Oral pharmaceutical composition containing loxoprofen or a salt thereof and bowi

Abstract

To provide an oral pharmaceutical composition that has a reduced risk of gastric mucosal injury caused by loxoprofen and is used as an antipyretic, an analgesic or a common cold therapeutic.SOLUTION: The present invention relates to an oral pharmaceutical composition containing loxoprofen or salt thereof and Sinomenium stem.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an oral pharmaceutical composition for antipyretic, analgesic, and anti-inflammatory purposes, which reduces gastric mucosal damage caused by loxoprofen or a salt thereof, and more particularly, to an oral pharmaceutical composition which reduces gastric mucosal damage by containing loxoprofen or a salt thereof and Bowie. [Background technology]

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

[0003] Techniques disclosed for further suppressing gastric mucosal damage by orally administering rofecoxib or a salt thereof in combination with other active ingredients include a technique for incorporating specific sugars (lactose, sucrose, maltitol, fructose, xylitol or lactitol) into rofecoxib (see Patent Document 1), a technique for incorporating an antacid (magnesium oxide) (see Patent Document 2), and a technique for incorporating the antiplasmin drug tranexamic acid (see Patent Document 3).

[0004] On the other hand, bowi is usually made by cutting the vine stems and rhizomes of Hemerocallis maxima crosswise, and its main component is sinomenin, and it also contains alkaloids such as disinomenin. It is mainly used in Kampo prescriptions and is formulated to promote water metabolism and for the purposes of analgesia and diuresis, and is included in general Kampo prescriptions such as Boi-ohgi-to, Boi-bukuryo-to, and Dokatsu-to. The main component, sinomenin, is known to have central nervous system depressant, blood pressure lowering, and histamine releasing effects, as well as local analgesic, anti-anaphylactic, anti-inflammatory effects, and negative inotropic effects (see Non-Patent Document 2).

[0005] As mentioned above, the effects of the combined use of loxoprofen or its salts with other active ingredients have been studied, but it is not known what effect the combined oral administration of loxoprofen or its salts with Bowie will have on the gastric mucosal damage suppression effect. Bowie has been shown to have analgesic and diuretic effects, as well as enhancement of reticuloendothelial system function and antiallergic effects. For example, when a liquid extracted by heating at pH 4.8 is continuously administered intramuscularly to a rabbit, there is no effect on blood pressure, red blood cell count, or hemoglobin content, but the white blood cell count increases significantly, enhancing the reticuloendothelial system function. It also suppresses histamine asthma in guinea pigs and has an antiallergic effect (see Non-Patent Document 2). Bowie has also been shown to have a direct effect on the salivary glands and promote saliva secretion (Patent Document 4). However, there is no report that Bowie suppresses gastric mucosal damage caused by loxoprofen or its salts. In addition, there are no known oral compositions combining rofecoxib and Bowi, and the effect of such a combination 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] Patent Publication No. 2005-162633 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 [Non-Patent Document 2] 17th Edition Japanese Pharmacopoeia Commentary (Hirokawa Shoten) Summary of the Invention [Problem to be solved by the invention]

[0008] Since loxoprofen is a prodrug, it is considered that gastric mucosal damage is less than other NSAIDs, but there is still a risk of gastric mucosal damage. On the other hand, it is known that Bowie is effective in analgesia, but it remains unclear what kind of results will be caused by the addition of Bowie to gastric mucosal damage caused by loxoprofen. That is, the object of the present invention is to clarify the effect of oral administration of Bowie in combination with loxoprofen on gastric mucosal damage caused by loxoprofen. The object of the present invention is to provide a new oral pharmaceutical composition containing loxoprofen, which is used as an antipyretic, analgesic, or cold treatment agent with reduced risk of gastric mucosal damage. [Means for solving the problem]

[0009] As a result of intensive research to solve the above-mentioned problems, the inventors discovered that the combined use of rofecoxib or a salt thereof with Bowie reduces gastric mucosal damage caused by rofecoxib or a salt thereof, and that Bowie does not affect the analgesic effect of rofecoxib or a salt thereof, and thus completed the present invention.

