Pharmaceutical composition containing loxoprofen, and diclofenac or naproxen

Abstract

The purpose of the present invention is to provide a pharmaceutical composition that improves the anti-inflammatory effect of loxoprofen. The present invention provides a pharmaceutical composition comprising: at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; and at least one selected from the group consisting of diclofenac, naproxen, salts thereof, and hydrates thereof.

Description

Pharmaceutical composition containing loxoprofen and diclofenac or naproxen

[0001] The present invention relates to a pharmaceutical composition comprising at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and at least one selected from the group consisting of diclofenac, naproxen, salts thereof, and hydrates thereof. More specifically, the present invention relates to a pharmaceutical composition containing at least one selected from the group consisting of diclofenac, naproxen, salts thereof, and hydrates thereof, thereby improving the anti-inflammatory effect of loxoprofen.

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter referred to as NSAIDs), is known to have potent antipyretic, analgesic, and anti-inflammatory effects, although it exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with weak gastric mucosal irritation after oral administration and becomes an active form in the body, and is therefore known to have the characteristic of causing less gastric mucosal damage than other NSAIDs (see, for example, Non-Patent Document 1).

[0003] Regarding examples of combined use of multiple NSAIDs, for example, Patent Document 1 describes the combined use of nabumetone with ethenzamide or ibuprofen. Also, Patent Document 2 describes the combined use of ibuprofen with naproxen sodium. Meanwhile, it has been reported that the combined use of multiple NSAIDs should be avoided because the combined use of NSAIDs does not increase the efficacy but increases side effects such as gastrointestinal disorders (Non-Patent Document 2).

[0004] Japanese Patent Application Laid-Open No. 2020-100610 Japanese Patent Application Laid-Open No. 2015-503583

[0005] Pharmacology and Therapy, Vol. 16, No. 2, 1988, pp. 611-619. Journal of the Japanese Society of Internal Medicine, 2011, Vol. 100, No. 10, p. 2900.

[0006] An object of the present invention is to provide a pharmaceutical composition having an improved anti-inflammatory effect of loxoprofen.

[0007] As a result of extensive research into solving the above problems, the inventors have discovered that the anti-inflammatory effect of loxoprofen can be further improved by using loxoprofen sodium hydrate in combination with a specific non-steroidal antipyretic, analgesic, and anti-inflammatory agent, and have thus completed the present invention.

[0008] That is, aspects of the present invention are as follows. <1> A pharmaceutical composition comprising at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof. <2> The pharmaceutical composition according to <1>, which is for anti-inflammatory use. <3> The pharmaceutical composition according to <1> or <2>, in which the dosage of at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof is an amount that does not exert an anti-inflammatory effect when administered alone. <4> The pharmaceutical composition according to <3>, in which the dosage of at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof is an amount such that the anti-inflammatory effect is enhanced by administering an amount of at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof that does not exert an anti-inflammatory effect when administered alone. <5> The pharmaceutical composition according to any one of <1> to <4>, wherein the pharmaceutical composition is an oral preparation, and the dosage of at least one compound selected from the group consisting of loxoprofen, its salts, and hydrates thereof is 0.06 mg / dose to 6 mg / dose, and the dosage of at least one compound selected from the group consisting of diclofenac, its salts, and hydrates thereof is 0.025 mg / dose to 2.5 mg / dose, or the dosage of at least one compound selected from the group consisting of naproxen, its salts, and hydrates thereof is 0.1 mg / dose to 10 mg / dose. <6> The pharmaceutical composition according to any one of <1> to <4>, wherein the pharmaceutical composition is an external preparation, and the dosage of at least one compound selected from the group consisting of loxoprofen, its salts, and hydrates thereof is 0.0007 mg / cm ２ ~0.07mg / cm ２and the dosage of at least one selected from the group consisting of diclofenac, its salts, and its hydrates is 0.0001 mg / cm ２ ~0.01mg / cm ２ <7> The pharmaceutical composition according to any one of <1> to <4>, wherein the pharmaceutical composition is an oral preparation, and the dosage of at least one drug selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof is such that the maximum plasma concentration after administration is 0.006 μg / mL to 0.6 μg / mL, the dosage of at least one drug selected from the group consisting of diclofenac, a salt thereof, and a hydrate thereof is such that the maximum plasma concentration after administration is 0.41 ng / mL to 41 ng / mL, or the dosage of at least one drug selected from the group consisting of naproxen, a salt thereof, and a hydrate thereof is such that the maximum plasma concentration after administration is 0.09 μg / mL to 9 μg / mL. <8> The pharmaceutical composition according to any one of <1> to <4>, wherein the pharmaceutical composition is an external preparation, and the dosage of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.05 ng / mL to 5 ng / mL, and the dosage of at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.003 ng / mL to 0.3 ng / mL.

[0009] The pharmaceutical composition of the present invention can exhibit excellent anti-inflammatory effects. It is an unexpected effect that the anti-inflammatory effects of loxoprofen can be further enhanced by using loxoprofen sodium hydrate in combination with a specific nonsteroidal antipyretic, analgesic, and anti-inflammatory agent.

[0010] FIG. 1 shows the PGE in the culture supernatant for ibuprofen. ２ The quantitative results are shown below. Bar = Mean ± SE, n = 3, Student's t-test: ##P < 0.01 (vs. 1 μg / mL LPS treatment, 0.1% DMSO). Figure 2 shows the dose-response curve of ibuprofen. IC50 value = 0.91 μM. Figure 3 shows the PGE in the culture supernatant for ibuprofen.２ The quantitative results (drug combination effect) are shown below. Bar = Mean ± SE, n = 3, Tukey-Kramer: *P<0.05, **P<0.01. Figure 4 shows the PGE in the culture supernatant for indomethacin. ２ The quantitative results (drug combination effect) are shown below. Bar = Mean ± SE, n = 3. Figure 5 shows the PGE in the culture supernatant for diclofenac Na. ２ The quantitative results (drug combination effect) are shown. Bar = Mean ± SE, n = 3, ** P < 0.01. Figure 6 shows the PGE in the culture supernatant of felbinac. ２ The quantitative results (drug combination effect) are shown in Table 1. Bar = Mean ± SE, n = 3. Figure 7 shows the PGE in the culture supernatant for aspirin. ２ The quantitative results (drug combination effect) are shown below. Bar = Mean ± SE, n = 3, Tukey-Kramer: ** P < 0.01. Figure 8 shows the PGE in the culture supernatant for meloxicam. ２ The quantitative results (drug combination effect) are shown below. Bar = Mean ± SE, n = 3, Tukey-Kramer: ** P < 0.01. Figure 9 shows the PGE in the culture supernatant for celecoxib. ２ The quantitative results (drug combination effect) are shown below. Bar = Mean ± SE, n = 3, Tukey-Kramer: *P<0.05, **P<0.01. Figure 10 shows the PGE in the culture supernatant for naproxen. ２ The quantitative results (drug combination effects) are shown below. Bar = Mean ± SE, n = 3, Tukey-Kramer: *P < 0.05, **P < 0.01. Figure 11 shows the results of comparing COX-2 expression levels by Western blot. Bar = Mean ± SE, n = 3, ##P < 0.01 (vs. 1 μg / mL LPS-treated 0.1% DMSO-added (test substance not added) group, Student's t-test).

