Oral pharmaceutical composition containing loxoprofen or a salt thereof and valerian.

Abstract

To provide a new oral pharmaceutical composition that has a reduced risk of gastric mucosal injury, contains loxoprofen, and is used as antipyretics, analgesics or common cold therapeutic agents.SOLUTION: An oral pharmaceutical composition contains loxoprofen or a salt thereof, and Japanese valerian.SELECTED DRAWING: None

Description

Technical Field

[0005] ,

[0001] The present invention relates to an oral pharmaceutical composition for antipyretic, analgesic and anti-inflammatory use with reduced gastric mucosal damage of loxoprofen or its salts. More specifically, it relates to an oral pharmaceutical composition with reduced gastric mucosal damage by containing loxoprofen or its salts and valerian root.

Background Art

[0002] Loxoprofen, which is a propionic acid-based non-steroidal anti-inflammatory drug (hereinafter referred to as NSAIDs), is known to have antipyretic, analgesic and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis similar to other NSAIDs. Loxoprofen is absorbed from the digestive tract as an unchanged form with a weak gastric mucosal irritation effect after oral administration and is a prodrug that becomes an active form in the body. Therefore, it is also known to have the characteristic of less gastric mucosal damage compared to other NSAIDs (see, for example, Non-Patent Document 1).

[0003] As a technique for further suppressing gastric mucosal damage by orally administering loxoprofen or its salts in combination with other active ingredients, techniques such as containing loxoprofen with specific saccharides (lactose, sucrose, maltitol, fructose, xylitol or lactitol) (see Patent Document 1), containing an antacid (magnesium oxide) (see Patent Document 2), and containing tranexamic acid, an antifibrinolytic drug (see Patent Document 3) have been disclosed.

[0004] On the other hand, valerian root is a crude drug obtained from the roots and rhizomes of Valeriana fauriei Briquet. The dichloromethane extract of valerian root and kesogulac diacetate, one of the main components, show sedative effects such as prolonging hexobarbital sleep, suppressing spontaneous behavior by the open field test, suppressing passive avoidance response, and suppressing fighting response in oral administration to mice (see Non-Patent Document 2).

[0005] As mentioned above, studies have been conducted on the effects of combining loxoprofen or its salts with other active ingredients. However, it is unknown what effect the combined oral administration of loxoprofen or its salts with valerian has on the inhibitory effect on gastric mucosal damage. To date, reports have indicated that valerian has effects such as sedation, choleretic activity, and blood pressure lowering, as well as preventing or improving wrinkles by inhibiting heparanase activity (see Patent Document 4), improving pain and insomnia when combined with acetaminophen, ethenzamide, and allyl isopropylacetylurea (Patent Document 5), and that a 50% ethanol extract of valerian showed anti-stress gastric ulcer activity in mice (Non-Patent Document 2). However, there are no reports investigating how gastric mucosal damage caused by loxoprofen or its salts, which differs from stress gastric ulcers in its cause and location, is affected by valerian, which has a sedative effect. Furthermore, no oral compositions containing loxoprofen and valerian are known, and therefore the combined effect of such compositions is unknown. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Patent No. 4585220 [Patent Document 2] Patent No. 6106727 [Patent Document 3] Patent No. 5835865 [Patent Document 4] Japanese Patent Publication No. 2016-169238 [Patent Document 5] Japanese Patent Publication No. 2015-189733 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmacology and Therapeutics Vol.16 No.2 1988 pp.611-619 [Non-Patent Document 2] The Seventeenth Revised Japanese Pharmacopoeia Commentary (Hirokawa Shoten) [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Although loxoprofen is a prodrug and is therefore thought to cause less gastric mucosal damage compared to other NSAIDs, there is still a risk of gastric mucosal damage occurring. On the other hand, while it is well known that valerian is effective for insomnia and other conditions, it remained unclear what effect the combination of loxoprofen and valerian would have on gastric mucosal damage caused by loxoprofen. In other words, the object of the present invention is to clarify the effect of oral co-administration of loxoprofen with valerian on gastric mucosal damage caused by loxoprofen. The present invention aims to provide a novel oral pharmaceutical composition containing loxoprofen that can be used as an antipyretic, analgesic, or cold treatment agent with a reduced risk of gastric mucosal damage. [Means for solving the problem]

[0009] As a result of diligent research to solve the above problems, the present inventors have found that the combined use of loxoprofen or its salt with valerian reduces gastric mucosal damage caused by loxoprofen or its salt, and that valerian does not affect the analgesic effect of loxoprofen or its salt, thus completing the present invention.

