A pharmaceutical composition containing loxoprofen and diclofenac or naproxen

Abstract

The objective of the present invention is to provide a pharmaceutical composition that enhances the anti-inflammatory effect of loxoprofen. According to the present invention, a pharmaceutical composition is provided 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.

Description

Technology Field

[0001] The present invention relates to 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. More specifically, the present invention relates to a pharmaceutical composition that enhances the anti-inflammatory action of loxoprofen by comprising at least one selected from the group consisting of diclofenac, naproxen, their salts and their hydrates. Background Technology

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (hereinafter referred to as "NSAIDs"), exerts an inhibitory effect on prostaglandin biosynthesis, similar to other NSAIDs, but is known to have strong antipyretic, analgesic, and anti-inflammatory effects. Loxoprofen is a prodrug that is absorbed through the digestive tract in an unchanged state with weak gastric mucosal irritation after oral administration and becomes an active substance in the body; therefore, it is known to cause less gastric mucosal damage compared to other NSAIDs (Reference: Non-patent Literature 1).

[0003] Regarding the combination of multiple NSAIDs, for example, Patent Document 1 describes the combination of nabumetone and ethenzamide or ibuprofen. Additionally, Patent Document 2 describes a method of combining ibuprofen and naproxen sodium. Meanwhile, there have been reports that when combining multiple NSAIDs, combining NSAIDs with each other should be avoided because it does not increase efficacy but increases side effects such as gastrointestinal disorders (see Non-Patent Document 2). Prior art literature

[0004] Patent Document 1: Patent Publication No. 2020-100610 Patent Document 2: Patent Publication No. 2015-503583

[0005] Non-patent Literature 1: Pharmacology and Therapy Vol. 16, No. 2, 1988, pp. 611-619 Non-patent Literature 2: Journal of Internal Medicine, 2011, Vol. 100, No. 10, p. 2,900 The problem to be solved

[0006] The present invention aims to provide a pharmaceutical composition that enhances the anti-inflammatory effect of loxoprofen. means of solving the problem

[0007] As a result of in-depth investigation to solve the above problem, the inventors discovered that the anti-inflammatory effect of loxoprofen can be further enhanced by combining loxoprofen sodium hydrate with a specific non-steroidal antipyretic, analgesic, and anti-inflammatory agent, and thus completed the present invention.

[0008] The aspects of the present invention are as set forth below:

[0009] <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.

[0010] <2> Anti-inflammatory agents, items <1> A pharmaceutical composition described in

[0011] <3> At least one dosage selected from the group consisting of loxoprofen, its salts, and their hydrates, which is an amount that does not exhibit an anti-inflammatory effect when administered alone, item <1> or <2> A pharmaceutical composition described in

[0012] <4> A dose of at least one type selected from the group consisting of diclofenac, naproxen, their salts and their hydrates is a dose in which the anti-inflammatory effect is enhanced by administering at least one type selected from the group consisting of loxoprofen, its salts and their hydrates, which does not exhibit an anti-inflammatory effect when administered alone, item <3> A pharmaceutical composition described in

[0013] <5> The pharmaceutical composition is an oral preparation, and

[0014] The dosage of at least one type selected from the group consisting of loxoprofen, its salts and their hydrates is 0.06 mg / dose to 6 mg / dose, and

[0015] A dosage of at least one selected from the group consisting of diclofenac, its salts and their hydrates, ranging from 0.025 mg / dose to 2.5 mg / dose, or a dosage of at least one selected from the group consisting of naproxen, its salts and their hydrates, ranging from 0.1 mg / dose to 10 mg / dose,

[0016] item <1> inside <4> A pharmaceutical composition described in any one of the following.

[0017] <6> The pharmaceutical composition is an external preparation, and

[0018] A dosage of at least one type selected from the group consisting of loxoprofen, its salts and their hydrates is 0.0007 mg / cm² to 0.07 mg / cm², and

[0019] A dosage of at least one selected from the group consisting of diclofenac, its salts and their hydrates, ranging from 0.0001 mg / cm² to 0.01 mg / cm²,

[0020] item <1> inside <4> A pharmaceutical composition described in any one of the following.

[0021] <7> The pharmaceutical composition is an oral preparation, and

[0022] At least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is between 0.006 μg / mL and 0.6 μg / mL, and

[0023] At least one dose selected from the group consisting of diclofenac, its salts and their hydrates is a dose such that the maximum plasma concentration after administration is 0.41 ng / mL to 41 ng / mL, or at least one dose selected from the group consisting of naproxen, its salts and their hydrates is a dose such that the maximum plasma concentration after administration is 0.09 μg / mL to 9 μg / mL,

[0024] item <1> inside <4> A pharmaceutical composition described in any one of the following.

[0025] <8> The pharmaceutical composition is an external preparation, and

[0026] At least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is between 0.05 ng / mL and 5 ng / mL, and

[0027] At least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is between 0.003 ng / mL and 0.3 ng / mL,

[0028] item <1> inside <4> A pharmaceutical composition described in any one of the following. Effects of the invention

[0029] The pharmaceutical composition of the present invention can exhibit an excellent anti-inflammatory effect. An unexpected effect is that the anti-inflammatory effect of loxoprofen can be further enhanced by combining loxoprofen sodium hydrate with a specified non-steroidal antipyretic, analgesic, and anti-inflammatory agent. Brief explanation of the drawing

[0030] Figure 1 shows the results of PGE2 quantification in the culture supernatant for ibuprofen. Bar=Mean±SE, n=3, Student's t-test: P<0.01 (vs1 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 results of PGE2 quantification in the culture supernatant for ibuprofen (drug combination effect). Bar=Mean±SE, n=3, Turkey-Kramer: *P<0.05, **P<0.01 Figure 4 shows the results of PGE2 quantification in the culture supernatant for indomethacin (drug combination effect). Bar=Mean±SE, n=3 Figure 5 shows the results of PGE2 quantification in the culture supernatant for diclofenac Na (drug combination effect). Bar=Mean±SE, n=3, **P<0.01 Figure 6 shows the results of PGE2 quantification in the culture supernatant for felbinac (drug combination effect). Bar=Mean±SE, n=3 Figure 7 shows the results of PGE2 quantification in the culture supernatant for aspirin (drug combination effect). Bar=Mean±SE, n=3, Turkey-Kramer: **P<0.01 Figure 8 shows the results of PGE2 quantification in the culture supernatant for meloxicam (drug combination effect). Bar=Mean±SE, n=3, Turkey-Kramer: **P<0.01 Figure 9 shows the results of PGE2 quantification in the culture supernatant for celecoxib (drug combination effect). Bar=Mean±SE, n=3, Turkey-Kramer: *P<0.05, **P<0.01 Figure 10 shows the results of PGE2 quantification in the culture supernatant for naproxen (drug combination effect). Bar=Mean±SE, n=3, Turkey-Kramer: *P<0.05, **P<0.01 Figure 11 shows the results of comparing COX-2 expression levels using Western blot. Bar=Mean±SE, n=3, P<0.01 (vs 1μg / mL LPS-treated group with 0.1% DMSO added (subjects without added), Student's t-test) Specific details for implementing the invention

[0031] The pharmaceutical composition of the present invention comprises 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.

[0032] Loxoprofen, its salts and their hydrates

[0033] The pharmaceutical composition of the present invention comprises at least one type selected from the group consisting of loxoprofen, its salts and their hydrates.

[0034] In the present invention, 'at least one type selected from the group consisting of loxoprofen, its salts and their hydrates' is also referred to as 'loxoprofen or its salts', loxoprofen or its salts (including hydrated salts) (the salts are preferably pharmacologically acceptable salts), suitable is loxoprofen sodium, and more suitable is loxoprofen sodium dihydrate.

[0035] At least one type selected from the group consisting of loxoprofen, its salts, and their hydrates used in the present invention is loxoprofen sodium hydrate, which is listed in the 18th revised edition of the Japanese Pharmacopoeia.

[0036] At least one type selected from the group consisting of loxoprofen, its salts, and their hydrates included in the pharmaceutical composition is not particularly limited, but is preferably 0.0001 to 80 mass% based on the total mass of the pharmaceutical composition, more preferably 0.001 to 80 mass%, even more preferably 0.01 to 80 mass%, 0.1 to 80 mass% is acceptable, 1 to 80 mass% is acceptable, 2 to 50 mass% is acceptable, and 5 to 20 mass% is acceptable.

[0037] Diclofenac, naproxen, their salts and their hydrates

[0038] The pharmaceutical composition of the present invention comprises at least one type selected from the group consisting of diclofenac, naproxen, and their salts and their hydrates.

[0039] At least one type selected from the group consisting of diclofenac, its salts and their hydrates used in the present invention is, for example, diclofenac, diclofenac sodium, and diclofenac potassium, and specifically, diclofenac sodium is listed in the 18th revised edition of the Japanese Pharmacopoeia.

