Pharmaceutical composition

Abstract

The present invention addresses the problem of providing a novel technique for suppressing pharyngitis and restoring water swallowing reflex by using loxoprofen and / or a salt thereof. According to the present invention, provided is a pharmaceutical composition having a pharyngitis-inhibiting effect and containing at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof.

Description

Technical Field , , , ,

[0001] The present invention relates to a pharmaceutical composition containing at least one selected from loxoprofen, its salts and their hydrates. More specifically, the present invention relates to a pharmaceutical composition suitable for inhibiting pharyngitis by containing loxoprofen and / or its salts. Background Art

[0002] Loxoprofen, known as a propionic acid-based non-steroidal antipyretics, analgesics and anti-inflammatory agents (hereinafter referred to as NSAIDs), shows the same prostaglandin biosynthesis inhibitory effect as other NSAIDs, but has a strong antipyretic / analgesic / anti-inflammatory effect. It is also known that loxoprofen is absorbed by the digestive tract in the form of an unchanged substance with a weak gastric mucosal irritation effect after oral administration, and is a prodrug that forms an active substance in the body. Therefore, it has the characteristic of less gastric mucosal damage compared with other NSAIDs (for example, refer to Non-Patent Document 1). [[ID=—10]]

[0003] Loxoprofen and / or its salts show an anti-inflammatory effect by inhibiting cyclooxygenase and are used for symptomatic treatment of pharyngitis (for example, refer to Patent Document 1).

[0004] On the other hand, the detailed mechanism of action of loxoprofen and / or its salts on pharyngitis has not been fully understood.

[0005] Prior Art Documents Patent Documents Patent Document 1: Japanese Patent Laid-Open No. 2001-10977 Non-Patent Documents[[ID=—24]] Non-Patent Document 1: Pharmacology and Therapy (Japanese: 薬理と治療) Vol. 16 No. 2 1988 p. 611-619. Summary of the Invention <00---0018>Problems to be Solved by the Invention That is, the present invention provides a novel technique for inhibiting pharyngitis and restoring the water swallowing reflex by using loxoprofen and / or its salts. [[ID=—33]]

[0007] Means for Solving the Problems The embodiments of the present invention are as follows. <1> A pharmaceutical composition comprising at least one selected from loxoprofen, its salts and their hydrates, and having an inhibitory effect on pharyngitis. <2> The pharmaceutical composition according to <1>, which has a restoring effect on the water swallowing reflex function. [[ID=—<42]] <3> The pharmaceutical composition according to <1> or <2>, which has an inhibitory effect on the swelling of the lamina propria of the mucosa. <4> The pharmaceutical composition according to any one of <1> to <3>, which has an effect of regenerating the mucosal epithelium. <5> according to <1> ~ <4> The pharmaceutical composition according to any one of the following, wherein the content of at least one of the above-mentioned components selected from loxoprofen, its salts and their hydrates or the salt thereof is 5 to 30% by mass. <6> according to <1> ~ <5> The pharmaceutical composition according to any one of the following, wherein, in a daily dose, at least one of the above-mentioned loxoprofen, its salts and their hydrates, or its salts, is 10 to 180 mg in anhydrous amount. <7> according to <1> ~ <6> The pharmaceutical composition described in any one of the following examples, wherein the dosage form is a solid dosage form or a liquid dosage form. <8> according to <1> ~ <6> The pharmaceutical composition described in any one of the following examples, wherein the dosage form is an oral liquid preparation, an oral liquid preparation, an oral spray, or a mouthwash. <9> according to <1> ~ <7> The pharmaceutical composition described in any one of the above is an oral pharmaceutical composition. <10> according to <1> ~ <7> The pharmaceutical composition further comprises at least one selected from antacids, caffeine derivatives, sedatives, medicinal herbs, antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergics, and vitamins. <11> according to <1> ~ <9> The pharmaceutical composition described in any one of the above is used as an antipyretic analgesic or cold medicine. <12> according to <1> ~ <7> , <9> The pharmaceutical composition according to any one of <1 0>, wherein the aforementioned dosage form is a solid dosage form, The aforementioned solid dosage forms are tablets, granules, pellets, or capsules.

[0008] Invention Effects The pharmaceutical composition of the present invention has excellent pharyngitis-suppressing effects and can restore the water swallowing reflex function. Attached Figure Description

[0009] Figure 1 This section outlines the method for creating a rat model of pharyngitis.

[0010] Figure 2 This section outlines the experimental method for measuring the water swallowing reflex.

[0011] Figure 3 This section outlines the experimental methods used in tissue analysis.

[0012] Figure 4 This indicates the result measured by the water swallowing reflex meter.

[0013] Figure 5 This indicates the results of water swallowing reflex measurements taken when loxoprofen is administered.

[0014] Figure 6This indicates the results of the organizational analysis. Detailed Implementation

[0015] The pharmaceutical composition of the present invention comprises at least one selected from loxoprofen, its salts and their hydrates, and has an anti-pharyngitis effect.

[0016] In addition, the pharmaceutical composition of the present invention has the effect of restoring the water swallowing reflex function.

[0017] In addition, the pharmaceutical composition of the present invention has the effect of inhibiting swelling of the lamina propria of the mucosa.

[0018] The pharmaceutical composition of the present invention has the effect of inhibiting swelling of the lamina propria of the mucosa.

[0019] The pharmaceutical composition of the present invention has the effect of regenerating mucosal epithelium.

[0020] The pharmaceutical compositions of the present invention comprise loxoprofen and / or its salts.

[0021] In this invention, "loxoprofen and / or its salts" means "at least one selected from loxoprofen, its salts and their hydrates", and is loxoprofen or its salts (including hydrated salts) (the salts are preferably pharmacologically acceptable salts), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.

[0022] The loxoprofen or its salt used in this invention is included in the 18th revised edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0023] <First Implementation Method> The content of loxoprofen or its salt contained in the pharmaceutical composition described in the first embodiment of the present invention is not limited. The amount of the ingredient contained in each dose (single dose) of the pharmaceutical composition for an adult is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg in anhydrous form, and is administered 1 to 3 times a day.

