Oral pharmaceutical composition containing loxoprofen or its salt, licorice, and magnesium oxide

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

Technical Field

[0001] The present invention relates to an oral pharmaceutical composition for antipyretic, analgesic and anti-inflammatory use capable of suppressing small intestinal ulcers caused by loxoprofen or a salt thereof. More specifically, the present invention relates to an oral pharmaceutical composition containing loxoprofen or a salt thereof, licorice, and magnesium oxide, which suppresses small intestinal ulcers.

Background Art

[0002] Loxoprofen, which is a propionic acid-based non-steroidal antipyretic, analgesic and anti-inflammatory agent (hereinafter referred to as NSAIDs), is known to have antipyretic, analgesic and anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis similar to other NSAIDs. Since loxoprofen is a prodrug that is absorbed from the digestive tract as an unchanged form with a weak gastric mucosal irritation effect after oral administration and becomes an active form in the body, it is also known to have the characteristic of less gastric mucosal damage compared to other NSAIDs (see, for example, Non-Patent Document 1). In addition, in tests on rats, the gastric mucosal irritation effect and ulcer formation effect in the small intestine of loxoprofen are weaker than those of ketoprofen, naproxen, and indomethacin. Nevertheless, ulcers in the small intestine and large intestine have also been reported as side effects of unknown frequency due to the administration of loxoprofen (see, for example, Non-Patent Document 2).

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

[0004] On the other hand, licorice refers to the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza gabra Linne (Leguminosae), sometimes with the periderm removed (peeled licorice). The active ingredient in licorice is glycyrrhizic acid, the main component, which is known for its anti-inflammatory and anti-allergic effects (see Non-Patent Literature 3).

[0005] As mentioned above, studies have been conducted on the effects of combining loxoprofen or its salts with other active ingredients on gastric mucosal damage. However, it is unknown whether oral administration of loxoprofen or its salts in combination with licorice and magnesium oxide can suppress small intestinal ulcers, or what effects it has on small intestinal ulcers. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Patent No. 4585220 [Patent Document 2] Patent No. 6106727 [Patent Document 3] Patent No. 5835865 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmacology and Therapeutics Vol.16 No.2 1988 pp.611-619 [Non-Patent Document 2] Drug Interview Form "Loxonin Tablets 60mg, Loxonin Granules 10%" Revised March 2018 (10th Edition) pp. 14 and 26 [Non-Patent Document 3] The Seventeenth Revised Japanese Pharmacopoeia Commentary (Hirokawa Shoten) [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The present invention aims to provide a novel oral pharmaceutical composition containing loxoprofen, which can be used as an antipyretic, analgesic, or cold treatment agent, etc., and which reduces the risk of developing small intestinal ulcers. [Means for solving the problem]

[0009] As a result of diligent research to solve the above problems, the inventors of the present invention found that the combined use of loxoprofen or its salt, licorice, and magnesium oxide suppresses small intestinal ulcers caused by loxoprofen or its salt, and thus completed the present invention.

[0010] In other words, the present invention is as follows: (1) An oral pharmaceutical composition comprising loxoprofen or a salt thereof, licorice, and magnesium oxide. (2) The oral pharmaceutical composition described in (1) used as an antipyretic, analgesic, or cold treatment agent. (3) The oral pharmaceutical composition according to (1) or (2), which is a tablet, capsule, pill, granule, powder, liquid, lozenge, or caplet. (4) The oral pharmaceutical composition according to (3), wherein the tablet is an orally disintegrating tablet or a chewable tablet. (5) An oral pharmaceutical composition according to any one of (1) to (4) that can suppress small intestinal ulcers. (6) An oral pharmaceutical composition according to any one of (1) to (5), comprising at least 1 part by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof. (7) An oral pharmaceutical composition according to any one of (1) to (6), containing 1 to 33 parts by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof. (8) An oral pharmaceutical composition according to any one of (1) to (7), containing at least 0.01 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof. (9) An oral pharmaceutical composition according to any one of (1) to (8), containing 0.01 to 30 parts by weight of magnesium oxide with respect to 1 part by weight of loxoprofen or a salt thereof.

Advantages of the Invention

[0011] The oral pharmaceutical composition of the present invention contains an effective amount of loxoprofen or a salt thereof that exhibits antipyretic, analgesic or anti-inflammatory effects, while reducing small intestine ulcers, which are side effects of loxoprofen or a salt thereof. That is, the oral pharmaceutical composition of the present invention exhibits effective antipyretic, analgesic, and anti-inflammatory effects, reduces small intestine ulcers during administration, and is useful, for example, as a highly safe antipyretic agent, analgesic agent or cold treatment agent.

