Topical pharmaceutical composition containing loxoprofen and diclofenac

Abstract

To provide a topical pharmaceutical composition comprising one or more substances selected from the group consisting of loxoprofen, its salts and hydrates thereof, and one or more substances selected from the group consisting of diclofenac, its salts and hydrates thereof, wherein crystal precipitation is suppressed. [Solution] A topical pharmaceutical composition comprising (a) one or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) one or more selected from the group consisting of diclofenac, its salts and hydrates thereof, (c) one or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, wherein the ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) is 1.2 or more and the HLB value is 17 or less, and (d) a lower alcohol, wherein the content of the lower alcohol in (d) is less than 35% by mass and the pH is 6.0 to 8.0.

Description

[Technical Field]

[0001] The present invention relates to an external pharmaceutical composition containing loxoprofen and diclofenac, in which crystal precipitation is suppressed. [Background Art]

[0002] Non-steroidal antipyretic analgesic anti-inflammatory drugs (hereinafter referred to as NSAIDs) are widely used as antipyretic analgesic anti-inflammatory drugs. Loxoprofen (hereinafter also referred to as LOX), which is a propionic acid-based NSAID, exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, and is known to have strong antipyretic, analgesic and anti-inflammatory effects. Diclofenac, which is a phenylacetic acid-based NSAID, also exhibits an inhibitory effect on prostaglandin biosynthesis and has analgesic and anti-inflammatory effects.

[0003] Patent Document 1 describes an external pharmaceutical composition characterized by containing (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) tocopherol and / or a derivative thereof, (C) menthol, and (D) water. In Patent Document 1, the problem that an external preparation containing diclofenac and / or a salt thereof, tocopherol and / or a derivative thereof, and water cannot be solubilized, resulting in white turbidity or precipitate formation, is addressed by blending menthol to suppress the formation of white turbidity or precipitates.

[0004] Patent Document 2 describes an external liquid composition containing (A) one or more selected from diclofenac, felbinac, loxoprofen and salts thereof, (B) one or more selected from malic acid and salts thereof, and (C) water, and having a pH of 6 to 8. In Patent Document 2, when one or more active ingredients selected from diclofenac, felbinac, loxoprofen and salts thereof are blended into an aqueous composition containing water, the content of the active ingredient in the composition decreases over time, and the composition discolors from yellowish brown to dark brown. This problem is solved by adjusting the pH of the composition to 6 to 8 and blending one or more selected from malic acid and salts thereof. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. WO2015 / 151990 [Patent Document 2] Patent No. 6060742 [Overview of the project] [Problems that the invention aims to solve]

[0006] The present inventors have found that in a pharmaceutical composition containing one or more substances selected from the group consisting of loxoprofen, its salts and hydrates thereof, one or more substances selected from the group consisting of diclofenac, its salts and hydrates thereof, and a lower alcohol, when the lower alcohol content is less than 35% by mass, crystal precipitates originating from diclofenac and its salts occur. The problem to be solved by the present invention is to provide a topical pharmaceutical composition containing one or more substances selected from the group consisting of loxoprofen, its salts and hydrates thereof, and one or more substances selected from the group consisting of diclofenac, its salts and hydrates thereof, in which crystal precipitation is suppressed. [Means for solving the problem]

[0007] The present inventors, after diligent research to solve the above problems, have found that crystal precipitation can be suppressed in an external pharmaceutical composition comprising one or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, one or more selected from the group consisting of diclofenac, its salts and hydrates thereof, and a lower alcohol, wherein the lower alcohol content is less than 35% by mass, by incorporating a predetermined surfactant and further adjusting the pH of the external pharmaceutical composition to a predetermined range. The present invention was completed based on the above findings.

