JP7264606B2 - pharmaceuticals - Google Patents

Description

The present invention relates to pharmaceuticals and the like.

Ibuprofen is a type of non-steroidal anti-inflammatory drug (NSAID), and is a drug used as a component of general cold medicines, antipyretic analgesics, etc. due to its excellent antipyretic analgesic action (Non-Patent Document 1). .
Ambroxol is an active metabolite of bromhexine, which is known as an expectorant component, and is known as a mucosal lubricating component. Patent document 2).

A pharmaceutical composition containing both ibuprofen and ambroxol (common cold medicine, etc.) is also already known (for example, Non-Patent Document 3). However, it has been reported that coexistence of both ibuprofen and ambroxol causes formulation changes, and that when blended in the same composition, the stability may be impaired over time (Patent Document 1). Therefore, providing a technique for suppressing such a change in formulation is useful for providing pharmaceuticals such as common cold remedies that contain both components, ibuprofen and ambroxol, that have excellent pharmacological effects and that have good storage stability. It is expected that this will contribute to the promotion of ties and ultimately self-medication in Japan and the curbing of national medical expenses.

JP 2017-43546 A

OTC Drug Handbook 2013 Jiho Co., Ltd., March 25, 2013, pp. 212-213 OTC drug handbook 2013 Jiho Co., Ltd., March 25, 2013, page 270 Package insert "Pabron Ace AX Tablets" Taisho Pharmaceutical Co., Ltd., July 2017

Therefore, the present invention provides a new technique for suppressing formulation changes in a pharmaceutical composition containing ibuprofen or a salt thereof or a solvate thereof and ambroxol or a salt thereof or a solvate thereof. is the subject.

Therefore, the present inventors have made intensive studies to solve the above problems, and surprisingly found that a The pharmaceutical composition containing tranexamic acid or a salt thereof, or a solvate thereof, and containing it in an airtight package such as a bottle package or a PTP package can suppress changes in formulation. completed the invention.

Thus, the present invention provides the following components (A), (B) and (C):
(A) ibuprofen or a salt thereof or a solvate thereof;
(B) ambroxol or a salt thereof or a solvate thereof;
(C) tranexamic acid or a salt thereof or a solvate thereof;
A pharmaceutical composition containing is provided in an airtight package.

ADVANTAGE OF THE INVENTION According to this invention, the compounding change between ibuprofen, its salt, or those solvates, and ambroxol, its salts, or those solvates can be suppressed. Therefore, a medicament containing ibuprofen or a salt thereof or a solvate thereof and ambroxol or a salt thereof or a solvate thereof having excellent storage stability can be provided.

As used herein, "ibuprofen or a salt thereof or a solvate thereof" includes ibuprofen itself, as well as pharmaceutically acceptable salts of ibuprofen (e.g., alkali metal salts such as sodium salts and potassium salts; calcium salts, magnesium Salts with metals of group 2 elements such as salts; organic amine salts such as phenethylamine salts; salts with amino acids such as lysine, etc.), and solvents of ibuprofen or its pharmaceutically acceptable salts with water, alcohol, etc. Also included are soybeans, and these can be used singly or in combination of two or more.
As ibuprofen or its salt or a solvate thereof, ibuprofen or its L-lysine salt is preferred, and ibuprofen listed in the Japanese Pharmacopoeia 17th Edition is particularly preferred.
Ibuprofen, salts thereof, or solvates thereof are known and can be produced by known methods or the like, and commercially available products may also be used. Examples of commercially available products include ibuprofen manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd., and the like.

The content of ibuprofen, a salt thereof, or a solvate thereof in the pharmaceutical composition is not particularly limited, and can be appropriately examined and determined according to the sex, age, symptoms, etc. of the recipient. For example, it can contain 200 to 1000 mg, more preferably 300 to 800 mg, and particularly preferably 400 to 600 mg of ibuprofen in free form per day. In the present invention, ibuprofen, a salt thereof, or a solvate thereof is preferably contained in an amount of 10 to 50% by mass, preferably 15 to 45% by mass, in terms of ibuprofen free form, based on the total mass of the pharmaceutical composition. is more preferable, and a content of 20 to 40% by mass is particularly preferable.

As used herein, "ambroxol or a salt thereof or a solvate thereof" includes ambroxol itself, as well as pharmaceutically acceptable salts of ambroxol (e.g., hydrochloride, hydrobromide, Acid addition salts with inorganic acids such as hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate , acid addition salts with organic acids such as maleate, fumarate, tartrate, citrate, acetate, etc.), and ambroxol or its pharmaceutically acceptable salts with water, alcohol, etc. Solvates are also included, and these can be used singly or in combination of two or more.
Ambroxol hydrochloride is preferred as ambroxol or a salt thereof or a solvate thereof.
Ambroxol, salts thereof, or solvates thereof are known and can be produced by known methods or the like, and commercially available products may also be used. Commercially available products include, for example, ambroxol hydrochloride manufactured by Shizuoka Caffeine Industry Co., Ltd., and the like.

