JP2024055826A - Loxoprofen or salt thereof and pharmaceutical composition containing salicylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that exhibits enhanced anti-inflammatory effects relative to the sole administration of loxoprofen.

SOLUTION: A pharmaceutical composition contains loxoprofen or a salt thereof and a salicylic acid.

SELECTED DRAWING: None

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof, and a salicylic acid. More specifically, the present invention relates to a pharmaceutical composition that contains a salicylic acid and thereby has an improved anti-inflammatory effect compared to a pharmaceutical composition containing loxoprofen or a salt thereof alone.

Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibition of prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the digestive tract as an unchanged form with weak gastric mucosa irritation after oral administration and becomes an active form in the body, and is known to have the characteristic of causing less gastric mucosa damage than the active form (see, for example, Non-Patent Document 1). In recent years, loxoprofen has been commercially available as a topical anti-inflammatory and analgesic agent in the form of a poultice, tape, gel, and liquid, and is provided clinically (see, for example, Non-Patent Document 2). It is also known that loxoprofen is converted to the trans-OH form (active form) by ketone reductase in the skin (see, for example, Patent Document 1).

"Salicylic acids" refers to one or more selected from salicylic acid and its derivatives (e.g., esters of salicylic acid (specifically, for example, methyl salicylate, ethyl salicylate, glycol salicylate, etc.)) and their salts (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). Salicylic acids are known as keratolytic, antibacterial and germicidal, and anti-inflammatory and analgesic ingredients (see, for example, Patent Document 2 and Non-Patent Document 3).

However, little is known about preparations that combine loxoprofen with salicylates.

JP 2008-074873 A Patent No. 4969050

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 JAPIC Medical Pharmaceuticals Collection 2013 Maruzen 2012 Pharmaceutical interview form (parasitic and keratotic skin disease drug, salicylic acid powder "Maruishi") January 2015 revised version (2nd edition)

That is, the present invention aims to provide a pharmaceutical composition that has an improved anti-inflammatory effect compared to administration of loxoprofen alone.

As a result of extensive research conducted by the inventors to solve the above problems, they discovered that the anti-inflammatory effect can be improved by combining loxoprofen sodium hydrate with a salicylic acid, as compared to the administration of loxoprofen alone, and thus completed the present invention.

That is, according to the present invention, the following inventions are provided.
<1> A pharmaceutical composition comprising loxoprofen or a salt thereof and a salicylic acid.
<2> The pharmaceutical composition according to <1>, which is an anti-inflammatory composition.
<3> The pharmaceutical composition according to <1> or <2>, wherein the content of the salicylic acid in the pharmaceutical composition is 0.001 to 50 mass%.
<4> The pharmaceutical composition according to <1> or <2>, wherein the content of the loxoprofen or a salt thereof in the pharmaceutical composition is 0.1 to 15 mass%.
<5> The pharmaceutical composition according to <1> or <2>, wherein the mass ratio of the content of the salicylic acids to the content of the loxoprofen or a salt thereof (salicylic acids/loxoprofen or a salt thereof) is 1.0×10 ⁻⁵ to 1,000.
<6> The pharmaceutical composition according to <1> or <2>, wherein the dosage form is a liquid for external use, an ointment, a cream, a spray, a gel, a patch, or a solid for external use.
<7> An agent for enhancing the anti-inflammatory effect of loxoprofen or a salt thereof, which contains a salicylic acid.
<8> An agent for sustaining the anti-inflammatory effect of loxoprofen or a salt thereof, which contains a salicylic acid.

The pharmaceutical composition of the present invention can exert an excellent anti-inflammatory effect. It is an unexpected effect that the combined use of loxoprofen sodium hydrate and glycol salicylate, which is a salicylic acid, can further improve the anti-inflammatory effect compared to the administration of loxoprofen alone.

FIG. 1 shows the results of the measurement of the sum of edema rates.

The pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, and a salicylic acid. The pharmaceutical composition of the present invention is useful as an anti-inflammatory composition.

Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibition of prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the digestive tract as an unchanged form with weak gastric mucosa irritation after oral administration and becomes an active form in the body, so it is known to cause less gastric mucosa damage than the active form. Loxoprofen is also known to be converted to the trans-OH form (active form) by ketone reductase in the skin, and in recent years, loxoprofen has been commercially available as a topical anti-inflammatory and analgesic agent in the form of poultices, tapes, gels, and liquids, and is provided clinically.

In the present invention, "loxoprofen or a salt thereof" includes loxoprofen or a salt thereof, as well as hydrates thereof. As a salt of loxoprofen, a pharmacologically acceptable salt is preferred, more preferably loxoprofen sodium or loxoprofen sodium hydrate (sometimes referred to as loxoprofen sodium dihydrate), and even more preferably loxoprofen sodium hydrate. In this specification, the term loxoprofen includes loxoprofen or a salt thereof, as well as hydrates thereof.

