Medicament

Abstract

Provided is a technique for suppressing discoloration that occurs when at least one selected from the group consisting of rupatadine, a salt thereof and a solvate thereof is enclosed in an airtight package.SOLUTION: A pharmaceutical product comprising a pharmaceutical composition packaged in an airtight package, the pharmaceutical composition comprising the following components (A) and (B-2): (A) one or more selected from the group consisting of rupatadine, a salt thereof and a solvate thereof; and (B-2) one or more selected from glycyrrhetinic acids.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceuticals and the like. [Background technology]

[0002] Rhinitis is a disease characterized by symptoms such as sneezing, runny nose (excessive nasal discharge), and nasal congestion. These symptoms are not only unpleasant, but can also have a significant impact on daily life, making it difficult to concentrate at work and disrupting sleep.

[0003] Rupatadine is known as a therapeutic agent for rhinitis caused by allergic reactions, particularly those caused by pollen, house dust, etc., and has selective histamine H1 receptor antagonism as well as antagonistic activity against PAF (platelet-activating factor), a chemical mediator involved in inflammation, bronchoconstriction, etc. (Non-patent document 1). Rupatadine (chemical name: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine) has the following formula:

[0004] [ka]

[0005] It is a compound represented by the formula: [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Package insert "Rupafin Tablets 10mg" Mitsubishi Tanabe Pharma Corporation, June 2022 Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have discovered that discoloration occurs when rupatadine is stored in an airtight package. Therefore, an object of the present invention is to provide a new means for suppressing discoloration of one or more selected from the group consisting of rupatadine, a salt thereof, and a solvate thereof during storage. [Means for solving the problem]

[0008] Therefore, the present inventors have conducted extensive research to solve the above-mentioned problems, and have found that by further adding a xanthine derivative typified by caffeine (hereinafter sometimes referred to as "component (B-1)"), or a glycyrrhetinic acid typified by dipotassium glycyrrhizinate or licorice extract powder (hereinafter sometimes referred to as "component (B-2)"; components (B-1) and (B-2) may be collectively referred to as "component (B)") to a pharmaceutical composition containing one or more members selected from the group consisting of rupatadine, its salts, and solvates thereof, discoloration when the composition is sealed in an airtight package and stored can be significantly suppressed compared to a composition not containing component (B), and have completed the present invention.

[0009] That is, the present invention provides a composition comprising the following components (A) and (B): (A) one or more selected from the group consisting of rupatadine, a salt thereof, and a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Xanthine derivatives (B-2) Glycyrrhetinic acid The pharmaceutical composition is packaged in an airtight package. [Effects of the Invention]

[0010] According to the present invention, discoloration of a pharmaceutical composition containing one or more selected from the group consisting of rupatadine, a salt thereof, and a solvate thereof can be suppressed when the pharmaceutical composition is enclosed in an airtight package, thereby providing a pharmaceutical having excellent storage stability. DETAILED DESCRIPTION OF THE INVENTION

[0011] <Component (A)> As used herein, "one or more selected from the group consisting of rupatadine, a salt thereof, and a solvate thereof" includes not only rupatadine itself, but also pharmaceutically acceptable salts of rupatadine, and solvates of rupatadine itself or a pharmaceutically acceptable salt thereof with water, alcohol, etc. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate; metal salts such as sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt; amine salts such as ammonia, trimethylamine, triethylamine, pyridine, collidine, and lutidine; and organic base salts such as lysine and arginine. These may be used alone or in appropriate combination of two or more.

[0012] Component (A) is preferably at least one member selected from the group consisting of rupatadine, its inorganic acid salts, its organic acid salts, and solvates thereof, with rupatadine fumarate being particularly preferred. Component (A) is a known component and can be produced by known methods, or a commercially available product such as that manufactured by LEE PHARMA LIMITED can be used.

[0013] The content of component (A) in the pharmaceutical composition is not particularly limited and may be determined appropriately depending on the gender, age, symptoms, etc. of the recipient. For example, the pharmaceutical composition may contain an amount that allows the recipient to take 0.1 to 300 mg, more preferably 0.5 to 200 mg, and particularly preferably 1 to 150 mg of component (A) per day in terms of the free form.

[0014] In the present invention, component (A) is preferably contained in a total amount of 0.1 to 75 mass %, more preferably 0.5 to 65 mass %, and particularly preferably 1 to 55 mass %, of the total mass of the pharmaceutical composition in terms of free form.

[0015] <Component (B-1)> As used herein, the "xanthine derivative" is preferably a compound represented by the following general formula (1).

[0016] [ka]

[0017] [In formula (1), R 1 and R 2 each independently represents a hydrogen atom or a methyl group, R 3 represents a hydrogen atom, a methyl group, a monohydroxypropyl group, or a dihydroxypropyl group.

