Loxoprofen-containing external preparation for skin

Abstract

To provide a novel external preparation for skin which contains at least loxoprofen and terpenes and / or tocopherols as active ingredients, and can have pharmaceutical storage stability.SOLUTION: An external preparation for skin contains the following components 1 to 5. 1) loxoprofen or a pharmaceutically acceptable salt thereof (e.g., sodium salt), 2) terpenes and / or tocopherols (e.g., l-menthol or tocopherol acetate), 3) ester within the range of carbon number 10 to 13 or molecular weight 185 to 250 (e.g., adipic acid diisopropyl), 4) pH regulator containing lactic acid within the range of 0.01 to 0.3 mass% and lactate within the range of 1.5 to 20 mass% by the ratio of 1:10 to 1:150 (lactic acid: lactate, mass ratio), and 5) solubilizer in the case where tocopherols is contained.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention belongs to the technical field of skin external preparations. The present invention relates to a novel skin external preparation containing loxoprofen or a pharma- ceutical acceptable salt thereof, terpenes such as menthol, and / or tocopherols such as tocopherol acetate. [Background technology]

[0002] The loxoprofen according to the present invention is a propionic acid derivative nonsteroidal antipyretic analgesic anti-inflammatory drug (NSAID), which exerts antipyretic, analgesic and anti-inflammatory effects by inhibiting the biosynthesis of prostaglandins. Due to its excellent analgesic and anti-inflammatory effects, loxoprofen is used not only as an oral preparation, but also as an external preparation in various forms such as liquid, gel and tape.

[0003] Terpenes are alcohols containing hydrocarbons whose structural unit is isoprene, and have a fragrant odor. Therefore, they are often used as ingredients in perfumes and as cooling agents in sweets and medicines. Menthol is a representative example of terpenes. Menthol can be added to topical preparations to give a cooling sensation to the subject, for example. Tocopherols, typified by tocopherol acetate, are drugs that are expected to promote blood circulation by dilating the peripheral blood vessels of the skin, prevent rough skin such as acne, age spots, and freckles, have antioxidant effects that prevent oxidation of the skin, correct hormone balance, and have anti-inflammatory effects.

[0004] Anti-inflammatory and analgesic external preparations containing loxoprofen and terpenes such as menthol are also well known. In addition, many inventions have been disclosed that contain these as active ingredients in pharmaceutical compositions for skin application, and that improve the stability of pharmaceutical preparations and enhance transdermal absorbability (e.g., Patent Documents 1 to 5). External preparations containing loxoprofen and tocopherols are also known (e.g., Patent Document 6). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2014-185132 A [Patent Document 2] JP 2015-083563 A [Patent Document 3] JP 2017-132816 A [Patent Document 4] JP 2019-006835 A [Patent Document 5] JP 2020-059666 A [Patent Document 6] JP 2018-021002 A Summary of the Invention [Problem to be solved by the invention]

[0006] As described above, anti-inflammatory and analgesic topical preparations containing at least rofecoxib and terpenes and / or tocopherols as active ingredients are widely known. The main objective of the present invention is to provide a new topical skin preparation that contains at least these two or three active ingredients and has formulation-like storage stability.

[0007] Here, "capable of having pharmaceutical storage stability" means that in an appropriate stability test such as an accelerated test, the appearance is not cloudy, is transparent or translucent, crystals do not precipitate, the liquid property (pH) is maintained, and the change in the content of the active ingredient (the formation of decomposition products) is within ±10%, preferably within ±5%. [Means for solving the problem]