Brief Description of the Drawings

[0012] [Figure 1] Figure 1 shows the results of changes in ulcer area regarding the effect of small intestine ulcers in the combined use of loxoprofen sodium dihydrate, licorice, and magnesium oxide.

Modes for Carrying Out the Invention

[0013] 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, by containing licorice and magnesium oxide, small intestine ulcers caused by loxoprofen or a salt thereof can be suppressed.

[0014] In the present invention, "loxoprofen or a salt thereof" means loxoprofen or a salt thereof (including hydrated salts), 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.

[0015] In the present invention, the "licorice" can preferably be the one listed in the 17th edition of the Japanese Pharmacopoeia. Other types of licorice are also commercially available and can be easily obtained. Furthermore, the oral pharmaceutical composition of the present invention may also contain any other crude drug in addition to licorice. While there are no particular limitations on the type of herbal medicine that can be used, examples include peony and valerian.

[0016] The crude drugs used in this invention, such as licorice, have been used medicinally since ancient times, either as single ingredients or in herbal formulas. The crude drug powders or extracts obtained according to conventional methods can be used as they are. The form of the crude drug powders or extracts can also be the form of commercially available products or processed products thereof. As for the crude drug powder, for example, a dried powder (fine powder) obtained by further grinding a dried chopped processed product may be used. Furthermore, the form of the extract from the crude drug is not particularly limited, and any form can be used, such as dried extract, extract powder, soft extract, fluid extract, ethanol, or a tincture containing ethanol and water. Preferred crude drugs include extracts that offer a high degree of freedom in formulation, such as soft extracts and dried extract powders.

[0017] The extracted components can be obtained by conventional methods, for example, by extracting the active components having antibacterial properties from the crude drug using an extraction solvent. Commonly used extraction solvents include water, hydrophilic solvents, or mixtures thereof. Examples of hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used individually or as a mixture of two or more. Furthermore, licorice may be used as in the conventional sense as an anti-inflammatory agent, cold medicine, antipyretic analgesic, cough suppressant and expectorant, gastrointestinal medicine, anthelmintic, oral medicine for rhinitis, throat freshener, stomachic freshener, vitamin-containing health supplement, sweetener, flavoring agent, coloring agent, flavoring agent, fragrance, or excipient.

[0018] In the present invention, the "licorice" can preferably be the one listed in the 17th edition of the Japanese Pharmacopoeia. Other types of licorice are also commercially available and can be easily obtained. Commercially available licorice products include those extracted using water or a 30% ethanol aqueous solution as the extraction solvent, and various types of extracts are sold with different crude drug equivalent ratios, such as licorice extract, dried licorice extract, soft licorice extract, and liquid licorice extract. In addition to these licorice extracts, licorice extracts and licorice extract solutions may also be used as appropriate, and are not particularly limited. When using commercially available licorice in an oral pharmaceutical composition, the amount of licorice used should be appropriate, for example, by considering the crude drug equivalent ratio, so that the licorice content in the oral pharmaceutical composition is suitable.

[0019] In the present invention, when using "Valeriana officinalis," it is preferable to use the "Valeriana officinalis" listed in the 17th edition of the Japanese Pharmacopoeia. Other varieties of valerian are also commercially available and can be easily obtained. Furthermore, commercially available valerian products can include, for example, valerian powder or valerian extract (such as soft extract or dried extract), and are not particularly limited. When using commercially available valerian in an oral pharmaceutical composition, the amount of valerian used should be appropriate, taking into account the crude drug equivalent ratio, so that the valerian content in the oral pharmaceutical composition is suitable. In the present invention, a specific example of using "valerian" is an oral pharmaceutical composition containing, for example, loxoprofen or a salt thereof, licorice, magnesium oxide, and valerian.

[0020] In the present invention, when using "peony," it is preferable to use the peony listed in the 17th edition of the Japanese Pharmacopoeia. Other types of peonies are also available commercially and can be easily obtained. Furthermore, commercially available peony products can be, for example, peony powder or peony extract (including dried extract or soft extract), and are not particularly limited. When using commercially available peony in an oral pharmaceutical composition, the amount of peony used should be appropriate, taking into account the crude drug equivalent ratio, so that the peony content in the oral pharmaceutical composition is suitable. In the present invention, a specific example of using "peony" is an oral pharmaceutical composition containing, for example, loxoprofen or a salt thereof, licorice, magnesium oxide, and peony.

