JP2024042681A - Pharmaceutical composition containing loxoprofen or its salt and crude drug - Google Patents

Abstract

[Problem] To provide a pharmaceutical composition which reduces the net amount of loxoprofen while improving the anti-inflammatory effect compared to administration of loxoprofen alone. [Solution] A pharmaceutical composition comprising (A) at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof, and (B) one or more herbal medicines selected from the group consisting of the following (B-1) to (B-7): (B-1) Cinnamon bark (B-2) Poria cocos (B-3) Ginseng (B-4) Cnidium officinalis (B-5) Magnolia arborescens (B-6) Euonymus chinensis (B-7) Kouka [Selected figure] None

Description

The present invention relates to a pharmaceutical composition containing at least one selected from the group consisting of loxoprofen, its salts, and their hydrates, and a herbal medicine. More specifically, the present invention relates to a pharmaceutical composition containing a herbal medicine, which improves the anti-inflammatory effect compared to a pharmaceutical composition containing at least one selected from the group consisting of loxoprofen, its salts, and their hydrates alone.

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

Compositions containing loxoprofen or a salt thereof and a crude drug include an analgesic and anti-inflammatory composition containing loxoprofen or a salt thereof, peonies and licorice (Patent Document 1), and a composition containing loxoprofen or a salt thereof and Bowie. Oral pharmaceutical compositions (Patent Document 2) are known. It is known that the above-mentioned peony, licorice, and bowie are combined with loxoprofen with herbal medicines that themselves have anti-inflammatory effects, but the anti-inflammatory effect is not enhanced by adding herbal medicines other than those mentioned above to loxoprofen. unknown.

Japanese Patent Application Publication No. 2014-114253 JP 2021-54722 A

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

That is, the present invention aims to provide a pharmaceutical composition that reduces the net amount of loxoprofen while improving the anti-inflammatory effect compared to administration of loxoprofen alone.

Therefore, as a result of intensive studies to solve the above problems, the present inventors found that by combining loxoprofen sodium hydrate and a prescribed herbal medicine, the anti-inflammatory effect was greater than when administering loxoprofen alone. They have discovered that it is possible to further improve this and reduce the net amount of loxoprofen, and have completed the present invention.

That is, aspects of the present invention are as shown below.
<1> (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; and (B) one selected from the group consisting of (B-1) to (B-7) below. A pharmaceutical composition comprising a species or two or more crude drugs.
(B-1) Keihi (B-2) Bukuriyo (B-3) Carrot (B-4) Cucumber (B-5) Koubushi (B-6) Goshuyu (B-7) Kouka <2> With anti-inflammatory composition The pharmaceutical composition according to <1>.
<3> The pharmaceutical composition according to <1> or <2>, wherein the content of the crude drug in the pharmaceutical composition is 1 to 60% by mass in terms of the crude drug.
<4> The content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in the pharmaceutical composition is 5 to 30% by mass, according to <1> or <2>. Pharmaceutical composition.
<5> Mass ratio of the content of crude drug to the content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (crude drug/loxoprofen, salts thereof, and hydrates thereof The pharmaceutical composition according to <1> or <2>, wherein the selected at least one type) is 0.1 to 5.
<6> Mass ratio of the daily dose of crude drug to the daily dose of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (crude drug (converted amount of crude drug)/loxoprofen, salt thereof and hydrates thereof) is 0.01 to 1000, the pharmaceutical composition according to <1> or <2>.
<7> The pharmaceutical composition according to <1> or <2>, wherein the crude drug is 10 mg to 10 g in terms of the crude drug equivalent amount in a daily dose.
<8> The method according to <1> or <2>, wherein the daily dose of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof is 10 to 180 mg as anhydrous amount. Pharmaceutical composition.
<9> The pharmaceutical composition according to <1> or <2>, wherein the dosage form is a solid preparation.
<10> The pharmaceutical composition according to <1> or <2>, which is an oral pharmaceutical composition.
<11> The pharmaceutical composition according to <1> or <2>, which is used as an antipyretic analgesic or a cold medicine.
<12> The pharmaceutical composition according to <9>, wherein the solid preparation is in the form of a tablet, fine granule, granule, or capsule.
<13> At least one anti-inflammatory effect selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, containing a crude drug selected from the group consisting of the following (B-1) to (B-7): enhancer.
(B-1) Keihi (B-2) Bukuryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka

The pharmaceutical composition of the present invention can exhibit excellent anti-inflammatory effects. It is an unexpected effect that the combined use of loxoprofen sodium hydrate and a prescribed herbal medicine can further improve the anti-inflammatory effect than when administering loxoprofen alone.

FIG. 1 shows the measurement results of the total edema rate.