[0024] In the daily dosage, loxoprofen or its salt, on an anhydrous basis, is preferably 10-180 mg, but can be 30-120 mg or 30-90 mg.

[0025] When the pharmaceutical composition of the present invention is a tablet, the content of loxoprofen or its salt contained in the granulated particles is not particularly limited. The amount of the ingredient contained in each adult dose unit (single dose) of the tablet, in anhydrous form, is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg. It can be 45 to 90 mg, and in this case, the frequency of administration is also 1 to 3 times a day.

[0026] The inclusion of loxoprofen or its salt in the pharmaceutical composition is not particularly limited, but is 1 to 80% by mass, preferably 2 to 50% by mass, more preferably 5 to 30% by mass, and can be 5 to 20% by mass, based on the total mass of the pharmaceutical composition.

[0027] <Acid neutralizer> In this embodiment, from the viewpoint of inhibiting gastric mucosal damage, the pharmaceutical composition preferably also includes an antacid.

[0028] Examples of antacids, such as those derived from alkaline earth metals and / or earth-based metals, include magnesium oxide, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, co-precipitates of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminate hydroxide, aluminum hydroxide gel, co-precipitates of aluminum hydroxide and sodium bicarbonate, mixed dried gels of aluminum hydroxide and magnesium carbonate, co-precipitates of aluminum hydroxide, magnesium carbonate, and calcium carbonate, and bentonite. Inorganic salts selected from magnesium, aluminum, and calcium, such as calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, are included. Additionally, as alkali metal-based basic inorganic compounds, examples include dry sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, and potassium carbonate, which are inorganic salts selected from sodium and potassium. Oyster shells and glycine are also included, and one or more components selected from these can be mixed. Preferably, one or more components selected from magnesium oxide, magnesium aluminosilicate, aluminum hydroxide gel, and glycine are preferred.

[0029] When using magnesium aluminosilicate in this invention, substances listed in the 18th revised edition of the Japanese Pharmacopoeia can be used, or substances listed in the Encyclopedia of Pharmaceutical Additives can be used, which are readily available.

[0030] There are no particular limitations on commercially available magnesium aluminate metasilicate; for example, there is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.

[0031] The content of magnesium aluminate metasilicate in the pharmaceutical composition of the present invention can be selected by taking into account the disintegration / dissolution of the pharmaceutical composition and its function as an antacid, and there is no particular limitation. Based on the total mass of the pharmaceutical composition, it can be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass.

[0032] When magnesium oxide is used in this invention, substances listed in the 18th revised edition of the Japanese Pharmacopoeia or substances listed in the Encyclopedia of Pharmaceutical Additives can be used, and these substances are readily available.

[0033] There are no particular restrictions on the commercially available magnesium oxide; for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceuticals or magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry can be used.

[0034] The content of magnesium oxide in the pharmaceutical composition of the present invention can be selected by taking into account the disintegration / dissolution of the pharmaceutical composition and its function as an antacid, and is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 0.1 to 90% by mass, or 1 to 90% by mass, preferably 5 to 80% by mass.

[0035] In the case of using aluminum hydroxide gel in this invention, the substance included as dried aluminum hydroxide gel in the 18th revised edition of the Japanese Pharmacopoeia can be used, or the substance included in the Pharmaceutical Additives Encyclopedia can be used, which can be easily obtained.

[0036] As commercially available aluminum hydroxide gel, there are no particular limitations, and products such as dried aluminum hydroxide gel (S-100 grade) manufactured by Kyowa Chemical Industry Co., Ltd., dried aluminum hydroxide gel (fine particle grade) manufactured by Kyowa Chemical Industry Co., Ltd., and dried aluminum hydroxide gel (FM grade) manufactured by Kyowa Chemical Industry Co., Ltd. can be used.

[0037] The proportion of aluminum hydroxide gel in the pharmaceutical composition of the present invention can be selected by taking into account the disintegration / dissolution of the pharmaceutical composition and its function as an antacid, and is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 0.1 to 90% by mass, or 1 to 90% by mass, preferably 5 to 80% by mass.

[0038] In the case of using glycine in this invention, substances included in the 18th revised edition of the Japanese Pharmacopoeia can be used, which are readily available.

[0039] Commercially available glycine is not particularly limited and can be, for example, glycine manufactured by organic synthetic pharmaceutical companies, glycine "manufacturing grade" manufactured by Fujifilm and Koujun Pharmaceutical Co., Ltd., glycine manufactured by AJINOMOTO HEALTHY SUPPLY Co., Ltd., glycine (crystalline) manufactured by MERCK Co., Ltd., glycine (granular) manufactured by MERCK Co., Ltd., etc. Additionally, commercially available glycine can be appropriately pulverized before use.

[0040] The glycine content in the pharmaceutical composition of the present invention can be selected by taking into account the disintegration / dissolution of the pharmaceutical composition and its function as an antacid, and is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 0.1 to 90% by mass, or 1 to 90% by mass, preferably 5 to 80% by mass.

[0041] The pharmaceutical composition of the present invention preferably further comprises one or more selected from caffeine and sedatives.

[0042] As a type of caffeine, examples include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citric acid.

[0043] The proportion of caffeine in the pharmaceutical composition of the present invention is not particularly limited. For example, based on the total mass of the pharmaceutical composition, it can be 1 to 80% by mass, 3 to 80% by mass, or 5 to 70% by mass.

[0044] Examples of sedatives include allyl isopropyl acetylurea and bromovalerate urea.

[0045] The proportion of sedative in the pharmaceutical composition of the present invention is not particularly limited. For example, based on the total mass of the pharmaceutical composition, it can be 1 to 80% by mass, 2 to 80% by mass, or 2 to 70% by mass.

[0046] The pharmaceutical compositions of the present invention preferably further comprise compounds having an amino group.

[0047] As a compound containing an amino group, there are no particular limitations on the composition of any compound containing an amino group. For example, it can be mixed with one or more components selected from amino acids such as isoleucine, leucine, lysine, methionine, phenylalanine, threonine (hydroxybutyric acid), tryptophan, valine, histidine, tyrosine, cysteine, aspartic acid, asparagine, serine, glutamic acid, glutamine, proline, glycine, alanine, arginine, carboxymethylcysteine, tranexamic acid or their salts.