[0040] At least one type selected from the group consisting of naproxen, its salts and their hydrates used in the present invention is, for example, naproxen, naproxen sodium, and naproxen potassium, and specifically, naproxen is listed in the 18th revised Japanese Pharmacopoeia.

[0041] At least one selected from the group consisting of diclofenac, naproxen, their salts and their hydrates included in the pharmaceutical composition is not particularly limited, but based on the total mass of the pharmaceutical composition, preferably 0.0001 to 80 mass%, more preferably 0.001 to 80 mass%, even more preferably 0.01 to 80 mass%, even more preferably 0.1 to 80 mass%, even more preferably 0.2 to 80 mass%, 0.5 to 80 mass% is acceptable, 0.5 to 50 mass% is acceptable, 0.5 to 30 mass% is acceptable, and 0.5 to 20 mass% is acceptable.

[0042] <Regarding Dosage>

[0043] At least one dosage selected from the group consisting of loxoprofen, its salts, and their hydrates is preferably an amount that does not exhibit an anti-inflammatory effect when administered alone.

[0044] Preferably, at least one dosage selected from the group consisting of diclofenac, naproxen, their salts and their hydrates is loxoprofen, which does not exhibit an anti-inflammatory effect when administered alone, and is a dosage in which the anti-inflammatory effect is enhanced by administering at least one selected from the group consisting of its salts and their hydrates.

[0045] Where the pharmaceutical composition is an oral preparation, preferably, the dosage of at least one type selected from the group consisting of loxoprofen, its salts and their hydrates is 0.06 mg / dose to 6 mg / dose (more preferably 0.12 mg / dose to 3 mg / dose), and

[0046] At least one dose selected from the group consisting of diclofenac, its salts and their hydrates is 0.025 mg / dose to 2.5 mg / dose (more preferably 0.05 mg / dose to 1.25 mg / dose), or at least one dose selected from the group consisting of naproxen, its salts and their hydrates is 0.1 mg / dose to 10 mg / dose (more preferably 0.2 mg / dose to 5 mg / dose).

[0047] In the case where the pharmaceutical composition is an external preparation, preferably,

[0048] A dosage of at least one type selected from the group consisting of loxoprofen, its salts and their hydrates is 0.0007 mg / cm² to 0.07 mg / cm² (more preferably 0.0014 mg / cm² to 0.035 mg / cm²), and

[0049] The dosage of at least one type selected from the group consisting of diclofenac, its salts and their hydrates is 0.0001 mg / cm² to 0.01 mg / cm² (more preferably 0.0002 mg / cm² to 0.005 mg / cm²).

[0050] In the case where the pharmaceutical composition is an oral preparation, preferably,

[0051] At least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage 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), and

[0052] At least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is a dosage in which the maximum plasma concentration after administration is approximately 0.41 ng / mL to 41 ng / mL (more preferably 0.82 ng / mL to 20.5 ng / mL), and

[0053] At least one dosage selected from the group consisting of naproxen, its salts and their hydrates is a dosage 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).

[0055] In the case where the pharmaceutical composition is an external preparation, preferably,

[0056] At least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage 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

[0057] At least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is a dosage 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).

[0058] <Regarding Oral Medications>

[0059] The case where the pharmaceutical composition of the present invention is an oral preparation is explained as follows.

[0060] The pharmaceutical composition of the present invention may include antacids for the purpose of inhibiting gastric mucosal damage.

[0061] Antacids include, for example, alkaline earth metals and / or earth metal-based basic inorganic compounds, such as magnesium oxide, magnesium silicate, magnesium aluminum silicate, magnesium hydroxide, co-precipitation products of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation products of aluminum hydroxide and sodium bicarbonate, mixed dry gel of aluminum hydroxide and magnesium carbonate, co-precipitation products of aluminum hydroxide, magnesium carbonate, and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, etc., and metal inorganic salts selected from magnesium, aluminum, and calcium are examples of alkali metal-based basic inorganic compounds, such as dry sodium carbonate and hydroxide There are metal inorganic salts selected from sodium and potassium, such as sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium hydrogen phosphate, potassium hydroxide, potassium bicarbonate, and potassium carbonate, and in addition, bore and glycine are included, and one or more of the components selected from these may be combined. In particular, one or more of the components selected from the group consisting of magnesium oxide, magnesium metasilicate aluminate, aluminum hydroxide gel, and glycine are preferred.

[0062] The pharmaceutical composition of the present invention may contain caffeine. Types of caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, citrate caffeine, etc.

[0063] The pharmaceutical composition of the present invention may include sedatives. Examples of sedatives include allyl isopropylacetylurea and bromovalerylurea.

[0064] In the pharmaceutical composition of the present invention, other active ingredients, such as antitussives and expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, and xanthine derivatives, may be appropriately incorporated as needed within a range that does not impair the present invention, and if there are contraindications to the incorporation of these, it is preferable to formulate the composition by appropriately separating granules, etc.

[0065] antitussives and expectorants ​Examples include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium dibunate, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, d-dextromethorphan, didextromethorphan bromate hydrate, didextromethorphan phenolphthalein, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, noscapine, noscapine hydrochloride, trimethoquinol hydrochloride, phenylephrine hydrochloride, and pseudoephedrine. Examples include pseudoephedrine hydrochloride, pseudoephedrine sulfate, L-methyl ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, L-ethylcysteine ​​hydrochloride, etc.

[0066] antihistamines ​As for, for example, azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyldisulfonate, carbinoxamine maleate, d-chlorphenylamine maleate, dl-chlorphenylamine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tanninate, triprolidine There are triprolidine hydrochloride, triperenamine hydrochloride, tonzilamine hydrochloride, fexofenadine, phenethazine hydrochloride, promethazine hydrochloride, promethazine, mekitazine, meddilazine hydrochloride, loratadine, isopentyl hydrochloride, diphetenol hydrochloride, meddilazine hydrochloride, mebhydrolin napadisylate, promethazine methylene disalicylate, diphetenol phosphate, etc.

[0067] anti-inflammatory agents Examples include glycyrrhizic acid, its derivatives and their salts (e.g., dipotassium glycyrrhizic acid, monoammonium glycyrrhizic acid, etc.), tranexamic acid, etc.

[0068] anticholinergic agents Examples include scopolamine bromide hydrochloride, datura extract, methylscopolamine bromide, methyl-L-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxiran iodide, lotus extract, lotus root, and total alkaloids of scopolia rhizome quinate.

[0069] Vitamins (other vitamins) Examples 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 potassium and magnesium aspartate, inositol, hexanicotine, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma-oryzanol, calcium glycerol phosphate, calcium gluconate, glucuronolactone, glucuronamide, sodium chondroitin sulfate, carrot, coix seed (coicis semen), and iodine.

[0070] Examples of xanthine derivatives other than the aforementioned caffeine include theophylline and theobromine.

[0071] ​​​In addition, vitamins include, for example, vitamin B1, its derivatives and their salts, such as thiamine, thiamine hydrate hydrochloride, thiamine nitrate, dicethiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, sicotiamine, thiamine disulfide, bisibutiamine, bisbentiamine, prosultiamine, and benfotiamine; vitamin B2, its derivatives and their salts, such as riboflavin, riboflavin phosphate ester, riboflavin butyric acid ester, and riboflavin sodium phosphate; vitamin B5, its derivatives and their salts, such as pantothenic acid, panthenol, panthetin, calcium pantothenate, and sodium pantothenate; It is acceptable to combine one or more ingredients selected from the group consisting of vitamin B6, such as pyridoxine hydrochloride and pyridoxar phosphate ester, its derivatives and their salts; vitamin B12, such as cyanocobalamin and mecobalamin, its derivatives and their salts; vitamin C, such as ascorbic acid, sodium ascorbate and calcium ascorbate, its derivatives and their salts; and hesperidin and its derivatives and their salts.

[0072] These additives are not limited to those listed above, and it is acceptable to use only one of them or to use a combination of two or more.

[0073] The pharmaceutical composition of the present invention can be formulated into an oral preparation according to conventional methods.

[0074] In the present invention, for example, a granular particle 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, its salts and their hydrates is prepared, and a tablet can be prepared by adding a subsequent component to the obtained granular particle to form the outer surface of the granular particle and then compressing it.

[0075] Specifically, the tablet may be produced through a process of manufacturing granular particles (at least one granular particle) comprising, for example, 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, its salts and their hydrates; and a process of manufacturing the tablet by mixing the granular particles described above with a desired additive (a trailing component) and compressing them. Additionally, 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, its salts and their hydrates may each be contained in separate granular particles, and the component placed outside the granule may freely be used in granular form.

[0076] The post-granulation powder (outer granule) constitutes the outer surface of the granules in the tablet, and may, for example, be configured to cover a single granule in the tablet or may be configured to cover multiple granules. Additionally, it may constitute the outer surface of the tablet while covering at least one granule. The tablet contains granulated granules, and at least one type selected from the group consisting of loxoprofen, its salts and their hydrates, and at least one type selected from the group consisting of diclofenac, its salts and its hydrates may be included in the granulated granules described above.

