Pharmaceutical Composition

Abstract

To provide a pharmaceutical composition that suppresses a change in properties such as solidification, discoloration, wetting, dissolution due to interaction when simultaneously blending a propionic acid-based nonsteroidal anti-inflammatory agent and diphenhydramine or a salt thereof, and also suppresses a degradation of appearance quality.SOLUTION: A pharmaceutical composition contains a propionic acid-based nonsteroidal anti-inflammatory agent, and diphenhydramine or a salt thereof, and at least one selected from the group consisting of a silicate compound, polyvinylpyrrolidone and low-degree-substitution hydroxypropyl cellulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing a propionic acid type nonsteroidal anti-inflammatory analgesic drug. [Background technology]

[0002] Propionate-type nonsteroidal anti-inflammatory drugs (propionate-type NSAIDs) inhibit cyclooxygenase (COX), thereby suppressing the production of prostaglandins and exerting antipyretic and analgesic effects. Ibuprofen and loxoprofen, which are included in propionate-type nonsteroidal anti-inflammatory drugs, are not only used in prescription drugs but are also incorporated into over-the-counter medicines such as cold medicines and antipyretics.

[0003] Known drugs used as active ingredients in general cold medicines include antipyretic analgesics and antihistamines such as diphenhydramine. Patent Document 1 discloses a bilayer tablet or bilayer caplet containing ibuprofen in a first layer and diphenhydramine or a salt thereof in a second layer for use in treating painful sleep disorders. This formulation was developed to eliminate the negative interaction between ibuprofen and diphenhydramine.

[0004] Furthermore, Patent Document 2 discloses a stable pharmaceutical composition containing a pharmaceutically active ingredient and silicic acid-treated crystalline cellulose (silicified crystalline cellulose), and lists ibuprofen, diphenhydramine, etc. as examples of the pharmaceutically active ingredient.

[0005] Patent Document 3 discloses a combination preparation containing a first total cold medicine containing an antihistamine and a second total cold medicine containing another antihistamine with a different hypnotic effect from the perspective of QOL, while effectively utilizing the hypnotic effect of antihistamines such as diphenhydramine and enhancing the effect of caffeine. Furthermore, Patent Document 4 discloses a combination preparation with a similar purpose, containing a first total cold medicine containing an antihistamine at a first dose and a second total cold medicine containing the antihistamine at a second dose different from the first dose. These documents also state that the preparation may further contain ibuprofen, etc.

[0006] Patent Document 5 discloses a pharmaceutical composition with improved stability with loxoprofen, and the stabilization is achieved by packaging in an airtight storage package such as a PTP package. Diphenhydramine and the like are listed as ingredients that interact with loxoprofen, and the pharmaceutical composition also describes that it may further contain a basic compound such as magnesium aluminosilicate, magnesium silicate, or magnesium aluminometasilicate. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Special Publication 2004-521104 [Patent Document 2] Special Publication 2008-523044 [Patent Document 3] Patent Publication No. 2007-302578 [Patent Document 4] Patent Publication No. 2008-100924 [Patent Document 5] Patent Publication No. 2012-046514 Summary of the Invention [Problem to be solved by the invention]