[0008] In other words, embodiments of the present invention are as follows. <1> (a) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (c) One or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, wherein the ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) is 1.2 or more, and the HLB value is 17 or less, and (d) Lower alcohols A topical pharmaceutical composition containing (d), wherein the lower alcohol content of (d) is less than 35% by mass, and the pH is 6.0 to 8.0. <2> (c) The surfactant is a surfactant having a fatty acid ester structure or an alkyl ether structure. <1> The topical pharmaceutical composition described above. <3> (c) The surfactant is one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene alkyl ether. <1> or <2> The topical pharmaceutical composition described above. <4> (c) The surfactant content is 1.5% by mass or more and 15% by mass or less. <1> from <3> A topical pharmaceutical composition as described in any one of the following. <5> (a) The content of the component is 0.1 to 10% by mass. <1> from <4> A topical pharmaceutical composition as described in any one of the following. <6> (b) The content of the component is 0.1 to 10% by mass. <1> from <5> A topical pharmaceutical composition as described in any one of the following. <7> The topical pharmaceutical composition contains water. <1> from <6> A topical pharmaceutical composition as described in any one of the following. <8> The topical pharmaceutical composition is one selected from the group consisting of liquids, gels, creams, sprays, ointments, hard gels, poultices, and tapes. <1> from <7> A topical pharmaceutical composition as described in any one of the following. <9> (a) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (c) One or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, wherein the ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) is 1.2 or more, and the HLB value is 17 or less, and (d) Lower alcohols A method for stabilizing a topical pharmaceutical composition, comprising: (d) blending such that the content of the lower alcohol is less than 35% by mass of the total mass of the topical pharmaceutical composition, and adjusting the pH of the resulting composition to 6.0 to 8.0. [Effects of the Invention]

[0009] According to the present invention, crystal precipitation can be suppressed in a topical pharmaceutical composition containing loxoprofen and diclofenac. [Modes for carrying out the invention]

[0010] The topical pharmaceutical composition of the present invention is a topical pharmaceutical composition that contains (a) one or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) one or more selected from the group consisting of diclofenac, its salts and hydrates thereof, (c) one or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, having a ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) of 1.2 or more and an HLB value of 17 or less, and (d) a lower alcohol, wherein the content of the lower alcohol in (d) is less than 35% by mass and the pH is 6.0 to 8.0.

[0011] The method for stabilizing the topical pharmaceutical composition of the present invention is a method comprising: (a) one or more selected from the group consisting of loxoprofen, its salts and hydrates thereof; (b) one or more selected from the group consisting of diclofenac, its salts and hydrates thereof; (c) one or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, having a ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) of 1.2 or more, and an HLB value of 17 or less; and (d) a lower alcohol, blending them such that the content of the lower alcohol in (d) is less than 35% by mass of the total mass of the topical pharmaceutical composition, and adjusting the pH of the resulting composition to 6.0 to 8.0.

[0012] <Loxoprofen, its salts, and their hydrates> In the present invention, "one selected from the group consisting of loxoprofen, its salts, and their hydrates" may also be referred to as "loxoprofen or its salt," and is loxoprofen or its salt (including hydrated salts) (the salt is preferably a pharmaceutically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate. At least one substance selected from the group consisting of loxoprofen, its salts, and their hydrates used in this invention is listed in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0013] The content of at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof in the topical pharmaceutical composition is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.2 to 10% by mass, even more preferably 0.5 to 10% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the topical pharmaceutical composition. As an example, the topical pharmaceutical composition of the present invention preferably contains 1 to 10% by mass of loxoprofen sodium as component (a).

[0014] <One selected from the group consisting of diclofenac, its salts, and their hydrates> Diclofenac sodium is listed in the 18th revised edition of the Japanese Pharmacopoeia. Examples of salts of diclofenac include diclofenac sodium, which is the sodium salt, and diclofenac potassium, which is the potassium salt.

[0015] The content of one or more selected from the group consisting of diclofenac, salts thereof, and hydrates thereof contained in the topical pharmaceutical composition is not particularly limited, but based on the total mass of the topical pharmaceutical composition, it is preferably 0.1 to 10% by mass, more preferably 0.2 to 10% by mass, still more preferably 0.5 to 10% by mass, and particularly preferably 1 to 10% by mass. As an example, the topical pharmaceutical composition of the present invention preferably contains 1 to 10% by mass of diclofenac sodium as component (b).