[0010] In other words, the present invention is as follows: (1) An oral pharmaceutical composition comprising loxoprofen or a salt thereof and valerian. (2) The oral pharmaceutical composition described in (1) used as an antipyretic, analgesic, or cold treatment agent. (3) The oral pharmaceutical composition according to (1) or (2), which is a tablet, granule, capsule, or liquid. (4) An oral pharmaceutical composition according to any one of (1) to (3), containing at least 1 part by weight of valerian (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof. (5) An oral pharmaceutical composition according to any one of (1) to (3), containing 1 to 33 parts by weight of valerian (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof. [Effects of the Invention]

[0011] The oral pharmaceutical composition of the present invention is characterized by containing an effective amount of loxoprofen or a salt thereof that exerts antipyretic, analgesic, or anti-inflammatory effects, while reducing gastric mucosal damage, which is a side effect of loxoprofen or a salt thereof. In other words, the oral pharmaceutical composition of the present invention is useful as a highly safe antipyretic, analgesic, or cold treatment agent that exerts effective antipyretic, analgesic, and anti-inflammatory effects while reducing gastric mucosal damage during administration. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the results of an investigation into the effects of loxoprofen sodium dihydrate alone and loxoprofen sodium dihydrate in combination with valerian. In the figure, ** indicates that the combination of loxoprofen sodium dihydrate and valerian showed a statistically significant difference compared to the loxoprofen sodium dihydrate alone group (p<0.01). [Figure 2] Figure 2 shows the results of an investigation into the analgesic effects of the medium, loxoprofen sodium dihydrate alone, and loxoprofen sodium dihydrate in combination with valerian. In the figure, ** indicates that the group receiving loxoprofen sodium dihydrate and valerian showed a statistically significant difference compared to the group receiving loxoprofen sodium dihydrate alone (p<0.01). [Modes for carrying out the invention]

[0013] In the present invention, "loxoprofen or its salt" means loxoprofen or its salt (including hydrated salts), preferably sodium loxoprofen, and more preferably sodium loxoprofen dihydrate. The loxoprofen or its salt used in the present invention is listed in the 17th revised Japanese Pharmacopoeia together with Herba Violae as sodium loxoprofen hydrate.

[0014] In the present invention, as "Herba Violae", preferably, those listed in the 17th revised Japanese Pharmacopoeia can be used. Since Herba Violae other than the above are also commercially available, they can be easily obtained.

[0015] Valerian used in this invention has been used medicinally since ancient times, either as a single ingredient or in herbal formulas, and the crude drug powder or extract obtained according to conventional methods can be used as is. The form of the crude drug powder or extract can also be the usual commercially available product or a processed product thereof. As the crude drug powder, for example, a dried powder (fine powder) obtained by further grinding a dried chopped processed product may be used. Furthermore, the form of the extract from the crude drug is not particularly limited and can be used in any form, such as dried extract, extract powder, soft extract, fluid extract, ethanol, or a tincture containing ethanol and water. Preferred crude drugs include extracts that offer a high degree of freedom in formulation, such as soft extract (5x concentrated) and dried extract powder. The extract can be obtained by conventional methods, for example, by extracting the active ingredient having antibacterial activity from the crude drug using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixture thereof is often used. Examples of the hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used individually or as a mixture of two or more solvents.

[0016] The amount of loxoprofen or its salt contained in the oral pharmaceutical composition of the present invention is not limited, but the amount of the component contained in the oral pharmaceutical composition per adult dose unit (single dose) is preferably 10 to 180 mg, more preferably 20 to 120 mg, and even more preferably 60 to 90 mg on an anhydrous basis, and the number of doses is 1 to 3 times a day.

[0017] In addition, there is no particular limitation on the content of *Cimicifuga simplex Wormsk.* in the oral pharmaceutical composition of the present invention. However, as the amount of the component contained in the oral pharmaceutical composition per adult single-dose unit (single dose), in terms of crude drug equivalent, it is preferably 10 to 2000 mg, more preferably 20 to 1440 mg, still more preferably 60 to 450 mg, and the number of administrations is 1 to 3 times a day.

[0018] Moreover, if the oral pharmaceutical composition of the present invention is a liquid preparation taken at 50 mL once a day, the content of loxoprofen or its salt in the liquid preparation is preferably 10 to 180 mg / 50 ml in terms of anhydride equivalent, and for *Cimicifuga simplex Wormsk.*, in terms of crude drug equivalent, it is preferably 10 to 2000 mg / 50 mL.