The content of ambroxol, a salt thereof, or a solvate thereof in the pharmaceutical composition is not particularly limited, and can be determined by appropriate examination according to the sex, age, symptoms, etc. of the recipient. For example, 10 to 100 mg, more preferably 20 to 80 mg, and particularly preferably 30 to 60 mg of ambroxol in terms of hydrochloride can be contained per day. In the present invention, ambroxol or a salt thereof or a solvate thereof is preferably contained in an amount of 0.1 to 10% by mass in terms of ambroxol hydrochloride relative to the total mass of the pharmaceutical composition. The content is more preferably 5 to 5% by mass, and particularly preferably 1 to 3% by mass.

In addition, the content ratio of ibuprofen or a salt thereof or a solvate thereof and ambroxol or a salt thereof or a solvate thereof in the pharmaceutical composition is not particularly limited, but ibuprofen or a salt thereof or a solvent thereof It is preferable to contain 0.01 to 0.5 parts by mass of ambroxol or a salt thereof or a solvate thereof in terms of its hydrochloride salt per 1 part by mass of the solvate in terms of its free form, and 0.03 It is more preferable to contain up to 0.3 parts by mass, and it is particularly preferable to contain 0.05 to 0.1 parts by mass.

As used herein, "tranexamic acid or a salt thereof or a solvate thereof" includes tranexamic acid itself, as well as pharmaceutically acceptable salts of tranexamic acid (e.g., hydrochloride, hydrobromide, hydrogen iodide). acid addition salts with inorganic acids such as acid salts, sulfates, nitrates, phosphates; benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, maleic acid acid addition salts with organic acids such as salts, fumarates, tartrates, citrates, and acetates; alkali metal salts such as sodium salts and potassium salts; and metals of Group 2 elements such as calcium salts and magnesium salts organic amine salts such as phenethylamine salts; salts with amino acids such as lysine, etc.), and solvates of tranexamic acid or a pharmaceutically acceptable salt thereof with water, alcohol, etc. species or a combination of two or more species can be used.
As tranexamic acid, a salt thereof, or a solvate thereof, tranexamic acid is preferred, and tranexamic acid listed in the Japanese Pharmacopoeia 17th Edition is particularly preferred.
Tranexamic acid, salts thereof, or solvates thereof are known and can be produced by known methods or the like, and commercially available products may also be used. Examples of commercially available products include tranexamic acid manufactured by Daiichi Sankyo Propharma Co., Ltd., and the like.

The content of tranexamic acid, a salt thereof, or a solvate thereof in the pharmaceutical composition is not particularly limited, and can be appropriately examined and determined according to the degree of change in formulation. For example, it can contain 200 to 1200 mg, more preferably 300 to 1000 mg, and particularly preferably 400 to 800 mg of free form tranexamic acid per day. In the present invention, from the viewpoint of suppressing formulation changes, tranexamic acid or a salt thereof or a solvate thereof is contained in an amount of 5 to 60% by mass in terms of the free form of tranexamic acid with respect to the total mass of the pharmaceutical composition. is preferred, more preferably 10 to 50% by mass, and particularly preferably 20 to 45% by mass.

In addition, the content ratio of ibuprofen or a salt thereof or a solvate thereof and tranexamic acid or a salt thereof or a solvate thereof in the pharmaceutical composition is not particularly limited. Alternatively, it is preferable to contain 0.1 to 5 parts by mass of tranexamic acid or a salt thereof or a solvate thereof per 1 part by mass of the salt or solvate thereof in terms of the free form. , more preferably 0.3 to 4 parts by mass, particularly preferably 0.5 to 2 parts by mass.
Furthermore, the content ratio of ambroxol or its salt or its solvate and tranexamic acid or its salt or their solvate in the pharmaceutical composition is not particularly limited, but from the viewpoint of suppressing formulation changes , containing 3 to 40 parts by mass of tranexamic acid or its salt or its solvate in terms of its free form per 1 part by mass of ambroxol or its salt or its solvate in terms of its hydrochloride salt is preferred, more preferably 5 to 30 parts by mass, and particularly preferably 7 to 20 parts by mass.

The pharmaceutical composition contains, as medicinal ingredients, ingredients other than those mentioned above, such as antipyretic analgesics, antihistamines, antitussives, noscapines, bronchodilators, expectorants, sedative hypnotics, vitamins, xanthine derivatives, anti-inflammatory agents, and gastric mucosa. It may contain one or more selected from the group consisting of protective agents, antacids, anticholinergics, herbal medicines, Chinese herbal formulations, and the like.

Specific examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrin, salicylamide, lactylphenetidine, sodium salicylate and the like.
Specific examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamindiphenyldisulfone acid, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difererol hydrochloride, difererol phosphate, diphenyl Pyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, tonjilamine hydrochloride, fe xofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydrolin napadisilate, loratadine, etc. be done.

Specific examples of antitussives include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, and other codeines, as well as aloclamide hydrochloride, eprazinone hydrochloride, carbetapentancitrate, cloperastine hydrochloride, Cloperastine Fendizoate, Dibunate Sodium, Dimemorphan Phosphate, Tipepidine Citrate, Tipepidine Hibenzate, Dextromethorphan, Dextromethorphan Hydrobromide Hydrate, Dextromethorphan Phenolphta Phosphorus salt etc. are mentioned. Among these, codeines are preferred. ADVANTAGE OF THE INVENTION According to this invention, even when a pharmaceutical composition contains codeines, a change in composition can be suppressed.