[0016] The mass ratio of one or more selected from the group consisting of diclofenac, salts thereof and hydrates thereof to one or more selected from the group consisting of loxoprofen, salts thereof and hydrates thereof (one or more selected from the group consisting of diclofenac, salts thereof and hydrates thereof / one or more selected from the group consisting of loxoprofen, salts thereof and hydrates thereof) is preferably 1.0×10 -4 to 200, more preferably 1.0×10 -2 to 100, still more preferably 1.0×10 -2 to 50, and particularly preferably 1.0×10 -1 to 10.

[0017] <Surfactant> The topical pharmaceutical composition of the present invention contains one or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerized structure, wherein the ratio of the average addition mole number P of polyoxyethylene chains to the carbon number C of the hydrocarbon chain (P / C) is 1.2 or more, and the HLB value is 17 or less.

[0018] In surfactants, the hydrocarbon chain structure refers to a structure that functions as a hydrophobic chain. As long as it functions as a hydrophobic chain, the hydrocarbon chain structure may have unsaturated bonds, ether bonds, ester bonds, amide bonds, carbonyl groups, carboxyl groups, hydroxyl groups, phosphates, amines, halogens, other heteroatom-containing bonds, side chains (branched structures), or cyclic structures in the middle of the hydrocarbon chain. Furthermore, if multiple hydrocarbon chains that function as hydrophobic chains are included in the molecular structure of the surfactant, the carbon number of the hydrocarbon chain in this invention refers to the sum of the carbon numbers of all hydrocarbon chains that function as hydrophobic chains.

[0019] The hydrocarbon chain structure may be a hydrocarbon chain derived from a higher fatty acid or higher alcohol that constitutes the structure of the surfactant. The number of carbon atoms in the hydrocarbon chain is not particularly limited, but for example, it is 10 to 30 carbon atoms, preferably 10 to 25 carbon atoms. Examples of fatty acids or alcohols having a hydrocarbon chain include, but are not particularly limited to, hydrogenated ricinoleic acid or stearic acid, cetanol, etc.

[0020] The average number of moles of polyoxyethylene chains added to a surfactant is not particularly limited, but is generally 5 to 100, preferably 10 to 80, more preferably 18 to 70, and even more preferably 20 to 60.

[0021] The ratio of the average number of added moles of polyoxyethylene chains to the number of carbon atoms in the hydrocarbon chain is 1.2 or more, preferably 1.2 to 5.0, more preferably 1.2 to 4.0, and even more preferably 1.25 to 3.5.

[0022] The HLB value (Hydrophile Lipophile Balance) of the surfactant is 17 or less, preferably 8 to 17, more preferably 10 to 17, and even more preferably 12 to 17. The HLB value of the surfactant may also be preferably 9 to 17, more preferably 11 to 17, and even more preferably 12 to 17. The HLB value of the surfactant may be particularly preferably 12.5 to 17.

[0023] The topical pharmaceutical composition according to claim 1, wherein the surfactant is preferably a surfactant having a fatty acid ester structure or an alkyl ether structure. The surfactant described above is preferably one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene alkyl ether. Examples of polyethylene glycol fatty acid esters include polyethylene glycol monostearate. Examples of polyethylene alkyl ethers include polyoxyethylene cetyl ether.

[0024] Details of the surfactants used in the examples described below are shown below.

[0025] [Table 1]

[0026] Details of the surfactants used in the comparative examples described below are shown below.

[0027] [Table 2]

[0028] The surfactant content of (c) is preferably 1.5% by mass or more and 15% by mass or less, more preferably 2% by mass or more and 15% by mass or less, even more preferably 2% by mass or more and 10% by mass or less, even more preferably 4% by mass or more and 10% by mass or less, or 6% by mass or more and 10% by mass or less. When the pH of the topical pharmaceutical composition of the present invention is 6.0 to 6.5, the content of the surfactant in (c) is preferably 2% by mass or more and 15% by mass or less, more preferably 6% by mass or more and 15% by mass or less, and even more preferably 10% by mass or more and 15% by mass or less.