[0010] That is, the present invention is as follows. (1) An oral pharmaceutical composition comprising rofecoxib or a salt thereof and bowel movement disorder. (2) The oral pharmaceutical composition according to (1), which is used as an antipyretic, analgesic, or cold remedy. (3) The oral pharmaceutical composition according to (1) or (2), which is in the form of a tablet, fine granules, capsule or liquid. (4) An oral pharmaceutical composition according to any one of (1) to (3), containing at least 1 part by weight of boui (equivalent to the original herbal medicine) per 1 part by weight of rofecoxib or a salt thereof. (5) The oral pharmaceutical composition according to any one of (1) to (3), comprising 1 to 60 parts by weight of Bowie (equivalent to raw herbal medicine) per 1 part by weight of loxoprofen or a salt thereof. Effect of the Invention

[0011] The oral pharmaceutical composition of the present invention is characterized in that it contains 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 remedy that exerts effective antipyretic, analgesic and anti-inflammatory effects and reduces gastric mucosal damage when taken. [Brief description of the drawings]

[0012] [Figure 1] Figure 1 shows the results of an investigation into the effects of loxoprofen sodium dihydrate alone and the combined use of loxoprofen sodium dihydrate and Bowie powder on gastric mucosal injury. [Diagram 2] Figure 2 shows the results of analgesic effects of vehicle, loxoprofen sodium dihydrate alone, and the combined use of loxoprofen sodium dihydrate and Bowie powder. The ** in the figure indicates that there is a significant difference between the group using the combined use of loxoprofen sodium dihydrate and Bowie powder and the group using loxoprofen sodium dihydrate alone (p<0.01). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In the present invention, "loxoprofen or a salt thereof" refers to loxoprofen or a salt thereof (including a hydrate salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. Loxoprofen or a salt thereof used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0014] In the present invention, the "Bowie" that can be used is preferably that listed in the 17th Edition of the Japanese Pharmacopoeia. Bowie models other than those mentioned above are also available commercially and are easily available.

[0015] The bowie used in the present invention has been used for medicinal purposes since ancient times as a single ingredient or as a Kampo prescription, and the herbal powder or extract component obtained according to the conventional method can be used as it is. The form of the herbal powder or extract component can be a normal commercially available product or a processed product thereof. For example, a dried chopped processed product may be further finely ground into a powder (fine powder) to be used as a dry powder. The form of the extract component from the herbal medicine is not particularly limited, and any form such as a dried extract, extract powder, soft extract, liquid extract, tincture containing ethanol or ethanol and water can be used. Preferred herbal medicines include extract components with a high degree of freedom in formulation, such as a dried extract powder. The extract component can be obtained by extracting the active ingredient from the herbal medicine by a conventional method, for example, an extraction solvent. For the extraction solvent, for example, water, a hydrophilic solvent, or a mixture thereof is often used. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, t-butanol, etc.; cellosolves such as methyl cellosolve, ethyl cellosolve, etc.; ketones such as acetone, etc.; ethers such as dioxane, tetrahydrofuran, etc.; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc. These hydrophilic solvents may be used alone or as a mixed solvent of two or more kinds.

[0016] The content of rofecoxib or a salt thereof 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 dosage unit (single dose) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 60 to 90 mg, calculated as the anhydrous amount, and the frequency of administration is 1 to 3 times a day.

[0017] There is also no particular limitation on the content of Bowie in the oral pharmaceutical composition of the present invention, but the amount of the component contained in the oral pharmaceutical composition per dosage unit (single dosage) for adults is preferably 1 to 4000 mg, more preferably 30 to 2000 mg, and even more preferably 60 to 1000 mg, calculated as the amount of raw herbal medicine, and the frequency of administration is 1 to 3 times a day.

[0018] Furthermore, if the oral pharmaceutical composition of the present invention is a liquid formulation to be taken in a volume of 50 ml once a day, the content of rofecoxib or a salt thereof in the liquid is preferably 10 to 180 mg / 50 ml in terms of the anhydrous substance, and in the case of bovine serum albumin, the content is preferably 1 to 4,000 mg / 50 ml in terms of the original herbal drug.