Specific examples of noscapines include noscapine hydrochloride and noscapine.
Specific examples of bronchodilators include trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, methoxyphenamine hydrochloride and the like.

Specific examples of expectorants include ammonia/fennel, ethylcysteine hydrochloride, ammonium chloride, carbocisteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, methylcysteine hydrochloride, l-menthol, and lysozyme hydrochloride. Salt etc. are mentioned.

Specific examples of sedative hypnotics include allylisopropylacetylurea and bromvalerylurea.
Specific examples of vitamins include vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, hesperidin and its derivatives, and salts thereof (specifically, for example, thiamine, thiamine chloride Hydrochloride, thiamine nitrate, dicetiamine hydrochloride, cetotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, cicotiamine, thiamine disulfide, bisivtiamine, bisbentiamine, prosultiamine, benfotiamine, riboflavin , riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc. ).

Specific examples of xanthine derivatives include caffeine (specifically, for example, caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, caffeine citrate, etc.), theophylline, theobromine, paraxanthine, Proxiphylline, Diprophylline and the like.
Specific examples of anti-inflammatory agents include glycyrrhizic acid, derivatives thereof, and salts thereof (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain, and the like. is mentioned.

Specific examples of gastric mucosal protective agents include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Specific examples of antacids include aminoacetic acid, magnesium aluminosilicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium aluminate hydroxide, magnesium hydroxide Aluminum gel, dried aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate mixed dry gel, aluminum hydroxide-sodium hydrogen carbonate co-precipitation product, aluminum hydroxide-calcium carbonate-magnesium carbonate co-precipitation product, magnesium hydroxide , coprecipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bones, stone decimation, boley etc.

Specific examples of anticholinergic agents include oxyphencyclamine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datura extract, tipepidium bromide, methylatropine bromide, methylanisotropine bromide, and methylscopolamine. Bromide, methyl-l-hyoscyamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Rohto extract, Rohto root, Rohto root total alkaloid citrate, and the like.

Specific examples of herbal medicines include Akamegashiwa (red bud oak), Asenyaku (Asenyaku), Inyoukaku (Lady yang), Fennel (Fennel), Corydalis (long husk), Scutellaria root (Ogon), Ousei (Osei), Phellodendron (yellow oak), ohi (cherry bark), coptis (huangren), onji (toshi), zedoary (gajutsu), valerian (bay), chamomile, caronin (bellflower), bellflower (bellflower), kyonin ( apricot kernel), wolfberry, kukoyou, keigai, cinnamon, cinnamon, gentian, gennoshoko (present evidence), kobushi, goou (cow yellow), garbage (Omise), Saishin (spicy), Sansho (Japanese pepper), Shion (Shion), Jikoppi (root skin), Peony (peony), Musk (Musk), Shajin (Sansan), Shazenshi , Shazensou (car front grass), Beast bile (including Yutan (bear bile)), Ginger (ginger), Jiryu (earth dragon), Shini (shini), Sekisan (stone garlic), Senega, Senkyu (river), Zenko (Maehu), Senburi (Senburi), Soujutsu (Aojutsu), Souhakuhi (Mulberry white bark), Soyou (Soyo), Taisan (Garlic garlic), Chikusetsu carrot (Bamboo ginseng), Clove (Clove), Chimpi (Chenpi) , Touki, Tokon, Nantenjitsu, Carrot, Bimbo, Bakumondo, Hange, Bankouka, Hampi Crude drugs and their extracts (extracts, tinctures, dried extract etc.) and the like.

Specific examples of Kampo prescriptions include Kakkonto (Kakkonto), Keishito (Keishito), Kososan (Kousosan), Saiko Keishito (Saiko Keishito), Shosaikoto (Shosaikoto), Shosaikoto, and Shosaikoto. Seiryuto (Shoseiryuto), Bakumontouto (Bakumontou), Hangekoubokuto (Hangekobokuto), Maotou (Maoto), and the like can be mentioned.

In the present specification, the dosage form of the "pharmaceutical composition" is not particularly limited, and may be solid, semi-solid, or liquid preparations, and can be selected according to the purpose of use. The dosage form of the pharmaceutical composition includes, for example, the dosage form described in the Japanese Pharmacopoeia 17th Edition, General Rules for Pharmaceutical Preparations, and the like. Specifically, for example, dosage forms for oral administration include tablets (e.g., regular tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules ( solid preparations such as effervescent granules), powders, pills; semi-solid preparations such as oral jelly; and the like. Dosage forms for parenteral administration include injections, inhalants, eye drops, ear drops, nasal drops, suppositories, external solids, external liquids, sprays, ointments, creams, and gels. , patches and the like.

The dosage form of the pharmaceutical composition is preferably a solid preparation from the viewpoint of ease of administration. Especially preferred are solid preparations selected from capsules, granules (including effervescent granules, etc.), powders and pills.

A pharmaceutical composition can be produced by a known method described in, for example, the Japanese Pharmacopoeia 17th Edition, General Rules for Pharmaceutical Preparations, etc., according to its dosage form. In this case, the pharmaceutical composition may contain a pharmaceutically acceptable carrier (formulation additive). Such formulation additives include, for example, excipients, disintegrants, binders, lubricants, plasticizers, film-forming agents, powders, sparingly water-soluble polymeric substances, antioxidants, corrigents, sweeteners, and the like. include, but are not limited to. In addition, as these formulation additives, specifically, for example, those listed in Pharmaceutical Excipient Dictionary 2016 (published by Yakuji Nippo Co., Ltd.), Handbook of Pharmaceutical Excipients, Seventh Edition (published by Pharmaceutical Press), etc. mentioned.

