JP2020169152A - Oral pharmaceutical composition containing loxoprofen or salt thereof and moutan bark - Google Patents

Abstract

To provide an oral pharmaceutical composition that has reduced risk of gastric mucosal injury due to loxoprofen, and is used as an antipyretic, an analgesic or a cold remedy.SOLUTION: An oral pharmaceutical composition contains loxoprofen or a salt thereof, and moutan bark.SELECTED DRAWING: None

Description

The present invention relates to an oral pharmaceutical composition for antipyretic analgesic and anti-inflammatory that reduces gastric mucosal damage of loxoprofen or a salt thereof. More specifically, it relates to an oral pharmaceutical composition in which gastric mucosal damage is reduced by containing loxoprofen or a salt thereof and buttonpi.

Loxoprofen, a propionic acid-based non-steroidal antipyretic analgesic and anti-inflammatory drug (hereinafter referred to as NSAIDs), exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, but has strong antipyretic, analgesic, and anti-inflammatory effects. It is known. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosal stimulating effect after oral administration and becomes an active substance in the body. It is also known (see, for example, Non-Patent Document 1).

Lactoprofen contains specific sugars (lactose, sucrose, maltitol, fructose, xylitol or lactitol) as a technique for further suppressing gastric mucosal damage by oral administration of loxoprofen or a salt thereof in combination with other active ingredients. A technique for adding lactose (see Patent Document 1), a technique for containing an antacid (magnesium oxide) (see Patent Document 2), a technique for containing tranexamic acid as an anti-prucmine drug (see Patent Document 3), and the like are disclosed.

On the other hand, peony is a crude drug extracted from the root bark of peony of the peony family, and its main component is peonol. It is mainly a prescription drug for Chinese medicine, and is included in prescriptions considered to be women's drugs and other prescriptions.
Peonol, the main ingredient, contains antibacterial, sedative, hypothermia, antipyretic, analgesic, anticonvulsant and other central nervous system inhibition, anti-inflammatory, stress-induced gastric ulcer inhibition, gastric juice secretion inhibition, anticoagulant, platelet aggregation inhibition, antithrombin It has been shown to have effects such as enhanced phagocyte phagulant action, suppression of uterine motility, and diuresis. In addition, paeoniflorin and its derivatives, which are one of the components of buttonpi, have an inhibitory effect on the release of histamine from mast cells, and tannin has an antiviral effect. (See Non-Patent Document 2)

As described above, the effects of the combined use of loxoprofen or its salt and other active ingredients have been investigated, but oral administration of loxoprofen or its salt in combination with buttonpi has an effect of suppressing gastric mucosal damage. It is not known what the impact will be. So far, Buttonpi is known to have anti-Helicobacter pylori activity in addition to anti-inflammatory, menstrual, and analgesic effects, and is a raw drug powder having anti-Helicobacter pylori activity including Buttonpi or its powder. In combination with the extracted component, a histamine H2 receptor antagonist, a proton pump inhibitor, a gastritis-defensive gastritis / peptic ulcer therapeutic agent, an antacid and a stagnation agent, gastritis and digestibility caused by Helicobacter pylori An oral composition effective for treating ulcers and preventing recurrence has been known (see Patent Document 4). However, there are no reports that the gastric mucosal damage caused by loxoprofen or a salt thereof was suppressed by the inclusion of buttonpi.
An oral composition containing loxoprofen and buttonpi is not known, and the combined effect of the composition is unknown.

Patent No. 4585220 Patent No. 6106727 Patent No. 5835865 JP-A-10-109942

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 Japanese Pharmacopoeia Manual (Hirokawa Bookstore)

Since loxoprofen is a prodrug, gastric mucosal damage is thought to be less than other NSAIDs, but there is still a risk of developing gastric mucosal damage. On the other hand, although it is known that buttonpi is effective in anti-inflammatory, menstrual and analgesic, it remains unclear what kind of result the gastric mucosal damage caused by loxoprofen will bring about the combination of buttonpi. That is, the subject of the present invention is to clarify what kind of effect loxoprofen has on gastric mucosal damage when Loxoprofen is orally used in combination with Buttonpi. An object of the present invention is to provide an oral pharmaceutical composition used as a novel antipyretic agent, analgesic agent or cold remedy agent containing loxoprofen, which reduces the risk of gastric mucosal damage.