[0019] In the oral pharmaceutical composition of the present invention, the mixing ratio of loxoprofen or its salt and Bowie is not particularly limited as long as the effects of the present invention are achieved, but it is preferable to contain at least 1 part by weight of Bowie (based on raw herbal medicine) per 1 part by weight (based on anhydrous substance) of loxoprofen or its salt. A more preferred mixing ratio is 1-60 parts by weight of Bowie (based on raw herbal medicine) per 1 part by weight (based on anhydrous substance) of loxoprofen or its salt, and more preferably 1-30 parts by weight (most preferably 1-6 parts by weight) of Bowie (based on raw herbal medicine) per 1 part by weight (based on anhydrous substance) of loxoprofen or its salt.

[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 a salt thereof, has antipyretic, analgesic, and anti-inflammatory effects, it can be preferably used as an analgesic and antipyretic, particularly for the pain relief of headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, trauma pain, etc., and for the fever reduction during chills and fever, and can also be preferably used as a cold remedy for the purpose of relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0021] The oral pharmaceutical composition of the present invention may be in the form of a solid preparation such as a tablet (including orally disintegrating tablet, chewable tablet, effervescent tablet, dispersible tablet, dissolving tablet, etc.), oral tablet (including lozenge, sublingual tablet, buccal tablet, adhesive tablet, etc.), hard capsule, soft capsule, granule, powder, pill, dry syrup, etc.; semi-solid preparation such as gum, oral jelly, etc.; liquid preparation such as a liquid preparation (including elixir, suspension, emulsion, lemonade, etc.), syrup, spirit, infusion, decoction, tea, tincture, aromatic perfume, and liquid extract, etc., as described in the General Provisions of Preparations of the 17th Revised Japanese Pharmacopoeia, etc. In the present invention, from the viewpoint of convenience of administration and manufacturing, etc., a solid preparation is preferable, and an oral pharmaceutical composition selected from the group consisting of a tablet, capsule, pill, granule, powder, and fine granule is more preferable, and a tablet or capsule is particularly preferable. These compositions may further contain other active ingredients, as necessary, such as antitussives / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal ingredients, antacids, anticholinergics, other vitamins, xanthine derivatives, and sedatives, within the scope of the present invention. If there are any contraindications for the inclusion of these ingredients, the ingredients may be formulated by dividing them into granules, etc.

[0022] Examples of antitussives / expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.

[0023] Examples of antihistamines include azelastine hydrochloride, alimemazine 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, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, etc.

[0024] Anti-inflammatory agents include glycyrrhizinic acid and its derivatives and salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, and the like.

[0025] Examples of gastrointestinal drug ingredients include gefarnate, cetraxate hydrochloride, repamibide, sofalcone, teprenone, methylmethionine sulfonium chloride, and the like. Examples of antacids include ingredients that increase the pH of gastric acid, such as magnesium, aluminum and calcium salts, such as glycine (also called aminoacetic acid), magnesium silicate, magnesium aluminium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminium metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and salts selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, and the like.

[0026] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scolytsum extract, Scolytsum root, and Scolytsum root total alkaloid citrate.

[0027] Vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, a mixture of equal parts of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine.

[0028] Xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate. Sedatives include allylisopropylacetylurea and bromvalerylurea.