[0077] In addition, although the above example presented a formulation using loxoprofen and diclofenac, naproxen may be used instead of diclofenac. Furthermore, formulations may be prepared using loxoprofen, diclofenac, and naproxen, such as by appropriately separating granules.

[0078] When formulating, the formulation can be performed by appropriately using known methods and additives. Additives may be appropriately added within a range that does not impair the effects of the present invention.

[0079] additives These include pharmaceutically acceptable carriers, e.g., diluents, binders, disintegrants, disintegration aids, lubricants, glidants, polishing agents, effervescent agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, flavorings, fragrances, colorants, base materials, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents, and previously known pharmaceuticals Formulation additives that can be used in the composition may be used according to the above purpose.

[0080] diluents ​​Amegal, gum arabic, gum arabic powder, cocoa fat, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminate, calcium silicate, magnesium silicate, hard anhydrous silica, 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·sodium carmellose, crystalline cellulose (fine particles), crystalline cellulose (particles), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate·hydroxypropyl starch·crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silica, refined white sugar, Examples include refined white sugar granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered malt syrup, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated himasioil, polyoxyethylene hydrogenated himasioil 60, maltitol, D-mannitol, calcium sulfate, erythritol, glucose, fructose, etc.

[0081] Binders ​For example, one or more components selected from gum arabic, gum arabic powder, kanbaiko, gelatin, cerac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully dried), polyvinyl alcohol (partially dried), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate·methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, etc. may be incorporated.

[0082] disintegrants Examples of such starches include sodium carboxymethylstarch, carmellose, calcium carmellose, sodium croscarmellose, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylstarch, and partially gelatinized starch.

[0083] disintegration aids Examples of such substances include sodium carboxymethyl starch, carmellose, calcium carmellose, sodium croscarmellose, hard anhydrous silica, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

[0084] lubricants Examples of such substances include magnesium stearate, calcium stearate, talc, sugar fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oil, sodium stearyl fumarate, etc.

[0085] Glidants For example, one or more components selected from among hydrated silicon dioxide, hard 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, etc. may be combined.​​​​

[0086] polishing agents For example, one or more ingredients can be mixed from among carnauba wax, bleached beeswax, refined Cerac, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, beeswax, etc.

[0087] Effervescent agents For example, one or more ingredients can be mixed from among dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium bicarbonate, anhydrous citric acid, etc.

[0088] Moisture-proofing agents For example, one or more components selected from ethylcellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hard anhydrous silica, hydrogenated oil, synthetic aluminum silicate, sugar fatty acid ester, stearic acid, magnesium stearate, refined ceramic, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid, stearic acid, polyvinyl acetal diethyl amino acetate, hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethyl amino acetate, etc. may be combined.

[0089] surfactants ​​​​For example, sugar fatty acid ester, polyoxyethylene hydrogenated Himasioil 20, polyoxyethylene hydrogenated Himasioil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol beeswax, polyoxyethylene ninylphenyl 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, monooleic acid sorbitan, monostearic acid glycerin, monostearic acid One or more ingredients selected from sorbitan, monolauric acid sorbitan, sodium lauryl sulfate, etc. may be combined.

[0090] stabilizers ​For example, adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate ester, 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, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa fat, carboxyvinyl polymer, carmellose calcium, sodium carmellose, hydrated silicon dioxide, dry carbonate Sodium, Glycine, Glycerin, Glycerin fatty acid ester, Calcium gluconosate hydrate, Sodium gluconosate, Magnesium gluconosate, Potassium L-glutamate, Sodium L-glutamate, L-lysine L-glutamate, Colloidal anhydrous silica, Sodium dihydrogen crystalline phosphate, Sodium chondroitin sulfate, Zinc oxide, L-cystine, L-cysteine, Tartaric acid, Sucrose fatty acid ester, Stearic acid, Refined gelatin, Refined soybean 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 ester, Lactose, High-concentration glycerin, Povidone, Polyoxyethylene hydrogenated Himasioil 60, Polyoxyethylene stearyl ether, Polyoxyethylene Cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hardened Himasis oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol,One or more components selected from polyoxyethylene coconut oil fatty acid glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially dried), macrogol 300, macrogol 400, macrogol 4000, citric acid anhydrous, sodium citrate anhydrous, sodium monohydrogen phosphate anhydrous, sodium dihydrogen phosphate anhydrous, 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 combined.

[0091] emulsifiers Examples of such as glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethyleneglycerin fatty acid esters, polyglycerin fatty acid esters, sugar fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids can be cited.

[0092] Antioxidants Examples of such as ascorbic acid, L-ascorbic acid stearate ester, citrate hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate ester, ascorbic palmitate, and sodium metabisulfite.

[0093] fillers Examples of such materials include RSS No. 1 raw rubber, acrylic acid starch 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide, and calcium monohydrogen phosphate.​​

[0094] preservatives Examples of such substances include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dihydroacetic acid, sodium dihydroacetate, sorbic acid, and phenoxyethanol.

[0095] sweeteners For example, one or more ingredients selected from aspartame, acesulfame potassium, hydrangea leaf, hydrangea powder, reduced maltose sugar sugar, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc. may be combined.

[0096] Flavoring agents For example, one or more ingredients selected from sodium chloride, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citrate hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, purified stevia extract, swertia herb, 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, DL-sodium malate, lemon oil, rose oil, etc. may be combined.

[0097] cooling agents Examples of such oils include fennel oil, d-campfur, dl-campfur, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0098] ​​​​ flavorings For example, one or more ingredients selected from orange scent, guarana extract, sweet orange, strawberry, brown sugar scent, strawberry scent, cherry scent, banana powder scent, peach essence, fruit essence, peppermint, melon powder scent, L-menthol, peppermint oil, etc. may be combined.

[0099] fragrances Examples of eucalyptus powder, eucalyptus oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder flavoring 51357, pineapple powder flavoring 59492, peppermint water, peppermint oil, vanilla powder flavoring 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0100] Colorants For example, one or more ingredients selected from iron sulfate, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium dioxide, ferric oxide, disazo yellow, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible blue No. 2 aluminum laike, edible yellow No. 4 aluminum laike, edible red No. 2, edible red No. 3, edible red No. 102, ferric oxide-glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin lactic acid ester, riboflavin phosphate ester sodium, green tea powder, rose oil, etc. may be combined.

[0101] base materials ​​​​Gum arabic powder, gelatinized starch, ethylcellulose, cocoa fat, carnauba wax, carboxyvinyl polymer, carmellose, sodium carmellose, reduced maltose syrup, moisture, silicon dioxide, dry aluminum hydroxide gel, cantene (agar), powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, hard anhydrous silica, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium dioxide, tartaric acid, sugar fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactic acid, calcium lactic acid hydrate, lactic acid-glycolic acid copolymer, high-concentration glycerin, varatio starch (potato starch), hydroxypropylcellulose, hypromellose, fullan, One or more ingredients selected from pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially crystalline), 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, bacillus monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, etc. may be combined.

[0102] coating agents ​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, hydrogenated oil, titanium dioxide, sugar fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified ceramic, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, heavy gold leaf, precipitated calcium carbonate, high-concentration glycerin, white ceramic, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910·Titanium Oxide·Macrogol 400 Mixture, Hypromellose, Fumaric Acid·Stearic Acid·Polyvinylacetyldiethylaminoacetate·Hydroxypropylmethylcellulose 2910 Mixture, Furan, Polysorbate 80, Polyvinylacetyldiethylaminoacetate, Povidone, Polyvinyl Alcohol (Partially Cured), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Macrogol 20000, Macrogol 35000, Methacrylic Acid Copolymer L, Methacrylic Acid Copolymer LD, Methacrylic Acid Copolymer S, Methyl Acrylate·Methaacrylic Acid·Methyl Methaacrylate Copolymer, Examples include methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate·methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolauric acid, calcium sulfate, and polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer.

[0103] Sugar-coating agents ​For example, one or more components selected from gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carmellose, titanium dioxide, stearic acid, polyoxyl stearate 40, refined gelatin, refined ceramic, refined white sugar, gelatin, ceramic, talc, precipitated calcium carbonate, white ceramic, white sugar, hydroxypropyl cellulose, hypromellose, pullan, povidone, polyvinyl alcohol (partially cured), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer, etc. may be incorporated.

[0104] plasticizers For example, one or more components selected from triethyl citrate, glycerin, glycerin fatty acid ester, D-sorbitol, medium-chain fatty acid triglyceride, triacetin, high-concentration glycerin, Himasioil, polyoxyethylene hydrogenated Himasioil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, monostearic acid glycerin, linoleic acid isopropyl, liquid paraffin, etc. may be combined.

