WO2024237309A1 - Pharmaceutical composition - Google Patents

Abstract

The present invention addresses the problem of providing a novel technology in which loxoprofen and/or a salt thereof are used to prevent pharyngitis and recover a water-swallowing reflex. The present invention provides a pharmaceutical composition which has a pharyngitis inhibitory action and which includes at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof.

Description

Pharmaceutical Compositions

The present invention relates to a pharmaceutical composition containing at least one selected from the group consisting of loxoprofen, its salts, and their hydrates. More specifically, the present invention relates to a pharmaceutical composition suitable for suppressing pharyngitis by containing loxoprofen and/or its salts.

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

Loxoprofen and/or a salt thereof exhibits an anti-inflammatory effect by inhibiting cyclooxygenase, and is used as a symptomatic treatment for pharyngitis (see, for example, Patent Document 1).
On the other hand, the details of the mechanism of action of loxoprofen and/or its salts against pharyngitis are not fully known.

Patent Publication 2001-10977

Pharmacology and Therapy Vol. 16 No. 2 1988 p. 611-619

In other words, the present invention provides a new technology that uses loxoprofen and/or its salts to suppress pharyngitis and restore the water swallowing reflex.

The aspects of the present invention are as follows.
<1> A pharmaceutical composition comprising at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and having an effect of suppressing pharyngitis.
<2> The pharmaceutical composition according to <1>, which has an effect of restoring water swallowing reflex function.
<3> The pharmaceutical composition according to <1> or <2>, which has an effect of suppressing swelling of the lamina propria mucosa.
<4> The pharmaceutical composition according to any one of <1> to <3>, which has an effect of regenerating mucosal epithelium.
<5> The pharmaceutical composition according to any one of <1> to <4>, wherein the content of the at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof or a salt thereof in the pharmaceutical composition is 5 to 30% by mass.
<6> The pharmaceutical composition according to any one of <1> to <5>, wherein the amount of at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof or a salt thereof in a daily dosage is 10 to 180 mg in terms of anhydrous amount.
<7> The pharmaceutical composition according to any one of <1> to <6>, wherein the pharmaceutical composition is in the form of a solid preparation or a liquid preparation.
<8> The pharmaceutical composition according to any one of <1> to <6>, wherein the dosage form is an oral liquid, an oral liquid, an oral spray, or a mouthwash.
<9> The pharmaceutical composition according to any one of <1> to <7>, which is an oral pharmaceutical composition.
<10> The pharmaceutical composition according to any one of <1> to <7>, further comprising at least one selected from the group consisting of antacids, caffeines, sedatives, herbal medicines, antitussives/expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, and vitamins.
<11> The pharmaceutical composition according to any one of <1> to <9>, which is used as an antipyretic analgesic or cold remedy.
<12> The dosage form is a solid formulation,
The pharmaceutical composition according to any one of <1> to <7>, <9> and <10>, wherein the solid preparation is in the form of a tablet, fine granules, granules or capsules.

The pharmaceutical composition of the present invention has an excellent effect of suppressing pharyngitis and can restore the water swallowing reflex function.

FIG. 1 shows an outline of a method for producing a rat model of pharyngitis. FIG. 2 shows an outline of the experimental method for measuring the water swallowing reflex. FIG. 3 shows an outline of the experimental method for the texture analysis. FIG. 4 shows the results of water swallowing reflex measurement. FIG. 5 shows the results of water swallowing reflex measurement when loxoprofen was administered. FIG. 6 shows the results of the texture analysis.

The pharmaceutical composition of the present invention contains at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and has an effect of suppressing pharyngitis.
In addition, the pharmaceutical composition of the present invention has the effect of restoring water swallowing reflex function.
In addition, the pharmaceutical composition of the present invention has the effect of suppressing swelling of the lamina propria mucosa.

The pharmaceutical composition of the present invention has the effect of suppressing swelling of the lamina propria mucosa.
The pharmaceutical composition of the present invention has the effect of regenerating mucosal epithelium.

The pharmaceutical composition of the present invention comprises loxoprofen and/or a salt thereof.
In the present invention, "loxacin and/or a salt thereof" means "at least one selected from the group consisting of loxacin, a salt thereof, and a hydrate thereof", i.e. loxacin or a salt thereof (including a hydrate salt) (the salt is preferably a pharmacologically acceptable salt), preferably loxacin sodium, and more preferably loxacin sodium dihydrate.
Loxoprofen or a salt thereof used in the present invention is listed in the Japanese Pharmacopoeia, 18th Edition, as loxoprofen sodium hydrate.

First Embodiment
The content of loxoprofen or a salt thereof in the pharmaceutical composition according to the first embodiment of the present invention is not limited, but the amount of the component contained in the pharmaceutical composition per dosage unit (single dosage) for an adult is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, calculated as an anhydrous amount, and the frequency of administration is 1 to 3 times a day.
In the daily dose, the amount of loxoprofen or a salt thereof is preferably 10 to 180 mg, or may be 30 to 120 mg, or may be 30 to 90 mg, in terms of the anhydrous amount.