As a result of diligent studies to solve the above problems, the present inventors can reduce gastric mucosal damage caused by loxoprofen or its salt by using loxoprofen or its salt in combination with buttonpi, and the analgesic effect of loxoprofen or its salt. We found that Buttonpi had no effect, and completed the present invention.

That is, the present invention is as shown below.
(1) An oral pharmaceutical composition containing loxoprofen or a salt thereof and buttonpi.
(2) The oral pharmaceutical composition according to (1), which is used as an antipyretic, an analgesic, or a cold remedy.
(3) The oral pharmaceutical composition according to (1) or (2), which is a tablet, a fine granule, a capsule or a liquid.
(4) The oral pharmaceutical composition according to any one of (1) to (3), which contains at least 1 part by weight of buttonpi (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.
(5) The oral pharmaceutical composition according to any one of (1) to (3), which contains 1 to 33 parts by weight of buttonpi (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.

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 an antipyretic, analgesic or anti-inflammatory effect, but reduces gastric mucosal damage which is a side effect of loxoprofen or a salt thereof. And. That is, the oral pharmaceutical composition of the present invention exerts effective antipyretic, analgesic, and anti-inflammatory effects, and as a highly safe antipyretic, analgesic, or cold remedy that reduces gastric mucosal damage when taken. It is useful.

FIG. 1 shows the results of investigating the effects of gastric mucosal injury on loxoprofen sodium dihydrate alone and in combination with loxoprofen sodium dihydrate and buttonpi. In addition, * in the figure means that the combined group of loxoprofen sodium / dihydrate and buttonpi has a significant difference as compared with the loxoprofen sodium / dihydrate alone group (p <0.05). FIG. 2 shows the results of examining the analgesic effect of the medium, loxoprofen sodium dihydrate alone, and the combination of loxoprofen sodium dihydrate and buttonpi. In addition, ** in the figure means that the combination group of loxoprofen sodium / dihydrate and buttonpi has a significant difference as compared with the loxoprofen sodium / dihydrate alone group (p <0.01).

In the present invention, the "loxoprofen or a salt thereof" is loxoprofen or a salt thereof (including a hydrous 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 revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.

In the present invention, as the "button pi", those listed in the 17th revised Japanese Pharmacopoeia can be preferably used.
Buttons other than the above are also commercially available, so they can be easily obtained.

The button pi used in the present invention has been used medicinally as a simple taste or a Chinese herbal medicine since ancient times, and the crude drug powder or the extracted component obtained according to the conventional methods can be used as they are. As the form of the crude drug powder or the extracted component, a normal commercial product or a processed product thereof can be used. As the crude drug powder, for example, it may be used as a powder (fine powder) dried powder obtained by further finely crushing a dry chopped product. The form of the extracted component from the crude drug is not particularly limited, and any form such as dry extract, extract powder, soft extract, stream extract, ethanol or tincture containing ethanol and water can be used. Preferred crude drugs include extract components with a high degree of freedom in formulation, such as dried extract powder. The extraction component can be obtained by extracting an active component having an antibacterial action from the crude drug by a conventional method, for example, an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent 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 and ethyl cellosolve; ketones such as acetone; Ethers such as dioxane and tetrahydrofuran; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N, N-dimethylformamide, dimethylacetamide and N-methylpyrrolidone can be mentioned. These hydrophilic solvents may be used alone or as a mixed solvent of two or more kinds.

The content of loxoprofen or a salt thereof 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 1 administration unit (single dose) is not limited. The amount in terms of anhydride is preferably 10 to 180 mg, more preferably 30 to 120 mg, still more preferably 60 to 90 mg, and the number of administrations is 1 to 3 times a day.

