JP7655706B2 - Pharmaceutical compositions containing fexofenadine - Google Patents

Description

The present invention relates to a pharmaceutical composition with excellent anti-inflammatory effects that can be used as a general cold remedy or a rhinitis remedy.

A general cold medicine is a generic term for medicines used to relieve cold symptoms, such as runny nose, stuffy nose, fever, sore throat, cough, phlegm, sneezing, chills, headache, joint pain, and muscle pain. General cold medicines contain a variety of ingredients, such as antipyretic and analgesic ingredients, antihistamine ingredients, and antitussive ingredients, to relieve these symptoms.

Rhinitis medication is a general term for medicines used to relieve symptoms caused by acute rhinitis, allergic rhinitis, or sinusitis, such as runny nose, stuffy nose, and sneezing. Rhinitis medications contain a variety of ingredients, including antihistamines and anti-inflammatory ingredients, to relieve these symptoms.

Fexofenadine hydrochloride has a selective antihistamine H1 receptor antagonistic effect as its main action, and also inhibits the production of inflammatory cytokines, eosinophil migration, and chemical mediator release. In Japan, it has been recognized as being effective against allergic rhinitis, urticaria, and pruritus associated with skin diseases (see, for example, Non-Patent Document 1).

Glycyrrhizic acid or its salts are ingredients found in licorice and are known to have excellent anti-inflammatory properties and to soothe throat swelling and pain.

Total belladonna alkaloids are alkaloid components extracted from the rhizomes and roots of Atropa belladonna, which is native to Europe. They suppress the activity of the parasympathetic nervous system and reduce secretions from the nasal and lacrimal glands, and are therefore used in rhinitis medications (see, for example, Non-Patent Document 2). In Japan, they are also included in general cold medicines (Non-Patent Document 3).

Currently, a combination of fexofenadine or its salts is prescribed for medical use as a treatment for allergies that combines fexofenadine hydrochloride and pseudoephedrine hydrochloride (Non-Patent Document 4). In addition, no comprehensive cold medicine containing fexofenadine or its salts is on the market, but tablets containing fexofenadine hydrochloride and glycyrrhizinic acid (see, for example, Patent Documents 1 and 2) are known.

JP 2002-212067 A JP 2016-222657 A

Allegra (registered trademark) Tablets 30 mg Allegra (registered trademark) Tablets 60 mg Allegra OD Tablets (registered trademark) 60 mg Package insert 17th Edition Japanese Pharmacopoeia, pages D-854 to D-857 JAPIC General Medicines Collection 2018, page 94 Pharmaceutical Interview Form Dilegra (registered trademark) combination tablets

The objective of the present invention is to provide a pharmaceutical composition containing fexofenadine or a salt thereof that has an excellent anti-inflammatory effect.

As a result of intensive research conducted by the inventors to solve the above problems, they discovered that a combination of fexofenadine or a salt thereof and glycyrrhizic acid or a salt thereof, or belladonna or an extract thereof, plus one or more of ephedrine or a derivative or a salt thereof, phenylephrine or a salt thereof, or caffeine, exhibits an excellent anti-inflammatory effect, and thus completed the present invention.

That is, the present invention relates to the following.
[1] (a) fexofenadine or a salt thereof;
(b) glycyrrhizic acid or a salt thereof, or belladonna or an extract thereof; and (c) one or more selected from ephedrine or a derivative or a salt thereof, phenylephrine or a salt thereof, and caffeine;
A pharmaceutical composition comprising:
[2] The pharmaceutical composition according to [1], wherein fexofenadine or a salt thereof is fexofenadine hydrochloride.
[3] The pharmaceutical composition according to [1] or [2], wherein glycyrrhizinic acid or a salt thereof is glycyrrhizinic acid.
[4] The pharmaceutical composition according to [1] or [2], wherein belladonna or an extract thereof is total belladonna alkaloids.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein ephedrine or a derivative thereof or a salt thereof is methylephedrine hydrochloride.
[6] The pharmaceutical composition according to any one of [1] to [5], wherein phenylephrine or a salt thereof is phenylephrine hydrochloride.
[7] The pharmaceutical composition according to any one of [1] to [6], wherein the caffeine is anhydrous caffeine.
[8] The pharmaceutical composition according to any one of [1] to [7], which is for anti-inflammatory purposes.
[9] The pharmaceutical composition described in any one of [1] to [7], which is for the prevention or treatment of rhinitis.
[10] The pharmaceutical composition described in any one of [1] to [7] for alleviating cold symptoms.
[11] The pharmaceutical composition according to any one of [1] to [3] and [5] to [10], wherein the daily dose of fexofenadine or a salt thereof for an adult is 1 mg to 200 mg, and the daily dose of glycyrrhizinic acid or a salt thereof for an adult is 1 mg to 300 mg.
[12] The pharmaceutical composition according to any one of [1], [2] and [4] to [10], wherein the daily dose of fexofenadine or a salt thereof for an adult is 1 mg to 200 mg, and the daily dose of belladonna or an extract thereof for an adult is 0.1 mg to 10 mg.