When the pharmaceutical composition of the present invention is in the form of a tablet, the content of loxoprofen or a salt thereof contained in the granules in the tablet is not particularly limited, but the amount of the ingredient contained in one dosage unit (single dose) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, or may be 45 to 90 mg, in terms of anhydrous equivalent, and in this case, the number of doses is 1 to 3 times a day.

The amount of loxoprofen or a salt thereof contained in the pharmaceutical composition is not particularly limited, but may be 1 to 80% by mass, preferably 2 to 50% by mass, more preferably 5 to 30% by mass, and may be 5 to 20% by mass, based on the total mass of the pharmaceutical composition.

<Antacids>
In this embodiment, the pharmaceutical composition may preferably further contain an antacid from the viewpoint of suppressing damage to the gastric mucosa.
Examples of antacids include alkaline earth metal and/or earth metal basic inorganic compounds, such as magnesium oxide, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, a co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, a co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, a mixed dried gel of aluminum hydroxide and magnesium carbonate, and a co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate. Examples of the inorganic salts include inorganic salts of metals selected from magnesium, aluminum and calcium, such as bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, and examples of the alkaline metal-based basic inorganic compounds include inorganic salts of metals selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, and potassium carbonate, and other examples include borey and glycine, and one or more components selected from these can be blended. Among these, one or more components selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, aluminum hydroxide gel, and glycine are preferred.

When magnesium aluminometasilicate is used in the present invention, it is possible to use one listed in the 18th Revised Japanese Pharmacopoeia or one listed in the Pharmaceutical Additives Dictionary, which are readily available.
Commercially available magnesium aluminometasilicate is not particularly limited, but an example thereof is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.
The content of magnesium aluminometasilicate in the pharmaceutical composition of the present invention may be selected taking into consideration the disintegrability of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited, but may be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass, based on the mass of the entire pharmaceutical composition.

When magnesium oxide is used in the present invention, it is possible to use magnesium oxide listed in the 18th Edition of the Japanese Pharmacopoeia or magnesium oxide listed in the Dictionary of Pharmaceutical Additives, which are readily available.
The commercially available magnesium oxide is not particularly limited, but for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd., magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd., and the like may be used.
The content of magnesium oxide in the pharmaceutical composition of the present invention may be selected taking into consideration the disintegrability of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited, but may be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass, based on the mass of the entire pharmaceutical composition.

When an aluminum hydroxide gel is used in the present invention, it is possible to use one listed as a dried aluminum hydroxide gel in the Japanese Pharmacopoeia, 18th Edition, or one listed in the Dictionary of Pharmaceutical Additives, which are readily available.
The commercially available aluminum hydroxide gel is not particularly limited, but for example, dried aluminum hydroxide gel (S-100 grade) manufactured by Kyowa Chemical Industry Co., Ltd., dried aluminum hydroxide gel (fine grain grade) manufactured by Kyowa Chemical Industry Co., Ltd., dried aluminum hydroxide gel (FM grade) manufactured by Kyowa Chemical Industry Co., Ltd. may be used.
The content of aluminum hydroxide gel in the pharmaceutical composition of the present invention may be selected taking into consideration the disintegrability of the pharmaceutical composition, the dissolution of the drug, and the function as an antacid, and is not particularly limited, but may be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass, based on the mass of the total pharmaceutical composition.

When glycine is used in the present invention, glycine listed in the 18th edition of the Japanese Pharmacopoeia may be used, and is readily available.
The commercially available glycine is not particularly limited, and examples thereof include glycine manufactured by Yuki Synthetic Chemicals Co., Ltd., glycine "for manufacturing only" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., glycine manufactured by Ajinomoto Healthy Supply Co., Ltd., glycine (crystal) manufactured by Merck Ltd., and glycine (granule) manufactured by Merck Ltd. Commercially available glycine may be appropriately pulverized before use.
The content of glycine in the pharmaceutical composition of the present invention may be selected taking into consideration the disintegrability of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited, and may be 0.1 to 90% by mass, 1 to 90% by mass, and preferably 5 to 80% by mass, based on the mass of the entire pharmaceutical composition.

The pharmaceutical composition of the present invention may preferably further contain one or more members selected from the group consisting of caffeines and sedatives.
Examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.
The content of caffeines in the pharmaceutical composition of the present invention is not particularly limited, and may be, for example, 1 to 80% by mass, 3 to 80% by mass, or 5 to 70% by mass, based on the mass of the entire pharmaceutical composition.

Examples of sedatives include allylisopropylacetylurea and bromovalerylurea.
The content of the sedative in the pharmaceutical composition of the present invention is not particularly limited, and may be, for example, 1 to 80% by mass, 2 to 80% by mass, or 2 to 70% by mass, based on the mass of the entire pharmaceutical composition.

