Pharmaceutical

Abstract

To provide a technique for inhibiting increased adhesion to a container wall surface during storage by combining one or more selected from the group consisting of bilastine, salts thereof, and solvates thereof with a glycyrrhetinic acid.SOLUTION: A pharmaceutical comprises a pharmaceutical composition packaged in an airtight package, wherein the pharmaceutical composition comprises the following components (A) and (B): (A) one or more selected from the group consisting of bilastine, salts thereof, and solvates thereof; and (B) a glycyrrhetinic acid.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Bilastine, which has histamine H1 receptor antagonistic activity, is known as a therapeutic agent for pruritus associated with allergic rhinitis, urticaria, and skin diseases (eczema / dermatitis, cutaneous pruritus) (Non-Patent Document 1). Bilastine (chemical name: 2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid) has the following formula

[0003]

Chemical Formula

[0004] and is a compound represented by the formula.

[0005] On the other hand, glycyrrhetinic acids typified by dipotassium glycyrrhizinate and licorice extract powder are used for the treatment of eczema, cutaneous pruritus, cold symptoms, etc. because they have an anti-inflammatory effect.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The inventor has discovered that when a pharmaceutical composition containing one or more selected from the group consisting of bilastine and its salts and their solvates is further stored in the presence of glycyrrhetinic acids, the adhesiveness to the container wall increases. An increase in adhesiveness may lead to a decrease in yield due to adhesion to manufacturing equipment during pharmaceutical production, cause tableting problems due to adhesion to the pestle, or require cleaning. Therefore, an object of the present invention is to provide a new means for suppressing the increase in adhesiveness to the container wall when storing a composition containing one or more selected from the group consisting of bilastine and its salts and their solvates and glycyrrhetinic acids.

Means for Solving the Problems

[0008] Therefore, the inventor intensively studied to solve the above problems. As a result, it was found that by enclosing a pharmaceutical composition containing one or more selected from the group consisting of bilastine and its salts and their solvates and glycyrrhetinic acids in an airtight package, the increase in adhesiveness during storage can be significantly suppressed as compared with the case of not enclosing, and the present invention was completed.

[0009] That is, the present invention provides the following components (A) and (B): (A) One or more selected from the group consisting of bilastine and its salts and their solvates; (B) Glycyrrhetinic acids; and provides a pharmaceutical product in which a pharmaceutical composition containing the same is packaged in an airtight package.

Effects of the Invention

[0010] According to the present invention, it is possible to suppress an increase in adhesiveness to the container wall when storing a composition containing one or more selected from the group consisting of bilastine and its salts and their solvates and glycyrrhetinic acids. Therefore, it is possible to provide a pharmaceutical having excellent storage stability.

Modes for Carrying Out the Invention

[0011] <Component (A)> As used herein, "one or more selected from the group consisting of bilastine and its salts and their solvates" includes bilastine itself, pharmaceutically acceptable salts of bilastine, and further solvates of bilastine itself or its pharmaceutically acceptable salts with water, alcohol, etc. Here, the salts are not particularly limited as long as they are pharmaceutically acceptable salts. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, etc.; organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, etc.; metal salts such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, etc.; amine salts such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine, etc.; organic base salts such as lysine, arginine, etc. In addition, these can be used alone or in appropriate combinations of two or more.

[0012] As component (A), bilastine is preferred. Component (A) is a known component and can be produced by known methods, or commercially available products may be used. Examples of commercially available products include "Bilastine" (Sumitomo Chemical Co., Ltd.).

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

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

[0015] <Component (B)> In the present invention, the term "glycyrrhetinic acids" means one or more selected from the group consisting of glycyrrhetinic acid and its derivatives (for example, glycyrrhetinic acid, sugar-added derivatives of glycyrrhetinic acid such as glycyrrhizinic acid, etc.), and pharmaceutically acceptable salts thereof (for example, alkali metal salts such as potassium salt, sodium salt, etc.; ammonium salt, etc.). In the present invention, as the glycyrrhetinic acids, from the viewpoint of the therapeutic or alleviating effect on allergies and cold symptoms, one or more selected from the group consisting of glycyrrhizinic acid and its salts are preferable, one or more selected from the group consisting of glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate and trisodium glycyrrhizinate are more preferable, one or more selected from the group consisting of glycyrrhizinic acid and dipotassium glycyrrhizinate are even more preferable, and dipotassium glycyrrhizinate is particularly preferable.