[0048] The amino compounds contained in the pharmaceutical composition are not particularly limited, and can be 1 to 90% by mass, 2 to 80% by mass, or 5 to 60% by mass, based on the total mass of the pharmaceutical composition.

[0049] The amount of amino compounds in the composition, for example, the amount of ingredients contained in the pharmaceutical composition for daily administration, may be 100-1000 mg per dose, or 200-700 mg per dose, administered 1-3 times per day.

[0050] When the pharmaceutical composition of the present invention uses tranexamic acid, which is also an anti-inflammatory component described later, the ratio of loxoprofen sodium or its salt to tranexamic acid is not particularly limited as long as it does not affect the effect of the present invention. The content ratio of tranexamic acid can be 0.1 to 20% by mass relative to 1% by mass of loxoprofen sodium dihydrate, preferably 0.1 to 10% by mass, and more preferably 0.1 to 5% by mass.

[0051] <Crude Drugs (Crude Drug Components)> The pharmaceutical compositions of the present invention may contain crude drugs.

[0052] The types of raw medicinal materials used in this invention are not particularly limited, and can be selected from, for example, ephedra, bamboo seed, cherry bark, polygala, licorice, platycodon, plantain seed, plantain herb, lycoris radiata, polygala tenuifolia, fritillaria, fennel, phellodendron bark, coptis chinensis, turmeric, chamomile, cinnamon, gentian, bezoar, animal bile (including bear bile), glehnia root, ginger, atractylodes lancea, clove, tangerine peel, atractylodes macrocephala, earthworm, bamboo ginseng, ginseng, wild parasol tree, asarum, epimedium, corydalis, scutellaria baicalensis, polygonatum, valerian. The ingredients include one or more of the following raw medicinal materials and their extracts (extracts, tinctures, dried extracts, etc.): Trichosanthes kirilowii seed, apricot kernel, wolfberry fruit, wolfberry leaf, schizonepeta, cassia seed, geranium, cyperus rhizome, schisandra fruit, asarum, Sichuan pepper, aster, lycium bark, peony root, musk, magnolia flower, chuanxiong rhizome, angelica root, swert, mulberry bark, perilla leaf, garlic, angelica root, ipecac root, ophiopogon root, pinellia tuber, saffron, robinin, angelica dahurica, poria cocos, peony bark, oyster shell, deer antler, and stephania tetrandra.

[0053] In this invention, it is preferred to include at least one of licorice extract, peony extract, and valerian extract.

[0054] The proportion of medicinal herbs in this invention is not particularly limited. For example, when each medicinal herb is an extract, the proportion is 1 to 80% by mass, 1 to 50% by mass, 1 to 40% by mass, or 1 to 30% by mass, based on the total mass of the composition.

[0055] The raw medicinal herbs used in this invention, such as licorice, peony, and valerian, have been used medicinally as single herbs or in traditional Chinese medicine formulas since ancient times. They can be directly used as raw herb powders or extracts obtained according to conventional methods. The form of the raw herb powders or extracts can also be commonly available commercial products or their processed forms. For example, raw herb powders can be used as dried powders (micro-powders) obtained by further finely pulverizing dried and chopped processed products. Furthermore, the form of the components extracted from the raw herbs is not particularly limited; for example, they can be used in any form, such as dried extracts, extract powders, soft extracts, fluid extracts, tinctures containing ethanol or ethanol and water. Preferred raw herbs include extracts with high formulation flexibility, such as soft extracts or dried extract powders.

[0056] The active ingredients with antibacterial activity can be obtained from the aforementioned crude drugs using conventional methods, such as extraction solvents. Common extraction solvents include water, hydrophilic solvents, or mixtures thereof. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, and tert-butanol; cellolytic agents such as methyl and ethyl cellolytic agents; 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 can be used alone or in mixtures of two or more.

[0057] Licorice can be used as an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive and expectorant, gastrointestinal medicine, anthelmintic, oral medicine for rhinitis, throat cooler, stomachic cooler, vitamin-containing health supplement, sweetener, flavoring agent, coloring agent, aromatizer, spice or excipient, as it has always been.

[0058] In this invention, when using "licorice", substances included in the 18th revised edition of the Japanese Pharmacopoeia can be used appropriately.

[0059] In addition to the above-mentioned types of licorice, there are also commercially available varieties, so they are readily available.

[0060] Commercially available licorice products include extracts that use water or 30% ethanol aqueous solutions as extraction solvents, such as licorice extract, dried licorice extract, soft licorice extract, and fluid licorice extract. Depending on the type of extract, a wide variety of products are available, including those based on the conversion ratio of the raw herb. In addition to these licorice extracts, licorice extract solutions can also be used appropriately, without particular limitations.

[0061] When commercially available licorice is used in pharmaceutical compositions, for example, licorice can be used in a manner that achieves an appropriate licorice content in tablets, taking into account the conversion ratio of the raw drug.

[0062] There is no particular limitation on the content of licorice (licorice or licorice extract) in the present invention. The amount of the ingredient contained in the pharmaceutical composition for the daily dosage, converted from the amount of raw drug, is preferably 10mg to 10g, more preferably 150mg to 5g, and even more preferably 500mg to 3000mg, and can be 500mg to 1500mg, and is administered 1 to 3 times a day.

[0063] In this invention, for example, when using dried licorice extract, the content of dried licorice extract is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 0.1 to 80% by mass, 1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0064] In this invention, when using "valerian", the substance included in the 18th revised edition of the Japanese Pharmacopoeia can be used as "valerian".

[0065] In addition to the above-mentioned varieties, valerian is also commercially available, so it is easily accessible.

[0066] Valerian, as a commercially available herb, can be used in various forms, such as valerian powder or valerian extracts (e.g., soft extracts, dried extracts, etc.), without any particular limitation.

[0067] When using commercially available valerian in pharmaceutical compositions, valerian can be used in a manner that ensures an appropriate valerian content in the tablet, taking into account the conversion ratio of the raw drug.