Further, the content of buttonpi in the oral pharmaceutical composition of the present invention is not particularly limited, but the amount of the component contained in the oral pharmaceutical composition per adult 1 administration unit (single dose) is the amount equivalent to the crude drug. It is preferably 67 to 2000 mg, more preferably 67 to 670 mg, still more preferably 67 to 335 mg, and the number of administrations is 1 to 3 times a day.

Further, if the oral pharmaceutical composition of the present invention is a liquid preparation to be taken 50 ml once a day, the content of loxoprofen or a salt thereof in the liquid preparation is preferably 10 to 180 mg / 50 ml in terms of anhydride, and the buttonpi is The amount converted to crude drug is preferably 67 to 2000 mg / 50 mL.

Further, in the oral pharmaceutical composition of the present invention, the blending ratio of loxoprofen or a salt thereof and buttonpi is not particularly limited as long as the effects of the present invention are exhibited, but with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. It is preferable to contain at least 1 part by weight of loxoprofen (equivalent to crude drug). A more preferable blending ratio is 1 to 33 parts by weight of buttonpi (equivalent to the drug substance) with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof, and more preferably 1 part by weight (anhydrous equivalent). 1 to 12 parts by weight (most preferably 1 to 6 parts by weight) of buttonpi (equivalent to the drug substance) with respect to loxoprofene or a salt thereof.

The oral pharmaceutical composition of the present invention can be preferably used for the purpose of suppressing fever, pain and inflammation. Since loxoprofen or a salt thereof, which is an active ingredient, has an antipyretic and anti-inflammatory effect, it is used as an analgesic and antipyretic, especially headache, menstrual pain (physiological pain), toothache, post-extraction pain, sore throat, and lower back pain. , Joint pain, muscle pain, stiff shoulder pain, ear pain, bruising pain, fracture pain, numbness pain, traumatic pain, etc., suitable for relieving fever during cold and fever, and as a cold remedy for cold It can be suitably used for the purpose of alleviating various symptoms (nasal discharge, stuffy nose, cough, tan, sore throat, fever, cold, headache, squeezing, joint pain, muscle pain).

The oral pharmaceutical composition of the present invention includes, for example, tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc.), oral tablets (troche agents, sublingual tablets, buccal tablets, adhesive tablets). Solid preparations such as hard capsules, soft capsules, granules, powders, pills, dry syrups, etc .; semi-solid preparations such as gums, oral jelly, etc .; liquid preparations (elixyl, suspension, etc.) (Including emulsions, limonades, etc.) Described in the 17th revised Japanese Pharmacy Regulations, etc. for liquid preparations such as syrups, alcoholic preparations, dipping agents, decoctions, tea agents, tincture agents, aromatic water agents, and pills. Can be in the form of. In the present invention, a solid preparation is preferable from the viewpoint of ease of administration, manufacturing aspect, etc., and an oral pharmaceutical composition selected from the group consisting of tablets, capsules, pills, granules, powders and fine granules. It is more preferably a product, and particularly preferably a tablet or capsule. These compositions may further include other active ingredients, such as antitussive / expectorant, antihistamine, anti-inflammatory, gastrointestinal ingredients, antacids, anticholinergic agents, other vitamins, xanthine derivatives, as needed. , The sedative may be appropriately blended within a range that does not impair the present invention, and if there are any contraindications to the blending, it may be formulated by appropriately granulating or the like.

Antitussives and expectorants include, for example, codeine, codeine phosphate hydrate, dihydrocodein, dihydrocodein phosphate, dibunato sodium, dimemorphan phosphate, tipepidin citrate, tipepidin hibenzate, dextrometrphan, dext. Lomethorphan hydrobromide hydrate, dextrometorphanphenol phthaline salt, noscapine hydrochloride, trimetokinol hydrochloride, phenilefurin hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methyl Examples thereof include ephedrine hydrochloride, ambroxol hydrochloride, bromhexin hydrochloride and the like.