[0018] In formula (1), R 3 In the above, the monohydroxypropyl group is preferably a 2-hydroxypropyl group, and the dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

[0019] In the above general formula (1), (1)R 1 is a methyl group, and R 2 is a methyl group, and R 3 When the group is a methyl group, it means caffeine. (2)R 1 is a methyl group, and R 2 is a methyl group, and R 3 When is a hydrogen atom, it means theophylline. (3)R 1 is a hydrogen atom, and R 2 is a methyl group, and R 3 When the is a methyl group, it means theobromine. (4)R 1 is a methyl group, and R2 is a hydrogen atom, and R 3 When the group is a methyl group, it means paraxanthine. (5)R 1 is a methyl group, and R 2 is a methyl group, and R 3 When is a 2-hydroxypropyl group, it means proxyphilin. (6)R 1 is a methyl group, and R 2 is a methyl group, and R 3 When is a 2,3-dihydroxypropyl group, it means diprophylline.

[0020] The compound represented by formula (1) is known, and in the present invention, a compound produced by a known method or a commercially available compound can be used, such as anhydrous caffeine (Shizuoka Caffeine Industry Co., Ltd.).

[0021] In the present invention, the xanthine derivative may be the compound represented by the above general formula (1) itself, or a pharmaceutically acceptable salt thereof (e.g., a double salt thereof (e.g., sodium benzoate caffeine (a double salt of sodium benzoate and caffeine), aminophylline (a double salt of theophylline and ethylenediamine)), or a solvate of the compound represented by the general formula (1) or a salt thereof with water, alcohol, or the like; these are also encompassed by the term "xanthine derivative," and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprophylline) also encompass the compound, its salt, and solvate thereof. Note that, in the present invention, one or more of the xanthine derivatives may be used.

[0022] From the viewpoint of suppressing discoloration of component (A), the xanthine derivative is preferably at least one selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprophylline, and particularly preferably at least one selected from the group consisting of caffeine, its salts, and solvates thereof. As the at least one selected from the group consisting of caffeine, its salts, and solvates thereof, preferably at least one selected from the group consisting of caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate, and particularly preferably at least one selected from the group consisting of caffeine hydrate, anhydrous caffeine, and sodium caffeine benzoate.

[0023] The content of component (B-1) in the pharmaceutical composition is not particularly limited and may be determined appropriately depending on the degree of discoloration of component (A). For example, the pharmaceutical composition may contain an amount that allows the component (B-1) to be taken daily in an amount of 10 to 1000 mg, more preferably 20 to 800 mg, and particularly preferably 30 to 600 mg, calculated as the free form. In the present invention, from the viewpoint of suppressing discoloration of component (A), component (B-1) is preferably contained in a total amount of 0.4 to 65 mass %, more preferably 0.8 to 60 mass %, and particularly preferably 1.6 to 50 mass %, calculated as the free form, relative to the total mass of the pharmaceutical composition.

[0024] The mass ratio of component (A) to component (B-1) contained in the pharmaceutical composition is not particularly limited, but from the viewpoint of suppressing discoloration of component (A), the pharmaceutical composition preferably contains 0.1 to 55 parts by mass, more preferably 0.5 to 35 parts by mass, and particularly preferably 1 to 25 parts by mass of component (B-1) in free form per 1 part by mass of component (A) in free form.

[0025] <Component (B-2)> In the present invention, the term "glycyrrhetinic acids" refers to one or more compounds selected from the group consisting of glycyrrhetinic acid and its derivatives (e.g., glycyrrhetinic acid, sugar-added derivatives of glycyrrhetinic acid such as glycyrrhizinic acid, etc.), and pharmaceutically acceptable salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). In the present invention, from the viewpoint of the discoloration inhibiting effect of component (A), the glycyrrhetinic acid is preferably one or more selected from the group consisting of glycyrrhizinic acid and its salts, more preferably one or more selected from the group consisting of glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate and trisodium glycyrrhizinate, even more preferably one or more selected from the group consisting of glycyrrhizinic acid and dipotassium glycyrrhizinate, with dipotassium glycyrrhizinate being particularly preferred.