[0021] The magnesium oxide used in this invention may be that listed in the 17th edition of the Japanese Pharmacopoeia, or that listed in the Dictionary of Pharmaceutical Additives, and is readily available. While not particularly limited, commercially available magnesium oxide can be used, for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd. or magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd.

[0022] Furthermore, the oral pharmaceutical composition of the present invention may also include "hesperidins (e.g., hesperidin)." In the present invention, when "hesperidins" are used, hesperidins include hesperidin and hesperidin derivatives such as glycosylhesperidin. Hesperidin is also called vitamin P and is listed in the Japanese Pharmacopoeia, Non-Official Pharmaceutical Standards 2002, etc. In the present invention, a specific example of using "hesperidin" is an oral pharmaceutical composition containing, for example, loxoprofen or a salt thereof, licorice, magnesium oxide, and hesperidin.

[0023] The amount of loxoprofen or its salt contained in the oral pharmaceutical composition of the present invention is not limited, but the amount of the component contained in the oral pharmaceutical composition per daily dose is preferably 10 to 180 mg, more preferably 20 to 120 mg, and even more preferably 60 to 90 mg on an anhydrous basis, and the number of doses is 1 to 3 times a day.

[0024] Furthermore, there are no particular restrictions on the content of licorice (licorice or licorice extract) in the oral pharmaceutical composition of the present invention. However, the amount of the component contained in the oral pharmaceutical composition per daily dose is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 1500 mg in terms of crude drug equivalent, and the number of doses is 1 to 3 times a day.

[0025] Furthermore, there are no particular restrictions on the magnesium oxide content in the oral pharmaceutical composition of the present invention, but the amount of the component contained in the oral pharmaceutical composition per daily dose is preferably 10 to 750 mg, more preferably 15 to 150 mg, and even more preferably 20 to 70 mg, and the number of doses is 1 to 3 times a day.

[0026] In the present invention, when using "Valeriana officinalis (Valeriana officinalis or its extract)", there are no particular restrictions on the content, but for example, the amount of the component contained in the oral pharmaceutical composition per day may be 1 to 6000 mg in terms of crude drug equivalent, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, and even more preferably 60 to 450 mg, and the number of administrations is 1 to 3 times a day.

[0027] In the present invention, when using "peony (peony or its extract)", there are no particular limitations on the amount contained, but it is preferable to administer 100 to 5000 mg per day in terms of crude drug equivalent of peony, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg, with administration occurring 1 to 3 times per day.

[0028] In the present invention, when using "hesperidins," there are no particular limitations on the content, but it is preferable to administer 1 to 1000 mg of hesperidin per day, more preferably 15 to 150 mg, and particularly preferably 50 to 120 mg, with administration occurring 1 to 3 times per day.

[0029] Furthermore, while there are no limitations on the content of loxoprofen or its salt in the oral pharmaceutical composition liquid of the present invention, the amount of the component contained in the oral pharmaceutical composition per adult dose unit (single dose) is preferably 1 to 18 mg / mL, more preferably 2 to 12 mg / mL, and even more preferably 6 to 9 mg / mL on an anhydrous basis, and the number of doses is 1 to 3 times a day.

[0030] Furthermore, in the oral pharmaceutical composition of the present invention, the ratio of loxoprofen or its salt to licorice is not particularly limited as long as the effects of the present invention are achieved, but it is preferable that the composition contains at least 1 part by weight of licorice (crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt. Regarding a more preferable ratio, the oral pharmaceutical composition of the present invention preferably contains 1 to 33 parts by weight of licorice (crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt, more preferably 1 to 25 parts by weight of licorice (crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt, and may also contain 1 to 10 parts by weight of licorice (crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt. The oral pharmaceutical composition of the present invention contains at least 1 part by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof, thereby suitably providing an inhibitory effect on small intestinal ulcers. The oral pharmaceutical composition of the present invention more preferably provides an inhibitory effect on small intestinal ulcers by containing 1 to 33 parts by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof.