Examples of antihistamines include azerastin hydrochloride, alimemazine tartrate, evastin, epinastine hydrochloride, emedastin fumarate, oxatomide, olopatazine hydrochloride, carbinoxamine, diphenyldisulfonate, carbinoxamine maleate, d-chlor. Phenilamine maleate, dl-chlorophenylamine maleate, ketotiphen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydraminetannate, triprolidine hydrochloride, Examples thereof include tryperenamine hydrochloride, tonsylamine hydrochloride, fexophenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, metodirazine hydrochloride, loratazine and the like.

Examples of the anti-inflammatory agent include glycyrrhizic acid and its derivatives, salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid and the like.

Examples of the gastrointestinal drug component include gefarnate, cetraxate hydrochloride, lepamivid, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Examples of the acid suppressant include glycine (also called aminoacetic acid), magnesium silicate, magnesium silicate aluminumate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, and co-precipitated products of magnesium hydroxide and potassium aluminum hydroxide. , Magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium hydrogen carbonate co-precipitate product, hydroxide Aluminum / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitated product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate and other magnesium, aluminum And sodium such as calcium salt, 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, etc. And components that raise the pH of gastric acid, such as salts selected from potassium.

Anticholinergic agents include scopolamine hydrobromide, dazzling extract, methylscopolamine bromide, methyl-l-hyostiamine bromide, pyrenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, isopropamide iodide, iodine. Examples thereof include diphenylpiperidinomethyldioxolane, funnel extract, funnel root, and funnel root total alkaloid citrate.

Vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, nicotinic acid, nicotinic acid amide, pantenol, calcium pantothenate, sodium pantothenate, Equal amounts of biotin, potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, glucnolactone, glucuronic acid amide , Chondroitin sodium sulfate, carrots, yoquinin, iodine.

Examples of the xanthine derivative include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate.
Examples of the sedative include allylisopropylacetylurea and bromvalerylurea.

The oral pharmaceutical composition of the present invention can be formulated according to a conventional method. Loxoprofen or a salt thereof and buttonpi may be formulated as the same granule to form one pharmaceutical composition. In addition, loxoprofen or a salt thereof and buttonpi may be formulated separately and then used as one pharmaceutical composition. For example, in the latter case, granules containing loxoprofen or a salt thereof and granules containing buttonpi are separately produced, and then additives (additives, etc.) are added to the granules containing loxoprofen or a salt thereof and the granules containing buttonpi. Can be produced to produce granules, fine granules or powders. Alternatively, the granules containing loxoprofen or a salt thereof and the granules containing buttonpi are separately produced, and then the granules containing loxoprofen or a salt thereof and the granules containing buttonpi are added to an additive (an excipient, a lubricant, etc.). The tablet may be produced by adding and tableting, or the capsule may be produced by filling the capsule with granules containing loxoprofen or a salt thereof and granules containing buttonpi. Alternatively, granules containing loxoprofen or a salt thereof and granules containing buttonpi are separately produced, and then an additive or the like is added between the single layer containing loxoprofen or a salt thereof and the single layer containing buttonpi. It is possible to produce a multi-layer tablet by locking. Alternatively, granules containing loxoprofen or a salt thereof and granules containing buttonpi are separately produced, and then tablets containing loxoprofen or a salt thereof or tablets containing buttonpi are produced, and the tablets are embedded in the tablets. Nuclear tablets can be manufactured.

The oral pharmaceutical composition of the present invention may be once packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, or the like and stored in an airtight manner. Further, they may be pillow-wrapped, or they may be stored in a box or the like. The material used for pillow packaging is not particularly limited, and for example, a resin film such as a polypropylene film, a polyethylene terephthalate film, or a polyethylene film, or a resin film to which an aluminum foil is attached can be used. If hygroscopicity is a concern, a desiccant or the like may be stored in a bottle package or a pillow package at the same time.