[0026] Furthermore, glycyrrhetinic acids may be used as glycyrrhetinic acids, such as licorice (liquorice root) or its extract. Here, "licorice" (liquorice root) refers to the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and also encompasses the roots and stolons from which the periderm has been removed (peeled licorice) (18th Revised Japanese Pharmacopoeia). The form of licorice can be adjusted as needed, and it can be cut or crushed into small pieces or chunks, or pulverized into powder. For example, "licorice powder," which is licorice powder, can also be used. Furthermore, in consideration of ease of handling during the production of pharmaceutical compositions, "licorice extract," which is licorice that has been subjected to some kind of extraction treatment, may also be used. Here, the "licorice extract" also encompasses those that have been subjected to processing treatments such as heating, drying, and pulverization in addition to extraction treatment. Specifically, the term "licorice extract" encompasses a liquid obtained by slicing licorice to an appropriate size as needed and then adding an appropriate infusion (extraction solvent) to the liquor, a concentrated liquid of the infusion (soft extract, tincture, etc.), and further a dried version of these (dried extract, etc.). Licorice and its extracts may also be those contained in herbal medicine prescriptions such as Kakkonto (Kakkonto), Keishito (Keishito), Kousosan (Kousosan), Saikokeishito (Saikokeishito), Shosaikoto (Shosaikoto), Shoseiryutou (Shoseiryutou), Bakumondoutou (Bakumondoutou), and Maoto (Maoto). In the present invention, the licorice or extract thereof is preferably the licorice, licorice powder, licorice extract, or crude licorice extract described in the 18th revised Japanese Pharmacopoeia.

[0027] The method for producing licorice extract is not particularly limited, and can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts," "Infusions / Decoctions," "Tinctures," and "Liquid Extracts" sections of the General Provisions for Preparations in the 18th Edition of the Japanese Pharmacopoeia. For example, licorice can be produced by cutting, heating, drying, or pulverizing licorice as needed, and then adding an appropriate extraction solvent to carry out extraction. The obtained extract may be further concentrated, dried, or the like, as needed.

[0028] Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin; ethers such as diethyl ether; ketones such as acetone and ethyl methyl ketone; esters such as ethyl acetate; nitriles such as acetonitrile; alkanes such as pentane, hexane, cyclopentane, and cyclohexane; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination of two or more. In the present invention, water, lower monohydric alcohols such as ethanol, or mixtures of water and lower monohydric alcohols are preferred, with water, ethanol, or mixtures of water and ethanol being particularly preferred. The extraction procedure is not particularly limited, and any known method used for extraction from plants can be employed, such as immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. To increase the extraction efficiency, stirring or homogenization in the extraction solvent may be performed. The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably from about 5°C to a temperature below the boiling point of the extraction solvent. The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably about 1 hour to 14 days.

[0029] In the present invention, the content of component (B-2) in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration. However, from the viewpoint of the effect of inhibiting discoloration of component (A), the content of component (B-2) is preferably 0.5 to 75% by mass, more preferably 1 to 70% by mass, and particularly preferably 3 to 60% by mass, of the total mass of the pharmaceutical composition, calculated as the free form. In particular, when one or more members selected from the group consisting of glycyrrhizinic acid and its salts are used as component (B-2), from the viewpoint of the discoloration-inhibiting effect of component (A), the content of glycyrrhizinic acid is preferably 0.01 to 5% by mass in total, more preferably 0.05 to 3% by mass, and particularly preferably 0.1 to 1% by mass, calculated as the free form of glycyrrhizinic acid, relative to the total mass of the pharmaceutical composition. Furthermore, when one or more members selected from the group consisting of licorice and its extracts are used as component (B-2), the total amount of the member(s) is preferably 0.05 to 200% by mass, more preferably 0.25 to 150% by mass, and particularly preferably 0.5 to 100% by mass, calculated as the crude drug, relative to the total mass of the pharmaceutical composition.

[0030] Furthermore, in the present invention, the mass ratio of component (A) to component (B-2) contained in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration. However, from the viewpoint of the discoloration-inhibiting effect of component (A), the pharmaceutical composition preferably contains 0.001 to 150 parts by mass, more preferably 0.005 to 70 parts by mass, and particularly preferably 0.01 to 30 parts by mass of component (B-2) in its free form per 1 part by mass of component (A) in its free form.

[0031] The pharmaceutical composition may contain, as an active ingredient, one or more ingredients other than those mentioned above, such as antipyretics, analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics and sedatives, vitamins, anti-inflammatory agents, gastric mucosa protective agents, antacids, anticholinergics, herbal medicines, and herbal prescriptions.

[0032] Examples of antipyretic analgesics include aspirin, aluminum aspirin, acetaminophen, ibuprofen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, loxoprofen, and sodium salicylate. Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyldisulfonate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, and diphenylpyraline hydrochloride. , diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine methylenedisalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydroline napadisilate, loratadine and the like.

[0033] Examples of antitussives include codeines such as codeine, codeine phosphate hydrate, dihydrocodeine, and dihydrocodeine phosphate, as well as alloclamide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, and dextromethorphan phenolphthalin salt.

[0034] Examples of noscapines include noscapine hydrochloride and noscapine. Examples of bronchodilators include trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, methoxyphenamine hydrochloride, etc.

