JP2022088344A - Oral pharmaceutical composition containing loxoprofen or salt thereof, licorice, and magnesium oxide - Google Patents

Abstract

To provide a new oral pharmaceutical composition that has a low risk of occurrence of small intestine ulcer, contains loxoprofen, and is used as an agent for antipyresis, analgesia or common cold treatment.SOLUTION: An oral pharmaceutical composition contains loxoprofen or a salt thereof, licorice, and magnesium oxide.SELECTED DRAWING: None

Description

The present invention relates to an oral pharmaceutical composition for antipyretic analgesia and anti-inflammatory capable of suppressing small intestinal ulcer caused by loxoprofen or a salt thereof. More specifically, the present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof, citrus, and magnesium oxide, which suppresses small intestinal ulcer.

It is known that loxoprofen, which is a propionic acid-based non-steroidal antipyretic antipyretic anti-inflammatory drug (hereinafter referred to as NSAIDs), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis similar to other NSAIDs. Has been done. 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).
In addition, loxoprofen has a weaker gastromucosal stimulating effect and ulcer-forming effect in the small intestine than ketoprofen, naproxen, and indomethacin in a test in rats, and nevertheless, there is an ulcer of the small intestine / large intestine as a side effect of unknown frequency due to taking loxoprofen. Has also been reported (see, for example, Non-Patent Document 2).

Loxoprofen contains specific saccharides (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 causing the sucrose (see Patent Document 1), a technique for containing an antacid (magnesium oxide) (see Patent Document 2), a technique for containing the anti-plasmin drug tranexamic acid (see Patent Document 3), and the like are disclosed.

On the other hand, licorice is the root and stron of Glycyrrhiza uralensis Fischer or Glycyrrhiza gabra Linne (Leguminosae), sometimes without the periderm (peeled licorice).
Examples of the active ingredient of licorice include glycyrrhizic acid, which is a main component, and anti-inflammatory and anti-allergic effects are known (see Non-Patent Document 3).

As described above, the effects of the combined use of loxoprofen or a salt thereof and other active ingredients on gastric mucosal damage have been investigated. However, loxoprofen or a salt thereof, ulcer and magnesium oxide are orally administered in combination. It is not known whether this can suppress small intestinal ulcer and what effect it has on small intestinal ulcer.

Patent No. 4585220 Patent No. 6106727 Patent No. 5835865

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 Pharmaceutical Interview Form "Loxonin Tablets 60mg, Loxonin Fine Granules 10%" Revised March 2018 (10th Edition) p14 and p26 17th revised Japanese Pharmacopoeia Manual (Hirokawa Bookstore)

An object of the present invention is to provide an oral pharmaceutical composition used as a novel antipyretic agent, analgesic agent, cold remedy agent, etc. containing loxoprofen, which reduces the risk of developing small intestinal ulcer.

As a result of diligent studies to solve the above problems, the present inventors have found that the combined use of loxoprofen or a salt thereof, citrus fruit, and magnesium oxide suppresses small intestinal ulcer caused by loxoprofen or a salt thereof, and the present invention has been developed. It was completed.

That is, the present invention is as shown below.
(1) An oral pharmaceutical composition containing loxoprofen or a salt thereof, licorice, and magnesium oxide.
(2) The oral pharmaceutical composition according to (1), which is used as an antipyretic agent, an analgesic agent, or a cold remedy.
(3) The oral pharmaceutical composition according to (1) or (2), which is a tablet, capsule, pill, granule, powder, liquid, troche or caplet.
(4) The oral pharmaceutical composition according to (3), wherein the tablet is an orally disintegrating tablet or a chewable tablet.
(5) The oral pharmaceutical composition according to any one of (1) to (4), which can suppress small intestinal ulcer.
(6) The oral pharmaceutical composition according to any one of (1) to (5), which contains at least 1 part by weight of licorice (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.
(7) The oral pharmaceutical composition according to any one of (1) to (6), which contains 1 to 33 parts by weight of licorice (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.
(8) The oral pharmaceutical composition according to any one of (1) to (7), which contains at least 0.01 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof.
(9) The oral pharmaceutical composition according to any one of (1) to (8), which contains 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof.

The oral pharmaceutical composition of the present invention contains an effective amount of loxoprofen or a salt thereof that exerts a fever-relieving, analgesic or anti-inflammatory effect, but alleviates small intestinal ulcer, which is a side effect of loxoprofen or a salt thereof. That is, the oral pharmaceutical composition of the present invention exerts effective antipyretic, analgesic, and anti-inflammatory effects, reduces small intestinal ulcers when taken, and is useful as, for example, a highly safe antipyretic, analgesic, or cold remedy. Is.