[0068] In this invention, when using "valerian (valerian or valerian extract)", there is no particular limitation on the content. For example, based on the amount of ingredients contained in a tablet for each daily dose, converted from the amount of raw drug, it can be 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, and even more preferably 60 mg to 1000 mg, or 60 to 450 mg, and the frequency of administration is 1 to 3 times per day.

[0069] In this invention, for example, when valerian extract is used, the proportion of valerian extract is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0070] In this invention, when using "peony", the substance included in the 18th revised edition of the Japanese Pharmacopoeia can be used as "peony".

[0071] Other types of peony besides those mentioned above are also commercially available, so they are easily accessible.

[0072] As commercially available peony, peony powder or peony extract (including dried extract, soft extract, etc.) can be used, without particular limitation.

[0073] When using commercially available peony in pharmaceutical compositions, as long as the conversion ratio of the raw drug is taken into account, peony can be used in a way that achieves an appropriate peony content in the tablets.

[0074] In this invention, when using "peony (peony or its extract)", there is no particular limitation on the content. Based on the conversion of raw peony, it is preferred to administer 100-5000 mg per day, more preferably 150-2000 mg, and particularly preferably 200-900 mg, and the number of administrations is 1-3 times per day.

[0075] In this invention, for example, when using dried peony extract, the content of dried peony extract is not particularly limited. Based on the total mass of the pharmaceutical composition, it can be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0076] The pharmaceutical compositions of the present invention can be formulated using conventional methods.

[0077] In this invention, tablets can be manufactured by, for example, producing granulated particles containing loxoprofen or its salt and containing crude drugs selected from (B-1) to (B-7), adding subsequent powder components to the resulting granulated particles in a manner that forms the exterior of the granulated particles, and then compressing them.

[0078] That is, tablets can be manufactured, for example, by the following steps: manufacturing granulated particles (at least one type of granulated particle) containing loxoprofen or its salt and containing crude drugs selected from (B-1) to (B-7); and manufacturing tablets by mixing the aforementioned granulated particles with a desired additive (subsequent powder component) and compressing them. Furthermore, loxoprofen or its salt and the crude drugs selected from (B-1) to (B-7) can be contained in different granulated particles, and the components disposed outside the particles can be arbitrarily formed into granules.

[0079] The subsequent powder component (outer part of the granulated particles) in this invention is a portion within the tablet that forms the outer part of the granulated particles. For example, it can be a portion within the tablet that covers one granulated particle, or it can be a portion that covers multiple granulated particles. Alternatively, it can be a portion within the tablet that covers at least one granulated particle and simultaneously forms the outer surface of the tablet. The tablet may have granulated particles within it, and loxoprofen or its salts and crude drugs selected from (B-1) to (B-7) may be contained within the aforementioned granulated particles.

[0080] During formulation, known methods and additives can be appropriately used. Additives should be added appropriately without impairing the effects of the invention.

[0081] Examples of pharmaceutically acceptable additives include excipients, binders, disintegrants, disintegration aids, lubricants, flow aids, gloss agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, aromas, colorants, substrates, coating agents, sugar coatings, plasticizers, dispersants, and defoamers. For the purposes described above, existing known formulation additives that can be used in pharmaceutical compositions may be used.

[0082] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, anhydrous dicalcium phosphate, anhydrous dicalcium phosphate granules, monocalcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, crystalline cellulose, crystalline cellulose-carboxymethyl cellulose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxyl Propylene starch - crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially α-substituted starch, powdered sugar, powdered maltose, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, calcium sulfate, erythritol, glucose, fructose, etc.

[0083] As an adhesive, it can be formulated with one or more components selected from, for example, gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0084] Examples of disintegrants include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, croscarmellose sodium, croscarmellose sodium, croscarmellose ketone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially α-substituted starch.

[0085] Examples of disintegration aids include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, light anhydrous silica, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0086] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerol fatty acid esters, polyethylene glycol, curing oil, and sodium stearate fumarate.

[0087] As a flow aid, it can be formulated with one or more components selected from, for example, hydrated silica, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and dicalcium phosphate granules.

[0088] As a glossing agent, it can be formulated with one or more ingredients selected from, for example, carnauba wax, white beeswax, refined shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc.

[0089] As a foaming agent, it can be formulated with one or more components selected from, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium bicarbonate, anhydrous citric acid, etc.

[0090] As a moisture-proofing agent, it can be formulated with one or more components selected from, for example, ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, curing oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylaminoacetate, etc.

[0091] As a surfactant, it can be blended with, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene dehydrated sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20)polyoxypropylene (20) diol, polyoxyethylene (105)polyoxypropylene (5) diol, polyoxyethylene ( 120) Polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, etc., one or more of the following components.

[0092] As a stabilizer, it can be blended with, for example, diacid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, calcium carboxymethyl cellulose, carboxylic acid, etc. Sodium methylcellulose, hydrated silica, dried sodium carbonate, glycine, glycerol, glycerol fatty acid esters, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamate, L-lysine, light anhydrous silica, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, refined gelatin, refined soybean lecithin, gelatin, gelatin hydrolysate, dehydrated sorbitan fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, carbonate Sodium hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54)polyoxypropylene (39) glycol, polyoxyethylene (160)polyoxypropylene (30) glycol, polyoxyethylene (196)polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceride (7E.O.), poly The following are one or more of the following components: sorbitol 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0093] Examples of emulsifiers include glycerol fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerol fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, dehydrated sorbitan fatty acid esters, polyoxyethylene dehydrated sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean lecithin.

[0094] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, ascorbate palmitate, and sodium metabisulfite.

[0095] Examples of fillers include RSS No.1 raw rubber, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0096] Examples of preservatives include benzoic acid, sodium benzoate, ethylparaben, propylparaben, methylparaben, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0097] As a sweetener, it can be blended with one or more ingredients selected from, for example, aspartame, acesulfame potassium, sweet tea, sweet tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, refined stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0098] As a flavoring agent, it can be blended with one or more ingredients selected from, for example, sodium chloride, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, monosodium L-glutamate, grapefruit extract, black sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sucralose, stevia extract, refined stevia extract, swertia, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0099] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0100] As a flavoring agent, it can be blended with one or more ingredients selected from, for example, orange flavoring, Brazilian cocoa extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach flavoring, fruit flavoring, mint, cantaloupe powder flavoring, L-menthol, peppermint oil, etc.