The loxoprofen used in the present invention is listed in the 18th revised edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

The salicylic acids in the present invention refer to one or more selected from salicylic acid and its derivatives (e.g., esters of salicylic acid (specifically, for example, methyl salicylate, ethyl salicylate, glycol salicylate, etc.)) and salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.).
In the present invention, as the salicylic acids, from the viewpoint of enhancing the anti-inflammatory effect, one or more types selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate are preferred, one or more types selected from the group consisting of glycol salicylate and methyl salicylate are more preferred, and glycol salicylate is particularly preferred.
These are all known compounds and can be produced by known methods, or commercially available products can be used.

The pharmaceutical composition of the present invention may further contain an alcohol.
The alcohols in the present invention refer to lower alcohols and polyhydric alcohols. The lower alcohols in the present invention refer to aliphatic alcohols having 1 to 4 carbon atoms that are used in external preparations for the purposes of solubilizing agents, bases, preservatives, solvents, dissolving aids, etc., and are, for example, one or more selected from the group consisting of methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol, etc., and are preferably ethanol. Ethanol with an ethanol content of 99.5% by volume or more is also called absolute ethanol.

The polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in external preparations for purposes such as solubilizers, bases, humectants, thickeners, solvents, and dissolution aids, and examples of such alcohols include propylene glycol, 1,3-butylene glycol, macrogol (also called polyethylene glycol), glycerin, D-sorbitol, and dipropylene glycol, which are listed in the Pharmaceutical Additives Encyclopedia 2021. The molecular weight of macrogol is not particularly limited, and may be, for example, 200 to 20,000 in number average molecular weight.
In addition, the molecular weight of the alcohols in the present invention is not particularly limited, but may be, for example, 400 or less, preferably less than 400, more preferably 300 or less, even more preferably 250 or less, particularly preferably 200 or less, and may be 100 or less.

The content of salicylic acids in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.001 to 50% by mass, more preferably 0.01 to 20% by mass, even more preferably 0.1 to 20% by mass, and particularly preferably 0.1 to 10% by mass, based on the total amount of the pharmaceutical composition. When the pharmaceutical composition is in the form of a patch (poultice or tape), the content of salicylic acids is not particularly limited, but is preferably 0.001 to 50% by mass, more preferably 0.01 to 20% by mass, and particularly preferably 0.1 to 10% by mass, based on the total amount of the paste in the patch.

When the pharmaceutical composition of the present invention contains alcohol, the ratio of the content of salicylic acids to the mass of alcohol (salicylic acids/alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 100, more preferably 1.4×10 ^-3 to 10, and even more preferably 2.0×10 ^-3 to 5.0.
When the pharmaceutical composition of the present invention contains a lower alcohol, the ratio of the content of salicylic acids to the mass of the lower alcohol (salicylic acids/lower alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 100, more preferably 1.4×10 ^-3 to 10, and even more preferably 2.0×10 ^-3 to 5.0.
When the pharmaceutical composition of the present invention contains a polyhydric alcohol, the ratio of the content of salicylic acids to the mass of the polyhydric alcohol (salicylic acids/polyhydric alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 100, more preferably 1.4×10 ^-3 to 10, and even more preferably 2.0×10 ^-3 to 5.0.

The content of loxoprofen or a salt thereof (e.g., loxoprofen sodium hydrate) in the pharmaceutical composition of the present invention is not particularly limited, but is preferably 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the pharmaceutical composition. Even when the pharmaceutical composition is in the form of a patch (poultice or tape), the content of loxoprofen or a salt thereof (e.g., loxoprofen sodium hydrate) is not particularly limited, but is preferably 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the paste in the patch.

When the pharmaceutical composition of the present invention contains alcohol, the ratio of the content of loxoprofen or a salt thereof to the mass of alcohol (loxoprofen or a salt thereof/alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 150, more preferably 1.4×10 ^-3 to 100, and even more preferably 2.0×10 ^-3 to 35.
When the pharmaceutical composition of the present invention contains a lower alcohol, the ratio of the content of loxoprofen or a salt thereof to the mass of the lower alcohol (loxoprofen or a salt thereof/lower alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 150, more preferably 1.4×10 ^-3 to 100, and even more preferably 2.0×10 ^-3 to 20.
When the pharmaceutical composition of the present invention contains a polyhydric alcohol, the ratio of the content of loxoprofen or a salt thereof to the mass of the polyhydric alcohol (loxoprofen or a salt thereof/polyhydric alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 ^-3 to 150, more preferably 1.4×10 ^-3 to 100, and even more preferably 2.0×10 ^-3 to 35.