The pharmaceutical composition of the present invention may preferably further contain a compound having an amino group.
The compound having an amino group is not particularly limited as long as it is a compound having an amino group, and may include, for example, one or more components selected from amino acids such as isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, tyrosine, cysteine, aspartic acid, asparagine, serine, glutamic acid, glutamine, proline, glycine, alanine, and arginine, carbocysteine, tranexamic acid, or a salt thereof, and the like.
The amount of the compound having an amino group contained in the pharmaceutical composition is not particularly limited, and may be 1 to 90 mass %, 2 to 80 mass %, or 5 to 60 mass %, based on the mass of the entire pharmaceutical composition.
The amount of the compound having an amino group in the composition may be, for example, 100 to 1000 mg per administration, or 200 to 700 mg per administration, in terms of the amount of the component contained in the pharmaceutical composition per daily dose, and the administration frequency is 1 to 3 times per day.
When the pharmaceutical composition of the present invention uses tranexamic acid, which is also an anti-inflammatory ingredient described later, the content ratio of rofecoxib sodium or a salt thereof to tranexamic acid is not particularly limited as long as it does not affect the effects of the present invention, but the content ratio of tranexamic acid per 1 mass% of rofecoxib sodium dihydrate may be 0.1 to 20 mass%, preferably 0.1 to 10 mass%, and more preferably 0.1 to 5 mass%.

<Herbal medicines (herbal medicine ingredients)>
The pharmaceutical composition of the present invention may contain herbal medicines.
The herbal medicines used in the present invention are not particularly limited, but include, for example, Ephedra, Nandina, Scutellaria, Onji, Licorice, Platycodon, Coptis, Coptis, Garlic, Senega, Fritillaria, Fennel, Phellodendron Bark, Coptis Rhizome, Zedoary, Chamomile, Cinnamon Bark, Gentiana, Bezoar, Animal Gall (including Yutang), Shajin, Ginger, Atractylodes Root, Clove, Tangerine, Atractylodes Root, Dioscorea Root, Carrot, Mallotus Japonicus, Acacia, Corydalis, Scutellaria Root, Coptis Root, Valerian, Calonin, Apricot Nerve, Lycium Bark, Lycium Herb, Cerastium Bark, Cassia, Gentian, Ginseng, It is possible to blend one or more ingredients selected from herbal medicines such as Magnolia officinalis, Gomizushi, Saishin, Zanthoxylum Root, Aster Root, Jikoppi, Peony Root, Musk, Cnidium Root, Zenko, Swertia Root, Sophora Root, Perilla Root, Taisan, Touki, Ipecac, Bakumondou, Pinellia Root, Japanese Root, Japanese Cardamom, Angelica Root, Poria Root, Peony Root, Borei, Rokujo, Bowi, etc., and extracts thereof (extracts, tinctures, dried extracts, etc.), etc.
In the present invention, it is preferable to contain at least one of licorice extract, peony extract, and valerian extract.
The content ratio of the herbal medicines in the present invention is not particularly limited, but for example, when each herbal medicine is an extract, it is 1 to 80 mass %, optionally 1 to 50 mass %, optionally 1 to 40 mass %, or optionally 1 to 30 mass %, based on the mass of the entire composition.

The herbal medicines used in the present invention, such as licorice, peony, and valerian, have been used for medicinal purposes since ancient times, either as a single ingredient or as a traditional Chinese medicine, and the herbal powder or extract obtained according to the conventional method can be used as is. The form of the herbal powder or extract can be a normal commercially available product or a processed product thereof. For example, a dried, chopped, processed product can be further pulverized into a powder (fine powder) to be used as a dry powder. The form of the extract from the herbal medicine is not particularly limited, and any form can be used, such as a dried extract, extract powder, soft extract, liquid extract, or tincture containing ethanol or ethanol and water. Preferred herbal medicines include extract components that have a high degree of freedom in formulation, such as soft extracts and dried extract powders.

The extract component can be obtained by a conventional method, for example, by extracting the active ingredient having antibacterial activity from the herbal medicine using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, t-butanol, etc.; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or as a mixed solvent of two or more kinds.
Licorice may be used as in the past as an anti-inflammatory agent, cold medicine, antipyretic analgesic, cough suppressant, expectorant, gastrointestinal medicine, anthelmintic, internal medicine for rhinitis, throat freshener, stomach freshener, vitamin-containing health supplement, sweetener, flavoring agent, colorant, flavoring agent, perfume, or excipient.

When "licorice" is used in the present invention, it is preferable to use the one listed in the 18th revised edition of the Japanese Pharmacopoeia.
Licorice other than those mentioned above is also commercially available and can be easily obtained.
Commercially available licorice extracts include those that use water or a 30% ethanol aqueous solution as an extraction solvent, and are sold with various raw drug equivalent ratios depending on the type of extract, such as licorice extract, licorice dry extract, licorice soft extract, licorice liquid extract, etc. In addition to these licorice extracts, licorice extracts, licorice extract liquids, etc. may also be used appropriately and are not particularly limited.
When using commercially available licorice in a pharmaceutical composition, for example, licorice may be used so that the licorice content in the tablet is appropriate, taking into consideration the raw drug conversion ratio.