[0019] In addition, in the oral pharmaceutical composition of the present invention, the mixing ratio of loxoprofen or its salt and *Cimicifuga simplex Wormsk.* is not particularly limited as long as the effects of the present invention are achieved. However, it is preferable to contain at least 1 part by weight of *Cimicifuga simplex Wormsk.* (in terms of crude drug equivalent) with respect to 1 part by weight of loxoprofen or its salt (in terms of anhydride equivalent). A more preferable mixing ratio is 1 to 33 parts by weight of *Cimicifuga simplex Wormsk.* (in terms of crude drug equivalent) with respect to 1 part by weight of loxoprofen or its salt (in terms of anhydride equivalent), and more preferably, 1 to 12 parts by weight of *Cimicifuga simplex Wormsk.* (in terms of crude drug equivalent) with respect to 1 part by weight of loxoprofen or its salt (in terms of anhydride equivalent), and most preferably, 1 to 5 parts by weight of *Cimicifuga simplex Wormsk.* (in terms of crude drug equivalent).

[0020] The oral pharmaceutical composition of the present invention can be preferably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient, loxoprofen or its salt, has an antipyretic, analgesic, and anti-inflammatory effect, as an analgesic and antipyretic agent, it is particularly preferably used for analgesia of headache, menstrual pain, toothache, pain after tooth extraction, sore throat, low back pain, joint pain, muscle pain, stiff shoulder pain, earache, contusion pain, fracture pain, sprain pain, trauma pain, etc., and for antipyretic during chills and fever. Also, as a cold treatment agent, it can be preferably used for the purpose of alleviating various symptoms of cold (runny nose, nasal congestion, cough, phlegm, throat pain, fever, chills, headache, sneezing, joint pain, muscle pain).

[0021] The oral pharmaceutical composition of the present invention may be in dosage forms described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc., such as solid preparations including tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), lozenges, drops, hard capsules, soft capsules, granules, fine granules, powders, pills, dry syrups, suppositories, poultices, and plasters; semi-solid preparations including licks, chewing gums, jellies, jelly drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; and liquid preparations including syrups, drinks, suspensions, alcoholic preparations, liquids, eye drops, aerosols, sprays, and aerosols. In the present invention, a solid preparation is preferred in terms of ease of administration and manufacturing, an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules is more preferred, and a tablet or capsule is particularly preferred. These compositions may further contain, as needed, other active ingredients, such as cough suppressants / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal drug components, antacids, anticholinergics, sedatives, other vitamins, and xanthine derivatives, within limits that do not impair the present invention. If there are any contraindications for the inclusion of these ingredients, they may be appropriately formulated by granulation or other means.

[0022] For example, one or more ingredients selected from codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibnate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, noscapine hydrochloride, trimethoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc., can be included as cough suppressants and expectorants.

[0023] As an antihistamine, one or more components selected from, for example, azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, triperenamine hydrochloride, tondilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methidilazine hydrochloride, loratadine, etc. may be included.

[0024] As an anti-inflammatory agent, one or more components selected from glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, licorice, etc. may be included.

[0025] The gastrointestinal medication may contain one or more ingredients selected from gefarnate, cetraxate hydrochloride, solfalcone, teprenone, methylmethionine sulfonium chloride, etc.

[0026] As antacids, alkaline earth metals and / or earth metal-based basic inorganic compounds include magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, coprecipitation products of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, coprecipitation products of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation products of aluminum hydroxide, magnesium carbonate and calcium carbonate, and Examples of inorganic salts of metals selected from magnesium, aluminum, and calcium include celandite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Examples of alkali metal basic inorganic compounds include anhydrous sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and other inorganic salts of metals selected from sodium and potassium. Other examples include oysterol and glycine. One or more components selected from these can be blended. Among these, magnesium oxide, magnesium aluminometasilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are particularly preferred.

[0027] As an anticholinergic agent, one or more components selected from scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, total belladonna root alkaloid citrate, etc. may be included.

[0028] As a sedative, one or more components selected from bromovalerylurea, allyl isopropylacetylurea, etc., may be included.

[0029] As for vitamins, one or more ingredients selected from vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B5, vitamin B12, vitamin P, hesperidin, vitamin D, vitamin E, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium magnesium aspartate, etc., inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma-oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronamide, sodium chondroitin sulfate, carrot, and coix seed may be included.