[0029] <Lower alcohol> The topical pharmaceutical composition of the present invention contains a lower alcohol. The lower alcohol in the present invention refers to aliphatic alcohols having 1 to 4 carbon atoms used in topical preparations for purposes such as solubilizers, bases, preservatives, solvents, and solubilizers. Examples include methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol. Preferably, it is ethanol or isopropanol, and more preferably ethanol. Ethanol with an ethanol content of 99.5% by volume or more is also called anhydrous ethanol, and this is also included in the ethanol of the present invention. Ethanol is listed in the Pharmaceutical Additives Dictionary 2021 (Yakuji Nippo Co., Ltd., 2021), and examples include ethanol, ethanol 95, and anhydrous ethanol.

[0030] The lower alcohol content in the topical pharmaceutical composition of the present invention is less than 35% by mass of the total mass of the topical pharmaceutical composition. The lower alcohol content may be 10% by mass or more and less than 35% by mass, 10% by mass or more and 30% by mass or less, or 10% by mass or more and 25% by mass or less, based on the total mass of the topical pharmaceutical composition. The lower alcohol content may be 15% by mass or more and less than 35% by mass, or 20% by mass or more and less than 35% by mass, based on the total mass of the topical pharmaceutical composition. The lower alcohol content may be 15% by mass or more and 30% by mass or less, 15% by mass or more and less than 25% by mass, or 20% by mass or more and 30% by mass or less, based on the total mass of the topical pharmaceutical composition.

[0031] The pH of the topical pharmaceutical composition of the present invention is 6.0 to 8.0, preferably 6.0 to 7.5, more preferably 6.0 to 7.2, and particularly preferably 6.0 to 7.0. The pH of the topical pharmaceutical composition of the present invention may also be 6.2 to 8.0, 6.2 to 7.5, 6.2 to 7.2, or 6.2 to 7.0.

[0032] The topical pharmaceutical composition of the present invention may be a composition containing water or a composition that does not contain water, but it is preferably a composition that contains water.

[0033] The topical pharmaceutical composition of the present invention can be manufactured by combining component (a), component (b), component (c), and component (d). For example, the topical pharmaceutical composition of the present invention may be manufactured by a process in which components (a), (b), (c), and (d) are combined, completely dissolved, then water is added, and finally a pH adjuster is added. In this case, if it is difficult to dissolve, component (c) may be heated before being added. As another example, the topical pharmaceutical composition of the present invention may be manufactured by preparing a solution in which component (d) is completely dissolved with component (a), component (b), and a pH adjuster, and then by adding component (c), a pH adjuster, and water.

[0034] <About topical medicinal compositions> The topical pharmaceutical composition of the present invention may contain drugs or pharmaceutical additives. The topical pharmaceutical composition of the present invention may contain one or more components selected from the group consisting of the following components (X-1) to (X-11). Ingredients (X-1): Tocopherols Components (X-2): Terpenes Ingredients (X-3): Glycyrrhizic acid derivatives Ingredients (X-4): Herbal medicines Ingredients (X-5): Tranexamic acid derivatives Ingredients (X-6): Vanilloids Ingredients (X-7): Nicotinic acid Ingredients (X-8): Chlorpheniramines Ingredients (X-9): Diphenhydramines Ingredients (X-10): Pyrrolidones Ingredients (X-11): Inorganic salts

[0035] (X-1) Examples of tocopherols include tocopherol, tocotrienol and their derivatives (e.g., esterified derivatives such as acetate, succinate, and nicotinate), and their salts (e.g., alkaline earth metal salts such as calcium and magnesium salts). The tocopherol may be α-tocopherol, β-tocopherol, γ-tocopherol, or δ-tocopherol, but α-tocopherol is preferred. The tocotrienol may be α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol, but α-tocotrienol is preferred. Among the tocopherols, tocopherol acetate is particularly preferred.

[0036] (X-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, or their derivatives. They may also be cyclic or chain-like. Examples of terpenes include isoborneol, ylone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, carone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, thymol, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampeol, pinol, piperitenon, phellandral, phellandrene, fenthen, phenthyl alcohol, periryl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

[0037] As terpenes, essential oils containing terpenes may be used. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, cajapto oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, gingergrass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, tere Examples include bottle oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, beniroyal oil, henopodium oil, bergamot oil, bois de rose oil, pine oil, marjoram 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, which may be used individually or in combination of two or more.

