Solid preparation containing loxoprofen and glycine and method for producing the same

Abstract

To provide a solid preparation containing loxoprofen or a salt thereof and glycine, the solid preparation being stable and less prone to a decrease in the content of active ingredients.SOLUTION: A solid preparation contains loxoprofen or a salt thereof, glycine, and dihydrogenphosphate potassium.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a highly stable solid preparation containing loxoprofen or a salt thereof and glycine, and a method for producing the same.The present invention further relates to a stabilizer for loxoprofen or a salt thereof. [Background technology]

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter referred to as NSAIDs), is known to have strong antipyretic, analgesic, and anti-inflammatory effects due to its inhibitory effect on prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract unchanged after oral administration, with little irritation to the gastric mucosa, and becomes active in the body. Therefore, it is known to cause less gastric mucosal damage than other NSAIDs (e.g., Non-Patent Document 1).

[0003] As techniques for further suppressing gastric mucosal damage by orally administering loxoprofen or a salt thereof in combination with other active ingredients, there have been disclosed techniques such as incorporating specific sugars (lactose, sucrose, maltitol, fructose, xylitol, or lactitol) into loxoprofen (Patent Document 1), incorporating an antacid (magnesium oxide) (Patent Document 2), and incorporating the antiplasmin drug tranexamic acid (Patent Document 3).

[0004] It has also been disclosed that loxoprofen sodium or its hydrate is highly hygroscopic, making it difficult to formulate it stably and to make it into a formulation with excellent storage stability after formulation (Patent Document 4).

[0005] Glycine, a type of amino acid, is used as a component of mixed amino acid preparations, and is also known to be effective as an antacid, being included in antipyretic and analgesic drugs. It is also used as a pharmaceutical additive for flavoring and other purposes.

[0006] Regarding the combined use of loxoprofen or a salt thereof with glycine, or a pharmaceutical composition containing loxoprofen or a salt thereof with glycine, a two-layer laminated tablet has been reported in which the drugs are contained in separate layers, with a first layer containing loxoprofen or a salt thereof and a second layer containing glycine (Patent Document 5).

[0007] However, there have been no reports on what changes occur when preparations or granules containing a mixture of loxoprofen or a salt thereof and glycine are produced. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 4585220 [Patent Document 2] Patent No. 6106727 [Patent Document 3] Patent No. 5835865 [Patent Document 4] Patent No. 6292744 [Patent Document 5] Patent No. 6517575 [Non-patent literature]

[0009] [Non-Patent Document 1] Pharmacology and Therapy Vol.16 No.2 1988 p.611-619 Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have found that when a solid preparation containing loxoprofen or a salt thereof and glycine is produced, there is a problem that the loxoprofen content decreases over time during storage. Therefore, an object of the present invention is to provide a stable solid preparation containing loxoprofen or a salt thereof and glycine, in which the decrease in the loxoprofen content in the preparation is suppressed, and a method for producing the same. Another object of the present invention is to provide a stabilizer for loxoprofen or a salt thereof in a solid preparation containing loxoprofen or a salt thereof and glycine. [Means for solving the problem]

[0011] As a result of intensive research conducted by the present inventors to solve the above-mentioned problems, they found that by adding potassium dihydrogen phosphate, the decrease in the loxoprofen content can be suppressed and an excellent preparation can be obtained, even in a solid preparation containing a mixture of loxoprofen or a salt thereof and glycine, and thus they have completed the present invention.