[0008] In order to solve the above problems, the present inventors conducted extensive research and found a composition capable of solving the above problems, which led to the completion of the present invention. The present invention can include, for example, the following aspects. [1] A skin preparation for external use, comprising the following ingredients 1 to 5: 1) loxoprofen or a pharma- ceutical acceptable salt thereof, 2) terpenes and / or tocopherols, 3) Esters having 10 to 13 carbon atoms or molecular weights of 185 to 250; 4) A pH adjuster containing lactic acid in the range of 0.01 to 0.3% by mass and a lactate salt in the range of 1.5 to 20% by mass in a ratio of 1:10 to 1:150 (lactic acid:lactate, mass ratio); 5) Solubilizers if tocopherols are included. [2] The topical skin preparation described in [1] above, further comprising a thickening agent, a lower alcohol, and / or water. [3] The topical skin preparation described in [1] above, wherein the terpene is l-menthol or dl-menthol. [4] The topical skin preparation according to the above [1], wherein the ester is diethyl adipate or diisopropyl adipate. [5] The topical skin preparation described in [1] above, wherein the pharma- ceutical acceptable salt of rofecoxib is rofecoxib sodium or a hydrate thereof. [6] The topical skin preparation according to [2] above, wherein the thickening agent is one or more polymers selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydrophobized hydroxypropyl methylcellulose, methylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose (carmellose sodium), polyvinyl alcohol, polyvinylpyrrolidone, and polyacrylic acid. [7] The topical skin preparation described in [2] above, wherein the lower alcohol is ethyl alcohol, propyl alcohol, or isopropyl alcohol. [8] The topical skin preparation described in [1] above, wherein the tocopherol is tocopherol acetate. [9] The topical skin preparation described in [1] above, wherein the solubilizing agent is one or more selected from the group consisting of polysorbates, polyoxyethylene hydrogenated castor oils, polyoxyethylene polyoxypropylene cetyl ethers, decaglyceryl laurate, and lauromacrogols.

[10] The topical skin preparation according to any one of the above [1] to [9], which is a semi-solid or liquid preparation.

[11] The topical skin preparation according to any one of the above [1] to [9], which is a liquid, gel, ointment, cream, foam, patch, or spray. Effect of the Invention

[0009] According to the present invention, it is possible to provide a new anti-inflammatory and analgesic external preparation for skin which contains loxoprofen and terpenes and / or tocopherols and which can have pharmaceutical storage stability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. Skin preparation for external use according to the present invention The skin external preparation according to the present invention (hereinafter referred to as the "external preparation of the present invention") is characterized by containing the following ingredients 1 to 5: 1) loxoprofen or a pharma- ceutical acceptable salt thereof, 2) terpenes and / or tocopherols, 3) Esters having 10 to 13 carbon atoms or molecular weights of 185 to 250; 4) A pH adjuster containing lactic acid in the range of 0.01 to 0.3% by mass and a lactate salt in the range of 1.5 to 20% by mass in a ratio of 1:10 to 1:150 (lactic acid:lactate, mass ratio); 5) Solubilizers if tocopherols are included.

[0011] 1.1 About Component 1 The topical preparation of the present invention includes "loxoprofen or a pharma- ceutically acceptable salt thereof" according to ingredient 1. Such loxoprofen (free form) or a pharma-ceutically acceptable salt thereof is a known compound (drug), and can be produced by known methods or can be obtained from the market. As a pharma-ceutically acceptable salt of loxoprofen, loxoprofen sodium is preferred, but this is not essential. In addition, "loxoprofen or a pharma-ceutically acceptable salt thereof" also includes hydrates of loxoprofen with water (e.g., loxoprofen sodium hydrate) and solvates of loxoprofen with alcohol or the like.

[0012] The content of component 1 in the topical preparation of the present invention is not particularly limited and can be appropriately set according to the desired anti-inflammatory and analgesic effect. Specifically, the content of loxoprofen is, for example, within the range of 0.01 to 10 mass%, preferably within the range of 0.1 to 5 mass%, and more preferably within the range of 0.5 to 3 mass%, based on the total mass of the topical preparation of the present invention. If it is less than 0.01 mass%, the anti-inflammatory and analgesic effect may not be obtained, and if it is more than 10 mass%, side effects may occur.

[0013] 1.2 Component 2 The topical preparation of the present invention contains the “terpenes and / or tocopherols” according to component 2. In the present invention, "terpenes" refers to cyclic or chain-shaped monoterpenes or sesquiterpenes that are medicamentally acceptable.Specific examples of the 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, isothujole, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillyl aldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene. Some of these terpenes have optical isomers, and any of these optical isomers can be used in the present invention.

[0014] Among these terpenes, for example, camphor, geraniol, citronellal, terpineol, borneol, menthol, and limonene are preferred, d-camphor, dl-camphor, thymol, borneol, l-menthol, and dl-menthol are more preferred, and l-menthol and dl-camphor are particularly preferred.