[0038] (X-3) Examples of glycyrrhizic acid derivatives 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 (Glycyrrhiza uralensis) or extracts thereof containing glycyrrhizic acid derivatives may be used as glycyrrhizic acid derivatives.

[0039] (X-4) Examples of crude drugs include licorice, arnica tincture, Japanese red oak, catechu, edamame, fennel, turmeric, Corydalis, scutellaria, aster, Phellodendron bark, parsley, Coptis japonica, Polygala tenuifolia, Curcuma longa, Valerian, chamomile, caronine, balloon flower, apricot kernel, goji berry, goji leucocephala, schizonepeta, cinnamon bark, Cassia seed, gentian, geranium, safflower, cypress, bezoar, schisandra, asarum, gardenia, sansho pepper, aster, peony, musk, dandelion, scutellaria, cypress Examples include crude drugs such as Shazenshi, Shazensou, animal bile (including bear bile), ginger, Ziziphus, Magnolia, horse chestnut, Sekisan, Senega, Cnidium, Zenko, Swertia, Atractylodes, Mulberry bark, Perilla, Southern laurel, Chikusetsuninjin, Citrus unshiu peel, Angelica, Tokon, Nandina, Ginseng, Fritillaria, Ophiopogon, Pinellia, Bankouka, Deer vine, Angelica, Atractylodes, Poria, Paeonia, Bamboo bark, and Deer antler, as well as extracts (extracts, tinctures, dried extracts, etc.) of these. Licorice may be used as glycyrrhizic acid derivatives, as well as as crude drugs, or may be used to fulfill both roles.

[0040] (X-5) Tranexamic acid derivatives may include, for example, tranexamic acid or its salts, tranexamic acid derivatives or their salts. There are no particular restrictions on the salts of tranexamic acid, but specific examples 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; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, and stearylamine. In addition, tranexamic acid derivatives or salts thereof may also be used, and specific examples include ester derivatives such as tranexamic acid cetyl ester and amide derivatives such as tranexamic acid methylamide.

[0041] (X-6) Vanilloids are a general term for compounds containing a vanillyl group. In the present invention, vanilloids are not particularly limited as long as they contain a vanillyl group, and examples include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), and vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol). Furthermore, the vanilloids in the present invention may include natural products containing compounds with a vanillyl group, derivatives of compounds having a vanillyl group, or synthetic compounds in which a functional group has been added to the vanillyl group. Furthermore, the vanilloids used in this invention may include peppers containing a compound with a vanillyl group, or they may be included as part of the vanilloids. As for the chili peppers, for example, the chili pepper (fruit of Capsicum annuum Linne (Solanaceae)) listed in the 18th edition of the Japanese Pharmacopoeia can be suitably used. The form of the chili peppers can be adjusted as needed, and they can be cut or crushed into small pieces or lumps, or ground into powder. For example, "chili pepper powder" made from powdered chili peppers can also be used as the "chili peppers" of this invention. Alternatively, chili peppers that have undergone some kind of extraction treatment (such as chili pepper extract or chili pepper tincture) may be used. In addition to extraction, the chili pepper extract may also be processed by heating, drying, or grinding. Furthermore, as the chili peppers, capsaicinoids, which are the main components of chili peppers, may be used. Capsaicin and vanillylamide nonanoate are preferred as capsaicinoids. Preferably, chili pepper extract, chili pepper tincture, vanillylamide nonylate, or capsaicin can be used as the chili peppers.

[0042] (X-7) Nicotinic acid derivatives include nicotinic acid and its derivatives, as well as salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, inositol hexanicotinate, hepronicate, etc.), nicotinic acid amide, nicotinic acid amide adenine dinucleotide, nicotinic acid amide adenine dinucleotide phosphate, etc.). As nicotinic acid esters, monoesters of nicotinic acid are preferred. As nicotinic acid derivatives, benzyl nicotinate is preferred.

[0043] (X-8) Chlorpheniramines include chlorpheniramines and their salts. Specifically, 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. Chlorpheniramine maleate is preferred among the chlorpheniramines.

[0044] (X-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, salicylate, diphenyl disulfonate, tannate, lauryl sulfate, and sulfate. Diphenhydramine or diphenhydramine hydrochloride are preferred as diphenhydramines.