[0031] Furthermore, in the oral pharmaceutical composition of the present invention, the ratio of loxoprofen or its salt to magnesium oxide is not particularly limited as long as the effects of the present invention are achieved, but it is preferable to contain at least 0.01 parts by weight of magnesium oxide per 1 part by weight (anhydrous basis) of loxoprofen or its salt. A more preferable ratio is 0.01 to 30 parts by weight of magnesium oxide per 1 part by weight (anhydrous basis) of loxoprofen or its salt, more preferably 0.02 to 12 parts by weight of magnesium oxide per 1 part by weight (anhydrous basis) of loxoprofen or its salt, even more preferably 0.05 to 5 parts by weight of magnesium oxide per 1 part by weight (anhydrous basis) of loxoprofen or its salt, and most preferably 0.1 to 1 part by weight of magnesium oxide. Furthermore, by containing magnesium oxide, the oral pharmaceutical composition of the present invention can suitably exhibit an inhibitory effect on small intestinal ulcers while also obtaining the functions of a conventional antacid and an inhibitory effect on gastric mucosal damage. The oral pharmaceutical composition of the present invention contains at least 0.01 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof, thereby suitably providing an inhibitory effect on small intestinal ulcers. The oral pharmaceutical composition of the present invention more preferably provides an inhibitory effect on small intestinal ulcers by containing 0.01 to 30 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof.

[0032] For example, the oral pharmaceutical composition of the present invention contains 1 to 33 parts by weight of licorice (in terms of crude drug equivalent) and 0.01 to 30 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof, thereby obtaining a suitable small intestinal ulcer inhibitory effect, such as a reduction in the area of ​​small intestinal ulcers.

[0033] Furthermore, when the oral pharmaceutical composition of the present invention contains valerian, the ratio of loxoprofen or its salt to valerian is not particularly limited, but it may contain at least 1 part by weight of valerian (in terms of crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt, or 1 to 33 parts by weight of valerian (in terms of crude drug equivalent) per 1 part by weight (anhydrous basis) of loxoprofen or its salt.

[0034] Furthermore, when the oral pharmaceutical composition of the present invention contains peony, the ratio of loxoprofen or its salt to peony is not particularly limited, but it may contain at least 1 part by weight of peony (crude drug equivalent) per 1 part by weight of loxoprofen or its salt (anhydrous basis), or it may contain 1 to 33 parts by weight of peony (crude drug equivalent) per 1 part by weight of loxoprofen or its salt (anhydrous basis).

[0035] Furthermore, when the oral pharmaceutical composition of the present invention contains hesperidins (for example, hesperidin), the ratio of loxoprofen or its salt to hesperidins is not particularly limited, but it may contain at least 0.1 parts by weight of hesperidins per 1 part by weight (anhydrous basis) of loxoprofen or its salt, or it may contain 0.1 to 33 parts by weight of hesperidins per 1 part by weight (anhydrous basis) of loxoprofen or its salt.

[0036] The oral pharmaceutical composition of the present invention can preferably be used to suppress fever, pain, and inflammation. Since the active ingredient, loxoprofen or its salt, has antipyretic, analgesic, and anti-inflammatory effects, it can be preferably used as an analgesic and antipyretic, particularly for the relief of pain such as headache, menstrual cramps, toothache, post-extraction pain, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, and traumatic pain, as well as for reducing fever during chills and fever. Furthermore, it can preferably be used as a cold treatment agent to alleviate various symptoms of the common cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0037] The oral pharmaceutical composition of the present invention may be in dosage forms described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc., such as solid preparations including tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets, etc.), lozenges, drops, capsules (hard capsules, soft capsules, etc.), granules, fine granules, powders, pills, dry syrups, suppositories, poultices, plasters, and caplets; semi-solid preparations including licks, chewing gums, jellies, jelly-like drops, whipped creams, ointments, creams, foams, inhalers, and nasal gels; and liquid preparations including syrups, drinks, suspensions, alcoholic preparations, liquids, sprays, and aerosols. In the present invention, a solid preparation is preferred in terms of ease of administration and manufacturing, an oral administration composition selected from the group consisting of tablets, capsules, pills, granules, powders, and fine granules is more preferred, and a tablet or capsule is particularly preferred.

[0038] These compositions may further contain, as needed, other active ingredients, such as cough suppressants / expectorants, antihistamines, anti-inflammatory agents, gastrointestinal drug components, antacids, anticholinergics, sedatives, other vitamins, and xanthine derivatives, within limits that do not impair the present invention. If there are any contraindications for the inclusion of these ingredients, they may be appropriately formulated by granulation or other means.

[0039] For example, one or more ingredients selected from codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibnate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, noscapine hydrochloride, trimethoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc., can be included as cough suppressants and expectorants.

[0040] As an antihistamine, one or more components selected from, for example, azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, triperenamine hydrochloride, tondilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methidilazine hydrochloride, loratadine, etc. may be included.

[0041] As an anti-inflammatory agent, one or more components selected from, for example, glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc., may be included.