FIG. 1 shows the change in ulcer area regarding the effect of small intestinal ulcer on the combined use of loxoprofen sodium dihydrate, licorice, and magnesium oxide.

The oral pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, licorice, and magnesium oxide.
In the oral pharmaceutical composition of the present invention, the small intestinal ulcer caused by loxoprofen or a salt thereof can be suppressed by containing licorice and magnesium oxide.

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.

As the "licorice" in the present invention, those listed in the 17th revised Japanese Pharmacopoeia can be preferably used.
Since licorice other than the above is also commercially available, it can be easily obtained.
In addition, the oral pharmaceutical composition of the present invention may further contain any crude drug in addition to licorice.
The optional crude drug is not particularly limited, and examples thereof include peony and valeriana.

The crude drug such as licorice used in the present invention has been used medicinally as a simple or 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 for 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 dried chopped product. The form of the extracted component from the crude drug is not particularly limited, and for example, any form such as dried extract, extract powder, soft extract, stream extract, ethanol or tincture containing ethanol and water can be used. Preferred crude drugs include extract components having a high degree of freedom in formulation, such as soft extracts and dried extract powders.

The extracted component can be obtained by extracting the active ingredient 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 methylcellosolve and ethylserosolve; ketones such as acetone; Ethers such as dioxane and methanol; 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.
In addition, as in the past, Kanzo is an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive expectorant, gastrointestinal medicine, pesticide, oral medicine for rhinitis, throat refreshing agent, stomachic refreshing agent, vitamin-containing health agent, sweetener. , May be used as a flavoring agent, a coloring agent, a flavoring agent, a fragrance, or an excipient.

As the "licorice" in the present invention, those listed in the 17th revised Japanese Pharmacopoeia can be preferably used.
Since licorice other than the above is also commercially available, it can be easily obtained.
As commercially available kanzo, for example, water or a 30% ethanol aqueous solution is used as an extraction solvent, and for example, types of extracts such as kanzo extract, kanzo dried extract, kanzo soft extract, and kanzo style extract. Various crude drug conversion ratios are sold according to the above. Further, in addition to these licorice extracts, licorice extract, licorice extract and the like may be appropriately used and are not particularly limited.
When commercially available licorice is used in an oral pharmaceutical composition, for example, licorice may be used so that the licorice content in the oral pharmaceutical composition is appropriate in consideration of the crude drug conversion ratio.

When "Valeriana fauriei" is used in the present invention, the "Valeriana fauriei" preferably described in the 17th revised Japanese Pharmacopoeia can be used.
Valeriana fauriei other than the above are also commercially available, so they can be easily obtained.
As the commercially available valerian, for example, valerian powder or valerian extract (for example, soft extract, dried extract, etc.) can be used, and the present invention is not particularly limited.
When commercially available valeriana is used in an oral pharmaceutical composition, valeriana may be used so that the valeriana content in the oral pharmaceutical composition is appropriate in consideration of the crude drug conversion ratio.
As a specific example when "Valeriana" is used in the present invention, it is conceivable to prepare an oral pharmaceutical composition containing, for example, loxoprofen or a salt thereof, licorice, magnesium oxide, and valeriana.

When "peony" is used in the present invention, the "peony" preferably described in the 17th revised Japanese Pharmacopoeia can be used.
Peony other than the above is also commercially available, so it can be easily obtained.
As the commercially available peony, for example, peony powder or peony extract (including, for example, dried extract, soft extract, etc.) can be used, and the present invention is not particularly limited.
When a commercially available peony is used in an oral pharmaceutical composition, the peony may be used so that the peony content in the oral pharmaceutical composition is appropriate in consideration of the crude drug conversion ratio.
As a specific example when "peony" is used in the present invention, for example, an oral pharmaceutical composition containing loxoprofen or a salt thereof, licorice, magnesium oxide, and peony can be considered.

As the magnesium oxide used in the present invention, those listed in the 17th revised Japanese Pharmacopoeia may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used and are easily available.
The commercially available magnesium oxide is not particularly limited, but for example, magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd. (light grade), magnesium oxide manufactured by Kyowa Chemical Industry Co., Ltd. (heavy grade) and the like may be used.