In the formulation, a known method and additives can be appropriately used for the formulation. Additives may be appropriately added as long as the effects of the present invention are not impaired. In the case of solid preparations (tablets, fine granules, capsules, etc.), additives include excipients, disintegrants, lubricants, coating agents, binders, fluidizers, plasticizers, sugar coating agents, and glossing agents. Agents, solvents, pH adjusters, colorants, flavoring agents, sweeteners, fragrances, flavoring agents / fragrances, etc. can be mentioned. In the case of liquids, excipients, solvents, pH adjusting agents, coloring agents, flavoring agents, etc. , Sweeteners, fragrances, flavoring agents, fragrances, etc.

Excipients include, for example, crystalline cellulose, powdered cellulose, potato starch, corn starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, silicic acid. One or more components selected from calcium, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose and the like can be blended.

As the disintegrant, for example, one or more components selected from carmellose, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite and the like are blended. can do.

As the lubricant, for example, one or more components selected from magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hydrogenated oil and the like can be blended.

Examples of the coating agent include aminoalkyl methacrylate copolymer, arabic rubber, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, talc, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, purulan, povidone, polyvinyl alcohol, macrogol and the like. One or more selected ingredients can be blended.

Examples of the binder include arabic rubber, arabic rubber powder, canten, canten powder, cold plum powder, gelatin, cellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, purulan, povidone, polyvinyl alcohol, methacrylic acid copolymer L, and methacrylic acid. One or more components selected from copolymers, butyl methacrylate / methyl methacrylate copolymers, methyl cellulose and the like can be blended.

Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium hydroxide hydroxide, calcium tertiary phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate. One kind or two or more kinds of components selected from granules and the like can be blended.

Plasticizers include triethyl citrate, glycerin, glycerin fatty acid ester, medium chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol. One or more components selected from 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, liquid paraffin, etc. may be blended. it can.

As sugar coating agents, arabic rubber, arabic rubber powder, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl stearate 40, refined gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, One or more components selected from white shellac, sucrose, hydroxypropyl cellulose, hypromellose, purulan, povidone, polyoxyethylene, polyvinyl alcohol, macrogol and the like can be blended.

As the brightener, one or more components selected from carnauba wax, purified shellac, macrogol, beeswax and the like can be blended.

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.

As the pH adjuster, one or two selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine and the like. The above ingredients can be blended.

Coloring agents include yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, citrus extract, black iron oxide, titanium oxide, yellow iron sesquioxide, iron sesquioxide, iron sesquioxide / glycerin suspension, Contains one or more ingredients selected from edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, sodium copper chlorophyllin, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc. be able to.

As a flavoring agent, sodium chloride, powdered pearl oyster, powdered pearl oyster, powdered aulen, powdered aulen, orange, orange oil, powdered cacao, fructose, caramel, citrus fruit, citrus extract, citrus powder, xylitol, calcium citrate, tartaric acid hydrate, Sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, kei powder, kei oil, saccharin, saccharin sodium hydrate, sansho powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL -Sodium tartaric acid, powdered ginger, sclerose, stevia extract, purified stevia extract, sembly, D-sorbitol, tannic acid, chow oil, chimpi tincture, peppercorn, powdered pepper, powdered pepper, trehalose hydrate, powdered nigaki, plum meat Extract, fructo-oligosaccharide, 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 One kind or two or more kinds of ingredients selected from the above can be blended.

As sweeteners, aspartame, acesulfame potassium, amacha, amacha powder, reduced malt sugar water candy, kanzo, kanzo extract, kanzo powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia One or more components selected from extracts, stevia extract purified products, purified saccharin, fructose, saccharin, maltitol, D-mannitol, erythritol and the like can be blended.

The flavor is selected from orange flavor, galana 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. One kind or two or more kinds of ingredients can be blended.

As flavoring agents and fragrances, uikyo powder, uikyo oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, kanzo powder, d-campul, dl-campul, keihi powder, keihi oil, Citronella oil, sugar flavor, spare mint oil, cherry flavor, chow oil, chili flavor, tohi tincture, touhi oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, bita base, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin Peppermint essence, bergamot oil, velmot flavor, d-bornole, dl-bornole, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, One or more components selected from rose water, rose oil, peppermint oil and the like can be blended.