[0042] As gastrointestinal drug ingredients, one or more ingredients selected from, for example, gefarnate, cetraxate hydrochloride, solfalcone, teprenone, methylmethionine sulfonium chloride, etc., may be included.

[0043] Examples of antacids include alkaline earth metals and / or earth metal-based basic inorganic compounds such as magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, magnesium hydroxide-potassium aluminum sulfate coprecipitation product, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitation product, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitation product, and vent. Examples of inorganic salts include magnesium, aluminum, and calcium, such as nitrite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Examples of alkali metal basic inorganic compounds include anhydrous sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and other inorganic salts of metals selected from sodium and potassium. Other examples include oyster shell and glycine. One or more components selected from these can be blended. In particular, magnesium aluminometasilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are preferred.

[0044] As an anticholinergic agent, one or more components selected from, for example, scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, total belladonna root alkaloid citrate, etc. may be included.

[0045] As a sedative, one or more components selected from, for example, bromovalerylurea and allyl isopropylacetylurea may be included.

[0046] As for vitamins, one or more ingredients selected from, for example, vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B5, vitamin B12, vitamin P, vitamin D, vitamin E, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium magnesium aspartate, etc., inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotin, gamma-oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronamide, sodium chondroitin sulfate, carrot, and coix seed may be included.

[0047] As xanthine derivatives, for example, one or more components selected from caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate can be included.

[0048] The oral pharmaceutical composition of the present invention can be formulated according to conventional methods. Loxoprofen or its salt and licorice may be formulated as the same granule to form a single pharmaceutical composition. Alternatively, loxoprofen or its salt and licorice may be formulated separately and then combined into a single pharmaceutical composition. For example, in the latter case, granules containing loxoprofen or its salt and granules containing licorice can be manufactured separately, and then granules, fine granules, or powders can be manufactured by adding additives (such as excipients) to the granules containing loxoprofen or its salt and the granules containing licorice.

[0049] Alternatively, tablets may be manufactured by separately producing granules containing loxoprofen or a salt thereof and granules containing licorice, and then adding additives (such as excipients and lubricants) to the granules containing loxoprofen or a salt thereof and the granules containing licorice, and compressing them into tablets. Capsules may also be manufactured by filling capsules with granules containing loxoprofen or a salt thereof and granules containing licorice. Alternatively, granules containing loxoprofen or its salt and granules containing licorice can be manufactured separately, and then a single layer containing loxoprofen or its salt and a single layer containing licorice can be combined with additives to produce a multilayer tablet. Alternatively, granules containing loxoprofen or its salt and granules containing licorice can be manufactured separately, and then tablets containing loxoprofen or its salt or tablets containing licorice can be manufactured, and a core tablet can be manufactured by embedding a tablet inside another tablet.

[0050] Loxoprofen or its salt and magnesium oxide may be formulated as the same granule to form a single pharmaceutical composition. Alternatively, loxoprofen or its salt and magnesium oxide may be formulated separately and then combined into a single pharmaceutical composition. For example, in the latter case, granules containing loxoprofen or its salt and granules containing magnesium oxide can be manufactured separately, and then granules, fine granules, or powders can be manufactured by adding additives (such as excipients) to the granules containing loxoprofen or its salt and the granules containing magnesium oxide.

[0051] Alternatively, tablets may be manufactured by separately producing granules containing loxoprofen or a salt thereof and granules containing magnesium oxide, and then adding additives (such as excipients and lubricants) to the granules containing loxoprofen or a salt thereof and the granules containing magnesium oxide, and compressing them into tablets. Capsules may also be manufactured by filling capsules with the granules containing loxoprofen or a salt thereof and the granules containing magnesium oxide. Alternatively, granules containing loxoprofen or its salt and granules containing magnesium oxide can be manufactured separately, and then a single layer containing loxoprofen or its salt and a single layer containing magnesium oxide can be combined with other additives to produce a multilayer tablet. Alternatively, granules containing loxoprofen or its salt and granules containing magnesium oxide can be manufactured separately, and then tablets containing loxoprofen or its salt or tablets containing magnesium oxide can be manufactured, and a core tablet can be produced by embedding a tablet within a tablet.

[0052] Licorice and magnesium oxide may be formulated as the same granule and combined into a single pharmaceutical composition. Alternatively, licorice and magnesium oxide may be formulated separately and then combined into a single pharmaceutical composition. For example, in the latter case, granules containing licorice and granules containing magnesium oxide can be manufactured separately, and then granules, fine granules, or powders can be manufactured by adding additives (such as excipients) to the granules containing licorice and the granules containing magnesium oxide.