Specific examples of excipients include aluminum silicate, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, calcium silicate, light anhydrous silicic acid, heavy anhydrous silicic acid, calcium sulfate, monophosphate Inorganic excipients such as calcium hydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate; starch, partially pregelatinized starch, etc.), fructose, caramel, agar, xylitol, paraffin, crystalline cellulose, sucrose, maltose, lactose, lactose hydrate, sucrose, glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, Organic excipients such as reduced maltose starch syrup, powdered reduced maltose starch syrup, erythritol, sorbitol, mannitol, lactitol, trehalose, reduced palatinose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, calcium citrate, and the like. These can be used singly or in combination of two or more.

Specific examples of disintegrants include super disintegrants such as carboxymethyl starch sodium, croscarmellose sodium and crospovidone, carmellose, carmellose calcium, starch, sucrose fatty acid esters, gelatin, sodium bicarbonate, dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil 60 and the like. These can be used singly or in combination of two or more.

Specific examples of binders include oils and fats such as hydrogenated beef tallow, hydrogenated oil, hydrogenated vegetable oil, hydrogenated soybean oil, carnauba wax, white beeswax, beeswax, and Japanese wax, as well as methyl cellulose, hydroxypropyl cellulose, hypromellose, and carme. Sodium loin, starch (wheat starch, rice starch, corn starch, partially pregelatinized starch, etc.), dextrin, pullulan, gum arabic, agar, gelatin, tragacanth, sodium alginate, povidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate and the like. These can be used singly or in combination of two or more.

Specific examples of lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, and sucrose fatty acid esters. These can be used singly or in combination of two or more.

Specific examples of plasticizers include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), and the like. These can be used singly or in combination of two or more.

Specific examples of film-forming agents include alkylcelluloses such as methylcellulose and ethylcellulose; alginic acid such as sodium alginate and salts thereof; carrageenan; sodium carboxymethylcellulose, calcium carboxymethylcellulose, potassium carboxymethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, and the like. carboxyalkyl cellulose; xanthan gum; hydroxyalkyl cellulose such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose (hydroxypropyl methyl cellulose); hydroxy alkyl cellulose phthalate such as hydroxypropyl methyl cellulose phthalate; pullulan; ; and polyvinylpyrrolidone. These can be used singly or in combination of two or more.

Examples of powders include organic powders and inorganic powders such as talc, titanium oxide, yellow iron sesquioxide, iron sesquioxide, legal pigments and the like. These can be used singly or in combination of two or more.

Specific examples of poorly water-soluble polymeric substances include carboxyvinyl polymer, aminoalkyl methacrylate copolymer, and the like. These can be used singly or in combination of two or more.
Specific examples of antioxidants include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopheryl acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole and the like. These can be used singly or in combination of two or more.

Specific examples of flavoring agents include limonene, pinene, camphene, cymen, cineole, citronellol, geraniol, nerol, linalool, menthol, terpineol, rhodinol, borneol, isoborneol, menthone, camphor, eugenol, synzeilanol, and the like. terpenes; spruce oil, orange oil, peppermint oil, white camphor oil, eucalyptus oil, turpentine oil, lemon oil, ginger oil, clove oil, cinnamon oil, lavender oil, fennel oil, chamomile oil, perilla oil, spearmint oil, etc. terpene-containing essential oils; acidulants such as ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof; These can be used singly or in combination of two or more.

Specific examples of sweeteners include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, saccharin sodium, and the like, and these can be used alone or in combination of two or more.

A pharmaceutical composition can be manufactured 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, and coating.
More specifically, for example, when the dosage form of the pharmaceutical composition is a granular formulation such as granules, powders, and pills, ibuprofen or a salt thereof or a solvate thereof, ambroxol or a salt thereof or a solvent thereof In addition to hydrates, tranexamic acid or its salts, or their solvates, if necessary, use excipients, binders, disintegrants, lubricants, and other formulation additives, all or part of these ingredients After mixing, the mixture is granulated by a known granulation method such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, melt granulation, crushing granulation, etc. to obtain granules. Furthermore, it can be produced by classifying, sizing, etc. as necessary. The obtained granules can also be coated with a coating agent or the like by a known method.
In addition, when the dosage form of the pharmaceutical composition is a tablet, in addition to ibuprofen or its salts or their solvates, ambroxol or its salts or their solvates, tranexamic acid or its salts or their solvates , If necessary, using suitable formulation additives such as excipients, binders, disintegrants, lubricants, etc., all or part of these ingredients are mixed to obtain a mixture, which is directly compressed (tablet ) (direct powder compression method), or compress (tablet) after classifying and sizing the above granules as necessary (semi-dry granule compression method, dry granule compression method, wet granule compression method, etc.). The obtained compressed product (tablet) can also be coated with a coating agent or the like by a known method.
Furthermore, when the dosage form of the pharmaceutical composition is a capsule, the above granulated product, compressed product, or the like may be filled into the capsule.