[0029] The oral pharmaceutical composition of the present invention can be formulated according to a conventional method, but in order to improve compliance by miniaturizing tablets, capsules, and granules, Bowie extract, which can be formulated in a smaller amount than Bowie powder, may be used. Loxoprofen or a salt thereof and Bowie dry extract may be formulated as the same granule to form one pharmaceutical composition. Loxoprofen or a salt thereof and Bowie dry extract may be formulated separately and then formulated into one pharmaceutical composition. For example, in the latter case, granules containing loxoprofen or a salt thereof and granules containing Bowie dry extract are separately produced, and then additives (excipients, etc.) are added to the granules containing loxoprofen or a salt thereof and the granules containing Bowie dry extract to produce granules, fine granules, or powders. Alternatively, granules containing loxoprofen or a salt thereof and granules containing Bowie dried extract may be separately produced, and then additives (excipients, lubricants, etc.) may be added to the granules containing loxoprofen or a salt thereof and the granules containing Bowie dried extract, and tableted to produce tablets, or granules containing loxoprofen or a salt thereof and granules containing Bowie dried extract may be filled into capsules to produce capsules. Alternatively, granules containing loxoprofen or a salt thereof and granules containing Bowie dried extract may be separately produced, and then additives may be added between the single layer containing loxoprofen or a salt thereof and the single layer containing Bowie dried extract, and tableted to produce multi-layer tablets. Alternatively, granules containing loxoprofen or a salt thereof and granules containing Bowie dried extract may be separately produced, and then tablets containing loxoprofen or a salt thereof or tablets containing Bowie dried extract may be produced, and dry-coated tablets in which tablets are embedded in tablets may be produced. Although a dried extract of Bowie was used in the formulation examples, any form such as extract powder, soft extract, liquid extract, tincture containing ethanol or ethanol and water, etc. may be used.

[0030] The oral pharmaceutical composition of the present invention may be once packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc. and stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and may be, for example, a resin film such as a polypropylene film, a polyethylene terephthalate film, or a polyethylene film, or a resin film with aluminum foil attached thereto. If hygroscopicity is a concern, a desiccant or the like may be stored simultaneously in the bottle packaging or pillow packaging.

[0031] The formulation can be prepared by using known methods and additives as appropriate. The additives may be added as appropriate within the range that does not impair the effects of the present invention. In the case of solid preparations (tablets, fine granules, capsules, etc.), the additives include excipients, disintegrants, lubricants, coating agents, binders, fluidizing agents, plasticizers, sugar-coating agents, glossing agents, solvents, pH regulators, colorants, flavoring agents, sweeteners, flavoring agents, flavoring agents, and flavoring agents, and in the case of liquid preparations, the additives include excipients, solvents, pH regulators, colorants, flavoring agents, sweeteners, flavoring agents, flavoring agents, and flavoring agents, and flavoring agents, and the like.

[0032] The excipient may be one or more components selected from, for example, crystalline cellulose, powdered cellulose, potato starch, corn 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.

[0033] The disintegrant may be one or more components selected from, for example, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite, etc.

[0034] As the lubricant, for example, one or more components selected from magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hardened oils, etc. can be blended.

[0035] The coating agent may contain one or more components selected from, for example, aminoalkyl methacrylate copolymer, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, talc, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol, macrogol, and the like.

[0036] The binder may be, for example, one or more components selected from gum arabic, powdered gum arabic, agar, powdered agar, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol, methacrylic acid copolymer L, methacrylic acid copolymer, butyl methacrylate-methyl methacrylate copolymer, methyl cellulose, etc.

[0037] The fluidizing agent may be, for example, one or more components selected from hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, calcium triphosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, etc.

[0038] As the plasticizer, one or more components selected from triethyl citrate, glycerin, glycerin fatty acid esters, medium-chain fatty acid triglycerides, 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, glycerin monostearate, isopropyl linoleate, liquid paraffin, etc. can be blended.

[0039] The sugar-coating agent may be one or more components selected from gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyoxyethylene, polyvinyl alcohol, macrogol, etc.

[0040] As the glossing agent, one or more components selected from carnauba wax, refined shellac, macrogol, beeswax, etc. can be blended.

[0041] As the solvent, one or more components selected from isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol, and the like can be blended.

[0042] The pH adjuster may be 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.

[0043] As colorants, one or more components selected from yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, black iron oxide, titanium oxide, yellow ferric oxide, ferric oxide, ferric oxide-glycerin suspension, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, sodium copper chlorophyllin, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil, etc. may be blended.