[0008] All of the above documents indicate that multiple active ingredients can be combined in pharmaceuticals such as general cold medicines, but they do not mention the problem that when (a) a propionic acid-based nonsteroidal anti-inflammatory analgesic and (b) diphenhydramine or its salts are combined simultaneously, the interaction between these drugs can cause changes in properties such as solidification, discoloration, wetting, and dissolution, resulting in a loss of appearance quality. That is, an object of the present invention is to provide a pharmaceutical composition that suppresses changes in properties such as solidification, discoloration, wetting, and dissolution due to the interaction that occurs when the above two components (a) and (b) are simultaneously blended, thereby suppressing deterioration in appearance quality. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have found that the above problems can be solved by blending, in addition to the above two components (a) and (b), (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose, and have thus completed the present invention. That is, the present invention includes the following aspects. [1] A pharmaceutical composition comprising (a) a propionic acid-based nonsteroidal anti-inflammatory drug, (b) diphenhydramine or a salt thereof, and (c) at least one member selected from the group consisting of a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose. [2] The pharmaceutical composition according to [1], wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.2 parts by mass or more relative to 1 part by mass of (a) a propionic acid type nonsteroidal anti-inflammatory analgesic. [3] The pharmaceutical composition according to [1] or [2], wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.2 parts by mass or more per part by mass of (b) diphenhydramine or a salt thereof. [4] The pharmaceutical composition according to any one of [1] to [3], wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.05 to 50% by mass relative to the total mass of the composition. [5] The pharmaceutical composition according to any one of [1] to [4], wherein (a) the propionic acid type nonsteroidal anti-inflammatory analgesic is ibuprofen, loxoprofen, or a salt thereof. [6] (b) The pharmaceutical composition according to any one of [1] to [5], wherein the diphenhydramine or a salt thereof is diphenhydramine hydrochloride. [7] (c) The pharmaceutical composition according to any one of [1] to [6], wherein the silicic acid compound is at least one selected from the group consisting of calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and wet silica. [8] (c) The pharmaceutical composition according to any one of [1] to [7], wherein the polyvinylpyrrolidone is crospovidone. [9] The pharmaceutical composition according to any one of [1] to [8], which is used for treating colds.

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder or pill. [Effects of the Invention]

[0010] According to the present invention, in a pharmaceutical composition containing (a) a propionic acid type nonsteroidal anti-inflammatory drug and (b) diphenhydramine or a salt thereof, by further adding (c) at least one selected from the group consisting of a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose, it is possible to suppress changes in properties such as solidification, discoloration, wetting, and dissolution due to interactions between these drugs, and to suppress deterioration in appearance quality. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition which contains the above two components (a) and (b) and in which deterioration of appearance quality is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0011] The pharmaceutical composition of the present invention is characterized by containing (a) a propionic acid type nonsteroidal anti-inflammatory analgesic, (b) diphenhydramine or a salt thereof, and (c) at least one member selected from the group consisting of a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose.

[0012] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a general term for drugs that have anti-inflammatory, antipyretic, and analgesic effects other than steroids. NSAIDs are divided into acidic and basic NSAIDs, and acidic NSAIDs are further classified into arylacetic acid, oxicams (enolic acid), salicylic acid, fenamic acid (anthranilic acid), and propionic acid. Examples of the "propionic acid type nonsteroidal anti-inflammatory analgesic" in the present invention include alminoprofen, ibuprofen, oxaprozin, ketoprofen, naproxen, zaltoprofen, suprofen, tiaprofenic acid, fenoprofen, fenbufen, pranoprofen, flurbiprofen, loxoprofen, and salts thereof. Preferably, ibuprofen, loxoprofen, or a salt thereof is used. The content of the propionic acid type nonsteroidal anti-inflammatory analgesic contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, but is, for example, 1 to 60% by mass, preferably 1.5 to 55% by mass, and more preferably 2 to 50% by mass of the total pharmaceutical composition.

[0013] The "ibuprofen" in the present invention can be produced by a known method, or a commercially available product can be used. For example, ibuprofen in accordance with the Japanese Pharmacopoeia can be used. The content of ibuprofen contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, but is, for example, 1 to 60% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass of the total pharmaceutical composition.

[0014] In the present invention, "loxoprofen or a salt thereof" includes loxoprofen and its pharmaceutically acceptable salts, as well as solvates of loxoprofen and its pharmaceutically acceptable salts with water, alcohol, or the like. Examples of loxoprofen and its salts include loxoprofen and loxoprofen sodium dihydrate, with loxoprofen sodium dihydrate being preferred. These can be produced by known methods, or commercially available products can be used. For example, loxoprofen or a salt thereof in accordance with the Japanese Pharmacopoeia can be used. The content of loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, but is, for example, 1 to 60% by mass, preferably 1.5 to 55% by mass, and more preferably 2 to 50% by mass, of the total pharmaceutical composition as loxoprofen sodium (anhydrate).