[0101] Examples of aromatic agents include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0102] As a coloring agent, it can be mixed with one or more of the following ingredients: yellow iron oxide, yellow ferric oxide, orange flavoring, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium dioxide, ferric oxide, diazo yellow, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, ferric oxide-glycerol suspension, sodium copper chlorophyllin, copper chlorophyllin, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc.

[0103] As a base agent, it can be formulated with a selection of gum arabic powder, α-starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymers, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, glycerol fatty acid esters, light anhydrous silicate, crystalline cellulose, curing oil, synthetic aluminum silicate, synthetic magnesium silicate sodium, titanium dioxide, tartaric acid, sucrose fatty acid esters, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerol, potato starch, and hydroxypropyl cellulose. The following are one or more of the following components: hydroxypropyl methylcellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, cetyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylate-methyl methacrylate copolymer.

[0104] Examples of coating agents include, for instance, ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers E and RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersions, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, glycerol fatty acid esters, curing oils, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, refined shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methyl cellulose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methyl cellulose The ingredients include: Vitamin B2910 mixture, pullulan polysaccharide, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, dehydrated sorbitan monostearate, dehydrated sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0105] As a sugar coating agent, it can be formulated with one or more components selected from, for example, gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyhydroxyalkanoate stearate 40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0106] As a plasticizer, it can be formulated with one or more of the following components: triethyl citrate, glycerol, glyceryl fatty acid esters, D-sorbitol, medium-chain triglycerides, triacetin, concentrated glycerol, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc.

[0107] As a dispersant, it can be formulated with a selection of aminoalkyl methacrylate polymers (RS), gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, glycerol fatty acid esters, magnesium silicate, light alumina, light anhydrous silicate, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and poly(hydroxypropyl cellulose). The ingredients include one or more of the following: vinacron, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, methylcellulose, glyceryl monooleate, dehydrated sorbitan monooleate, aluminum monostearate, glyceryl monostearate, dehydrated sorbitan monostearate, dehydrated sorbitan monopalmitate, dehydrated sorbitan monolaurate, and sodium lauryl sulfate.

[0108] As an antifoaming agent, it can be formulated with one or more ingredients selected from ethanol, glycerol fatty acid esters, dimethyl polysiloxane (for internal use), dimethyl polysiloxane-silica mixture, sucrose fatty acid esters, silicone defoamers, silicone oil, dehydrated sorbitan fatty acid esters, polysorbate 80, etc.

[0109] These additives are not limited to the substances listed above. In addition, one of these additives may be used, or two or more may be used in combination.

[0110] The pharmaceutical compositions of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. Preferably, the pharmaceutical compositions of the present invention are anti-inflammatory compositions.

[0111] Loxoprofen or its salts, as the active ingredient, have antipyretic, analgesic, and anti-inflammatory effects. Therefore, as an antipyretic and analgesic, it is particularly suitable for relieving pain such as headache, menstrual pain (menstrual cramps), toothache, post-extraction pain, sore throat, back pain, joint pain, muscle pain, shoulder pain, earache, bruise pain, fracture pain, sprain pain, and traumatic pain, as well as reducing fever in cases of chills / fever. In addition, as a cold treatment, it can be used appropriately to relieve various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0112] The pharmaceutical compositions of the present invention can be formulated into dosage forms such as those described in the 18th revised General Rules for Formulations of the Japanese Pharmacopoeia, including oral administration formulations (including tablets, intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and oral administration formulations (including oral tablets, lozenges, sublingual tablets, buccal lozenges, adhesive tablets, chewing gum, etc.). The pharmaceutical compositions are preferably solid dosage forms. Oral pharmaceutical compositions are preferred.

[0113] Solid dosage forms are preferably tablets, powders, fine granules, granules, capsules, or pills as described in the 18th revised edition of the Japanese Pharmacopoeia, more preferably granules or tablets, and most preferably tablets. Furthermore, for granules, when conducting particle size testing according to the 18th revised edition of the Japanese Pharmacopoeia, a formulation in which all material passes through an 18-gauge (850 μm) sieve and the amount of material remaining on a 30-gauge (500 μm) sieve is less than 10% of the total is sometimes referred to as a fine granule.

[0114] As a form of granules or tablets, it can be a form in which the formulation is coated with water-soluble polymers, etc. Examples include film-coated granules and film-coated tablets. Additionally, solid dosage forms can be sugar-coated.

[0115] In the case of solid dosage forms in tablet form, in addition to single-layer tablets, multilayer tablets can also be made by stacking two or three or more layers of powders or granules with different compositions and then compressing them. It should be noted that when tablets are made into multilayer tablets, loxoprofen or its salts and the prescribed crude drug can be contained in the same layer or in different layers.

[0116] In the pharmaceutical composition of the present invention, other active ingredients, such as antipyretics, analgesics, antitussives / expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, may be appropriately mixed as needed without impairing the present invention. If there are contraindications to their mixing, they can be formulated by properly separating the particles.

[0117] As an antipyretic and analgesic, it can be formulated with one or more ingredients selected from aspirin, aluminum aspirin, acetaminophen, ethylsalicylate, salicylsalicylic acid, salicylamide, lactylphenylethylamine, ibuprofen, isopropyl antipyrine, pranoprofen, diclofenac sodium, mefenamic acid, indomethacin, farnesyl ester, acemetacin, etodoxacin, naproxen, meloxicam, celecoxib, sodium salicylate, and thiamide hydrochloride.

[0118] Examples of antitussive / expectorant agents include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium debufenozide, dimethionine phosphate, teperidine citrate, teperidine hydroxybenzyl salt, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein, alloramine hydrochloride, clopidogrel hydrochloride, clopidogrel biphenylbenzyl salt, pentoxyverine citrate, noscapine, noscapine hydrochloride, trotoquinone hydrochloride, norepinephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, L-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaiacol, guaiacol potassium sulfonate, cresol potassium sulfonate, L-carboxymethylcysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-cysteine ​​ethyl ester hydrochloride.