[0105] dispersants ​​Ro is Aminoalkyl Methacrylate Polymer RS, Gum Arabic, Gum Arabic Powder, Carboxyvinyl Polymer, Sodium Carboxymethyl Starch, Kanthene Powder, Citrate Hydrate, Sodium Citrate Hydrate, Glycerin, Glycerin Fatty Acid Ester, Magnesium Silicate, Hard Aluminum Oxide, Hard Anhydrous Silicate, Crystalline Cellulose, Titanium Dioxide, Sugar Fatty Acid Ester, Stearic Acid, Magnesium Stearate, D-Sorbitol, Soybean Lecithin, Low-Substituted Hydroxypropyl Cellulose, Dextrin, Corn Starch, Lactose Hydrate, High-Concentration Glycerin, Varatio Starch (Potato Starch), Hydroxyethyl Cellulose, Hydroxypropyl Starch, Hydroxypropyl Cellulose, Hypromellose, Povidone, Polyoxyethylene Cured Himasioil, Polyoxyethylene Cured Himasioil 40, Polyoxyethylene Cured Himasioil 50, Polyoxyethylene Cured One or more ingredients selected from Himasoil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, sodium anhydrous citrate, methylcellulose, glycerin monooleic acid, sorbitan monooleic acid, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitic acid, sorbitan monolauric acid, sodium lauryl sulfate, etc. may be combined.

[0106] antifoaming agents One or more ingredients selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for oral use), dimethylpolysiloxane-silicon dioxide mixture, sugar fatty acid ester, silicone defoamer, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc. may be combined.

[0107] These additives are not limited to those listed above, and it is acceptable to use only one type or to use a combination of two or more types.

[0108] ​The pharmaceutical composition of the present invention may be in the form described in the General Principles of Preparations of the 18th Revised Japanese Pharmacopoeia, etc., such as preparations administered orally (including tablets, oral disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and preparations applied in the oral cavity (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The pharmaceutical composition is preferably a solid dosage form.

[0109] Solid dosage Preferably, it is a tablet, dispersant, fine particle, granule, capsule, or pill as described in the 18th edition of the Japanese Pharmacopoeia (Pharmacopoeia), more preferably a granule or tablet, and most preferably a tablet. In addition, when performing the particle size test method for preparations in accordance with the guidelines of the 18th edition of the Japanese Pharmacopoeia for granules, if the entire amount passes through a No. 18 (850 μm) sieve and remains on a No. 30 (500 μm) sieve, 10% or less of the total amount is also referred to as fine granules.

[0110] Granules or tablets, or formulations coated with water-soluble polymers, are also permitted. That is, film-coated granules, film-coated tablets, etc. In addition, solid formulations may be coated with sugar.

[0111] In the case where the solid dosage form is a tablet, in addition to a single-layer tablet, it may also be made into a multilayer tablet by compression molding two or three or more layers of powders or granules with different ingredients. Furthermore, when making a multilayer tablet, it does not matter whether at least one type selected from the group consisting of loxoprofen, its salts, and their hydrates, and a specified herbal medicine are in the same layer or in a different layer.

[0112] The pharmaceutical composition of the present invention may be temporarily packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and stored in an airtight manner. In addition, they may be packaged in a film or placed in a box, etc.

[0113] ​In other words, a pharmaceutical product corresponding to an embodiment of the present invention may have both a pharmaceutical composition and a packaging material for packaging the pharmaceutical composition described above.

[0114] The materials that can be used for SP packaging, PTP packaging, stick packaging, and peel packaging are not particularly limited, and 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 aluminum foil attached to these resin films can be used.

[0115] For example, the packaging material for the pharmaceutical composition of the present invention is preferably a packaging made of a material that is resistant to moisture (a packaging composed of at least one of a moisture barrier material and a gas barrier material).

[0116] For example, a packaging material with low moisture influence (moisture barrier) such as PTP (polypropylene) + polyethylene aluminum pillow packaging (packaging combining PTP and polyethylene aluminum pillow) may also be used. Additionally, considering the suppression of moisture content increase in the pharmaceutical composition, preservation stability, and stability of the pharmaceutical composition after opening, it is acceptable to apply PTP packaging with aluminum on both sides (Al-Al packaging) as a packaging material resistant to moisture influence (moisture barrier). Furthermore, if hygroscopicity is a concern, a desiccant, etc., may be stored simultaneously inside the bottle packaging or inside the pillow packaging.

[0117] As for the gas barrier material, known materials may be used, and although not specifically limited, laminate films having a functional barrier layer, for example, may also be used. It may serve the role of the moisture barrier material mentioned above, or be used in combination with the moisture barrier material mentioned above.

[0118] In addition, the packaging material for the pharmaceutical composition of the present invention may use environmentally conscious materials such as recycled plastic, biomass plastic, and biodegradable plastic in part or all of the packaging material as needed, and may use environmentally conscious containers and packaging, and is not particularly limited.

[0119] <Regarding External Preparations>

[0120] The case where the pharmaceutical composition of the present invention is an external preparation is described as follows.

[0121] The pharmaceutical composition of the present invention may include drugs or pharmaceutical additives commonly used in topical skin preparations for pain relief and anti-inflammatory purposes.

[0122] The external formulation of the present invention may contain one or more selected from the group consisting of the following components (A-1) to (A-11).

[0123] (A-1) Tocopherols

[0124] (A-2) Terpenes

[0125] (A-3) Glycyrrhizates

[0126] (A-4) Crude drugs

[0127] (A-5) Tranexamic acid derivatives

[0128] (A-6) Vanilloids

[0129] (A-7) Nicotinic acid derivatives

[0130] (A-8) Chlorpheniramine derivatives

[0131] (A-9) Diphenhydramine derivatives

[0132] (A-10) Pyrrolidones

[0133] (A-11) Inorganic salts

[0134] (A-1) Tocopherols Examples include tocopherols, tocotrienols, and their derivatives (e.g., esterified derivatives such as acetic acid esters, succinic acid esters, and nicotinic acid esters) and their corresponding salts (e.g., alkaline earth metal salts such as calcium salts and magnesium salts). The tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, or δ-tocopherol, but α-tocopherol is preferred. Additionally, the tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol, but α-tocotrienol is preferred. Among the tocopherols, tocopherol acetate esters are particularly preferred.

[0135] (A-2) TerpenesIt refers to a general term (terpenoid) that includes, in addition to terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and its structure is not particularly limited and includes monoterpenes, sesquiterpenes, or derivatives thereof. In addition, it does not matter whether it is cyclic or chain-like. Terpenes include, for example, isoborneol, iron, ocimene, carveol, carvotanacetone, carvomenthone, carvone, carene, carone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, sylvestrene, thymol, isothujol, thujone, terpineol, and terpinene. There are terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, limonene, etc.

[0136] For terpenes, essential oils containing terpenes may be used. Essential oils include, for example, anise oil, ylang-ylang oil, orris oil, fennel oil, orange oil, cananga oil, chamomile oil, cajeput 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, gingergrass oil, spearmint oil, peppermint oil, Geranium oil, aniseed oil, clove oil, turpentine oil, spruce oil, neroli oil, basil oil, mint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, bonne wood oil, marjoram oil, mandarin oil, melissa oil, eucalyptus oil, lime oil,Examples include lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil; these may be used individually or in combination of two or more.

[0137] (A-3) Glycyrrhizates Examples 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. Additionally, as glycyrrhizic acid derivatives, licorice containing glycyrrhizic acid or its extract may be used.

[0138] (A-4) Crude drugsFor example, Glycyrrhiza, Arnica tincture, Mallotus japonicus, Gambir, Epimedium, Fennel, Turmeric, Corydalis tuber, Scutellaria root, Solomon's seal, Phellodendron bark, Cortex phellodendri, Coptis rhizome, Polygala root, Zedoary, Valerian root, Chamomile, Karonin, Platycodon root, Apricot kernel, Goji berry, Goji leaf, Schizonepeta spike, Cinnamon bark, Cassia seed, Gentian, Cranesbill herb, Safflower, Cyperus rhizome, Bezoar, Schisandra fruit, Asarum, Gardenia fruit, Japanese pepper, Aster root, Lycium root bark, Lithospermum root, Peony root, Musk, Adenophora root, Plantago seed, Plantago herb, Animal bile (including bear bile), Ginger, Earthworm, Magnolia flower bud, Horse chestnut, Sweet flag, Senega root, Cnidium rhizome, Peucedanum root,There are medicinal herbs such as swertia herb, atractylodes rhizome, mulberry root bark, perilla leaf, taisan, panax japonicus, citrus unshiu peel, angelica root, rhatany root, nandina fruit, ginseng, fritillaria bulb, ophiopogon tuber, pinellia tuber, safflower, softshell turtle shell, angelica dahurica root, atractylodes macrocephala rhizome, poria, moutan bark, bayberry bark, and deer antler, as well as their extracts (extract, tincture, dried extract, etc.). In addition, licorice may be used as a glycyrrhizic acid derivative or as a medicinal herb, and it may be utilized to perform both roles simultaneously.