The present invention provides a pharmaceutical composition with excellent anti-inflammatory effects.

An embodiment of the present invention will be described below.
The pharmaceutical composition of the present invention comprises:
(a) fexofenadine or a salt thereof;
(b) glycyrrhizic acid or a salt thereof, or belladonna or an extract thereof; and (c) one or more selected from ephedrine or a derivative or a salt thereof, phenylephrine or a salt thereof, and caffeine;
A pharmaceutical composition comprising:

In the present invention, "fexofenadine or a salt thereof" includes, for example, fexofenadine, fexofenadine hydrochloride, etc. These are known compounds and can be produced by known methods, or commercially available products can be used.

In the present invention, the content of "fexofenadine or a salt thereof" is not particularly limited and may be appropriately determined depending on the gender, age, symptoms, etc. of the person taking the drug. For example, when the fexofenadine or a salt thereof is fexofenadine hydrochloride, the daily dose is usually 1 mg to 200 mg, preferably 30 mg to 150 mg, and most preferably 60 mg to 120 mg.

In the present invention, "glycyrrhizinic acid or a salt thereof" includes, for example, glycyrrhizinic acid, dipotassium glycyrrhizinate, trisodium glycyrrhizinate, diammonium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, etc. These are known substances and can be produced by known methods, or commercially available products can be used.

In the present invention, the content of "glycyrrhizinic acid or a salt thereof" is not particularly limited, and may be appropriately determined depending on the gender, age, symptoms, etc. of the recipient. For example, when glycyrrhizinic acid or a salt thereof is glycyrrhizinic acid, the daily dose is usually 1 mg to 300 mg, preferably 5 mg to 200 mg, and more preferably 10 mg to 200 mg.

In the present invention, "Belladonna or an extract thereof" includes, for example, belladonna, belladonna cone, belladonna extract, and total belladonna alkaloids. These are known substances and can be produced by known methods, or commercially available products can be used.

In the present invention, the content of "Belladonna or an extract thereof" is not particularly limited, and may be appropriately determined depending on the gender, age, symptoms, etc. of the person taking it. For example, when belladonna or an extract thereof is total belladonna alkaloids, the daily dose (preferably for an adult) is usually 0.1 mg to 10 mg, preferably 0.12 mg to 0.6 mg, and more preferably 0.3 mg to 0.6 mg.

In the present invention, "ephedrine or its derivatives or salts thereof" includes, for example, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, etc. These are known substances and can be produced by known methods, or commercially available products can be used.

In the present invention, the content of "ephedrine or its derivative or its salt" is not particularly limited, and may be appropriately determined depending on the gender, age, symptoms, etc. of the person taking the drug. For example, when the ephedrine or its derivative or its salt is dl-methylephedrine hydrochloride, the daily dose is usually 1 mg to 300 mg, preferably 10 mg to 250 mg, and more preferably 25 mg to 200 mg. Furthermore, when the ephedrine or its derivative or its salt is pseudoephedrine hydrochloride, the daily dose is usually 1 mg to 1000 mg, preferably 50 mg to 500 mg, and more preferably 100 mg to 250 mg.

In the present invention, "phenylephrine or a salt thereof" includes, for example, phenylephrine, phenylephrine hydrochloride, etc. These are known compounds and can be produced by known methods, or commercially available products can be used. Phenylephrine hydrochloride is listed in the 17th revised edition of the Japanese Pharmacopoeia.

In the present invention, the content of "phenylephrine or a salt thereof" is not particularly limited, and may be appropriately determined depending on the gender, age, symptoms, etc. of the person taking the drug. For example, when the phenylephrine or a salt thereof is phenylephrine hydrochloride, the daily dose is usually 1 mg to 50 mg, preferably 5 mg to 30 mg, and more preferably 10 mg to 30 mg.

In the present invention, caffeine may be used in the form of caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, caffeine citrate, etc., with anhydrous caffeine and caffeine hydrate being preferred, and anhydrous caffeine being particularly preferred. Anhydrous caffeine and caffeine hydrate are listed in the 17th revised edition of the Japanese Pharmacopoeia.

In the present invention, the amount of "caffeine" is not particularly limited, and may be determined appropriately depending on the gender, age, symptoms, etc. of the person taking the medicine. For example, when the caffeine is anhydrous caffeine, the daily amount is usually 1 mg to 1000 mg, preferably 75 mg to 600 mg, and more preferably 150 mg to 300 mg.