The mass ratio of salicylates to loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, but the salicylic acids/loxoprofen or a salt thereof (salicylic acids/Lox mass ratio) may be 1.0× ^10-5 to 1,000, preferably 5.0× ^10-5 to 750, more preferably 6.6× ^10-5 to 500, and particularly preferably 0.1 to 20.

The range of the alcohol content in the pharmaceutical composition of the present invention is not particularly limited, but may be selected depending on the dosage form, and may be preferably 0.1 to 70.0% by mass based on the total amount of the pharmaceutical composition. Even when the dosage form of the pharmaceutical composition is a patch (poultice, tape), the alcohol content is not particularly limited, but is preferably 0.1 to 70.0% by mass based on the total amount of the paste of the patch.
Furthermore, the range of the content of the lower alcohol in the pharmaceutical composition of the present invention is not particularly limited, and may be selected depending on the dosage form, and is preferably 0.1 to 70.0% by mass, more preferably 0.1 to 50.0% by mass, based on the total amount of the pharmaceutical composition.

For example, when the pharmaceutical composition of the present invention is a liquid or gel for external use, the range of the content of the lower alcohol added is not particularly limited, but is preferably 10.0 to 70.0 mass%, and more preferably 10.0 to 60.0 mass%, based on the total amount of the liquid or gel for external use.
For example, when the pharmaceutical composition of the present invention is a cataplasm, the range of the content of the lower alcohol added is, for example, preferably 0.1 to 50% by mass, and more preferably 0.1% to 30% by mass, based on the total amount of the cataplasm.
For example, when the pharmaceutical composition of the present invention is in the form of a tape preparation, it may or may not contain a lower alcohol. When a lower alcohol is contained, the content range is, for example, preferably 0.1 to 10% by mass, and more preferably 0.1% to 5% by mass, relative to the total amount of the paste in the tape preparation.

Furthermore, the range of the content of the polyhydric alcohol in the pharmaceutical composition of the present invention is not particularly limited, and may be selected depending on the dosage form, and is preferably 0.1 to 70 mass %, more preferably 0.1 to 20 mass %, more preferably 0.5 to 20 mass %, and even more preferably 1.0 to 15 mass %, based on the total amount of the pharmaceutical composition.
For example, when the pharmaceutical composition of the present invention is a liquid or gel for external use, the range of the content of the added amount of the polyhydric alcohol is not particularly limited, but is, for example, preferably 0.5 to 20 mass %, more preferably 1.0 to 15 mass %, based on the total amount of the liquid or gel for external use.

For example, when the pharmaceutical composition of the present invention is a cataplasm, the range of the content of the polyhydric alcohol added is not particularly limited, but is, for example, preferably 0.1 to 70% by mass, and more preferably 3 to 60% by mass, based on the total amount of the cataplasm.
For example, when the pharmaceutical composition of the present invention is in the form of a tape preparation, it may or may not contain a polyhydric alcohol. When a polyhydric alcohol is contained, the content range is, for example, preferably 0.1 to 15% by mass, and more preferably 0.1% to 10% by mass, relative to the total amount of the paste in the tape preparation.

The pH range of the pharmaceutical composition is not particularly limited, but is preferably 5.0 to 7.5, and more preferably 6.0 to 7.5.

The pharmaceutical composition of the present invention may contain drugs and pharmaceutical additives that are typically used in pharmaceutical compositions other than the above ingredients.

The pharmaceutical composition of the present invention may further contain component (A), and the component (A) may contain one or more types selected from the group consisting of the following components (A-1) to (A-11).
(A-1) Tocopherols;
(A-2) terpenes;
(A-3) Glycyrrhizic acids;
(A-4) Herbal medicines;
(A-5) Tranexamic acids;
(A-6) Vanilloids;
(A-7) nicotinic acids;
(A-8) Chlorpheniramines;
(A-9) Diphenhydramines;
(A-10) Pyrrolidones;
(A-11) inorganic salt;

(A-1) Examples of tocopherols include tocopherol, tocotrienol, and derivatives thereof (e.g., esterified derivatives such as acetate, succinate, and nicotinate) and salts thereof (e.g., alkaline earth metal salts such as calcium salt and magnesium salt). The tocopherol may be any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, with α-tocopherol being preferred. The tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, with α-tocotrienol being preferred. The tocopherol is particularly preferably tocopherol acetate.

When tocopherols are used, the content of tocopherols in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.03 to 4% by mass, and particularly preferably 0.05 to 2% by mass, based on the total mass of the pharmaceutical composition.

(A-2) Terpenes are a general term (terpenoids) that includes terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and their structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. They may be cyclic or chain. Examples of terpenes include isoborneol, irone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, sylvestrene, thymol, isothujol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

Terpenes may be used as essential oils containing terpenes. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, and terephthalic acid oil. Examples of such oils include bottle oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, henopodium oil, bergamot oil, borealis oil, hosho oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil. These may be used alone or in combination of two or more.