There is no particular restriction on the amount of licorice (licorice or licorice extract) contained in the present invention, but the amount of the component contained in the pharmaceutical composition per daily dose, calculated as the amount of raw drug, is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, and may be 500 mg to 1500 mg, and the number of doses is 1 to 3 times a day.

In the present invention, for example, when licorice dry extract is used, the content of the licorice dry extract is not particularly limited, but may 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, based on the total mass of the pharmaceutical composition.

When "Valeriana officinalis" is used in the present invention, the "Valeriana officinalis" that can be used is preferably that listed in the 18th revised Japanese Pharmacopoeia.
Other valerian plants besides those mentioned above are also available commercially and are easily available.
As commercially available valerian, for example, valerian powder or valerian extract (for example, soft extract or dry extract) can be used, and is not particularly limited.
When using commercially available valerian in a pharmaceutical composition, valerian may be used so that the valerian content in the tablet is appropriate, taking into consideration the ratio of the original herbal medicine.

When "Valeriana (Valeriana or Valeriana extract)" is used in the present invention, the content is not particularly limited, but for example, the amount of the ingredient contained in a tablet per daily dose, calculated as the amount of raw herbal medicine, may 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 may be 60 to 450 mg, and the number of doses is 1 to 3 times a day.

In the present invention, for example, when valerian extract is used, the content of valerian extract is not particularly limited, but may be 1 to 50 mass% based on the mass of the entire pharmaceutical composition, preferably 2 to 40 mass%, and more preferably 3 to 20 mass%.

When "peony" is used in the present invention, the "peony" that can be used is preferably that listed in the 18th revised Japanese Pharmacopoeia.
Other peonies than those mentioned above are also available commercially and are easily available.
As commercially available peonies, for example, peony powder or peony extract (including, for example, dried extract or soft extract) can be used, and there is no particular limitation.
When using commercially available peony root in a pharmaceutical composition, the peony root may be used so that the peony root content in the tablet is appropriate, taking into consideration the raw herb equivalent ratio.

When "peony (peony or extract thereof)" is used in the present invention, the content is not particularly limited, but it is preferable to administer 100 to 5000 mg per day, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg, calculated as the raw herb of peony, and the number of administrations is 1 to 3 times per day.

In the present invention, for example, when peony dry extract is used, the content of the peony dry extract is not particularly limited, but may be 1 to 50 mass% based on the mass of the entire pharmaceutical composition, preferably 2 to 40 mass%, and more preferably 3 to 20 mass%.

The pharmaceutical composition of the present invention can be formulated in accordance with conventional methods.
In the present invention, for example, a granule containing loxoprofen or a salt thereof and a herbal medicine selected from the group consisting of (B-1) to (B-7) is produced, and a powder component is added to the obtained granule so as to form a granule outer portion, followed by tableting to produce a tablet.

In other words, the tablet can be manufactured by, for example, a process of manufacturing a granulated granule (at least one granulated granule) containing loxoprofen or a salt thereof and a herbal medicine selected from the group consisting of (B-1) to (B-7); and a process of manufacturing a tablet by mixing the granulated granule with a desired additive (final component) and compressing the mixture into a tablet. Also, loxoprofen or a salt thereof and the herbal medicine selected from the group consisting of (B-1) to (B-7) may each be contained in a different granulated granule, and the component placed outside the granule may be optionally in the form of a granule.

The final component (outside of granulated granules) in the present invention is a portion that constitutes the outside of granulated granules in a tablet, and may be, for example, a portion that is configured to cover one granulated granule in a tablet, or may be a portion that is configured to cover multiple granulated granules. It may also be a portion that covers at least one granulated granule in a tablet and a portion that constitutes the outer surface of the tablet. The tablet may have granulated granules therein, and loxoprofen or a salt thereof and a herbal medicine selected from the group consisting of (B-1) to (B-7) may be contained in the granulated granules.

The formulation can be prepared using known methods and additives as appropriate. Additives may be added as appropriate within the range that does not impair the effects of the present invention.

Additives include pharma- ceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, flow agents, gloss agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavorings, cooling agents, flavors, fragrances, colorants, base materials, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents. Any formulation additive that can be used in conventionally known pharmaceutical compositions can be used for the above-mentioned purposes.

Examples of excipients include candy powder, gum arabic, powdered gum arabic, cacao butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate These include hydroxypropyl starch, crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical 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 pregelatinized starch, powdered sugar, powdered candy, 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.

As a binder, for example, one or more components selected from gum arabic, powdered gum arabic, cold plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, 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. can be blended.

Disintegrants include, for example, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, etc.

