Pharmaceutical composition

Abstract

To provide a technique for inhibiting discoloration that occurs during high-temperature preservation of vitamin B2.SOLUTION: A pharmaceutical composition comprises the following components (A) and (B): (A) vitamin B2; and (B) one or more selected from the group consisting of bilastine, salts thereof, and solvates thereof.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Vitamin B2 such as riboflavin, riboflavin butyrate, and riboflavin phosphate is used for the treatment of vitamin B2 deficiency, eczema, dermatitis, etc. (Non-Patent Document 1).

[0003] On the other hand, Virastin (chemical name: 2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid) is a compound represented by the following formula

[0004]

Chemical Formula

[0005] and is used for the treatment of itching associated with allergic rhinitis, urticaria, skin diseases (eczema / dermatitis, skin pruritus) (Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0007] The inventor of the present invention has discovered that vitamin B2 discolors when stored at high temperatures. Therefore, an object of the present invention is to provide a new means for suppressing the discoloration of vitamin B2 during storage at high temperatures.

Means for Solving the Problems

[0008] Therefore, the inventor of the present invention conducted intensive studies to solve the above problems. Surprisingly, it was discovered that when a pharmaceutical composition containing vitamin B2 is stored containing one or more selected from the group consisting of bilastine and its salts and their solvates, discoloration is suppressed, and the present invention was completed.

[0009] That is, the present invention provides the following components (A) and (B): (A) Vitamin B2; (B) One or more selected from the group consisting of bilastine and its salts and their solvates; and provides a pharmaceutical composition containing the same.

Effects of the Invention

[0010] According to the present invention, discoloration when vitamin B2 is stored at high temperatures can be suppressed. Therefore, a pharmaceutical having excellent storage stability can be provided.

Modes for Carrying Out the Invention

[0011] <Component (A)> In the present invention, vitamin B2 includes riboflavin itself, its derivatives (such as flavin adenine dinucleotide, riboflavin butyrate, riboflavin phosphate ester, etc.) and their salts (such as alkali metal salts such as sodium salt, etc.). In the present invention, these can be used alone or in combination of two or more.

[0012] In the present invention, the content of component (A) in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the therapeutic or alleviating effect of allergies and the like, it is preferable that component (A) 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 based on the total mass of the pharmaceutical composition.

[0013] <Component (B)> In this specification, "one or more selected from the group consisting of bilastine and its salts and their solvates" includes, in addition to 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; organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate; metal salts such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt; amine salts such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine; organic base salts such as lysine, arginine, etc. can be mentioned. These can be used alone or in appropriate combinations of two or more.

[0014] Bilastine is preferable as component (B). Component (B) 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.).

[0015] The content of component (B) in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration. However, from the perspective of the discoloration inhibitory effect of component (A), it is preferably 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 with respect to the total mass of the pharmaceutical composition in terms of the free form.

[0016] Also, 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 determined by appropriate consideration. However, from the perspective of the discoloration inhibitory effect of component (A), 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 the free form with respect to 1 part by mass in total of component (A).

[0017] The daily dose of component (B) in the pharmaceutical composition is not particularly limited and may be determined by appropriate consideration according to the gender, age, symptoms, etc. of the user. For example, it can be made to contain an amount that can be taken in an amount of 0.1 to 300 mg, more preferably 0.5 to 200 mg, and particularly preferably 1 to 150 mg of component (B) in terms of the free form per day.

[0018] 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.

[0019] 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, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclizine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydroline napadisylate, loratadine, rupatadine fumarate, and the like.

[0020] Examples of antitussives include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, and other codeine derivatives, as well as alloclamide hydrochloride, eplazinone 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.

[0021] 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.

[0022] 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.

[0023] Examples of hypnotics and sedatives include allylisopropylacetylurea, bromvalerylurea, and the like. Examples of vitamins include vitamin B1, vitamin B5, vitamin B6, vitamin B 12 , vitamin C, hesperidin and its derivatives, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine nitrite, dithiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, ciclotiamine, thiamine disulfide, bisibuthiamine, bisbentiamine, prosultiamine, benfotiamine, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate ester, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

[0024] Examples of amino carboxylic 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, yoke 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 hydrate, calcium carbonate, precipitated calcium carbonate, calcium lactate hydrate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate hydrate, ammonium ferric citrate, ferrous fumarate, magnesium carbonate, and the like.

[0025] Examples of glucuronic acids include glucuronolactone, glucuronic acid, glucuronic acid amide, and the like. Examples of chondroitins include sodium chondroitin sulfate ester, 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.