[0016] In addition, as glycyrrhetinic acids, licorice (Glycyrrhiza) containing glycyrrhetinic acids or its extract may be used. Here, "licorice" means the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and includes the concept of those excluding the periderm (peeled licorice) (the 18th revised Japanese Pharmacopoeia). Licorice can be adjusted in its form as needed, and can be cut, crushed, or pulverized into small pieces, small lumps, or powder. For example, "licorice powder" obtained by pulverizing licorice can also be used. Also, in consideration of the convenience of handling during the production of pharmaceutical compositions, etc., "extract of licorice" obtained by subjecting licorice to some extraction treatment may be used. Here, the "extract of licorice" includes those subjected to processing treatments such as heating, drying, and pulverizing in addition to the extraction treatment. Specifically, after making licorice into an appropriate size as needed, a suitable leaching solution (extraction solvent) is added for leaching, or the concentrated solution of the leaching solution (soft extract, tincture, etc.), and further those obtained by drying these (dry extract, etc.) are also included in the "extract of licorice". In addition, as licorice or its extract, those contained in traditional Chinese medicine prescriptions such as Kakkonto (Kakkontō), Keishito (Keishi-tō), Kōsosan (Kōso-san), Saiko Keishito (Saiko-keishi-tō), Shosaikoto (Shōsaiko-tō), Shoseiryūtō (Shōseiryū-tō), Bakumondōto (Maimendō-tō), Maōto (Makkō-tō), etc. may be used. In the present invention, as licorice or its extract, licorice, licorice powder, licorice extract, and crude licorice extract described in the 18th revised Japanese Pharmacopoeia are preferred.

[0017] The method for producing the extract of licorice is not particularly limited, and for example, it can be produced with reference to the production methods of known plant extracts, such as the descriptions in the sections of "Extracts", "Infusions and Decoctions", "Tinctures", and "Fluid Extracts" in the General Rules of Preparations of the 18th revised Japanese Pharmacopoeia. For example, it can be produced by cutting, heating, drying, pulverizing, etc. licorice as needed, and then adding a suitable extraction solvent for extraction. The obtained extract may be further concentrated, dried, etc. as needed.

[0018] 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; water (including hot water), etc. These may be used alone or in combination of two or more. In the present invention, water, lower monohydric alcohols such as ethanol, or a mixture of water / lower monohydric alcohol is preferred, and water, ethanol, or a mixture of water / ethanol is particularly preferred. The extraction operation is not particularly limited, and known methods used for extraction operations from plants can be adopted. For example, immersion in an extraction solvent (cold extraction, warm extraction, percolation, etc.), extraction using a supercritical fluid or a subcritical fluid, etc. may be mentioned. In addition, in order 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 operation, etc., but it is preferably set to a temperature of about 5°C to 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 operation, etc., but it is preferably about 1 hour to 14 days.

[0019] In the present invention, the content of component (B) in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration. However, from the viewpoint of treating or alleviating allergic or cold symptoms, it is preferable that component (B) is contained in an amount of 0.5 to 75% by mass, more preferably 1 to 70% by mass, and particularly preferably 3 to 60% by mass, in terms of the free form, based on the total mass of the pharmaceutical composition. Among them, when using one or more selected from the group consisting of glycyrrhizic acid and its salts as component (B), from the viewpoint of the treatment or alleviating effect of allergies and cold symptoms, it is preferably contained in a total amount of 0.01 to 50% by mass, more preferably 0.05 to 40% by mass, and particularly preferably 0.1 to 35% by mass based on the total mass of the pharmaceutical composition in terms of glycyrrhizic acid. Also, when using one or more selected from the group consisting of licorice and its extracts as component (B), it is preferably contained in a total amount of 0.05 to 200% by mass, more preferably 0.25 to 150% by mass, and particularly preferably 0.5 to 100% by mass based on the total mass of the pharmaceutical composition in terms of crude drug.

[0020] In the present invention, the content mass ratio of component (A) and component (B) contained in the pharmaceutical composition is not particularly limited and may be appropriately considered and determined. However, from the viewpoint of the treatment or alleviating effect of allergies and cold symptoms, it is preferably contained in a total amount of 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) in terms of its free form per 1 part by mass of component (A) in terms of its free form.