Disintegration aids include, for example, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

Lubricants include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hardened oils, sodium stearyl fumarate, etc.

The flow agent may be, for example, one or more components selected from hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, calcium hydrogen phosphate granules, etc.

The glossing agent may be, for example, one or more components selected from carnauba wax, white beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, etc.

The foaming agent may be, for example, one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc.

As the moisture-proofing agent, for example, one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened 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, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylamino acetate, etc. can be blended.

Surfactants include, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene One or more components selected from ethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, etc. may be blended.

Stabilizers include, for example, adipic acid, 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, carmellose calcium, carmellose. sodium sucrose, hydrous silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid esters, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, Magnesium carbonate, natural vitamin E, tocopherol, tocopherol 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 glycerin It can contain one or more ingredients selected from the group consisting of glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glycerin monostearate, medicinal 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.

Examples of emulsifiers include glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids.

Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, sodium pyrosulfite, etc.

Fillers include, for example, RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide, calcium hydrogen phosphate, etc.

Examples of preservatives include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

Sweetening agents that can be blended include, for example, one or more ingredients selected from aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, refined stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

As flavoring agents, for example, one or more ingredients selected from sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, refined stevia extract, Swertia japonica, 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, DL-sodium malate, lemon oil, rose oil, etc. can be blended.

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

Flavors that can be blended include, for example, 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.

Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

Colorants that can be used include, for example, one or more of the following: yellow iron oxide, yellow iron oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, iron oxide, diaz azo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide/glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil, etc.

The bases include: powdered acacia, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, 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 glycerin, potato starch, hydroxypropyl cellulose. It is possible to blend one or more components selected from the group consisting of cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

Coating agents include, for example, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hardened oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, refined shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, mixture of hydroxypropyl methylcellulose 2910, titanium oxide and macrogol 400, hypromellose, fumaric acid, stearic acid and polyvinyl acetal diethylamino Examples of the copolymer include acetate/hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 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 methylacrylate/methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc.

The sugar-coating agent may be one or more components selected from the group consisting of gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, and hypromellose. , povidone, 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, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc. can be blended with one or more components selected from the group consisting of glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

As an antifoaming agent, one or more components selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silicon dioxide mixture, sucrose fatty acid ester, silicon antifoaming agent, silicon oil, sorbitan fatty acid ester, polysorbate 80, etc. can be blended.

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

The pharmaceutical composition of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. The pharmaceutical composition of the present invention is preferably an anti-inflammatory composition.
The active ingredient, loxoprofen or a salt thereof, has antipyretic, analgesic and anti-inflammatory effects and is therefore suitably used as an antipyretic and analgesic drug, particularly for relieving pain from headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, fractures, sprains, and trauma, and for reducing fever during chills and fever, and can also be suitably used as a cold treatment for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

The pharmaceutical composition of the present invention can be in a dosage form described in the General Provisions for Preparations of the 18th Revised Japanese Pharmacopoeia, etc., such as a preparation for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and a preparation for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The pharmaceutical composition is preferably a solid preparation. The pharmaceutical composition is preferably an oral pharmaceutical composition.

The solid preparation is preferably a tablet, powder, fine granule, granule, capsule or pill as described in the Japanese Pharmacopoeia, 18th Edition, more preferably a granule or tablet, and most preferably a tablet. In addition, when a granule is subjected to a test for particle size of a preparation according to the Japanese Pharmacopoeia, 18th Edition, the granule that passes entirely through a No. 18 (850 μm) sieve and has 10% or less of the total amount remaining on a No. 30 (500 μm) sieve is sometimes referred to as a fine granule.

In the form of granules or tablets, the preparation may be coated with a water-soluble polymer or the like. Examples include film-coated granules and film-coated tablets. In addition, solid preparations may be sugar-coated.

When the solid preparation is a tablet, in addition to a single-layer tablet, it can also be a multi-layer tablet made by compressing and molding two or more layers of powders or granules of different compositions. When the tablet is a multi-layer tablet, loxoprofen or a salt thereof and the specified herbal medicine may be in the same layer or in different layers.

The pharmaceutical composition of the present invention may further contain other active ingredients, such as antipyretics, analgesics, cough suppressants, expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, and xanthine derivatives, as necessary, within the scope of the present invention. If there are any contraindications for the inclusion of these ingredients, they may be formulated by dividing them into granules, etc.

As an antipyretic analgesic, one or more ingredients selected from aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, planopfen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate, and tiaramide hydrochloride can be blended.

Examples of antitussives and expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, and nosca These include vincristine, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine hydrochloride.

Examples of antihistamines include azelastine hydrochloride, alimemazine 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 teoclate, dif These include phenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, diphenthenol hydrochloride, methdilazine hydrochloride, mebhydrozine napadisalicylate, promethazine methylenedisalicylate, diphenthenol phosphate, etc.