[0015] In the present invention, the above terpenes can be used alone or in combination of any two or more kinds.

[0016] In addition, when the above-mentioned terpenes are contained in the topical agent of the present invention, essential oils containing the above-mentioned terpenes may be used. Examples of such 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, daisy oil, and daisy oil. Examples of oils that may be mentioned include ginseng oil, clove oil, turpentine oil, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, chenopodium oil, bergamot oil, bois de rose oil, linalool 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.

[0017] Among these essential oils, for example, ylang-ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, peppermint oil, geranium oil, clove oil, turpentine, spruce oil, neroli oil, peppermint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, and Roman chamomile oil are preferred, with camphor oil, peppermint oil, turpentine, peppermint oil, and eucalyptus oil being more preferred, and peppermint oil being particularly preferred.

[0018] In the present invention, the above essential oils can be used alone or in combination of any two or more kinds.

[0019] The content of terpenes in the topical preparation of the present invention varies depending on the terpenes or essential oils used, but for example, the terpenes are suitably in the range of 0.01 to 15% by mass, preferably in the range of 0.1 to 10% by mass, and more preferably in the range of 0.5 to 7% by mass, based on the total mass of the topical preparation of the present invention. In addition, when the above-mentioned essential oil is used, the essential oil is suitably in the range of, for example, 0.1 to 40% by mass, preferably in the range of 0.5 to 30% by mass, and more preferably in the range of 1 to 20% by mass, based on the total mass of the topical preparation of the present invention. If the content of terpenes is less than 0.01% by mass, the desired effect such as a refreshing feeling may not be obtained, and if it is more than 15% by mass, side effects may become large or storage stability may not be guaranteed.

[0020] In the present invention, "tocopherols" refers to 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 salt and magnesium salt). Specifically, examples of tocopherol include α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol. Among these, α-tocopherol is preferred. Examples of tocotrienol include α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. Among these, α-tocotrienol is preferred. In the present invention, α-tocopherol, its acetate, its succinate, its nicotinate, and their salts are suitable.

[0021] Some tocopherols and tocotrienols have optical isomers, and any optical isomer can be used in the present invention. In the present invention, unless a specific optical isomer is specified as the component name of a tocopherol, the component name includes all of the various optical isomers alone and their mixtures in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the description "acetate of α-tocopherol" includes both acetate of dl-α-tocopherol and acetate of d-α-tocopherol).

[0022] Preferred tocopherols include, for example, tocopherol, tocopherol succinate, tocopherol acetate, tocopherol nicotinate, and salts thereof. More preferred are dl-α-tocopherol, dl-α-tocopherol calcium succinate, dl-α-tocopherol acetate, and dl-α-tocopherol nicotinate, and particularly preferred is dl-α-tocopherol acetate.

[0023] In the present invention, the above tocopherols can be used alone or in combination of any two or more kinds.

[0024] The content of tocopherols in the topical preparation of the present invention varies depending on the type of tocopherol used, but is, for example, within the range of 0.01 to 8% by mass, preferably within the range of 0.03 to 4% by mass, and more preferably within the range of 0.05 to 2% by mass or 0.1 to 1% by mass, based on the total mass of the topical preparation of the present invention. The same applies when tocopherol acetate is used.

[0025] 1.3 Component 3 The topical preparation of the present invention includes "an ester having 10 to 13 carbon atoms or a molecular weight of 185 to 250" according to component 3. Such an ester is used as a base. Specific examples of the ester include diethyl adipate and diisopropyl adipate. Among these, diisopropyl adipate is preferred.

[0026] In the present invention, the esters can be used alone or in combination of any two or more kinds. The content of component 3 in the topical preparation of the present invention varies depending on the type of ester used and the contents of other components, but is, for example, within the range of 1 to 10% by mass, preferably within the range of 1.5 to 8% by mass, and more preferably within the range of 2.5 to 6% by mass, based on the total mass of the topical preparation of the present invention. If it is less than 1% by mass or more than 10% by mass, the effect as a base may not be obtained and storage stability may not be maintained.

[0027] 1.4 Component 4 The topical preparation of the present invention contains a "pH adjuster containing lactic acid in the range of 0.01-0.3% by mass and lactate in the range of 1.5-20% by mass, in a ratio of 1:10 to 1:150 (lactic acid:lactate, mass ratio)" according to component 4. Such a pH adjuster is used to maintain the liquid pH of the topical preparation of the present invention at approximately pH 6.5.

