JP7325969B2 - Pharmaceutical composition containing olopatadine - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition excellent in anti-inflammatory action, which can be used as a common cold medicine or a medicine for rhinitis.

Common cold medicines are medicines used for the purpose of relieving cold symptoms such as runny nose, stuffy nose, fever, sore throat, cough, phlegm, sneezing, chills, headache, joint pain, muscle pain, etc. is a generic term for Common cold medicines contain various ingredients such as antipyretic analgesic ingredients, antihistamine ingredients, and antitussive ingredients to alleviate these symptoms.

A drug for rhinitis is a general term for pharmaceuticals used for the purpose of alleviating various symptoms caused by acute rhinitis, allergic rhinitis, or sinusitis, such as runny nose, nasal congestion, sneezing, and the like. In order to alleviate these symptoms, rhinitis medicines contain various ingredients such as antihistamine ingredients and anti-inflammatory ingredients.

Olopatadine hydrochloride has a selective antihistamine H1 receptor antagonistic action as its main action, and furthermore has an inhibitory action on the production and release of chemical mediators (leukotrienes, thromboxane, PAF, etc.), and an inhibitory action on the release of neurotransmitters tachykinin. In Japan, it is recognized to be effective for allergic rhinitis, urticaria, and itching associated with skin diseases (see, for example, Non-Patent Document 1).

Belladonna total alkaloids are alkaloid components extracted from the rhizomes and roots of the belladonna Atropa belladonna, which is native to Europe. It is used as a medicine for rhinitis because it suppresses the action of the parasympathetic nerves and reduces the secretion of mucus and lacrimal glands. (For example, see Non-Patent Document 2). In Japan, it is also included in common cold medicines (Non-Patent Document 3).

At present, there are no general cold remedies containing olopatadine or its salts on the market. , a liquid composition containing pseudoephedrine hydrochloride and methylephedrine hydrochloride (see Patent Document 2).

Tranexamic acid is known to have a hemostatic effect based on antiplasmin action and an effect on hives, stomatitis and pharyngitis based on anti-allergic/anti-inflammatory action. Examples of pharmaceutical compositions containing tranexamic acid include (A) fexofenadine or salts thereof, (B) nonsteroidal anti-inflammatory drugs (NSAIDs), and (C) xanthine derivatives, tranexamic acid or salts thereof, acid A pharmaceutical composition containing one or more selected from a basic compound having neutralizing ability and ascorbic acid or a salt thereof is known (Patent Document 3).

JP 2014-84275 A JP 2013-193981 A JP 2016-155761 A

Allelock (registered trademark) tablets 2.5, Allelock (registered trademark) tablets 5 package insert Japanese Pharmacopoeia, 17th Edition, pp. D-854 to pp. D-857 JAPIC OTC drug collection 2018 p.94

The inventors have found that combining olopatadine or its salts with belladonna or its extract or tranexamic acid or its salts significantly reduces the anti-inflammatory effect. An object of the present invention is to solve the above problems and to provide a pharmaceutical composition containing olopatadine or a salt thereof having excellent anti-inflammatory action.

As a result of intensive studies to solve the above problems, the present inventors have found that a combination of olopatadine or a salt thereof and belladonna or an extract thereof or tranexamic acid or a salt thereof, further, phenylephrine or a salt thereof, glycyrrhizic acid or By blending any one or more of its salts, ephedrine or its derivatives or their salts, or caffeine, the anti-inflammatory action that was reduced by the addition of belladonna or its extract or tranexamic acid or its salt can be remarkably improved. and completed the present invention.

That is, the present invention relates to the following.
[1] (a) olopatadine or a salt thereof;
(b) belladonna or its extract, or tranexamic acid or its salt; and (c) when the component (b) is belladonna or its extract, phenylephrine or its salt and glycyrrhizic acid or its salt 1 or 2 or more selected from phenylephrine or its salts, ephedrine or its derivatives or their salts, and caffeine when the component (b) is tranexamic acid or its salts ;
A pharmaceutical composition containing
[2] The pharmaceutical composition of [1], wherein the olopatadine or a salt thereof is olopatadine hydrochloride.
[3] The pharmaceutical composition of [1] 1 or [2], wherein the belladonna or its extract is a belladonna total alkaloid.
[4] The pharmaceutical composition of [1] or [2], wherein the tranexamic acid or a salt thereof is tranexamic acid.
[5] The pharmaceutical composition of any one of [1] to [4], wherein the phenylephrine or its salt is phenylephrine hydrochloride.
[6] The pharmaceutical composition according to any one of [1] to [3], wherein the glycyrrhizic acid or its salt is glycyrrhizic acid.
[7] The pharmaceutical composition according to any one of [1], [2] and [4], wherein the ephedrine or its derivative or salt thereof is methylephedrine hydrochloride.
[8] The pharmaceutical composition according to any one of [1] to [3] and [6], comprising belladonna or its extract as a component (b) and glycyrrhizic acid or a salt thereof as a component (c). .
[9] The pharmaceutical composition according to any one of [1] to [8], which is for anti-inflammatory use.
[10] The pharmaceutical composition according to any one of [1] to [8], which is used for preventing or treating rhinitis.
[11] The pharmaceutical composition according to any one of [1] to [8] for alleviating symptoms of colds.
[12] The daily adult dosage of olopatadine or a salt thereof is 1 mg to 20 mg, and the daily adult dosage of belladonna or its extract is 0.1 mg to 10 mg, [1 The pharmaceutical composition according to any one of ] to [11].
[13] The daily dose for adults of olopatadine or a salt thereof is 1 mg to 20 mg, and the daily dose for adults of tranexamic acid or a salt thereof is 100 mg to 3000 mg, from [1] The pharmaceutical composition according to any one of [7] and [9] to [11].

ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition excellent in anti-inflammatory action can be provided.

Embodiments of the present invention are described below.
The pharmaceutical composition of the present invention is
(a) olopatadine or a salt thereof;
(b) belladonna or its extract, or tranexamic acid or its salt; and (c) when the component (b) is belladonna or its extract, phenylephrine or its salt and glycyrrhizic acid or its salt 1 or 2 or more selected from phenylephrine or its salts, ephedrine or its derivatives or their salts, and caffeine when the component (b) is tranexamic acid or its salts ;
is a pharmaceutical composition containing
An example of the present invention is the above pharmaceutical composition containing belladonna or its extract as component (b) and glycyrrhizic acid or its salt as component (c).

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

In the present invention, the content of "olopatadine or a salt thereof" is not particularly limited, and may be determined by appropriate consideration according to the sex, age, symptoms, etc. of the recipient. For example, when olopatadine or a salt thereof is olopatadine hydrochloride, the daily dose (preferably for adults) is generally 1 mg to 20 mg, preferably 5 mg to 10 mg, most preferably 10 mg.

In the present invention, "belladonna or its extract" includes, for example, belladonna, belladonnacon, belladonna extract and belladonna total alkaloids. These are known substances, can be produced by known methods, and can be commercially available.

In the present invention, the content of "belladonna or its extract" is not particularly limited, and may be determined by appropriate consideration according to the sex, age, symptoms, etc. of the recipient. For example, when the belladonna or its extract is a belladonna total alkaloid, the daily dose (preferably for adults) is usually 0.1 mg to 10 mg, preferably 0.12 mg to 0.6 mg, More preferably 0.3 mg to 0.6 mg.

In the present invention, "tranexamic acid or a salt thereof" means tranexamic acid or a salt of tranexamic acid. Salts of tranexamic acid include mineral salts such as hydrochlorides, nitrates and sulfates; organic acid salts such as methanesulfonates; alkali metal salts such as sodium salts, potassium salts, calcium salts and magnesium salts; A metal salt etc. can be mentioned. "Tranexamic acid" used in the present invention is listed in the Japanese Pharmacopoeia 17th Edition, is commercially available, and can be easily obtained.

In the present invention, the content of "tranexamic acid or a salt thereof" is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the recipient. For example, when "tranexamic acid or a salt thereof" is tranexamic acid, the daily dose is generally 100 mg to 3000 mg, preferably 210 mg to 1500 mg, more preferably 420 mg to 750 mg.

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

In the present invention, the content of "phenylephrine or a salt thereof" is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the recipient. For example, when phenylephrine or a salt thereof is phenylephrine hydrochloride, the daily dose (preferably for adults) is usually 1 mg to 50 mg, preferably 5 mg to 30 mg, more preferably 10 mg to 30 mg. be.

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

In the present invention, the content of "glycyrrhizic acid or a salt thereof" is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the recipient. For example, when glycyrrhizic acid or a salt thereof is glycyrrhizic acid, the daily dose (preferably for adults) is usually 1 mg to 300 mg, preferably 5 mg to 200 mg, more preferably 10 to 200 mg. .

In the present invention, "ephedrine or a derivative thereof or a salt thereof" includes, for example, pseudoephedrine hydrochloride, pseudoephedrine sulfate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt and the like. These are known substances, can be produced by known methods, and can be commercially available.

In the present invention, the content of "ephedrine or a derivative thereof or a salt thereof" is not particularly limited, and may be determined after appropriate examination according to the sex, age, symptoms, etc. of the recipient. For example, when ephedrine or a derivative thereof or a salt thereof is dl-methylephedrine hydrochloride, the daily dose (preferably for adults) is usually 1 mg to 300 mg, preferably 10 mg to 150 mg, and more Preferably 25 mg to 75 mg.