[0035] Examples of expectorants include ammonia, fennel extract, ethylcysteine ​​hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, methylcysteine ​​hydrochloride, l-menthol, and lysozyme hydrochloride.

[0036] Examples of hypnotic sedatives include allylisopropylacetylurea and bromvalerylurea. Examples of vitamins include vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, hesperidin and its derivatives and salts thereof (e.g., thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibutiamine, bis-bentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

[0037] Anti-inflammatory agents include, for example, arnica tincture, seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain, and the like.

[0038] Examples of gastric mucosa protecting agents include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like. Examples of antacids include aminoacetic acid, magnesium aluminosilicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium alumina hydroxide, aluminum hydroxide gel, dried aluminum hydroxide gel, dried mixed gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, co-precipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, magnesium hydroxide, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bone, stone jelly, and sea urchin.

[0039] Examples of anticholinergic agents include oxyphencyclamine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, Datura extract, tipepidium bromide, methylatropine bromide, methylanisotropine bromide, methylscopolamine bromide, methyl-l-hyoscyamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia extract, Scopolia root, and Scopolia root total alkaloid citrate.

[0040] Examples of crude drugs include Mallotus japonicus (Mallotus japonicus), Asarum japonica (Asarum japonica), Euonymus chinensis (Euonymus chinensis), Fennel (Fennel), Corydalis chinensis (Corydalis chinensis), Scutellaria baicalensis (Scutellaria baicalensis), Phellodendron bark (Phellodendron bark), Coptis chinensis (Coptis chinensis), Onji (Citrus orientalis), Zedoary (Citrus zedoary), Valerian (Valeriana japonica), Chamomile, Calonin (Carolina chinensis), Platycodon grandiflorum (Platycodon grandiflorum), and Apricot kernel ( Apricot kernel, wolfberry, wolfberry leaf, mustard green, cinnamon bark, Cassia berry, gentian, geranium herb, magnolia berry, bezoar, schisandra berry, asarum, Chinese pepper, asarum, Chinese peony, musk, Shajin, Shazenshi , Shazensou (Winged Carrot), Animal Gall (including Yutan (Bear Gall)), Shokyo (Ginger), Jiryu (Earth Dragon), Shini (Magnolia), Sekisan (Garlic), Senega (Wood), Cnikyu (Czech Root), Zenko (Chinese Huang), Swertia bristlecone, Soujutsu (Atractylodes Root), Sohakuhi (Mulberry Bark), Soyou (Perilla Leaf), Taisan (Garlic), Chikusetsuninjin (Bamboo Joint Ginseng), Clove, Chinpi (Citrus Citrus Peel) Examples of herbal medicines include Angelica acutiloba (Angelica Root), Ipecac (Ipecac Root), Nandina Fruit, Ginseng, Fritillaria Root, Ophiopogon, Pinellia Root, Saffron Flower, Anemone Root, Angelica Root, Atractylodes Rhizome, Poria Cocos, Peony Bark, and Deer Antler, as well as extracts thereof (extracts, tinctures, dried extracts, etc.).

[0041] Examples of Chinese herbal medicine prescriptions include Hange Koubokuto (Hange Koubokuto).

[0042] The dosage form of the "pharmaceutical composition" herein is not particularly limited and may be any of solid, semi-solid, or liquid preparations, and can be selected depending on the intended use, etc. Examples of dosage forms of pharmaceutical compositions include those described in the General Provisions of Preparations in the 18th Edition of the Japanese Pharmacopoeia. For example, dosage forms for oral administration include solid preparations such as tablets (e.g., regular tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (e.g., effervescent granules, etc.), powders, and pills; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (e.g., elixirs, suspensions, emulsions, lemonades, etc.). Dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, solid preparations for topical application, liquid preparations for topical application, sprays, ointments, creams, gels, patches, etc.

[0043] The dosage form of the pharmaceutical composition is preferably a solid preparation from the viewpoint of ease of administration, and is particularly preferably a solid preparation selected from tablets (including, for example, normal tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, and pills.

[0044] Pharmaceutical compositions can be manufactured by known methods, depending on the dosage form, such as those described in the General Provisions for Preparations of the 18th Revised Japanese Pharmacopoeia. In this case, a pharmaceutically acceptable carrier (formulation additive) may be added to the pharmaceutical composition. Examples of such formulation additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymeric substances, antioxidants, pH adjusters, flavoring agents, and sweeteners. These formulation additives include, for example, those listed in the Pharmaceutical Additives Dictionary 2021 (published by Yakuji Nippo Co., Ltd.) and the Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press).

[0045] Examples of excipients include inorganic excipients such as aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; and organic excipients such as candy powder, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, reduced maltose syrup, powdered reduced maltose syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and calcium citrate. These may be used alone or in combination of two or more.