[0119] Examples of antihistamines include azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emesartine fumarate, oxamide, olopatadine hydrochloride, carbisamine, clomastine fumarate, diphenyl disulfonate, carbisamine maleate, d-chlorophenamine maleate, dl-chlorophenamine maleate, ketotifen fumarate, diphenhydramine hydrochloride, diphenhydramine theophylline, diphenhydramine hydrochloride, diphenhydramine salicylate, and diphenhydramine... Lamindanine hydrochloride, triprolidine hydrochloride, triprolidine hydrochloride, sinepromine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequinatazine, methazine hydrochloride, loratadine, isopentyl hydrochloride, difenidol hydrochloride, methazine hydrochloride, naphthalene disulfide, methaqualene, promethazine methylene disalicylic acid, difenidol phosphate, etc.

[0120] As anti-inflammatory agents, glycyrrhizic acid and its derivatives, as well as their salts (such as dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), tranexamic acid, etc. can be listed.

[0121] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-scopolamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropyl iodine ammonium, diphenylpiperidinyl methyldioxolane iodide, scopolamine extract, scopolamine root, and total scopolamine root alkaloids citrate.

[0122] Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, niacin, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium / magnesium aspartate, hexanicotinic acid inositol ester, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, gluconamide, chondroitin sulfate sodium, ginseng, coix seed, and folic acid.

[0123] Other xanthine derivatives besides caffeine (such as theophylline and theobromine) can be listed.

[0124] In addition, as a vitamin, it can be blended with, for example, vitamin B1 and its derivatives and their salts selected from thiamine, thiamine chloride hydrochloride, thiamine nitrate, citothiamine hydrochloride, citothiamine hydrochloride, furazolidone, furazolidone hydrochloride, thiamine lipoic acid, cyprothiamine, thiamine disulfide, subuthiamine, bisbenzoylthiamine, propoxurylthiamine, and phenylphosphine; and vitamin B2 and its derivatives and their salts selected from riboflavin, riboflavin phosphate, riboflavin butyrate, and sodium riboflavin phosphate. Salts of vitamins; vitamin B5 and its derivatives, such as pantothenic acid, panthenol, panthenylthioethylamine, calcium pantothenate, and sodium pantothenate, and their salts; vitamin B6 and its derivatives, such as pyridoxine hydrochloride and pyridoxal phosphate, and their salts; vitamin B12 and its derivatives, such as cyanocobalamin and methylcobalamin, and their salts; vitamin C and its derivatives, such as ascorbic acid, sodium ascorbate, and calcium ascorbate, and their salts; and one or more of the following components: hesperidin and its derivatives, and their salts.

[0125] These additives are not limited to the substances listed above. In addition, one of them may be used, or two or more may be used in combination.

[0126] The pharmaceutical compositions of the present invention can be temporarily packaged in SP packaging, PTP packaging, strip bag packaging, bottle packaging, etc., for airtight preservation. Furthermore, they can be pillow-shaped or stored in boxes or the like.

[0127] In other words, the pharmaceutical product described in one embodiment of the present invention may comprise a pharmaceutical composition and packaging materials for packaging the aforementioned pharmaceutical composition.

[0128] There are no particular limitations on the materials used in SP packaging, PTP packaging, strip bag packaging, and pillow packaging. For example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, multilayer films composed of these resin films, and materials made by attaching aluminum foil to these resin films can be used.

[0129] The packaging material for the pharmaceutical composition of the present invention is preferably a packaging material that is not easily affected by moisture (a packaging formed from at least one of a moisture-proof material and an air-barrier material).

[0130] For example, packaging made of materials with minimal moisture impact (moisture-proof materials) can be manufactured as PTP (polypropylene) + polyethylene aluminum pillow packaging (a combination of PTP and polyethylene aluminum pillow packaging). Furthermore, considering factors such as inhibiting the rise in moisture content in pharmaceutical compositions, the storage stability of pharmaceutical compositions, and the stability of pharmaceutical compositions after opening, packaging made of materials less susceptible to moisture impact (moisture-proof materials) can utilize PTP packaging with aluminum on both sides (Al-Al packaging).

[0131] It should be noted that if there are concerns about moisture absorption, desiccants can be stored inside the bottle packaging or in a pillow-shaped package.

[0132] As a gas barrier material, any known material can be used without particular limitation. For example, it can be a laminated film with a functional barrier layer, or it can have the functions of the aforementioned moisture-proof material or be used together with the aforementioned moisture-proof material.

[0133] In addition, the packaging materials for the pharmaceutical compositions of the present invention may use environmentally friendly raw materials such as recycled plastics, biomass plastics, and biodegradable plastics as needed, and environmentally friendly containers / packaging may be used, without particular limitation.

[0134] <Second Implementation Method> As a second embodiment of the present invention, the dosage form of the pharmaceutical composition can be set as a liquid formulation.

[0135] In this embodiment, when the dosage form is a liquid preparation, it can be used as an oral liquid pharmaceutical composition, for example, as an oral liquid preparation, an oral liquid preparation, an oral spray (spray) or a mouthwash.

[0136] In this embodiment, the content of at least one selected from loxoprofen, its salt and their hydrates can be 0.016 to 3.0 W / V relative to the total amount of the liquid pharmaceutical composition, and preferably 0.05 to 1.5 W / V relative to the total amount of the oral liquid pharmaceutical composition.

[0137] In this embodiment, in addition to at least one selected from loxoprofen, its salts and their hydrates, the following substances may be included.

[0138] In this embodiment, sodium azulene sulfonate may be included.

[0139] Sodium azulene sulfonate is known as a preventive and therapeutic agent for inflammatory diseases in the digestive tract, oral cavity and throat, otolaryngology, ophthalmology, and other fields.

[0140] Sodium azulene sulfonate is a known substance and is readily available on the market.

[0141] When using sodium azulene sulfonate, the mixing amount relative to the total volume of the liquid formulation can be 0.02 w / v% to 0.5 w / v, preferably 0.02 w / v% to 0.4 w / v, and particularly preferably 0.02 w / v% to 0.1 w / v.

[0142] It should be noted that the unit "w / v%" of the mixing volume refers to the percentage of mass relative to volume (the content of the ingredient (g) in a liquid formulation (100 mL)) (the same applies to other ingredients below).