[0139] (A-5) Tranexamic acid derivatives It may contain, for example, tranexamic acid or its salt, tranexamic acid derivative or its salt.

[0140] There are no specific restrictions on the salts of tranexamic acid, but specifically, 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. Additionally, tranexamic acid derivatives or their salts may be used, and specifically, ester derivatives such as tranexamic acid cetyl ester; and amide derivatives such as tranexamic acid methylamide may be examples.

[0141] (A-6) Vanilloids Vanilloids are a general term for compounds containing a vanillyl group, and the vanilloids covered in this invention are not limited to compounds containing a vanillyl group. Examples include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), vanillylbutyl ether (4-butoxymethyl-2-methoxyphenol), etc.

[0142] In addition, the vanilloids covered in the present invention may include natural products containing compounds containing vanillyl groups, derivatives of compounds having vanillyl groups, or synthetic compounds having functional groups added to vanillyl groups.

[0143] In addition, the vanilloids used in the present invention may include chili peppers containing a compound containing a vanillyl group, and may also be included as part of the vanilloids.

[0144] For chili peppers, for example, the chili pepper listed in the 18th revised edition of the Japanese Pharmacopoeia (fruit of Capsicum annuum Linne (Solanaceae)) may be appropriately utilized. The form of the chili pepper may be adjusted as needed, and it may be cut into small pieces or chunks, crushed, or ground into powder. For example, "chili powder" made by grinding chili peppers into powder may also be used as the "chili pepper" of the present invention. Additionally, a chili pepper that has undergone some extraction treatment (chili pepper extract, chili pepper extract liquid, etc.) may be used. Furthermore, the chili pepper extract may be one that has undergone processing treatments such as heating, drying, or grinding in addition to the extraction process. Additionally, capsaicinoids, which are the main components of chili peppers, may be used. Capsaicin and nonyl acid vanillylamide are preferred as capsaicinoids. For chili peppers, chili pepper extract, chili pepper extract liquid, nonyl acid vanillylamide, or capsaicin may be used.

[0145] (A-7) Nicotinic acid derivatives Nicotinic acid, its derivatives, and their salts are included. 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.), nicotinic acid amide, nicotinic acid amide adenine dinucleotide, nicotinic acid amide adenine dinucleotide phosphate, etc. Among nicotinic acid esters, nicotinic acid monoesters are preferred. Among nicotinic acids, nicotinic acid benzyl esters are preferred.

[0146] (A-8) Chlorpheniramine derivatives It includes chlorpheniramines and their salts. Specifically, salts of chlorpheniramine include organic salts such as maleates and fumarates; inorganic salts such as hydrochlorides and sulfates; and various other salts such as metal salts. Among chlorpheniramines, chlorpheniramine maleate is preferred.

[0147] (A-9) Diphenhydramine derivativesExamples include diphenhydramine or its salts. Salts of diphenhydramine include acidic additive salts such as hydrochloride, citrate, kohakuate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. Among diphenhydramines, diphenhydramine or diphenhydramine hydrochloride is preferred.

[0148] (A-10) Pyrrolidones The dl-pyrrolidone carbosan or its salt is used, and, for example, sodium pyrrolidone carbosan is preferred.

[0149] (A-11) Inorganic salts Salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium, or ammonium salts are available, and for example, sodium chloride, potassium chloride, and ammonium chloride are preferred.

[0150] In addition to the above ingredients, pharmaceutical additives may be added as needed, for example, to improve content stability over time or further enhance the feel of use, and examples include wetting agents, humectants, viscosity modifiers, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, emollients, preservatives, percutaneous absorption enhancers, stabilizers, solubilizing agents, pH adjusters, antioxidants, cooling agents, surfactants, and emulsifiers. Furthermore, the topical skin preparation of the present invention may include any other ingredients.

[0151] Wetting agentsFor example, hyaluronic acid, dl-pyrrolidone carboate sodium or its salt (e.g., dl-pyrrolidone carboate sodium) can be used.

[0152] Humectants Polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol can be used.

[0153] Viscosity modifiers For example, hypromellose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (sodium carmellose), methylcellulose, carrageenan, locust bean gum, propylene glycol alginate, etc. may be used.

[0154] AdhesivesAs such, for example, acrylic acid-octyl acrylate ester copolymer, acrylic acid ester-vinyl acetate copolymer, acrylic acid 2-ethylhexyl-vinylpyrrolidone copolymer solution, acrylic acid 2-ethylhexyl-methacrylate 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, methacrylate-acrylate n-butyl copolymer, acrylic acid silk fibroin copolymer resin, acrylic acid starch 300, acrylic acid starch 1000, acrylic acid butyl acrylate-2-ethylhexyl methacrylate-diacetone acrylamide copolymer, acrylic acid butyl acrylate-2-hydroxyethyl methacrylate-diacetone acrylamide Copolymer, butyl acrylate·ethyl acrylate·2-hydroxyethyl methacrylate·diacetone acrylamide copolymer, butyl acrylate·2-ethylhexyl acrylate·2-hydroxyethyl methacrylate·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, butyl acrylate·ethyl acrylate·3-hydroxypropyl methacrylate·diacetone acrylamide copolymer, acrylic adhesive such as butyl acrylate·ethyl acrylate·3-hydroxypropyl methacrylate·diacetone acrylamide copolymer; Synthetic rubber-based 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, SBR synthetic latex, etc.;In addition to silicone-based adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane, polyacrylic acid, sodium polyacrylate, polyacrylic acid partial neutralization, N-vinylacetoamide·sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, guar gum, tragant gum, gum arabic, etc., the above may be used, in addition to those cross-linked with metal salts such as aluminum, zinc, magnesium, and calcium.

[0155] Tackifying resins For example, rosin, hydrogenated rosin glycerol ester, ester gum, maleic acid resin, maleated rosin glycerol ester, terpene resin, petroleum resin, aliphatic cyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, etc. can be used.

[0156] crosslinking agents For example, dried aluminum hydroxide gel, magnesium aluminum hydroxide, magnesium aluminum silicate, magnesium aluminum metasilicate, synthetic hydrotalcite, dihydroxy aluminum aminoacetate, etc. can be used.

[0157] fillers For example, alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, silica (silicon dioxide), etc. can be used.

[0158] oils and fatsFor example, hydrocarbons such as squalane, paraffin, liquid paraffin, hard liquid paraffin, wax, and gelled hydrocarbons; fatty acid esters such as isopropyl myristate and octyldecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyl decanol, isostearyl alcohol, and octyl decanol; 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, bleached beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oil may be used.

[0159] emollients Examples include petroleum oils such as paraffinic process oils, naphthenic process oils, and aromatic process oils; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, himasi oil, tall oil, and lac casei oil; silicone oils; 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 lauricate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; salicylic acid glycol; propylene glycol; dipropylene glycol; triacetin; Propyl citric acid, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, benzetium chloride, aminoethylsulfonic acid, etc. may be used.

[0160] percutaneous absorption enhancersFor example, alcohols, fatty acids, fatty acid esters such as diisopropyl adipic acid, fatty acid ethers, lactic acid esters, acetic acid esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbide, azons or their derivatives may be used.

[0161] stabilizers For example, oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, UV absorbers (e.g., dibenzoylmethane derivatives) can be used.

[0162] solubilizing agents For example, 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, diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; and oxyalkylene fatty acid esters such as polyethylene glycol monostearate may be used.

[0163] pH adjusters For example, 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.), phosphoric acid, etc. can be used.

[0164] AntioxidantsVarious substances can be used, such as ascorbic acid, ascorbic palmitate, sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, sodium edetate, citrate hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutyl hydroxytoluene, butyl hydroxyanisole, butyl hydroxyanisole, soybean lecithin, pentaerythritol tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate, etc.

[0165] cooling agents Examples of such oils include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

[0166] surfactants For the use of non-ionic surfactants, it is acceptable to use ionic surfactants.

[0167] Nonionic surfactantsFor example, polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methylglucoside fatty acid ester, alkyl polyglucoside, polyethylene glycol fatty acid ester, etc.; polyoxyethylene ethers such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytosterol, polyoxyethylene polyoxypropylene alkyl ester, etc.; There are nonionic surfactants such as polyoxyethylene mono fatty acid esters, polyethylene glycol di fatty acid esters, polyoxyethylene glycerin fatty acid esters, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methylglucoside fatty acid esters, polyoxyethylene hydrogenated Himasioil 20, polyoxyethylene hydrogenated Himasioil 40, polyoxyethylene hydrogenated Himasioil 50, polyoxyethylene hydrogenated Himasioil 60, polyoxyethylene hydrogenated Himasioil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid esters, polyoxyethylene polyoxypropylene glycol, etc. ether esters; ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; and higher alcohols such as octyl decanol. Examples of polyoxyethylene alkyl ethers covered in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether, etc.

[0168] Examples of polyoxyethylene polyoxypropylene alkyl ethers include polyoxyethylene polyoxypropylene cetyl ether.