In the present invention, in addition to the above-mentioned ingredients, other ingredients that are usually used in general cold medicines or rhinitis medicines can be blended as necessary, so long as the effects are not impaired. For example, ingredients listed in the OTC drug manufacturing and sales approval standards can be blended. Specifically, one or more ingredients selected from antipyretics, antihistamines, vasoconstrictors, antitussives, noscapines, bronchodilators, expectorants, anticholinergics, anti-inflammatory agents, vitamins, gastric mucosa protectants, herbal medicines, hypnotics and sedatives, and Chinese herbal prescriptions can be blended.

As the antipyretic, anti-inflammatory, and analgesic agent, for example, one or more components selected from aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, pranophen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, and tiaramide hydrochloride can be blended.

Examples of antihistamines include isothipendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, and tannins. It may contain one or more ingredients selected from diphenhydramine acid, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, ketotifen fumarate, promethazine hydrochloride, epinastine hydrochloride, emedastine fumarate, olopatadine hydrochloride, azelastine hydrochloride, and cetirizine hydrochloride.

As a vasoconstrictor, one or more ingredients selected from methoxyphenamine hydrochloride, etc. can be blended.

As antitussives, for example, one or more ingredients selected from alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, tipepidine citrate, tipepidine hibenzate, dibunate sodium, pentoxyverine citrate, dimemorfan phosphate, eprazinone hydrochloride, pentoxyverine citrate, benproperine phosphate, and clofedanol hydrochloride can be blended.

As the noscapine derivative, for example, one or more components selected from noscapine and noscapine hydrochloride hydrate can be blended.

As a bronchodilator, for example, one or more components selected from aminophylline, diprophylline, theophylline, proxyphylline, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, and isoprenaline hydrochloride can be blended.

The expectorant may contain one or more components selected from, for example, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, l-carbocysteine, l-ethylcysteine hydrochloride, l-methylcysteine hydrochloride, ambroxol hydrochloride, ammonium chloride, l-menthol, ammonia-fennel extract, cherry bark extract, methylcysteine hydrochloride, and fudosteine.

Anticholecin agents that can be included include, for example, isopropamide iodide.

As an anti-inflammatory agent, one or more components selected from tranexamic acid, serrapeptase, bromelain, semi-alkaline proteinase, pronase, seaprose, proctase, lysozyme hydrochloride, etc. can be blended.

Examples of vitamins include vitamin B1 and its derivatives and salts such as thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibuthiamine, bis-bentiamine, prosultiamine, and benfotiamine; vitamin B2 and its derivatives and salts such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate; pantothenic acid, panthenol, panthenol, and panthenol. It can contain one or more ingredients selected from vitamin B5 and its derivatives and their salts, such as vitamin B12, cyanocobalamin and mecobalamin, vitamin B6 and its derivatives and their salts, such as vitamin B12, cyanocobalamin and mecobalamin, vitamin B7 and its derivatives and their salts, such as vitamin B12, cyanocobalamin and mecobalamin, vitamin B8 and its derivatives and their salts, such as vitamin B12, cyanocobalamin and mecobalamin, vitamin B9 and its derivatives and their salts, such as vitamin B12, cyanocobalamin and mecobalamin, vitamin B12 ...

As a gastric mucosa protective agent, one or more components selected from glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum alnoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, magnesium aluminometasilicate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, teprenone, and rebamipide can be blended.

Herbal medicines include ephedra, nandina, scutellaria, onji, licorice, bellflower, chinese quince, chinese quince, stone garlic, senega, fritillary, fennel, phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yuutan), sappan, ginger, atractylodes, clove, tangerine peel, atractylodes rhizome, sage, ginseng, carrot, Mallotus japonicus, einkorn, corydalis, Scutellaria baicalensis, celery, valerian, calonin, apricot kernel, wolfberry, wolfberry herb, scutellaria, valerian, calonin, apricot kernel, wolfberry, wolfberry herb, scutellaria, scutellaria, valerian, calonin, apricot kernel, wolfberry, scutellaria, scutellaria, gentiana, geranium, It can contain one or more ingredients selected from herbal medicines such as Magnolia officinalis, Gomizushi, Saishin, Zanthoxylum Root, Aster Root, Jikoppi, Peony Root, Musk, Cnidium Root, Zenko, Swertia Root, Sophora Root, Perilla Root, Taisan, Touki, Ipecac, Bakumondou, Pinellia Root, Japanese Root, Japanese Cardamom, Angelica Root, Byakushi, Poria Root, Peony Root, Borei, and Rokujo, as well as their extracts (extracts, tinctures, dried extracts, etc.).

As a hypnotic sedative, one or more components selected from bromvalerylurea, allylisopropylacetylurea, etc. can be blended.