[0028] The "lactate" of component 4 is not particularly limited as long as it is a salt that generates lactate ions, but specific examples include alkali metal salts such as potassium salts and sodium salts, and alkaline earth metal salts such as magnesium salts and calcium salts. Among these, sodium salts of lactic acid are preferred.

[0029] The content of lactic acid in the topical preparation of the present invention is within the range of 0.01-0.3% by mass, preferably within the range of 0.02-0.2% by mass, more preferably within the range of 0.03-0.1 to 0.15% by mass, based on the total mass of the topical preparation of the present invention. The content of lactate in the topical preparation of the present invention is within the range of 1.5-20% by mass, preferably within the range of 2-15% by mass, more preferably within the range of 2.5-8 to 10% by mass, based on the total mass of the topical preparation of the present invention. The same is true for the preferred sodium lactate. The mass ratio of lactic acid to lactate in the topical preparation of the present invention is within the range of 1:10-1:150, preferably within the range of 1:20-1:100, more preferably within the range of 1:30-1:50.

[0030] 1.5 Component 5 The topical preparation of the present invention contains a “solubilizer” when it contains “tocopherols” according to component 2. Such a solubilizer dissolves tocopherols.

[0031] The "solubilizer" is not particularly limited as long as it can dissolve tocopherols, but specific examples include polysorbates, polyoxyethylene hydrogenated castor oils, polyoxyethylene polyoxypropylene cetyl ethers, decaglyceryl laurate, and lauromacrogols. Among these, polyoxyethylene hydrogenated castor oils are preferred.

[0032] The content of the solubilizer in the topical preparation of the present invention is suitably within the range of 0.01 to 10.0% by mass, preferably within the range of 1.0 to 10.0% by mass, and more preferably within the range of 2.0 to 3.0 to 8.0 to 10.0% by mass, based on the total mass of the topical preparation of the present invention. If it is less than 0.01%, the tocopherols may not dissolve, and if it is more than 10.0%, skin irritation may occur.

[0033] 1.6 Other ingredients In addition to the above ingredients 1 to 5, the topical preparation of the present invention may contain a thickener, a lower alcohol, water, and various additives as appropriate depending on the dosage form.

[0034] The thickening agent is not particularly limited as long as it is used as a thickening agent in pharmaceutical preparations, but specific examples of the thickening agent include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydrophobized hydroxypropyl methylcellulose, and methylcellulose; polymers such as carboxyvinyl polymer, sodium carboxymethylcellulose (carmellose sodium), polyvinyl alcohol, polyvinylpyrrolidone, and polyacrylic acid, and magnesium aluminum silicate. One or more of these may be contained in an appropriate amount. The appropriate amount varies depending on the dosage form and the thickening agent used, but may be, for example, an amount within the range of 0.01 to 10% by mass based on the total mass of the topical preparation of the present invention.

[0035] The lower alcohol is, for example, an alcohol having 1 to 4 carbon atoms, and specific examples thereof include ethyl alcohol, propyl alcohol, and isopropyl alcohol. One or more of these may be contained in an appropriate amount. The appropriate amount varies depending on the formulation type and the lower alcohol used, and may be, for example, an amount within the range of 10 to 70% by mass based on the total mass of the topical preparation of the present invention.

[0036] The water is not particularly limited as long as it is usable as water, and specific examples include purified water, distilled water, ion-exchanged water, ultrapure water, sterilized water, and RO water. These can be used in an appropriate amount depending on the dosage form, etc. The appropriate amount can be, for example, 10 to 70% by mass based on the total mass of the external preparation of the present invention.