The pharmaceutical composition of the present invention consists of (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof; and (B) the following (B-1) to (B-7): and one or more crude drugs selected from the group.
(B-1) Keihi (B-2) Bukryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka

The pharmaceutical composition of the present invention contains at least one member selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof.
In the present invention, "at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof" is also referred to as "loxoprofen or a salt thereof", and includes loxoprofen or a salt thereof (including a hydrated salt). (The salt is preferably a pharmacologically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.
At least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof used in the present invention is listed as loxoprofen sodium hydrate in the 18th edition of the Japanese Pharmacopoeia.

The content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof contained in the pharmaceutical composition of the present invention is not limited, but one dosage unit for adults (one dose) The amount of the component contained in each pharmaceutical composition is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg in terms of anhydride, and the number of administrations is 1 to 3 times a day. be.
In the daily dosage, at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof is preferably in an anhydrous amount of 10 to 180 mg, may be 30 to 120 mg, and may be 30 to 90 mg. It may be.

When the pharmaceutical composition of the present invention is a tablet, the content of at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof contained in the granules in the tablet is particularly Although not limited, the amount of ingredients contained in a tablet per adult dosage unit (one dose) is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg in terms of anhydride. The dose may be 45 to 90 mg, and in this case as well, the number of doses is 1 to 3 times a day.

At least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof contained in the pharmaceutical composition is not particularly limited, but is 1 to 80% by mass based on the mass of the entire pharmaceutical composition. , preferably 2 to 50% by weight, more preferably 5 to 30% by weight, and may be 5 to 20% by weight.

The pharmaceutical composition of the present invention contains one or more crude drugs selected from the group consisting of (B-1) to (B-7) below.
(B-1) Keihi (B-2) Bukryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka

Among the herbal medicines mentioned above, (B-1) Keihi or (B-6) Goshuyu are preferred, and (B-6) Goshuyu is particularly preferred.
The crude drug may be used as crude drug powder or as an extract (extract, tincture, dry extract, soft extract, etc.).

The content of the above-mentioned herbal medicines in the pharmaceutical composition of the present invention is not particularly limited, but may be, for example, 1 to 80% by mass, 1 to 70% by mass, 1 to 60% by mass, or 1 to 50% by mass of each herbal medicine, calculated as the ratio of the original herbal medicine based on the mass of the entire pharmaceutical composition.

Regarding the above-mentioned herbal medicine in the pharmaceutical composition of the present invention, the amount contained in the pharmaceutical composition per daily dose is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably is 500 mg to 3000 mg, and may be 500 mg to 1500 mg. The frequency of administration is 1 to 3 times a day.

The mass ratio of the content of the crude drug to the content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in the pharmaceutical composition of the present invention (crude drug (in terms of crude drug)/loxoprofen, salts thereof, and hydrates thereof) (at least one selected from the group consisting of hydrates thereof) is preferably 0.1 to 10, more preferably 0.15 to 9, and even more preferably 0.18 to 8.
The mass ratio of the daily dose of crude drug to the daily dose of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in the pharmaceutical composition of the present invention (crude drug (original crude drug equivalent amount)/ (at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof) is 0.01 to 1000, may be 0.02 to 60, and preferably 0.05 to 8.

The above-mentioned herbal medicines used in the present invention have been used medicinally since ancient times as single herbs or herbal medicines, and the herbal medicine powders or extracted components obtained according to commonly used methods can be used as they are. As for the form of crude drug powder or extracted components, ordinary commercially available products or processed products thereof can be used. As the crude drug powder, for example, a dry powder obtained by finely pulverizing a dried chopped product (fine powder) may be used. Further, the form of extract components from crude drugs is not particularly limited, and any form such as a dry extract, extract powder, soft extract, liquid extract, ethanol or a tincture containing ethanol and water can be used. Preferred herbal medicines include extract components that have a high degree of freedom in formulation, such as soft extracts and dried extract powders.

The extracted component can be obtained by a conventional method, for example, by extracting the active component 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, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; Examples include 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.

<(B-1) Keihi>
In the case of using "keihi" in the present invention, it is preferable to use cinnamon bark, cinnamon powder, and cinnamon bark oil listed in the 18th edition of the Japanese Pharmacopoeia.
In addition, various types of cinnamon in addition to the above and those mentioned above are commercially available and can be easily obtained.
Commercially available Keihi nuts include, for example, Keihi powder, extracts using water or 30% ethanol aqueous solution as extraction solvents (Keichin extract/extract liquid), and extract powders. , products with various crude drug conversion ratios are on sale. These extracts of cinnamon bark and the like may be used as appropriate and are not particularly limited.
When commercially available cinnamon bark is used in a solid preparation, cinnamon may be used in such a way that the content of cinnamon in the solid preparation is appropriate, for example, taking into account the conversion ratio of the original herbal medicine.