In addition, "hesperidins (for example, hesperidin)" may be included in the oral pharmaceutical composition of the present invention.
When "hesperidins" are used in the present invention, the hesperidins include hesperidin and hesperidin derivatives such as glycosyl hesperidin. Hesperidin is also called vitamin P and is listed in the Japanese Pharmacopoeia Non-Pharmaceutical Standard 2002.
As a specific example when "hesperidin" is used in the present invention, an oral pharmaceutical composition containing, for example, loxoprofen or a salt thereof, licorice, magnesium oxide, and hesperidin can be considered.

The content of loxoprofen or a salt thereof contained in the oral pharmaceutical composition of the present invention is not limited, but is preferable as the amount of the component contained in the oral pharmaceutical composition per daily dose as an anhydride-equivalent amount. Is 10 to 180 mg, more preferably 20 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 licorice (licorice or licorice extract) 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 daily dose is the crude drug. The converted amount is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, still more preferably 500 mg to 1500 mg, and the number of administrations is 1 to 3 times a day.

The content of magnesium oxide in the oral pharmaceutical composition of the present invention is also not particularly limited, but the amount of the components contained in the oral pharmaceutical composition per daily dose is preferably 10 to 750 mg, more preferably 10 to 750 mg. , 15 to 150 mg, more preferably 20 to 70 mg, and the number of administrations is 1 to 3 times a day.

When "Valeriana fauriei (Valeriana fauriei or its extract)" is used in the present invention, the content is not particularly limited, but for example, the amount of the component contained in the oral pharmaceutical composition per day is the amount equivalent to the crude drug. It may be 1 to 6000 mg, 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.

When "peony (peony or its extract)" is used in the present invention, the content is not particularly limited, but it is preferable to administer 100 to 5000 mg per day in terms of the crude drug of peony, and 150 to 2000 mg. It is more preferable to administer it, and it is particularly preferable to administer 200 to 900 mg, and the number of administrations is 1 to 3 times a day.

When "hesperidins" are used in the present invention, the content is not particularly limited, but it is preferable to administer 1 to 1000 mg of hesperidin per day, more preferably 15 to 150 mg, and 50 to 120 mg. This is particularly preferable, and the number of administrations is 1 to 3 times a day.

Further, even in the oral pharmaceutical composition liquid preparation of the present invention, the content of loxoprofen or a salt thereof is not limited, but the components contained in the oral pharmaceutical composition per adult 1 administration unit (single dose). The amount is preferably 1 to 18 mg / mL, more preferably 2 to 12 mg / mL, still more preferably 6 to 9 mg / mL in terms of anhydride, and the number of administrations is 1 to 3 times a day.

Further, in the oral pharmaceutical composition of the present invention, the blending ratio of loxoprofen or a salt thereof and licorice is not particularly limited as long as the effect of the present invention is obtained, but with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. , Licorice (equivalent to crude drug) is preferably contained in at least 1 part by weight. With respect to a more preferable compounding ratio, the oral pharmaceutical composition of the present invention preferably contains 1 to 33 parts by weight of licorice (herbal medicine equivalent) with respect to 1 part by weight of loxoprofen or a salt thereof (anhydrous equivalent). It is more preferable to contain 1 to 25 parts by weight of licorice (herbal medicine equivalent) with respect to 1 part by weight (anhydrous equivalent) of the salt, and licorice (herbal medicine) with respect to 1 part by weight (anhydrous equivalent) of loxoprofene or its salt. (Conversion) may be contained in an amount of 1 to 10 parts by weight.
By containing at least 1 part by weight of licorice (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 preferably has an effect of suppressing small intestinal ulcer.
The oral pharmaceutical composition of the present invention more preferably has a small intestinal ulcer inhibitory effect by containing 1 to 33 parts by weight of licorice (equivalent to a crude drug) with respect to 1 part by weight of loxoprofen or a salt thereof.

Further, in the oral pharmaceutical composition of the present invention, the blending ratio of loxoprofen or a salt thereof and magnesium oxide is not particularly limited as long as the effect of the present invention is obtained, but with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. Therefore, it is preferable to contain at least 0.01 parts by weight of magnesium oxide. A more preferable blending ratio is 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofene or a salt thereof (anhydrous equivalent), and more preferably 1 part by weight of loxoprofene or a salt thereof (anhydrous equivalent). ) Magnesium oxide is 0.02 to 12 parts by weight, more preferably 1 part by weight (anhydrous equivalent) magnesium oxide of loxoprofene or a salt thereof, and most preferably magnesium oxide. 0.1 to 1 part by weight.
In addition, the oral pharmaceutical composition of the present invention preferably exhibits a small intestinal ulcer inhibitory effect by containing magnesium oxide, and can also obtain a function as a conventional antacid and an inhibitory effect on gastric mucosal damage.
The oral pharmaceutical composition of the present invention preferably contains at least 0.01 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof, whereby a small intestinal ulcer inhibitory effect can be preferably obtained.
The oral pharmaceutical composition of the present invention more preferably has a small intestinal ulcer inhibitory effect by containing 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof.