[0037] The various additives can be used without any particular limitation as long as they are medicamentously acceptable, and examples thereof include stabilizers (e.g., ascorbic acid, sodium edetate hydrate, sodium chloride, magnesium chloride), solubilizers (e.g., in addition to the above, triacetin, D-mannitol, D-sorbitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate), antioxidants (e.g., butylhydroxyanisole, sodium sulfite, ascorbic acid and its salts, sodium hydrogensulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, cysteine ​​hydrochloride, citric acid), liquefied gas propellants (e.g., chlorofluoride, Examples of suitable additives include carbon, chlorofluorocarbons, liquefied petroleum gases, and dimethyl ethers, compressed gas propellants (e.g., nitrogen gas, carbon dioxide gas, and nitrous oxide gas), humectants (e.g., 1,3-butylene glycol, methylcellulose, and sodium lauryl sulfate), colorants (e.g., tar dyes (brown No. 201, blue No. 201, yellow No. 4, and yellow No. 403, etc.), caramel, sodium copper chlorophyll, methylene blue, gardenia dye, marigold dye, carotene dye, anthocyanin dye, fruit juice dye, vegetable dye, and synthetic or naturally derived dyes such as ferric oxide), emulsifiers (e.g., sucrose fatty acid esters and hydrogenated soybean phospholipids), surfactants, preservatives, chelating agents, and irritation reducers. If necessary, one or more of these may be included in an appropriate amount.

[0038] If desired, other pharmacological ingredients may also be included. Examples of such other pharmacological ingredients include anti-inflammatory analgesics (other than ingredient 1), such as diclofenac and / or its pharma- ceutical acceptable salts; anti-inflammatory agents, such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, and stearyl glycyrrhizinate; antihistamines, such as diphenylimidazole, diphenhydramine and its pharma-ceutical acceptable salts, and chlorpheniramine maleate; local anesthetics, such as lidocaine and its pharma-ceutical acceptable salts, dibucaine and its pharma-ceutical acceptable salts, and ethyl aminobenzoate; nicotinic acid ester derivatives (e.g., nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid methyl ester, etc.), and herbal medicines, such as arnica tincture, Phellodendron bark extract, Sanshishi extract, Horse chestnut extract, Scopolia extract, belladonna extract, Angelica acutiloba extract, Lithospermum root extract, and Zanthoxylum pepper extract. Among these, preferred examples of other pharmacological ingredients include tocopherol ester derivatives, more preferably tocopherol acetate, and one or more of these may be contained in an amount that has pharmacological activity.

[0039] 1.7 Dosage Form The dosage form of the topical preparation of the present invention is not particularly limited as long as it is a form that can be applied topically to the skin, and examples thereof include liquids (including lotions, sprays, aerosols, pump sprays, emulsions, and liniments), gels, ointments, creams, foams, and patches (including tapes and poultices). Of these, liquids, gels, and creams are preferred.

[0040] 2. Method of use and manufacturing of the topical agent of the present invention The topical preparation of the present invention can be used by topically administering it to the skin where anti-inflammatory and analgesic effects are required, depending on the dosage form. The topical preparation of the present invention can be used as an anti-inflammatory and analgesic agent for external use for the purpose of treating shoulder pain associated with stiff shoulders, joint pain, lower back pain, muscle pain, tendonitis (pain in the hand and wrist), elbow pain (tennis elbow, etc.), bruise pain, sprain pain, fracture pain, neuralgia, osteoarthritis, arthritis, etc.

[0041] The topical preparation of the present invention can be prepared by a conventional method according to its dosage form.When the topical preparation of the present invention is a liquid preparation, for example, a solution in which desired amounts of component 1 and component 2 are dissolved is prepared, and a solution in which desired amounts of component 3 are dissolved is added to this and mixed, and after mixing, a desired amount of component 4 is added and mixed uniformly, thereby preparing the topical preparation of the present invention (liquid preparation). EXAMPLES

[0042] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to the following examples in any way.

[0043] [Test Example] Study of ester-based agents Six esters, shown in Table 1, were evaluated.

[0044] [Table 1]

[0045] According to the formulation shown in Table 2 or Table 3, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous) and the prescribed amount of l-menthol were weighed into a stainless steel container, and 45.0 g of ethanol was added and dissolved at room temperature. 0.2 g of hypromellose (Metolose (registered trademark) 60SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.; the same applies below) previously dispersed in each ester in Table 1 and purified water were added and dissolved at room temperature. After dissolution, 0.12 g of lactic acid and 4.0 g of sodium lactate were added, and further purified water was added to make a total amount of 100 g, and the mixture was stirred at room temperature until it became uniform, to produce a liquid preparation. In addition, the unit of each ingredient amount in the table below is "g".