As a Chinese herbal medicine prescription, one or more ingredients selected from Kakkonto, Kakkonto-ka-kikyo, Keishito, Kososan, Saiko-keishito, Sho-saikoto, Sho-seiryuto, Bakumondoto, Hange-koubokuto, Mao-to, etc. can be blended.

Furthermore, the pharmaceutical composition of the present invention may contain pharmaceutical additives necessary for producing the formulation, within the scope that does not impair the effects of the present invention. For example, the pharmaceutical additives may be those described in Yakushoku Shinkan Hatsu 1204-1 (Pharmaceutical Affairs Administration Act), Pharmaceutical Additives Dictionary 2016 (edited by Japan Pharmaceutical Additives Association, Yakuji Nipposha), and the 8th Edition of Food Additives Official Specification (Japan Food Additives Association). Specifically, one or more components selected from excipients, binders, disintegrants, disintegration aids, flow agents, lubricants, plasticizers, coating agents, sugar coating agents, gloss agents, solvents, pH regulators, colorants, flavorings, sweeteners, flavorings, flavorings/flavorings, etc. may be contained.

Excipients include candy powder, pregelatinized starch, isomalt, cacao butter, dried hydrolyzed starch, caramel, carmellose, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrated anhydrous silicon oxide, dried aluminum hydroxide gel, dried potato starch, licorice powder, dried magnesium sulfate, agar, agar powder, winter plum powder, xylitol, croscarmellose sodium, crospovidone, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, calcium silicate, magnesium silicate, light anhydrous silicic acid, cinnamon powder, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), synthetic aluminum silicate, synthetic aluminum silicate-hydroxyp propyl starch, crystalline cellulose, synthetic hydrotalcite, wheat starch, rice flour, rice starch, β-cyclodextrin, heavy anhydrous silicic acid, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide, D-sorbitol, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, corn starch, corn starch granules, trehalose hydrate, silicon dioxide, lactose hydrate, lactose granules, nonpareils, white sugar, potato starch, microcrystalline cellulose, hydroxypropyl starch, Hydroxypropyl cellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose phthalate (200731 type), hypromellose phthalate (220824 type), fine silicon dioxide, partially pregelatinized starch, pullulan, powdered sugar, powdered reduced maltose syrup, powdered cellulose, powdered cellulose (average degree of polymerization: 800-1100), povidone (K25), povidone (K30), povidone (K90), polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal It can contain one or more ingredients selected from the group consisting of diethyl acetoacetate, polyvinyl alcohol/diethylene glycol mixture, maltitol, maltose hydrate, D-mannitol, D-mannitol/crospovidone/D-sorbitol/hydrated silicon dioxide mixture, anhydrous silicic acid hydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, methacrylic acid copolymer LD, magnesium aluminometasilicate, methyl acrylate/methacrylic acid copolymer, methyl acrylate/methyl methacrylate, methylcellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, and erythritol.

Examples of binders include gum arabic, powdered gum arabic, agar, powdered agar, cold plum powder, crystalline cellulose, copolyvidone, gelatin, shellac, low-substituted hydroxypropyl cellulose, corn starch, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, vinylpyrrolidone-vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731 type), hypromellose phthalate (220824 type), type), fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropylcellulose 2910 mixture, pullulan, povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol graft polymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, magnesium aluminometasilicate, and methylcellulose can be blended with one or more components.

As disintegrants, for example, one or more components selected from pregelatinized starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium starch glycolate, potato starch, hydroxypropyl starch, and partially pregelatinized starch can be blended.

As disintegration aids, for example, one or more components selected from carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium starch glycolate, and hydroxypropyl starch can be blended.

The fluidizing agent may be, for example, one or more components selected from hydrous silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, calcium triphosphate, talc, corn starch, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

The lubricant may be one or more components selected from the group consisting of hydrous silicon dioxide, hydrous amorphous silicon oxide, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hardened oil, heavy anhydrous silicic acid, sucrose fatty acid ester, stearyl alcohol, stearic acid, zinc stearate, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, soybean hardened oil, talc, sodium stearyl fumarate, beeswax, anhydrous silicic acid hydrate, magnesium aluminometasilicate, and glycerin monostearate.