[0011] The pharmaceutical composition of the present invention comprises at least one member selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and at least one member selected from the group consisting of diclofenac, naproxen, their salts, and hydrates thereof.

[0012] <Loxoprofen, its salts, and hydrates thereof> The pharmaceutical composition of the present invention contains at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof. In the present invention, "at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof" is sometimes referred to as "loxoprofen or its salt," and refers to loxoprofen or a salt thereof (including a hydrate salt) (the salt is preferably a pharmacologically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. The at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof used in the present invention is listed as loxoprofen sodium hydrate in the 18th Edition of the Japanese Pharmacopoeia.

[0013] The amount of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof contained in the pharmaceutical composition is not particularly limited, but is preferably 0.0001 to 80% by mass, more preferably 0.001 to 80% by mass, even more preferably 0.01 to 80% by mass, alternatively 0.1 to 80% by mass, 1 to 80% by mass, 2 to 50% by mass, 5 to 30% by mass, or 5 to 20% by mass, based on the total mass of the pharmaceutical composition.

[0014] <Diclofenac, naproxen, their salts, and their hydrates> The pharmaceutical composition of the present invention contains at least one selected from the group consisting of diclofenac, naproxen, their salts, and their hydrates. The at least one selected from the group consisting of diclofenac, its salts, and its hydrates used in the present invention includes, for example, diclofenac, diclofenac sodium, and diclofenac potassium, which are specifically listed as diclofenac sodium in the Japanese Pharmacopoeia, 18th Edition. The at least one selected from the group consisting of naproxen, its salts, and their hydrates used in the present invention includes, for example, naproxen, naproxen sodium, and naproxen potassium, which are specifically listed as naproxen in the Japanese Pharmacopoeia, 18th Edition.

[0015] The amount of at least one selected from the group consisting of diclofenac, naproxen, salts thereof, and hydrates thereof contained in the pharmaceutical composition is not particularly limited, but is preferably 0.0001 to 80% by mass, more preferably 0.001 to 80% by mass, more preferably 0.01 to 80% by mass, more preferably 0.1 to 80% by mass, even more preferably 0.2 to 80% by mass, or alternatively 0.5 to 80% by mass, 0.5 to 50% by mass, 0.5 to 30% by mass, or 0.5 to 20% by mass, based on the mass of the entire pharmaceutical composition.

[0016] <Regarding Dosage> The dosage of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof is preferably an amount that does not exert an anti-inflammatory effect when administered alone.

[0017] Preferably, the dosage of at least one selected from the group consisting of diclofenac, naproxen, salts thereof, and hydrates thereof is such that the anti-inflammatory effect is enhanced by administering at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in an amount that does not exert anti-inflammatory effects when administered alone.

[0018] When the pharmaceutical composition is an oral dosage form, preferably, the dosage of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof is 0.06 mg / dose to 6 mg / dose (more preferably 0.12 mg / dose to 3 mg / dose), the dosage of at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof is 0.025 mg / dose to 2.5 mg / dose (more preferably 0.05 mg / dose to 1.25 mg / dose), or the dosage of at least one selected from the group consisting of naproxen, its salts, and hydrates thereof is 0.1 mg / dose to 10 mg / dose (more preferably 0.2 mg / dose to 5 mg / dose).

[0019] When the pharmaceutical composition is an external preparation, preferably, the dosage of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof is 0.0007 mg / cm２ ~0.07mg / cm ２ (More preferably 0.0014 mg / cm ２ ~0.035mg / cm ２ ) and the dosage of at least one selected from the group consisting of diclofenac, its salts, and its hydrates is 0.0001 mg / cm ２ ~0.01mg / cm ２ (More preferably 0.0002 mg / cm ２ ~0.005mg / cm ２ )

[0020] When the pharmaceutical composition is an oral preparation, preferably, the dosage of at least one compound selected from the group consisting of loxoprofen, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.006 μg / mL to 0.6 μg / mL (more preferably 0.012 μg / mL to 0.3 μg / mL), the dosage of at least one compound selected from the group consisting of diclofenac, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.41 ng / mL to 41 ng / mL (more preferably 0.82 ng / mL to 20.5 ng / mL), or the dosage of at least one compound selected from the group consisting of naproxen, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.09 μg / mL to 9 μg / mL (more preferably 0.18 μg / mL to 4.5 μg / mL).

[0021] When the pharmaceutical composition is an external preparation, preferably, the dosage of at least one compound selected from the group consisting of loxoprofen, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.05 ng / mL to 5 ng / mL (more preferably 0.1 ng / mL to 2.5 ng / mL), and the dosage of at least one compound selected from the group consisting of diclofenac, its salts, and hydrates thereof is such that the maximum plasma concentration after administration is 0.003 ng / mL to 0.3 ng / mL (more preferably 0.006 ng / mL to 0.15 ng / mL).

[0022] <Regarding Oral Preparations> The case where the pharmaceutical composition of the present invention is an oral preparation will be described below. The pharmaceutical composition of the present invention may contain an antacid from the viewpoint of suppressing gastric mucosal damage. Examples of antacids include alkaline earth metal and / or earth metal basic inorganic compounds such as magnesium oxide, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, a co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, a co-precipitation product of aluminum hydroxide and sodium bicarbonate, a mixed dried gel of aluminum hydroxide and magnesium carbonate, and a co-precipitation product of aluminum hydroxide, magnesium carbonate, and calcium carbonate. Examples of alkali metal basic inorganic compounds include inorganic salts of metals selected from magnesium, aluminum, and calcium, such as bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate; examples of alkali metal basic inorganic compounds include inorganic salts of metals selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, and potassium carbonate; and other compounds include borax and glycine, and one or more components selected from these may be blended. Among these, one or more components selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, aluminum hydroxide gel, and glycine are preferred.

[0023] The pharmaceutical composition of the present invention may contain caffeines, such as caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.