[0046] [Table 2]

[0047] [Table 3]

[0048] Each liquid preparation was evaluated according to the following evaluation criteria. The results are shown in Tables 2 and 3. As shown in Tables 2 and 3, the pH decreased in ethyl acetate, ethylene glycol salicylate, and methyl salicylate, crystals were precipitated in methyl salicylate, and the appearance became cloudy in diethyl sebacate and isopropyl myristate. On the other hand, no particular problems were observed in diisopropyl adipate as a skin topical preparation. Taking these results together, it was found that esters with 10 to 13 carbon atoms or molecular weights in the range of 185 to 250 are good.

[0049] <Evaluation criteria> (1) Appearance: After the formulation is returned to room temperature, it is visually observed. ○:Transparent △: Translucent ×: Cloudy (2) pH: After the formulation was returned to room temperature, it was directly measured using a pH meter (F-2000PI, manufactured by Horiba Advanced Techno Co., Ltd.).

[0050] (3) Crystal precipitation: After the formulation was returned to room temperature, crystal precipitation was visually observed. ○: No crystal precipitation ×: Crystal precipitation observed (4) Loxoprofen content: The loxoprofen content in the formulation was measured by HPLC using the following columns and equipment. Column: Inertsil ODS-2 (GL Sciences) Equipment: Prominence-i LC-2030C Plus (manufactured by Shimadzu Corporation) (5) l-Menthol content: The l-menthol content in the formulation was measured by GC using the following column and equipment. Column: G-column G-250 (manufactured by Chemicals Evaluation and Research Institute, Japan) Equipment: GC-2014 (Shimadzu Corporation)

[0051] [Examples 1 to 7] Preparation and evaluation of topical preparations (liquids) of the present invention According to the formulation shown in Table 4 or Table 5, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous) and the prescribed amount of l-menthol were weighed into a stainless steel container, and 45.0 g of ethanol was added and dissolved at room temperature. 0.2 g of hypromellose previously dispersed in the prescribed amount of diisopropyl adipate and purified water were added and dissolved at room temperature. After dissolution, lactic acid and sodium lactate were added, and purified water was further added to make a total amount of 100 g, and the mixture was stirred at room temperature to become uniform, thereby producing the topical agent (liquid) of the present invention.

[0052] [Table 4]

[0053] [Table 5]

[0054] Examples 1 to 7 were evaluated according to the above-mentioned evaluation criteria. The results are shown in Tables 4 and 5. As is clear from Tables 4 and 5, no particular problems were observed in any of the liquid preparations as external preparations for the skin.

[0055] [Example 8, Comparative Example 6] Preparation of topical preparation (gel) of the present invention and comparative topical preparation (gel) According to the formulation shown in Table 6, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous) and 3 g of l-menthol were weighed into a stainless steel container, and 45.0 g of ethanol was added to dissolve at room temperature. 1 g of hypromellose, which had been previously dispersed in 5.0 g of diisopropyl adipate, 1.0 g of hydrophobized hydroxypropylcellulose (Sangelose (registered trademark) 60L, manufactured by Daido Chemical Industry Co., Ltd.), and 30 g of purified water were added and mixed at room temperature. After mixing, the prescribed amount of lactic acid and the prescribed amount of sodium lactate were added, and further purified water was added to make a total amount of 100 g, and mixed uniformly at room temperature to produce the topical agent (gel) of the present invention.

[0056] [Table 6]

[0057] As shown in Table 6, when the amount of lactic acid was within the range of 0.03 to 0.12 g and sodium lactate was within the range of 2.0 to 8.0 g (lactic acid:sodium lactate = 1:33 to 1:100), the appearance was transparent, the pH hardly changed from the initial state, there was no crystal precipitation, and almost no decrease in the contents of loxoprofen and l-menthol was observed. In Comparative Example 6, in which lactic acid was 0.6 g and sodium lactate was 12.0 g (lactic acid:sodium lactate=1:20), the appearance was cloudy, the pH was decreased, and the contents of loxoprofen and l-menthol were low.