The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, medium-chain triglycerides, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

Coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, acetyl glycerin fatty acid ester, aminoalkyl methacrylate copolymer E, gum arabic, gum arabic powder, ammonioalkyl methacrylate copolymer, ethyl cellulose, ethyl cellulose aqueous dispersion, octyldecyl triglyceride, Opadry OY-6950, Opadry OY-L-28900, Opadry OY -LS-20291, Opadry OY-LS-23016, Opadry OY-S-7135, Opadry OY-S-8471, Opadry OY-S-9607, Opadry OY-S-22829, Opadry OY-S-22835, Opadry OY-S-22961, Opadry OY-S-28924, Opadry YS-1-7003 white, Opadry YS-1-12524-A, Opadry YS-1-14762-A, Opadry YS-1-15585-A, Opadry YS-1-19025A, Opadry YS-2-19114-A, Opadry II Yellow, Opadry Clear (YS-2-19114-A), Opadry II Gray 85F17659, Opadry White 03K280000, Opadry Pink (02F34337), Opadry II Pink, Opadry II Pink 85F97191, Opadry II Blue (85G 20427), Opadry II Beige 85F17438, Opadry White (15B180002), Opadry White OY-LS-28914, Opadry White YS-1-18177-A, Opadry White (YS-1-18202-A), Opadry II White (33G28523), Opadry II White (85F28751), Opadry II White (OY-LS-28914), Opadry Opadry II Light Blue (85G20426), Opadry II Light Beige 85F17498, Opadry II Red (32K15441), carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, dried aluminum hydroxide gel, dried methacrylic acid copolymer LD, triethyl citrate, glycerin, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropylcellulose, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, magnesium oxide, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, sucrose fatty acid ester, aluminum hydroxide gel, stearyl alcohol, stearic acid, aluminum stearate, calcium stearate, polyoxyl 40 stearate, stearic acid Magnesium, refined gelatin, refined shellac, refined sucrose, gelatin, shellac, D-sorbitol, D-sorbitol liquid, talc, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, concentrated glycerin, white shellac, sucrose, paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910-titanium oxide-macrogol mixture, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (200731 type), hypromellose phthalate (220824 type), fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropylmethylcellulose 2910 mixture, pullulan, premix additive Opadry White, bentonite, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethyl acetoacetate, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 600 It can contain one or more ingredients selected from 0EP, Macrogol 20000, Macrogol 35000, D-mannitol, anhydrous citric acid, anhydrous silicic acid hydrate, phthalic anhydride, anhydrous calcium hydrogen phosphate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl methacrylate-methacrylic acid-methyl methacrylate copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, and DL-malic acid.

As sugar-coating agents, one or more components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, crystalline cellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hypromellose (2208), hypromellose (2910), pullulan, povidone (K25), povidone (K30), povidone (K90), polyoxyethylene (105) polyoxypropylene (5) glycol, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, and D-mannitol can be blended.

The glossing agent may be one or more components selected from carnauba wax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, and beeswax.

The solvent may be one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol, etc.

The pH adjuster may be one or more components selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and triethanolamine.

As coloring agents, one or more components selected from yellow iron oxide, Yellow No. 5 premix, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium oxide, iron sesquioxide, iron sesquioxide-glycerin suspension, Food Blue No. 1, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, sodium copper chlorophyllin, copper chlorophyll, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil can be blended.

Flavoring agents include: erythritol, sodium chloride, Phellodendron bark powder, Phellodendron arborescens extract, Coptis chinensis, Coptis chinensis powder, dried Ononis root extract, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, crude licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-arginine L-glutamate, L-glutamic acid hydrochloride, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon tincture, cinnamon powder, cinnamon oil, kelp powder, saccharin, sodium saccharin hydrate, saffron, saffron tincture, Japanese pepper tincture, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, ginger chinensis It can contain one or more ingredients selected from the following: ginger powder, sucralose, stevia extract, stevia extract refined product, refined licorice extract powder, refined white sugar, Swertia japonica, Perilla japonica powder, D-sorbitol, Chinese laurel powder, taurine, dried Atractylodes oryzae root and grass extract, tannic acid, clove tincture, clove oil, tangerine tincture, capsicum, capsicum tincture, capsicum powder, spruce tincture, spruce powder, trehalose hydrate, bittern powder, plum flesh extract, white sugar, fructooligosaccharide, sugar powder, peppermint powder, maltose hydrate, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil.

Sweetening agents that can be blended include one or more ingredients selected from aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, refined white sugar, refined white sugar spherical granules, white sugar, powdered reduced maltose syrup, maltitol, D-mannitol, and erythritol.

Flavors may include one or more ingredients selected from orange flavor, orange flavor powder SH-1171-A, orange micron H-800092, guarana extract, flavor (sweet orange), flavor (strawberry), flavor (lemon), brown sugar flavor, strawberry essence, strawberry flavor B86173, cherry flavor 181612, dent mint 1148J, banana powder flavor, peach essence, cypress 6E-84211, black current flavor 290012SYM, fruit essence, peppermint NAEFCOPO551957685, peppermint micron H-81550, mixed flavor powder, melon powder flavor, l-menthol, and menthol L163592SYM.