<(B-2) Bukryō>
When using "Bukuryo" in the present invention, it is preferable to use "Bukuryo" and "Bukuryo powder" listed in the 18th edition of the Japanese Pharmacopoeia.
In addition, various types of bukuryo, such as those mentioned above and other than those mentioned above, are commercially available and can be easily obtained.
Examples of commercially available blackberry powder include blackberry powder and a soft extract using water as an extraction solvent. Bukryo is not particularly limited, and may be used with various crude drug conversion ratios depending on the type of extract.
When using a commercially available Bucryophyllinum in a solid preparation, it is sufficient to use Bucryophyllum in such a manner that the Bucryophyllum content in the solid preparation is appropriate, for example, taking into account the conversion ratio of the original herbal drug.

<(B-3) Carrot>
When using "carrot" in the present invention, carrots and carrot powder listed in the 18th edition of the Japanese Pharmacopoeia can be preferably used.
In addition, various carrots other than those mentioned above are commercially available and can be easily obtained.
Commercially available carrots include, for example, carrot powder and carrot extract using an aqueous ethanol solution as an extraction solvent. Carrots having various crude drug conversion ratios may be used as appropriate depending on the type of extract, and are not particularly limited.
When using commercially available carrots in a solid preparation, carrots may be used so that the carrot content in the solid preparation is appropriate, for example, taking into account the conversion ratio of the original herbal medicine.

<(B-4) Cinnamon>
When "Cnidium officinalis" is used in the present invention, it is preferable to use Cnidium officinalis and Cnidium officinalis powder listed in the 18th Revised Japanese Pharmacopoeia.
In addition, various types of cnidium, including those mentioned above, are commercially available and easily available.
Commercially available Cnidium officinalis products include, for example, Cnidium officinalis powder and Cnidium officinalis extracts (dried extracts, liquid extracts) using water or an aqueous ethanol solution as an extraction solvent. Cnidium officinalis extracts with various ratios of raw herbal medicine may be used appropriately depending on the type of extract, and are not particularly limited.
When using commercially available Cnidium officinalis in a solid preparation, Cnidium officinalis can be used so that the Cnidium officinalis content in the solid preparation is appropriate, taking into account, for example, the ratio of the original herbal drug.

<(B-5) Koubushi>
When using "Kobusi" in the present invention, it is preferable to use "Kobusi" and "Kobusi powder" listed in the 18th edition of the Japanese Pharmacopoeia.
In addition, various types of Koubushi mentioned above and other than those mentioned above are commercially available and can be easily obtained.
Examples of commercially available Kobusi include Kobusi powder. Kobushi is not particularly limited, and may be used with various crude drug conversion ratios depending on the type of extract.
When using Aspergillus elegans in a solid preparation, for example, the amount of Aspergillus elegans in the solid preparation may be appropriate, taking into account the conversion ratio of the original drug.

<(B-6) Goshuyu>
When "goshuyu" is used in the present invention, goshuyu listed in the 18th edition of the Japanese Pharmacopoeia can be preferably used.
In addition, various goshuyus mentioned above and other than those mentioned above are commercially available and can be easily obtained.
Examples of commercially available goshuyu include goshuyu powder and goshuyu extract (goshuyu extract) using an aqueous ethanol solution as an extraction solvent. Goshuyu may be appropriately used with various crude drug conversion ratios depending on the type of extract, and is not particularly limited.
When commercially available goshuyu is used in a solid preparation, for example, goshuyu may be used in such a way that the goshuyu content in the solid preparation is appropriate, taking into account the conversion ratio of the original herbal drug.

<(B-7) Kouka>
When using "kōka" in the present invention, it is preferable to use kōka listed in the 18th edition of the Japanese Pharmacopoeia.
In addition, the above-mentioned and various other Kouka other than those mentioned above are commercially available and can be easily obtained.
Commercially available Kouka includes, for example, Kouka powder.
Kouka is not particularly limited, and may have various crude drug conversion ratios depending on the type of extract.
When Koka is used in a solid preparation, Koka may be used in such a manner that the Koka content in the solid preparation is appropriate, for example, taking into consideration the crude drug conversion ratio.