[0015] In the present invention, "diphenhydramine or a salt thereof" includes diphenhydramine and its pharmaceutically acceptable salts, as well as solvates of diphenhydramine and its pharmaceutically acceptable salts with water, alcohol, or the like. Examples of diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine citrate, diphenhydramine salicylate, diphenhydramine tannate, and diphenhydramine lauryl sulfate, with diphenhydramine hydrochloride being preferred. These can be produced by known methods, or commercially available products can be used. For example, diphenhydramine or a salt thereof conforming to the Japanese Pharmacopoeia can be used. The content of diphenhydramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, but is, for example, 0.1 to 20% by mass, preferably 0.5 to 10% by mass, of the total pharmaceutical composition.

[0016] The "silicic acid compound" in the present invention is not particularly limited as long as it produces the effects of the present invention, and examples thereof include known silicic acid compounds listed in the Japanese Pharmacopoeia, Pharmaceutical Additives Standards, Quasi-drug Raw Materials Standards, etc. Examples of silicic acid compounds include light anhydrous silicic acid, hydrous silicon dioxide, silica (e.g., wet silica, dry silica), metal silicates (e.g., aluminum silicate, calcium silicate, magnesium silicate), metal metasilicates (e.g., magnesium aluminosilicate, magnesium aluminometasilicate), etc., and preferably at least one selected from calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and wet silica. The content of the silicic acid compound contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately depending on the contents of the propionic acid type nonsteroidal anti-inflammatory drug, diphenhydramine or a salt thereof, and other active ingredients, and is, for example, 0.01 to 70% by mass, preferably 0.05 to 50% by mass, more preferably 0.2 to 40% by mass of the total pharmaceutical composition.

[0017] The "polyvinylpyrrolidone" in the present invention is not particularly limited as long as it produces the effects of the present invention, and examples thereof include known polyvinylpyrrolidones listed in the Japanese Pharmacopoeia, Pharmaceutical Additives Standards, Quasi-drug Raw Materials Standards, etc. Examples of the "polyvinylpyrrolidone" in the present invention include linear polymers of 1-vinyl-2-pyrrolidone (povidone), crosslinked polymers of 1-vinyl-2-pyrrolidone (crospovidone), and copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate (copolyvidone), with crospovidone being preferred. The content of polyvinylpyrrolidone contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately depending on the contents of the propionic acid type nonsteroidal anti-inflammatory drug, diphenhydramine or a salt thereof, and other active ingredients, and is, for example, 0.01 to 70% by mass, preferably 0.05 to 50% by mass, and more preferably 0.2 to 40% by mass of the total pharmaceutical composition.

[0018] The "low-substituted hydroxypropyl cellulose" of the present invention can be produced by known methods, or commercially available products can be used. For example, low-substituted hydroxypropyl cellulose in accordance with the Japanese Pharmacopoeia can be used. Low-substituted hydroxypropyl cellulose refers to hydroxypropyl cellulose with a low degree of substitution, in which the hydroxy groups of cellulose are substituted with hydroxypropyl groups. Specifically, it refers to hydroxypropyl cellulose with a degree of substitution (content) of hydroxypropoxy groups (-OCH2CHOHCH3) of 5 to 16% by mass. The content of low-substituted hydroxypropyl cellulose contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately depending on the contents of the propionic acid type nonsteroidal anti-inflammatory drug, diphenhydramine or a salt thereof, and other active ingredients, and is, for example, 0.01 to 70% by mass, preferably 0.05 to 50% by mass, and more preferably 0.2 to 40% by mass of the total pharmaceutical composition.