[0143] In this embodiment, sugar alcohols may be included.

[0144] Examples of sugar alcohols include maltitol, erythritol, xylitol, and sorbitol.

[0145] When using sugar alcohols, the sugar alcohol content relative to the total volume of the liquid formulation can be 20 w / v% to 40 w / v, preferably 25 w / v% to 40 w / v, and particularly preferably 25 w / v% to 35 w / v.

[0146] In this embodiment, a quaternary ammonium salt may be included.

[0147] Examples of quaternary ammonium salts include cetylpyridinium chloride, benzyl chloride, and benzalkonium chloride. One of these salts can be mixed alone or in combination with two or more.

[0148] The content of quaternary ammonium salt relative to the total volume of the liquid formulation is 0.05 w / v% to 0.5 w / v, preferably 0.05 w / v% to 0.3 w / v, and particularly preferably 0.1 w / v% to 0.3 w / v.

[0149] The liquid formulation described in this embodiment may contain alcohols such as monohydric alcohols and polyhydric alcohols.

[0150] Examples of monohydric alcohols include methanol, ethanol, propanol, isopropanol, and butanol. One of these can be used alone or in combination of two or more. Ethanol is particularly suitable.

[0151] The polyol is preferably one or more selected from glycerol, ethylene glycol, propylene glycol, and butylene glycol. Glycerol is preferred.

[0152] There is no particular limit to the alcohol content, but it can be less than 40 w / v relative to the total volume of the liquid formulation.

[0153] In this embodiment, a pH adjuster may be included.

[0154] Examples of pH adjusters include citric acid, sodium citrate, lactic acid, sodium lactate, and sodium hydroxide.

[0155] The pH of the aqueous formulation of the present invention can be about 6 to 9, preferably adjusted to about 7.0 to 8.5, and particularly preferably adjusted to about 7.0 to 8.0.

[0156] In this embodiment, there are no particular limitations, and the water content can be 15-80%, preferably 15-75%.

[0157] In this embodiment, flavoring agents, buffers, preservatives, stabilizers, etc., that are commonly mixed into pharmaceutical preparations can be incorporated, as long as the purpose of this invention is not violated.

[0158] Flavoring agents have the function of mitigating the characteristic taste of medicinal ingredients. For example, erythritol and L-menthol function as flavoring agents.

[0159] Suitable examples of buffers include phosphate, acetate, carbonate, citrate, and other buffer solutions.

[0160] In addition, parabens can also be used as preservatives for the aqueous formulations used in this invention.

[0161] Stabilizers include, for example, surfactants (such as polyoxyethylene hydrogenated castor oil, polysorbate, polylaurin, polyethylene glycol, sodium lauryl sulfate, etc.), sodium edetate, cyclodextrin, sulfites, citric acid or its salts.

[0162] The oral liquid pharmaceutical composition of this embodiment can be manufactured by known preparation methods, such as those described in the Liquid Preparations section of the 18th revised Japanese Pharmacopoeia.

[0163] For example, the oral liquid pharmaceutical composition described in this embodiment can be prepared by homogenizing and physically mixing other additives.

[0164] The oral liquid pharmaceutical composition of this embodiment can be easily manufactured by dissolving the above-mentioned components in, for example, distilled water or sterile purified water.

[0165] For example, when used as an oral medication, it can be used for inflammatory diseases of the oral cavity, specifically such as sore throat, dry throat, swollen throat, throat discomfort, hoarseness, and stomatitis caused by throat inflammation.

[0166] Regarding the dosage, for example, when using the oral liquid medicine composition of this embodiment for adults, the oral liquid medicine composition can be filled into a spray-type container and sprayed onto the affected area several times a day as a throat spray.

[0167] It should be noted that the frequency of administration may be adjusted according to the severity of the indications.

[0168] As specific dosage forms of the oral liquid pharmaceutical composition in this embodiment, examples include oral liquid preparations, oral liquid preparations, mouthwashes, oral sprays (e.g., aerosols filled with gas or pumps can be used), and additives and bases suitable for each dosage form can be used appropriately, and the composition can be manufactured according to the usual methods described in the 18th revised edition of the Japanese Pharmacopoeia.

[0169] Alternatively, the formulation can be contained in glass containers / packaging, metal containers / packaging such as aluminum, or olefin resin containers / packaging such as polyethylene or polypropylene, and sealed. Furthermore, it can be contained in a moisture-proof bag containing metal such as aluminum.

[0170] In addition, containers / packaging can use environmentally friendly raw materials / materials such as recycled plastics and biomass raw materials. As needed, laminated materials, gas-barrier materials, and any materials that prevent the deterioration of topical skin agents caused by external factors / elements / environmental changes such as heat and light from the pharmaceutical container / packaging at high temperatures can be used to appropriately maintain the quality of the topical skin agents.

[0171] The following examples illustrate the present invention in more detail, but the present invention is not limited to these examples at all. Example

[0172] <Experimental Materials> (1) Matter The following substances were used in the experiment. Loxoprofen sodium hydrate (LOX) 10% (w / w) aqueous solution of acetic acid (sometimes referred to as AA below) physiological saline Three types of combined anesthesia (metoprolol, midazolam, and butorphanol).

[0173] <Experimental Methods> <Experiment 1. Establishment of a rat model of pharyngitis> Figure 1The image shows an endoscopic photograph of the pharynx of a rat model of pharyngitis.

[0174] During filming Figure 1 When taking endoscopic photographs of the pharynx of rats with a pharyngitis model, the rats were positioned on a fixed platform, and rubber was placed in the anterior teeth of the upper and lower jaws to create an opening, so that the position could be adjusted in a way that allowed the epiglottis to be observed through the endoscope.

[0175] like Figure 1 As shown, male Wister rats weighing 300g-450g were anesthetized in three different ways (50mg / kg, intraperitoneal administration). Using a micro-application device, 10μl of a 10% acetic acid aqueous solution diluted with distilled water was applied to the posterior pharyngeal wall of the rats. Figure 1 (AA treatment in the middle) can induce pharyngitis.