Preferably, terpenes that can be used include l-menthol, dl-camphor, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1,2-diol, p-menthane-3,8-diol, isopulegol, thymol, peppermint oil, and eucalyptus oil.

When terpenes are used, the content of the terpenes in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 6% by mass, and particularly preferably 0.1 to 4% by mass, based on the total mass of the pharmaceutical composition.

(A-3) Examples of glycyrrhizic acids include glycyrrhizic acid or its salts, and glycyrrhetinic acid or its salts. Examples of salts include alkali metal salts such as potassium salts and sodium salts; and ammonium salts. In addition, licorice (liquorice) or an extract thereof, which contains glycyrrhizic acids, may be used as glycyrrhizic acids.

When glycyrrhizic acids are used, the content of glycyrrhizic acids in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 3% by mass, based on the total mass of the pharmaceutical composition.

(A-4) Examples of herbal medicines include licorice, tincture of arnica, Mallotus japonicus, Acacia japonica, Coix seed, fennel, turmeric, Corydalis chinensis, Scutellaria baicalensis, Chinese holly, Phellodendron bark, Coptis chinensis, Onji, Zedoary, valerian, chamomile, calonin, bellflower, apricot kernel, wolfberry, wolfberry, cinnamon bark, Cassia japonica, gentian, geranium herb, koka ka, magnolia berry, bezoar, gomoku, saishin, shiso, Japanese pepper, ash, japonicus, Lithospermum officinalis, peony root, musk, sappanha, Examples of herbal medicines include Shazenshi, Shazensou, animal gall (including Yutan (bear gall)), Zingiber officinale, Jiryu, Xin-i, European horse chestnut, Sekisan, Senega, Cnidium rhizome, Zenko, Swertia britannica, Atractylodes rhizome, Sohakuhi, Soybean, Taisan, Chikusetsuninjin, Tianpi, Dongqi, Ipecac, Nandinafrica, Carrot, Fritillaria, Bakumondou, Pinellia gracilis, Bankouka, Hanpi, Byakushi, Byakushu, Poria columbine, Peony peel, Japanese laurel, Rokujo, and their extracts (extracts, tinctures, dried extracts, etc.). Licorice may be used as a glycyrrhizic acid compound, as a herbal medicine, or it may be used as both a glycyrrhizic acid compound and a herbal medicine.

When herbal medicines are used, the content of the herbal medicines in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 3% by mass, based on the total mass of the pharmaceutical composition.

(A-5) Tranexamic acids may include, for example, tranexamic acid or a salt thereof, or a tranexamic acid derivative or a salt thereof.
The salt of tranexamic acid is not particularly limited, and specific examples thereof include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, metal salts such as aluminum, iron and zinc, basic amino acid salts such as lysine, arginine, histidine and ornithine, organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine and stearylamine, etc. Also usable are tranexamic acid derivatives or salts thereof, and specific examples thereof include ester derivatives such as tranexamic acid cetyl ester, and amide derivatives such as tranexamic acid methylamide.

When tranexamic acids are used, the content of tranexamic acids in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the pharmaceutical composition.

(A-6) Vanilloids is a general term for compounds containing a vanillyl group. The vanilloids in the present invention are not particularly limited as long as they are compounds containing a vanillyl group, and examples thereof include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol), etc.
Furthermore, the vanilloids in the present invention may include natural products containing compounds containing a vanillyl group, and may also include derivatives of compounds having a vanillyl group and synthetic compounds in which a functional group has been added to the vanillyl group.
In addition, as the vanilloids in the present invention, capsicums containing a compound containing a vanillyl group may be used, and may be included as part of the vanilloids.
As the chili peppers, for example, chili peppers (fruits of Capsicum annuum Linne (Solanaceae)) listed in the 18th revised Japanese Pharmacopoeia can be suitably used. The form of chili peppers can be adjusted as necessary, and they can be cut or crushed into small pieces or small chunks, or crushed into powder. For example, "chili pepper powder" made by powdering chili peppers can also be used as the "chili pepper" of the present invention. In addition, chili peppers that have been subjected to some kind of extraction treatment (chili pepper extract, chili pepper tincture, etc.) may be used. In addition to the extraction treatment, the chili pepper extract may be processed by heating, drying, crushing, etc. Furthermore, capsaicinoids, which are the main components of chili peppers, may be used as the chili peppers. As the capsaicinoids, capsaicin and nonanoic acid vanillylamide are preferred. As the chili peppers, chili pepper extract, chili pepper tincture, nonanoic acid vanillylamide, or capsaicin can be preferably used.

When vanilloids are used, the content of the vanilloids in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the mass of the total amount of the pharmaceutical composition.
In addition, when capsicums are used, the content of capsicums in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10 mass%, more preferably 0.05 to 4 mass%, and particularly preferably 0.1 to 2 mass%, relative to the mass of the total amount of the pharmaceutical composition.