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

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Formulation Examples, but the present invention is not limited to these examples.

(Formulation Example 1) Capsules

Take the above ingredients and amounts, and manufacture capsules in accordance with the "Capsules" section of the Japanese Pharmacopoeia General Regulations.

(Formulation example 2) Tablet

Take the above ingredients and amounts, and manufacture tablets in accordance with the "Tablets" section of the Japanese Pharmacopoeia General Regulations. If desired, a skin is applied.

(Formulation Example 3) Granules

Take the above ingredients and amounts, and manufacture granules according to the section of "Granule" in the general rules of Japanese Pharmacopoeia.

(Formulation Example 4) Liquid preparation

Take the above ingredients and amounts, and manufacture the liquid preparation according to the section of "Oral liquid preparation" in the general rules of Japanese Pharmacopoeia.

(Test Example 1) Gastric mucosal disorder test (1) The test substance loxoprofen sodium dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma. The button pie was made by Nippon Powder Chemicals. These test substances were prepared by suspending Tragant (manufactured by SIGMA) in a 0.5% Tragant solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used Crl: CD male rats 6 weeks old (Japan SLC) were used after a quarantine period of 5 days and acclimatization for 3 days. Animals were individually bred in a rat breeding room controlled at a temperature of 20-26 ° C., a humidity of 40-70% and a lighting time of 6-18 o'clock. A solid sample (Oriental Yeast Co., Ltd. rat solid feed, CRF-1) and tap water were freely ingested, and animals with good general symptoms such as fur and weight gain were selected and tested.

(3) Test method The test substance was orally administered to rats fasted for 18 hours or more using a polypropylene disposable injection tube (manufactured by Terumo) equipped with an oral sonde for disposable rats (manufactured by Fuchigami Kikai). The test substance was used with stirring using a magnetic stirrer.
Four hours after administration of the test substance, the animal was euthanized by cervical spine dislocation under light anesthesia of isoflurane, the stomach was immediately removed, 10 ml of physiological saline was filled inside, and the animal was immersed in 1% formalin and fixed until the next day. ..
An incision is made in the fixed stomach along the bay and a digital caliper is used to measure the length of gastric mucosal injury. For the length of gastric mucosal injury in an individual, the major axis was measured and the sum of them (total injury length) was calculated.

(4) Test Results Table 5 and FIG. 1 show gastric mucosal injury in the loxoprofen sodium (anhydrous equivalent) (LOX) single administration group and the loxoprofen sodium (anhydrous equivalent) (LOX) and buttonpi combined administration group (LOX + buttonpi). It shows the total length. Here, the numerical values in parentheses are the dose mg / Kg of each test drug (loxoprofen sodium in terms of anhydride and buttonpi in terms of crude drug), and the results for each group are n = 5. For statistical analysis, t-test was performed for each group, and the suppression rate (%) was calculated from the total length of gastric mucosal damage obtained using the following formula.

* Significant difference compared to LOX (80) (p <0.05)

From Table 5 and FIG. 1, it was found that the combined use of loxoprofen sodium (LOX) and buttonpi significantly reduced gastric mucosal injury caused by loxoprofen.

(Test Example 2) Analgesic effect test (1) The test substance loxoprofen sodium / dihydrate used was manufactured by Daiichi Sankyo Chemical Pharma. The button pie was made by Nippon Powder Chemicals. These test substances were prepared by suspending sodium carboxymethyl cellulose (CMC-Na) (manufactured by Kanto Chemical Co., Inc.) in a 0.5% CMC-Na solution dissolved in water for injection (manufactured by Otsuka Pharmaceutical Factory).

(2) Animals used Crl: CD male rats 4 weeks old (Japan SLC) were used for an 8-day quarantine period and after acclimation. Animals were individually bred in a rat breeding room controlled at a temperature of 19-25 ° C., a humidity of 30-70% and a lighting time of 8-20 o'clock. Solid samples (solid feed for rats manufactured by Nosan Corporation, laboratory MR stock) and tap water were freely ingested, and animals with good general symptoms such as fur and weight gain were selected and tested.