[0044] Flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron extract, Coptis chinensis, Coptis chinensis 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 hydrogen tartrate, DL-sodium tartrate, and ginger. It can contain one or more ingredients selected from the following: sucralose, stevia extract, purified stevia extract, Swertia jasmine, D-sorbitol, tannic acid, clove oil, tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, rose oil, etc.

[0045] As sweeteners, 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, purified stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc. may be blended.

[0046] The flavoring may be 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.

[0047] Flavoring agents and fragrances 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 can 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, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0048] These additives are not limited to those listed above, and one of these may be used alone or two or more of them may be used in combination.

[0049] The present invention will be described in more detail below with reference to test examples and formulation examples, but is not limited to these examples. Note that the Bowie dried extract shown in the formulation examples is used in a ratio of 1:12.5 (extract:original drug=1:12.5) in terms of raw drug. EXAMPLES

[0050] (Formulation Example 1) Capsules [Table 1]

[0051] The above ingredients and amounts are taken and capsules are produced in accordance with the "Capsules" section of the Japanese Pharmacopoeia General Provisions for Preparations.

[0052] (Formulation Example 2) Tablets [Table 2]

[0053] The above ingredients and amounts are taken and tablets are prepared in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Provisions for Preparations. If desired, a coating may be applied.

[0054] (Formulation Example 3) Granules [Table 3]

[0055] The above ingredients and amounts are taken and granules are produced in accordance with the "Granules" section of the Japanese Pharmacopoeia General Provisions for Preparations.

[0056] (Formulation Example 4) Liquid [Table 4]

[0057] The above ingredients and amounts are taken and a liquid preparation is manufactured in accordance with the section on "Oral Liquid Preparations" of the Japanese Pharmacopoeia General Provisions for Preparations.

[0058] (Test Example 1) Gastric mucosal damage test (1) Test substance The loxoprofen sodium dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and the Bowie powder was manufactured by Nippon Funa Yakuhin Co., Ltd. These test substances were prepared by suspending tragacanth (manufactured by SIGMA) in 0.5% tragacanth solution in water for injection (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.).

[0059] (2) Animals used Six-week-old Crl:CD male rats (Japan SLC) were used after a five-day quarantine period and three days of acclimation. The animals were individually housed in a rat breeding room with a controlled temperature of 20-26°C, humidity of 40-70%, and lighting hours of 6-6 p.m. The animals were allowed free access to solid food (Oriental Yeast Co., Ltd. solid rat feed, CRF-1) and tap water, and animals with good general symptoms such as good fur and weight gain were selected for use in the study.

[0060] (3) Test method The test substance was orally administered to rats that had been fasted for 18 hours or more using a disposable polypropylene syringe (Terumo) equipped with a disposable oral probe for rats (Fuchigami Kikai).The test substance was used while stirring using a magnetic stirrer. Four hours after administration of the test substance, the animals are euthanized by cervical dislocation under light anesthesia with isoflurane, and the stomach is promptly removed and filled with 10 ml of physiological saline, and then immersed in 1% formalin and fixed until the next day. The fixed stomach was incised along the greater vein, and the length of the gastric mucosal lesion was measured using a digital caliper. The length of the gastric mucosal lesion in each individual was calculated by measuring the major axis and adding them together (total lesion length).

[0061] (4) Test results Table 5 and Figure 1 show the sum of the gastric mucosal lesion lengths in the group administered loxoprofen sodium (anhydrous equivalent) (LOX) alone and the group administered the combination of loxoprofen sodium (anhydrous equivalent) (LOX) and Bowie powder (LOX + Bowie). The numbers in parentheses indicate the dose of each test drug (loxoprofen sodium is anhydrous equivalent) in mg / kg, and each group is a result of n=5. The inhibition rate (%) was calculated from the obtained sum of the gastric mucosal lesion lengths using the following formula.

[0062]

number

[0063] [Table 5]

[0064] From Table 5 and FIG. 1, it was found that the combined use of loxoprofen sodium (LOX) and Bowie powder significantly reduced gastric mucosal damage caused by loxoprofen.