[0021] The pharmaceutical composition may contain, as a medicinal ingredient, one or more selected from the group consisting of components other than the above, for example, antipyretics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, hypnotics, vitamins, aminocarboxylic acids, steroids, calcium salts, magnesium salts, iron salts, glucuronic acids, chondroitins, sugar alcohols, glycosides, thioctic acids, anti-inflammatory agents, gastric mucosal protectants, antacids, anticholinergics, caffeine, xanthine components, crude drugs, traditional Chinese medicine prescriptions, etc.

[0022] Examples of the antipyretics include aspirin, aluminum aspirin, acetaminophen, ibuprofen, ethenzamide, salsalate, salicylamide, lactylphenetidine, loxoprofen, sodium salicylate and the like. Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, dipheteol hydrochloride, dipheteol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, ciproheptazine hydrochloride hydrate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, fexofenadine, phenethazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydroline napadisylate, loratadine, rupatadine fumarate, and the like.

[0023] Examples of antitussives include, in addition to codeine and its derivatives such as codeine phosphate hydrate and dihydrocodeine phosphate, alloclamide hydrochloride, eprazinone hydrochloride, carbetapentane citrate, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dextromethorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, and the like.

[0024] Examples of noscapines include noscapine hydrochloride, noscapine, and the like. Examples of bronchodilators include trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methyl ephedrine hydrochloride, dl-methyl ephedrine hydrochloride, l-methyl ephedrine saccharinate, dl-methyl ephedrine saccharinate, methoxyphenamine hydrochloride, and the like.

[0025] Examples of expectorants include ammonia liquorice essence, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, methylcysteine hydrochloride, l-menthol, lysozyme hydrochloride, and the like.

[0026] Examples of hypnotics and sedatives include allylisopropylacetylurea, bromvalerylurea, and the like. Examples of vitamins include vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B 12 , vitamin C, hesperidin and its derivatives, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine nitrate, dithiothiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, ciclotiamine, thiamine disulfide, bisibuthiamine, bisbentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate ester, riboflavin butyrate ester, sodium riboflavin phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate ester, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

[0027] Examples of aminocarboxylic acids include L-arginine hydrochloride, L-isoleucine, carnitine chloride, glycine, L-glutamic acid, diisopropylamine dichloroacetate, choline bitartrate, taurine, L-threonine, L-valine, L-histidine hydrochloride monohydrate, DL-methionine, yolk lecithin, L-lysine hydrochloride, L-leucine, L-cysteine, L-cysteine hydrochloride monohydrate, orotic acid, choline orotate, and the like. Examples of sterols include ursodeoxycholic acid, gamma oryzanol, dehydrocholic acid, and the like. Examples of calcium salts, magnesium salts, and iron salts include calcium citrate, calcium glycerophosphate, calcium gluconate monohydrate, calcium carbonate, precipitated calcium carbonate, calcium lactate pentahydrate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate dihydrate, ammonium ferric citrate, ferrous fumarate, magnesium carbonate, and the like.

[0028] Examples of glucuronic acids include glucuronolactone, glucuronic acid, glucuronic acid amide, and the like. Examples of chondroitins include sodium chondroitin sulfate, and the like. Examples of sugar alcohols include inositol, gluconic acid and its salts, and the like. Examples of glycosides include rutin hydrate, and the like. Examples of thioctic acids include thioctic acid, thioctic acid amide, and the like.

[0029] Examples of anti-inflammatory agents include serrapeptase, semi-alkali protease, serrapeptase, tranexamic acid, proctase, pronase, bromelain, and the like.

[0030] Examples of gastric mucosal protectants 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 aluminum hydroxide, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitated product of aluminum hydroxide and sodium bicarbonate, coprecipitated product of aluminum hydroxide, calcium carbonate and magnesium carbonate, magnesium hydroxide, coprecipitated product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, sodium bicarbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, cuttlefish bone, nacre, boleite, etc.

[0031] Examples of anticholinergics include oxyfencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datura extract, tipepidium bromide, methylatropine bromide, methylanisotropine bromide, methylscopolamine bromide, methyl-l-hyoscyamine bromide, methylbenactyzium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, total belladonna alkaloid, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, rhubarb extract, rhubarb root, citrate of total alkaloids from rhubarb root, etc. Examples of caffeine compounds include sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine, etc. Examples of xanthine components include aminophylline, diprophylline, theophylline, proxiphylline, etc.