(3) Test method A test substance was tested using a polypropylene disposable injection tube (manufactured by Terumo) to which an oral sonde for disposable rats (manufactured by Fuchigami Instruments) was attached 30 minutes before administration of the inflammatory substance to rats fasted for 12 hours or more. Was orally administered. Thirty minutes after administration of the substance to be administered, 0.7% physiological saline of acetate as a inflammatory substance was filled in a syringe (made by Terumo) equipped with a 26 G injection needle (made by Terumo) and administered intraperitoneally. A video camera was used to take a picture from 10 minutes to 20 minutes after the administration of the inflammatory substance, and the number of rising symptoms appearing in 10 minutes was measured using PLUS HAND COUNTER (manufactured by PLUS).

(4) Test result 2
Table 6 and FIG. 2 show the number of rising symptoms (per 10 minutes) in the loxoprofen sodium (LOX) single administration group and the loxoprofen sodium and buttonpi combined administration group (LOX + buttonpi). Here, the numerical values in parentheses are the dose mg / Kg of each test drug (loxoprofen sodium in terms of anhydride and buttonpi in terms of crude drug), and the results for each group are n = 5. For statistical analysis, t-test was performed for each group, and the suppression rate (%) of rising symptoms was calculated from the number of obtained rising symptoms using the following formula.

** Significant difference compared to control group (p <0.01)
No significant difference between LOX (18) and LOX (18) + Button Pi (75)

From Table 6 and FIG. 2, the analgesic effect was shown in the loxoprofen sodium dihydrate (LOX) group and the buttonpi combination group (LOX + buttonpi), but there was no statistically significant difference between the two groups. Buttonpi was found to have no effect on the analgesic effect of loxoprofen.

The dose of Buttonpi (81.1 mg / Kg) in the gastric mucosal disorder test is larger than the dose (75 mg / Kg) in the analgesic effect test, but when the dose ratio with loxoprofen sodium is taken, the ratio is gastric. The mucosal disorder test is smaller than the dose ratio in the analgesic effect test (gastric mucosal disorder test dose ratio: 1.01, analgesic effect test dose ratio: 4.17). Since Buttonpi did not affect the analgesic effect of loxoprofen sodium at a dose ratio of 4.17 in the analgesic effect test, the analgesic effect of loxoprofen sodium was similarly attenuated at a dose ratio of 1.01 in the gastric mucosal disorder test. It is unlikely that it will have an adverse effect. In other words, Buttonpi does not affect the analgesic effect of loxoprofen sodium and is considered to suppress gastric mucosal damage.

The oral pharmaceutical composition containing loxoprofen or a salt thereof and buttonpi of the present invention is extremely useful because it significantly suppresses gastric mucosal damage caused by loxoprofen and thus reduces the side effect rate. The oral pharmaceutical composition of the present invention is used as an antipyretic agent and an analgesic, in particular, headache, menstrual pain (physiological pain), toothache, post-extraction pain, throat pain, lower back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruising It is preferably used to relieve pain, fracture pain, numbness, traumatic pain, etc., and to relieve fever during cold and fever, and as a treatment for sensation, various symptoms of cold (nasal discharge, stuffy nose, cough, tan, throat). It is preferably used to relieve pain, fever, cold, headache, squeezing, joint pain, muscle pain).

Claims (5)

An oral pharmaceutical composition comprising loxoprofen or a salt thereof and buttonpi. The oral pharmaceutical composition according to claim 1, which is used as an antipyretic, an analgesic, or a cold remedy. The oral pharmaceutical composition according to claim 1 or 2, which is a tablet, a fine granule, a capsule or a liquid. The oral pharmaceutical composition according to any one of claims 1 to 3, which contains at least 1 part by weight of buttonpi (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof. The oral pharmaceutical composition according to any one of claims 1 to 3, which contains 1 to 33 parts by weight of buttonpi (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.