[0046] Examples of disintegrants include super disintegrants such as carboxymethyl starch sodium, croscarmellose sodium, and crospovidone, as well as carmellose, carmellose calcium, starch, sucrose fatty acid esters, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, povidone, and polyoxyethylene hydrogenated castor oil 60. These can be used alone or in combination of two or more.

[0047] Examples of binders include fats and oils such as hardened beef tallow oil, hardened oil, hydrogenated vegetable oil, hardened soybean oil, carnauba wax, white beeswax, beeswax, and Japan wax, as well as methyl cellulose, hydroxypropyl cellulose, hypromellose, carmellose sodium, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. These may be used alone or in combination of two or more.

[0048] Examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, etc. These can be used alone or in combination of two or more.

[0049] Examples of plasticizers include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), etc. These may be used alone or in combination of two or more.

[0050] Examples of film-forming agents include alkylcelluloses such as methyl cellulose and ethyl cellulose; alginic acid or a salt thereof such as sodium alginate; carrageenan; carboxyalkylcelluloses such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, potassium carboxymethyl cellulose, carboxymethyl cellulose, and carboxymethyl ethyl cellulose; xanthan gum; hydroxyalkylcelluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hypromellose (hydroxypropyl methylcellulose); hydroxyalkylcellulose phthalates such as hydroxypropyl methylcellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; and polyvinylpyrrolidone. These may be used alone or in combination of two or more.

[0051] Examples of powders include organic or inorganic powders such as talc, titanium oxide, yellow ferric oxide, ferric oxide, legal pigments, etc. These can be used alone or in combination of two or more.

[0052] Examples of poorly water-soluble polymeric substances include carboxyvinyl polymers, aminoalkyl methacrylate copolymers, etc. These may be used alone or in combination of two or more.

[0053] Examples of antioxidants include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole, etc. These can be used alone or in combination of two or more.

[0054] Examples of pH adjusters include organic acids or salts thereof such as citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and glacial acetic acid; inorganic acids or salts thereof such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, and sodium hydrogen carbonate; alkali hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide; and amines such as triethanolamine (2,2',2"-nitrilotriethanol), diethanolamine, and diisopropanolamine.

[0055] Examples of flavoring agents include terpenes such as limonene, pinene, camphene, cymene, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol, and cinzeylanol; terpene-containing essential oils such as spruce oil, orange oil, peppermint oil, camphor oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, and spearmint oil; and acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid, and salts thereof. These may be used alone or in combination of two or more.

[0056] Examples of sweeteners include aspartame, stevia, sucralose, thaumatin, acesulfame potassium, saccharin, and saccharin sodium, and these can be used alone or in combination of two or more.

[0057] The pharmaceutical composition can be prepared by a known method depending on the dosage form. For example, when the pharmaceutical composition is a solid preparation, it can be produced by appropriately combining unit operations such as pulverization, mixing, granulation, drying, sizing, classification, filling, tableting, and coating. More specifically, when the pharmaceutical composition is in the form of a granular preparation such as granules, powders, or pills, the pharmaceutical composition can be produced by mixing all or a part of component (A) and component (B), and optionally other active ingredients, formulation additives such as excipients, binders, disintegrants, and lubricants, and then granulating the mixture by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, or crushing granulation to obtain a granulated product, which can then be further classified, sized, etc., as necessary. The obtained granulated product can also be coated with a coating agent or the like by a known method. When the pharmaceutical composition is in the form of a tablet, it can be produced by mixing all or part of component (A) and component (B), and, if necessary, other medicinal ingredients, and appropriate formulation additives such as excipients, binders, disintegrants, and lubricants, to obtain a mixture, and then directly compressing (tabletting) this mixture (direct powder compression method), or by compressing (tabletting) the above-mentioned granules after classifying and sizing them as necessary (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). The obtained compressed product (tablet) can also be coated with a coating agent or the like by a known method. Furthermore, when the dosage form of the pharmaceutical composition is a capsule, the above-mentioned granulated or compressed product may be filled into the capsule.

[0058] The pharmaceutical composition of the present invention is further housed in an airtight package (hereinafter, in this specification, a pharmaceutical composition housed in an airtight package will be referred to as a "drug.") In the present invention, the pharmaceutical may further comprise, in addition to the airtight package, a package that does not fall under the category of "airtight package" described below, and the pharmaceutical composition may be housed directly or indirectly in the airtight package. As used herein, the term "airtight packaging" refers to packaging that can prevent the intrusion of solid or liquid foreign matter under normal handling, transportation, storage, and other conditions, and is a concept that encompasses "airtight containers" and "sealed containers" as defined in the General Rules of the 18th Edition of the Japanese Pharmacopoeia. Airtight packaging can be of either a fixed or irregular shape, and examples include bottle packaging, SP (Strip Package) packaging, PTP (Press-Through Package) packaging, pillow packaging, and stick packaging. The airtight packaging may also be a combination of these, such as a pharmaceutical composition first packaged in a PTP package and then packaged in a pillow packaging. From the viewpoint of preventing discoloration of the pharmaceutical composition, the airtight packaging is preferably one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging, and is particularly preferably one that includes at least PTP packaging (a combination of PTP packaging and, if necessary, other packaging such as bottle packaging, SP packaging, pillow packaging, or stick packaging), or one that includes at least bottle packaging.