For example, the oral pharmaceutical composition of the present invention contains 1 to 33 parts by weight of licorice (equivalent to a crude drug) and 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof. Thereby, a suitable effect of suppressing small intestinal ulcer such as reduction of the area of small intestinal ulcer can be obtained.

When valeriana is contained in the oral pharmaceutical composition of the present invention, the blending ratio of loxoprofen or a salt thereof and valeriana is not particularly limited, but with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. At least 1 part by weight of valeriana (herbal medicine equivalent) may be contained, and 1 to 33 parts by weight of valeriana (herbal medicine equivalent) may be contained with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. ..

When the oral pharmaceutical composition of the present invention contains peony, the blending ratio of loxoprofen or a salt thereof and peony is not particularly limited, but with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. At least 1 part by weight of peony (equivalent to crude drug) may be contained, and 1 to 33 parts by weight of peony (equivalent to crude drug) may be contained with respect to 1 part by weight (anhydrous equivalent) of loxoprofen or a salt thereof. ..

When the oral pharmaceutical composition of the present invention contains hesperidins (for example, hesperidin), the blending ratio of loxoprofen or a salt thereof and hesperidins is not particularly limited, but loxoprofen or a salt thereof is 1 part by weight (anhydrous). It may contain at least 0.1 parts by weight of hesperidin with respect to physical conversion), and may contain 0.1 to 33 parts by weight of hesperidin with respect to 1 part by weight of loxoprofen or a salt thereof (in terms of anhydride). You may.

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 agent, especially for headache, menstrual pain (physiological pain), toothache, post-extraction pain, sore throat, and low back pain. , Joint pain, muscle pain, stiff shoulder pain, ear pain, bruise pain, fracture pain, numbness pain, traumatic pain, etc. 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 may be, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), troches, drops, capsules (hard capsules, soft capsules, etc.), granules, etc. Solid formulations such as fine granules, powders, rounds, dry syrups, suppositories, poultices, plasters, capsules; licking agents, chewing gum agents, jelly agents, jelly-like drops, whipping agents, ointments, creams, Semi-solid preparations such as foams, inhalers, nazar gels; liquid preparations such as syrups, drinks, suspensions, alcoholic drinks, liquids, sprays, sprays, etc., 17th revised Japanese Pharmacy The dosage form can be the one described in the general rules for formulations. In the present invention, a solid preparation is preferable from the viewpoint of ease of administration, manufacturing aspect, etc., and an oral administration 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.

In addition, other active ingredients such as antitussive / expectorant, antihistamine, anti-inflammatory agent, gastrointestinal drug component, antacid, anticholinergic agent, sedative, and other vitamins may be added to these compositions. , Xanthin derivatives may be appropriately blended within a range that does not impair the present invention, and if there are contraindications for blending, the pharmaceutical product may be formulated by appropriately granulating.

Antitussives and expectorants include, for example, codeine, codeine phosphate hydrate, dihydrocodein, dihydrocodein phosphate, dibunato sodium, dimemorphan phosphate, chipepidin citrate, tipepidine hibenzate, dextrometholphan, and dext. Rometrphan hydrobromide hydrate, dextrometholfanphenol phthaline salt, noscapin hydrochloride, trimetokinol hydrochloride, phenilefurin hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylepedrin hydrochloride, dl-methyl One or more components selected from ephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride and the like can be blended.

Examples of the antihistamine include azelastin hydrochloride, alimemazine tartrate, evastin, epinastine hydrochloride, emedastin fumarate, oxatomide, olopatazine hydrochloride, carbinoxamine, cremastine fumarate, diphenyldisulfonate, and carbinoxamine maleic acid. Salt, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotiphenfumarate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydraminetannate, Blending one or more components selected from triprolysine hydrochloride, triperenamine hydrochloride, tonsylamine hydrochloride, fexophenazine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mekitadine, metodirazine hydrochloride, loratazine, etc. Can be done.

As the anti-inflammatory agent, for example, one or more components selected from glycyrrhizic acid and its derivatives, salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc. are blended. Can be done.

As the gastrointestinal drug component, for example, one or more components selected from gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like can be blended.