In the present invention, as caffeine, caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, citrate caffeine, etc. can be used, and anhydrous caffeine and caffeine hydrate are preferred. Caffeine is particularly preferred. Anhydrous caffeine and caffeine hydrate are listed in the Japanese Pharmacopoeia 17th Edition.

In the present invention, the content of "caffeine" is not particularly limited, and may be determined by appropriate consideration according to the sex, age, symptoms, etc. of the recipient. For example, when the caffeine is anhydrous caffeine, the daily dose (preferably for adults) is generally 1 mg to 1000 mg, preferably 75 mg to 600 mg, more preferably 150 mg to 300 mg.

In the present invention, in addition to the components described above, other components commonly used in common cold remedies or rhinitis remedies can be blended as needed within a range that does not impair the effects. For example, it is possible to mix ingredients described in the approval standards for manufacturing and marketing of over-the-counter drugs. Specifically, antipyretic analgesics, antihistamines, vasoconstrictors, antitussives, noscapines, bronchodilators, expectorants, anticholinergic agents, anti-inflammatory agents, vitamins, gastric mucosal protective agents, crude drugs, sedative hypnotics, and one or two or more components selected from Chinese herbal formulations and the like can be blended.

Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, loxoprofen sodium hydrate, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, One or two or more components selected from acemethacin, etodolac, naproxen, meloxicam, celecoxib, tiaramide hydrochloride and the like can be blended.

Examples of antihistamines include isothipendyl hydrochloride, diferol hydrochloride, tripelennamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride. salt, diphenylpyraline teocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, arimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylene disalicylate, carbinoxamine maleate, diferol phosphate, clemastine One or two or more ingredients selected from fumarate, mequitazine, ketotifen fumarate, promethazine hydrochloride, epinastine hydrochloride, emedastine fumarate, fexofenadine, azelastine hydrochloride, cetirizine hydrochloride, etc. can be blended.

As the vasoconstrictor, one or more components selected from methoxyphenamine hydrochloride and the like can be blended.

Antitussives include, for example, aloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate, dextromethorphan hydrobromide hydrate, dextromethorphan/phenolphta Phosphate, Tipepidine Citrate, Tipepidine Hibenzate, Dibunate Sodium, Pentoxyverine Citrate, Dimemorphan Phosphate, Eprazinone Hydrochloride, Pentoxyverine Citrate, Benproperine Phosphate, and Clofeda One or two or more components selected from nor hydrochloride and the like can be blended.

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

Bronchodilators include, for example, one or more selected from aminophylline, diprophylline, theophylline, proxyphylline, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, and isoprenaline hydrochloride. Ingredients can be blended.

Expectorants include, 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 essence, cherry bark extract, methylcysteine hydrochloride, fudosteine, and the like.

As an anticholinergic agent, for example, a component such as isopropamide iodide can be blended.

As the anti-inflammatory agent, one or more components selected from serrapeptase, bromelain, semi-alkaline proteinase, pronase, seaprose, proctase, lysozyme hydrochloride, and the like can be blended.

Vitamins include, for example, thiamine, thiamine chloride hydrochloride, thiamine nitrate, disetiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, sicothiamine, thiamine disulfide, bis-butiamine, bis Vitamin B1 and its derivatives and their salts such as benchamine, prosultiamine and benfotiamine, vitamin B2 and its derivatives and their salts such as riboflavin, riboflavin phosphate, riboflavin butyrate and riboflavin sodium phosphate , vitamin B5 and derivatives thereof such as pantothenic acid, panthenol, pantethine, calcium pantothenate and sodium pantothenate, vitamin B6 and derivatives thereof and salts thereof such as pyridoxine hydrochloride and pyridoxal phosphate, From vitamin B12 and its derivatives and their salts such as cyanocobalamin and mecobalamin, vitamin C and its derivatives and their salts such as ascorbic acid, sodium ascorbate and calcium ascorbate, hesperidin and its derivatives and their salts, etc. One or two or more selected components can be blended.

Glycine, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxy aluminum alnoacetate (aluminum glycinate), aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide・Sodium hydrogen carbonate coprecipitate, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide/aluminum potassium sulfate coprecipitate, magnesium carbonate, Contains one or more ingredients selected from magnesium aluminometasilicate, aldioxa, sodium copper chlorophyllin, potassium copper chlorophyllin, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, teprenone, rebamipide, etc. can do.