(A-7) Examples of nicotinic acids include nicotinic acid and its derivatives and salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically, nicotinic acid methyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid benzyl ester, inositol hexanicotinate, hepronicate, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc.). As the nicotinic acid esters, monoesters of nicotinic acid are preferred. As the nicotinic acids, nicotinic acid benzyl ester is preferred.

When nicotinic acids are used, the content of nicotinic acids in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.015 to 4% by mass, and particularly preferably 0.02 to 2% by mass, based on the total mass of the pharmaceutical composition.

(A-8) Examples of chlorpheniramines include chlorpheniramines and their salts. Specific examples of chlorpheniramine salts include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. As the chlorpheniramines, chlorpheniramine maleate is preferred.

When chlorpheniramines are used, the content of chlorpheniramines in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the pharmaceutical composition.

(A-9) Examples of diphenhydramines include diphenhydramine or its salts. Examples of diphenhydramine salts include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. As diphenhydramines, diphenhydramine or diphenhydramine hydrochloride is preferred.

When diphenhydramines are used, the content of diphenhydramines in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the pharmaceutical composition.

(A-10) Pyrrolidones include dl-pyrrolidone carboxylic acid or a salt thereof, and for example, sodium pyrrolidone carboxylate is preferred.
When pyrrolidones are used, the content of the pyrrolidones in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10 mass %, more preferably 0.1 to 10 mass %, and particularly preferably 1 to 10 mass %, based on the mass of the total amount of the pharmaceutical composition.

(A-11) Examples of inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or ammonium salts, and the like. For example, sodium chloride, potassium chloride, and ammonium chloride are preferred.

When an inorganic salt is used, the content of the inorganic salt in the pharmaceutical composition is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the pharmaceutical composition.

Preferably, the drug for component (A) may be, for example, an anti-inflammatory agent such as glycyrrhizic acid or glycyrrhetinic acid, an antihistamine such as diphenhydramine or its salt, or chlorpheniramine maleate, a blood circulation improving component such as tocopherol acetate or nicotinic acid benzyl ester, a local irritant component such as l-menthol, dl-camphor, d-camphor, nonanoic acid vanillylamide (nonylic acid vanillylamide), capsicum extract, capsicum tincture, capsaicin, peppermint oil, eucalyptus oil, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), or 3-(l-menthoxy)-2-methylpropane-1,2-diol, a herbal medicine component such as arnica tincture, a bactericidal component such as isopropylmethylphenol, a moisturizer such as dl-pyrrolidonecarboxylic acid or its salt, or an inorganic salt such as sodium chloride, and these components (A) may be blended within a range that does not impair the effects of the present invention.

Pharmaceutical additives other than the above-mentioned components are added as necessary, for example, for the purpose of further improving the stability of the content over time and the feeling of use, and examples thereof include wetting agents, moisturizing agents, thickening agents, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption promoters, stabilizers, solubilizing agents, pH regulators, antioxidants, cooling agents, surfactants, emulsifiers, etc. The pharmaceutical composition of the present invention may also contain other optional components. The pharmaceutical composition of the present invention preferably does not contain N-methylpyrrolidone (N-methyl-2-pyrrolidone).

As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (eg, sodium dl-pyrrolidone carboxylate), etc. can be used.
As the moisturizing agent, for example, polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol can be used.
Examples of thickening agents (thickening agents/gelling agents) that can be used include hypromellose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose (carmellose sodium), methyl cellulose, carrageenan, locust bean gum, and propylene glycol alginate.

Examples of adhesives include acrylic acid/octyl acrylate copolymer, acrylic ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, 2-ethylhexyl acrylate/2-ethylhexyl methacrylate/dodecyl methacrylate copolymer solution, ethyl acrylate/methyl methacrylate copolymer dispersion, methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid/n-butyl acrylate copolymer, acrylic acid silk fibroin copolymer resin, starch acrylate 300, starch acrylate 1000, butyl acrylate, butyl acrylate, 2-ethylhexyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, ethyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, isononyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, 2-ethylhexyl acrylate, 2-hydroxyethyl methacrylate, diacetone acrylamide copolymer, butyl acrylate, Acrylic adhesives such as ethyl acrylate, 3-hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate, and diacetone acrylamide copolymers, and butyl acrylate, ethyl acrylate, 3-hydroxypropyl methacrylate, and diacetone acrylamide copolymers; cis-isoprene rubber, styrene-isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene-butadiene rubber (SBR), styrene-isoprene-styrene block copolymers (SIS), styrene-butadiene-styrene block copolymers (SBS), polyisoprene, polyisobutylene (PIB), chloroprene rubber, polybutene, and natural rubber latex Synthetic rubber adhesives such as synthetic rubber cellulose and synthetic SBR latex; silicone adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane; polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide-sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, gum arabic, and the like, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium can also be used.

Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, and aliphatic hydrocarbon resin.
As the crosslinking agent, for example, dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosaltite, dihydroxyaluminum aminoacetate, etc. can be used.
Examples of the filler that can be used include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, and silica (silicon dioxide).
Examples of fats and oils that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, and gelled hydrocarbons; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, and oleyl alcohol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oils.

As softeners, for example, petroleum-based oils such as paraffin-based process oil, naphthenic process oil, and aromatic process oil; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, castor oil, tall oil, and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; glycerin, etc. can be used.

Examples of preservatives that can be used include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and aminoethylsulfonic acid.
Examples of the percutaneous absorption enhancer that can be used include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbonate, azone or derivatives thereof, and the like.
As the stabilizer, for example, oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, UV absorbers (for example, dibenzoylmethane derivatives), etc. can be used.

Examples of the solubilizing agent that can be used include benzyl alcohol; pyrrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; polybasic acids such as diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, and diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; and oxyalkylene fatty acid esters such as polyethylene glycol monostearate.
Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), phosphoric acid, and the like.
Examples of antioxidants that can be used include ascorbic acid, ascorbic acid palmitate, sodium hydrogen sulfite, dried sodium sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythryl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, and propyl gallate.
Examples of the cooling agent include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

As the surfactant, a nonionic surfactant or an ionic surfactant may be used.

Examples of nonionic surfactants include polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol mono fatty acid esters, ethylene glycol mono fatty acid esters, glycerin mono fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, alkyl polyglucosides, and polyethylene glycol fatty acid esters; polyoxyethylene ethers such as polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; polyoxyethylene mono fatty acid esters, polyethylene glycol di fatty acid esters, and polyoxyethylene glycerin fatty acid esters; Examples of the polyoxyethylene sorbitan fatty acid esters include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80; polyoxyethylene sorbitol fatty acid esters; polyoxyethylene methyl glucoside fatty acid esters; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyethylene castor oil; polyoxyethylene vegetable oils; polyoxyethylene alkyl ether fatty acid esters; and nonionic surfactants such as ether esters such as polyoxyethylene polyoxypropylene glycol; ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; and higher alcohols such as octyldodecanol. Examples of the polyoxyethylene alkyl ethers in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether.

The polyoxyethylene polyoxypropylene alkyl ether in the present invention may, for example, be polyoxyethylene polyoxypropylene cetyl ether.
Examples of the polyoxyethylene polyoxypropylene alkyl ether in the present invention include polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyethylene glycol monooleate.

The nonionic surfactants used in the present invention are listed in the Pharmaceutical Additives Encyclopedia 2021.

Examples of ionic surfactants include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, and dioctyl sodium sulfosuccinate, and cationic surfactants such as benzalkonium chloride and benzethonium chloride.

The ionic surfactant of the present invention is listed in the Pharmaceutical Additives Encyclopedia 2021 and the 18th Revised Edition of the Japanese Pharmacopoeia.
As the emulsifier in the present invention, for example, any of the above-mentioned various surfactants and higher alcohols may be used.
Other optional ingredients in the present invention include, for example, herbal medicines such as tranexamic acid and licorice.
Specifically, the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof and a salicylic acid may further contain at least one of tranexamic acid and licorice.

Specific dosage forms of the pharmaceutical composition of the present invention include, for example, liquid for external use, ointment, cream, spray (aerosol for external use, pump spray), gel, patch (tape, cataplasm), or solid for external use. Each dosage form can be produced by using appropriate additives and bases suitable for the dosage form, according to the usual method described in the 18th edition of the Japanese Pharmacopoeia, etc. As the dosage form of the pharmaceutical composition of the present invention, liquid for external use is particularly preferred. In the present invention, when preparing a patch such as a cataplasm or tape, the concentration of loxoprofen or a salt thereof (e.g., loxoprofen sodium) may vary depending on the amount of ointment, but the amount of ointment, etc. may be appropriately adjusted to obtain an appropriate concentration of loxoprofen or a salt thereof (e.g., loxoprofen sodium).

In addition, the pharmaceutical composition formulation of the present invention can be housed and sealed in, for example, a glass container/package, or a metal container/package such as aluminum, or an olefin resin container/package such as polyethylene or polypropylene. In addition, the container/package may be made of environmentally friendly raw materials such as recycled plastics or biomass raw materials, and if necessary, any material that prevents deterioration of the pharmaceutical composition due to factors, elements, or environmental changes from outside the pharmaceutical container/package, such as heat or light in a high-temperature environment, and appropriately maintains the quality of the pharmaceutical composition, may be used. In one embodiment of the present invention, the pharmaceutical may be a pharmaceutical in which a formulation/composition of a skin topical agent is housed in an appropriate container/package. The gas barrier material is not particularly limited, but examples thereof include "GL FILM" manufactured by Toppan Printing Co., Ltd.
According to the pharmaceutical composition of the present invention, the anti-inflammatory effect can be improved by blending salicylic acids with loxoprofen or a salt thereof. Also, according to the pharmaceutical composition of the present invention, the anti-inflammatory effect can be sustained by blending salicylic acids with loxoprofen or a salt thereof.