[0012] That is, the aspects of the present invention are as follows. (1) A solid preparation containing loxoprofen or its salt, glycine, and potassium dihydrogen phosphate. (2) The solid formulation according to (1), wherein the loxoprofen or a salt thereof is loxoprofen sodium dihydrate. (3) A solid formulation according to (1) or (2), which contains at least in part a homogeneously mixed mixture of the loxoprofen or a salt thereof, the glycine, and the potassium dihydrogen phosphate. (4) The solid formulation according to any one of (1) to (3), which is in the form of a tablet, a powder, a granule, a capsule, or a pill. (5) A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising the steps of: a step of homogeneously mixing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate to obtain a mixture; wet granulating the mixture; A method for producing a tablet, comprising: (6) The method for producing a tablet according to (5), further comprising a step of compressing the obtained granules after the step of wet granulating the mixture. (7) The method for producing tablets according to (6), further comprising a step of coating the obtained tablets after the step of compressing the granules. (8) A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising the steps of: A step of separately granulating loxoprofen or a salt thereof and glycine, in which potassium dihydrogen phosphate is added to at least one of the granules containing loxoprofen or a salt thereof and the granules containing glycine. A method for producing a tablet, comprising: (9) A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising the steps of: a step of separately granulating loxoprofen or a salt thereof and glycine; Thereafter, adding potassium dihydrogen phosphate as a finishing powder; A method for producing a tablet, comprising: (10) The method for producing a tablet according to any one of (5) to (9), wherein the loxoprofen or a salt thereof is loxoprofen sodium dihydrate. (11) A stabilizer for loxoprofen or a salt thereof in a solid preparation containing loxoprofen or a salt thereof and glycine, which contains potassium dihydrogen phosphate. (12) A stabilizer for a solid preparation containing loxoprofen or its salt and glycine, containing potassium dihydrogen phosphate. [Effects of the Invention]

[0013] According to the present invention, by adding potassium dihydrogen phosphate to a composition containing loxoprofen or a salt thereof and glycine, a stable solid preparation can be provided which avoids incompatibility such as a decrease in content due to the coexistence of loxoprofen or a salt thereof and glycine. DETAILED DESCRIPTION OF THE INVENTION

[0014] The solid preparation of the present invention contains loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate. The "solid preparation" of the present invention is a tablet, powder, granule, capsule, or pill as described in the Japanese Pharmacopoeia, 17th Edition, and is preferably a granule or tablet. Tablets are most preferred. Furthermore, when a granule is subjected to the particle size test method of a preparation according to the Japanese Pharmacopoeia, 17th Edition, a granule that passes entirely through a No. 18 (850 μm) sieve and has 10% or less of its total amount remaining on a No. 30 (500 μm) sieve is sometimes referred to as a fine granule.

[0015] Furthermore, as an embodiment of the granules or tablets of the present invention, those coated with a water-soluble polymer or the like are also suitable, such as film-coated granules and film-coated tablets. The solid preparation of the present invention may also be sugar-coated.

[0016] Furthermore, when the solid preparation of the present invention is a tablet, in addition to the single-layer tablet mainly shown in this specification, it can also be a multi-layer tablet made by stacking powders or granules of different compositions in two or more layers and compressing them. In the present invention, when the tablet is made into a multi-layer tablet, loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate are contained in the same layer.

[0017] The term "loxoprofen or a salt thereof" used in the present invention refers to loxoprofen or a pharmacologically acceptable salt thereof, including, for example, an alkali metal salt such as the sodium salt. Furthermore, when left in the air or upon recrystallization, loxoprofen or a salt thereof may absorb moisture, become adsorbed with water, or become a hydrate. The present invention also encompasses such various hydrates. Preferred examples of loxoprofen or a salt thereof include loxoprofen sodium or a hydrate thereof, and more preferred examples include loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 17th Edition of the Japanese Pharmacopoeia as "loxoprofen sodium hydrate." The content of loxoprofen or a salt thereof in the solid formulation of the present invention is not particularly limited, but the amount of the ingredient contained in one tablet per dosage unit (single dose) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 60 to 90 mg, calculated as the anhydrous amount, and the dosage is 1 to 3 times a day (up to 3 times a day).

[0018] The "glycine" used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia, and is readily available as a commercially available product. Commercially available glycine may be crushed as appropriate before use. Examples include glycine (Yuko Gosei Yakuhin Kogyo Co., Ltd.), glycine "For manufacturing purposes only" (Fujifilm Wako Pure Chemical Industries, Ltd.), glycine (Ajinomoto Healthy Supply Co., Ltd.), glycine (crystals) (Merck Co., Ltd.), and glycine (granules) (Merck Co., Ltd.). The content of glycine contained in the solid preparation of the present invention is not particularly limited, but the amount of the ingredient contained in one tablet per dosage unit (single dose) for adults is preferably 5 to 1390 mg, more preferably 60 to 900 mg, and even more preferably 60 to 200 mg, and the number of doses is 1 to 3 times a day.