[0065] (Test Example 2) Analgesic effect test (1) Test substance The loxoprofen sodium dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., and the Bowie powder was manufactured by Nippon Funa Yakuhin Co., Ltd. These test substances were prepared by suspending sodium carboxymethylcellulose (CMC-Na) (manufactured by Kanto Chemical Co., Ltd.) in a 0.5% CMC-Na solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.).

[0066] (2) Animals used Four-week-old Crl:CD male rats (Japan SLC) were used after an 8-day quarantine period and acclimatization. The animals were individually housed in a rat breeding room with a controlled temperature of 19-25°C, humidity of 30-70%, and lighting time of 8-8 p.m. The animals were allowed free access to solid food (solid rat feed made by Nippon Nosan Kogyo, Lab MR Stock) and tap water, and animals with good general symptoms such as fur and weight gain were selected for use in the study.

[0067] (3) Test method The test substance was orally administered to rats that had been fasted for 12 hours or more using a disposable polypropylene syringe (Terumo) with a disposable rat oral probe (Fuchigami Kikai) attached 30 minutes before administration of the inflammatory substance. 30 minutes after administration of the substance, 0.7% acetic acid saline was filled into a syringe (Terumo) with a 26G needle (Terumo) and administered intraperitoneally as the inflammatory substance. The period from 10 to 20 minutes after administration of the inflammatory substance was recorded with a video camera, and the number of writhing symptoms that occurred within 10 minutes was measured using a PLUS HAND COUNTER (Plus).

[0068] (4) Test result 2 Table 6 and Figure 2 show the number of writhing episodes (per 10 minutes) in the group administered with loxoprofen sodium (LOX) alone and the group administered with loxoprofen sodium and Bowie powder in combination (LOX + Bowie). The numbers in parentheses indicate the dose of each test drug (loxoprofen sodium is calculated as anhydrous) in mg / kg, and each group is a result of n=5. For statistical analysis, a t-test was performed for each group, and the inhibition rate of writhing episodes (%) was calculated from the obtained number of writhing episodes using the following formula.

[0069]

number

[0070] [Table 6]

[0071] As shown in Table 6 and Figure 2, analgesic effects were observed in the loxoprofen sodium dihydrate (LOX) group and the group administered with Bowie powder (LOX + Bowie) in combination, but there was no statistically significant difference between the two groups, indicating that Bowie does not affect the analgesic effects of loxoprofen.

[0072] Since the dose of Bowie powder in the gastric mucosal damage test (80 mg / kg) was almost the same as the dose in the analgesic effect test (75 mg / kg), it is unlikely to have an effect that weakens the analgesic effect of loxoprofen sodium. In other words, Bowie is thought to suppress gastric mucosal damage without affecting the analgesic effect of loxoprofen sodium. [Industrial Applicability]

[0073] The oral pharmaceutical composition of the present invention containing loxoprofen or a salt thereof and Bowie 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 preferably used as an antipyretic or analgesic, particularly for pain relief from headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, trauma pain, etc., and for fever reduction during chills and fever, and is also preferably used as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

Claims

1. A tablet containing rofecoxib or a salt thereof and Bowie in the same tablet.

2. The tablet according to claim 1, which is used as an antipyretic, analgesic, or cold remedy.

3. 3. The tablet according to claim 1 or 2, which contains at least 1 part by weight of boui (equivalent to raw herbal medicine) per 1 part by weight of rofecoxib or a salt thereof.

4. The tablet according to any one of claims 1 to 3, containing 1 to 60 parts by weight of Bowie (calculated as raw herbal medicine) per 1 part by weight of loxoprofen or a salt thereof.

5. The tablet according to any one of claims 1 to 3, containing 1 to 6 parts by weight of Bowie (calculated as raw herbal medicine) per 1 part by weight of loxoprofen or a salt thereof.

6. A tablet according to any one of claims 1 to 5, wherein the rofecoxib or a salt thereof and the bowi are contained in the same granule.

7. The tablet according to any one of claims 1 to 5, wherein granules containing rofecoxib or a salt thereof are provided separately from granules containing rofecoxib or a salt thereof.

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