[0030] As xanthine derivatives, one or more components selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate can be included.

[0031] The oral pharmaceutical composition of the present invention can be formulated according to conventional methods. Loxoprofen or its salt and valerian may be formulated as the same granule to form a single pharmaceutical composition. Alternatively, loxoprofen or its salt and valerian may be formulated separately and then combined into a single pharmaceutical composition. For example, in the latter case, granules containing loxoprofen or its salt and granules containing valerian may be manufactured separately, and then additives (such as excipients) can be added to the granules containing loxoprofen or its salt and the granules containing valerian to produce granules, fine granules, or powders. Alternatively, tablets may be manufactured by separately manufacturing granules containing loxoprofen or its salt and granules containing valerian, then adding additives (such as excipients and lubricants) to the granules containing loxoprofen or its salt and the granules containing valerian, and compressing them into tablets. Alternatively, capsules may be manufactured by filling capsules with granules containing loxoprofen or its salt and granules containing valerian. Alternatively, multilayer tablets can be manufactured by separately manufacturing granules containing loxoprofen or its salt and granules containing valerian, then adding additives between a single layer containing loxoprofen or its salt and a single layer containing valerian, and compressing them into tablets. Alternatively, granules containing loxoprofen or its salt and granules containing valerian may be manufactured separately, then tablets containing loxoprofen or its salt or tablets containing valerian may be manufactured, and a core tablet can be manufactured by embedding a tablet within a tablet.

[0032] The oral pharmaceutical composition of the present invention may be initially packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and stored airtight. Furthermore, they may be pillow-packaged, and stored in boxes or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, polyethylene film, or these resin films with aluminum foil attached can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle packaging or pillow packaging.

[0033] The formulation can be prepared using known methods and additives as appropriate. Additives should be added as appropriate, as long as they do not impair the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, coating agents, binders, fluidizers, plasticizers, sugar coating agents, glossing agents, solvents, pH adjusters, colorants, flavoring agents, sweeteners, fragrances, and other flavoring agents.

[0034] Examples of excipients include crystalline cellulose, powdered cellulose, potato starch, light anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, and the like.

[0035] Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, and bentonite.

[0036] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, and hydrogenated oils.

[0037] Examples of coating agents include aminoalkyl methacrylate copolymer, acacia gum, ethylcellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, povidone, polyvinyl alcohol, and macrogol.

[0038] As a binder, one or more components selected from, for example, gum arabic, gum arabic powder, agar, agar powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol, methacrylate copolymer L, methacrylate copolymer, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, etc. may be incorporated.

[0039] As a fluidizing agent, one or more components selected from, for example, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, tricalcium phosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, etc., can be blended.

[0040] As plasticizers, one or more components selected from triethyl citrate, glycerin, glycerin fatty acid ester, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc. may be incorporated.

[0041] As a sugar coating agent, one or more ingredients selected from gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyoxyethylene, polyvinyl alcohol, macrogol, etc. may be included.

[0042] As a glossing agent, one or more ingredients selected from carnauba wax, refined shellac, macrogol, beeswax, etc., may be included.

[0043] As a solvent, one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol, etc., may be included.

[0044] As a pH adjuster, one or more components selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine, etc., may be included.

[0045] As coloring agents, one or more ingredients selected from yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium dioxide, yellow ferric oxide, ferric oxide, ferric oxide / glycerin suspension, food-grade blue No. 2 aluminum lake, food-grade yellow No. 4 aluminum lake, copper chlorophyllin sodium, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc. may be included.

[0046] The flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, and ginger. One or more ingredients selected from the following may be included: powder, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, porcini powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0047] As a sweetener, one or more ingredients selected from aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. may be included.

[0048] As for the flavoring, one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc. may be included.

[0049] The fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, and Vitabase. It may contain one or more ingredients selected from the following: Himalayan cedar oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0050] These additives are not limited to those listed above, and one of them may be used, or two or more may be used in combination.

[0051] The present invention will be described in more detail below with reference to test examples and formulation examples, but it is not limited to these examples. [Examples]

[0052] (Example of formulation 1) Capsule [Table 1]

[0053] Using the above ingredients and quantities, manufacture the capsules in accordance with the "Capsules" section of the General Provisions for Preparations of the Japanese Pharmacopoeia.