[0019] The mass ratio of (a) a propionic acid type nonsteroidal anti-inflammatory drug to (b) diphenhydramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of the amount of diphenhydramine or a salt thereof relative to 1 part by mass of the propionic acid type nonsteroidal anti-inflammatory drug is, for example, 0.005 parts by mass or more, preferably 0.01 parts by mass or more, and more preferably 0.02 parts by mass or more, and the upper limit is 5 parts by mass or less, preferably 2 parts by mass or less, and more preferably 1.5 parts by mass or less. In particular, when component (a) is ibuprofen, the mass ratio of ibuprofen to diphenhydramine or a salt thereof is not particularly limited, but for example, the lower limit of the amount of diphenhydramine or a salt thereof relative to 1 part by mass of ibuprofen is 0.01 part by mass or more, preferably 0.02 part by mass or more, and the upper limit is 2 parts by mass or less, preferably 1.5 parts by mass or less.

[0020] The mass ratio of (a) a propionic acid type nonsteroidal anti-inflammatory drug to (c) a silicic acid compound, polyvinylpyrrolidone and / or low-substituted hydroxypropyl cellulose contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the mass ratio of the silicic acid compound, polyvinylpyrrolidone and / or low-substituted hydroxypropyl cellulose relative to 1 part by mass of the propionic acid type nonsteroidal anti-inflammatory drug is, for example, at least 0.01 part by mass, preferably at least 0.05 part by mass, more preferably at least 0.1 part by mass, and even more preferably at least 0.2 part by mass, and at most 100 parts by mass, preferably at most 50 parts by mass, and more preferably at most 10 parts by mass. In particular, when component (a) is ibuprofen and component (c) is a silicate compound, the mass ratio of ibuprofen to silicate compound is not particularly limited, but for example, the lower limit of the amount of silicate compound relative to 1 part by mass of ibuprofen is 0.01 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 50 parts by mass or less, preferably 10 parts by mass or less.

[0021] The mass ratio of (b) diphenhydramine or a salt thereof to (c) a silicic acid compound, polyvinylpyrrolidone and / or low-substituted hydroxypropyl cellulose contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the mass ratio of the silicic acid compound, polyvinylpyrrolidone and / or low-substituted hydroxypropyl cellulose relative to 1 part by mass of diphenhydramine or a salt thereof is, for example, a lower limit of 0.01 part by mass or more, preferably 0.05 part by mass or more, more preferably 0.1 part by mass or more, and even more preferably 0.2 part by mass or more, and an upper limit of 200 parts by mass or less, preferably 100 parts by mass or less, and more preferably 20 parts by mass or less. In particular, when component (c) is a silicate compound, the mass ratio of diphenhydramine or a salt thereof to the silicate compound is not particularly limited, but for example, the lower limit of the amount of silicate compound per 1 part by mass of diphenhydramine or a salt thereof 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, preferably 20 parts by mass or less.

[0022] The mass ratio of the combination of (a) a propionic acid type nonsteroidal anti-inflammatory drug and (b) diphenhydramine or a salt thereof, and (c) a silicic acid compound, polyvinylpyrrolidone and / or low-substituted hydroxypropylcellulose contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the amount of component (c) relative to 1 part by mass of the combination of components (a) and (b) is, for example, at least 0.01 part by mass, preferably at least 0.05 part by mass, and more preferably at least 0.1 part by mass, and at most 50 parts by mass, preferably at most 10 parts by mass, and more preferably at most 5 parts by mass. In particular, when component (a) is ibuprofen and component (c) is a silicate compound, the mass ratio of the combination of ibuprofen and diphenhydramine or a salt thereof to the silicate compound is not particularly limited, but for example, the lower limit of the amount of the silicate compound relative to 1 part by mass of the combination is 0.05 parts by mass or more, preferably 0.1 parts by mass or more, and the upper limit is 10 parts by mass or less, preferably 5 parts by mass or less.