[0019] The "potassium dihydrogen phosphate" used in the present invention is listed in the Japanese Pharmacopoeia Extra-Drug Standards 2002, and is readily available as a commercially available product. Commercially available potassium dihydrogen phosphate may be crushed as appropriate before use. Examples include dipotassium phosphate (Taihei Chemical Industry Co., Ltd.), potassium dihydrogen phosphate "For manufacturing only" (Fujifilm Wako Pure Chemical Industries Co., Ltd.), and potassium dihydrogen phosphate (Kanto Chemical Co., Ltd.).

[0020] The content of potassium dihydrogen phosphate in the solid preparation of the present invention is not particularly limited, but taking into consideration the stabilizing effect of potassium dihydrogen phosphate on loxoprofen, the amount of the ingredient contained in one tablet per dosage unit (single dose) for adults is preferably 0.5 to 72 mg, more preferably 9 to 72 mg, and may be 25 to 72 mg, and the number of doses is 1 to 3 times per day. For example, if the content of potassium dihydrogen phosphate is 9 to 72 mg, the stabilizing effect of potassium dihydrogen phosphate on loxoprofen can be satisfactorily achieved.

[0021] In the present invention, potassium dihydrogen phosphate is used as a stabilizer for loxoprofen or a salt thereof in a solid preparation containing loxoprofen or a salt thereof and glycine. The stabilizer for loxoprofen or a salt thereof means an agent that has the effect of suppressing the decrease in the content of loxoprofen or a salt thereof during long-term storage of a solid preparation containing loxoprofen or a salt thereof and glycine.

[0022] In the present invention, it is preferred that at least a portion of the composition contains a homogeneous mixture of loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate (a homogeneous mixture of three components). For example, at least a portion of the homogeneous mixture of the three components may be contained within the same granule, or may be contained in a later powder.

[0023] By containing a homogeneous mixture of the three components in a solid preparation, it is possible to obtain a solid preparation in which the loss of the contents of loxoprofen or a salt thereof and glycine is suppressed. Furthermore, it is preferable that a homogeneous mixture of the three components is contained in the same granule, since this can significantly suppress a decrease in the content of loxoprofen or a salt thereof while suppressing a decrease in the content of glycine.

[0024] Furthermore, in the present invention, by including potassium dihydrogen phosphate, a solid preparation can be obtained in which the decrease in the content of both loxoprofen or a salt thereof and glycine is suppressed. Therefore, potassium dihydrogen phosphate can also be used as a stabilizer for solid preparations containing loxoprofen or a salt thereof and glycine.

[0025] The content ratio of loxoprofen or a salt thereof to glycine in the solid formulation of the present invention is not particularly limited, but may be 0.8 to 5 parts by mass, preferably 1 to 5 parts by mass, and more preferably 1 to 2 parts by mass of glycine per part by mass of loxoprofen sodium (as anhydrous).

[0026] The content ratio of loxoprofen or a salt thereof to potassium dihydrogen phosphate in the solid preparation of the present invention is not particularly limited, and may be 0.001 to 0.6 parts by mass, preferably 0.001 to 0.4 parts by mass, more preferably 0.01 to 0.35 parts by mass, and particularly preferably 0.1 to 0.35 parts by mass of potassium dihydrogen phosphate per part by mass of loxoprofen sodium (as anhydrous). In the present invention, for example, if the content of potassium dihydrogen phosphate is 0.1 part by mass or more per part by mass of loxoprofen sodium (as anhydrous), a more excellent effect of suppressing the loss of the content of loxoprofen or a salt thereof can be obtained.

[0027] The method for producing the solid preparation according to the first embodiment of the present invention is not particularly limited as long as it includes a step of homogeneously mixing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate. Here, "mixing homogeneously" means that loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate are mixed and blended using a commonly used mixer, such as a stirring mixer or a fluidized bed granulation dryer.