In the present invention, the pharmaceutical composition is further contained in an airtight package (hereafter, in the present specification, a product containing the pharmaceutical composition in an airtight package is referred to as "drug"). In addition, in the present invention, in addition to the airtight package, the pharmaceutical may be provided with a package that does not fall under the following "airtight package", and the pharmaceutical composition is directly or indirectly contained in the airtight package. It is good if it is.
As used herein, the term "airtight packaging" refers to packaging that can prevent solid or liquid foreign matter from entering during normal handling, transportation, storage, etc. It is a concept that includes an “airtight container” and a “sealed container”. As the airtight package, both fixed and irregular shapes can be used, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, and the like. is mentioned. The airtight package may be a combination of a plurality of these, and specific examples thereof include a mode in which the pharmaceutical composition is first packaged by PTP packaging and then further packaged by pillow packaging. .
The airtight package is preferably one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging, from the viewpoint of suppressing change in composition, and includes at least PTP packaging ( A combination of PTP packaging and, if necessary, other packaging such as bottle packaging, SP packaging, pillow packaging, stick packaging, etc.) is particularly preferable.

The packaging material (material) of the airtight package is not particularly limited, and examples thereof include glass, plastic (polyester such as polyethylene terephthalate and polyethylene naphthalate; Polyolefins such as polypropylene; polycarbonate; polystyrene, etc.), metals (aluminum, etc.), materials used in the fields of pharmaceuticals and foods, etc., can be used singly or in combination of two or more. can.

For example, packaging materials used for bottle packaging are not particularly limited, and include glass, plastic, metal, etc., and one or more of these can be appropriately combined. Glass, polyethylene, and polypropylene are preferred as materials for bottle packaging, glass, low-density polyethylene (LDPE), and high-density polyethylene (HDPE) are more preferred, and glass and high-density polyethylene (HDPE) are particularly preferred.
For bottle packaging, for example, a suitable amount of the pharmaceutical composition may be stored in the bottle and then sealed with a suitable stopper or lid. The size of the bottle may be appropriately selected according to the quantity of the pharmaceutical composition to be stored. is more preferred.

In addition, packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are not particularly limited. PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), none Oriented polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH ), polyvinyl chloride (PVC), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid vinyl chloride (VSC), and aluminum foil (AL). metal foil and the like, and one or more of these can be appropriately combined.

When performing SP packaging, PTP packaging, pillow packaging, stick packaging, etc., it may be manufactured by a known method using a sheet using one or more of the above packaging materials. can also have a multi-layered structure in which they are appropriately combined. As a method of forming a multilayer structure using two or more types of packaging materials as a sheet, there is a method of manufacturing a laminated sheet by laminating the packaging materials. The laminated sheet can be produced by known methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination and heat lamination. Also, known commercial products can be used as sheets for SP packaging, PTP packaging, pillow packaging, and stick packaging.

Among the above-mentioned sheets, examples of single-layer sheets using one type of packaging material include PVC sheets and CPP sheets. Laminated sheets using two or more types of packaging materials include, for example, Laminated PVC and PVDC (PVC/PVDC. Hereinafter abbreviated similarly), 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 sheets on the left use two or more types of CPP), etc., but are limited to these not to be

As a form of PTP packaging, a desired number of pockets are formed in a resin sheet or the like by a known method, and the pharmaceutical composition is stored one by one or by one dosage unit. For example, it can be used as a lid material to form a lid. A so-called double-sided aluminum PTP package using a sheet made of aluminum foil as a constituent material of the pocket forming sheet may also be used. In the present invention, the PTP packaging is preferably further packaged with a pillow packaging (for example, an aluminum pillow packaging) from the viewpoint of suppressing change in composition.
Examples of forms of SP packaging, pillow packaging, and stick packaging include packaging the pharmaceutical composition one by one or by one dosage unit using a sheet or the like having a resin sheet or aluminum foil as a constituent material by a known method. . In the present invention, from the viewpoint of suppressing change in composition, it is preferable to use a sheet made of aluminum foil as a constituent material.

In the present specification, the occupancy rate (volume ratio) of the pharmaceutical composition in the package inside the pharmaceutical composition is usually 25 to 90%, preferably 28 to 75%, when the package is a bottle package. 30-50% is more preferred. Also, when the package is SP packaging, PTP packaging, pillow packaging, or stick packaging, 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. etc. are not taken into account when calculating the space occupancy.

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 packages include glass bottles (manufactured by Isoya Glass Industry Co., Ltd.), tablet bottles (manufactured by Tokyo Glass Co., Ltd.), Z-series (manufactured by Hanshin Chemical Industry Co., Ltd.), and the like. be done. Examples of commercially available pillow packaging include Lamizip (registered trademark) (manufactured by Seisan Nippon Co., Ltd.). Furthermore, as packaging materials for SP packaging, PTP packaging, pillow packaging and stick packaging, SUMILITE VSS, SUMILITE VSL, SUMILITE NS, SUMILITE FCL (manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (Taisei Kako Co., Ltd.) ), vinyl foil for PTP, super foil for PTP (manufactured by Mitsubishi Plastics Co., Ltd.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), aluminum foil silver plain (manufactured by Daiwa Chemical Industry Co., Ltd.), etc. be done.