Herbal medicines include Ephedra, Nantenjitsu, Touhi, Onji, Glycyrrhiza, Bellflower, Shazenshii, Shazensou, Seksan (Stone garlic), Senega, Fritillaria, Fennel, Phellodendron bark, Coptis japonica, Zeddaceae, Chamomile, Cinnamon bark, Gentian, Goou, Beast bile ( (including sagebrush), shoji, ginger, sojutsu, clove, chimpi, bayakujutsu, jiryu, chikusetsu carrot, carrot, red-clawed wrinkle, acacia, inyo-kaku, corydalis, scutellaria root, licorice, valerian, caronin, kyonin, wolfberry, wolfberry, kelp, ketsumeishi , Gennoshoko, Koubushi, Gomishi, Saishin, Sansho, Shion, Jikoppi, Peony, Musk, Shini, Senkyuu, Zenko, Assembly, Souhakuhi, Soyou, Taisan, Touki, Tokon, Bakumondou, Hange, Bankoka, Hampi, Byakushi, Bukuryo, One or two or more components selected from herbal medicines such as Botanpi, Borei, Rokujou, and extracts thereof (extracts, tinctures, dried extracts, etc.) can be blended.

As the hypnotic sedative, one or two or more components selected from bromvalerylurea, allylisopropylacetylurea and the like can be blended.

As Kampo prescription, one type selected from Kakkonto, Kakkonto Kakikyo, Keishito, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto, Bakumondoto, Hangekobokuto, Maoto, etc. Alternatively, two or more components can be blended.

Further, the pharmaceutical composition of the present invention may contain pharmaceutical additives necessary for manufacturing the formulation as long as the effects of the present invention are not impaired. For example, pharmaceutical additives are PFSB/ELD Notification No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), Pharmaceutical Additives Dictionary 2007 (edited by Japan Pharmaceutical Excipients Association, Yakuji Nippo), and 8th Edition Food Additives Official Code (Japan Food Additives Association), etc., can be blended. Specifically, excipients, binders, disintegrants, disintegration auxiliaries, fluidizers, lubricants, plasticizers, coating agents, sugar coating agents, glossing agents, solvents, pH adjusters, coloring agents, flavoring agents One or two or more components selected from agents, sweeteners, flavors, flavoring agents/flavors, etc. can be blended.

Excipients include candy powder, pregelatinized starch, isomalt, cocoa butter, dried hydrolyzed starch, caramel, carmellose, carmellose calcium, carmellose sodium, hydrous silicon dioxide, hydrous amorphous silicon oxide, and dried aluminum hydroxide. Gel, dried potato starch, licorice powder, dried magnesium sulfate, agar, agar powder, cold plum powder, xylitol, croscarmellose sodium, crospovidone, magnesium aluminate silicate, 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 (fine particles), crystalline cellulose (grains), synthetic aluminum silicate, synthetic aluminum silicate/hydroxypropyl Starch/Microcrystalline Cellulose, Synthetic Hydrotalcite, Wheat Starch, Rice Flour, Rice Starch, β-Cyclodextrin, Heavy Silicic Anhydride, 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 carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, starch glycol sodium phosphate, corn starch, corn starch granules, trehalose hydrate, silicon dioxide, lactose hydrate, lactose granules, nonpareil, sucrose, potato starch, microcrystalline cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose phthalate (type 200731), hypromellose phthalate (type 220824), fine silicon dioxide, partially pregelatinized starch, pullulan, powdered sugar, Powdered reduced maltose starch 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 diethylacetoacetate, polyvinyl alcohol-diethylene glycol mixture, multi Tall, maltose hydrate, D-mannitol, D-mannitol/crospovidone/D-sorbitol/hydrous silicon dioxide mixture, anhydrous silicic acid hydrate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation methacrylic acid copolymer LD, magnesium aluminometasilicate, methyl acrylate/methacrylic acid copolymer, methyl acrylate/methyl methacrylate, methyl cellulose, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate , potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate, erythritol, and the like.

Binders include, for example, gum arabic, gum arabic powder, agar, agar powder, kanbai powder, crystalline cellulose, copolyvidone, gelatin, shellac, low-substituted hydroxypropylcellulose, corn starch, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl Starch, hydroxypropylcellulose, vinylpyrrolidone-vinyl acetate copolymer, hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (type 200731), hypromellose Loth phthalate (type 220824), fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl cellulose 2910 mixture, pullulan, povidone (K25), povidone (K30), povidone (K90), polyvinyl alcohol (fully saponified) , polyvinyl alcohol (partially saponified product), 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 methyl cellulose 1 type or 2 types or more of components chosen from etc. can be mix|blended.

Examples of disintegrants include pregelatinized starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, potato One or more components selected from starch, hydroxypropyl starch, partially pregelatinized starch, and the like can be blended.

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

Fluidizing agents include, for example, hydrous silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminate hydroxide, tribasic calcium phosphate, talc, corn starch, and alumina metasilicate. One or two or more components selected from magnesium, calcium hydrogen phosphate granules, and the like can be blended.