[0026] Examples of anti-inflammatory agents include glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), seraprozyme, semi-alkali proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain, and the like.

[0027] Examples of gastric mucosal protectants include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like. Examples of antacids include aminoacetic acid, magnesium aluminum metasilicate, magnesium metasilicate, 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 aluminum metasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, cuttlefish bone, nacre, boleite, and the like.

[0028] 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, diphenylpiperidinomethyl dioxolane iodide, rhubarb extract, rhubarb root, total alkaloid citrate of rhubarb root, and the like. Examples of caffeine compounds include sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine, and the like. Examples of xanthine components include aminophylline, diprophylline, theophylline, proxiphylline, and the like.

[0029] Examples of crude drugs include, for example, Akamegashiwa (Red Bud Cypress), Asenyaku (Arsenic Drug), Inyoukaku (Epimedium), Inchinkou (Artemisia capillaris), Uikyou (Fennel), Engosaku (Rhizoma Corydalis), Ougon (Scutellaria baicalensis), Ousei (Polygonatum sibiricum), Oubaaku (Phellodendron amurense), Ouhi (Cherry Bark), Ouren (Coptis chinensis), Onji (Polygala tenuifolia), Gajutsu (Atractylodes lancea), Kanokosou (Pyrola incarnata), Kakkon (Kudzu Root), Chamomile, Karonin (Balsam Pear Seed), Kanzou (Licorice Root), Kikyou (Platycodon grandiflorum), Kyou'nin (Apricot Seed), Kukoshi (Wolfberry Fruit), Kukoyou (Wolfberry Leaf), Keigai (Schizonepeta tenuifolia), Keihi (Cinnamon Bark), Ketsumeishi (Cassia Seed), Gentiana, Gennoshouko (Evidence), Koubushi (Cyperus rotundus), Gouou (Calculus Bovis), Gomishi (Schisandra chinensis), Saishin (Asarum sieboldii), Saiko (Bupleurum falcatum), Sanshou (Prickly Ash), Sanshishi (Gardenia jasminoides), Shion (Aster tataricus), Jikoppi (Lycium chinense Mill.), Shakuyaku (Paeonia lactiflora), Jakou (Moschus), Shajin (Adenophora stricta), Shazenshi (Plantago asiatica L.), Shazenso (Plantago major L.), Animal Bile (including Yutan (Bear Bile)), Shoukyou (Ginger), Jiryuu (Pheretima aspergillum), Shin'i (Magnolia biondii), Sekisan (Lycoris radiata), Senega, Senkyuu (Curcuma longa), Zenko (Peucedanum praeruptorum), Senburi (Unknown), Soushutsu (Atractylodes lancea), Souhakuhi (Mulberry Bark), Soyou (Perilla frutescens), Taisan (Garlic), Daiou (Rheum palmatum), Chikusetsuninjin (Panax japonicus Torr.), Chouji (Clove), Chinpi (Dried Tangerine Peel), Touki (Angelica sinensis), Dokkatsu (Angelica pubescens), Tokon (Ipecacuanha), Toshishi (Unknown), Nantenjitsu (Nandina Fruit), Ninjin (Ginseng), Baimo (Fritillaria thunbergii), Bakumondou (Ophiopogon japonicus), Hamaboufuu (Unknown), Hange (Pinellia ternata), Bankouka (Crocus sativus), Hanpi (Unknown), Byakushi (Unknown), Byakujutsu (Atractylodes macrocephala), Bukuryou (Poria cocos), Botanpi (Paeonia suffruticosa), Maoou (Ephedra sinica), Yokuin'nin, Rokujou (Cornu Cervi Pantotrichum), etc. of crude drugs and their extracts (extracts, tinctures, dried extracts, etc.).

[0030] Examples of Kampo prescriptions include, for example, Kakkontou (Kudzu Decoction), Keishitou (Cinnamon Twig Decoction), Kousosan (Aromatic Perilla Powder), Saikokeishitou (Bupleurum and Cinnamon Twig Decoction), Shousaikotou (Minor Bupleurum Decoction), Shouseiryoutou (Minor Green Dragon Decoction), Bakumondoutou (Ophiopogon Decoction), Hangekoubokutou (Pinellia and Magnolia Bark Decoction), Maooutou (Ephedra Decoction), Inchinkoutou (Artemisia capillaris Decoction), etc.

[0031] 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, and 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 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; 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 preparations, external liquid preparations, sprays, ointments, creams, gels, patches, etc.

[0032] From the viewpoint of ease of administration and the like, 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.