[0028] In addition, when dividing the solid preparation according to the first embodiment of the present invention into granules, it is preferable that, for example, the three components of loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate (e.g., a homogeneous mixture of the three components) are placed in a granule (first granule), and only a portion of the blended amount of one of the three components of loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate is placed in a separate granule (second granule).

[0029] Furthermore, in the solid formulation according to the first embodiment of the present invention, when components are added outside the granules, it is preferable that, for example, the three components of loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate (e.g., a homogeneous mixture of the three components) are placed inside the granules, and only a portion of the blended amount of one of the three components of loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate is placed outside the granules.

[0030] Thus, in the first embodiment of the present invention, even when dividing a solid formulation into granules or adding ingredients outside the granules, it is preferable to include a step of homogeneously mixing the three ingredients, i.e., rofecoxib or a salt thereof, glycine, and potassium dihydrogen phosphate (homogeneous mixture of the three ingredients).

[0031] Furthermore, the terms "mixing" and "admixing" used in the present invention refer to the mixing of two or more ingredients using, for example, a mixer commonly used in pharmaceutical formulations, such as an agitator mixer or a fluidized bed granulation dryer, and "admixing" refers to a state in which two or more ingredients are homogeneously mixed together and the original ingredients cannot be identified.

[0032] Furthermore, as a method for producing a solid preparation according to the first embodiment of the present invention, it is preferable to granulate a composition containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate. Examples of such granulation include dry granulation and wet granulation, but wet granulation is preferred in the present invention. The wet granulation used to produce the solid preparation of the present invention is not particularly limited as long as it is a wet granulation method commonly used in the field of pharmaceuticals, such as agitation granulation, spray granulation, tumbling granulation, fluidized bed granulation, or extrusion granulation. For example, the method for producing a solid formulation according to the first embodiment of the present invention may include the steps of homogeneously mixing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate to obtain a mixture, and wet granulating the mixture.

[0033] Furthermore, in the method for producing a solid preparation according to the second embodiment of the present invention, for example, loxoprofen or a salt thereof and glycine may be granulated separately, and during the granulation, potassium dihydrogen phosphate may be blended into at least one of the granules containing loxoprofen or a salt thereof and the granules containing glycine. In the second embodiment, the solid preparation can be produced by the same method as in the first embodiment, except that the production method is changed as described above.

[0034] Furthermore, in the method for producing a solid preparation according to the third embodiment of the present invention, for example, loxoprofen or a salt thereof and glycine may be granulated separately, and potassium dihydrogen phosphate may be added to the powder later. In the third embodiment, the solid preparation can be produced by the same method as in the first embodiment, except that the production method is changed as described above.

[0035] As in the second embodiment, for example, by separating the granules into granules of loxoprofen or a salt thereof and granules of glycine and incorporating potassium dihydrogen phosphate into at least one of the granules, or as in the third embodiment, for example, by separating the granules into granules of loxoprofen or a salt thereof and granules of glycine and adding potassium dihydrogen phosphate to the final powder, it is possible to suppress changes in the formulation composition.

[0036] Furthermore, in the present invention, it is preferable that the granules obtained by the granulation are compressed and molded into tablets. For example, after the step of wet granulating the mixture, a step of compressing and molding the resulting granules may be further included. Furthermore, after the step of compressing and molding the granules, a step of coating the obtained tablets (plain tablets) may be further included.

[0037] When preparing the solid preparation of the present invention, other medicinal ingredients may be blended as necessary, and further, if necessary, formulation additives other than potassium dihydrogen phosphate as listed above may be added. Examples of formulation additives used to prepare the solid preparation of the present invention include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, refreshing agents, flavors, aromas, colorants, base materials, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. Formulation additives that can be used for the above-mentioned purposes in conventionally known solid preparations may also be used.

[0038] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose , dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0039] The binder may be one or more components selected from the group consisting of gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0040] Examples of disintegrants include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, and the like.

[0041] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0042] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oil, and sodium stearyl fumarate.

[0043] The fluidizing agent may be one or more components selected from the group consisting of hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0044] The glossing agent may be one or more components selected from, for example, carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, etc.

[0045] As the foaming agent, for example, one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc. may be blended.