Examples of lubricants include hydrous silicon dioxide, hydrous amorphous silicon oxide, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, heavy anhydrous silicic acid, sucrose fatty acid ester, stearyl alcohol, and stearic acid. , zinc stearate, aluminum stearate, calcium stearate, polyoxyl 40 stearate, magnesium stearate, hydrogenated soybean oil, talc, sodium stearyl fumarate, beeswax, anhydrous silicate hydrate, magnesium aluminometasilicate, and monostearin One or two or more components selected from acid glycerin and the like can be blended.

Plasticizers include triethyl citrate, glycerin, glycerin fatty acid ester, medium-chain fatty acid triglyceride, 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 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc. can be done.

Coating agents include ethyl acrylate/methyl methacrylate copolymer dispersion, acetylglycerin 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 (85G20427), 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 II Light Blue (85G20426), Opadry II Light Beige 85F17498, Opadry II Red (32K15441), Carnauba Wax, Carmellose Calcium, Carmellose Sodium, Hydrous Silicon Dioxide, Dry Aluminum Hydroxide Gel, Dry Methacrylic Acid Copolymer LD, Triethyl Citrate, Glycerin, Glycerin Fatty acid ester, magnesium silicate, light anhydrous silicic acid, hydroxypropyl cellulose containing light anhydrous silicic acid, 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, magnesium stearate, 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, white sugar, paraffin, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910/titanium oxide/macrogol mixture, Hypromellose (2208), hypromellose (2906), hypromellose (2910), hypromellose acetate succinate, hypromellose phthalate (type 200731), hypromellose phthalate (type 220824), fumaric acid, stearic acid, Polyvinyl Acetal Diethylaminoacetate-Hydroxypropyl Methylcellulose 2910 Mixture, Pullulan, Premixed 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 diethylacetoacetate, polyvinyl alcohol (partially saponified product), macrogol 300, macrogol 400, macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 6000EP, Macrogol 20000, Macrogol 35000, D-mannitol, anhydrous citric acid, anhydrous silicic acid hydrate, phthalic anhydride, phosphoric anhydride Calcium hydrogen, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl methacrylate/methacrylic acid/methyl methacrylate copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate , sorbitan monolaurate, calcium sulfate, and DL-malic acid.

Sugar coating agents include gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, crystalline cellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined sucrose, gelatin, shellac, talc, sedimentation. 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 product), macrogol 1500, macrogol 4000, macrogol 6000, D-mannitol and the like can be blended.

As the brightening agent, one or more components selected from carnauba wax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, beeswax and the like can be blended.

As the solvent, one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol and the like can be blended.

As the pH adjuster, one or two selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine, etc. More than one species can be blended.

Coloring agents include 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 One or more components selected from chlorophyll, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil and the like can be blended.

Flavoring agents include erythritol, sodium chloride, Phellodendron bark powder, Peppermint extract, coptis, Coptis japonica powder, dried ononis root extract, orange, orange oil, cacao 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, saccharin sodium hydrate, saffron, saffron tincture, Japanese pepper tincture, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, ginger tincture, ginger powder, Sucralose, stevia extract, purified stevia extract, refined licorice extract powder, refined sucrose, assembly, soybean powder, D-sorbitol, turmeric powder, taurine, taraxacum root/grass dried extract, tannic acid, clove tincture, clove oil, chimp tincture, Red pepper, red pepper tincture, red pepper powder, spruce tincture, spruce powder, trehalose hydrate, bittersweet powder, plum extract, sucrose, fructooligosaccharide, powdered sugar, peppermint powder, maltose hydrate, D-mannitol, dl-menthol, l - One or two or more components selected from menthol, menthol powder, ryuno, ryu no powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, rose oil, etc. can be blended.

Sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, One or two selected from saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, refined sucrose spherical granules, sucrose, powdered reduced maltose starch syrup, maltitol, D-mannitol, erythritol, etc. More than one species can be blended.

Flavors include 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 or the like can be blended.

Flavoring agents and fragrances 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, vita base, cedar 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, ryuno, ryuno powder, lemon powder, lemon oil, One or two or more components selected from rose water, rose oil, funnel oil, Roman chamomile oil and the like can be blended.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and examples include capsules, pills, granules, fine granules, powders, tablets, liquids, syrups, jellies, and lozenges. Orally administered formulations such as external liquids, ointments, creams, gel creams, poultices, transdermal absorption formulations, patches, liniments, lotions, suppositories, eye drops, nasal drops, etc. Parenteral Dosage formulations are included. Orally administered preparations, nasal drops or eye drops are preferable, orally administered preparations are more preferable, and solid preparations such as capsules, pills, granules, fine granules, powders and tablets are more preferable. In addition, these solid preparations may be coated with sugar coating, film coating, or the like by a known method, if necessary.