[0032] Examples of crude drugs include Berberis thunbergii DC. var. atropurpurea Rehd., Acacia catechu (L.f.) Willd., Epimedium brevicornu Maxim., Artemisia capillaris Thunb., Foeniculum vulgare Mill., Corydalis yanhusuo W. T. Wang, Scutellaria baicalensis Georgi, Polygonatum sibiricum Redoute, Phellodendron amurense Rupr., Prunus jamasakura Sieb. et Zucc., Coptis chinensis Franch., Polygala tenuifolia Willd., Atractylodes lancea (Thunb.) DC., Pueraria lobata (Willd.) Ohwi, Matricaria recutita L., Momordica grosvenori Swingle, Platycodon grandiflorus (Jacq.) A. DC., Armeniaca vulgaris Lam., Lycium barbarum L., Lycium chinense Mill., Schizonepeta tenuifolia Briq., Cinnamomum cassia Presl, Cassia obtusifolia L., Gentiana scabra Bunge, Gentiana macrophylla Pall., Cyperus rotundus L., Calculus bovis, Schisandra chinensis (Turcz.) Baill., Asarum sieboldii Miq., Bupleurum chinense DC., Zanthoxylum piperitum DC., Gardenia jasminoides Ellis, Aster tataricus L. f., Lycium chinense Mill., Paeonia lactiflora Pall., Moschus moschiferus L., Adenophora stricta Miq., Plantago asiatica L., Plantago depressa Willd., Animal bile (including Ursus thibetanus G. Cuvier bile), Zingiber officinale Rosc., Pheretima aspergillum (E. Perrier), Magnolia liliflora Desr., Lycoris radiata (L’Her.) Herb., Senega canadensis L., Ligusticum wallichii Franch., Peucedanum praeruptorum Dunn., Bupleurum falcatum L., Atractylodes lancea (Thunb.) DC., Morus alba L., Perilla frutescens (L.) Britt., Allium sativum L., Rheum palmatum L., Panax japonicus Torr., Eugenia caryophyllata Thunb., Citrus reticulata Blanco, Angelica sinensis (Oliv.) Diels, Heracleum hemsleyanum Diels, Cephaelis ipecacuanha (Brot.) A. Rich., Gardenia jasminoides Ellis, Nandina domestica Thunb., Panax ginseng C. A. Mey., Fritillaria thunbergii Miq., Ophiopogon japonicus (Thunb.) Ker-Gawl., Saposhnikovia divaricata (Turcz.) Schischk., Pinellia ternata (Thunb.) Breit., Crocus sativus L., Gloydius blomhoffii (Boie), Anemarrhena asphodeloides Bunge, Atractylodes macrocephala Koidz., Poria cocos (Schw.) Wolf, Paeonia suffruticosa Andr., Ephedra sinica Stapf., Achyranthes bidentata Blume, Cornu cervi Pantotrichum, etc. and their extracts (such as extracts, tinctures, dry extracts, etc.).

[0033] Examples of Kampo prescriptions include Pinelliae Rhizoma et Cortex Magnoliae Officinalis Decoction, Artemisiae Capillaris Decoction, etc.

[0034] In this specification, the dosage form of the "pharmaceutical composition" is not particularly limited and may be any of solid, semi-solid, or liquid preparations, which can be selected according to the purpose of use and the like. Examples of the dosage form of the pharmaceutical composition include those described in the General Rules of Pharmaceutical Preparations of the Japanese Pharmacopoeia, Eighteenth Revision, etc. For example, dosage forms for oral administration include solid preparations such as tablets (including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, pills, etc.; semi-solid preparations such as oral jellies; and liquid preparations such as oral liquids (including, for example, elixirs, suspensions, emulsions, lemonades, etc.). In addition, dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solid agents, external liquid agents, sprays, ointments, creams, gels, patches, etc.

[0035] From the viewpoint of ease of administration, etc., the dosage form of the pharmaceutical composition is preferably a solid preparation, and particularly preferably a solid preparation selected from tablets (including, for example, ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.), capsules, granules (including, for example, effervescent granules, etc.), powders, and pills.

[0036] The pharmaceutical composition can be produced by a known method described in, for example, the General Rules of Pharmaceutical Preparations of the Japanese Pharmacopoeia, Eighteenth Revision, etc., according to its dosage form. In this case, a pharmaceutically acceptable carrier (pharmaceutical additive) may be added to the pharmaceutical composition. Examples of such pharmaceutical additives include, but are not limited to, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, poorly water-soluble polymer substances, antioxidants, pH adjusters, flavoring agents, sweetening agents, etc. These pharmaceutical additives include, for example, those listed in the Pharmaceutical Additives Dictionary 2021 (published by Yakujutsu Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc.