[0058] [Example 9] Preparation of the topical preparation of the present invention (liquid preparation containing loxoprofen and tocopherol acetate) 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous) was weighed into a stainless steel container, and 45.0 g of ethanol was added and dissolved at room temperature. 0.2 g of hypromellose, which had been previously dispersed in 5 g of diisopropyl adipate, 0.5 g of tocopherol acetate, and 5 g of polysorbate 60, and 30 g of purified water were added and dissolved at room temperature. After dissolution, 0.1 g of lactic acid and 4.0 g of sodium lactate were added, and further purified water was added to make a total of 100 g, and the mixture was stirred at room temperature until it became homogeneous, to produce the topical agent of the present invention (loxoprofen-tocopherol acetate liquid preparation).

[0059] [Examples 10 to 14, Comparative Example 7] Preparation of the topical preparation of the present invention (liquid preparation containing loxoprofen, l-menthol and tocopherol acetate) and comparative topical preparation (liquid preparation containing loxoprofen, l-menthol and tocopherol acetate) According to the formulations shown in Tables 7 to 9, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous), 3 g of l-menthol, and 0.5 g of tocopherol acetate were weighed into a stainless steel container, and 45.0 g of ethanol was added and dissolved at room temperature. 0.2 g of hypromellose previously dispersed in 5 g of diisopropyl adipate and 30 g of purified water were added and dissolved at room temperature. After dissolution, the prescribed amount of solubilizer (polyoxyethylene hydrogenated castor oil 60 (Nikkol HCO-60 (registered trademark), Nikko Chemicals Co., Ltd.), polyoxyethylene propylene cetyl ether (20EO) (4PO) (Nikkol PBC-34 (registered trademark), Nikko Chemicals Co., Ltd.), decaglyceryl laurate (Nikkol Decaglyn 1-L (registered trademark), Nikko Chemicals Co., Ltd.), or polyoxyethylene hydrogenated castor oil 50 (Nikkol HCO-50 (registered trademark), Nikko Chemicals Co., Ltd.)), lactic acid 0.1 g, and sodium lactate 4.0 g were added, and purified water was added to make a total amount of 100 g. The mixture was stirred at room temperature until homogenous to produce the topical preparation of the present invention (loxoprofen-l-menthol-tocopherol acetate combination liquid) or the topical preparation for comparison (loxoprofen-l-menthol-tocopherol acetate combination liquid).

[0060] [Table 7]

[0061] [Table 8]

[0062] [Table 9]

[0063] As shown in Table 7, the topical preparation of the present invention containing a solubilizing agent (a solution containing loxoprofen, l-menthol and tocopherol acetate) was a transparent liquid, whereas the comparative topical preparation not containing a solubilizing agent (a solution containing loxoprofen, l-menthol and tocopherol acetate) was cloudy. Furthermore, as shown in Table 8, the topical preparation of the present invention (liquid preparation of loxoprofen, l-menthol, and tocopherol acetate) containing 4 to 6% by mass of polyoxyethylene hydrogenated castor oil 60 as a solubilizer showed no problems with appearance, pH, crystal precipitation, or the contents of loxoprofen, l-menthol, and tocopherol acetate. As shown in Table 9, no problems were found in the appearance, pH, crystal precipitation, or the contents of loxoprofen, l-menthol, and tocopherol acetate for the topical preparation of the present invention (liquid preparation containing loxoprofen, l-menthol, and tocopherol acetate) containing 10% by mass of decaglyceryl laurate as a solubilizer, or for the topical preparation of the present invention (liquid preparation containing loxoprofen, l-menthol, and tocopherol acetate) containing 4.0% by mass of polyoxyethylene hydrogenated castor oil 50 as a solubilizer.

[0064] [Example 15] Preparation of the topical preparation of the present invention (a liquid preparation containing loxoprofen, l-menthol and tocopherol acetate) According to the formulation shown in Table 10, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous), 3.0 g of l-menthol, and 0.5 g of tocopherol acetate were weighed into a stainless steel container, and 45.0 g of ethanol was added to dissolve at room temperature. 0.2 g of hypromellose previously dispersed in 5 g of diisopropyl adipate and 30 g of purified water were added and dissolved at room temperature. After dissolution, 5 g of polyoxyethylene hydrogenated castor oil 60 (Nikkol HCO-60 (registered trademark), manufactured by Nikko Chemicals Co., Ltd.) was added as a solubilizing agent, and the prescribed amount of lactic acid and the prescribed amount of sodium lactate were added, and purified water was added so that the total amount became 100 g, and the mixture was stirred at room temperature until it became uniform, to produce the topical agent of the present invention (a liquid formulation containing loxoprofen, l-menthol, and tocopherol acetate).