[0059] The packaging material (raw material) of the airtight packaging body is not particularly limited, and for example, materials used in the fields of pharmaceuticals, food, etc., such as glass, plastics (polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyethylene (including low density (LDPE), medium density (MDPE), and high density (HDPE)), polyolefins such as polypropylene; polycarbonate; polystyrene, etc.), and metals (aluminum, etc.), can be used alone or in combination of two or more types as appropriate.

[0060] For example, packaging materials used for bottle packaging are not particularly limited, and examples include glass, plastic, metal, etc., and one or more of these can be combined as appropriate. Preferred materials for bottle packaging are glass, polyethylene, and polypropylene, more preferably glass, low-density polyethylene (LDPE), and high-density polyethylene (HDPE), and particularly preferably glass and high-density polyethylene (HDPE). For bottle packaging, for example, an appropriate amount of pharmaceutical composition is placed in a bottle, which is then sealed with an appropriate stopper or lid. The size of the bottle may be selected appropriately depending on the amount of pharmaceutical composition to be placed, and the bottle capacity is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL.

[0061] Furthermore, packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are not particularly limited, and examples thereof include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glycol-modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), ionomer resin (IO ), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid polyvinyl chloride (VSC), and other resins, as well as metal foils such as aluminum foil (AL), and one or more of these can be used in combination as appropriate.

[0062] When SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are produced, a sheet using one or more of the above-mentioned packaging materials may be produced by a known method, and in this case, the packaging materials may be appropriately combined to form a multilayer structure. A method for producing a multilayer structure using two or more packaging materials as a sheet includes a method of laminating the packaging materials to produce a laminated sheet. Laminated sheets can be produced by known methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. Furthermore, sheets for SP packaging, PTP packaging, pillow packaging, and stick packaging can also be commercially available products.

[0063] Among the above-mentioned sheets, examples of single-layer sheets using one type of packaging material include PVC sheets and CPP sheets, and examples of laminated sheets using two or more types of packaging materials include, but are not limited to, sheets laminated with PVC and PVDC (PVC / PVDC; hereinafter the same abbreviation), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, and CPP / CPP / CPP (the above-mentioned sheets use two or more types of CPP).

[0064] An example of a PTP packaging configuration is to store pharmaceutical compositions one by one or one dosage unit in a desired number of pockets formed in a resin sheet or the like by a known method, and then cover the pockets with a sheet made of a metal foil such as aluminum foil. It is also possible to use a so-called double-sided aluminum PTP package, in which the sheet used to form the pockets is also made of aluminum foil. In the present invention, from the viewpoint of preventing discoloration of the pharmaceutical composition, it is preferable to further package the PTP package in a pillow package (e.g., aluminum pillow package). Examples of the SP packaging, pillow packaging, and stick packaging include packaging the pharmaceutical composition individually or in individual dosage units using a known method, using a resin sheet, a sheet made of aluminum foil, etc. In the present invention, it is preferable to use a sheet made of aluminum foil from the viewpoint of suppressing discoloration of the pharmaceutical composition.

[0065] In this specification, the occupancy rate (volume rate) of a pharmaceutical composition in a package of a pharmaceutical product is typically 25 to 90%, preferably 28 to 75%, and more preferably 30 to 50% when the package is a bottle. Furthermore, when the package is a SP package, PTP package, pillow package, or stick package, the occupancy rate is typically 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. In this case, the occupancy rate refers to the occupancy rate of the pharmaceutical composition relative to the total volume inside the package; fillers, inner stoppers, and the like used to prevent damage to the pharmaceutical composition stored inside the package are not taken into consideration when calculating the space occupancy rate.

[0066] As the airtight packaging body, commercially available packaging bodies may be used as they are, or commercially available packaging materials may be processed and used. Examples of commercially available bottle packaging bodies include glass bottles (manufactured by Isoya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), and the Z-series (manufactured by Hanshin Chemical Industry Co., Ltd.). Examples of commercially available pillow packaging bodies include Lamizip (registered trademark) (manufactured by Seisan Nippon Sha). Examples of packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include SUMILITE VSS, SUMILITE VSL, SUMILITE NS, and SUMILITE FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), the TAS series (manufactured by Taisei Chemical Co., Ltd.), PTP vinyl foil, and PTP super foil (manufactured by Mitsubishi Plastics, Inc.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Daiwa Chemical Industry Co., Ltd.).