[0023] The problem of the present invention, which is the changes in properties such as solidification, discoloration, wetting, and dissolution that occur when (a) a propionic acid-based nonsteroidal anti-inflammatory drug and (b) diphenhydramine or a salt thereof are simultaneously blended, and the resulting deterioration in appearance quality, are thought to be caused by physical contact between components (a) and (b). Therefore, examples of the pharmaceutical composition of the present invention include pharmaceutical compositions in which components (a) and (b) are not physically separated but are contained in a state where they can come into contact with each other. Such pharmaceutical compositions include, for example, tablets obtained by mixing and granulating these components in the same group and compressing the mixture, or tablets obtained by granulating these components in separate groups and then mixing the granulated powders and compressing the mixture.

[0024] The pharmaceutical composition of the present invention may contain other active ingredients besides the above-mentioned active ingredients, such as antipyretics, analgesics, rhinitis medications, antihistamines, antitussives, expectorants, bronchodilators, gastric mucosa protective agents, vitamins, hypnotics and sedatives, phlegm dissolving agents, anti-inflammatory agents, anticholinergic agents, herbal medicines, and Chinese herbal prescriptions, as long as the effects of the present invention are not inhibited.

[0025] Examples of antipyretic analgesics include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, and isopropylantipyrine. Medication for rhinitis includes pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, dipotassium glycyrrhizinate, etc. Examples of antihistamines include alimemazine tartrate, isothipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, isothipendyl hydrochloride, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, thondylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydroline napadisilate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, carbinoxamine diphenyldisulfonate, alimemazine tartrate, fenethazine tannate, promethazine methylene disalicylate, clemastine fumarate, and mequitazine. Examples of narcotic antitussives include codeine phosphate hydrate, dihydrocodeine phosphate, etc. Examples of non-narcotic antitussives include alloclamide, isoaminil, eprazinone, oxeladin, clofedanol, clobutinol, cloperastine, dibunate, dimemorfan, tipepidine, dextromethorphan, noscapine, hydrocotalnin, pentoxyverine, benproperine, and fominoben, as well as salts and hydrates thereof. Examples of salts and hydrates thereof include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, pentoxyverine citrate, and hydrates thereof. Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia-fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosa protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate mixed dried gel, co-precipitation product of aluminum hydroxide-sodium bicarbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, co-precipitation product of magnesium hydroxide-aluminum potassium sulfate, and magnesium carbonate. Examples of vitamins include vitamin B1 or a derivative thereof or a salt thereof, vitamin B2 or a derivative thereof or a salt thereof, vitamin C or a derivative thereof or a salt thereof, vitamin P (hesperidin) or a derivative thereof or a salt thereof, etc. Examples of hypnotics and sedatives include allylisopropylacetylurea and bromvalerylurea. Examples of sputum dissolving agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizinic acid, and glycyrrhizinic acid and its salts. Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide. Examples of medicinal herbs include ephedra, nandina, scutellaria, onji, licorice, bellflower, chinese quince, chinese quince, sekisan, senega, fritillary, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yutan), shanghai, ginger, atractylodes, clove, tangerine peel, atractylodes rhizome, jiru, chinese ginseng, and ginseng. Examples of Chinese herbal prescriptions include Neto, Neto-ka-kikyo, Keipi-to, Koso-san, Saiko-keipi-to, Sho-saiko-to, Sho-sei-ryu-to, Bakumondo-to, Hange-kouboku-to, and Mao-to.

[0026] The pharmaceutical composition of the present invention is preferably caffeine-free. Examples of caffeine compounds include caffeine, caffeine hydrate, anhydrous caffeine, and pharmaceutically acceptable salts of caffeine (such as sodium caffeine benzoate).

[0027] The pharmaceutical composition of the present invention may be in the form of a formulation prepared by combining the above-mentioned active ingredient with a pharmaceutically acceptable carrier or additive conventionally used in the technical field of formulation. Examples of the carrier or additive include excipients, disintegrants, binders, fluidizing agents, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, etc. These additives are used in amounts conventionally used in the technical field of formulation.