[0045] Examples of (X-10) pyrrolidone compounds include dl-pyrrolidone carboxylic acid or its salts, with sodium pyrrolidone carboxylate being preferred, for example.

[0046] (X-11) Inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium, or ammonium salts. For example, sodium chloride, potassium chloride, and ammonium chloride are preferred.

[0047] The topical pharmaceutical composition of the present invention may contain pharmaceutical additives other than the above-mentioned components, as necessary, for purposes such as further improving content stability over time or the feel of use. Examples include humectants, moisturizers, thickeners, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, and cooling agents. Furthermore, the topical pharmaceutical composition of the present invention may contain any other components.

[0048] Examples of humectants that can be used include hyaluronic acid, dl-pyrrolidone carboxylate sodium or its salts (e.g., dl-pyrrolidone carboxylate sodium). Examples of humectants that can be used include sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol, which are polyhydric alcohols.

[0049] Examples of thickening agents (viscosity enhancers / gelling agents) that can be used include hypromellose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (carmellose sodium), methylcellulose, carrageenan, locust bean gum, propylene glycol alginate, and acrylic copolymer.

[0050] Examples of adhesives include acrylic acid / octyl acrylate copolymer, acrylic acid 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, silk fibroin acrylate copolymer resin, 300 acrylate starch, 1000 acrylate starch, 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 methacrylate / methacrylamide Acrylic adhesives such as 2-hydroxyethyl acrylate / diacetone acrylamide copolymer, isononyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, and butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / diacetone acrylamide copolymer; synthetic rubber adhesives such as cis-isoprene rubber, styrene-isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene-butadiene rubber (SBR), styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), polyisoprene, polyisobutylene (PIB), chloroprene rubber, polybutene, natural rubber latex, and SBR synthetic latex;In addition to silicone-based 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, and gum arabic, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium, can be used.

[0051] Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerol ester, ester gum, maleic acid resin, maleated rosin glycerol ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and the like.

[0052] Examples of crosslinking agents that can be used include dried aluminum hydroxide gel, magnesium aluminum hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosaltite, and dihydroxyaluminum aminoacetate. Examples of fillers 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).

[0053] Examples of oils and fats that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, and gelling 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, oleyl alcohol, hexyldecanol, isostearyl alcohol, and octyldodecanol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, whale wax, shellac, jojoba oil, beeswax, bleached beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oils.

[0054] Examples of softening agents that can be used include petroleum oils such as paraffinic process oils, naphthenic process oils, and aromatic process oils; 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; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; glycerin, etc.

[0055] 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, aminoethylsulfonic acid, etc. Examples of transdermal absorption enhancers include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactic acid esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbide, azeon, or derivatives thereof. Examples of stabilizers that can be used include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (e.g., dibenzoylmethane derivatives).

[0056] Examples of solubilizers 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.

[0057] Examples of pH adjusting agents that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), and phosphoric acid. It is preferable to use a pH adjusting agent other than malic acid. That is, it is preferable that the topical pharmaceutical composition of the present invention does not contain malic acid as a pH adjusting agent. It is more preferable to use one or more pH adjusting agents selected from the group consisting of hydrochloric acid, lactic acid, and diisopropanolamine, their salts, and their hydrates. Examples of antioxidants that can be used include ascorbic acid, ascorbic palmitate, sodium bisulfite, anhydrous 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, soy lecithin, pentaerythritol-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, and propyl gallate. Examples of cooling agents include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

[0058] Specific dosage forms of topical pharmaceutical compositions include, for example, any of the following selected from the group consisting of liquids, gels, creams, sprays (topical aerosols, pump sprays), ointments, hard gels, poultices, and tapes. Each dosage form can be manufactured using appropriate additives and bases, following the usual methods described in the 18th edition of the Japanese Pharmacopoeia. Preferred dosage forms for topical preparations are liquids, gels, creams, sprays, hard gels, and poultices, with liquids, gels, or sprays being particularly preferred.