[0024] The pharmaceutical composition of the present invention may contain a sedative, such as allylisopropylacetylurea or bromovalerylurea.

[0025] The pharmaceutical composition of the present invention may further contain other active ingredients, such as antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, and xanthine derivatives, as needed, within the scope of the present invention. If there are any contraindications for these ingredients, the composition may be formulated by dividing the ingredients into granules or the like.

[0026] Examples of antitussives / expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, and nosca pine, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, L-ethylcysteine ​​hydrochloride, and the like.

[0027] Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, difenyl pyraline hydrochloride, diphenyl pyraline teoclate ... Examples of such antihistamines include phenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, diphenthenol hydrochloride, methdilazine hydrochloride, mebhydrozine napadisilate, promethazine methylenedisalicylate, and diphenthenol phosphate.

[0028] Anti-inflammatory agents include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

[0029] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia root extract, Scopolia root total alkaloid citrate, and the like.

[0030] Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, a mixture of equal parts of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine. Examples of xanthine derivatives other than the above-mentioned caffeine (other xanthine derivatives) include theophylline and theobromine.

[0031] Examples of vitamins include vitamin B1 and derivatives thereof, such as thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibutiamine, bis-bentiamine, prosultiamine, and benfotiamine, and salts thereof; vitamin B2 and derivatives thereof, such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate, and salts thereof; pantothenic acid, panthenol, pantethine, pantothenic acid, panthenol ... One or more ingredients selected from the group consisting of vitamin B5 and its derivatives and salts such as calcium pantothenate and sodium pantothenate; vitamin B6 and its derivatives and salts such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 and its derivatives and salts such as cyanocobalamin and mecobalamin; vitamin C and its derivatives and salts such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and salts.

[0032] 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.

[0033] The pharmaceutical composition of the present invention can be formulated into an oral preparation according to a conventional method. In the present invention, for example, tablets may be produced by preparing granules containing at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof, adding a powder component to the obtained granules so as to form an outer granule portion, and compressing the mixture.

[0034] That is, the tablet can be manufactured by, for example, the steps of: preparing granules (at least one granule) containing at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof; and mixing the granules with desired additives (powders) and compressing the mixture to prepare tablets. Furthermore, the at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and the at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof, may each be contained in a separate granule, and the component placed outside the granule may optionally be in the form of a granule.

[0035] The final component (external part of the granulated granules) is a portion of the tablet that constitutes the exterior of the granulated granules. For example, it may be a portion of the tablet that covers one granulated granule, or a portion that covers multiple granulated granules. It may also be a portion that covers at least one granulated granule and constitutes the outer surface of the tablet. The tablet may have granulated granules therein, and the granulated granules may contain at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and at least one selected from the group consisting of diclofenac, its salts, and hydrates thereof. While the above example illustrates a formulation using loxoprofen and diclofenac, naproxen may be used instead of diclofenac. Alternatively, a formulation may be prepared using loxoprofen, diclofenac, and naproxen, with appropriate granulation and other procedures.

[0036] The formulation can be prepared using known methods and additives as appropriate, provided that the additives do not impair the effects of the present invention.

[0037] Examples of additives 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, fragrances, colorants, base materials, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. Conventionally known formulation additives that can be used in pharmaceutical compositions can be used for the above-mentioned purposes.

[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, potassium dihydrogen phosphate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), 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 sucrose, refined sucrose 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, sucrose, 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, calcium sulfate, erythritol, glucose, fructose, etc.

[0039] The binder may be one or more components selected from 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, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0040] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, 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, calcium hydrogen phosphate granules, and the like.

[0044] The glossing agent may be, for example, one or more components selected from 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, purified shellac, purified sucrose, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, and polyvinyl acetal diethylaminoacetate.

[0047] The surfactant may be one or more components selected from, for example, 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, sodium lauryl sulfate, and the like.

[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, ferric chloride, sodium chloride, magnesium chloride, and calcium chloride. Stain, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester Stearic acid, refined gelatin, refined 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, poly Polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid,One or more ingredients selected from anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc. may be blended.

[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 components selected from, for example, aspartame, acesulfame potassium, hydrangea, hydrangea 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, and the like.

[0054] The flavoring agent may be one or more ingredients selected from sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, and the like.

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

[0056] As the flavoring, for example, one or more components 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, 1-menthol, peppermint oil, etc. can be blended.

[0057] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine, 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, gold leaf, black iron oxide, titanium oxide, ferric oxide, dizazo 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] The bases include gum arabic powder, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic magnesium sodium 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. The composition may contain one or more ingredients selected from the group consisting of cellulose, 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, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hardened 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, hydroxypropyl methylcellulose 2910-titanium oxide-macrogol 400 mixture, hypromellose, fumaric acid-stearic acid-polyvinyl acetal diethylamino Examples of the acrylic acid copolymer include methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, 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 components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified 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, and the like.

[0062] Examples of the plasticizer that can be blended include one or more components selected from 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 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0063] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, powdered agar, 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, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like can be blended.

[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 pharmaceutical composition of the present invention can be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as a preparation for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and a preparation for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The pharmaceutical composition is preferably a solid preparation.

[0067] The solid preparation is preferably a tablet, powder, fine granule, granule, capsule, or pill as described in the Japanese Pharmacopoeia, 18th Edition, more preferably a granule or tablet, and most preferably a tablet. Furthermore, when a granule is subjected to a particle size test according to the Japanese Pharmacopoeia, 18th Edition, a granule that passes entirely through a No. 18 (850 μm) sieve and retains 10% or less of the total amount on a No. 30 (500 μm) sieve is sometimes referred to as a fine granule.

[0068] Granules or tablets may be prepared by coating the preparation with a water-soluble polymer, etc. Examples include film-coated granules and film-coated tablets. Solid preparations may also be sugar-coated.

[0069] When the solid preparation is a tablet, it can be a single-layer tablet or a multi-layer tablet made by compressing two or more layers of powders or granules of different compositions. When the tablet is a multi-layer tablet, the at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof and the specified herbal medicine may be in the same layer or in different layers.

[0070] The pharmaceutical composition of the present invention may be temporarily packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and then stored airtight. These may also be pillow-packaged, and stored in a box, etc. In other words, a pharmaceutical according to one embodiment of the present invention may comprise a pharmaceutical composition and a packaging material for packaging the pharmaceutical composition. Materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and include, for example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, multi-layer films combining these resin films, and resin films with aluminum foil attached thereto.