The herbal medicine selected from the group consisting of (B-1) to (B-7) below is capable of enhancing the anti-inflammatory effect of at least one selected from the group consisting of loxoprofen, its salts and hydrates thereof. can. Therefore, according to the present invention, at least one selected from the group consisting of loxoprofen, salts thereof and hydrates thereof, containing a crude drug selected from the group consisting of (B-1) to (B-7) below. A type of anti-inflammatory enhancer is provided.
(B-1) Keihi (B-2) Bukryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka

<Antacid>
In this embodiment, the pharmaceutical composition may preferably further contain an antacid from the viewpoint of suppressing gastric mucosal damage.
Examples of antacids include alkaline earth metals and/or earth metal basic inorganic compounds such as magnesium oxide, magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium hydroxide, and magnesium hydroxide.・Co-precipitated product of potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide/carbonate Sodium hydrogen coprecipitation product, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, anhydrous Inorganic salts of metals selected from magnesium, aluminum, and calcium, such as calcium hydrogen phosphate, etc., and alkali metal basic inorganic compounds include, for example, dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, Examples include inorganic salts of metals selected from sodium and potassium, such as sodium hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, etc. and glycine, and one or more components selected from these can be blended. Among these, one or more selected from the group consisting of magnesium oxide, magnesium aluminate metasilicate, aluminum hydroxide gel, and glycine are preferred.

When using magnesium aluminate metasilicate in the present invention, those listed in the 18th edition of the Japanese Pharmacopoeia may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used, and it is easy to use. available at.
Commercially available magnesium aluminate metasilicate is not particularly limited, but for example, there is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.
The content ratio of magnesium aluminate metasilicate in the pharmaceutical composition of the present invention may be selected in consideration of the disintegration property of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited. Based on the weight of the entire composition, it may be 0.1 to 90% by weight, 1 to 90% by weight, preferably 5 to 80% by weight.

When using magnesium oxide in the present invention, those listed in the Japanese Pharmacopoeia, 18th edition may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used, which are easily available. It is.
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, etc. may be used.
The content ratio of magnesium oxide in the pharmaceutical composition of the present invention may be selected in consideration of the disintegration property of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited. may be 0.1 to 90% by weight, may be 1 to 90% by weight, preferably 5 to 80% by weight, based on the weight of .

When using aluminum hydroxide gel in the present invention, those listed in the Japanese Pharmacopoeia, 18th edition as dry aluminum hydroxide gel may be used, and those listed in the Encyclopedia of Pharmaceutical Additives may be used. It is readily available.
Commercially available aluminum hydroxide gels are not particularly limited, but include, for example, dry aluminum hydroxide gel (S-100 grade) manufactured by Kyowa Chemical Industry Co., Ltd., dried aluminum hydroxide gel (fine granules) manufactured by Kyowa Chemical Industry Co., Ltd. grade), dried aluminum hydroxide gel (FM grade) manufactured by Kyowa Chemical Industry Co., Ltd., etc. may also be used.
The content ratio of aluminum hydroxide gel in the pharmaceutical composition of the present invention may be selected in consideration of the disintegration property of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited. The amount may be 0.1 to 90% by weight, 1 to 90% by weight, preferably 5 to 80% by weight, based on the weight of the entire product.

When using glycine in the present invention, glycine listed in the 18th edition of the Japanese Pharmacopoeia may be used and is easily available.
Commercially available glycine is not particularly limited, but includes, for example, glycine manufactured by Organic Synthetic Pharmaceutical Industry Co., Ltd., glycine "manufacturing only" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., glycine manufactured by Ajinomoto Healthy Supply Co., Ltd., and glycine manufactured by Merck Co., Ltd. Glycine (crystals), glycine (granules) manufactured by Merck Co., Ltd., etc. may also be used. Furthermore, commercially available glycine may be used after being ground as appropriate.
The content ratio of glycine in the pharmaceutical composition of the present invention may be selected in consideration of the disintegration property of the pharmaceutical composition, the dissolution property of the drug, and the function as an antacid, and is not particularly limited. Based on the mass, it may be 0.1 to 90% by weight, 1 to 90% by weight, preferably 5 to 80% by weight.

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

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

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

The pharmaceutical composition of the present invention can be formulated according to conventional methods.
In the present invention, for example, granules containing at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof and a crude drug selected from the group consisting of (B-1) to (B-7) A tablet may be manufactured by manufacturing granules, adding a final component to the obtained granules so as to form the outside of the granules, and then tableting.

That is, the tablet is, for example, a granulated product containing at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and a crude drug selected from the group consisting of (B-1) to (B-7). It can be manufactured by a step of manufacturing granules (at least one granulated granule); and a step of manufacturing a tablet by mixing the granulated granules and a desired additive (sub-end component) and compressing the mixture. can. Furthermore, at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof and crude drugs selected from the group consisting of (B-1) to (B-7) are contained in separate granules. The components placed outside the granules may optionally be in the form of granules.