The method of housing the pharmaceutical composition in an airtight package is not particularly limited, and can be achieved by placing the pharmaceutical composition in the package by an appropriate means such as putting the pharmaceutical composition into the package. In this case, means for putting a desiccant (for example, cylindrical (tablet-shaped) or sheet-shaped) into the package together with the pharmaceutical composition may be used.

In the present invention, the pharmaceutical composition or drug contains ibuprofen, which is a type of NSAID, a salt thereof, or a solvate thereof, and ambroxol having an expectorant action, a salt thereof, or a solvate thereof, For example, headache, toothache, pain after tooth extraction, sore throat, earache, arthralgia, neuralgia, back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain), trauma pain It has effects such as analgesia, antipyretic during chills and fever, and alleviation of cold symptoms (sore throat, chills, fever, headache, phlegm, joint pain, muscle pain). It is useful as a drug) and as an antipyretic analgesic.

The route of administration of the pharmaceutical composition is not particularly limited, and can be appropriately determined according to the disease to be applied, the type of preparation, the sex, age, symptoms, etc. of the user. , oral administration is preferred. In addition, the pharmaceutical composition can be taken in about 1 to 4 divided doses per day before meals, between meals, after meals, before bedtime, and the like.

Although the present specification is not limited to these, for example, the following aspects of the invention are disclosed.
[1A] The following components (A), (B) and (C):
(A) ibuprofen or a salt thereof or a solvate thereof;
(B) ambroxol or a salt thereof or a solvate thereof;
(C) tranexamic acid or a salt thereof or a solvate thereof;
A pharmaceutical composition containing a pharmaceutical composition contained in an airtight package.
[2A] The pharmaceutical of [1A], wherein the pharmaceutical composition is a solid formulation.
[3A] The pharmaceutical of [1A] or [2A], wherein the dosage form of the pharmaceutical composition is tablet, capsule, granule, powder or pill.
[4A] The drug according to any one of [1A] to [3A], 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.
[5A] The drug according to any one of [1A] to [4A], wherein the airtight package comprises at least PTP packaging.

[1B] The following components (A), (B) and (C) for inclusion in an airtight package:
(A) ibuprofen or a salt thereof or a solvate thereof;
(B) ambroxol or a salt thereof or a solvate thereof;
(C) tranexamic acid or a salt thereof or a solvate thereof;
A pharmaceutical composition containing
[2B] The pharmaceutical composition of [1B], which is a solid formulation.
[3B] The pharmaceutical composition of [1B] or [2B], whose dosage form is tablet, capsule, granule, powder or pill.
[4B] The pharmaceutical composition according to any one of [1B] to [3B], 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.
[5B] The pharmaceutical composition according to any one of [1B] to [4B], wherein the airtight package comprises at least PTP packaging.

[1C] The following components (A) and (B):
(A) ibuprofen or a salt thereof or a solvate thereof;
(B) ambroxol or a salt thereof or a solvate thereof;
In addition to the following component (C):
(C) tranexamic acid or a salt thereof or a solvate thereof;
and containing the pharmaceutical composition in an airtight package (for example, a method for stabilizing components (A) and / or (B). Note that "stabilization The "method" is preferably a "method for suppressing change in composition", and particularly preferably a "method for suppressing change in composition between components (A) and (B)").
In this method, the order of the step of adding component (A), component (B) and component (C) into the pharmaceutical composition and the step of housing the pharmaceutical composition in an airtight package is not particularly limited. For example, components (A), (B), and (C) may be contained in an arbitrary order in a pharmaceutical composition and then placed in an airtight package. , (C) is contained in the pharmaceutical composition, this is placed in an airtight package, and then the remaining components may be contained in the pharmaceutical composition.
[2C] The method of [1C], wherein the pharmaceutical composition is a solid formulation.
[3C] The method of [1C] or [2C], wherein the dosage form of the pharmaceutical composition is tablet, capsule, granule, powder or pill.
[4C] The method according to any one of [1C] to [3C], 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.
[5C] The method according to any one of [1C] to [4C], wherein the airtight package comprises at least PTP packaging.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

[Test Example 1] Stability test 1
Samples 1 to 4 shown below were each stored at 40 ° C. and 75% relative humidity (RH) for 1 week after preparation, and the state of the mixture in the sample immediately after the start of storage, 1 day, 2 days and 1 week later. was evaluated, and the presence or absence of change in composition was confirmed.
Table 1 shows the results.

[Sample 1]
Mix 24.0 parts by mass of ibuprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.: ibuprofen) and 1.8 parts by mass of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho Co., Ltd.: trade name ambroxol hydrochloride) After that, 5.0 parts by mass of purified water was added and kneaded to obtain a mixture, which was designated as Sample 1.
[Sample 2]
Mix 24.0 parts by mass of ibuprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.: ibuprofen) and 1.8 parts by mass of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho Co., Ltd.: trade name ambroxol hydrochloride) After that, 5.0 parts by mass of purified water was added and kneaded to obtain a mixture. 3.0 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and capped. The occupancy rate (volume ratio) of the mixture inside the glass bottle was 41.7%.