[0046] The moisture-proofing agent may be one or more components selected from the group consisting of ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

[0047] The surfactant may be one or more components selected from the group consisting of sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0048] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and chloride Ferric iron, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, chondroitin Sodium stearic acid sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Stearyl Ether, Polyoxyethylene Cetyl Ether, Polyoxyethylene Nonylphenyl Ether, Polyoxyethylene Hydrogenated Castor Oil, Polyoxyethylene (42) Polyoxypropylene (67) Glycol, Polyoxyethylene (54) Polyoxypropylene (39) Glycol, Polyoxyethylene (160) Polyoxypropylene (30) Glycol, Polyoxyethylene (196) Polyoxypropylene (67) Glycol, Polyoxyethylene Coconut Fatty Glyceryl (7E.O.)), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0049] Examples of emulsifiers include glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids.

[0050] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium pyrosulfite.

[0051] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

[0052] Examples of preservatives include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0053] The sweetener may be one or more ingredients selected from, for example, aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc.

[0054] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron bark extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and ginger. It can contain one or more ingredients selected from the group consisting of powdered sorghum, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, and rose oil.

[0055] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0056] The flavoring may be, for example, one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc.

[0057] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0058] Examples of colorants that can be blended include one or more components selected from yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium oxide, ferric oxide, diaz azo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide-glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0059] Bases include: gum arabic powder, pregelatinized starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, and hydroxypropyl cellulose. It may contain one or more ingredients selected from the group consisting of hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0060] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, aqueous ethyl cellulose dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydrolyzed hydroxypropyl methylcellulose. Examples of suitable surfactants include hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0061] Examples of sugar-coating agents that can be blended include one or more ingredients selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, refined sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0062] Examples of plasticizers that can be blended include one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0063] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0064] The antifoaming agent may be one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane-silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc.

[0065] These additives are not limited to those listed above, and one of these may be used alone or two or more of them may be used in combination.

[0066] The solid preparation of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient, loxoprofen or a salt thereof, has antipyretic, analgesic, and anti-inflammatory effects, it can be suitably used as an analgesic and antipyretic, particularly for the pain relief of headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, fracture pain, sprain pain, and trauma pain, as well as for the fever reduction during chills and fever, and can also be suitably used as a cold remedy for the purpose of alleviating various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0067] The packaging form of the solid preparation of the present invention is not particularly limited, and the solid preparation of the present invention may be once packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc. and then stored airtight. Furthermore, these may be pillow-packaged, and these may be stored in a box, etc. The materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples thereof include resin films such as polyethylene, polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached thereto. [Example]

[0068] In order to explain the present invention in more detail, examples and comparative examples are described below, but the present invention is not limited to these.

[0069] Test Example 1: Storage stability test of physical mixtures

[0070] 1. Manufacturing of physical mixtures (Reference example 1) Loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.) was sieved through a sieve (No. 30).

[0071] (Comparative Example 1) 22.68 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.) and 20.00 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.) were mixed in a plastic bag, and the mixed powder was sieved through a sieve (No. 30). Then, the mixture was mixed again in the plastic bag to obtain a physical mixture.

[0072] Example 1 22.68 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 20.00 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), and 10.00 g of mortar-ground potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag, and the mixed powder was passed through a sieve (No. 30). The mixture was then mixed again in the plastic bag to obtain a physical mixture.

[0073] (Comparative Example 2) 22.68 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 20.00 g of glycine (FUJIFILM Wako Pure Chemical Industries Co., Ltd.), and 10.00 g of mortar-ground sodium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag.

[0074] (Comparative Example 3) 22.68 g of loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.), 20.00 g of glycine (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), and 10.00 g of mortar-ground citric acid hydrate (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) were mixed in a plastic bag.

[0075] Comparative Example 4 22.68 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 20.00 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), and 10.00 g of ascorbic acid (DSM Nutrition Japan, Inc.) were mixed in a plastic bag.

[0076] 2. Test Method The physical mixtures of Reference Example 1, Comparative Example 1, and Example 1 were filled into glass bottles (3kg standard bottles) and left for 3 months under open conditions of 40°C and 75% RH. After storage, the content of loxoprofen sodium was measured by HPLC, and the residual rate from before storage was calculated.