Fragrances and flavorings include: fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, vitabase, Himalayan It can contain one or more ingredients selected from the following: oak oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, locust oil, and Roman chamomile oil.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include oral preparations such as capsules, pills, granules, fine granules, powders, tablets, liquids, syrups, jellies, and lozenges, and parenteral preparations such as topical liquids, ointments, creams, gel creams, poultices, transdermal preparations, patches, liniments, lotions, suppositories, eye drops, and nasal drops. Oral preparations, nasal drops, and eye drops are preferred, and oral preparations are even more preferred, and solid preparations such as capsules, pills, granules, fine granules, powders, and tablets are even more preferred. These solid preparations may be coated with sugar coating, film coating, or the like by known methods, if necessary.

The pharmaceutical composition of the present invention can be formulated in the above-mentioned dosage form according to the method described in the 17th edition of the Japanese Pharmacopoeia, etc. For example, when the pharmaceutical composition of the present invention is in the form of a tablet, it can be manufactured in accordance with the section on "tablets" in the General Provisions of Preparations of the Japanese Pharmacopoeia. When the pharmaceutical composition of the present invention is in the form of a granule, it can be manufactured in accordance with the section on "granules" in the General Provisions of Preparations of the Japanese Pharmacopoeia. When the pharmaceutical composition of the present invention is a solid formulation, if there are problems with storage stability due to incompatibility between the components specified in the present invention and other components and additives in such a solid formulation, the solid formulation can be formulated so that they do not come into contact with each other by dividing the components into granules, forming multiple layers, etc.

When the dosage form of the pharmaceutical composition of the present invention is a solid preparation, it may be temporarily packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. There are no particular limitations on the material used for the pillow packaging, and examples of materials that can be used include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and these resin films with aluminum foil attached. If hygroscopicity is a concern, a desiccant or the like may be stored simultaneously in the bottle packaging or pillow packaging.

The pharmaceutical composition of the present invention can be administered for anti-inflammatory purposes. Diseases to which the anti-inflammatory pharmaceutical composition is applied include colds, rhinitis, eczema, urticaria, tonsillitis, pharyngitis, hemorrhoids, stomatitis, and the relief of various symptoms associated with these diseases. That is, it can be used as a cold medicine, a nasal drop for rhinitis (allergic rhinitis, sinusitis, etc.), an insect bite, an anti-itching agent, a preventive and/or therapeutic agent for dermatitis, a medicine for athlete's foot and ringworm, and a preventive and/or therapeutic agent for symptoms such as itching in hemorrhoids, and a preventive and/or therapeutic agent for throat irritation and pain caused by throat inflammation, etc.

The pharmaceutical composition of the present invention can be administered to relieve cold symptoms (fever, chills, headache, sore throat, runny nose, stuffy nose, cough, phlegm, joint pain, muscle pain, sneezing).

Furthermore, the pharmaceutical composition of the present invention can be administered for the prevention or treatment of rhinitis, and in particular for the relief of various symptoms (runny nose, stuffy nose, sneezing) due to acute rhinitis, allergic rhinitis caused by pollen or house dust, or sinusitis.

Furthermore, the pharmaceutical composition of the present invention can be administered for the prevention and/or treatment of dermatitis, in particular for the prevention and/or treatment of skin itch, eczema, hives, dermatitis, and rash.

The following examples and manufacturing examples are provided, but the present invention is not limited to the following examples.

Test Example: Anti-inflammatory test against bradykinin-plasmin paw edema using rats 1-1. Test substance and inflammatory reagents In this test, methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd., fexofenadine hydrochloride (hereinafter, fexofenadine) manufactured by Dipharma Inc., glycyrrhizic acid manufactured by Alps Pharmaceutical Co., Ltd., belladonna total alkaloids (hereinafter, belladonna) manufactured by Alps Pharmaceutical Co., Ltd., phenylephrine hydrochloride (hereinafter, phenylephrine) manufactured by Wako Pure Chemical Industries, Ltd., dl-methylephedrine hydrochloride (hereinafter, methylephedrine) manufactured by Alps Pharmaceutical Co., Ltd., and anhydrous caffeine (hereinafter, caffeine) manufactured by Shizuoka Caffeine Co., Ltd. were used. Bradykinin was manufactured by Wako Pure Chemical Industries, Ltd., and Human Plasmin (hereinafter, plasmin) was manufactured by Haemagtologic Technology Inc. Each sample was prepared by dissolving or suspending each test substance in a 0.5% aqueous solution of methylcellulose.