[0169] Examples of polyoxyethylene polyoxypropylene alkyl ethers covered in the present invention include polyethylene glycol monolauric acid, polyethylene glycol monostearic acid, and polyethylene glycol monooleic acid.

[0170] Nonionic surfactants It is listed in the 2021 Dictionary of Pharmaceutical Additives.

[0171] ionic surfactants Examples include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, and dioctyl sodium sulfosuccinate, and cationic surfactants such as benzalkonium chloride and benzethonium chloride.

[0172] The ionic surfactant used in the present invention is listed in the 18th edition of the Japanese Pharmacopoeia No. 18, 2021.

[0173] The emulsifier used in the present invention may freely use, for example, the various surfactants or higher alcohols described above.

[0174] External preparations Specific formulations include, for example, external liquids, ointments, creams, sprays (external aerosols, pump sprays), gels, adhesives (tapes, patches), or external solids, and can be manufactured according to general methods specified in the 18th Revised Japanese Pharmacopoeia, etc. by appropriately using additives or bases suitable for each formulation. External liquids are particularly preferred as formulations for external use.

[0175] In addition, the topical formulation may be sealed in, for example, glass containers / packaging, metal containers / packaging such as aluminum, or olefin resin containers / packaging such as polyethylene / polypropylene, and may also be placed in moisture-proof bags containing metal such as aluminum. Furthermore, for the containers / packaging, containers containing environmentally conscious raw materials such as recycled plastic or biomass raw materials may be used. In an embodiment of the present invention in which, if necessary, materials with a laminate structure, gas barrier materials, or any other materials that prevent the deterioration of the topical skin formulation due to external factors, elements, or environmental changes in the pharmaceutical container / packaging, such as heat or light generated in high-temperature environments, and ensure the quality of the topical skin formulation is properly maintained, may be used, the formulation / composition of the topical skin formulation can be utilized as a pharmaceutical product in which it is contained in a suitable container / packaging.

[0176] <Regarding Usage>

[0177] The pharmaceutical composition of the present invention can be used for the purpose of appropriately suppressing fever, pain, and inflammation. The pharmaceutical composition of the present invention is preferably for anti-inflammatory purposes.

[0178] According to the pharmaceutical composition of the present invention, the amount of PGE2 produced in cells can be reduced. That is, the pharmaceutical composition of the present invention can be used as a PGE2 production reducing agent.

[0179] According to the pharmaceutical composition of the present invention, intracellular COX-2 expression can be reduced. That is, the pharmaceutical composition of the present invention can be used as a COX-2 expression reducing agent.

[0180] According to the present invention, a method for suppressing inflammation is provided, comprising administering to a subject 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.

[0181] According to the present invention, a method for reducing PGE2 production is provided, comprising administering to a subject 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.

[0182] According to the present invention, a method for reducing COX-2 expression is provided, comprising administering to a subject 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.

[0183] According to the present invention, a pharmaceutical composition for treating inflammation is provided, 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.

[0184] According to the present invention, a pharmaceutical composition for use in a treatment to reduce PGE2 production is provided, 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.

[0185] According to the present invention, a pharmaceutical composition for use in a treatment to reduce COX-2 expression is provided, 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.

[0186] According to the present invention, for the manufacture of anti-inflammatory agents, at least one type selected from the group consisting of loxoprofen, its salts and their hydrates, and at least one type selected from the group consisting of diclofenac, naproxen, their salts and their hydrates are provided.

[0187] According to the present invention, for the manufacture of a PGE2 production reducing agent, at least one type selected from the group consisting of loxoprofen, its salts and their hydrates, and at least one type selected from the group consisting of diclofenac, naproxen, their salts and their hydrates are provided.

[0188] According to the present invention, for the manufacture of a COX-2 expression reducing agent, at least one type selected from the group consisting of loxoprofen, its salts and their hydrates, and at least one type selected from the group consisting of diclofenac, naproxen and its salts and hydrates are provided.

[0189] At least one selected from the group consisting of loxoprofen, its salts, and their hydrates as active ingredients, and at least one selected from the group consisting of diclofenac, naproxen, their salts, and their hydrates, have antipyretic, analgesic, anti-inflammatory, and anti-inflammatory effects. Accordingly, the pharmaceutical composition of the present invention is suitable for use as an antipyretic and analgesic agent, particularly for pain relief in headaches, menstrual pain (dysmenorrhea), toothaches, post-extraction pain, sore throat, back pain, joint pain, muscle pain, stiff shoulders, ear pain, bruises, fracture pain, sprain pain, traumatic pain, and for antipyretic relief during chills and fever. Additionally, it can be effectively used as a cold treatment agent for the purpose of alleviating various symptoms of the common cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain). The present invention will be explained more specifically below with reference to examples, but the present invention is not limited by these examples.

[0190] <Test Materials>

[0191] (1) Test substance

[0192] loxoprofen sodium hydrate (LOX)

[0193] Loxoprofen sodium hydrate (LOX) was obtained from Fujifilm Wako Junyak Co., Ltd.

[0194] A 100 mM solution was prepared by dissolving in a proliferation medium (DMEM with 10% FBS and 1% Penicillin-Streptomycin mixed solution). Using the proliferation medium, 1 / 100 dilution was repeated to prepare a 0.0001 mM solution, and then 1 / 10 dilution was performed again to prepare a 0.00001 mM solution. A LOX-added test medium was prepared by adding a 1 / 1,000-fold amount to a proliferation medium with 0.1% DMSO, and a LOX-added proliferation medium was prepared by adding a 1 / 1,000-fold amount to the proliferation medium for the preparation of a LOX+ combination drug test medium.

[0195] ibuprofen

[0196] Ibuprofen was obtained from Fujifilm Wako Junyak Co., Ltd.

[0197] A 100 mM solution was prepared by dissolving in DMSO (Nacalai Tesque product). A series of dilutions down to 0.1 mM was prepared using DMSO through 3-fold serial dilution. A test medium with concomitant drugs was prepared by adding 1 / 1,000th of the amount to the growth medium, and a test medium with LOX+ concomitant drugs was prepared by adding 1 / 1,000th of the amount to the LOX-added growth medium.

[0198] Indomethacin

[0199] Indomethacin was obtained from Fujifilm Wako Junyak Co., Ltd.

[0200] A 100 mM solution was prepared by dissolving in DMSO. A 0.0001 mM solution was prepared by repeatedly diluting by 1 / 100 using DMSO, and then a 0.00001 mL solution was prepared by diluting by 1 / 10 again. A test medium for the combination drug was prepared by adding a 1 / 1,000-fold amount to the growth medium, and a test medium for the LOX+ combination drug was prepared by adding a 1 / 1,000-fold amount to the LOX-added growth medium.

[0201] diclofenac sodium

[0202] Diclofenac Na was obtained from Fujifilm Wako Pure Pharmaceutical Co., Ltd.

[0203] A 100 mM solution was prepared by dissolving in DMSO. A 0.0001 mM solution was prepared by repeatedly diluting by 1 / 100 using DMSO, and then a 0.00001 mL solution was prepared by diluting by 1 / 10 again. A test medium for the combination drug was prepared by adding a 1 / 1,000-fold amount to the growth medium, and a test medium for the LOX+ combination drug was prepared by adding a 1 / 1,000-fold amount to the LOX-added growth medium.

[0204] Felbinac

[0205] Felbinac was obtained from Fujifilm Wako Pure Pharmaceutical Co., Ltd.

[0206] A 100 mM solution was prepared by dissolving in DMSO. A 0.1 mM solution was prepared by repeating 1 / 10 dilution using DMSO. A test medium with combined drugs was prepared by adding a 1 / 1,000-fold amount to the proliferation medium, and a test medium with LOX+ combined drugs was prepared by adding a 1 / 1,000-fold amount to the LOX-added proliferation medium.

[0207] aspirin

[0208] Aspirin was obtained from Fujifilm Wako Junyak Co., Ltd.

[0209] A 100 mM solution was prepared by dissolving in DMSO. A 0.1 mM solution was prepared by repeating 1 / 10 dilution using DMSO. A test medium with combined drugs was prepared by adding a 1 / 1,000-fold amount to the proliferation medium, and a test medium with LOX+ combined drugs was prepared by adding a 1 / 1,000-fold amount to the LOX-added proliferation medium.

[0210] Meloxicam

[0211] Meloxicam was obtained from Fujifilm Wako Junyak Co., Ltd.

[0212] A 100 mM solution was prepared by dissolving in DMSO. A 0.0001 mM solution was prepared by repeatedly diluting by 1 / 100 using DMSO, and then a 0.00001 mL solution was prepared by diluting by 1 / 10 again. A test medium for the combination drug was prepared by adding a 1 / 1,000-fold amount to the growth medium, and a test medium for the LOX+ combination drug was prepared by adding a 1 / 1,000-fold amount to the LOX-added growth medium.