[0077] 3. Test Results In Comparative Examples 2 to 4, wet solidification occurred immediately during the mixing step, making it impossible to achieve homogeneous mixing, and thus making it impossible to obtain a physical admixture. The residual rates of loxoprofen sodium in Reference Example 1, Comparative Example 1, and Example 1 are shown in Table 1. As shown by the results of Reference Example 1 and Comparative Example 1, loxoprofen sodium is stable when used alone, but a significant decrease in the loxoprofen sodium content was observed in the physical mixture of loxoprofen sodium dihydrate and glycine. On the other hand, as shown by the results of Example 1, the decrease in the content of loxoprofen sodium observed in the physical mixture of loxoprofen sodium dihydrate and glycine was found to be suppressed by the addition of potassium dihydrogen phosphate.

[0078] [Table 1]

[0079] Test Example 2: Storage stability test of tablets

[0080] 1. Tablet manufacturing (Reference example 2) 163.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 234.3 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 64.00 g of microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation) were added, mixed, and blended, and then an aqueous solution of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed on as a binder to prepare granules. 285.0 g of the granules were mixed and blended with 12.00 g of croscarmellose sodium (Ac-Di-Sol, DuPont Nutrition USA Inc.) and 3.00 g of magnesium stearate (Magnesium stearate (vegetable), Taihei Chemical Industry Co., Ltd.), and then compressed to produce uncoated tablets.

[0081] (Comparative Example 5) 163.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 144.0 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 90.32 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 64.00 g of microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation) were mixed and blended, and then an aqueous solution of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed onto the mixture to prepare granules. 285.0 g of the granules were mixed and blended with 12.00 g of croscarmellose sodium (Ac-Di-Sol, DuPont Nutrition USA Inc.) and 3.00 g of magnesium stearate (Vegetable Magnesium Stearate, Taihei Chemical Industry Co., Ltd.), followed by compression to produce uncoated tablets.

[0082] (Comparative Example 6) 163.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 144.0 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 13.68 g of light anhydrous silicic acid (Fuji Silysia Chemical Ltd., Sylysia 320), 76.64 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 64.00 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) were charged, mixed, and blended, and an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) was sprayed on as a binder to prepare granules. 12.00 g of croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Nutrition USA Inc.) and 3.00 g of magnesium stearate (Magnesium stearate (vegetable) manufactured by Taihei Chemical Industry Co., Ltd.) were added to 285.0 g of the granules, mixed and blended, and then compressed into uncoated tablets.

[0083] Example 2 163.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 144.0 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 22.80 g of potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.), 67.52 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 64.00 g of microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation) were mixed and blended, and then an aqueous solution of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed onto the mixture to prepare granules. 285.0 g of the granules were mixed and blended with 12.00 g of croscarmellose sodium (Ac-Di-Sol, DuPont Nutrition USA Inc.) and 3.00 g of magnesium stearate (Vegetable Magnesium Stearate, Taihei Chemical Industry Co., Ltd.), followed by compression to produce uncoated tablets.

[0084] Example 3 163.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 144.0 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 22.80 g of potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.), 13.68 g of light anhydrous silicic acid (Fuji Silysia Chemical Ltd., Sylysia 320), 53.84 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 64.00 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) were charged, mixed, and blended, and an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) was sprayed on as a binder to prepare granules. 12.00 g of croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Nutrition USA Inc.) and 3.00 g of magnesium stearate (Magnesium stearate (vegetable) manufactured by Taihei Chemical Industry Co., Ltd.) were added to 285.0 g of the granules, mixed and blended, and then compressed into uncoated tablets.

[0085] Example 4 215.1 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 189.5 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 10.5 g of potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.), 108.4 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 84.2 g of microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation) were mixed and blended, and then an aqueous solution of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed onto the mixture to prepare granules. 331.5 g of the granules were mixed and blended with 15 g of croscarmellose sodium (Ac-Di-Sol, DuPont Nutrition USA Inc.) and 3.5 g of magnesium stearate (Vegetable Magnesium Stearate, Taihei Chemical Industry Co., Ltd.), followed by compression to produce uncoated tablets.

