the present invention also provides a method for suppressing deterioration of the appearance of a solid dosage form containing (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin, characterized by incorporating at least one selected from the group consisting of (d) a silicate compound and magnesium stearate. Each requirement in this method (each component, its amount used, its usage ratio, etc.) is as described for the solid dosage form of the present invention.

[0032] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0033] (Examples 1-8 and Comparative Examples 1-4) The main active ingredient and additives shown in Table 1 were weighed in predetermined amounts and physically mixed in a mortar to obtain a mixture. [Table 1-1] [Table 1-2]

[0034] (Example test) The mixtures obtained above (Examples 1-8 and Comparative Examples 1-4) were placed in glass bottles, sealed tightly, and stored at 60°C for 3 weeks. The properties of the mixtures after storage were compared and evaluated with those immediately after storage began. [Table 2-1] [Table 2-2]

[0035] As shown in Table 2, the mixtures containing calcium silicate or other silicate compounds or magnesium stearate maintained their state even after storage at 60°C for 3 weeks (Examples 1-8). On the other hand, in the groups without silicate compounds or magnesium stearate, dissolution and wetting of the mixture were observed, making it difficult to maintain the mixture's state (Comparative Examples 1-4). From these results, it was revealed that silicate compounds, including calcium silicate, and magnesium stearate have the effect of suppressing the interaction between chlorpheniramine or its salts, dextromethorphan or its salts, and guaifenesin.

[0036] (Manufacturing example) The components were mixed and granulated according to the formulation shown in Category A of Table 3 below to obtain granules. The obtained granules were mixed with the components according to the formulation shown in Category B and compressed into tablets to obtain uncoated tablets. The obtained uncoated tablets were coated according to the formulation shown in Category C to obtain coated tablets. [Table 3] [Industrial applicability]

[0037] According to the present invention, a solid dosage form can be provided in which wetting and / or dissolution due to the interaction of (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, and (c) guaifenesin is suppressed by at least one selected from the group consisting of (d) silicate compounds and magnesium stearate, thereby suppressing deterioration of appearance quality.

Claims

1. A solid preparation comprising (a) chlorpheniramine or a salt thereof, (b) dextromethorphan or a salt thereof, (c) guaifenesin, and (d) at least one member selected from the group consisting of a silicic acid compound and magnesium stearate.

2. 2. The solid preparation according to claim 1, wherein (d) at least one selected from the group consisting of silicic acid compounds and magnesium stearate is present in an amount of 0.05 part by mass or more per part by mass of (a) chlorpheniramine or a salt thereof.

3. 2. The solid formulation according to claim 1, wherein (d) at least one selected from the group consisting of silicic acid compounds and magnesium stearate is present in an amount of 0.01 part by mass or more per part by mass of (b) dextromethorphan or a salt thereof.

4. 2. The solid preparation according to claim 1, wherein (d) at least one selected from the group consisting of a silicic acid compound and magnesium stearate is present in an amount of 0.005 part by mass or more per part by mass of (c) guaifenesin.

5. 5. The solid preparation according to claim 1, wherein the content of (d) at least one selected from the group consisting of silicic acid compounds and magnesium stearate is 0.05 to 50% by mass based on the total mass of the composition.

6. The solid formulation according to any one of claims 1 to 4, wherein (a) chlorpheniramine or a salt thereof is at least one selected from chlorpheniramine maleate and d-chlorpheniramine maleate.

7. The solid formulation according to any one of claims 1 to 4, wherein (b) dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate.

8. The solid preparation according to any one of claims 1 to 4, wherein the silicic acid compound (d) is at least one selected from the group consisting of calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and silica.

9. The solid preparation according to any one of claims 1 to 4, which is used for treating colds.

10. The solid preparation according to any one of claims 1 to 4, which is in the form of a tablet, a capsule, a granule, a powder or a pill.