[0037] Examples of excipients include inorganic excipients such as aluminum silicate, sodium sulfate anhydride, calcium hydrogen phosphate anhydride, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium hydrogen phosphate monohydrate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodium dihydrogen phosphate; organic excipients such as starch syrup, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, granulated sugar, 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 can be used alone or in combination of two or more kinds.

[0038] Examples of disintegrants include super disintegrants such as sodium starch glycolate, croscarmellose sodium, and crospovidone, as well as carmellose, carmellose calcium, starch, sucrose fatty acid ester, gelatin, sodium hydrogen carbonate, dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil 60, etc. These can be used alone or in combination of two or more kinds.

[0039] Examples of the binder include, in addition to fats and oils such as beef tallow hardened oil, hardened oil, hydrogenated vegetable oil, soybean hardened oil, carnauba wax, bleached beeswax, beeswax, and candelilla wax, methyl cellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, starch (such as wheat starch, rice starch, corn starch, and partially pregelatinized starch), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like. These can be used alone or in combination of two or more kinds.

[0040] Examples of the lubricant include, for example, calcium stearate, magnesium stearate, sodium stearyl fumarate, sucrose fatty acid ester, and the like. These can be used alone or in combination of two or more kinds.

[0041] Examples of the plasticizer include, for example, triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), and the like. These can be used alone or in combination of two or more kinds.

[0042] Examples of film-forming agents include alkyl celluloses such as methyl cellulose and ethyl cellulose; alginic acid or its salts such as sodium alginate; carrageenan; carboxyalkyl celluloses such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, potassium carboxymethyl cellulose, carboxymethyl cellulose, and carboxymethyl ethyl cellulose; xanthan gum; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hypromellose (hydroxypropyl methyl cellulose); hydroxyalkyl cellulose phthalates such as hydroxypropyl methyl cellulose phthalate; pullulan; polyvinyl acetate; polyvinyl acetate phthalate; polyvinyl pyrrolidone and the like. These can be used alone or in combination of two or more.

[0043] Examples of powders include organic powders or inorganic powders such as talc, titanium oxide, yellow ferric oxide, ferric oxide, and legal pigments. These can be used alone or in combination of two or more.

[0044] Examples of water-insoluble high molecular substances include carboxyvinyl polymer, aminoalkyl methacrylate copolymer and the like. These can be used alone or in combination of two or more.

[0045] Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole and the like. These can be used alone or in combination of two or more.

[0046] Examples of pH adjusters include organic acids or their salts 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, glacial acetic acid, etc.; inorganic acids or their salts such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium bicarbonate, etc.; alkali hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc.; amines such as triethanolamine, diethanolamine, diisopropanolamine, etc.

[0047] 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, cinnzeylanol, etc.; essential oils containing terpenes such as cedarwood oil, orange oil, peppermint oil, camphor white oil, eucalyptus oil, terpin oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, perilla oil, spearmint oil, etc.; acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid and their salts, etc. These can be used alone or in combination of two or more.

[0048] Examples of sweeteners include aspartame, stevia, sucralose, thaumatin, acesulfame potassium, saccharin, sodium saccharin, etc., and these can be used alone or in combination of two or more.

[0049] The pharmaceutical composition can be produced by a known method according to its 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, coating, etc. More specifically, when the dosage form of the pharmaceutical composition is a granular preparation such as granules, powders, pills, etc., components (A) and (B), other medicinal ingredients as necessary, and pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. are used. After mixing all or part of these components, granulation is carried out by known granulation methods such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, and crushing granulation to obtain granulated products, and further classification, sizing, etc. can be carried out as necessary to produce them. In addition, the obtained granulated products can also be coated with a coating agent or the like by a known method. Also, when the dosage form of the pharmaceutical composition is tablets, components (A) and (B), other medicinal ingredients as necessary, and appropriate pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. are used. All or part of these components are mixed to obtain a mixture, which can be directly compressed (tableted) (direct powder compression method), or the above granulated products are classified, sized, etc. as necessary and then compressed (tableted) (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). In addition, the obtained compressed products (tablets) 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 capsules, the above granulated products, compressed products, etc. may be filled into capsules.