[0071] The packaging material for the pharmaceutical composition of the present invention is preferably, for example, packaging made of a material that is less susceptible to moisture (packaging made of at least one of a moisture-proof material and a gas barrier material). For example, a packaging made of a material that is less susceptible to moisture (moisture-proof material) may be PTP (polypropylene) + polyethylene aluminum pillow packaging (a combination of PTP and polyethylene aluminum pillow packaging). Furthermore, taking into consideration the suppression of an increase in the moisture content of the pharmaceutical composition, the storage stability of the pharmaceutical composition, and the stability of the pharmaceutical composition after opening, PTP packaging (Al-Al packaging) using aluminum on both sides may be used as a packaging made of a material that is less susceptible to moisture (moisture-proof material). If moisture absorption is a concern, a desiccant or the like may be simultaneously stored within the bottle packaging or pillow packaging. Known gas barrier materials may be used and are not particularly limited. For example, a laminate film having a functional barrier layer may be used, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material. Furthermore, the packaging material for the pharmaceutical composition of the present invention is not particularly limited, and environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material, as needed, and environmentally friendly containers and packaging may also be used.

[0072] <About topical preparations> The case where the pharmaceutical composition of the present invention is a topical preparation will be described below. Drugs and pharmaceutical additives that are commonly used in topical analgesic and anti-inflammatory skin preparations can be added to the pharmaceutical composition of the present invention.

[0073] The topical preparation of the present invention may contain one or more components selected from the group consisting of the following components (A-1) to (A-11): (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acids; (A-4) herbal medicines; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) nicotinic acids; (A-8) chlorpheniramines; (A-9) diphenhydramines; (A-10) pyrrolidones; (A-11) inorganic salts;

[0074] (A-1) Examples of tocopherols include tocopherol, tocotrienol, and derivatives thereof (e.g., esterified derivatives such as acetate ester, succinate ester, and nicotinate ester), as well as salts thereof (e.g., alkaline earth metal salts such as calcium salt and magnesium salt). The tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. The tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. The tocopherol is particularly preferably tocopherol acetate.

[0075] (A-2) Terpenes are a general term (terpenoids) that includes terpene hydrocarbons as well as terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc. The structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, they may be cyclic or chain. Examples of terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

[0076] Terpenes may be used in the form of essential oils containing terpenes. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, Japanese pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, and terephthalate. Examples of oils that can be used include bottle oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, hosho oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil, and these may be used alone or in combination of two or more.

[0077] (A-3) Examples of glycyrrhizic acids include glycyrrhizic acid or its salts, and glycyrrhetinic acid or its salts. Examples of salts include alkali metal salts such as potassium salts and sodium salts; and ammonium salts. Furthermore, glycyrrhetinic acids may be used in the form of licorice or extracts thereof, which contain glycyrrhizinic acids.

[0078] (A-4) Examples of crude drugs include licorice, arnica tincture, Mallotus japonicus, Acacia japonica, Coriaceae, fennel, turmeric, Corydalis chinensis, Scutellaria baicalensis, Phellodendron amurense, Phellodendron bark, Coptis chinensis, Onion, Zedoary, valerian, chamomile, calonin, platycodon, apricot kernel, lycium bark, wolfberry, cinnamon bark, Cassia japonica, gentian, Geranium herb, Kouka, Magnolia officinalis, Bezoar, Gomoku berry, Chinese rhizome, Chinese holly, Chinese pepper, Aster rhizome, Juglans chinensis, Lithospermum root, Peony root, Musk, Shajin, and Shi. Examples of herbal medicines that can be used include: jasmine, rhododendron, animal gall (including bear gall), ginger, jiru, shino, horse chestnut, sekisan, senega, cnidium, zenko, swertia bristlecone, soju, mulberry bark, perilla, tang, tang, ginseng, tangerine peel, angelica, ipecac, nandina, carrot, fritillary, chinese ginseng, pinecone, asiatic ginseng, angelica, peony, angelica tree, white berry, atractylodes rhizome, poria, moutan peel, columbine, and rokujo, as well as extracts thereof (extract, tincture, dried extract, etc.). Licorice may be used as a glycyrrhizic acid compound, as a herbal medicine, or may serve both the roles of a glycyrrhizic acid compound and a herbal medicine.

[0079] (A-5) Tranexamic acids may include, for example, tranexamic acid or a salt thereof, or a tranexamic acid derivative or a salt thereof. The salt of tranexamic acid is not particularly limited, but specific examples include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; metal salts such as aluminum, iron, and zinc; basic amino acid salts such as lysine, arginine, histidine, and ornithine; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, and stearylamine. Tranexamic acid derivatives or salts thereof may also be used, and specific examples include ester derivatives such as tranexamic acid cetyl ester; and amide derivatives such as tranexamic acid methylamide.

[0080] (A-6) Vanilloids is a general term for compounds containing a vanillyl group. Vanilloids in the present invention are not particularly limited as long as they contain a vanillyl group, and examples include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), and vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol). Furthermore, vanilloids in the present invention may include natural products containing compounds containing a vanillyl group, derivatives of compounds containing a vanillyl group, and synthetic compounds in which a functional group has been added to the vanillyl group. Furthermore, as vanilloids in the present invention, chili peppers containing compounds containing a vanillyl group may be used, or may be included as part of the vanilloids. Suitable chili peppers include, for example, the fruit of Capsicum annuum Linne (Solanaceae), listed in the 18th Edition of the Japanese Pharmacopoeia. The form of chili peppers can be adjusted as needed, and they can be cut or crushed into small pieces or chunks, or pulverized into powder. For example, "chili pepper powder" obtained by powdering chili peppers can also be used as the "chili pepper" of the present invention. Chili peppers that have been subjected to some kind of extraction process (chili pepper extract, chili pepper tincture, etc.) can also be used. Chili pepper extracts may also be those that have been subjected to processing processes such as heating, drying, and pulverization in addition to the extraction process. Furthermore, capsaicinoids, which are the main components of chili peppers, can also be used as chili peppers. Capsaicin and nonanoic acid vanillylamide are preferred capsaicinoids. Chili pepper extracts, chili pepper tincture, nonanoic acid vanillylamide, or capsaicin can preferably be used as chili peppers.

[0081] (A-7) Examples of nicotinic acids include nicotinic acid and its derivatives, as well as salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically, nicotinic acid methyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid benzyl ester, inositol hexanicotinate, hepronicate, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc.). Preferred nicotinic acid esters are monoesters of nicotinic acid. Preferred nicotinic acids are nicotinic acid benzyl esters.

[0082] (A-8) Examples of chlorpheniramines include chlorpheniramines and their salts. Specific examples of chlorpheniramine salts include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. Preferred chlorpheniramines are chlorpheniramine maleate.