[0054] (Example of formulation 2) Tablets [Table 2]

[0055] The above ingredients and quantities are used to manufacture tablets in accordance with the "Tablets" section of the General Provisions for Preparations of the Japanese Pharmacopoeia. A tablet coating may be applied as desired.

[0056] (Formulation example 3) Tablets [Table 3]

[0057] The above ingredients and quantities are used to manufacture tablets in accordance with the "Tablets" section of the General Provisions for Preparations of the Japanese Pharmacopoeia. A tablet coating may be applied as desired.

[0058] (Formulation example 4) Tablets [Table 4]

[0059] The above ingredients and quantities are used to manufacture tablets in accordance with the "Tablets" section of the General Provisions for Preparations of the Japanese Pharmacopoeia. A tablet coating may be applied as desired.

[0060] (Formulation example 5) Granules [Table 5]

[0061] The above ingredients and quantities are used to prepare the granules in accordance with the "Granules" section of the Japanese Pharmacopoeia (JP) General Provisions. A coating may be applied as desired.

[0062] (Test Example 1) Gastric Mucosal Damage Test (1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma. Valerian extract (Valerian extract-T; crude drug equivalent ratio 5:1) was manufactured by Nippon Powder Pharmaceutical Co., Ltd. These test substances were prepared by suspending them in a 0.5% tragacanth solution prepared by dissolving tragacanth (manufactured by SIGMA) in sterile water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).

[0063] (2) Animals used Six-week-old male Crl:CD rats (Nippon SLC) were used after a five-day quarantine period and a three-day acclimatization period. The animals were individually housed in a rat enclosure controlled to a temperature of 20-26°C, humidity of 40-70%, and lighting hours of 6:00-18:00. They were given free access to solid samples (Oriental Yeast Industry rat feed, CRF-1) and tap water, and animals with good general symptoms such as coat condition and weight gain were selected for the study.

[0064] (3) Test method Rats that had been fasted for more than 18 hours were orally administered the test substance using a disposable polypropylene syringe (Terumo) fitted with a disposable oral tube for rats (Fuchigami Kikai). The test substance was stirred using a magnetic stirrer during administration. Four hours after administration of the test substance, the animals were euthanized by cervical dislocation under mild isoflurane anesthesia. The stomach was promptly removed, filled with 10 mL of physiological saline solution, and then immersed in 1% formalin for fixation until the following day. The fixed stomach was incised along the greater curvature, and the length of gastric mucosal injury was measured using a digital caliper. For each individual, the length of the gastric mucosal injury was calculated by measuring the longest diameter and summing them up (total injury length).

[0065] (4) Test results Table 5 and Figure 1 show the sum of the lengths of gastric mucosal injury in the groups treated with loxoprofen sodium (anhydrous basis) (LOX) and valerian (LOX + valerian group). The numbers in parentheses represent the dose of each test drug in mg / kg (valerian is shown in terms of crude drug equivalent), and each group had n=5 results. Statistical analysis was performed using t-tests for each group, and the inhibition rate (%) was calculated from the sum of the lengths of gastric mucosal injury using the following formula.

[0066]

number

[0067] [Table 6] **Significant difference observed compared to LOX(80) (p<0.01)** L indicates low dose, and H indicates high dose.

[0068] Table 6 and Figure 1 show that when loxoprofen sodium dihydrate (LOX) is used in combination with valerian, a low dose of valerian (equivalent to 89 mg / kg of crude drug) tends to reduce gastric mucosal damage caused by loxoprofen, while a high dose of valerian (equivalent to 355.5 mg / kg of crude drug) significantly reduces gastric mucosal damage caused by loxoprofen.

[0069] (Test Example 2) Analgesic Effect Test (1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma. Valerian (valerian powder) was manufactured by Nippon Powder Pharmaceutical Co., Ltd. These test substances were prepared by suspending them in a 0.5% CMC-Na solution, which was obtained by dissolving carboxymethylcellulose sodium (CMC-Na) (manufactured by Kanto Chemical) in sterile water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).

[0070] (2) Animals used Four-week-old male Crl:CD rats (Nippon SLC) were used after an eight-day quarantine and acclimatization period. The animals were individually housed in a rat enclosure controlled to a temperature of 19-25°C, humidity of 30-70%, and lighting hours of 8-20:00. Solid samples (solid rat feed manufactured by Nippon Nosan Kogyo, Lab MR Stock) and tap water were freely available, and animals with good general symptoms such as coat condition and weight gain were selected for the study.