Examples of the acid suppressant include alkaline earth metal and / or earth metal-based basic inorganic compounds such as magnesium silicate, magnesium silicate aluminate, magnesium aluminum silicate, magnesium hydroxide, magnesium hydroxide and aluminum sulfate. Co-precipitated product of potassium, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium hydroxide alumina, aluminum hydroxide gel, aluminum hydroxide and sodium hydrogen carbonate Precipitated product, aluminum hydroxide / 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 hydrogen phosphate Examples thereof include magnesium such as calcium, inorganic salts of metals selected from aluminum and calcium, and examples of the alkali metal-based basic inorganic compound include dry sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, and sodium carbonate hydration. Substances, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, inorganic salts of metals selected from sodium and potassium such as potassium carbonate, and the like, as well as volley and glycine and the like. , And one or more of the components selected from these can be blended. Of these, magnesium aluminometasilicate, synthetic aluminum silicate, precipitated calcium carbonate and glycine are particularly preferable.

Examples of the anticholinergic agent include scopolamine hydrobromide, datsura extract, methylscopolamine bromide, methyl-l-hyostiamine bromide, pyrenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, and isopropamide iodide. , Diphenylpiperidinomethyldioxorane iodide, scopolia extract, scopolia root, scopolamine total alkaloid citrate and the like can be blended with one or more components.

As the sedative, for example, one or more components selected from bromvalerylurea, allylisopropylacetylurea and the like can be blended.

Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B5, vitamin B12, vitamin P, vitamin D, vitamin E, nicotinic acid, nicotinic acid amide, pantenol, calcium pantothenate. , Sodium pantothenate, biotin, potassium / magnesium aspartate equal amount mixture, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-chloride cysteine, orotin, gamma orizanol, calcium glycerophosphate, calcium gluconate, glucno One or more components selected from lactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, and yoquinin can be blended.

As the xanthine derivative, for example, one or more components selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate can be blended.

The oral pharmaceutical composition of the present invention can be formulated according to a conventional method.
Loxoprofen or a salt thereof and licorice may be formulated as the same granule to form one pharmaceutical composition.
In addition, loxoprofen or a salt thereof and licorice 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 licorice are separately produced, and then additives (additives, etc.) are added to the granules containing loxoprofen or a salt thereof and the granules containing licorice. Can be added to produce granules, fine granules or powders.

Alternatively, granules containing loxoprofen or a salt thereof and granules containing kanzo are separately produced, and then additives (excipients, lubricants, etc.) are added to the granules containing loxoprofen or a salt thereof and the granules containing kanzo. 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 kanzo.
Alternatively, granules containing loxoprofen or a salt thereof and granules containing licorice 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 licorice. It is possible to produce a multi-layer tablet by locking it. Alternatively, granules containing loxoprofen or a salt thereof and granules containing licorice are separately produced, and then tablets containing loxoprofen or a salt thereof or tablets containing licorice are produced, and the tablets are embedded in the tablets. Nuclear tablets can be manufactured.

Loxoprofen or a salt thereof and magnesium oxide may be formulated as the same granule to form one pharmaceutical composition.
In addition, loxoprofen or a salt thereof and magnesium oxide 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 magnesium oxide are separately produced, and then an additive (adductant) is added to the granules containing loxoprofen or a salt thereof and the granules containing magnesium oxide. Etc.) can be added to produce granules, fine granules or powders.

Alternatively, granules containing loxoprofen or a salt thereof and granules containing magnesium oxide are separately produced, and then additives (applicants and lubricants) are added to the granules containing loxoprofen or a salt thereof and the granules containing magnesium oxide. Etc.) may be added and tableted to produce tablets, or granules containing loxoprofen or a salt thereof and granules containing magnesium oxide may be filled into capsules to produce capsules.
Alternatively, granules containing loxoprofen or a salt thereof and granules containing magnesium oxide are separately produced, and then an additive or the like is added between the monolayer containing loxoprofen or a salt thereof and the monolayer containing magnesium oxide. It can be tableted to produce a multi-layer tablet. Alternatively, granules containing loxoprofen or a salt thereof and granules containing magnesium oxide are separately produced, and then tablets containing loxoprofen or a salt thereof or tablets containing magnesium oxide are produced, and the tablets are embedded in the tablets. However, nucleated tablets can be manufactured.

Licorice and magnesium oxide may be formulated as the same granule to form one pharmaceutical composition.
In addition, licorice and magnesium oxide may be formulated separately and then used as one pharmaceutical composition.
For example, in the latter case, the granules containing kanzo and the granules containing magnesium oxide are separately produced, and then additives (additives, etc.) are added to the granules containing kanzo and the granules containing magnesium oxide. , Granules, fine granules or powders can be produced.