In one embodiment of the present invention, a salicylic acid may be used as an enhancer for the anti-inflammatory effect of loxoprofen or a salt thereof.
In one embodiment of the present invention, a salicylic acid may be used as an agent for sustaining the anti-inflammatory action of loxoprofen or a salt thereof.

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) Test substance: A solution prepared by mixing absolute ethanol, water, diisopropanolamine, and malic acid and adding a pH adjuster (lactic acid) to adjust the pH to about 6.5 was used as a base (A below: base "38% by weight absolute ethanol + 3% by weight diisopropanolamine + 1% by weight malic acid + water, appropriate amount of lactic acid").
In each of groups B to D, the same base was used, and the pH was adjusted to about 6.5 using lactic acid to prepare solutions with the compositions shown for each group B to D.
A: Base (38% by weight of absolute ethanol + 3% by weight of diisopropanolamine + 1% by weight of malic acid + water, appropriate amount of lactic acid)
B: Loxoprofen sodium hydrate (LOX, 0.5% by mass solution as anhydrous)
C: Loxoprofen sodium hydrate (LOX, 1.0% by mass solution as anhydrous)
D: LOX (0.5% by mass) + glycol salicylate (GS, 5.0% by mass) (a solution containing 0.5% by mass of Lox and 5.0% by mass of glycol salicylate)

(2) Reagent λ-Carrageenan (hereinafter referred to as carrageenan): Tokyo Chemical Industry Co., Ltd.
Japanese Pharmacopoeia Physiological Saline Solution (Otsuka Normal Saline Injection) Otsuka Pharmaceutical Factory, Inc. Isoflurane Mylan Pharmaceuticals Co., Ltd.

(3) Animals used
Four-week-old male rats (Iar:Wistar-Imamichi (SPF)) were obtained from the Animal Reproduction Institute (Incorporated Foundation). On the day of arrival, the animals were individually identified by ear punching. However, the acclimatization period for the animals was from arrival to the day of grouping, and the quarantine period was from the day of arrival to the 7th day, with the day of arrival being considered as day 0. General observations were conducted daily.

(4) Rearing method The animals were individually housed in a section (255W×185D×200H mm) of a stainless steel mesh double cage attached to a stainless steel movable rack (1790W×470D×1650H mm) in a rearing room with a temperature of 22±3°C (actual value: 21.2-23.6°C), humidity of 50±20% (actual value: 42.6-53.0%), ventilation rate of 13-17 times/hour (all-fresh method filtered with a HEPA filter), and lighting time of 8:00-20:00 (12 hours light, 12 hours dark). The animals were fed solid feed Lab MR Stock (Nosan Corporation) from a stainless steel solid feeder ad libitum, except when the lick-prevention hood was worn. Drinking water was provided ad libitum from a polysulfone waterer (stainless steel tip) except when the lick-prevention hood was worn.

<Test Method>
(1) Body weight measurement, footpad volume measurement, and group allocation After the quarantine and acclimation period, the body weight of 5-week-old rats was measured, and the right hind footpad volume was measured using a rat footpad volume measuring device. Using the footpad volume as an index, the rats were assigned to groups according to the following group composition table by a stratified sequential randomization method.

a) For liquid preparations, the volume (μL) equivalent to 100 mg was confirmed in advance.
b) The amount of active ingredient (LOX as anhydrous substance) is indicated.
c) A single dose was administered, and the administration site was wiped one hour after administration, at which point administration was completed.

(2) Preparation of test substance and inflammatory substance A required amount of the test substance was dispensed and used as it was for administration.
A 0.5% carrageenan solution in saline was prepared as an inflammatory substance. 0.1 g of carrageenan was weighed out using an analytical electronic balance, added to saline solution stirred with a stirrer and a rotor, and stirred overnight. Saline was added to make the total volume 20 mL. The remaining inflammatory substance was diluted with a large amount of tap water and discarded the remaining solution the day before administration.

(3) Method of administering the test substance Using a pipette, the test substance was applied to the entire right hind paw at the tarsal joint on the distal side of the ankle, evenly from the instep to the plantar side. The application site was then covered with 2.5 x 2.8 cm gauze, fixed with an elastic net bandage, and secured with surgical tape. Furthermore, a lick-prevention hood was placed over the area during application of the test substance to prevent oral ingestion of the test substance.