[0065] [Table 10]

[0066] As shown in Table 10, within the range of 0.03 to 0.12 g of lactic acid and 2.5 to 10.0 g of sodium lactate (lactic acid:sodium lactate = 1:33 to 1:100), the appearance was transparent, the pH hardly changed from the initial state, there was no crystal precipitation, and there was almost no decrease in the content of any of the loxoprofen, l-menthol, and tocopherol acetate.

[0067] [Example 16] Preparation of topical preparation of the present invention (liquid preparation containing loxoprofen and tocopherol acetate) According to the formulation shown in Table 11, 1.13 g of loxoprofen sodium hydrate (1 g as anhydrous form) and 0.5 g of tocopherol acetate were weighed into a stainless steel container, and 45.0 g of ethanol was added to dissolve at room temperature. 0.2 g of hypromellose, which had been previously dispersed in 5 g of diisopropyl adipate, and 30 g of purified water were added and dissolved at room temperature. After dissolution, 5 g of polyoxyethylene hydrogenated castor oil 60 (Nikkol HCO-60 (registered trademark), manufactured by Nikko Chemicals Co., Ltd.) as a solubilizing agent, the prescribed amount of lactic acid and the prescribed amount of sodium lactate were added, and purified water was further added so that the total amount became 100 g, and the mixture was stirred at room temperature until it became uniform, to produce the topical agent of the present invention (a liquid formulation containing loxoprofen and tocopherol acetate).

[0068] [Table 11]

[0069] As shown in Table 11, within the range of 0.03 to 0.12 g of lactic acid and 2.5 to 10.0 g of sodium lactate (lactic acid:sodium lactate = 1:33 to 1:100), the appearance was transparent, the pH showed almost no change from the initial stage, there was no crystal precipitation, and almost no decrease in the contents of rofecoxib and tocopherol acetate was observed. [Industrial Applicability]

[0070] The topical preparation of the present invention is useful as an anti-inflammatory and analgesic topical preparation for the skin for humans, etc. Therefore, the topical preparation of the present invention can be used, for example, in the pharmaceutical industry.

Claims

1. A skin topical preparation comprising the following ingredients 1 to 5: 1) loxoprofen or a pharma- ceutical acceptable salt thereof, 2) terpenes and / or tocopherols; 3) Esters having 10 to 13 carbon atoms or molecular weights ranging from 185 to 250; 4) A pH adjuster containing 0.01 to 0.3% by mass of lactic acid and 1.5 to 20% by mass of a lactate salt in a ratio of 1:10 to 1:150 (lactic acid:lactate, mass ratio); 5) Solubilizers, if tocopherols are included.

2. The skin topical preparation according to claim 1 , further comprising a thickening agent, a lower alcohol, and / or water.

3. 2. The external skin preparation according to claim 1, wherein the terpene is l-menthol or dl-menthol.

4. 2. The skin topical preparation according to claim 1, wherein the ester is diethyl adipate or diisopropyl adipate.

5. 2. The external skin preparation according to claim 1, wherein the pharma- ceutical acceptable salt of rofecoxib is rofecoxib sodium or a hydrate thereof.

6. The topical skin preparation according to claim 2, wherein the thickening agent is one or more polymers selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose, carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and polyacrylic acid.

7. The skin topical preparation according to claim 2 , wherein the lower alcohol is ethyl alcohol, propyl alcohol, or isopropyl alcohol.

8. 2. The skin topical preparation according to claim 1, wherein the tocopherol is tocopherol acetate.

9. The skin topical preparation according to claim 1, wherein the solubilizing agent is one or more selected from the group consisting of polysorbates, polyoxyethylene hydrogenated castor oils, polyoxyethylene polyoxypropylene cetyl ethers, decaglyceryl laurate, and lauromacrogols.

10. The external skin preparation according to any one of claims 1 to 9, wherein the external skin preparation is a semi-solid or liquid preparation.

11. The external skin preparation according to any one of claims 1 to 9, wherein the external skin preparation is a liquid, a gel, an ointment, a cream, a foam, a patch, or a spray.

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