[0067] The method for placing the pharmaceutical composition in the airtight package is not particularly limited, and can be achieved by placing the pharmaceutical composition in the package by any appropriate means, such as by pouring the pharmaceutical composition into the package. In this case, a desiccant (e.g., a cylindrical (tablet) or sheet-shaped desiccant) may be poured into the package together with the pharmaceutical composition.

[0068] In the present invention, the pharmaceutical composition or drug contains rupatadine, a second-generation antihistamine, and also contains a xanthine derivative exhibiting central stimulant, cardiotonic, diuretic, and smooth muscle relaxant effects, and / or glycyrrhetinic acids, an anti-inflammatory agent, and is therefore particularly effective for treating or alleviating rhinitis symptoms. Therefore, the pharmaceutical composition or drug can be suitably used for treating or alleviating rhinitis symptoms, more specifically, for treating or alleviating symptoms caused by acute rhinitis, allergic rhinitis, or sinusitis (sneezing, runny nose (excessive nasal discharge), nasal congestion, watery eyes, sore throat, heavy head, etc.), or cold symptoms (runny nose, nasal congestion, sneezing, etc.), and can be used, for example, as an oral medication for rhinitis or a cold medicine (cold medicine). The present invention can be suitably used to treat or alleviate symptoms of rhinitis not caused by colds, particularly alleviating nasal allergy symptoms (sneezing, runny nose, stuffy nose) caused by pollen, house dust (indoor dust), etc.

[0069] The route of administration of the pharmaceutical composition is not particularly limited and can be determined appropriately depending on the disease to be treated, the type of formulation, the gender, age, symptoms, etc. of the recipient, but oral administration is preferred from the viewpoint of ease of administration. Furthermore, the pharmaceutical composition can be taken in divided doses about 1 to 4 times a day, before meals, between meals, after meals, before bedtime, etc.

[0070] The present specification discloses the following embodiments, for example, but is not limited to these. [1A] The following components (A) and (B): (A) one or more compounds selected from the group consisting of rupatadine, salts thereof, and solvates thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Xanthine derivatives (B-2) Glycyrrhetinic acid A pharmaceutical product comprising a pharmaceutical composition containing the above-mentioned compound packaged in an airtight package. [2A] The pharmaceutical product according to [1A], wherein component (B-1) is one or more selected from the group consisting of caffeine and its salts and solvates thereof, and component (B-2) is one or more selected from the group consisting of glycyrrhizinic acid and its salts, and licorice and its extracts. [3A] A pharmaceutical product according to [1A] or [2A], wherein the pharmaceutical composition is a solid formulation. [4A] The pharmaceutical product according to any one of [1A] to [3A], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder, or pill. [5A] The pharmaceutical product according to any one of [1A] to [4A], wherein the airtight packaging is one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging. [Example]

[0071] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In the following test examples, the amount of each component used is the amount of the indicated component itself, unless otherwise specified as a converted amount.

[0072] [Test Example 1] Storage test Samples 1 to 5 shown below were prepared and then stored at 60°C, and the presence or absence of discoloration of the samples was visually confirmed after 14 days. The results are shown in Table 1.

[0073] [Sample 1] Rupatadine fumarate was placed in an open glass container and used as Sample 1. [Sample 2] 0.3 g of rupatadine fumarate was placed in a glass bottle (Thermo Fisher Scientific: screw cap vial C5000-192W, capacity 1.5 mL) and the bottle was capped. This was designated Sample 2. [Sample 3] A mixture was obtained by mixing 1 part by mass of rupatadine fumarate with 1 part by mass of anhydrous caffeine, and 0.3 g of the mixture was placed in a glass bottle (Thermo Fisher Scientific: screw cap bottle C5000-192W, capacity 1.5 mL) and the bottle was capped. This was designated Sample 3. [Sample 4] A mixture was obtained by mixing 1 part by mass of rupatadine fumarate and 1 part by mass of dipotassium glycyrrhizinate, and 0.3 g of the mixture was placed in a glass bottle (Thermo Fisher Scientific: screw cap bottle C5000-192W, capacity 1.5 mL) and capped. This was designated Sample 4. [Sample 5] A mixture was obtained by mixing 1 part by mass of rupatadine fumarate with 1 part by mass of licorice extract powder, and 0.3 g of the mixture was placed in a glass bottle (Thermo Fisher Scientific: screw cap bottle C5000-192W, capacity 1.5 mL) and capped. This was designated Sample 5.