Anti-inflammatory agents include glycyrrhizinic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

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

Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, a mixture of equal parts of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine.
Examples of the xanthine derivatives other than caffeine (other xanthine derivatives) include theophylline and theobromine.

Furthermore, examples of vitamins include vitamin B1 and its derivatives and salts such as thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibuthiamine, bis-bentiamine, prosultiamine, and benfotiamine; vitamin B2 and its derivatives and salts such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate; pantothenic acid, panthenol, pantethin, One or more components selected from the group consisting of vitamin B5 and its derivatives and salts, such as calcium pantothenate and sodium pantothenate; vitamin B6 and its derivatives and salts, such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 and its derivatives and salts, such as cyanocobalamin and mecobalamin; vitamin C and its derivatives and salts, such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and salts.

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

The pharmaceutical composition of the present invention may be temporarily packaged in an SP package, a PTP package, a stick package, a bottle package, etc., and then stored airtight. Furthermore, these may be packaged in a pillowcase, and these may be stored in a box or the like.
In other words, a pharmaceutical product according to one embodiment of the present invention may include a pharmaceutical composition and a packaging material for packaging the pharmaceutical composition.
Materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples of materials that can be used include single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, multi-layer films combining these resin films, and these resin films with aluminum foil attached.

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 material formed from at least one of a moisture-proof material and a gas barrier material), for example.
For example, as a packaging material (moisture-proof material) that is less susceptible to the effects of moisture, PTP (polypropylene) + polyethylene aluminum pillow packaging (combined packaging of PTP and polyethylene aluminum pillow) may be used. In addition, in consideration of the suppression of an increase in the moisture content of the pharmaceutical composition, the storage stability of the pharmaceutical composition, and the stability of the pharmaceutical composition after opening, PTP packaging (Al-Al packaging) using aluminum on both sides may be used as a packaging material (moisture-proof material) that is less susceptible to the effects of moisture.
If moisture absorption is a concern, a desiccant or the like may be stored in the bottle or pillowcase packaging.
The gas barrier material may be any known material and is not particularly limited. For example, it may be a laminate film having a functional barrier layer, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material.
Furthermore, the packaging material for the pharmaceutical composition of the present invention may be, as necessary, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics for all or part of the packaging material, and environmentally friendly containers and packaging may be used, and is not particularly limited.

Second Embodiment
In a second embodiment of the present invention, the pharmaceutical composition may be in the form of a liquid.
In this embodiment, when the dosage form is a liquid, it may be used as an oral liquid pharmaceutical composition, for example, as an oral liquid, an oral liquid, an oral spray (atomized agent), or a mouthwash.

In this embodiment, the content of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof may be 0.016 to 3.0 W/V % based on the total amount of the liquid pharmaceutical composition, and is preferably 0.05 to 1.5 W/V % based on the total amount of the oral liquid pharmaceutical composition.

In this embodiment, in addition to at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, the composition may contain the following substances.
In this embodiment, sodium azulene sulfonate may be included.
Sodium azulene sulfonate is known as an agent for preventing and treating inflammatory diseases in the fields of the digestive system, oral cavity and throat, otolaryngology, ophthalmology, and the like.
Sodium azulene sulfonate is a known substance and is readily available on the market.
When sodium azulene sulfonate is used, the amount to be blended may be 0.02 w/v% to 0.5 w/v% relative to the total volume of the liquid, preferably 0.02 w/v% to 0.4 w/v%, and particularly preferably 0.02 w/v% to 0.1 w/v%.
The unit of blend amount "w/v %" refers to mass to volume percentage (content (g) of component in liquid preparation (100 mL)) (the same applies to other components below).

In this embodiment, a sugar alcohol may be contained.
Examples of sugar alcohols include maltitol, erythritol, xylitol, and sorbitol.
When a sugar alcohol is used, the content of the sugar alcohol may be 20 w/v% to 40 w/v% relative to the total volume of the liquid, preferably 25 w/v% to 40 w/v%, and particularly preferably 25 w/v% to 35 w/v%.

In this embodiment, a quaternary ammonium salt may be contained.
Examples of the quaternary ammonium salt include cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, etc. One type selected from these may be used alone, or two or more types may be used in combination.
The content of the quaternary ammonium salt 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 %, based on the total volume of the liquid.

The liquid formulation according to this embodiment may contain alcohols, such as monohydric alcohols and polyhydric alcohols.
Examples of the monohydric alcohol include methanol, ethanol, propanol, isopropanol, butanol, etc., and one selected from these may be used alone or two or more may be used in combination. Ethanol is particularly preferred.
The polyhydric alcohol is preferably one or more selected from the group consisting of glycerin, ethylene glycol, propylene glycol and butylene glycol, with glycerin being preferred.
The alcohol content is not particularly limited, but may be less than 40 w/v % based on the total volume of the liquid preparation.