[0213] Celecoxib

[0214] Celecoxib was obtained from Tokyo Chemical Industry Co., Ltd.

[0215] A 100 mM solution was prepared by dissolving in DMSO. A 0.0001 mM solution was prepared by repeatedly diluting by 1 / 100 using DMSO, and then a 0.00001 mL solution was prepared by diluting by 1 / 10 again. A test medium for the combination drug was prepared by adding a 1 / 1,000-fold amount to the growth medium, and a test medium for the LOX+ combination drug was prepared by adding a 1 / 1,000-fold amount to the LOX-added growth medium.

[0216] Naproxen

[0217] Naproxen was obtained from Fujifilm Wako Pure Pharmaceutical Co., Ltd.

[0218] A 100 mM solution was prepared by dissolving in DMSO. A 0.0001 mM solution was prepared by repeatedly diluting by 1 / 100 using DMSO, and then a 0.00001 mM solution was prepared by diluting by 1 / 10 again. A test medium for the combined drug was prepared by adding a 1 / 1,000-fold amount to the growth medium, and a test medium for the LOX+ combined drug was prepared by adding a 1 / 1,000-fold amount to the LOX-added growth medium.

[0219] Dexamethasone (positive control)

[0220] Dexamethasone was obtained from Sigma-Aldrich.

[0221] 5 mM was prepared by dissolving in DMSO.

[0222] Cell line

[0223] RAW264.7 cells were obtained from ATCC. DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution was used as the medium.

[0224] <lps>

[0225] LPS from E. coli. O55:B5 was obtained from Sigma-Aldrich.

[0226] It was dissolved in DPBS and adjusted to 5 mg / mL.

[0227] [Test Example 1]

[0228] <PGE2방출량 ELISA 측정 군 구성>

[0229] · No chemical additives - LPS untreated

[0230] · No medication added - LPS treatment

[0231] · Addition of LOX+ concomitant medication (treatment concentrations are as follows) - LPS treatment

[0232] 1) LOX: 0.00001μM (All LOX concentrations below are the same)

[0233] 2) LOX + Ibuprofen: 0.1μM

[0234] 3) Ibuprofen: 0.1μM

[0235] 4) LOX + Indomethacin 0.00001μM

[0236] 5) Indomethacin 0.00001μM

[0237] 6) LOX + Diclofenac Na 0.00001μM

[0238] 7) Diclofenac Na 0.00001μM

[0239] 8) LOX + Felbinac: 0.1μM

[0240] 9) Felbinac: 0.1μM

[0241] 10) LOX + Aspirin: 0.1μM

[0242] 11) Aspirin: 0.1μM

[0243] 12) LOX + Meloxicam: 0.00001μM

[0244] 13) Meloxicam: 0.00001μM

[0245] 14) LOX + Celecoxib 0.00001μM

[0246] 15) Celecoxib 0.00001μM

[0247] 16) LOX + Naproxen 0.00001μM

[0248] 17) Naproxen 0.00001μM

[0249] 1μM Dexamethasone-LPS Treatment

[0250] Ibuprofen: 0.1, 0.3, 1, 3, 10, 30, 100μM (IC50 calculation)

[0251] n was set to 3, and test media were prepared so that the DMSO concentration of each group was 0.1%.

[0252] Test Method

[0253] Reagent, equipment name manufacturing company Cat. No. DMEM Nacalai Tesque 08456-65 Penicillin-Streptomycin Mixed Solution Nacalai Tesque 09367-34 Fetal Bovine Serum (FBS) Thermo Fisher Scientific 10437028 DPBS without calcium, magnesium (DPBS) Thermo Fisher Scientific 14190250 Prostaglandin E2 Parameter Assay Kit R&D Systems KGE004B Cell-attached filter cap flask SUMILON MS-21250 Plate 96F for adherent cells SUMILON MS-8096F

[0254] Device name Format, etc. manufacturing company Independent culture microscope CKX53 Olympus safety cabinet 1300 SERIES A2 Thermo Fisher Scientific CO2 incubator SCA-165DRS Aztec 4℃ Showcase MPR-514-PJ Panasonic -30℃ freezer MDF-539-PJ Panasonic -80℃ freezer NIHON FREEZER CLN-50CD1 Microplate Reader VARIOSKAN Flash Thermo Fisher Scientific

[0255] (1) Cell culture

[0256] Cells were cultured in a CO2 incubator (5% CO2, 37°C, humidified, same applies hereinafter) using medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) until the required number of cells was reached. For cell passage, cells were separated from the flask using a scraper, then recovered, and resuspended in the medium to be used as a cell suspension.

[0257] (2) LPS, test substance, concomitant drug treatment

[0258] Cells were cultured in a CO2 incubator using medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution). When the cells reached 60 to 80% confluence, they were detached from the flask using a scraper, recovered, and resuspended in the medium to reach 3.0 x 10⁶ cells. 4 Cells were seeded into a 96-well plate at 0.1 mL / well and cultured overnight in a CO₂ incubator.

[0259] Then, the medium was replaced with 0.1 mL of the LPS non-treatment group or LPS treatment group·LOX / concomitant drug / LOX+concomitant drug / positive control test medium listed in the group composition column, or the LPS treatment group·drug-free test medium, and cultured in a CO₂ incubator for 24 hours.

[0260] After the treatment was completed, the culture supernatant was recovered and stored at -80℃ until the time of measurement.

[0261] (3) ELISA measurement

[0262] The culture supernatant was dissolved and diluted to 1 / 5, and the amount of PGE2 in the culture supernatant was measured using the ELISA method. The absorbance was measured using a VARIOSKAN FLASH plate reader, and the amount of PGE2 was calculated by constructing a calibration curve.

[0263] (4) Statistical analysis

[0264] The difference between the drug-free LPS treatment group and the Dex-added LPS treatment group was examined using Student's t-test.

[0265] The drug-free LPS treatment group, LOX-added LPS treatment group, concomitant drug-added LPS treatment group, and LOX+concomitant drug-added LPS treatment group were evaluated using the Tukey-Kramer method.

[0266] As a result of conducting a two-sided test, P < 0.05 was found to be a significant difference.

[0267] The statistical analysis software 'Excel Statistics' was used for each statistical significance test.

[0268] The IC50 value was calculated by constructing a capacity response curve using XLfit software (version 5.5.0.5, ID Business Solutions, Ltd.) and a four-parameter logistic model (y=(A+((BA) / (1+((C / x)^D)))), model No. 205 in XLfit).

[0269] <Result>

[0270] To confirm the reproducibility of the test, the PGE2 measurement results upon the addition of ibuprofen are presented in Fig. 1, and the IC50 value calculation results using the dose-response curve are presented in Fig. 2.

[0271] In the positive control, the amount of PGE2 induced by LPS was significantly reduced due to dexamethasone treatment, and the validity of the test was proven as the IC50 value of the anti-inflammatory action of ibuprofen in this test was 0.91 μM.

[0272] The results of PGE2 measurements in the drug combination effect review test with LOX are shown in Figures 3 to 10.

[0273] In the treatment with 0.00001μM LOX alone, no significant decrease in PGE2 production was observed, and no anti-inflammatory effect was observed.

[0274] For indomethacin and felbinac, no significant decrease in PGE2 production was observed at the treatment concentrations in this study when treated alone, and there was no change in PGE2 production when used in combination with LOX.

[0275] For ibuprofen, aspirin, meloxicam, and celecoxib, it was confirmed that PGE2 production was significantly reduced with single treatments at the concentrations tested in this study. Meanwhile, when combined with LOX, a decrease in PGE2 production was observed compared to LOX alone; however, no significant decrease was confirmed when compared to the combined drug alone.

[0276] Regarding naproxen, no significant decrease in PGE2 production was observed with single treatment at the concentrations tested in this study. On the other hand, when used in combination with LOX, a decrease in PGE2 was observed compared to treatment with LOX alone. Although there was no significant difference when compared to treatment with the combination drug alone, a decrease in PGE2 production was confirmed.

[0277] Regarding diclofenac Na, no significant decrease in PGE2 production was observed with single treatment at the concentrations used in this study. However, when combined with LOX, a significant decrease in PGE2 production was confirmed in both cases compared to LOX alone and diclofenac Na alone. This demonstrates that the anti-inflammatory effect of diclofenac Na is enhanced when combined with LOX.

[0278] As a result of the test, the IC50 value of ibuprofen was confirmed in this test.

[0279] It was confirmed that the anti-inflammatory effect of diclofenac Na was enhanced by co-administration with LOX. It was also confirmed that the anti-inflammatory effect of naproxen was enhanced by co-administration with LOX.