[0028] 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 hydrate, refined sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, and calcium carbonate. Examples of disintegrants that can be used include carmellose, carmellose calcium, carboxymethyl starch sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and hydroxypropyl starch, and preferred are croscarmellose sodium and L-HPC. Examples of binders that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, powdered gum arabic, methylcellulose, low-substituted hydroxypropyl cellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropyl cellulose and hydroxypropyl methylcellulose being preferred. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, kaolin, and talc. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and sucrose fatty acid esters. Examples of coloring agents include yellow ferric oxide, ferric 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 color, riboflavin, and riboflavin sodium phosphate. Examples of pH adjusters include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and salts thereof. Surfactants include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. 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 flavoring agents include L-menthol, mint oil, lemon oil, and vanillin. The above-mentioned carriers or additives may be used alone or in a suitable mixture of two or more.

[0029] The pharmaceutical composition of the present invention can be formulated using general methods described in publications such as Granulation Handbook (edited by the Japan Powder Industry and Engineering Association, Ohmsha), Formulation Design of Orally Administered Preparations (edited by Hashida Mitsuru, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Times), Powder Compression Molding Technology (edited by the Powder Engineering, Formulation and Particle Design Committee, Nikkan Kogyo Shimbun), and Pharmaceutical Machinery Technology Handbook (2nd Edition, edited by the Editorial Committee for the Publication Commemorating the 20th Anniversary of the Pharmaceutical Machinery Technology Research Association, Pharmaceutical Machinery Technology Research Association), and there are no particular limitations on the method.

[0030] For example, when the pharmaceutical composition of the present invention is formulated into tablets, the active ingredient and conventional pharmaceutically acceptable carriers or additives are mixed and granulated, and then the mixture is compressed into tablets using various tablet presses commonly used in pharmaceutical formulations (e.g., rotary tablet presses, etc.). When the pharmaceutical composition of the present invention is formulated into capsules, the active ingredient and conventional pharmaceutically acceptable carriers or additives are mixed and granulated, and then the granulated mixture is filled into capsules to form capsules.

[0031] The pharmaceutical composition of the present invention may take various forms, but is preferably in the form of a solid preparation, such as tablets (including plain 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, preferably tablets.

[0032] The solid preparation may be coated by a conventional method using a coating base that is usually blended in. For example, a tablet may be coated with a coating base to form a film-coated tablet. Examples of coating bases include water-soluble bases such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, and macrogol; water-insoluble bases such as ethyl cellulose; enteric bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, acrylic acid copolymers, and carboxyvinyl polymers; gastrosoluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, and polyvinyl acetate diethylaminoacetate; gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. 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, such as light blocking agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate.

[0033] The present invention also provides a method for suppressing deterioration of the appearance of a pharmaceutical composition containing (a) a propionic acid-based nonsteroidal anti-inflammatory drug and (b) diphenhydramine or a salt thereof, which method comprises blending (c) at least one component selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose. The requirements for this method (e.g., each component, its amount, and its proportion) are as described for the pharmaceutical composition of the present invention. [Example]

[0034] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0035] (Examples 1 to 12 and Comparative Examples 1 to 8) The main ingredients and additive ingredients shown in Tables 1 and 2 were weighed out in predetermined amounts and physically mixed in a mortar to obtain a mixture. [Table 1] [Table 2-1] [Table 2-2]

[0036] (Test example) The mixtures obtained above (Examples 1 to 5 and Comparative Examples 1 to 3) were placed in glass bottles and stored at 40°C and 75% RH for 3 weeks under unopened conditions. The properties of the mixtures after storage were compared with those immediately after storage and evaluated. The results are shown in Table 3. [Table 3]

[0037] The mixtures obtained above (Examples 6 to 12 and Comparative Examples 4 to 8) were placed in glass bottles and stored at 25°C and 75% RH for 5 days under unopened conditions. The properties of the mixtures after storage were compared with those immediately after storage and evaluated. The results are shown in Table 4. [Table 4-1] [Table 4-2]