[0083] (A-9) Examples of diphenhydramines include diphenhydramine or its salts. Examples of diphenhydramine salts include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. Preferred diphenhydramines are diphenhydramine or diphenhydramine hydrochloride.

[0084] (A-10) Pyrrolidones include dl-pyrrolidonecarboxylic acid and salts thereof, and sodium pyrrolidonecarboxylate is preferred.

[0085] (A-11) Examples of inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or ammonium salts, and preferred examples include sodium chloride, potassium chloride, and ammonium chloride.

[0086] Pharmaceutical additives other than the above-mentioned components may be added as needed, for example, for the purpose of further improving the stability of content over time and the feel when used, and examples thereof include humectants, moisturizers, thickeners, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, cooling agents, surfactants, emulsifiers, etc. The topical skin preparation of the present invention may also contain other optional components.

[0087] Examples of usable humectants include hyaluronic acid, sodium dl-pyrrolidone carboxylate, or a salt thereof (e.g., sodium dl-pyrrolidone carboxylate). Examples of usable moisturizers include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol. Examples of usable thickeners include hypromellose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, carrageenan, locust bean gum, and propylene glycol alginate.

[0088] Examples of the adhesive include acrylic acid-octyl acrylate copolymer, acrylic acid ester-vinyl acetate copolymer, 2-ethylhexyl acrylate-vinylpyrrolidone copolymer solution, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer solution, ethyl acrylate-methyl methacrylate copolymer dispersion, methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid-n-butyl acrylate copolymer, acrylic acid silk fibroin copolymer resin, starch acrylate 300, starch acrylate 1000, butyl acrylate-2-ethylhexyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-ethyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-ethyl acrylate-2-hydroxyethyl methacrylate-diacetoneacrylamide copolymer, butyl acrylate-2-ethylhexyl ... Acrylic pressure-sensitive adhesives such as 2-hydroxyethyl acrylate / diacetone acrylamide copolymer, isononyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, and butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / diacetone acrylamide copolymer; synthetic rubber pressure-sensitive adhesives such as cis-isoprene rubber, styrene-isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene-butadiene rubber (SBR), styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), polyisoprene, polyisobutylene (PIB), chloroprene rubber, polybutene, natural rubber latex, and SBR synthetic latex;In addition to silicone-based adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide-sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, gum arabic, and the like, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium can also be used;

[0089] Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, and aliphatic hydrocarbon resin. Examples of crosslinking agents that can be used include dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosultite, and dihydroxyaluminum aminoacetate. Examples of fillers that can be used include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, and silica (silicon dioxide). Examples of fats and oils that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, and gelled hydrocarbons; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyldecanol, isostearyl alcohol, and octyldodecanol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, purified lanolin, and reduced lanolin; and silicone oils.

[0090] Examples of softeners that can be used include petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, castor oil, tall oil, and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; and glycerin.

[0091] Examples of preservatives that can be used include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and aminoethylsulfonic acid. Examples of percutaneous absorption enhancers that can be used include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbonate, and azone or derivatives thereof. Examples of stabilizers that can be used include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives).

[0092] Examples of solubilizing agents that can be used include benzyl alcohol, pyrothiodecane, isopropyl myristate, crotamiton, pyrrolidones such as N-methyl-2-pyrrolidone, higher alcohols, polybasic acids such as diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, and diethyl sebacate, polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol, and oxyalkylene fatty acid esters such as polyethylene glycol monostearate. Examples of pH adjusting agents that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), and phosphoric acid. Examples of antioxidants that can be used include ascorbic acid, ascorbic acid palmitate, sodium bisulfite, dried sodium sulfite, sodium metabisulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythryl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate, etc. Examples of freshening agents that can be used include 1-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, thymol, etc.

[0093] As the surfactant, a nonionic surfactant or an ionic surfactant may be used.

[0094] Examples of nonionic surfactants include polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol mono fatty acid esters, ethylene glycol mono fatty acid esters, glycerin mono fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, alkyl polyglucosides, and polyethylene glycol fatty acid esters; polyoxyethylene ethers such as polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; polyoxyethylene mono fatty acid esters, polyethylene glycol di fatty acid esters, and polyoxyethylene glycerin fatty acid esters; Examples of the polyoxyethylene alkyl ether include polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid esters, and ether esters such as polyoxyethylene polyoxypropylene glycol; ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; and higher alcohols such as octyldodecanol. Examples of the polyoxyethylene alkyl ethers used in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether.

[0095] Examples of polyoxyethylene polyoxypropylene alkyl ethers include polyoxyethylene polyoxypropylene cetyl ether, etc. Examples of polyoxyethylene polyoxypropylene alkyl ethers in the present invention include polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol monooleate, etc.

[0096] Nonionic surfactants are listed in the Pharmaceutical Additives Encyclopedia 2021.

[0097] Examples of ionic surfactants include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, polyoxyethylene lauryl ether sodium phosphate, and dioctyl sodium sulfosuccinate; and cationic surfactants such as benzalkonium chloride and benzethonium chloride.

[0098] The ionic surfactants of the present invention are listed in the Pharmaceutical Additives Encyclopedia 2021 and the 18th Edition of the Japanese Pharmacopoeia.

[0099] As the emulsifier in the present invention, for example, any of the above-mentioned various surfactants and higher alcohols may be used.

[0100] Specific dosage forms of topical preparations include, for example, topical liquid preparations, ointments, creams, sprays (topical aerosols, pump sprays), gels, patches (tapes, poultices), and topical solid preparations, and these can be produced by appropriately using additives and bases suitable for each dosage form, according to the usual methods described in the 18th edition of the Japanese Pharmacopoeia, etc. As the dosage form of topical preparations, topical liquid preparations are particularly preferred.

[0101] Furthermore, the topical preparation can be housed and sealed in, for example, a glass container / packaging, a metal container / packaging such as aluminum, or an olefin resin container / packaging such as polyethylene or polypropylene, and further housed in a moisture-proof bag containing a metal such as aluminum. Furthermore, the container / packaging may be made from environmentally friendly raw materials such as recycled plastic or biomass raw materials, and, if necessary, any material may be used that prevents deterioration of the topical skin preparation due to factors, elements, or environmental changes from outside the pharmaceutical container / packaging, such as heat or light in a high-temperature environment, and that properly maintains the quality of the topical skin preparation. In one embodiment of the present invention, the topical skin preparation formulation / composition may be housed in a suitable container / packaging to provide a pharmaceutical product.

[0102] <Uses> The pharmaceutical composition of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. The pharmaceutical composition of the present invention is preferably for anti-inflammatory purposes.