[0053] Alternatively, tablets may be manufactured by separately producing granules containing licorice and granules containing magnesium oxide, then adding additives (such as excipients and lubricants) to the granules containing licorice and magnesium oxide, and compressing them into tablets. Capsules may also be manufactured by filling capsules with the granules containing licorice and the granules containing magnesium oxide. Alternatively, granules containing licorice and granules containing magnesium oxide can be manufactured separately, and then additives can be added between the licorice-containing single layer and the magnesium oxide-containing single layer to produce a multilayer tablet. Alternatively, granules containing licorice and granules containing magnesium oxide can be manufactured separately, and then tablets containing licorice or tablets containing magnesium oxide can be manufactured, and a core tablet can be produced by embedding a tablet within a tablet.

[0054] The oral pharmaceutical composition of the present invention may be initially packaged in SP packaging, PTP packaging, stick packaging, bottle packaging, etc., and stored airtight. Furthermore, they may be pillow-packaged, and stored in boxes or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene film, polyethylene terephthalate film, polyethylene film, or these resin films with aluminum foil attached can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle packaging or pillow packaging.

[0055] The formulation can be prepared using known methods and additives as appropriate. Additives should be added as appropriate, as long as they do not impair the effects of the present invention. Examples of additives include excipients, disintegrants, lubricants, coating agents, binders, fluidizers, plasticizers, sugar coating agents, glossing agents, solvents, pH adjusters, colorants, flavoring agents, sweeteners, fragrances, and other flavoring agents.

[0056] Examples of excipients include crystalline cellulose, powdered cellulose, potato starch, light anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium lactate, calcium silicate, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, lactose, sucrose, D-mannitol, erythritol, glucose, fructose, and the like.

[0057] Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, alginic acid, partially pregelatinized starch, and bentonite.

[0058] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hydrogenated oil, and sodium stearyl fumarate.

[0059] Examples of coating agents include aminoalkyl methacrylate copolymer, acacia gum, ethylcellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, povidone, polyvinyl alcohol, macrogol, and the like.

[0060] As a binder, one or more components selected from, for example, gum arabic, gum arabic powder, agar, agar powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol, methacrylate copolymer L, methacrylate copolymer, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, etc. may be incorporated.

[0061] As a fluidizing agent, one or more components selected from, for example, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, tricalcium phosphate, talc, magnesium aluminometasilicate, calcium hydrogen phosphate granules, etc., can be blended.

[0062] As plasticizers, one or more components selected from, for example, triethyl citrate, glycerin, glycerin fatty acid ester, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc., may be incorporated.

[0063] As a sugar coating agent, one or more components selected from, for example, gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyoxyethylene, polyvinyl alcohol, macrogol, etc. may be included.

[0064] As a glossing agent, one or more components selected from, for example, carnauba wax, refined shellac, macrogol, beeswax, etc., can be incorporated.

[0065] As a solvent, one or more components selected from, for example, isopropanol, ethanol, glycerin, 1,3-butylene glycol, propylene glycol, macrogol, etc., can be included.

[0066] As a pH adjusting agent, 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., can be included.

[0067] As coloring agents, one or more components selected from, for example, yellow iron oxide, brown iron oxide, carbon black, caramel, β-carotene, black iron oxide, titanium dioxide, yellow ferric oxide, ferric oxide, ferric oxide / glycerin suspension, food-grade blue No. 2 aluminum lake, food-grade yellow No. 4 aluminum lake, copper chlorophyllin sodium, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc. may be included.

[0068] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, ginger powder, and sucralose. One or more ingredients selected from the following may be included: syrup, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, porcini powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flake powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0069] As a sweetener, one or more ingredients selected from, for example, aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. may be included.

[0070] As for the flavoring, one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc. may be included.

[0071] The fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, 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. One or more ingredients selected from the following may be included: Himalayan cedar oil, fruit flavor, flavor G1, peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0072] These additives are not limited to those listed above, and one of them may be used, or two or more may be used in combination.