[0038] As shown in Table 3, in the groups containing either a silicic acid compound, crospovidone, or low-substituted hydroxypropyl cellulose as an additive, the mixture maintained its state even after 3 weeks of storage at 40°C and 75% RH under unopened conditions (Examples 1 to 5). On the other hand, in the groups not containing a silicic acid compound, the mixture solidified significantly, making it difficult to maintain its state as a mixture (Comparative Examples 1 to 3). Furthermore, as shown in Table 4, it was confirmed that in the groups containing any of the additives, silicic acid compounds, crospovidone, or low-substituted hydroxypropyl cellulose, the mixture maintained its state even after 5 days of storage at 25°C and 75% RH under open conditions (Examples 6 to 12). On the other hand, in the groups containing no silicic acid compounds or other additives, or containing other additives instead, dissolution of the mixture (Comparative Example 4) or solidification (Comparative Examples 5 to 8) was observed, making it difficult to maintain the mixture state. From the above, it was revealed that silicic acid compounds, crospovidone, or low-substituted hydroxypropyl cellulose have the effect of suppressing the interaction between propionic acid-based nonsteroidal anti-inflammatory drugs and diphenhydramine or a salt thereof.

[0039] (Manufacturing Examples 1 to 7) The ingredients were mixed according to the formulation and blending ratio shown in Section A of Table 5 below, and compressed to obtain uncoated tablets. The obtained uncoated tablets were coated according to the formulation shown in Section B to obtain a coating agent. [Table 5] [Industrial Applicability]

[0040] According to the present invention, it is possible to provide a pharmaceutical composition in which changes in properties such as solidification, discoloration, wetting, and dissolution due to the interaction between (a) a propionic acid type nonsteroidal anti-inflammatory drug and (b) diphenhydramine or a salt thereof are suppressed by at least one member selected from the group consisting of (c) a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose, and thus deterioration in appearance quality is suppressed.

Claims

1. A solid preparation comprising (a) a propionic acid nonsteroidal anti-inflammatory drug, (b) diphenhydramine or a salt thereof, and (c) at least one member selected from the group consisting of a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose, wherein the propionic acid nonsteroidal anti-inflammatory drug is ibuprofen, the diphenhydramine or a salt thereof is diphenhydramine hydrochloride, the silicic acid compound is at least one member selected from the group consisting of calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and wet silica, and the dosage form is a tablet, capsule, granule, powder, or pill (however, excluding a preparation whose dosage form is a capsule and contains a solution containing (a) ibuprofen, (b) diphenhydramine hydrochloride, and (c) polyvinylpyrrolidone).

2. (c) A solid formulation as described in claim 1, wherein at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose is at least one selected from the group consisting of calcium silicate, light anhydrous silicic acid, magnesium aluminometasilicate, and wet silica.

3. A solid preparation comprising (a) a propionic acid non-steroidal anti-inflammatory drug, (b) diphenhydramine or a salt thereof, and (c) at least one member selected from the group consisting of a silicic acid compound, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose, wherein the propionic acid non-steroidal anti-inflammatory drug is loxoprofen or a salt thereof, the silicic acid compound is at least one member selected from the group consisting of light anhydrous silicic acid, hydrous silicon dioxide, and wet silica, and the solid preparation is in the form of a tablet, capsule, granule, powder, or pill.

4. 4. The solid preparation according to claim 1, wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.2 parts by mass or more relative to 1 part by mass of (a) the propionic acid type nonsteroidal anti-inflammatory analgesic.

5. 5. The solid formulation according to claim 1, wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.2 parts by mass or more relative to 1 part by mass of (b) diphenhydramine or a salt thereof.

6. 6. The solid preparation according to claim 1, wherein (c) at least one selected from the group consisting of silicic acid compounds, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose is present in an amount of 0.05 to 50% by mass relative to the total mass of the preparation.

7. 7. The solid formulation according to claim 3, wherein (b) diphenhydramine or a salt thereof is diphenhydramine hydrochloride.

8. The solid preparation according to any one of claims 1 and 3 to 7, wherein (c) polyvinylpyrrolidone is crospovidone.

9. The solid preparation according to any one of claims 1 to 8, which is used for treating colds.

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