[0103] According to the pharmaceutical composition of the present invention, PGE in cells ２ That is, the pharmaceutical composition of the present invention can reduce the amount of PGE ２ The pharmaceutical composition of the present invention can be used as an agent for reducing COX-2 production. The pharmaceutical composition of the present invention can reduce COX-2 expression in cells. That is, the pharmaceutical composition of the present invention can be used as an agent for reducing COX-2 expression.

[0104] According to the present invention, there is provided a method for suppressing inflammation, which comprises administering to a subject at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof. According to the present invention, there is provided a method for suppressing inflammation, which comprises administering to a subject at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof. ２According to the present invention, there is provided a method for reducing COX-2 expression, which comprises administering to a subject at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one member selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof.

[0105] According to the present invention, there is provided a pharmaceutical composition for use in treating inflammation, comprising at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof. According to the present invention, there is provided a pharmaceutical composition for use in treating inflammation, comprising at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof. ２ According to the present invention, there is provided a pharmaceutical composition for use in a treatment to reduce COX-2 expression, comprising at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one member selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof.

[0106] According to the present invention, there is provided use of at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof, for the manufacture of an anti-inflammatory agent. ２The present invention provides use of at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and at least one member selected from the group consisting of diclofenac, naproxen, a salt thereof, and a hydrate thereof, for the manufacture of an agent for lowering COX-2 expression.

[0107] The active ingredients, loxoprofen, its salts, and hydrates thereof, and diclofenac, naproxen, their salts, and hydrates thereof, each have antipyretic, analgesic, and anti-inflammatory effects. Therefore, the pharmaceutical composition of the present invention is suitable for use as an antipyretic analgesic, particularly for relieving pain from headache, menstrual pain, toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, fractures, sprains, and trauma, and for reducing fever during chills and fever. It is also suitable for use as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0108] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples in any way.

[0109] <Test Materials> (1) Test Substance: Loxoprofen Sodium Hydrate (LOX) Loxoprofen sodium hydrate (LOX) was obtained from Fujifilm Wako Pure Chemical Industries, Ltd. It was dissolved in growth medium (DMEM supplemented with 10% FBS and 1% penicillin-streptomycin mixed solution) to prepare a 100 mM solution. A 1 / 100 dilution with growth medium was repeated to prepare a 0.0001 mM solution, followed by a 1 / 10 dilution to prepare a 0.00001 mM solution. LOX-added test medium was prepared by adding 1 / 1000 of the amount to 0.1% DMSO-added growth medium. Additionally, LOX-added growth medium was prepared by adding 1 / 1000 of the amount to growth medium for LOX + combination drug-added test medium.

[0110] Ibuprofen: Ibuprofen was obtained from Fujifilm Wako Pure Chemical Industries, Ltd. It was dissolved in DMSO (Nacalai Tesque) to prepare a 100 mM solution. A dilution series down to 0.1 mM was prepared using DMSO at a common ratio of 3. A test medium containing a combination drug was prepared by adding 1 / 1000 of the amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding 1 / 1000 of the amount to the LOX-added growth medium.

[0111] Indomethacin was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.0001 mM solution was prepared by repeated 1 / 100 dilutions with DMSO, and then a 0.00001 mM solution was prepared by further dilution at 1 / 1000. A test medium containing a combination drug was prepared by adding a 1 / 1000-fold amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding a 1 / 1000-fold amount to the LOX-added growth medium.

[0112] Diclofenac Na Diclofenac Na was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.0001 mM solution was prepared by repeated 1 / 100 dilutions with DMSO, and then a 0.00001 mM solution was prepared by further dilution at 1 / 1000. A test medium containing a combination drug was prepared by adding a 1 / 1000-fold amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding a 1 / 1000-fold amount to the LOX-added growth medium.

[0113] Felbinac Felbinac was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.1 mM solution was prepared by repeated 1 / 10 dilutions with DMSO. A test medium containing a combination drug was prepared by adding 1 / 1000 of the amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding 1 / 1000 of the amount to the LOX-added growth medium.

[0114] Aspirin: Aspirin was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.1 mM solution was prepared by repeated 1 / 10 dilutions with DMSO. A test medium containing a combination drug was prepared by adding 1 / 1000 of the amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding 1 / 1000 of the amount to the LOX-added growth medium.

[0115] Meloxicam Meloxicam was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.0001 mM solution was prepared by repeated 1 / 100 dilutions with DMSO, and then a 0.00001 mM solution was prepared by further dilution at 1 / 1000. A test medium containing a combination drug was prepared by adding a 1 / 1000-fold amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding a 1 / 1000-fold amount to the LOX-added growth medium.

[0116] Celecoxib was obtained from Tokyo Chemical Industry Co., Ltd. Celecoxib was dissolved in DMSO to prepare a 100 mM solution. A 0.0001 mM solution was prepared by repeated 1 / 100 dilutions with DMSO, followed by a 1 / 10 dilution to prepare a 0.00001 mM solution. A 1 / 1000 volume of celecoxib was added to the growth medium to prepare a test medium containing a combination drug. A 1 / 1000 volume of celecoxib was added to the LOX-added growth medium to prepare a test medium containing LOX and a combination drug.

[0117] Naproxen was obtained from Fujifilm Wako Pure Chemical Corporation. It was dissolved in DMSO to prepare a 100 mM solution. A 0.0001 mM solution was prepared by repeated 1 / 100 dilutions with DMSO, and then a 0.00001 mM solution was prepared by further dilution at 1 / 1000. A test medium containing a combination drug was prepared by adding a 1 / 1000-fold amount to the growth medium. Furthermore, a test medium containing LOX and a combination drug was prepared by adding a 1 / 1000-fold amount to the LOX-added growth medium.

[0118] Dexamethasone (positive control) Dexamethasone was obtained from Sigma-Aldrich and dissolved in DMSO to prepare a 5 mM solution.

[0119] <Cell line> RAW264.7 cells were obtained from ATCC. The culture medium used was DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution.

[0120] <LPS> LPS from E. coli O55:B5 was obtained from Sigma-Aldrich and dissolved in DPBS to a concentration of 5 mg / mL.