[0280] [Test Example 2]

[0281] <COX-2 단백질 발현 측정 군 구성>

[0282] · No test substance added - LPS untreated

[0283] · No test substance added - LPS treatment

[0284] · Addition of concomitant medication (treatment concentrations are as follows) - LPS treatment

[0285] army LOX concomitant medications １ 0.00001μM － ２ － 0.00001μM diclofenac Na ３ 0.00001μM naproxen ４ 0.00001μM 0.00001μM diclofenac Na ５ 0.00001μM 0.00001μM naproxen

[0286] 1μM Dexamethasone-LPS Treatment

[0287] n=3

[0288] Test media were prepared so that the DMSO concentration of each group was 0.1%.

[0289] Test Method

[0290] Primary antibody manufacturing company Cat. No. Lot No. Secondary antibody Cox2 (D5H5) XP Rabbit MAb Cell Signalimg Technology 12282 6 Anti-Rabbit Detection Module for Jess

[0292] Reagent, equipment name manufacturing company Cat. No. DMEM Nacalai Tesque 08456-65 Penicillin-Streptomycin mixed solution Nacalai Tesque 09367-34 Fetal Bovine Serum (FBS) Thermo Fisher Scientific 10437028 DPBS without calcium, magnesium (DPBS) Thermo Fisher Scientific 14190250 DMSO Nacalai Tesque 13408-64 RIPA buffer (x1) Nacalai Tesque 16488-34 Protease and Phosphatase inhibitor Cocktail (100x) Thermo Fisher Scientific 78442 Anti-Rabbit Detection Module for Jess Protein Simple DM-001 Protein Normalization Module for Jess Protein Simple DMM-TP02 12-230 kDa Jess Separation Module, 8 x 25 capillary cartridges Protein Simple SM-W004 24F Plate for Adherent Cells SUMILON MS-80240 Ring lock tube 1.5mL BM Bio NT-175S

[0293] Device name Format, etc. manufacturing company Independent culture microscope CKX53 Olympus safety cabinet 1300 SERIES A2 Thermo Fisher Scientific CO₂ incubator SCA-165DRS Aztec 4℃ Showcase MPR-514-PJ Panasonic -30℃ freezer MDF-539-PJ Panasonic -80℃ freezer NIHON FREEZER CLN-50CD1 Microplate Reader VARIOSKAN Flash Thermo Fisher Scientific Ultrasonic grinder TOMY UR-21P Simple Western System Protein Simple Jess System

[0294] (1) Cell culture

[0295] Cells were cultured in a CO₂ incubator (5% CO₂, 37°C, humidified, same applies hereinafter) using medium (DMEM supplemented with 10% FBS and 1% Penicillin-Streptomycin mixed solution) until the required number of cells was reached. For cell passage, cells were separated from the flask using a scraper, then recovered, and resuspended in the medium to be used as a cell suspension.

[0296] (2) LPS, treatment of test substances

[0297] Cells were cultured in a CO₂ incubator using medium (DMEM supplemented with 10% FBS and 1% penicillin-streptomycin mixed solution). When the cells reached 60 to 80% confluence, they were detached from the flask using a scraper; after retrieving the cells, they were resuspended in the medium to reach 1.8 x 10⁶ 5 Cells were seeded into a 24-well plate at 0.6 mL / well and cultured overnight in a CO₂ incubator.

[0298] Then, the medium was replaced with 0.6 mL of the LPS non-treatment group or LPS treatment group·LOX / combination drug alone / LOX+combination drug / subject alone / positive control added test medium or LPS treatment group·subject not added test medium as listed in the group composition column, and cultured in a CO₂ incubator for 24 hours.

[0299] After incubation, the culture plates were transferred to ice, washed twice with cold DPBS, and RIPA buffer solution containing 1% protease / phosphatase inhibitor was added. Cells were harvested and incubated on ice for 30 minutes with occasional stirring. The cells were completely lysed using a sonicator to produce a cell lysate. The cell lysate was stored at -80°C until the time of measurement.

[0300] (3) Western blot

[0301] Protein content in cell lysates was quantified using the Micro BCA Protein Assay kit (Thermo Fisher Scientific, 23235) according to the enclosed manual. Western blot was performed using Simple Western Jess according to the manual. The cell lysate concentration was 0.3 mg / mL, and electrophoresis was performed using a 12-230 kDa Jess separation module with Protein Normalization reagents. Regarding antibody dilution ratios, the primary antibody was diluted 1 / 50, while the secondary antibody was used undiluted. 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 exposure conditions using Compass for SW software, and then calculated by correcting the Area Under the Curve (AUC) of the emission peak region.

[0302] (4) Statistical analysis

[0303] The difference between the group treated with no added substance-LPS and the group treated with Dex added-LPS was examined using Student's t-test.

[0304] Combined drug addition experiment: The group without drug addition-LPS, the group with LOX addition-LPS, the group with concomitant drug addition-LPS, and the group with LOX + concomitant drug addition-LPS were evaluated using the Tukey-Kramer method.

[0305] Test substance addition experiment: The group without test substance addition and the group with test substance addition and LPS were evaluated using Dunnett's test.

[0306] As a result of conducting a two-sided test, P < 0.05 was found to be a significant difference.

[0307] The statistical analysis software 'Excel Statistics' was used for each statistical significance test.

[0308] <Result>

[0309] The results of comparing COX-2 expression levels using Western blot are presented in Figure 11.

[0310] LOX: 0.00001μM Loxoprofen sodium hydrate

[0311] Dic: 0.00001μM diclofenac Na

[0312] LOX+Dic: 0.00001μM LOX+0.00001μM Diclofenac Na

[0313] Nap: 0.00001μM Naproxen

[0314] LOX+Nap: 0.00001μM LOX+0.00001μMμ Naproxen

[0315] Dex: 1μM dexamethasone

[0316] When comparing the LPS-untreated group with the LPS-treated group, a clear increase in COX-2 expression levels was confirmed in the LPS-treated group. In addition, the COX-2 expression levels in the positive control group with 1 μM dexamethasone added were significantly reduced compared to the LPS-treated group, proving the validity of the test system.

[0317] In the review of the effects of drug combination therapy, no significant decrease in COX-2 expression levels was observed when only 0.00001μM LOX, 0.00001μM diclofenac Na, and 0.00001μM naproxen were used. When 0.00001μM LOX + 0.00001μM diclofenac Na and 0.00001μM LOX + 0.00001μM naproxen were used together, COX-2 expression levels tended to decrease compared to 0.00001μM LOX alone.

[0318] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Addition, omission, replacement, and other modifications to the components are possible within the scope of the present invention without departing from its spirit.

[0319] Industrial applicability

[0320] The pharmaceutical composition of the present invention is suitable for use as an antipyretic and analgesic, particularly for relieving pain such as headache, menstrual pain, toothache, pain after tooth extraction, sore throat, back pain, joint pain, muscle pain, stiff shoulder, ear pain, bruise, fracture pain, pain caused by sprain, and traumatic pain, and for reducing fever during chills and fever. It is also effectively utilized as a cold medicine to relieve various symptoms of the common cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0321] In addition, the pharmaceutical composition of the present invention is used as an external anti-inflammatory and analgesic agent, particularly for relieving pain such as back pain, joint pain, muscle pain, stiff shoulder, ear pain, bruises, fracture pain, pain caused by sprains, traumatic pain, and eye pain; it is also used as an anti-inflammatory agent for muscle fatigue and frostbite. Furthermore, as an oral pharyngeal agent, it is used for pharyngitis, tonsillitis, stomatitis, oral and pharyngeal edema, sterilization and disinfection of the oral cavity and throat, and removal of bad breath. Additionally, as a hemorrhoid treatment, it is used to relieve pain, bleeding, swelling, and itching caused by hemorrhoids and anal fissures.< / lps>

Claims

Claim 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. Claim 2 A pharmaceutical composition according to claim 1, characterized as being for anti-inflammatory purposes. Claim 3 A pharmaceutical composition according to claim 2, characterized in that at least one dosage 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. Claim 4 A pharmaceutical composition according to claim 3, characterized in that at least one dosage selected from the group consisting of diclofenac, naproxen, their salts and their hydrates is a dosage in which 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. Claim 5 A pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an oral preparation, and at least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is 0.06 mg / dose to 6 mg / dose, at least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is 0.025 mg / dose to 2.5 mg / dose, or at least one dosage selected from the group consisting of naproxen, its salts and their hydrates is 0.1 mg / dose to 10 mg / dose. Claim 6 A pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an external preparation, and at least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is 0.0007 mg / cm² to 0.07 mg / cm², and at least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is 0.0001 mg / cm² to 0.01 mg / cm². Claim 7 A pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an oral preparation, and at least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is 0.006 μg / mL to 0.6 μg / mL, and at least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is 0.41 ng / mL to 41 ng / mL, or at least one dosage selected from the group consisting of naproxen, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is 0.09 μg / mL to 9 μg / mL. Claim 8 A pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an external preparation, and at least one dosage selected from the group consisting of loxoprofen, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is 0.05 ng / mL to 5 ng / mL, and at least one dosage selected from the group consisting of diclofenac, its salts and their hydrates is a dosage such that the maximum plasma concentration after administration is 0.003 ng / mL to 0.3 ng / mL.

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