[0050] The pharmaceutical composition of the present invention is further contained in an airtight package (hereinafter, in this specification, a product obtained by containing the pharmaceutical composition in an airtight package is referred to as a "pharmaceutical product"). In the present invention, the pharmaceutical product may further have a package other than the airtight package that does not fall under the following "airtight package", and the pharmaceutical composition only needs to be directly or indirectly contained in the airtight package. As used herein, the term "hermetically sealed package" means a package that can suppress the intrusion of solid or liquid foreign matter under normal handling, transportation, storage, etc., and is a concept that includes "hermetically sealed container" and "sealed container" defined in the General Rules of the 18th Revised Japanese Pharmacopoeia. As the hermetically sealed package, either a regular-shaped or an irregular-shaped one can be used. For example, bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. can be mentioned. As the hermetically sealed package, a combination of a plurality of these may be used. For example, a mode in which a pharmaceutical composition is first packaged in a PTP package and then further packaged in a pillow package can be mentioned. From the viewpoint of suppressing the adhesion of the pharmaceutical composition to the container wall surface, the hermetically sealed package is preferably at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging, and particularly preferably one having at least PTP packaging (a combination of PTP packaging and other packaging such as bottle packaging, SP packaging, pillow packaging, stick packaging, etc. as necessary), or one having at least bottle packaging.

[0051] The packaging material of the hermetically sealed package is not particularly limited. For example, materials used in the fields of pharmaceuticals, foods, etc., such as glass, plastics (polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyolefins such as polyethylene (including low density (LDPE), medium density (MDPE), and high density (HDPE)), polypropylene, etc.; polycarbonate; polystyrene, etc.), metals (such as aluminum), etc., can be appropriately used alone or in combination of two or more.

[0052] For example, the packaging material used for bottle packaging is not particularly limited, and examples include glass, plastics, metals, etc., and one or a combination of two or more of these can be appropriately combined. As the material for bottle packaging, glass, polyethylene, and polypropylene are preferred, glass, low density polyethylene (LDPE), and high density polyethylene (HDPE) are more preferred, and glass and high density polyethylene (HDPE) are particularly preferred. When bottling, for example, the pharmaceutical composition may be stored in an appropriate quantity in the bottle and then sealed with an appropriate stopper or cap. The bottle may be appropriately selected according to the quantity of the pharmaceutical composition to be stored, etc. The capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL.

[0053] Also, the packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are not particularly limited. For example, 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 olefin copolymer (COC), unoriented nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid vinyl chloride (VSC), etc. resins, and metal foils such as aluminum foil (AL) can be mentioned, and one or more of these can be appropriately combined.

[0054] When performing SP packaging, PTP packaging, pillow packaging, stick packaging, etc., it may be manufactured by a known method using a sheet made of one or more of the above-mentioned packaging materials. In this case, the packaging materials may also be in a multilayer structure in an appropriate combination. As a method of forming a multilayer structure using two or more packaging materials as the sheet, a method of laminating the packaging materials to manufacture a laminated sheet can be mentioned. The laminated sheet can be manufactured by known methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, heat lamination, etc. Also, commercially available products known to the public can be used as the sheet for SP packaging, PTP packaging, pillow packaging, and stick packaging.

[0055] In the above sheet, examples of the single-layer sheet using one type of packaging material include PVC sheet, CPP sheet, etc. Examples of the laminated sheet using two or more types of packaging materials include those with a sheet structure such as laminated PVC and PVDC (PVC / PVDC; hereinafter abbreviated in the same manner), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / PCTFE, CPP / PCTFE, PVC / AL / PA, PVC / AL, CPP / AL, CPP / CPP / CPP (the left sheet uses two or more types as CPP), etc., but the present invention is not limited thereto.

[0056] As a form of PTP packaging, a pharmaceutical composition is stored one by one or in one dosage unit in pockets formed in a resin sheet or the like by a known method, and then a sheet made of a metal foil such as aluminum foil is used as a lid material to cover it. Note that a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as the sheet for forming the pockets may also be used. In the present invention, from the viewpoint of suppressing the adhesion of the pharmaceutical composition to the container wall surface, it is preferable to further package the PTP packaging by pillow packaging (for example, aluminum pillow packaging, etc.). As forms of SP packaging, pillow packaging, and stick packaging, it is possible to package a pharmaceutical composition one by one or in one dosage unit using a resin sheet, a sheet made of aluminum foil as a constituent material, or the like by a known method. In the present invention, from the viewpoint of suppressing the adhesion of the pharmaceutical composition to the container wall surface, it is preferable to use a sheet made of aluminum foil as a constituent material.