[Sample 3]
24.0 parts by mass of ibuprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.: ibuprofen), 1.8 parts by mass of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho Co., Ltd.: trade name ambroxol hydrochloride) and tranexam After mixing 30.0 parts by mass of acid (manufactured by Daiichi Sankyo Propharma Co., Ltd.: trade name, Japanese Pharmacopoeia tranexamic acid), 11.2 parts by mass of purified water was added and kneaded to obtain a mixture. This is sample 3.
[Sample 4]
24.0 parts by mass of ibuprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.: ibuprofen), 1.8 parts by mass of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho Co., Ltd.: trade name ambroxol hydrochloride) and tranexam After mixing 30.0 parts by mass of an acid (manufactured by Daiichi Sankyo Propharma Co., Ltd.; trade name: Japanese Pharmacopoeia tranexamic acid), 11.2 parts by mass of purified water was added and kneaded to obtain a mixture. 3.0 g of the obtained mixture was placed in a glass bottle (manufactured by Isoya Glass Industry Co., Ltd.: A-102K) and capped. The occupancy rate (volume ratio) of the mixture inside the glass bottle was 41.7%.

From the test results shown in Table 1, it was found that in Sample 1, in which ibuprofen and ambroxol hydrochloride were mixed, the formulation changed and the mixture solidified two days after the start of storage.
In addition, sample 2 in which ibuprofen and ambroxol hydrochloride were mixed and housed in an airtight package, and sample 3 in which tranexamic acid was further mixed in addition to ibuprofen and ambroxol hydrochloride were tested in the same manner as sample 1. , it was found that the composition changed and the mixture solidified 2 days after the start of storage.
On the other hand, in Sample 4, in which ibuprofen, ambroxol hydrochloride, and tranexamic acid were further mixed and contained in an airtight package, the state of white powder was maintained even after one week of storage in the same manner as immediately after the start of storage. Turned out to be dripping.

Based on the above test results, the blending change between ibuprofen or its salts or their solvates and ambroxol or its salts or their solvates is the formulation of tranexamic acid or its salts or their solvates. It has been clarified that while either one of the means for carrying out and the means for housing in an airtight package cannot be used alone, a combination of both means exhibits an excellent suppressing effect.

[Test Example 2] Stability test 2
Sample 5 shown below was stored under conditions of 40 ° C. and 75% relative humidity (RH) for 1 week after preparation, and the state of the mixture in the sample was evaluated immediately after the start of storage and after 1 week, and whether there was a change in composition. It was confirmed.
Table 2 shows the results.

[Sample 5]
24.0 parts by mass of ibuprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.: ibuprofen), 1.8 parts by mass of ambroxol hydrochloride (manufactured by Shizuoka Caffeine Kogyosho Co., Ltd.: trade name ambroxol hydrochloride) and tranexam After mixing 30.0 parts by mass of an acid (manufactured by Daiichi Sankyo Propharma Co., Ltd.; trade name: Japanese Pharmacopoeia tranexamic acid), 11.2 parts by mass of purified water was added and kneaded to obtain a mixture. 0.3 g of the obtained mixture was placed on a resin sheet (manufactured by Sumitomo Bakelite Co., Ltd.: trade name Sumilite VSS-1202-R) in which pockets (cylindrical depressions with a diameter of 12 mm and a height of 6 mm) were formed in advance. It was placed in the pocket, covered with aluminum foil for PTP (manufactured by Daiwa Kagaku Kogyo Co., Ltd.; product name: plain silver aluminum foil), and PTP-packaged. In addition, the occupancy rate (volume ratio) of the mixture in the pocket portion of the PTP sheet was 73.7%.

From the test results shown in Table 2, even when PTP packaging was used as an airtight package instead of the bottle packaging used in Sample 4 of Test Example 1, ibuprofen or a salt thereof or a solvate thereof was added as in Sample 4. It was confirmed that an excellent inhibitory action was exhibited against compounding changes between ambroxol, a salt thereof, or a solvate thereof.

[Test Example 3] Stability test 3
Exactly the same test as in Test Example 2 was performed except that the storage conditions were changed to a temperature of 40° C. and humidity not adjusted.
Table 3 shows the results.

From the test results shown in Table 3, even when the storage conditions are changed, it is also excellent against blending changes between ibuprofen or its salts or their solvates and ambroxol or its salts or their solvates. It was confirmed that the inhibitory effect was exerted.

[Production Example 1]
Tablets containing the following ingredients per 6 tablets (2.4 g) were prepared by a conventional method. The resulting tablet was PTP-packaged by a conventional method to obtain the drug of Production Example 1.
Ibuprofen 600mg
Tranexamic acid 750mg
Ambroxol hydrochloride 45mg
Clemastine fumarate 1.34 mg
Anhydrous caffeine 75mg
dl-methylephedrine hydrochloride 60 mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate 25mg
Riboflavin 12mg
Microcrystalline cellulose Appropriate amount Trehalose 300mg
Macrogol 12mg
Croscarmellose sodium 80mg
Polyvinyl alcohol (partially saponified) 10 mg
Light silicic anhydride 4mg
Hydrogenated oil 10mg
Magnesium stearate 48mg
Hypromellose 65mg
Titanium oxide 6.5mg
Carnauba wax Trace amount