(Specimen)
Group 0: Vehicle (0.5% methylcellulose) *Inflammatory control group Group 1: Fexofenadine 0.3 mg/kg
Group 2: fexofenadine 0.3 mg/kg + glycyrrhizic acid 200 mg/kg
Group 3: methylephedrine 110 mg/kg
Group 4: phenylephrine 30 mg/kg
Group 5: caffeine 150 mg/kg
Group 6: fexofenadine 0.3 mg/kg + glycyrrhizic acid 200 mg/kg + methylephedrine 110 mg/kg
Group 7: fexofenadine 0.3 mg/kg + glycyrrhizic acid 200 mg/kg + phenylephrine 30 mg/kg
Group 8: fexofenadine 0.3 mg/kg + glycyrrhizic acid 200 mg/kg + caffeine 150 mg/kg
Group 9: fexofenadine 0.3 mg/kg + belladonna 0.6 mg/kg
Group 10: fexofenadine 0.3 mg/kg + belladonna 0.6 mg/kg + methylephedrine 110 mg/kg
Group 11: fexofenadine 0.3 mg/kg + belladonna 0.6 mg/kg + phenylephrine 30 mg/kg
Group 12: fexofenadine 0.3 mg/kg + belladonna 0.6 mg/kg + caffeine 150 mg/kg

(Inflammatory Agent)
1 mg of bradykinin and 0.5 U of plasmin were dissolved in physiological saline to make up 20 mL.

1-2. Test method Five-week-old Crij:WI male rats (Charles River Japan, Inc.) were subjected to a 5-day quarantine period, and then allowed to acclimate for 2-4 days. After acclimatization, the rats were divided into groups (5 rats per group) based on the weight measurement results, and the test substance was orally administered using a probe. Thirty minutes later, 0.1 ml of bradykinin-plasmin solution was subcutaneously injected into the right hind footpad as an inflammation inducer to induce inflammation. The footpad volume of each rat was measured before grouping and 60 minutes after inflammation induction, and the edema rate, area under the curve, and inhibition rate were calculated using the formula described below.

1-3. Measurement of paw volume and calculation of edema rate, area under the curve (AUC) and inhibition rate Before grouping, and 15, 30, 45 and 60 minutes after inflammation onset, the right hind paw volume (mL) was measured using a mouse/rat hind paw edema volume measuring device (TK-101CMP, manufactured by Unicom Co., Ltd.). The edema rate was calculated for each individual from the paw volume before grouping and the paw volume at each measurement time using the following formula.

Furthermore, for each individual, the area under the curve (AUC _0-1hr ) was calculated from the edema rate at each time point using the following formula.

a: Edema rate 15 minutes after onset b: Edema rate 30 minutes after onset c: Edema rate 45 minutes after onset d: Edema rate 60 minutes after onset

Furthermore, the inhibition rate of each drug group was calculated from the AUC _0-1hr value of the inflammation control group (group 0) and the AUC _0-1hr value of each drug group (groups 1 to 12) using the following formula.

2. Test results The test results are shown in Table 1.

In Table 1, compared to group 1, where fexofenadine was administered alone, group 2, where fexofenadine was administered in combination with glycyrrhizinic acid, had a lower edema inhibition rate, but group 6, where fexofenadine, glycyrrhizinic acid, and methylephedrine were administered in combination, group 7, where fexofenadine, glycyrrhizinic acid, and phenylephrine were administered in combination, and group 8, where fexofenadine, glycyrrhizinic acid, and caffeine were administered in combination, showed a significantly improved edema inhibition rate compared to group 1, where fexofenadine was administered alone, group 3, where methylephedrine was administered alone, group 4, where phenylephrine was administered alone, and group 2, where fexofenadine and glycyrrhizinic acid were administered in combination, confirming a high anti-inflammatory effect.

In addition, compared to group 1, which was administered fexofenadine alone, group 9, which was administered fexofenadine in combination with belladonna, had a lower edema suppression rate. However, group 10, which was administered fexofenadine, belladonna, and methylephedrine in combination, group 11, which was administered fexofenadine, belladonna, and phenylephrine in combination, and group 12, which was administered fexofenadine, belladonna, and caffeine in combination, showed a significantly improved edema suppression rate compared to group 1, which was administered fexofenadine alone, group 4, which was administered phenylephrine alone, group 5, which was administered caffeine alone, and group 9, which was administered fexofenadine and belladonna in combination, demonstrating a high anti-inflammatory effect.

A manufacturing example is shown below. The values indicate the amount of each ingredient contained in the formulation per day.
(Production Example 1)
The following ingredients are used to prepare tablets in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations.
Acetaminophen 900mg
Fexofenadine hydrochloride 120mg
Dextromethorphan hydrobromide hydrate 48mg
dl-Methylephedrine hydrochloride 60mg
Bromhexine hydrochloride 12mg
Belladonna total alkaloids 0.3mg
Glycyrrhizic acid 39mg
Caffeine anhydrous 60mg
Benfotiamine 24mg
Crystalline cellulose, appropriate amount Carmellose calcium, 10 mg
Hydroxypropyl cellulose 5mg
Magnesium stearate trace amount