The latter component (outside of the granule) in the present invention is a part that constitutes the outside of the granule in the tablet, and may be a part configured to cover one granule in the tablet, for example. , it may be a portion configured to cover a plurality of granules. In addition, it may be a region that covers at least one granule in the tablet and a region that constitutes the outer surface of the tablet. The tablet has granules in the tablet, at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof, and selected from the group consisting of (B-1) to (B-7). The herbal medicine may be contained in the granules.

For formulation, known methods and additives can be used as appropriate. Additives may be added as appropriate within a range that does not impair the effects of the present invention.

Additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, flow agents, brightening agents, foaming agents, moisture-proofing agents, surfactants, Stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, fragrances, colorants, base materials, coating agents, sugar coating agents, plasticizers, dispersants, and Conventionally known formulation additives that can be used in pharmaceutical compositions, such as antifoaming agents, can be used for the above purpose.

Examples of excipients include candy powder, gum arabic, gum arabic powder, cacao butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminate silicate, calcium silicate, Magnesium silicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, 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/hydroxypropyl starch/crystalline cellulose, wheat starch, rice flour, rice starch, heavy silicic anhydride, 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 starch syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, calcium sulfate, erythritol, glucose , fructose, etc.

Examples of binders include gum arabic, gum arabic powder, cold plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified) , methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate/methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. Ingredients can be blended.

Examples of the disintegrant include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially pregelatinized starch, and the like.

Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, and polysorbate. 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

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

Examples of the fluidizing agent include hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy silicic anhydride, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and phosphorus. One or more components selected from calcium oxyhydrogen granules and the like can be blended.

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.

As the blowing agent, one or more components selected from, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc. can be blended.

Examples of moisture-proofing agents include ethyl cellulose, olive oil, dry aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, and purified One or more components selected from shellac, refined white sugar, talc, anhydrous neutral sodium sulfate, precipitated calcium carbonate, fumaric acid/stearic acid/polyvinyl acetal diethylamino acetate/hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylamino acetate, etc. can be blended.

Examples of the surfactant include sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monolaurate. Oxyethylene sorbitol beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (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, and the like can be blended.

Examples of the stabilizer include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate ester, benzoic acid. , sodium benzoate, ethylenediamine, calcium edetate disodium, sodium edetate, edetate tetrasodium, edetate tetrasodium 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, hydrated silicon dioxide, dry sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate water sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine , L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolyzate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, 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 fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified product), macrogol 300, macro Gol 400, Macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, One type selected from DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. Alternatively, two or more types of components can be blended.

Examples of emulsifiers include glycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, Examples include polyethylene glycol fatty acid ester, hydrogenated soybean phospholipid, and the like.

Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium pyrosulfite. etc. can be mentioned.

As the filler, for example, RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide, calcium monohydrogen phosphate, and the like.

Examples of the preservative include benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, phenoxyethanol, and the like.

Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose starch syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, and sucralose. , stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. One or more components can be blended.

The flavoring agent may be one or more selected from the following: 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, sodium saccharin 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, fructooligosaccharide, 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.

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

Examples of flavoring agents include 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. One or more selected components can be blended.

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.

Examples of colorants include yellow iron oxide, yellow iron sesquioxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, iron sesquioxide, dizuazo yellow, and edible iron oxide. 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, Iron Sesquioxide/Glycerin Suspension One or more ingredients selected from liquid, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc. Can be blended.

As a base, gum arabic powder, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose starch syrup, hydrated silicon dioxide, dry aluminum hydroxide gel, agar, agar powder, Xanthan gum, glycine, glycerin, glycerin fatty acid ester, light silicic anhydride, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, stearic acid Magnesium, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid/glycolic acid copolymer, concentrated glycerin, potato starch, hydroxypropylcellulose, 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, macro Gol 6000, Macrogol 6000NF, Macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol. One or more components selected from acrylic acid/methyl methacrylate copolymers and the like can be blended.

Examples of coating agents include ethyl acrylate/methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, Gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, carbonic acid Calcium, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose 2910, titanium oxide, macrogol 400 mixture, hypromellose, fumaric acid, stearic acid, Polyvinyl acetal diethylaminoacetate/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, methyl cellulose, 2-Methyl-5-vinylpyridine methyl acrylate/methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can be mentioned.

Examples of sugar coating agents include gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, refined white sugar, gelatin, shellac, talc, precipitated carbonic acid. Calcium, white shellac, white sugar, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, phosphorus One or more components selected from calcium acid dihydrogen hydrate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can be blended.

Examples of the plasticizer include triethyl citrate, glycerin, glycerin fatty acid ester, D-sorbitol, medium chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105 ) Polyoxypropylene (5) selected from glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc. One or more types of components can be blended.