[0057] In this specification, the occupancy rate (volume ratio) of the pharmaceutical composition inside the package of the pharmaceutical product is usually 25 to 90%, preferably 28 to 75%, and more preferably 30 to 50% when the package is a bottle package. Also, when the package is an SP package, PTP package, pillow package, or stick package, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. In this case, the occupancy rate means the occupancy rate of the pharmaceutical composition with respect to the total volume inside the package, and fillers, inner stoppers, etc. for preventing damage to the pharmaceutical composition stored inside the package are not considered when calculating the space occupancy rate.

[0058] As the airtight package, a commercially available package may be used as it is, or a commercially available packaging material may be processed and used. Examples of commercially available bottle package include glass bottles (manufactured by Isuya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), Z-series (manufactured by Hanshin Kasei Kogyo Co., Ltd.), etc. Also, examples of commercially available pillow package include Lamidip (registered trademark) (manufactured by Seisan Nippon Co., Ltd.). Furthermore, examples of packaging materials for SP packages, PTP packages, pillow packages, and stick packages include Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Daisheng Chemical Industry Co., Ltd.), PTP vinyl foil, PTP super foil (both manufactured by Mitsubishi Rayon Co., Ltd.), Nippaku aluminum foil (manufactured by Nippon Foil Mfg. Co., Ltd.), aluminum foil plain silver (manufactured by Daiwa Chemical Industry Co., Ltd.), etc.

[0059] The method of accommodating the pharmaceutical composition in the airtight package is not particularly limited and can be achieved by disposing the pharmaceutical composition inside the package by appropriate means such as introducing the pharmaceutical composition into the package. In this case, a means of introducing a desiccant (for example, a cylindrical (tablet type) or sheet-like one) together with the pharmaceutical composition into the package may be used.

[0060] In the present invention, since the pharmaceutical composition or drug contains bilastine having histamine H1 receptor antagonistic action and anti-allergic action and contains glycyrrhetinic acids which are anti-inflammatory agents, it is particularly effective for treating or alleviating allergies and cold symptoms. Therefore, the pharmaceutical composition and drug can be preferably used for treating or alleviating allergies and cold symptoms. More specifically, they can be used for treating or alleviating itching, swelling, redness caused by urticaria, eczema, blisters, skin pruritus, symptoms (sneezing, rhinorrhea (excessive nasal discharge), nasal congestion, watering eyes, sore throat, feeling of heaviness in the head, etc.) caused by acute rhinitis, allergic rhinitis or sinusitis, or various cold symptoms (runny nose, nasal congestion, sneezing, etc.). For example, they can be made into oral medications for allergies, oral medications for rhinitis, cold medications, etc. In the present invention, it can also be used for treating or alleviating rhinitis symptoms not caused by colds, particularly for alleviating nasal allergic symptoms (sneezing, rhinorrhea, nasal congestion) caused by pollen, house dust (indoor dust), etc.

[0061] The administration route of the pharmaceutical composition is not particularly limited and can be appropriately determined in consideration of the disease to be applied, the type of formulation, the gender, age, symptoms, etc. of the taker. However, from the viewpoint of ease of administration, oral administration is preferred. Also, the pharmaceutical composition can be taken 1 to 4 times a day, divided before meals, between meals, after meals, before bedtime, etc.

[0062] Note that this specification discloses, but is not limited to, for example, the following aspects. [1A] The following components (A) and (B): (A) At least one selected from the group consisting of bilastine and its salts and their solvates; (B) Glycyrrhetinic acids; A pharmaceutical composition containing the above and packaged in an airtight package. [2A] The pharmaceutical product according to [1A], wherein component (B) is at least one selected from the group consisting of glycyrrhizic acid and its salts, and licorice and its extracts. [3A] The pharmaceutical composition is a solid preparation, the pharmaceutical product according to [1A] or [2A]. [4A] The dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder or pill, the pharmaceutical product according to any one of [1A] to [3A]. [5A] The hermetic package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging, the pharmaceutical product according to any one of [1A] to [4A].

Examples

[0063] Hereinafter, the present invention will be described more specifically by way of examples, but the present invention is not limited thereto. In the following test examples, the amounts of each component used are the amounts of the components as shown, unless otherwise specified for the conversion amounts.

[0064] [Test Example] Storage Test After preparing each of the samples 1 to 4 shown below, they were stored under the condition of 60 ° C for 3 days, and the presence or absence of an increase in the adhesion to the wall of the storage container of the samples after 1 day and 3 days was confirmed. The results are shown in Table 1.