[0033] The pharmaceutical composition can be produced by a known method described in, for example, the General Rules of Preparations of the Japanese Pharmacopoeia, Eighteenth Revision, etc., according to its dosage form. 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 high-molecular substances, antioxidants, pH adjusters, flavoring agents, sweetening agents, etc. These formulation additives include, for example, those listed in the Dictionary of Pharmaceutical Additives 2021 (published by Yakujutsu Shimbun Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc.

[0034] Examples of excipients include inorganic excipients such as aluminum silicate, sodium sulfate anhydrous, calcium hydrogen phosphate anhydrous, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, calcium dihydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc.; 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, calcium citrate, etc. These can be used alone or in combination of two or more kinds.

[0035] Examples of disintegrants include super disintegrants such as sodium starch glycolate, croscarmellose sodium, crospovidone, and 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.

[0036] Examples of the binder include, in addition to fats and oils such as hardened beef tallow, hardened oil, hydrogenated vegetable oil, hardened soybean 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 α - modified 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.

[0037] Examples of the lubricant include 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.

[0038] Examples of the plasticizer include 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.

[0039] 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.

[0040] Examples of powders include organic powders or inorganic powders such as talc, titanium oxide, yellow ferric oxide, ferric oxide, and legal dyes. These can be used alone or in combination of two or more.

[0041] Examples of water-insoluble high molecular substances include carboxyvinyl polymer and aminoalkyl methacrylate copolymer. These can be used alone or in combination of two or more.

[0042] Examples of antioxidants include ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole. These can be used alone or in combination of two or more.

[0043] 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.

[0044] 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.

[0045] Examples of sweeteners include aspartame, stevia, sucralose, thaumatin, acesulfame potassium, saccharin, sodium saccharin, etc., and one or more of these can be used in combination.

[0046] 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 components 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, crushing granulation, etc. to obtain granulated products, and further classification, sizing, etc. can be carried out as necessary to manufacture 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 components as necessary, and appropriate pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. are used. After mixing all or part of these components to obtain a mixture, it can be directly compressed (tableted) (direct powder compression method), or the above granulated products can be 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.

[0047] The pharmaceutical composition may further be 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 addition to the airtight package, the pharmaceutical product may further be provided with a package that does not correspond to 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 "airtight 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 "airtight containers" and "sealed containers" defined in the General Rules of the 18th Revised Japanese Pharmacopoeia. As the airtight package, either a shaped or an unshaped 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. The airtight package may be a combination of a plurality of these. 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 discoloration of the pharmaceutical composition, the airtight 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.

[0048] The packaging material (material) of the airtight 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.

[0049] 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.

[0050] In addition, the packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are not particularly limited. For example, biaxially stretched polypropylene (OPP), biaxially stretched polyester (PET), glycol-modified PET (PET-G), biaxially stretched nylon (ONy, PA), cellophane, paper, low-density polyethylene (LDPE), linear low-density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unstretched polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched 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.

[0051] 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 combined as appropriate. 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 produce 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. In addition, commercially available products known to the public can also be used as the sheets for SP packaging, PTP packaging, pillow packaging, and stick packaging.

[0052] In the above sheet, examples of the single-layer sheet using one type of packaging material include PVC sheets and CPP sheets. 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. However, the present invention is not limited to these.

[0053] 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 lid is made using a sheet made of a metal foil such as aluminum foil as a lid material. Note that a so-called double-sided aluminum PTP packaging using a sheet made of aluminum foil as a sheet for forming the pocket may also be used. In the present invention, from the viewpoint of suppressing discoloration of the pharmaceutical composition, 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 or a sheet made of aluminum foil as a constituent material by a known method. In the present invention, from the viewpoint of suppressing discoloration of the pharmaceutical composition, it is preferable to use a sheet made of aluminum foil as a constituent material.

[0054] In this specification, the occupancy rate (volume ratio) of the pharmaceutical composition inside the package of the pharmaceutical product is usually 25 to 90% when the package is a bottle package, preferably 28 to 75%, and more preferably 30 to 50%. 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.

[0055] 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 the 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. Examples of the commercially available pillow package include Lamidip (registered trademark) (manufactured by Seisan Nippon Co., Ltd.). Furthermore, as packaging materials for SP packages, PTP packages, pillow packages, and stick packages, Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Daisheng Chemical Industry Co., Ltd.), vinyl foil for PTP, super foil for PTP (both manufactured by Mitsubishi Chemical Corporation), Nippaku aluminum foil (manufactured by Nippon Foil Mfg. Co., Ltd.), aluminum foil plain silver (manufactured by Yamato Chemical Industry Co., Ltd.), etc. can be mentioned.