The pharmaceutical composition of the present invention can be prepared in the dosage forms listed above according to the methods described in the Japanese Pharmacopoeia 17th Edition. For example, when the dosage form of the pharmaceutical composition of the present invention is a tablet, it can be produced according to the Japanese Pharmacopoeia General Rules for Preparations, Section "Tablet". In addition, when the dosage form of the pharmaceutical composition of the present invention is granules, it can be produced according to the Japanese Pharmacopoeia General Rules for Preparations, Section "Granules". In addition, when the pharmaceutical composition of the present invention is a solid formulation, the components specified in the present invention and other components/additives in the solid formulation may cause problems such as storage stability due to issues such as incompatibility with each other. In some cases, they can be formulated into formulations by dividing them into granules, forming them into multiple layers, or the like, so that they do not come into contact with each other.

When the dosage form of the pharmaceutical composition of the present invention is a solid preparation, it can be appropriately packaged in a glass bottle, PTP, or the like. Additionally, if desired, a desiccant can be enclosed with the pharmaceutical composition of the present invention.

The pharmaceutical composition of the invention can be administered for anti-inflammatory purposes. Diseases to which the anti-inflammatory pharmaceutical composition is applied include colds, rhinitis, eczema, hives, tonsillitis, laryngopharyngitis, hemorrhoids, stomatitis, and alleviation of various symptoms associated with these diseases. Namely, prophylactic and/or therapeutic agents for colds, prophylactic and/or therapeutic agents for rhinitis, insect bites, antipruritic agents, prophylactic and/or therapeutic agents for dermatitis, drugs for athlete's foot and tinea, and for hemorrhoids. It can be used as a preventive and/or therapeutic agent for symptoms such as itching of the throat, and as a preventive and/or therapeutic agent for sore throat and sore throat due to inflammation of the throat.

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

Furthermore, the pharmaceutical composition of the present invention can be administered for relief of various symptoms (runny nose, nasal congestion, sneezing) caused by acute rhinitis, allergic rhinitis or sinusitis.

Examples and production examples are shown below, but the present invention is not limited to the following examples.

(Test Example 1) Anti-inflammatory test on bradykinin-plasmin paw edema using rats 1-1. Test Substances and Inflammatory Reagents In this test, methyl cellulose manufactured by Shin-Etsu Chemical Co., Ltd., olopatadine hydrochloride (hereinafter, olopatadine) manufactured by TORONTO RESEARCH CHEMICAL SINC, and belladonna total alkaloids (hereinafter, belladonna) were used. is manufactured by Alps Pharmaceutical Co., Ltd., phenylephrine hydrochloride (hereinafter referred to as phenylephrine) is manufactured by Wako Pure Chemical Industries, Ltd., glycyrrhizic acid is manufactured by Alps Pharmaceutical Co., Ltd., tranexamic acid is manufactured by Alps Pharmaceutical Co., Ltd. Ichi Fine Chemical Co., Ltd. Anhydrous caffeine (hereinafter referred to as caffeine) is manufactured by Shizuoka Caffeine Kogyo Co., Ltd. dl-methylephedrine hydrochloride (hereinafter referred to as methylephedrine) is Alps Pharmaceutical Industry Co., Ltd. ) was used. Bradykinin from Wako Pure Chemical Industries, Ltd. and Human Plasmin (hereinafter referred to as plasmin) from Haemagtological Technology Inc were used.

(specimen)
Group 0: Vehicle (0.5% methylcellulose) *Inflammatory control group Group 1: Olopatadine 0.1 mg/kg
Group 2: olopatadine 0.1 mg/kg + belladonna 0.6 mg/kg
Group 3: Olopatadine 0.1 mg/kg + Phenylephrine 30 mg/kg
Group 4: olopatadine 0.1 mg/kg + belladonna 0.6 mg/kg + phenylephrine 30 mg/kg
Group 5: Olopatadine 0.1 mg/kg + glycyrrhizic acid 200 mg/kg
Group 6: olopatadine 0.1 mg/kg + belladonna 0.6 mg/kg + glycyrrhizic acid 200 mg/kg
Group 7: olopatadine 0.1 mg/kg + tranexamic acid 100 mg/kg
Group 8: Olopatadine 0.1 mg/kg + tranexamic acid 100 mg/kg + phenylephrine 30 mg/kg
Group 9: olopatadine 0.1 mg/kg + tranexamic acid 100 mg/kg
+ Methylephedrine 110 mg/kg
Group 10: Olopatadine 0.1 mg/kg + tranexamic acid 100 mg/kg + caffeine 150 mg/kg
Group 11: Olopatadine 0.1 mg/kg + tranexamic acid 100 mg/kg + phenylephrine 30 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 20 mL.