[0121] <Test Example 1> <PGE ２Group composition for ELISA measurement of released amount: No drug added - no LPS treatment No drug added - LPS treatment LOX + concomitant drug added (treatment concentrations as follows) - LPS treatment 1) LOX: 0.00001 μM (hereinafter, the same LOX concentration for all) 2) LOX + ibuprofen: 0.1 μM 3) Ibuprofen: 0.1 μM 4) LOX + indomethacin 0.00001 μM 5) indomethacin 0.00001 μM 6) LOX + diclofenac Na 0.00001 μM 7) diclofenac Na 0.00001 μM 8) LOX + felbinac: 0.1 μM 9) felbinac: 0.1 μM 10) LOX + aspirin: 0.1 μM 11) aspirin: 0.1 μM 12) LOX + meloxicam: 0.00001 μM 13) Meloxicam: 0.00001 μM 14) LOX + celecoxib 0.00001 μM 15) celecoxib 0.00001 μM 16) LOX + naproxen 0.00001 μM 17) naproxen 0.00001 μM

[0122] 1 μM Dexamethasone-LPS treatment Ibuprofen: 0.1, 0.3, 1, 3, 10, 30, 100 μM (IC50 calculation)

[0123] The test medium was prepared so that n=3 and the DMSO concentration in each group was 0.1%.

[0124] <Test Method>

[0125]

[0126] (1) Cell culture Cells were cultured in a medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) under CO ２ Incubator (5% CO ２ The cells were cultured at 37°C, humidified (hereinafter the same) until the required number of cells was reached. For cell passage, the cells were detached from the flask using a scraper, collected, and resuspended in medium to be used as a cell suspension.

[0127] (2) Treatment with LPS, test substance, and concomitant drugs Cells were cultured in a medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) under CO ２ The cells were cultured in an incubator. When the cells reached 60-80% confluence, they were detached from the flask using a scraper, collected, and resuspended in the medium. ４　 Cells were seeded at 0.1 mL / well in a 96-well plate and incubated with CO ２ The cells were cultured overnight in an incubator. Then, the medium was replaced with 0.1 mL of test medium containing LOX / combined drug / LOX + combined drug / positive control for the LPS-untreated group or LPS-treated group (listed in the group composition column), or test medium containing no drug for the LPS-treated group, and incubated in CO ２ After the treatment was completed, the culture supernatant was collected and stored at −80°C until measurement.

[0128] (3) ELISA Measurement After thawing the culture supernatant, it was diluted 1 / 5 and the PGE in the culture supernatant was measured. ２ The amount of PGE was measured by ELISA. The measurement was carried out using a plate reader VARIOSKAN FLASH, and the absorbance was measured. A calibration curve was prepared to measure the amount of PGE. ２ The amount was calculated.

[0129] (4) Statistical Analysis The differences between the drug-free LPS-treated group and the Dex-added LPS-treated group were examined using Student's t-test. The drug-free LPS-treated group, LOX-added LPS-treated group, combined drug-added LPS-treated group, and LOX + combined drug-added LPS-treated group were examined using the Tukey-Kramer method. A two-tailed test was performed, and a P value of < 0.05 was considered significant. The statistical analysis software "Excel Statistics" was used for each statistical significance test. The IC50 value was calculated by creating a dose-response curve using XLfit software (version 5.5.0.5, ID Business Solutions, Ltd.) using a four-parameter logistic model (y = (A + ((B - A) / (1 + ((C / x)^D)))), model No. 205 in XLfit).

[0130] <Results> PGE when ibuprofen is added to confirm test reproducibility ２ The measurement results are shown in Figure 1 and the results of calculating IC50 values ​​from the dose-response curve are shown in Figure 2. The PGE induced by LPS was reduced by treatment with dexamethasone, a positive control. ２ The amount of production was significantly reduced, and the IC50 value of the anti-inflammatory effect of ibuprofen in this test was 0.91 μM, demonstrating the validity of the test.

[0131] PGE in a study examining the combined effects of LOX and other drugs ２ The measurement results are shown in Figures 3 to 10. Treatment with 0.00001 μM LOX alone did not significantly increase PGE ２ No decrease in production was observed, and no anti-inflammatory effect was observed.

[0132] Regarding indomethacin and felbinac, at the treatment concentrations tested in this study, there was no significant increase in PGE when treated alone. ２ There was no decrease in the amount of PGE produced, and even when used in combination with LOX ２ No change in production was observed.

[0133] For ibuprofen, aspirin, meloxicam, and celecoxib, at the treatment concentrations tested in this study, single treatment significantly reduced PGE. ２ On the other hand, when combined with LOX, the amount of PGE produced was significantly reduced compared to LOX treatment alone. ２ Although a decrease in the amount of PGE production was observed, there was a significant decrease in the amount of PGE production compared to treatment with the combined drug alone. ２ No decrease in production was observed.

[0134] Regarding naproxen, at the treatment concentration in this test, there was no significant PGE ２ No decrease in the amount of PGE production was observed. On the other hand, when combined with LOX, the amount of PGE production was significantly reduced compared to LOX treatment alone. ２ There was no significant difference when compared with treatment with the combined drug alone, but a decrease in PGE ２ A decrease in production was observed.

[0135] Regarding diclofenac Na, at the treatment concentration in this test, there was no significant PGE ２On the other hand, when combined with LOX, there was a significant decrease in PGE production compared with LOX alone and diclofenac Na alone. ２ This indicates that the anti-inflammatory effect of diclofenac sodium is enhanced when used in combination with LOX.

[0136] The results of this test confirmed the IC50 value of ibuprofen in this test. For diclofenac Na, the anti-inflammatory effect was confirmed to be enhanced by the combined use of LOX and diclofenac Na. The anti-inflammatory effect of naproxen was also enhanced by the combined use of LOX and naproxen.

[0137] <Test Example 2> <Group composition for measuring COX-2 protein expression> No test substance added - no LPS treatment No test substance added - LPS treatment Concomitant drug added (treatment concentrations as follows) - LPS treatment

[0138] 1 μM Dexamethasone-LPS treatment

[0139] n=3 Test medium was prepared so that the DMSO concentration in each group was 0.1%.

[0140] <Test Method>

[0141]

[0142]

[0143] (1) Cell culture Cells were cultured in a medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) under CO ２ Incubator (5% CO ２ The cells were cultured at 37°C in a humidified atmosphere (the same applies below) until the required number of cells was reached. For cell passage, the cells were detached from the flask using a scraper, collected, and resuspended in medium to be used as a cell suspension.

[0144] (2) Treatment with LPS and test substance Cells were cultured in a medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) under CO ２ The cells were cultured in an incubator. When the cells reached 60-80% confluence, they were detached from the flask using a scraper, collected, and resuspended in the medium. ５　 Cells were seeded at 0.6 mL / well in a 24-well plate and incubated with CO ２ The cells were cultured overnight in an incubator. Then, the medium was replaced with 0.6 mL of test medium containing LOX / combined drug alone / LOX + combined drug / test substance alone / positive control for the LPS-untreated group or LPS-treated group (listed in the group composition column), or test medium containing no test substance for the LPS-treated group. ２ The cells were cultured in an incubator. After culturing, the culture plate was transferred to ice, washed twice with chilled DPBS, and RIPA buffer containing 1% protease / phosphatase inhibitor was added. After collecting the cells, the plate was left to stand on ice for 30 minutes with occasional vortexing. The cells were completely disrupted using a sonicator to obtain a cell lysate. The cell lysate was stored at -80°C until measurement.