Alternatively, granules containing kanzo and granules containing magnesium oxide are separately produced, and then additives (excipients, lubricants, etc.) are added to the granules containing kanzo and the granules containing magnesium oxide. Tablets may be produced by tableting, or capsules may be produced by filling granules containing granules containing kanzo and granules containing magnesium oxide into capsules.
Alternatively, granules containing licorice and granules containing magnesium oxide are separately produced, and then an additive or the like is added between the single layer containing licorice and the single layer containing magnesium oxide to tablet the multi-layer tablet. Can be manufactured. Alternatively, granules containing kanzo and granules containing magnesium oxide are separately manufactured, and then tablets containing kanzo or tablets containing magnesium oxide are manufactured, and nucleated tablets in which the tablets are embedded are manufactured. can do.

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, it can be produced by appropriately using a known method and additives. Additives may be appropriately added as long as the effects of the present invention are not impaired. Additives include excipients, disintegrants, lubricants, coatings, binders, fluidizers, plasticizers, sugar coatings, brighteners, solvents, pH adjusters, colorants, flavoring agents, sweeteners. , Fragrances, flavoring agents, fragrances, etc.

Examples of excipients include crystalline cellulose, powdered cellulose, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium lactate, calcium silicate, and aluminic acid metasilicate. Examples thereof include magnesium, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose and the like.

Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, bentonite and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hydrogenated oil, sodium stearyl fumarate and the like.

Examples of the coating agent include aminoalkyl methacrylate copolymer, arabic rubber, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, cellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pullulan, povidone, polyvinyl alcohol, macrogol and the like. Can be done.

Examples of the binder include arabic rubber, arabic rubber powder, canten, canten powder, cold plum flour, 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 alumina hydroxide, tertiary calcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate. One kind or two or more kinds of ingredients selected from granules and the like can be blended.

Examples of the plasticizer 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, and polysorbate 80. Contains one or more components selected from macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, liquid paraffin, and the like. be able to.

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

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

As the solvent, for example, 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, for example, one selected from hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citric acid, succinic acid, tartaric acid, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethanolamine and the like, or Two or more kinds of ingredients can be blended.

Examples of the colorant include yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, black iron oxide, titanium oxide, yellow ferrous sesquioxide, iron sesquioxide, iron sesquioxide / glycerin suspension, and edible. Blend one or more ingredients selected from blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, copper chlorophyllin sodium, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc. Can be done.

Examples of the flavoring agent include sodium chloride, powdered pearl oyster, powdered pearl oyster extract, oleum, powdered aulen powder, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citrate hydrate, and sodium citrate hydrate. , L-Glutamic acid, L-Glutamic acid sodium, Grapefruit extract, Brown sugar, Keihi powder, Keihi oil, Saccharin, Saccharin sodium hydrate, Sansho powder, Tartaric acid, D-Tartaric acid, Potassium hydrogen tartrate, DL-Sodium tartrate, Shokyo Powder, sucralose, stevia extract, stevia extract purified product, sembry, D-sorbitol, tannic acid, tartaric acid, chimpi tincture, capsicum, capsicum powder, pepper powder, trehalose hydrate, bittern powder, plum extract, fructo-oligosaccharide, powder One selected from sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryuno, ryuno powder, green tea powder, DL-tartaric acid, DL-sodium malate, lemon oil, rose oil, etc. Alternatively, two or more kinds of ingredients can be blended.

Examples of the sweetener include aspartame, acesulfame potassium, amacha, amacha powder, reduced malt sugar water candy, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, sucralose, saccharin sodium hydrate, sucralose, stevia extract, and purified stevia extract. , Purified sucralose, fructose, sucralose, martitol, D-mannitol, erythritol and the like can be blended with one or more components.

The fragrance is 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 and the like. 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, d-kanfuru, dl-kanfuru, keihi powder, keihi oil, citronella oil, Sugar Flavor, Spare Mint Oil, Cherry Flavor, Chouji Oil, Chili Flavor, Tohi Tinki, Tohi Oil, Pine Oil, Hacka Oil, Vanilla Flavor, Vanillin, Bitter Essence, Vita Base, Himalayan Sugi Oil, Fruit Flavor, Flavor G1, Peppermint Essence, Bergamotte Oil, Belmot Flavor, d-Bornool, dl-Bornool, Matcher, Mixed Flavor, Mint Flavor, dl-Mentor, l-Mentor, Eucalyptus Oil, Lavender Oil, Ryunou, Ryunou Powder, Lemon Powder, Lemon Oil, Rose Water, Rose One kind or two or more kinds of ingredients selected from 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 pharmaceutical examples, but the present invention is not limited to these examples.