[0176] <Experiment 2. Measurement of Water Swallowing Reflex> Using the pharyngitis model rats obtained in Experiment 1, such as Figure 2 As shown, the latency time, number of swallowing reflexes, and time interval of swallowing reflexes were measured as an evaluation of pharyngitis. As a method for measuring the water swallowing reflex, under three mixed anesthesia methods (50 mg / kg, intraperitoneal administration), water was administered for 10 seconds via a syringe pump through a cannula inserted into the rat's pharynx using an endoscope. The time until the first reflex occurred (swallowing reflex latency time), the number of swallowing reflexes in 10 seconds from the first reflex, and the time interval of each swallowing reflex were measured.

[0177] The whitening of the endoscopic image was measured as swallowing.

[0178] It should be noted that, as Figure 2 As shown, the preparation groups [1] Sham+Veh group (pharyngeal swab: distilled water, intraperitoneal administration: physiological saline (Veh)), [2] AA10%+Veh group (pharyngeal swab: 10% acetic acid aqueous solution (AA10%), intraperitoneal administration: physiological saline (Veh)), and [3] AA10%+Lox group (pharyngeal swab: 10% acetic acid aqueous solution (AA10%), intraperitoneal administration: loxoprofen 4m / kg) were tested for water swallowing reflex in each group 1 hour after intraperitoneal administration.

[0179] <Experiment 3. Tissue Analysis> Subsequently, rats were perfused and fixed with 4% paraformaldehyde (PFA), and pharyngeal tissue was collected, embedded in paraffin, and then stained with hematoxylin / eosin (HE staining) (refer to...). Figure 3 ).

[0180] like Figure 3 As shown, the degree of edema caused by inflammation is determined by measuring the thickness of the lamina propria.

[0181] One day after acetic acid treatment, in which the water swallowing reflex was most reduced, loxoprofen was administered intraperitoneally at 4 mg / kg. The water swallowing reflex was then measured one hour later (refer to...). Figure 2 , Figure 3 ).

[0182] The control group was given physiological saline (refer to) Figure 2 ).

[0183] <Experimental Results: Experiments 1-3> The results of Experiment 2, such as Figure 4 As shown, in rats with pharyngitis (10% acetic acid aqueous solution treatment group and AA group), the intervals and frequency of swallowing reflexes increased, indicating a decrease in water swallowing reflex function.

[0184] On the other hand, such as Figure 5 As shown, in the loxoprofen administration group of Experiment 2, compared with the control group, the number of swallowing reflexes increased significantly and the time interval between swallowing reflexes was shortened 1 hour after administration. According to... Figure 5 The results showed that loxoprofen tended to restore the reduced water swallowing reflex function caused by pharyngitis.

[0185] like Figure 6 As shown, in HE staining in Experiment 3, infiltration of inflammatory cells was observed in both the loxoprofen administration group and the control group, but in the loxoprofen administration group, the swelling of the submucosa (laminarum propria) was significantly inhibited.

[0186] <Examination of the results of Experiments 1-3> It can be confirmed that acetic acid treatment caused damage to the pharyngeal mucosal epithelium, and simultaneously, inflammation led to swelling of the lamina propria. It can be concluded that this damage to the pharyngeal mucosal epithelium and swelling of the lamina propria result in a decrease in the water swallowing reflex. Figure 4 ).

[0187] In the loxoprofen administration group, recovery of swallowing frequency and swallowing interval, and inhibition of swelling of the lamina propria were observed. Figure 5 , Figure 6 ).

[0188] It should be noted that, 6 days after acetic acid treatment, the latency of the water swallowing reflex, the frequency of swallowing, the regeneration of the mucosal epithelium, and the inhibition of swelling of the lamina propria were confirmed over time. Figure 6 ).

[0189] Based on the results of this experiment, it can be concluded that the recovery of the water swallowing reflex is influenced by [1] the recovery of the mucosal epithelium and [2] the inhibition of swelling of the mucosal lamina propria.

[0190] In addition, based on the results of this experiment, it can be concluded that loxoprofen is particularly helpful in the recovery of the water swallowing reflex by inhibiting the swelling of the mucosal lamina propria [2].

[0191] The above results suggest the possibility that loxoprofen can restore the water swallowing reflex by inhibiting pharyngeal swelling.

[0192] The preferred embodiments and examples of the present invention have been described above, but the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications can be made to the structure without departing from the spirit of the present invention.

[0193] Industrial utilization The pharmaceutical composition of the present invention is particularly suitable as an antipyretic and analgesic for relieving headaches, menstrual pain (menstrual pain), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, shoulder pain, earaches, bruise pain, fracture pain, sprain pain, traumatic pain, etc., and for reducing fever in cases of chills / fever. In addition, as a cold medicine, it is suitable for relieving various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

Claims

1. A pharmaceutical composition comprising at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, and having a pharyngitis inhibiting effect.

2. The pharmaceutical composition according to claim 1, having an effect of recovering water swallow reflex function.

3. The pharmaceutical composition according to claim 1, having an effect of inhibiting swelling of a mucosal lamina propria.

4. The pharmaceutical composition according to claim 1, having an effect of regenerating mucosal epithelium.

5. The pharmaceutical composition according to claim 1, wherein, The content of the at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in the pharmaceutical composition is 5 to 30 mass%.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein, In a single day administration amount, the at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof is 10 to 180 mg as an anhydrous amount.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein, The dosage form is a solid preparation or a liquid preparation.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein, The dosage form is an oral liquid preparation, an oral cavity liquid preparation, an oral cavity spray, or a gargle.

9. The pharmaceutical composition according to any one of claims 1 to 5, which is an oral pharmaceutical composition.

10. The pharmaceutical composition according to any one of claims 1 to 5, further comprising at least one selected from the group consisting of antacids, caffeine-based agents, sedatives, crude drugs, antitussive / expectorant agents, antihistamine agents, anti-inflammatory agents, anticholinergic agents, and vitamins.

11. The pharmaceutical composition according to any one of claims 1 to 5, which is used as an antipyretic analgesic or a cold medicine.

12. The pharmaceutical composition according to claim 7, wherein, The dosage form is a solid preparation, The dosage form of the solid preparation is a tablet, a fine granule, a granule, or a capsule.

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