[0073] The present invention will be described in more detail below with reference to test examples and formulation examples, but the present invention is not limited to these examples. [Examples]

[0074] (Test Example 1) Small Intestinal Ulcer Inhibition Test (1) Loxoprofen and the test substance Loxoprofen sodium dihydrate (hereinafter sometimes referred to as loxoprofen) used was manufactured by Daiichi Sankyo Chemical Pharma. Furthermore, the test substance 1, lafutidine, was manufactured by Central Glass Co., Ltd. The test substance 2, magnesium oxide (hereinafter sometimes referred to as MgO), was manufactured by Tomita Pharmaceutical Co., Ltd. The test substance 3, licorice (licorice dry extract; crude drug equivalent ratio 5:1), was manufactured by Alps Pharmaceutical Co., Ltd. For the solvents of loxoprofen and the test substance, a 0.5 w / v% aqueous solution of carboxymethylcellulose sodium (abbreviated as CMC, manufactured by Kanto Chemical Co., Ltd., stored at room temperature) and sterile water for injection (Otsuka distilled water, manufactured by Otsuka Pharmaceutical Factory Co., Ltd., stored at room temperature) was used.

[0075] (2) Test method The study used rats (Crl:CD(SD)(SPF), 7 weeks old, male). Each test substance was dissolved in a 0.5 w / v% CMC aqueous solution to obtain the concentrations shown in Table 1. In addition, the notation "33.3 + 50.4" for the dosage (mg / kg) in Group E "MgO + Licorice" means that the dosage of MgO is 33.3 mg / kg, and the dosage of licorice (licorice dry extract; crude drug equivalent ratio 5:1) is 50.4 mg / kg (equivalent to 252 mg / kg in crude drug terms). In addition, the notation "6.66 + 10.08" for the administration solution concentration (mg / mL) in Group E "MgO + Licorice" means that the administration solution concentration of MgO is 6.66 mg / mL, and the administration solution concentration of licorice (licorice dry extract; crude drug equivalent ratio 5:1) is 10.08 mg / mL (equivalent to 50.4 mg / mL in crude drug terms).

[0076] (3) General condition observation The patient's general condition was observed on the day of administration and on the day of small bowel resection.

[0077] (4) Weight measurement The measurement was taken using an electronic balance before administration on the day of administration.

[0078] (5) Method of administering the test substance and loxoprofen Each test substance was administered orally to non-fasted animals using an oral tube (disposable oral tube, Fuchigami Kikai Co., Ltd.) and a syringe (disposable syringe, Terumo Corporation). The test substance was administered twice: 30 minutes before and 6 hours after the administration of loxoprofen. The amount of solution administered was calculated using the patient's body weight on the day of administration, at a rate of 5 mL / kg for each dose, and rounded to one decimal place by rounding to the second decimal place. Loxoprofen was administered orally using an oral tube (disposable oral tube, Fuchigami Kikai Co., Ltd.) and a syringe (disposable syringe, Terumo Corporation). The amount of solution administered was calculated using the patient's body weight on the day of administration, at a rate of 5 mL / kg, and rounded to one decimal place.

[0079] (6) Removal of the small intestine The animal was euthanized by bleeding under isoflurane anesthesia 24 hours after administration of loxoprofen. The digestive tract from the stomach to the ileocecal region was removed. The duodenum was cut, and the stomach and small intestine were separated. The stomach and small intestine were washed with physiological saline to remove the intestinal contents, passed through 1% neutral buffered formalin solution, and then immersed in the same fixative solution for at least 30 minutes for light fixation. To ensure that the top and bottom orientation of the small intestine could not be determined during fixation, a portion of the cecal end of the ileum was left intact before immersion in the fixative solution.

[0080] (7) Photographs of the ulcerated area The lightly fixed small intestine was cut at approximately 20 cm intervals, incised along the mesenteric body, and attached to filter paper. To enhance the contrast of the ulcerated areas, 10% povidone-iodine solution was applied using a cotton ball, and then photographed along with a scale. After photography, the small intestine was stored in 10% neutral buffered formalin solution while still attached to the filter paper.

[0081] (8) Image analysis and calculation of ulcer count The following method is used to count ulcers (ulcer area mm²). 2 ) was calculated. (a) Import the captured images into Photoshop (Adobe Photoshop Elements). (b) Enlarge the image to a size suitable for the work, outline the ulcerated area, which has been highlighted with 10% povidone-iodine solution, with black and fill it in. (c) Extract the filled-in ulcer area and convert it to a binarized image. (d) Convert the file format to BMP format. (e) Using the image analysis software ImageJ (NIH) to measure ulcer area in mm² 2 Calculate.

[0082] (9) Statistical processing The obtained ulcer count (ulcer area mm) 2 The mean and standard error were calculated for each group.