As a dispersant, aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, silicon Magnesium acid, light aluminum oxide, light silicic anhydride, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose Hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxy Ethylene 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, monooleic acid One or more components selected from sorbitan, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc. can be blended.

The antifoaming agent is selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc. One or more types of components can be blended.

These additives are not limited to those listed above, and one type of these additives may be used, or two or more types 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 invention is preferably an anti-inflammatory composition.
At least one active ingredient selected from the group consisting of loxoprofen, its salts, and their hydrates has antipyretic, analgesic, and antiinflammatory effects, and is therefore used as an antipyretic and analgesic, particularly for headaches, menstrual pain ( Menstrual pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, fracture pain, sprain pain, trauma pain, etc. Relief, fever relief for chills and fever It is also used as a cold treatment agent to relieve various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain). It can be suitably used for this purpose.

The pharmaceutical composition of the present invention can be used, for example, in formulations for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), formulations for oral administration (buccal tablets, troches, etc.). The dosage forms listed in the 18th revised Japanese Pharmacopoeia, General Rules for Preparations, etc., such as tablets, sublingual tablets, buccal tablets, adhesive tablets, gums, etc., can be used. The pharmaceutical composition is preferably a solid formulation. The pharmaceutical composition is preferably an oral pharmaceutical composition.

The solid preparation is preferably a tablet, powder, fine granule, granule, capsule, or pill, more preferably a granule or tablet, and most preferably a tablet, as described in the Japanese Pharmacopoeia, 18th edition. is a pill. In addition, when testing the particle size of granules according to the 18th edition of the Japanese Pharmacopoeia, the amount that passes through a No. 18 (850 μm) sieve and remains on a No. 30 (500 μm) sieve is 10% of the total amount. The following may be referred to as fine granules.

In the form of granules or tablets, the preparation may be coated with a water-soluble polymer or the like. That is, examples include film-coated granules, film-coated tablets, and the like. Moreover, solid preparations may be coated with sugar coating.

When the solid preparation is a tablet, in addition to a single-layer tablet, it can also be a multi-layer tablet obtained by stacking two or three or more layers of powders or granules with different compositions and compression-molding them. In addition, when the tablet is made into a multilayer tablet, at least one selected from the group consisting of loxoprofen, its salts, and their hydrates and the prescribed crude drug may be in the same layer or in different layers. It's okay.

The pharmaceutical composition of the present invention may further contain other active ingredients as necessary, such as antipyretic analgesics, antitussives and expectorants, antihistamines, antiinflammatory agents, anticholinergics, other vitamins, and xanthine derivatives. They may be blended as appropriate within a range that does not impair the present invention, and if there is any contraindication to their blending, they may be divided into granules as appropriate to form a formulation.

Antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesil, acemethacin, etodolac, naproxen, meloxicam, One or more components selected from celecoxib, sodium salicylate, tialamide hydrochloride, etc. can be blended.

Antitussive and expectorant agents include, for example, codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibnate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextrose. Lomethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, allocramide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, noscapine, noscapine hydrochloride, trimethoquinol Hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L- Examples include 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, and carbinoxamine maleate. salt, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theocurate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, Triprolidine hydrochloride, tripelenamine hydrochloride, tonzilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, difethenol hydrochloride, methdilazine hydrochloride, mebhydrozine napadisylate, promethazine methylene Examples include disalicylic acid and difetenol phosphate.

Examples of anti-inflammatory agents include glycyrrhizic acid, derivatives thereof, salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, and the like.

Anticholinergic 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, and iodine. Examples thereof include diphenylpiperidinomethyldioxolane, funnel root extract, funnel root total alkaloid citrate, and the like.

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, mixture of equal amounts of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, glucnolactone , glucuronic acid amide, sodium chondroitin sulfate, ginseng, yokuinin, and ioic acid.
Examples of xanthine derivatives (other xanthine derivatives) other than the above-mentioned caffeine include theophylline and theobromine.

In addition, examples of vitamins include thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, cetothiamine hydrochloride, fursulthiamine, fursulthiamine hydrochloride, octothiamine, cicotiamine, thiamine disulfide, bisbuthiamine. Vitamin B1 and its derivatives and their salts, such as , bisbenziamine, prosultiamine, and benfotiamine; Vitamin B2 and its derivatives, and their salts, such as riboflavin, riboflavin phosphate, riboflavin butyrate, and riboflavin sodium phosphate. ; Vitamin B5 and its derivatives and their salts such as pantothenic acid, panthenol, pantethine, calcium pantothenate and sodium pantothenate; Vitamin B6 and its derivatives and their salts such as pyridoxine hydrochloride and pyridoxal phosphate; cyanocobalamin and Selected from the group consisting of vitamin B12 and its derivatives and their salts such as mecobalamin; vitamin C and its derivatives and their salts such as ascorbic acid, sodium ascorbate and calcium ascorbate; and hesperidin and its derivatives and their salts. One or more components may be blended.