(Formulation Example 2)
The ingredients listed below were mixed with the ingredients other than magnesium stearate, and then granulated to produce granules. Magnesium stearate was then added to the granules, which were then filled into hard capsules to produce capsules.
Pseudoephedrine hydrochloride 180mg
Phenylephrine hydrochloride 30mg
Fexofenadine hydrochloride 120mg
Belladonna total alkaloids 0.3mg
Glycyrrhizic acid 45mg
Caffeine anhydrous 100mg
Benfotiamine 24mg
Corn starch, appropriate amount Lactose, appropriate amount Crystalline cellulose, appropriate amount Carmellose calcium 20mg
Hydroxypropyl cellulose 15mg
Magnesium stearate trace amount

(Production Example 3)
The following ingredients are used to prepare film-coated tablets in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations.
Ibuprofen 600mg
Fexofenadine hydrochloride 120mg
Dihydrocodeine phosphate 24mg
dl-Methylephedrine hydrochloride 60mg
Ambroxol hydrochloride 48mg
Belladonna total alkaloids 0.3mg
Glycyrrhizic acid 39mg
Caffeine anhydrous 60mg
Benfotiamine 24mg
Crystalline cellulose (appropriate amount) Carmellose calcium 20mg
Hydroxypropyl cellulose 15mg
Magnesium stearate, trace amount of hypromellose 20mg
Macrogol 10mg
Titanium oxide 10mg
Carnauba wax 7mg

(Formulation Example 4)
The ingredients listed below were mixed with the ingredients other than magnesium stearate, and then granulated to produce granules. Magnesium stearate was then added to the granules, which were then filled into hard capsules to produce capsules.
Pseudoephedrine hydrochloride 180mg
Phenylephrine hydrochloride 30mg
Fexofenadine hydrochloride 120mg
Tranexamic acid 420mg
Glycyrrhizic acid 45mg
Caffeine anhydrous 100mg
Benfotiamine 24mg
Corn starch, appropriate amount Lactose, appropriate amount Crystalline cellulose, appropriate amount Carmellose calcium 10mg
Povidone (K30) 10mg
Magnesium stearate trace amount

(Production Example 5)
The following ingredients are used to prepare film-coated tablets in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations.
Loxoprofen sodium (as anhydrous) 180mg
Tranexamic acid 750mg
Fexofenadine hydrochloride 120mg
Dextromethorphan hydrobromide hydrate 48mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Ambroxol hydrochloride 48mg
Glycyrrhizic acid 39mg
Caffeine anhydrous 60mg
Benfotiamine 24mg
Crystalline cellulose, appropriate amount Crospovidone, 15 mg
Hydroxypropyl cellulose 20mg
Magnesium stearate, trace amount of hypromellose 10mg
Macrogol 6mg
Titanium oxide 10mg

(Production Example 6)
The following ingredients are used to prepare film-coated tablets in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations.
Ibuprofen 450mg
Tranexamic acid 420mg
Dihydrocodeine phosphate 24mg
Methylephedrine hydrochloride 60mg
Bromhexine hydrochloride 12mg
Fexofenadine hydrochloride 120mg
Belladonna total alkaloids 0.3mg
Caffeine anhydrous 75mg
Crystalline cellulose (appropriate amount) Croscarmellose sodium 20mg
D-mannitol (appropriate amount) Hydroxypropyl cellulose 10mg
Magnesium stearate, trace amount of hypromellose 9mg
Macrogol 5mg
Titanium oxide 7mg
Talc 10mg
Carnauba wax 5mg

Claims (7)

(a) fexofenadine or a salt thereof;
(b) glycyrrhizinic acid or a salt thereof; and (c) caffeine;
An anti-inflammatory pharmaceutical composition comprising the above formula (I), excluding pharmaceutical compositions containing one or more selected from the group consisting of phenethylamines or tropane alkides, and excluding compositions containing (A) fexofenadine and salts thereof and (B) one or more selected from phenylpropanolamine, methylephedrine, phenylephrine, methoxyphenamine and salts thereof. The pharmaceutical composition according to claim 1, wherein the fexofenadine or a salt thereof is fexofenadine hydrochloride. The pharmaceutical composition according to claim 1 or 2, wherein the glycyrrhizinic acid or a salt thereof is glycyrrhizinic acid. The pharmaceutical composition according to any one of claims 1 to 3, wherein the caffeine is anhydrous caffeine. The pharmaceutical composition according to any one of claims 1 to 4, for the prevention or treatment of rhinitis. A pharmaceutical composition according to any one of claims 1 to 4 for relieving cold symptoms. The pharmaceutical composition according to any one of claims 1 to 6, wherein the daily dose of fexofenadine or its salt for an adult is 1 mg to 200 mg, and the daily dose of glycyrrhizic acid or its salt for an adult is 1 mg to 300 mg.