[0071] (3) Test method Rats that had been fasted for more than 12 hours were orally administered the test substance using a disposable polypropylene syringe (Terumo) fitted with a disposable oral tube for rats (Fuchigami Kikai) 30 minutes before administration of the inflammatory substance. Thirty minutes after administration of the test substance, 0.7% acetate saline was administered intraperitoneally as the inflammatory substance by filling a syringe (Terumo) fitted with a 26G needle (Terumo). Video recording was made using a video camera to capture the period from 10 to 20 minutes after administration of the inflammatory substance, and the number of rising symptoms occurring in 10 minutes was measured using a PLUS HAND COUNTER (Plus).

[0072] (4) Test results Table 6 and Figure 2 show the mean number of rising symptoms (per 10 minutes) in the loxoprofen sodium (calculated as anhydrous) (LOX) and valerian (LOX + valerian group). Here, the numbers in parentheses are the dose mg / kg of each test drug (valerian represents the amount of crude drug), and the results for each group were n=5. Statistical analysis was performed using t-tests for each group, and the suppression rate (%) of rising symptoms was calculated from the number of rising symptoms obtained using the following formula.

[0073]

number

[0074] [Table 7] **Significant difference observed compared to the control group (p<0.01)** There was no significant difference between LOX(18) and LOX(18) + Valerian (75).

[0075] Table 7 and Figure 2 show that both the loxoprofen sodium dihydrate (LOX) group and the group receiving valerian (LOX(18) + valerian(75)) (valerian was administered at a crude drug dose of 75 mg / kg) showed analgesic effects. However, there was no statistically significant difference between the two groups, indicating that valerian does not affect the analgesic effect of loxoprofen.

[0076] Tables 6 and 7, and Figures 1 and 2 show that combining loxoprofen with valerian significantly reduces gastric mucosal damage without affecting the analgesic effect of loxoprofen. The effects of combining loxoprofen and valerian on gastric mucosal damage were previously unknown, making the results obtained in Study 1 unexpected.

[0077] When examining the dose ratios of loxoprofen sodium to valerian (valerian / LOX) in the gastric mucosal damage test and the analgesic efficacy test, the dose ratio in the gastric mucosal damage test was 4.44 (high dose of valerian), and the dose ratio in the analgesic efficacy test was 4.17, which are almost equivalent. Since valerian had almost no effect on the analgesic effect of loxoprofen sodium in the analgesic efficacy test, it is unlikely that the dose ratio in the gastric mucosal damage test would similarly have an effect that weakens the analgesic effect of loxoprofen sodium. In other words, it is thought that valerian suppresses gastric mucosal damage without affecting the analgesic effect of loxoprofen sodium. [Industrial applicability]

[0078] The oral pharmaceutical composition of the present invention, containing loxoprofen or a salt thereof and valerian, is extremely useful because it significantly suppresses gastric mucosal damage caused by loxoprofen, thereby reducing the rate of side effects. The oral pharmaceutical composition of the present invention is suitably used as an antipyretic and analgesic, particularly for the relief of pain such as headache, menstrual cramps, toothache, post-extraction pain, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, and traumatic pain, as well as for reducing fever during chills and fever. It is also suitably used as a cold treatment agent to alleviate various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims

1. An oral pharmaceutical composition containing valerian to alleviate gastric mucosal damage, The aforementioned gastric mucosal damage is gastric mucosal damage caused by loxoprofen. The mixture is formulated such that, per 1 part by weight of loxoprofen or its salt, valerian is present in an amount equivalent to at least 1 part by weight of crude drug. The oral pharmaceutical composition.

2. Furthermore, the oral pharmaceutical composition according to claim 1 further comprises one or more selected from cough suppressants / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal drug components, antacids, anticholinergics, sedatives, vitamins, and xanthine derivatives.

3. An oral pharmaceutical composition according to claim 1 or 2, which is a tablet, granule, capsule, or liquid.

4. An oral pharmaceutical composition according to claim 2, comprising an antacid, wherein the antacid is one or more selected from magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium hydroxide / potassium aluminum sulfate coprecipitation product, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, dried aluminum hydroxide / magnesium carbonate mixed gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, dried sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, oyster shell, and glycine.

5. The oral pharmaceutical composition according to claim 2, comprising a sedative, wherein the sedative is one or two selected from bromovalerylurea and allyl isopropylacetylurea.

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