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

The pharmaceutical composition of the present invention may be temporarily packaged and stored airtight using SP packaging, PTP packaging, stick packaging, bottle packaging, or the like. Furthermore, they may be wrapped in pillows or stored in a box or the like.
In other words, the pharmaceutical according to one embodiment of the present invention may include a pharmaceutical composition and a packaging material for packaging the pharmaceutical composition.
The materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples include single-layer resins such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film. A film, a multilayer film made by combining these resin films, or a film made by adhering aluminum foil to these resin films can be used.

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.

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 material>
(1) Test substances The following test substances were used.
Loxoprofen sodium hydrate (LOX) Contains 100.5% LOX (calculated as anhydrous)
Keihi end (hereinafter sometimes referred to as Keihi)
The end of Bukryo (hereinafter sometimes referred to as Bukryo)
Carrot powder (hereinafter sometimes referred to as carrot)
Senkyu end (hereinafter sometimes referred to as Senkyu)
Koubushi end (hereinafter sometimes referred to as Koubushi)
End of Goshuyu (hereinafter sometimes referred to as Goshuyu)
Kouka end (hereinafter sometimes referred to as Kouka)

Loxoprofen sodium hydrate (LOX) was obtained from Fujifilm Wako Pure Chemical Industries, Ltd.
Keihi powder, Bukuriyo powder, Carrot powder, Senkyu powder, Kobushi powder, Goshuyu powder, and Kouka powder were all obtained from Nippon Powdered Yakuhin Co., Ltd.

(2) Reagent λ-Carrageenan (hereinafter referred to as carrageenan): Tokyo Chemical Industry Co., Ltd.
Carboxymethylcellulose sodium (hereinafter abbreviated as CMC-Na): Kanto Chemical Co., Ltd.
Japanese Pharmacopoeia Physiological saline solution (Otsuka raw food note): Otsuka Pharmaceutical Factory Co., Ltd. Japanese Pharmacopoeia Water for injection (Otsuka distilled water): Otsuka Pharmaceutical Factory Co., Ltd.
Isoflurane: Mylan Pharmaceutical Co., Ltd.

(3) Animals used Slc:SD (SPF), 4-week-old male rats were obtained from Japan SLC Co., Ltd. Animals were identified by the ear punch method on the day of arrival. However, the acclimatization period for animals was from arrival until the day of grouping, and the quarantine period continued from day 0 to day 7. General conditions were observed daily.

(4) Breeding method Animals are kept at a temperature of 22±3℃ (actual value: 22.0-23.5℃), humidity of 50±20% (actual value: 43.0-55.5%), ventilation frequency 13-17 times/hour (filtered with a HEPA filter) A stainless steel movable rack (1790W x 470D x 1650H mm) was mounted on a stainless steel movable rack (1790W x 470D x 1650H mm) in a breeding room with a lighting time of 8:00 to 20:00 (12 hours of light, 12 hours of darkness). They were housed individually in one section (255W x 185D x 200H mm) of a double wire mesh cage. As feed, solid feed Lab MR Stock (Nippon Nosan Kogyo Co., Ltd.) was provided ad libitum using a stainless steel solid feed feeder, except when fasting. Drinking water was provided ad libitum using a polysulfone water dispenser (stainless steel pipe) except when water was depleted.

<Test method>
(1) Body weight measurement, footpad volume measurement, and group division After measuring the weight of 5-week-old rats after the quarantine and acclimatization period, the right hind footpad volume was measured using a rat footpad volume measuring device. Using footpad volume as an index, subjects were divided into groups based on the following group composition table using a stratified continuous randomization method.

(2) Preparation of substance to be administered (2-1) Vehicle A 0.5% CMC-Na aqueous solution was prepared as a vehicle. Weighed 5.0002 g of CMC-Na, added it little by little to water for injection that was being stirred using a stirrer and rotor, and dissolved it.Water for injection was added to give a concentration of 0.5% to make the total volume 1000 mL.

(2-2) Test substance
15 mg of anhydrous LOX was weighed out, added to the vehicle, and dissolved to make a total volume of 300 mL, which was used as the substance to be administered in Group B.
A small amount of the Group B administration substance was added to the test substance weighed as shown in the table below, and the mixture was stirred and dispersed to make a total volume of 20 mL.