[0086] Example 5 215.1 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 189.5 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 61.1 g of potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.), 57.9 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 84.2 g of microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation) were mixed and blended, and then an aqueous solution of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed onto the mixture to prepare granules. 331.5 g of the granules were mixed and blended with 15 g of croscarmellose sodium (Ac-Di-Sol, DuPont Nutrition USA Inc.) and 3.5 g of magnesium stearate (Vegetable Magnesium Stearate, Taihei Chemical Industry Co., Ltd.), followed by compression to produce uncoated tablets.

[0087] (Comparative Example 7) 215.1 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 189.5 g of glycine (FUJIFILM Wako Pure Chemical Industries, Ltd.), 30.5 g of calcium hydrogen phosphate (Budenheim, DICAFOS A150), 88.4 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 84.2 g of microcrystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) were mixed and blended, and then an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) was sprayed onto the mixture as a binder to prepare granules. 331.5 g of the granules were mixed and blended with 15 g of croscarmellose sodium (DuPont Nutrition USA Inc., Ac-Di-Sol) and 3.5 g of magnesium stearate (Taihei Chemical Industry Co., Ltd., magnesium stearate (vegetable)), followed by compression to produce uncoated tablets.

[0088] Example 6 Granules (A) were prepared by adding 255.4 g of loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.), 267.8 g of D-mannitol (Bussan Food Science Co., Ltd.), and 89.5 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) to the mixture, mixing the ingredients together, and then spraying the mixture with an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) as a binder. Granules (B) were prepared by adding 225.0 g of glycine (Fujifilm Wako Pure Chemical Corporation), 267.8 g of D-mannitol (Bussan Food Science Co., Ltd.), and 89.5 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) to the mixture, mixing the ingredients together, and then spraying the mixture with an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) as a binder. To 160.9 g of granulated granules (A) and 160.9 g of granulated granules (B), 14.8 g of croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Nutrition USA Inc.), 10.1 g of potassium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.), and 3.4 g of magnesium stearate (Magnesium stearate (vegetable), manufactured by Taihei Chemical Industry Co., Ltd.) were added, mixed and blended, and then compressed into uncoated tablets.

[0089] (Comparative Example 8) Loxoprofen sodium dihydrate (KOLON LIFE SCIENCE, INC.) 255.4 g, D-mannitol (Butsusan Food Science Co., Ltd.) 267.8 g Granules (A) were prepared by adding 225.0 g of glycine (Fujifilm Wako Pure Chemical Industries, Ltd.), 267.8 g of D-mannitol (Butsusan Food Science Co., Ltd.), and 89.5 g of crystalline cellulose (Asahi Kasei Corporation, Ceolus PH101) to the mixture, mixing, and blending. Then, an aqueous solution of hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L) was sprayed onto the mixture to prepare granules (B). To 160.9 g of granulated granules (A) and 160.9 g of granulated granules (B), 14.8 g of croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Nutrition USA Inc.), 10.1 g of microcrystalline cellulose (Ceolas PH301, manufactured by Asahi Kasei Corporation), and 3.4 g of magnesium stearate (Magnesium stearate (vegetable) manufactured by Taihei Chemical Industry Co., Ltd.) were added, mixed and blended, and then compressed into uncoated tablets.

[0090] 2. Test Method The tablets of Reference Example 2, Comparative Examples 5 to 8, and Examples 2 to 6 were filled into glass bottles (standard 3k bottles) and left to stand for 6 months under open conditions of 40°C and 75% RH. After storage, the content of loxoprofen sodium was measured by HPLC, and the remaining rate from before storage was calculated. In addition, in Comparative Example 5, Comparative Example 6, Example 2, and Example 3, the glycine content of the samples after storage was measured by HPLC, and the residual rate from before storage was calculated.