[0074] [Table 1]

[0075] As is clear from the test results shown in Table 1, Sample 1, which contained only rupatadine fumarate that was not sealed in an airtight package, did not discolor after 14 days of storage at 60°C. On the other hand, Sample 2, which contained only rupatadine fumarate that was sealed in an airtight package, was found to discolor after 14 days of storage at 60°C. In contrast, Sample 3-5, which contained a component corresponding to component (B), did not discolor even after storage for 14 days.

[0076] The above test results demonstrate that the discoloration that occurs when component (A), such as rupatadine fumarate, is stored in an airtight package can be suppressed by adding component (B).

[0077] [Manufacturing Examples 1 to 6] Tablets containing the ingredients and amounts (mg) listed in Table 2 below per tablet (Production Examples 1 to 5: film-coated tablets, Production Example 6: orally disintegrating tablets) are produced by a conventional method, and the resulting tablets are packaged in press-through packages (PTPs) by a conventional method, then packaged in aluminum pillow bags, and then placed in a paper box to obtain the pharmaceuticals of Production Examples 1 to 6. In the tables below, the amount of each ingredient indicates the amount of the ingredient itself, unless otherwise specified as a converted amount.

[0078] [Table 2]

[0079] [Manufacturing Examples 7 to 12] Tablets (film-coated tablets) containing the ingredients and amounts (mg) per tablet shown in Table 3 below are produced by a conventional method, and the resulting tablets are bottled by a conventional method to obtain the pharmaceuticals of Production Examples 7 to 12. In the tables below, the amount of each ingredient indicates the amount of the ingredient itself, unless otherwise specified as a converted amount.

[0080] [Table 3]

[0081] [Manufacturing Example 13] An eye drop containing the following ingredients and amounts can be produced by a conventional method, and the resulting eye drop can be stored in an airtight container by a conventional method to obtain a pharmaceutical product. Note that the amount of each ingredient below indicates the amount of the ingredient itself, unless otherwise specified as a converted amount. Rupatadine fumarate 0.1% (w / v) Dipotassium glycyrrhizinate 0.25% (w / v) pH adjuster: appropriate amount Purified water...Remainder (total volume 100mL)

[0082] [Manufacturing Example 14] A semi-solid composition containing the ingredients and amounts listed below per 100 g is prepared by a conventional method, and then placed in a tube container (laminated tube) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film on the outer layer of that, to obtain a pharmaceutical preparation (gel). Note that the amount of each ingredient below indicates the amount of the ingredient itself, unless otherwise specified as a converted amount. Loxoprofen sodium hydrate 1.13g l-Menthol 3g Tocopherol acetate 2g Hypromellose, carboxyvinyl polymer, edetate sodium hydrate, 2,2',2"-nitrilotriethanol, polyoxyethylene behenyl ether, liquid paraffin, ethanol, purified water

[0083] [Manufacturing Example 15] A semi-solid composition containing the ingredients and amounts listed below per 100 g is prepared by a conventional method, and then placed in a tube container (laminated tube) made of laminated film, with a low-density polyethylene film as the innermost layer, aluminum foil as the outer layer (middle layer), and a low-density polyethylene film on the outer layer of that, to obtain a pharmaceutical preparation (gel). Note that the amount of each ingredient below indicates the amount of the ingredient itself, unless otherwise specified as a converted amount. Loxoprofen sodium hydrate 1.13g l-Menthol 3g Arnica tincture: 0.5g (equivalent to 0.1g of the original herb) Hypromellose, carboxyvinyl polymer, edetate sodium hydrate, 2,2',2"-nitrilotriethanol, polyoxyethylene behenyl ether, liquid paraffin, ethanol, purified water [Industrial Applicability]

[0084] According to the present invention, a pharmaceutical product containing one or more compounds selected from the group consisting of rupatadine, salts thereof, and solvates thereof, which have excellent pharmacological effects, and which has excellent storage stability, can be provided, and therefore can be used, for example, in the pharmaceutical industry.

Claims

1. The following components (A) and (B-2): (A) one or more selected from the group consisting of rupatadine, a salt thereof, and a solvate thereof; (B-2) one or more selected from glycyrrhetinic acids; A pharmaceutical product comprising a pharmaceutical composition containing the above-mentioned compound packaged in an airtight package.

2. 2. The pharmaceutical product according to claim 1, wherein the component (B-2) is at least one selected from the group consisting of dipotassium glycyrrhizinate and licorice extract powder.

3. The pharmaceutical product according to claim 1 or 2, wherein the pharmaceutical composition is a solid formulation.

4. The pharmaceutical product according to claim 1 or 2, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder or pill.

5. 3. The pharmaceutical product according to claim 1, wherein the airtight packaging is one or more types selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

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