(2-3) Inflammatory substance A 1% carrageenan saline solution was prepared as an inflammatory substance. After weighing 0.2003 g or 0.2004 g of carrageenan, it was added to the physiological saline solution stirred using a stirrer and a rotor, and stirring was continued overnight, and the physiological saline solution was added to bring the total volume to 20 mL.

(3) Measurement of body weight and measurement of footpad volume before administration After measuring the body weight before administration of the substance to be administered, the footpad volume of the right hind paw was measured in the same manner as at the time of grouping.

(4) Method of administration and volume of administered substance Thirty minutes before administration of the inflammatory substance, the substance was loaded into a syringe equipped with an oral probe and administered orally.

(5) Administration of inflammatory substances
0.1 mL of 1% carrageenan saline solution filled in a syringe fitted with a 26G needle was subcutaneously administered to the right hind footpad.

(6) Measurement of right hind paw volume The right hind paw volume was measured using a rat paw volume measuring device before administration of the administered substance and 3, 4, and 5 hours after administration of the inflammatory substance.

(7) Calculation of edema rate and total edema rate From the obtained footpad volume, the edema rate and total edema rate were calculated using the following formula.

<Results>
The edema rate and the total edema rate are shown in Table 3, and the total edema rate is shown in FIG.
As a result, loxoprofen sodium hydrate (0.5 mg/kg), cinnamon bark (3.5 mg/kg), blackberry (2.9 mg/kg), carrot (0.7 mg/kg), Chinese cabbage (1.7 mg/kg), and black cabbage ( The anti-inflammatory effect of loxoprofen sodium hydrate was confirmed by oral administration in combination with Goshuyu (0.8 mg/kg), Goshuyu (0.7 mg/kg), and Kouka (0.8 mg/kg). It has been shown to enhance

(Formulation example)
The ingredients listed in Tables 4-22 below can be used to obtain the pharmaceutical compositions listed in Tables 4-22.

Specifically, tablets having the compositions shown in Tables 4 to 22 below can be obtained by conventional methods.
Granulated granules may be obtained by a conventional method, and after mixing the final component with the granulated granules, the mixture may be compressed using a tablet machine to obtain tablets.
Note that a coating may be applied if desired.

Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other changes to the configuration are possible without departing from the spirit of the invention.

The pharmaceutical composition of the present invention can be used as an antipyretic analgesic, particularly for headaches, menstrual pain (menstrual pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, and bruise pain. It is suitable for pain relief for fracture pain, sprain pain, trauma pain, etc., and for relieving fever during chills and fever.It is also used as a cold medicine for various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, etc.). It is suitable for alleviating symptoms (fever, chills, headache, sneezing, joint pain, muscle pain).

Claims (13)

(A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, and (B) one or two selected from the group consisting of (B-1) to (B-7) below. A pharmaceutical composition comprising more than one type of crude drug.
(B-1) Keihi (B-2) Bukryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka The pharmaceutical composition according to claim 1, which is an anti-inflammatory composition. The pharmaceutical composition according to claim 1 or 2, wherein the content of the crude drug in the pharmaceutical composition is 1 to 60% by mass in terms of the crude drug. The pharmaceutical composition according to claim 1 or 2, wherein the content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof in the pharmaceutical composition is 5 to 30% by mass. Mass ratio of the content of crude drug to the content of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (crude drug (converted amount of crude drug)/loxoprofen, salts thereof, and hydrates thereof The pharmaceutical composition according to claim 1 or 2, wherein the at least one selected from the group consisting of: 0.1 to 10; Mass ratio of daily dose of crude drug to daily dose of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (crude drug (converted amount of crude drug)/loxoprofen, salts thereof, and hydrates thereof The pharmaceutical composition according to claim 1 or 2, wherein the amount of at least one selected from the group consisting of hydrates is 0.01 to 1000. The pharmaceutical composition according to claim 1 or 2, wherein the herbal medicine is in an amount of 10 mg to 10 g in terms of the original herbal medicine in a daily dose. The pharmaceutical composition according to claim 1 or 2, wherein the anhydrous amount of at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof is 10 to 180 mg in a daily dose. The pharmaceutical composition according to claim 1 or 2, wherein the dosage form is a solid preparation. The pharmaceutical composition according to claim 1 or 2, which is an oral pharmaceutical composition. The pharmaceutical composition according to claim 1 or 2, which is used as an antipyretic analgesic or a cold medicine. The pharmaceutical composition according to claim 9, wherein the dosage form of the solid preparation is a tablet, fine granule, granule, or capsule. At least one anti-inflammatory effect enhancer selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, containing a crude drug selected from the group consisting of the following (B-1) to (B-7): .
(B-1) Keihi (B-2) Bukuryo (B-3) Carrot (B-4) Senkyu (B-5) Kobushi (B-6) Goshuyu (B-7) Kouka