In this embodiment, a pH adjuster may be contained.
Examples of pH adjusters include citric acid, sodium citrate, lactic acid, sodium lactate, and sodium hydroxide.
The pH of the aqueous preparation of the present invention may be adjusted to about 6 to 9, preferably about 7.0 to 8.5, and particularly preferably about 7.0 to 8.0.

In this embodiment, although not particularly limited, the water content may be 15-80%, and is preferably 15-75%.

In this embodiment, flavoring agents, buffers, preservatives, stabilizers, and the like that are typically added to pharmaceutical preparations can be added, as long as they do not go against the purpose of the present invention.

The flavoring agent has the effect of mitigating the taste specific to the medicinal ingredient. For example, erythritol and L-menthol act as flavoring agents.
Suitable examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate.
Parabens can also be used as a preservative in the aqueous preparation used in the present invention.
Examples of the stabilizer include surfactants (e.g., polyoxyethylene hydrogenated castor oil, polysorbate, lauromacrogol, macrogol, sodium lauryl sulfate, etc.), sodium edetate, cyclodextrin, sulfites, citric acid or a salt thereof, etc.

The oral liquid pharmaceutical composition of the present embodiment can be prepared by known preparation methods, for example, the methods described in the 18th Edition of the Japanese Pharmacopoeia and General Rules for Preparations for Liquids.
For example, the oral liquid pharmaceutical composition according to this embodiment can be prepared by homogeneous physical mixing with other additives.

The oral liquid pharmaceutical composition of this embodiment can be easily produced by dissolving the above-mentioned components in, for example, distilled water or sterilized purified water.
For example, when used as an oral preparation, it may be used for inflammatory diseases of the oral cavity, specifically, for example, throat pain, sore throat, swollen throat, throat discomfort, hoarseness, stomatitis, and the like, caused by throat inflammation.
The dosage, for example, when the oral liquid pharmaceutical composition of this embodiment is used for adults, may be such that the oral liquid pharmaceutical composition is filled into a spray-type container and an appropriate amount is sprayed onto the affected area several times a day as a throat spray.
The number of administrations may be increased or decreased as appropriate depending on the severity of the symptoms.

Specific dosage forms of the oral liquid pharmaceutical composition in this embodiment include, for example, oral liquids, oral liquids, mouthwashes, and oral sprays (for example, gas-filled aerosol types and pump types may be used), and each dosage form can be produced using appropriate additives and bases according to standard methods described in the 18th Edition of the Japanese Pharmacopoeia, etc.

The formulation can be contained and sealed, for example, in a glass container or package, or a container or package made of a metal such as aluminum, or a container or package made of an olefin resin such as polyethylene or polypropylene, and may further be contained in a moisture-proof bag containing a metal such as aluminum.
In addition, the containers and packaging may be made of environmentally friendly raw materials such as recycled plastics and biomass raw materials, and, if necessary, any material may be used that prevents deterioration of the topical skin preparation due to external factors, elements, or environmental changes of the pharmaceutical container or packaging, such as laminated materials, gas barrier materials, or heat or light in a high-temperature environment, and that properly maintains the quality of the topical skin preparation.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

<Test materials>
(1) Materials The following materials were used in the experiment.
Loxoprofen sodium hydrate (LOX)
10% by weight acetic acid aqueous solution (hereinafter sometimes referred to as AA)
Three-way saline anesthesia (medetomidine, midazolam, butorphanol)

<Test Method>
<Experiment 1. Creation of a pharyngitis model rat>
FIG. 1 shows an endoscopic photograph of the pharynx of a pharyngitis model rat.
When taking endoscopic photographs of the pharyngitis model rat pharynx in FIG. 1, the rat was placed on a fixed stand, rubber bands were placed around the upper and lower anterior teeth to open the mouth, and the position was adjusted so that the epiglottis could be seen with the endoscope.
As shown in FIG. 1, male Wister rats weighing 300 g to 450 g were used, and under triple anesthesia (50 mg/kg, intraperitoneal administration), 10 μl of a 10% by mass aqueous solution of acetic acid diluted with distilled water was applied to the posterior pharyngeal wall of the rat using a microapplicator (AA treatment in FIG. 1) to induce pharyngitis.

<Experiment 2. Water swallowing reflex measurement>
Using the pharyngitis model rats obtained in Experiment 1, the water swallowing reflex latency, the number of swallowing reflexes, and the swallowing reflex time interval were measured as an evaluation of pharyngitis, as shown in Figure 2. The water swallowing reflex was measured by using an endoscope under triple anesthesia (50 mg/kg, intraperitoneal administration) and administering water for 10 seconds at a flow rate of 3 μl/s using a syringe pump from a cannula inserted into the pharynx of the rat, and the time until the first reflex occurred (swallowing reflex latency), the number of swallowing reflexes in 10 seconds from the first reflex, and the time interval of each swallowing reflex were measured.
Swallowing was measured as whiteout on the endoscopic image.
As shown in FIG. 2, the following groups were prepared: Group [1] Sham + Veh group (pharyngeal application: distilled water, intraperitoneal administration: saline (Veh)); Group [2] AA10% + Veh group (pharyngeal application: 10% by mass aqueous acetic acid (AA10%), intraperitoneal administration: saline (Veh)); Group [3] AA10% + Lox group (pharyngeal application: 10% by mass aqueous acetic acid (AA10%), intraperitoneal administration: loxoprofen 4 m/kg). The water swallowing reflex in each group was measured 1 hour after intraperitoneal administration.