[0065] [Sample 1] Viralstin was placed in a container of a transparent vial (manufactured by Thermo Fisher Scientific: screw tube bottle C5000-192W with an internal volume of 1.5 mL) with the lid open, and it was used as Sample 1 without a lid. [Sample 2] Dipotassium glycyrrhizinate was placed in a container of a transparent vial (manufactured by Thermo Fisher Scientific: screw tube bottle C5000-192W with an internal volume of 1.5 mL) with the lid open, and it was used as Sample 2 without a lid. [Sample 3] 1 part by mass of Viralstin and 1 part by mass of dipotassium glycyrrhizinate were placed in a transparent vial (manufactured by Thermo Fisher Scientific: screw tube bottle C5000-192W with an internal volume of 1.5 mL), mixed, and used as Sample 3 without a lid. [Sample 4] 1 part by mass of bilastine and 1 part by mass of dipotassium glycyrrhizinate were placed in a transparent vial (manufactured by Thermo Fisher Scientific: screw tube vial C5000-192W with an internal volume of 1.5 mL), mixed, and capped, and this was designated as Sample 4.

[0066]

Table 1

[0067] As is clear from the test results shown in Table 1, in Samples 1 and 2 containing only bilastine or dipotassium glycyrrhizinate that were not enclosed in an airtight package, no increase in adhesion to the container wall occurred even after storage at 60°C for 3 days. On the other hand, in Sample 3 in which bilastine and dipotassium glycyrrhizinate that were not enclosed in an airtight package were mixed, it was found that an increase in adhesion to the container wall occurred when stored at 60°C for 3 days. In contrast, in Sample 4 enclosed in an airtight package, no increase in adhesion to the container wall was observed even after 3 days of storage.

[0068] From the above test results, it became clear that the increase in adhesion to the container wall caused by formulating and storing the component (A) represented by bilastine and the component (B) represented by dipotassium glycyrrhizinate was suppressed by enclosing them in an airtight package.

[0069] Production Example 1 (Tablets) Tablets containing the following components and amounts in a daily dose were produced by a conventional method and PTP-packaged. Bilastine 20 mg Dipotassium glycyrrhizinate 25 mg Riboflavin 6 mg Orotic acid 20 mg Crystalline cellulose, sodium starch glycolate, light anhydrous silicic acid, magnesium stearate

[0070] Production Example 2 (Tablets) Tablets containing the following ingredients and amounts in a daily dose are produced by a conventional method and PTP-packaged. Vilasutin 20 mg Dipotassium glycyrrhizinate 25 mg Pyridoxine hydrochloride 15 mg Orotic acid 20 mg Crystalline cellulose, sodium starch glycolate, light anhydrous silicic acid, magnesium stearate

[0071] Production Example 3 (Tablets) Tablets containing the following ingredients and amounts in a daily dose are produced by a conventional method and PTP-packaged. Vilasutin 20 mg Dipotassium glycyrrhizinate 25 mg Riboflavin 6 mg Pyridoxine hydrochloride 15 mg Crystalline cellulose, sodium starch glycolate, light anhydrous silicic acid, magnesium stearate

[0072] Production Example 4 (Tablets) Tablets containing the following ingredients and amounts in a daily dose are produced by a conventional method and PTP-packaged. Vilasutin 20 mg Riboflavin 6 mg Pyridoxine hydrochloride 15 mg Orotic acid 20 mg Crystalline cellulose, sodium starch glycolate, light anhydrous silicic acid, magnesium stearate

Industrial Applicability

[0073] According to the present invention, it is possible to provide a pharmaceutical product containing one or more selected from the group consisting of vilasutin and its salts and their solvates having excellent pharmacological actions and glycyrrhetinic acids, and suppressing an increase in the adhesiveness to the container wall surface, and thus it can be used, for example, in the pharmaceutical industry.

Claims

1. The following components (A) and (B): (A) One or more selected from the group consisting of bilastine and its salts and their solvates; (B) Glycyrrhetinic acids; A pharmaceutical product, wherein the pharmaceutical composition containing the same is packaged in an airtight package.

2. The pharmaceutical product according to Claim 1, wherein the component (B) is one or more selected from the group consisting of glycyrrhizic acid and its salts, and licorice and its extracts.

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

4. The pharmaceutical product according to Claim 1 or 2, wherein the dosage form of the pharmaceutical composition is tablets, capsules, granules, powders or pills.

5. The pharmaceutical product according to Claim 1 or 2, wherein the airtight package is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.

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