[0091] 3. Test Results The results of the residual rate of loxoprofen sodium are shown in Tables 2 to 4. In Tables 2 to 4, "-" means that the tablet does not contain the corresponding substance. The residual rate of loxoprofen sodium in this test was evaluated according to the following criteria: A to C is acceptable for practical use. A (Excellent): Remaining rate of loxoprofen sodium is 95% or more B (Good): Loxoprofen sodium remaining rate is 90% or more but less than 95% C (Acceptable): Remaining loxoprofen sodium is 85% or more but less than 90% D (Not acceptable): Less than 85% of loxoprofen sodium remains

[0092] [Table 2]

[0093] [Table 3]

[0094] [Table 4]

[0095] The results shown in Table 2 indicate that, although no effect was observed when loxoprofen sodium dihydrate and glycine were homogeneously mixed (Example 2) or when light anhydrous silicic acid, an adsorbent, was mixed (Comparative Example 6), the homogeneous mixing of both with potassium dihydrogen phosphate prevented a significant decrease in the loxoprofen sodium content. Furthermore, as shown in Example 2, the glycine content remained stable even when loxoprofen sodium was added. In other words, it was found that when loxoprofen sodium dihydrate and glycine were homogeneously mixed, a significant decrease in the loxoprofen sodium content could be prevented while the glycine content was also kept stable.

[0096] The results shown in Tables 2 and 3 indicate that when rofecoxib sodium dihydrate and glycine are homogeneously mixed, the residual rate of rofecoxib is maintained at a high level by increasing the amount and ratio of potassium dihydrogen phosphate (Examples 2, 4, and 5). It was also found that even when calcium hydrogen phosphate, a type of phosphate-containing compound, was used, the residual rate of loxoprofen decreased (Comparative Example 7).

[0097] The results shown in Table 4 reveal that even when loxoprofen sodium and glycine were granulated, the residual rate of loxoprofen decreased (Comparative Example 8). Furthermore, as shown in Example 6, even when rofecoxib sodium and glycine are granulated, adding potassium dihydrogen phosphate to the final powder tends to suppress the decrease in the residual rate of rofecoxib.

[0098] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention. [Industrial Applicability]

[0099] According to the present invention, a solid preparation containing loxoprofen or a salt thereof and glycine can be produced simply and at low cost. The solid preparation of the present invention is suitably used as an antipyretic analgesic, particularly for relieving pain such as headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, pain from bruises, bone fractures, sprains, pain from trauma, etc., and for reducing fever during chills and fever, and is also suitably used as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

Claims

1. A solid preparation containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate.

2. The solid formulation according to claim 1, wherein the loxoprofen or a salt thereof is loxoprofen sodium dihydrate.

3. 3. The solid formulation according to claim 1, wherein at least a portion of the solid formulation comprises a homogeneously mixed mixture of the loxoprofen or a salt thereof, the glycine, and the potassium dihydrogen phosphate.

4. The solid preparation according to any one of claims 1 to 3, which is in the form of a tablet, powder, granule, capsule, or pill.

5. A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising: a step of homogeneously mixing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate to obtain a mixture; wet granulating the mixture; A method for producing a tablet, comprising:

6. The method for producing tablets according to claim 5, further comprising a step of compressing the obtained granules after the step of wet granulating the mixture.

7. The method for producing tablets according to claim 6, further comprising a step of coating the obtained tablets after the step of compressing the granules.

8. A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising: A step of separately granulating loxoprofen or a salt thereof and glycine, in which potassium dihydrogen phosphate is added to at least one of the granules containing loxoprofen or a salt thereof and the granules containing glycine. A method for producing a tablet, comprising:

9. A method for producing a tablet containing loxoprofen or a salt thereof, glycine, and potassium dihydrogen phosphate, comprising: a step of separately granulating loxoprofen or a salt thereof and glycine; Thereafter, adding potassium dihydrogen phosphate as a finishing powder; A method for producing a tablet, comprising:

10. The method for producing a tablet according to any one of claims 5 to 9, wherein the loxoprofen or a salt thereof is loxoprofen sodium dihydrate.

11. A stabilizer for loxoprofen or a salt thereof in a solid preparation containing loxoprofen or a salt thereof and glycine, which contains potassium dihydrogen phosphate.

12. A stabilizer for a solid preparation containing loxoprofen or a salt thereof and glycine, which contains potassium dihydrogen phosphate.

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