[0059] Furthermore, the preparation of the topical agent can be contained and sealed in, for example, a glass container or packaging, a metal container or packaging such as aluminum, or a container or packaging made of olefin resin such as polyethylene or polypropylene, and can be further contained in a moisture-proof bag containing metal such as aluminum. In addition, the container or packaging may contain environmentally friendly raw materials such as recycled plastic or biomass raw materials, and if necessary, any material that prevents deterioration of the topical agent due to external factors, elements, or environmental changes to the pharmaceutical container or packaging, such as heat and light in high-temperature environments, and that appropriately maintains the quality of the topical agent may be used. In one embodiment of the present invention, the pharmaceutical product may be a preparation or composition of the topical agent contained in an appropriate container or packaging.

[0060] <Regarding Uses> The topical pharmaceutical composition of the present invention can preferably be used for anti-inflammatory or analgesic purposes. The topical pharmaceutical composition of the present invention is preferably used as an anti-inflammatory agent, an analgesic agent, an oral / pharyngeal agent, or a hemorrhoid agent.

[0061] At least one selected from the group consisting of loxoprofen, its salts, and their hydrates has antipyretic, analgesic, and anti-inflammatory effects. Therefore, the topical pharmaceutical composition of the present invention is used as an analgesic, particularly for the relief of pain from lower back pain, joint pain, muscle pain, stiff shoulders, earaches, bruises, fractures, sprains, trauma, and eye pain. It is also used as an anti-inflammatory agent for muscle fatigue and chilblains. Furthermore, it is used as an oral and pharyngeal drug for pharyngitis, tonsillitis, stomatitis, swelling of the mouth and pharynx, sterilization and disinfection of the mouth and throat, and removal of bad breath. It is also used as a hemorrhoid drug to relieve pain, bleeding, swelling, and itching from hemorrhoids and anal fissures. The topical pharmaceutical composition of the present invention can be applied, sprayed, or patched to the affected area in an appropriate amount to the patient one to several times a day.

[0062] The application site for the topical pharmaceutical composition of the present invention may be any surface of the body, specifically the skin, mucous membranes, oral mucosa, pharyngeal mucosa, surface of the eyeball, nasal cavity, outer ear, anus, etc.

[0063] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to these examples. [Examples]

[0064] The sources for the ingredients used are listed below. Loxoprofen sodium hydrate (LOX): KOLONLIFE SCIENCE INC. Diclofenac sodium: Tokyo Chemical Industry Co., Ltd. l-Menthol: Suzuki Peppermint Co., Ltd. Japanese Pharmacopoeia Ethanol (95% Ethanol): Kaneichi Kogyo Co., Ltd. Isopropanol: Kosakai Pharmaceutical Co., Ltd. Propylene glycol: Maruishi Pharmaceutical Co., Ltd. Hydroxypropylcellulose: Nippon Soda Co., Ltd. Hydrochloric acid: Kosakai Pharmaceutical Co., Ltd. HCO-20 (Polyoxyethylene Hydrogenated Castor Oil 20): Nikko Chemicals Co., Ltd. HCO-40 (Polyoxyethylene Hydrogenated Castor Oil 40): Nikko Chemicals Co., Ltd. HCO-60 (Polyoxyethylene Hydrogenated Castor Oil 60): Nikko Chemicals Co., Ltd. MYL-10 (Polyethylene Glycol Monolaurate 10): Nikko Chemicals Co., Ltd. MYS-10V (Polyethylene Glycol Monostearate 10): Nikko Chemicals Co., Ltd. MYS-25V (Polyethylene Glycol Monostearate 25): Nikko Chemicals Co., Ltd. MYS-40MV (Polyethylene Glycol Monostearate 40): Nikko Chemicals Co., Ltd. BB-20 (Polyoxyethylene Behenyl Ether 20): Nikko Chemicals Co., Ltd. BC-10 (Polyoxyethylene Cetyl Ether 10): Nikko Chemicals Co., Ltd. BC-20 (Polyoxyethylene Cetyl Ether 20): Nikko Chemicals Co., Ltd. BC-30 (Polyoxyethylene Cetyl Ether 30): Nikko Chemicals Co., Ltd.

[0065] (1) Preparation of pharmaceutical compositions The ingredients shown in the table below were added to Japanese Pharmacopoeia ethanol in a beaker, and their dissolution was confirmed. Next, purified water was added and stirred to prepare 100 g of the pharmaceutical composition. Then, diluted hydrochloric acid was added in appropriate amounts until the pH was adjusted to the level shown in the table below. The prepared pharmaceutical composition was filled into a clear glass bottle and sealed tightly.