[0083] <Test Results> (1) Test results The results for ulcer area are shown in Figure 1 and Table 1. Note that the dosage and concentration of loxoprofen in Table 1 are based on the anhydrous form of loxoprofen. Furthermore, the fact that the dose (mg / kg) of the "test substance" in the "A: control" group (Group A) was 0, and the concentration of the administered solution (mg / mL) was 0, indicates that the rats were administered 5 mL / kg of 0 CMC aqueous solution, which was the solvent used for the test substance.

[0084] Group A: The control group measured 416±169 mm. 2 Ulcers were identified with a value of (mean ± standard error). Group B: Lafutidine group: 283±153mm 2 Ulcers were identified with a value of (mean ± standard error). Group C:MgO group is 228±56mm 2 Ulcers were identified with a value of (mean ± standard error). Group D: Licorice group is 250±52mm 2 Ulcers were identified with a value of (mean ± standard error). Group E: MgO + Licorice group: 192±68mm 2 Ulcers were identified with a value of (mean ± standard error).

[0085] [Table 1]

[0086] As described above, oral administration of loxoprofen resulted in ulcers being observed in the small intestines of rats (control group), and the therapeutic and prophylactic effects of each test substance on these small intestinal ulcers were investigated. As a result, the group using the anti-ulcer agent lafutidine as a positive control showed suppression of ulcers compared to the control group, confirming that this experimental system is valid as a test to confirm the suppression of small intestinal ulcers. Both the MgO group and the licorice group showed suppressed ulcer formation compared to the control group. Furthermore, the group receiving both MgO and licorice (MgO + licorice group) showed suppressed ulcer formation compared to the groups receiving either drug alone.

[0087] These results demonstrate that combining loxoprofen with licorice and magnesium (MgO) can suppress small intestinal ulcers. The effects of combining loxoprofen, licorice, and MgO on small intestinal ulcers were previously unknown, making the results obtained in this study unexpected. Furthermore, while orally administered loxoprofen is a precursor of the active form, it exhibits enterohepatic circulation characteristic of NSAIDs. Therefore, it is absorbed in the small intestine, converted to the active form in the liver, and then excreted in the bile. It is therefore suspected that repeated contact with the small intestinal mucosa is the cause of ulcers. In other words, the mechanisms of gastric mucosal damage caused by the precursor and small intestinal ulcers where the active form is present are different. Additionally, while small intestinal ulcers are known to be influenced by intestinal bacteria, the bacterial environment in the small intestine differs significantly from that in the stomach. Consequently, knowledge regarding gastric mucosal damage cannot predict the influence on small intestinal ulcers.

[0088] (Example of formulation 1) Tablets Tablets are manufactured by conventional methods using the compositions shown in Tables 2 to 5 below. A coating may be applied as desired.

[0089] [Table 2]

[0090] [Table 3]

[0091] [Table 4]

[0092] [Table 5] [Industrial applicability]

[0093] The oral pharmaceutical composition of the present invention, containing loxoprofen or a salt thereof, licorice, and magnesium oxide, is extremely useful because it significantly suppresses loxoprofen-induced small intestinal ulcers, thereby reducing the rate of side effects. The oral pharmaceutical composition of the present invention is suitably used, for example, as an antipyretic and analgesic, particularly for the relief of pain such as headache, menstrual cramps, toothache, post-extraction pain, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, and traumatic pain, as well as for reducing fever during chills and fever. It is also suitably used as a cold treatment agent to alleviate various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims

1. An oral pharmaceutical composition comprising loxoprofen or a salt thereof, magnesium oxide, and further comprising licorice as a crude drug.

2. An oral pharmaceutical composition according to claim 1, used as an antipyretic, analgesic, or cold treatment agent.

3. The oral pharmaceutical composition according to claim 1 or 2, which is a tablet, capsule, pill, granule, powder, liquid, lozenge, or caplet.

4. The oral pharmaceutical composition according to claim 3, wherein the tablet is an orally disintegrating tablet or a chewable tablet.

5. An oral pharmaceutical composition according to any one of claims 1 to 4, which can suppress small intestinal ulcers.

6. An oral pharmaceutical composition according to any one of claims 1 to 5, comprising at least 1 part by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof.

7. An oral pharmaceutical composition according to any one of claims 1 to 6, comprising 1 to 33 parts by weight of licorice (in terms of crude drug equivalent) per 1 part by weight of loxoprofen or a salt thereof.

8. An oral pharmaceutical composition according to any one of claims 1 to 7, comprising at least 0.01 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof.

9. An oral pharmaceutical composition according to any one of claims 1 to 8, comprising 0.01 to 30 parts by weight of magnesium oxide per 1 part by weight of loxoprofen or a salt thereof.

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