(Test Example 1) Small intestinal ulcer suppression test (1) Loxoprofen and the test substance loxoprofen sodium dihydrate (hereinafter, may be referred to as loxoprofen) used were manufactured by Daiichi Sankyo Chemical Pharma.
Further, as the test substance 1, lafutidine, a substance manufactured by Central Glass Co., Ltd. was used.
As the test substance 2, magnesium oxide (hereinafter, may be referred to as MgO), a substance manufactured by Tomita Pharmaceutical Co., Ltd. was used.
The licorice (dried licorice extract; crude drug conversion ratio 5: 1), which is the test substance 3, was manufactured by Alps Pharmaceutical Industry Co., Ltd.
As the solvent for loxoprofen and the test substance, sodium carboxymethyl cellulose (abbreviated as CMC; manufactured by Kanto Chemical Co., Ltd., stored at room temperature) and water for injection (distilled water from Otsuka, manufactured by Otsuka Pharmaceutical Factory, stored at room temperature) were used. The 0.5 w / v% CMC aqueous solution prepared in the above was used.

(2) Test method Rats (Crl: CD (SD) (SPF), 7 weeks old, male) were used for the test.
Each test substance was dissolved in a 0.5 w / v% CMC aqueous solution to obtain the respective concentrations so as to have the composition shown in Table 1.
In addition, in the description of "33.3 + 50.4" of the dose (mg / kg) in the group E "MgO + licorice", the dose of MgO is 33.3 mg / kg and the licorice (dried licorice extract; crude drug). It means that the dose of the crude drug conversion ratio 5: 1) is 50.4 mg / kg (252 mg / kg in terms of the crude drug).
The description of "6.66 + 10.08" of the administration solution concentration (mg / mL) in the group E "MgO + Kanzo" is that the administration solution concentration of MgO is 6.66 mg / mL, and Kanzo (dried Kanzo extract; It means that the concentration of the administration solution of 5: 1) in terms of crude drug is 10.08 mg / mL (50.4 mg / mL in terms of crude drug).

(3) Observation of general condition The general condition was observed on the day of administration and the day of small intestinal resection.

(4) Body weight measurement Using an electronic balance, the body weight was measured before administration on the day of administration.

(5) Administration of test substance and loxoprofen Forced oral administration of each test substance to non-fasting animals using an oral sonde (disposable oral sonde, Fuchigami instrument) and an injection tube (disposable syringe, Terumo Corporation) did.
The test substance was administered twice, 30 minutes before and 6 hours after the administration of loxoprofen.
The amount of the administered solution was converted at a ratio of 5 mL / kg each time using the body weight on the day of administration, and the second decimal place was rounded off to the first decimal place.
Loxoprofen was orally administered using an oral sonde (disposable oral sonde, Fuchigami Instrument Co., Ltd.) and an injection tube (disposable syringe, Terumo Corporation). The dose amount was converted at a ratio of 5 mL / kg using the body weight on the day of administration, rounded off to the first decimal place, and calculated to the first decimal place.

(6) Removal of small intestine 24 hours after administration of loxoprofen, the patient was euthanized by exsanguination under isoflurane anesthesia.
The gastrointestinal tract from the stomach to the ileocecal region was removed. It was amputated in the duodenum to separate the stomach and small intestine. The stomach and small intestine were washed with physiological saline to wash the contents of the intestinal tract, passed through a 1% neutral buffered formalin solution, immersed in the fixative, and lightly fixed for 30 minutes or longer. The small intestine was immersed in the fixation solution with a part of the cecum side of the ileum left uncut so that the vertical direction would not be lost during fixation.

(7) Photographing the ulcer site The lightly fixed small intestine was cut at intervals of about 20 cm, incised along the mesenteric body side, and attached to filter paper. In order to clarify the contrast of the ulcer site, 10% isodine solution was applied using a cotton ball, and then the image was taken together with the scale. The small intestine after photography was stored in a 10% neutral buffered formalin solution while still attached to a filter paper.

(8) Image analysis and calculation of ulcer count The ulcer count (ulcer area mm ² ) was calculated by the following method.
(A) The captured image is imported into Photoshop (Adobe Photoshop Elements).
(B) The image is enlarged to a size suitable for work, and the ulcer site clarified with 10% isodine solution is bordered and filled with black.
(C) The filled ulcer site is extracted and binarized.
(D) Convert the file format to BMP format.
(E) The ulcer area mm ² is calculated using the image analysis software ImageJ (NIH).