[0066] (2) Evaluation of the presence or absence of crystals The following table shows the results of evaluating crystal precipitation for each pharmaceutical composition immediately after manufacturing and one day after the start of storage at room temperature. ○: No crystal precipitation ×: Crystals precipitate

[0067] [Table 3]

[0068] [Table 4]

[0069] [Table 5]

[0070] [Table 6]

[0071] <Explanation of Results> As shown in Table 3, when a surfactant was used that had a hydrocarbon chain structure and a polyoxyethylene polymerization structure, with a ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) of 1.2 or more, and an HLB value of 17 or less, no crystal precipitation occurred at room temperature after 1 day. As shown in Tables 4 and 5, when the lower alcohol content was less than 35% by mass and the pH was between 6.0 and 8.0, no crystal precipitation occurred immediately after production and after 1 day at room temperature. However, when the pH was less than 6.0, crystal precipitation occurred immediately after production and after 1 day at room temperature. As shown in Table 6, the same effect as with ethanol was confirmed when isopropanol was used as the lower alcohol. Furthermore, as shown in Table 6, the effects of the present invention were also confirmed in formulations to which l-menthol, propylene glycol, or hydroxypropyl cellulose were added.

[0072] 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 modifications to the configuration are possible without departing from the spirit of the present invention. [Industrial applicability]

[0073] The topical pharmaceutical composition of the present invention is used as an anti-inflammatory and analgesic agent, particularly for the pain relief of lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, traumatic pain, and eye pain. It is also used as an anti-inflammatory agent for muscle fatigue and chilblains. Furthermore, as an oral and pharyngeal agent, it is used for pharyngitis, tonsillitis, stomatitis, swelling of the mouth and throat, sterilization and disinfection of the mouth and throat, and removal of bad breath. It is also used as a hemorrhoid agent to relieve pain, bleeding, swelling, and itching associated with hemorrhoids and anal fissures.

Claims

1. (a) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (c) One or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, wherein the ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) is 1.2 or more, and the HLB value is 17 or less, and (d) Lower alcohols A topical pharmaceutical composition containing (d), wherein the content of the lower alcohol in (d) is less than 35% by mass, and the pH is 6.0 to 8.

0.

2. The topical pharmaceutical composition according to claim 1, wherein the surfactant in (c) is a surfactant having a fatty acid ester structure or an alkyl ether structure.

3. The topical pharmaceutical composition according to claim 1, wherein the surfactant in (c) is one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and polyoxyethylene alkyl ether.

4. The topical pharmaceutical composition according to claim 1, wherein the content of the surfactant in (c) is 1.5% by mass or more and 15% by mass or less.

5. (a) The topical pharmaceutical composition according to claim 1, wherein the content of the component is 0.1 to 10% by mass.

6. (b) The topical pharmaceutical composition according to claim 1, wherein the content of component is 0.1 to 10% by mass.

7. The topical pharmaceutical composition according to any one of claims 1 to 6, wherein the topical pharmaceutical composition contains water.

8. The topical pharmaceutical composition according to any one of claims 1 to 6, wherein the topical pharmaceutical composition is selected from the group consisting of liquids, gels, creams, sprays, ointments, hard gels, poultices, and tapes.

9. (a) One or more selected from the group consisting of loxoprofen, its salts and hydrates thereof, (b) One or more selected from the group consisting of diclofenac, its salts and their hydrates, (c) One or more surfactants having a hydrocarbon chain structure and a polyoxyethylene polymerization structure, wherein the ratio of the average number of added moles P of the polyoxyethylene chain to the number of carbon atoms C of the hydrocarbon chain (P / C) is 1.2 or more, and the HLB value is 17 or less, and (d) Lower alcohols A method for stabilizing a topical pharmaceutical composition, comprising: (d) blending such that the content of the lower alcohol is less than 35% by mass of the total mass of the topical pharmaceutical composition, and adjusting the pH of the resulting composition to 6.0 to 8.0.

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