[0056] The method of accommodating the pharmaceutical composition in the airtight package is not particularly limited and can be achieved by arranging the pharmaceutical composition in 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.

[0057] In the present invention, the pharmaceutical composition or drug contains bilastine having histamine H1 receptor antagonistic action and anti-allergic action, and also contains vitamin B2 useful for treating dermatitis, supplementing vitamin B2, etc. Therefore, it is particularly effective in treating or alleviating allergies and cold symptoms. Accordingly, 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, runny nose (excessive nasal discharge), nasal congestion, watery eyes, sore throat, heavy 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 allergy symptoms (sneezing, runny nose, nasal congestion) caused by pollen, house dust (indoor dust), etc.

[0058] The administration route of the pharmaceutical composition is not particularly limited and can be appropriately determined according to the disease to be applied, the type of formulation, the gender, age, symptoms, etc. of the taker. However, from the perspective 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.

[0059] Note that this specification is not limited to these, but discloses, for example, the following aspects. [1A] The following components (A) and (B): (A) Vitamin B2; (B) One or more selected from the group consisting of bilastine and its salts and their solvates; A pharmaceutical composition containing the same. [2A] The pharmaceutical composition according to [1A], wherein component (A) is one or more selected from the group consisting of riboflavin, flavin adenine dinucleotide, riboflavin butyrate ester, riboflavin phosphate ester, and their salts. [3A] The pharmaceutical composition according to [1A] or [2A], wherein the pharmaceutical composition is a solid preparation. [4A] The pharmaceutical composition according to any one of [1A] to [3A], wherein the dosage form of the pharmaceutical composition is a tablet, capsule, granule, powder or pill.

Examples

[0060] Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto. In the following test examples, the amounts of each component used indicate the amounts of the components as shown, unless otherwise specified for the conversion amounts.

[0061] [Test Example] Storage Test After preparing Samples 1 to 2 shown below, they were stored at 80 ° C for 14 days, and the presence or absence of discoloration of the samples after 3 days, 7 days, and 14 days was confirmed. The results are shown in Table 1.

[0062] [Sample 1] Riboflavin was placed in a transparent vial (manufactured by Thermo Fisher Scientific: screw tube bottle C5000-192W with an internal volume of 1.5 mL) and capped, and this was designated as Sample 1. [Sample 2] 1 part by mass of riboflavin and 1 part by mass of viraztin 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 capped, and this was designated as Sample 2.

[0063]

Table 1

[0064] As is clear from the test results shown in Table 1, it was found that discoloration occurred when Sample 1 containing only riboflavin was stored at 80 ° C for 14 days. In contrast, in Sample 2 mixed with bilastine, there was no discoloration even after storage for 14 days.

[0065] From the above test results, it became clear that the discoloration that occurs when the component (A) represented by riboflavin is stored at high temperature is suppressed by blending the component (B) represented by bilastine.

[0066] Production Example 1 (Tablets) Tablets containing the following components and amounts in a daily dose are 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

[0067] Production Example 2 (Tablets) Tablets containing the following components and amounts in a daily dose are produced by a conventional method and PTP-packaged. Bilastine 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

[0068] Production Example 3 (Tablets) Tablets containing the following components and amounts in a daily dose are produced by a conventional method and PTP-packaged. Bilastine 20 mg Dipotassium glycyrrhizinate 25 mg Riboflavin 6 mg Pyridoxine hydrochloride 15 mg Crystalline cellulose, sodium starch glycolate, light anhydrous silicic acid, magnesium stearate

[0069] Production Example 4 (Tablets) Tablets containing the following ingredients and amounts are produced by a conventional method and packaged in PTP. Virasutin 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

[0070] According to the present invention, a pharmaceutical composition containing vitamin B2 having excellent pharmacological effects and with suppressed discoloration can be provided, and thus it can be used, for example, in the pharmaceutical industry.

Claims

**Claim 1** The following components (A) and (B): (A) Vitamin B ２ ; (B) One or more selected from the group consisting of bilastine and its salts and their solvates; A pharmaceutical composition containing the same. **Claim 2** The pharmaceutical composition according to claim 1, wherein component (A) is one or more selected from the group consisting of riboflavin, flavin adenine dinucleotide, riboflavin butyrate, riboflavin phosphate and their salts. **Claim 3** The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a solid preparation. **Claim 4** The pharmaceutical composition according to claim 1 or 2, wherein the dosage form of the pharmaceutical composition is tablets, capsules, granules, powders or pills.

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