[Production Example 2]
Granules containing the following ingredients (3 packs: 3.6 g) were produced by a conventional method. The resulting granules were packed in aluminum pillows by a conventional method so that each packet weighed 1.2 g, and the drug of Production Example 2 was obtained.
Ibuprofen 450mg
Tranexamic acid 750mg
Ambroxol hydrochloride 45mg
Clemastine fumarate 1.34 mg
Anhydrous caffeine 40mg
dl-methylephedrine hydrochloride 60 mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate 25mg
Riboflavin 12mg
Microcrystalline cellulose Appropriate amount Erythritol 850mg
Trehalose 590mg
Pullulan 184mg
Ammonio alkyl methacrylate copolymer 10 mg
Croscarmellose sodium 80mg
Aspartame 82mg

[Production Example 3]
Tablets containing the following ingredients per 9 tablets (4.5 g) were prepared by a conventional method. The resulting tablet was PTP-packaged by a conventional method, and further packaged with an aluminum pillow to obtain the drug of Production Example 3.
Ibuprofen 600mg
Tranexamic acid 750mg
Ambroxol hydrochloride 45mg
Dihydrocodeine phosphate 24mg
dl-methylephedrine hydrochloride 60 mg
Isopropamide iodide 6 mg
7.5 mg of chlorpheniramine maleate
Anhydrous caffeine 75mg
Magnesium oxide 300mg
Ascorbic acid 300mg
Thiamine nitrate 24mg
Riboflavin 12mg
Microcrystalline cellulose appropriate amount Light silicic anhydride 12mg
Lactose 6mg
Low substituted hydroxypropyl cellulose 678mg
D-mannitol 650mg
Corn starch 60mg
Magnesium stearate 24mg
Talc 6mg
Hypromellose 70mg
Macrogol 11mg
Titanium oxide 8mg

[Production Example 4]
Granules containing the following ingredients (3 packs: 4.5 g) were produced by a conventional method. The resulting granules were packed in aluminum pillows by a conventional method so that each packet weighed 1.5 g, and the drug of Production Example 4 was obtained.
Ibuprofen 450mg
tranexamic acid 420mg
Ambroxol hydrochloride 45mg
Dihydrocodeine phosphate 24mg
dl-methylephedrine hydrochloride 60 mg
Isopropamide iodide 6 mg
7.5 mg of chlorpheniramine maleate
Anhydrous caffeine 75mg
Ascorbic acid 300mg
Thiamine nitrate 24mg
Riboflavin 12mg
Crystalline cellulose Appropriate amount Carmellose calcium 1106mg
Light silicic anhydride 4mg
Low substituted hydroxypropyl cellulose 1380mg
Talc 4mg
Tartaric acid 105mg
Saccharin sodium 100mg
l-menthol 4mg

[Production Example 5]
Tablets containing the following ingredients per 2 tablets (1.5 g) were prepared by a conventional method. The resulting tablets were PTP-packaged by a conventional method, and then placed in a paper box to obtain the drug of Production Example 5.
200 mg of ibuprofen
250 mg of tranexamic acid
Ambroxol hydrochloride 15mg
L-carbocysteine 250mg
Dihydrocodeine phosphate 8mg
dl-methylephedrine hydrochloride 20 mg
Chlorpheniramine maleate 2.5 mg
Anhydrous caffeine 25mg
Magnesium oxide 100mg
Ascorbic acid 100mg
Thiamine nitrate 8mg
Riboflavin 4mg
Microcrystalline cellulose appropriate amount Light silicic anhydride 20mg
Lactose 150mg
Hypromellose 45mg
45 mg of low-substituted hydroxypropyl cellulose
Talc 70mg
Sodium starch glycolate 50mg

[Production Example 6]
Tablets containing the following ingredients per 9 tablets (2.52 g) were prepared by a conventional method. The resulting tablet was PTP-packaged by a conventional method to obtain a drug of Production Example 6.
Ibuprofen 600mg
Tranexamic acid 750mg
Ambroxol hydrochloride 45mg
Dihydrocodeine phosphate 24mg
dl-methylephedrine hydrochloride 60 mg
Chlorpheniramine maleate 3.5 mg
Anhydrous caffeine 75mg
Lactose appropriate amount Hypromellose 60mg
Anhydrous citric acid 40mg
Calcium silicate 30mg
Hydroxypropyl cellulose 84mg
Carmellose calcium 100mg
Light silicic anhydride 70mg
Magnesium stearate 70mg
Triacetin 7mg
Talc 13mg
Titanium oxide 10mg
Carnauba wax Trace amount

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition containing both ibuprofen and ambroxol, which have excellent pharmacological actions, and excellent storage stability.

Claims (4)

The following components (A), (B) and (C):
(A) ibuprofen or a salt thereof or a solvate thereof;
(B) ambroxol or a salt thereof or a solvate thereof;
(C) tranexamic acid or a salt thereof or a solvate thereof;
A pharmaceutical composition containing a pharmaceutical composition contained in an airtight package. The pharmaceutical product according to claim 1, wherein the pharmaceutical composition is a solid formulation. 3. The pharmaceutical according to claim 1 or 2, wherein the dosage form of the pharmaceutical composition is tablet, capsule, granule or powder . The pharmaceutical product according to any one of claims 1 to 3, wherein the hermetic packaging is one or more selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging and stick packaging.