(9) Statistical processing For the obtained ulcer count (ulcer area mm ² ), the average value and standard error were calculated for each group.

<Test results>
(1) Test results The results of the ulcer area are shown in FIGS. 1 and 1.
The dose of loxoprofen and the concentration of the administration solution in Table 1 show the values of loxoprofen in terms of anhydride.
Further, the fact that the dose (mg / kg) of the "test substance" in the "A: control" group (group A) is 0 and the concentration of the administration solution (mg / mL) is 0 is used for the test substance. The case where the 0.5 w / v% CMC aqueous solution which was the solvent was administered to the rat to 5 mL / kg is shown.

Group A: In the control group, ulcers of 416 ± 169 mm ² (mean ± standard error) were confirmed.
Group B: In the lafutidine group, ulcers of 283 ± 153 mm ² (mean ± standard error) were confirmed.
Group C: In the MgO group, ulcers of 228 ± 56 mm ² (mean ± standard error) were confirmed.
Group D: In the licorice group, ulcers of 250 ± 52 mm ² (mean ± standard error) were confirmed.
Group E: In the MgO + licorice group, ulcers of 192 ± 68 mm ² (mean ± standard error) were confirmed.

As described above, ulcers were observed in the rat small intestine by oral administration of loxoprofen (control group), and the therapeutic and preventive effects of each test substance on this small intestinal ulcer were examined.
As a result, it was confirmed that the anti-ulcer agent as a positive control: lafutidine group suppressed ulcers more than the control group, and this experimental system was established as a test to confirm the suppression of small intestinal ulcers.
Both the MgO group and the licorice group had more suppressed ulcers than the control group. In the combined group of MgO and licorice (MgO + licorice group), ulcer formation was suppressed as compared with the group of each single administration.

From these results, it was clarified that the combined use of loxoprofen with licorice and MgO can suppress small intestinal ulcer. So far, the effect of the combined use of loxoprofen, licorice and MgO on small intestinal ulcer is unknown, and the results obtained in this study example are unpredictable.
Loxoprofen administered orally is a precursor of an active substance, but since it has enterohepatic circulation peculiar to NSAIDs, it is absorbed in the small intestine, converted to an active substance in the liver, and then excreted in bile. It is speculated that repeated contact with the small intestinal mucosa causes ulcers. That is, the mechanism of development is different between the gastric mucosal disorder caused by the precursor and the small intestinal ulcer in which the active substance is present. It is also known that small intestinal ulcers are affected by intestinal bacteria, but the bacterial environment in the small intestine and the bacterial environment in the stomach are significantly different. Therefore, the effects on small intestinal ulcer cannot be predicted from the findings on gastric mucosal disorders.

(Pharmaceutical Example 1) Tablets Tablets are produced by a conventional method with the compositions shown in Tables 2 to 5 below. If desired, a skin is applied.

The oral pharmaceutical composition containing loxoprofen or a salt thereof, citrus fruit, and magnesium oxide of the present invention is extremely useful because it significantly suppresses small intestinal ulcer caused by loxoprofen and thus reduces the rate of side effects.
The oral pharmaceutical composition of the present invention is, for example, as a fever-reducing agent and an analgesic, in particular, headache, menstrual pain (physiological pain), tooth pain, post-extraction pain, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, ear. It is suitable for pain relief such as pain, headache, fracture pain, numbness, traumatic pain, and fever reduction during cold and fever, and as a cold remedy, various symptoms of cold (nasal discharge, stuffy nose, cough, tan). , Throat pain, fever, cold, headache, squeezing, joint pain, muscle pain).

Claims (9)

An oral pharmaceutical composition comprising loxoprofen or a salt thereof, licorice, and magnesium oxide. The oral pharmaceutical composition according to claim 1, which is used as an antipyretic agent, an analgesic agent, or a cold remedy. The oral pharmaceutical composition according to claim 1 or 2, which is a tablet, capsule, pill, granule, powder, liquid, troche or caplet. The oral pharmaceutical composition according to claim 3, wherein the tablet is an orally disintegrating tablet or a chewable tablet. The oral pharmaceutical composition according to any one of claims 1 to 4, wherein the small intestinal ulcer can be suppressed. The oral pharmaceutical composition according to any one of claims 1 to 5, which contains at least 1 part by weight of licorice (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 6, which contains 1 to 33 parts by weight of licorice (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 7, which contains at least 0.01 parts by weight of magnesium oxide 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 8, which contains 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof.

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