<Experiment 3. Tissue analysis>
Furthermore, the rats were perfused and fixed with 4% paraformaldehyde (PFA), and pharyngeal tissue was collected and embedded in paraffin, followed by hematoxylin-eosin staining (HE staining) (see FIG. 3).
As shown in FIG. 3, the thickness of the lamina propria was measured to determine the degree of edema due to inflammation.
One day after acetic acid treatment, when the water swallowing reflex was most depressed, 4 mg/kg of loxoprofen was intraperitoneally administered, and the water swallowing reflex was measured one hour later (see Figures 2 and 3).
The control group was administered physiological saline (see FIG. 2).

<Experimental Results: Experiments 1 to 3>
As a result of Experiment 2, as shown in FIG. 4, the pharyngitis model rats (group administered with 10% by mass acetic acid aqueous solution, group AA) had a decreased water swallowing reflex function, such as a longer interval between swallowing reflexes and a reduced number of swallowing reflexes.
On the other hand, as shown in Figure 5, in the loxoprofen administration group in Experiment 2, the swallowing reflex frequency increased significantly and the swallowing reflex time interval was shortened one hour after administration compared to the control group. From the results in Figure 5, it was found that loxoprofen tended to restore the reduced water swallowing reflex function caused by pharyngitis.
As shown in Figure 6, HE staining in Experiment 3 revealed infiltration of inflammatory cells in both the loxoprofen-administered group and the control group, but swelling of the submucosa (lamina propria mucosa) was significantly suppressed in the loxoprofen-administered group.

<Consideration of the results of Experiments 1 to 3>
Acetic acid treatment damaged the mucosal epithelium of the pharyngitis patient, and inflammation was also observed, leading to swelling of the lamina propria. This damage to the mucosal epithelium of the pharyngitis patient and swelling of the lamina propria are thought to have led to a decrease in the water swallowing reflex (Figure 4).
In the loxoprofen-administered group, a recovery in swallowing frequency and swallowing interval, and a tendency for swelling of the lamina propria mucosa to be suppressed were observed (FIGS. 5 and 6).
Six days after the acetic acid treatment, the latency of the water swallowing reflex, recovery of the swallowing frequency, regeneration of the mucosal epithelium, and inhibition of swelling of the mucosal lamina propria were confirmed over time (FIG. 6).
The results of this experiment suggest that the recovery of the water swallowing reflex is influenced by (1) recovery of the mucosal epithelium and (2) inhibition of swelling of the lamina propria of the mucosa.
In addition, the results of this experiment suggest that rofecoxib contributes specifically to the inhibition of swelling of the lamina propria mucosal membrane in restoring the water swallowing reflex [2].
These results suggest that loxoprofen may restore water swallowing reflex function by suppressing pharyngeal swelling.

The above describes preferred embodiments and examples of the present invention, but the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

The pharmaceutical composition of the present invention is suitable for use as an antipyretic analgesic, particularly for relieving pain from headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruises, bone fractures, sprains, and trauma, and for reducing fever during chills and fever. It is also suitable for use as a cold remedy for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

Claims (12)

A pharmaceutical composition containing at least one selected from the group consisting of loxoprofen, its salts and their hydrates, and having an effect of suppressing pharyngitis. The pharmaceutical composition according to claim 1, which has the effect of restoring water swallowing reflex function. The pharmaceutical composition according to claim 1, which has the effect of suppressing swelling of the lamina propria of the mucosa. The pharmaceutical composition according to claim 1, which has the effect of regenerating mucosal epithelium. The pharmaceutical composition according to claim 1, wherein the content of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof in the pharmaceutical composition is 5 to 30% by mass. The pharmaceutical composition according to any one of claims 1 to 5, wherein the daily dose of at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof is 10 to 180 mg as anhydrous amount. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dosage form is a solid preparation or a liquid preparation. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dosage form is an oral liquid, an oral liquid, an oral spray, or a mouthwash. The pharmaceutical composition according to any one of claims 1 to 5, which is an oral pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 5 further comprises at least one selected from the group consisting of antacids, caffeines, sedatives, herbal medicines, antitussives/expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, and vitamins. The pharmaceutical composition according to any one of claims 1 to 5, which is used as an antipyretic analgesic or cold remedy. The dosage form is a solid formulation,
The pharmaceutical composition according to claim 7, wherein the solid formulation is in the form of a tablet, fine granules, granules or capsule.