1-2. Test Method Five-week-old male Crij:WI rats (Charles River Japan, Inc.) were quarantined for 5 days, and then acclimatized for 2 to 4 days. After acclimatization, the animals were divided into groups (5 animals per group) using the body weight measurement results, and the test substance was orally administered using a sonde. Thirty minutes later, 0.1 ml of a bradykinin-plasmin solution was subcutaneously injected as an inflammatory agent into the right hind leg footpad to induce inflammation. The footpad volume was measured for each individual before grouping and 60 minutes after inflammation, and the edema rate, the area under the curve, and the inhibition rate were calculated using the formulas described later.

1-3. Measurement of paw volume and calculation of edema rate, area under the curve (AUC) and inhibition rate 101CMP (manufactured by Unicom Co., Ltd.) was used to measure the right hind leg paw volume (mL). The edema rate was calculated for each individual using the following formula from the footpad volume before grouping and the footpad volume at each measurement time.

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

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

Furthermore, from the AUC _0-1hr value of the inflammation control group (group 0) and the AUC _0-1hr value of each drug group (groups 1-6), the inhibition rate of each drug group was calculated using the following formula: Calculated.

1.4. Test Results Table 1 shows the test results.

In Table 1, the 2 groups in which olopatadine was administered in combination with belladonna had a lower edema suppression rate than the group in which olopatadine was administered alone, while the 4 groups in which olopatadine and belladonna were administered in combination with phenylephrine had lower edema suppression rates. Compared to the 3 groups combined with , the suppression rate of edema was remarkably improved, and a high anti-inflammatory effect was confirmed.

In addition, compared to Group 1, in which olopatadine was administered alone, Group 5, in which glycyrrhizic acid was administered in combination with olopatadine, had a lower edema suppression rate. Despite these results, the edema suppression rate was remarkably improved, confirming a high anti-inflammatory effect.

In addition, compared to the 1 group in which olopatadine was administered alone, the 7 groups in which olopatadine was administered in combination with tranexamic acid had a lower edema suppression rate. In group 9, in which methylephedrine was used in combination, and in group 10, in which caffeine was used in combination with olopatadine and tranexamic acid, the suppression rate of edema was significantly improved, confirming a high anti-inflammatory effect. Furthermore, 11 groups in which phenylephrine and caffeine were used in combination with olopatadine and tranexamic acid were confirmed to have extremely high anti-inflammatory effects.

(Test Example 2) Anti-inflammatory test on bradykinin-plasmin paw edema using rats 2-1. Test Substances and Inflammatory Reagents In this test, methyl cellulose manufactured by Shin-Etsu Chemical Co., Ltd., olopatadine hydrochloride (hereinafter, olopatadine) manufactured by TORONTO RESEARCH CHEMICAL SINC, and belladonna total alkaloids (hereinafter, belladonna) were used. was manufactured by Alps Pharmaceutical Industry Co., Ltd., and glycyrrhizic acid was manufactured by Alps Pharmaceutical Industry Co., Ltd. Bradykinin from Fujifilm Wako Pure Chemical Industries, Ltd. and Human Plasmin (hereinafter referred to as plasmin) from Haemagtological Technology Inc were used.

(specimen)
Group 0: Vehicle (0.5% methylcellulose) *Inflammatory control group Group 1: Olopatadine 0.1 mg/kg
Group 2: belladonna 0.006 mg/kg
Group 3: glycyrrhizic acid 2.0 mg/kg
Group 4: olopatadine 0.1 mg/kg + belladonna 0.006 mg/kg + glycyrrhizic acid 2.0 mg/kg

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

2-2. Test Method A test was performed in the same manner as in Test Example 1, “1-2. Test Method”.

2-3. Measurement of footpad volume and calculation of edema rate, area under the curve (AUC) and inhibition rate Test Example 1 "1-3. Measurement of footpad volume and calculation of edema rate, area under the curve (AUC) and inhibition rate" The inhibition rate of each drug group was calculated by the same method as described above.

2-4. Test Results Table 2 shows the test results.

In Table 2, the 4 groups in which olopatadine, belladonna and glycyrrhizic acid were administered in combination were compared with the edema suppression rate in group 1 in which olopatadine was administered alone, group 2 in which belladonna was administered alone, and group 3 in which glycyrrhizic acid was administered alone. As a result, the suppression rate of edema was remarkably improved, confirming a high anti-inflammatory effect.