(4) Number of doses and duration of administration of the test substance A single dose was administered, and the administration duration was 1 hour. Immediately after the administration time had elapsed, the administration site was wiped with absorbent cotton soaked in lukewarm water, and administration was completed.

(5) Administration of inflammatory substances
0.1 mL of 0.5% carrageenan in physiological saline solution filled in a syringe equipped with a 26G needle was administered subcutaneously into the right hind footpad.

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

(7) Calculation of edema rate and sum of edema rates The edema rate and sum of edema rates were calculated from the obtained paw volume using the following formula.

<Results>
The edema rate and the sum of the edema rates are shown in Table 2, and the sum of the edema rates is shown in FIG.
As a result, the sum of the edema rates for LOX (0.5% by mass) and glycol salicylate (5.0% by mass) was similar to that for LOX (1.0% by mass), demonstrating that glycol salicylate has the effect of enhancing the anti-inflammatory effect of loxoprofen.
In addition, in terms of the edema rate (%) at each time point, LOX (0.5% by mass) + glycol salicylate (5.0% by mass) (Group D: LOX + glycol salicylate) showed a particularly superior edema inhibition rate after 5 hours compared to LOX (1.0% by mass) (Group C: high LOX). Thus, it was shown that LOX (0.5% by mass) + glycol salicylate (5.0% by mass) (Group D: LOX + glycol salicylate) has the effect of sustaining the anti-inflammatory action (maintaining the action of LOX).

(Formulation example)
After the ingredients shown in Tables 3 to 14 below are dissolved by stirring and mixing, the pharmaceutical compositions of each formulation example can be obtained.
The preparation can be produced by taking the above-mentioned ingredients and amounts and following the procedures prescribed in the General Provisions for Preparations in the Japanese Pharmacopoeia, sections on "external solutions,""gels,""poultices," and "tapes."
For example, when a liquid or semi-solid composition is formulated as a specific dosage form, a known means may be applied to each dosage form, such as placing the liquid or semi-solid composition in a container (e.g., a bottle-shaped container, a tube-shaped container, a sheet-shaped container, a spray container, etc.) as appropriate for the dosage form, spreading the liquid or semi-solid composition on a support to form a shape, or mixing with a propellant and then placing it in an aerosol can.
In addition, when producing a poultice or tape, a known method may be applied, such as spreading a liquid or semi-solid composition on a support and molding it.

In Tables 2 to 5,
*1 Equivalent to 1g of loxoprofen sodium (anhydrous equivalent) *2 Equivalent to 2g of loxoprofen sodium (anhydrous equivalent) *3 Equivalent to 0.1g of raw herbal medicine *4 Equivalent to 0.44g of raw herbal medicine *5 One or more types may be selected and added in appropriate amounts

In Tables 6 to 8,
*1 Equivalent to 1g of loxoprofen sodium (anhydrous equivalent) *2 Equivalent to 2g of loxoprofen sodium (anhydrous equivalent) *3 Equivalent to 0.1g of raw herbal medicine *4 Equivalent to 0.44g of raw herbal medicine *5 One or more types may be selected and added in appropriate amounts

In Tables 9 to 11, *1 is equivalent to 1g of loxoprofen sodium (anhydrous equivalent) *2 is equivalent to 2g of loxoprofen sodium (anhydrous equivalent) *3 is equivalent to 0.5g of loxoprofen sodium (anhydrous equivalent) *4 is equivalent to 0.2g of raw herbal medicine

In Tables 12 to 14, *1 is equivalent to 5g of loxoprofen sodium (anhydrous equivalent) *2 is equivalent to 7.14g of loxoprofen sodium (anhydrous equivalent) *3 is equivalent to 8.33g of loxoprofen sodium (anhydrous equivalent)

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 of the configuration are possible without departing from the spirit of the present invention.

The pharmaceutical composition of the present invention containing loxoprofen or a salt thereof and a salicylic acid has excellent anti-inflammatory effects and is extremely useful.

Claims (8)

A pharmaceutical composition containing loxoprofen or a salt thereof, and a salicylic acid. 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 salicylic acid in the pharmaceutical composition is 0.001 to 50% by mass. The pharmaceutical composition according to claim 1 or 2, wherein the content of the loxoprofen or a salt thereof in the pharmaceutical composition is 0.1 to 15% by mass. 3. The pharmaceutical composition according to claim 1, wherein the mass ratio of the content of the salicylic acids to the content of the loxoprofen or a salt thereof (salicylic acids/loxoprofen or a salt thereof) is 1.0×10 ⁻⁵ to 1,000. The pharmaceutical composition according to claim 1 or 2, wherein the dosage form is a liquid for external use, an ointment, a cream, a spray, a gel, a patch, or a solid for external use. An agent that enhances the anti-inflammatory effect of loxoprofen or its salts, containing salicylates. A sustainer of the anti-inflammatory effect of loxoprofen or its salts that contains salicylic acids.