[0145] (3) Western Blot Lysate protein was quantified using a Micro BCA Protein Assay kit (Thermo Fisher Scientific, 23235) according to the accompanying manual. Western blot was performed using Simple Western Jess according to the manual. Cell lysates were electrophoresed using a 12-230 kDa Jess separation module with Protein Normalization Reagents at 0.3 mg / mL. The primary antibody was diluted 1 / 50, and the secondary antibody was used undiluted. Electrophoretic images were captured using Compass for SW software (version 4.1.0, Protein Simple). Protein expression levels were detected by chemiluminescence. Specifically, the total protein amount was determined based on the exposure conditions using Compass for SW software, and then the AUC (Area Under the Curve) of the luminescence peak area was corrected and calculated.

[0146] (4) Statistical Analysis The differences between the test substance-free LPS-treated group and the Dex-added LPS-treated group were examined using Student's t-test. Combined drug addition experiment: The drug-free LPS-treated group, LOX-added LPS-treated group, combined drug-added LPS-treated group, and LOX + combined drug-added LPS-treated group were examined using the Tukey-Kramer method. Test substance addition experiment: The test substance-free LPS-treated group and test substance-added LPS-treated group were examined using Dunnett's test. A two-tailed test was performed, and P < 0.05 was considered significant. The statistical analysis software "Excel Statistics" was used for each statistical significance test.

[0147] <Results> The results of comparing COX-2 expression levels by Western blotting are shown in Figure 11. LOX: 0.00001 µM loxoprofen sodium hydrate Dic: 0.00001 µM diclofenac Na LOX + Dic: 0.00001 µM LOX + 0.00001 µM diclofenac Na Nap: 0.00001 µM naproxen LOX + Nap: 0.00001 µM LOX + 0.00001 µM naproxen Dex: 1 µM dexamethasone

[0148] Comparing the LPS-treated group with the non-LPS-treated group, a clear increase in COX-2 expression level was confirmed in the LPS-treated group. Furthermore, in the positive control group containing 1 μM dexamethasone, COX-2 expression level was significantly decreased compared to the LPS-treated group, demonstrating the validity of the test system.

[0149] Regarding the effects of drug combinations, no significant decrease in COX-2 expression was observed when 0.00001 μM LOX, 0.00001 μM diclofenac Na, or 0.00001 μM naproxen were used alone. When 0.00001 μM LOX + 0.00001 μM diclofenac Na or 0.00001 μM LOX + 0.00001 μM naproxen were used in combination, a tendency toward a decrease in COX-2 expression was observed compared to 0.00001 μM LOX alone.

[0150] 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.

[0151] The pharmaceutical composition of the present invention is preferably used as an antipyretic analgesic, particularly for the relief of pain from headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, fracture pain, sprains, and trauma pain, and for the reduction of fever during chills and fever. It is also preferably used as a cold medicine for the relief of cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain). The pharmaceutical composition of the present invention is also preferably used as an external anti-inflammatory and analgesic, particularly for the relief of pain from lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, fracture pain, sprains, trauma pain, and eye pain. It is also preferably used as an anti-inflammatory drug for the treatment of muscle fatigue and chilblains. It is also used as an oropharyngeal medicine to treat pharyngitis, tonsillitis, stomatitis, swelling of the mouth and pharynx, sterilize and disinfect the mouth and throat, and remove bad breath.It is also used as a hemorrhoid medicine to relieve pain, bleeding, swelling, and itching caused by hemorrhoids and anal fissures.

Claims

1. A pharmaceutical composition comprising at least one selected from the group consisting of loxoprofen, its salts and their hydrates, and at least one selected from the group consisting of diclofenac, naproxen, their salts and their hydrates.

2. The pharmaceutical composition according to claim 1, which is for anti-inflammatory use.

3. The pharmaceutical composition according to claim 2, wherein the dosage of at least one selected from the group consisting of loxoprofen, its salts and their hydrates is an amount that does not exhibit an anti-inflammatory effect when administered alone.

4. The pharmaceutical composition according to claim 3, wherein the dosage of at least one selected from the group consisting of diclofenac, naproxen, their salts and their hydrates is an amount such that the anti-inflammatory effect is enhanced by administering at least one selected from the group consisting of loxoprofen, its salts and their hydrates in an amount that does not exhibit an anti-inflammatory effect when administered alone.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an oral preparation, the dosage of at least one selected from the group consisting of loxoprofen, its salts and their hydrates is 0.06 mg / dose to 6 mg / dose, the dosage of at least one selected from the group consisting of diclofenac, its salts and its hydrates is 0.025 mg / dose to 2.5 mg / dose, or the dosage of at least one selected from the group consisting of naproxen, its salts and its hydrates is 0.1 mg / dose to 10 mg / dose.

6. The pharmaceutical composition is a topical agent, and the dosage of at least one selected from the group consisting of loxoprofen, its salts and their hydrates is 0.0007 mg / cm ２ to 0.07 mg / cm ２ and the dosage of at least one selected from the group consisting of diclofenac, its salts and its hydrates is 0.0001 mg / cm ２ to 0.01 mg / cm ２ The pharmaceutical composition according to any one of claims 1 to 4.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an oral preparation, the dosage of at least one selected from the group consisting of loxoprofen, its salts and their hydrates is an amount such that the maximum plasma concentration after administration is 0.006 μg / mL to 0.6 μg / mL, the dosage of at least one selected from the group consisting of diclofenac, its salts and its hydrates is an amount such that the maximum plasma concentration after administration is 0.41 ng / mL to 41 ng / mL, or the dosage of at least one selected from the group consisting of naproxen, its salts and its hydrates is an amount such that the maximum plasma concentration after administration is 0.09 μg / mL to 9 μg / mL.

8. The pharmaceutical composition is a topical agent, and the dosage of at least one selected from the group consisting of loxoprofen, its salts and their hydrates is such that the maximum plasma concentration after administration is 0.05 ng / mL to 5 ng / mL, and the dosage of at least one selected from the group consisting of diclofenac, its salts and its hydrates is such that the maximum plasma concentration after administration is 0.003 ng / mL to 0.3 ng / mL. The pharmaceutical composition according to any one of claims 1 to 4.

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