Production examples are shown below. In addition, the numerical value indicates the compounding amount per day of the component contained in the formulation.
(Production example 1)
Using the following ingredients, manufacture tablets according to the Japanese Pharmacopoeia General Rules for Preparations "Tablets".
Acetaminophen 900mg
Olopatadine hydrochloride 10 mg
Dextromethorphan hydrobromide hydrate 48mg
60 mg of dl-methylephedrine hydrochloride
Bromhexine hydrochloride 12mg
Belladonna total alkaloids 0.3mg
Glycyrrhizic acid 39mg
Anhydrous caffeine 60mg
Benfotiamine 24mg
Microcrystalline cellulose appropriate amount Carmellose appropriate amount Hydroxypropyl cellulose appropriate amount Magnesium stearate appropriate amount Hypromellose appropriate amount Macrogol appropriate amount Titanium oxide appropriate amount

(Formulation example 2)
After mixing ingredients other than magnesium stearate using the following ingredients, the mixture was granulated to produce granules. Furthermore, magnesium stearate is added to the granules and the mixture is encapsulated in hard capsules to produce capsules.
Pseudoephedrine hydrochloride 120mg
Phenylephrine hydrochloride 10 mg
Olopatadine hydrochloride 10 mg
Belladonna Total Alkaloids 0.4mg
Glycyrrhizic acid 45mg
Anhydrous caffeine 100mg
Benfotiamine 24mg
Corn starch appropriate amount Lactose appropriate amount Crystalline cellulose appropriate amount Carmellose calcium appropriate amount Hydroxypropyl cellulose appropriate amount Magnesium stearate appropriate amount

(Production example 3)
Using the following ingredients, manufacture tablets according to the Japanese Pharmacopoeia General Rules for Preparations "Tablets".
Ibuprofen 600mg
Olopatadine hydrochloride 10 mg
Dihydrocodeine phosphate 24mg
60 mg of dl-methylephedrine hydrochloride
Bromhexine hydrochloride 12mg
Belladonna total alkaloids 0.3mg
Glycyrrhizic acid 39mg
Anhydrous caffeine 60mg
Benfotiamine 24mg
Microcrystalline cellulose appropriate amount Carmellose appropriate amount Hydroxypropyl cellulose appropriate amount Magnesium stearate appropriate amount Hypromellose appropriate amount Macrogol appropriate amount Titanium oxide appropriate amount Carnauba wax appropriate amount

(Formulation example 4)
After mixing ingredients other than magnesium stearate using the following ingredients, the mixture was granulated to produce granules. Furthermore, magnesium stearate is added to the granules and the mixture is encapsulated in hard capsules to produce capsules.
Pseudoephedrine hydrochloride 120mg
Phenylephrine hydrochloride 10 mg
Olopatadine hydrochloride 10 mg
tranexamic acid 420mg
Glycyrrhizic acid 45mg
Anhydrous caffeine 100mg
Benfotiamine 24mg
Corn starch appropriate amount Lactose appropriate amount Crystalline cellulose appropriate amount Carmellose calcium appropriate amount Hydroxypropyl cellulose appropriate amount Magnesium stearate appropriate amount

(Production example 5)
Using the following ingredients, manufacture tablets according to the Japanese Pharmacopoeia General Rules for Preparations "Tablets".
Loxoprofen 180mg
Tranexamic acid 750mg
Olopatadine hydrochloride 10 mg
Dextromethorphan hydrobromide hydrate 48mg
60 mg of dl-methylephedrine hydrochloride
Bromhexine hydrochloride 12mg
Glycyrrhizic acid 39mg
Anhydrous caffeine 60mg
Benfotiamine 24mg
Microcrystalline cellulose appropriate amount Carmellose appropriate amount Hydroxypropyl cellulose appropriate amount Magnesium stearate appropriate amount Hypromellose appropriate amount Macrogol appropriate amount Titanium oxide appropriate amount Carnauba wax appropriate amount

Claims (7)

(a) olopatadine or a salt thereof;
(b) belladonna or an extract thereof; and (c) phenylephrine or a salt thereof;
A pharmaceutical composition for anti- bradykinin-induced edema comprising: 2. The pharmaceutical composition according to claim 1, wherein the olopatadine or salt thereof is olopatadine hydrochloride. 3. The pharmaceutical composition according to claim 1 or 2, wherein the belladonna or its extract is a belladonna total alkaloid. 4. The pharmaceutical composition according to any one of claims 1 to 3 , wherein phenylephrine or a salt thereof is phenylephrine hydrochloride. 5. The pharmaceutical composition according to any one of claims 1 to 4, which is used for prevention or treatment of rhinitis. 5. The pharmaceutical composition according to any one of claims 1 to 4 for alleviating symptoms of colds. Claims 1 to 6, wherein the daily dosage for adults of olopatadine or its salt is 1 mg to 20 mg, and the daily dosage for adults of belladonna or its extract is 0.1 mg to 10 mg. The pharmaceutical composition according to any one of