Loxoprofen-containing topical skin preparation

Abstract

To provide an external preparation having a markedly improved percutaneous absorbency, compared to conventional loxoprofen external preparations and preparation techniques thereof, by blending loxoprofen with a specific active ingredient.SOLUTION: A skin external preparation contains the following (a) to (e) components: (a) loxoprofen, (b) l-menthol, (c) ethanol, (d) one or more selected from nonanoic acid vanillylamide, glycyrrhetinic acid, benzyl nicotinate ester and vitamin E, and (e) chlorpheniramine maleate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a topical skin preparation containing loxoprofen, which has excellent analgesic and anti-inflammatory effects. More specifically, the present invention relates to a topical skin preparation that has significantly improved transdermal absorbability compared to previous topical loxoprofen preparations and their formulation technologies by incorporating a specific active ingredient into loxoprofen. [Background technology]

[0002] Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and anti-inflammatory drug (NSAID), has antipyretic, analgesic, and anti-inflammatory effects based on its inhibitory action on prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract unchanged after oral administration, with little irritation to the gastric mucosa, and becomes activated in the body. Therefore, it is known to cause less gastric mucosal damage than the active form (see, for example, Non-Patent Document 1).

[0003] In recent years, loxoprofen has been commercially available as a topical anti-inflammatory analgesic in the form of patches, tapes, and gels, and has been used clinically (see, for example, Non-Patent Document 2). It is known that loxoprofen is also converted to the trans-OH form (active form) by ketone reductase in the skin (see, for example, Patent Document 1).

[0004] Chlorpheniramine maleate is used as an antihistamine in topical preparations to treat urticaria and itching associated with skin diseases (eczema, dermatitis, cutaneous pruritus, drug rash). l-Menthol is used as a circulation-promoting ingredient in topical preparations, and as a cooling agent and fragrance in pharmaceutical additives. Glycyrrhetinic acid is used as an anti-inflammatory ingredient in topical preparations. Nonanoic acid vanillylamide is used as a warming stimulant and circulation-improving ingredient in topical preparations. Nicotinic acid benzyl ester is used as a circulation-improving ingredient in topical preparations, and as a solubilizing agent in pharmaceutical additives. Vitamin E is used as a circulation-improving ingredient in topical preparations, and as a stabilizer and antioxidant in pharmaceutical additives.

[0005] Previously, topical preparations containing loxoprofen have been disclosed, including a gel formulation for topical use that incorporates a carboxyvinyl polymer to enhance the transdermal absorption of loxoprofen (see Patent Document 2), and a formulation that incorporates propylene glycol and propylene glycol fatty acid esters as additives to enhance the transdermal absorption of loxoprofen (see Patent Document 3). Furthermore, polyhydric alcohols such as propylene glycol, butylene glycol, and glycerin are often added to topical liquid preparations for skin to improve the feel of use, and these polyhydric alcohols are known to be used as transdermal absorption enhancers for medicinal ingredients (see Patent Document 4).

[0006] It is also known that antihistamines enhance the skin permeability of nonsteroidal anti-inflammatory drugs and increase the pharmacological effect of the main drug (see Patent Document 5).Furthermore, liquid preparations that have been formulated to improve storage stability by combining loxoprofen and isopropanol and further contain glycyrrhetinic acid, nonanoic acid vanillylamide, chlorpheniramine maleate, etc. are also known (Patent Document 6).

[0007] However, it is not known that the skin permeability of loxoprofen sodium decreases when a topical preparation containing loxoprofen and l-menthol is blended with one or more ingredients selected from glycyrrhetinic acid, nicotinic acid benzyl ester, nonanoic acid vanillylamide, vitamin E, etc. Furthermore, it is not known at all how chlorpheniramine maleate affects the percutaneous absorption of loxoprofen in such topical preparations. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] JP 2008-074873 A [Patent Document 2] Patent No. 4195178 [Patent Document 3] JP 2016-79180 A [Patent Document 4] Japanese Patent Application Publication No. 5-000946 [Patent Document 5] JP 2002-128698 A [Patent Document 6] JP 2017-200909 A [Non-patent literature]

[0009] [Non-Patent Document 1] Pharmacology and Therapy Vol.16 No.2 1988 p.611-619 [Non-patent document 2] JAPIC Medical Drug Collection 2013 Maruzen 2012 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to find an ingredient that further enhances the percutaneous absorption of loxoprofen in an external skin preparation (combination preparation) containing loxoprofen and other active ingredients. [Means for solving the problem]

[0011] The present inventors investigated the transdermal absorbability of topical skin preparations (combination preparations) containing loxoprofen, l-menthol, and ethanol, in order to develop topical skin preparations further containing ingredients such as glycyrrhetinic acid, nicotinic acid benzyl ester, nonanoic acid vanillylamide, and vitamin E, with the aim of imparting or enhancing anti-inflammatory, warming, and blood circulation-promoting effects. As a result, they found that the transdermal absorbability of loxoprofen was reduced by adding one or more ingredients selected from glycyrrhetinic acid, nonanoic acid vanillylamide, nicotinic acid benzyl ester, and vitamin E to topical skin preparations containing loxoprofen, l-menthol, and ethanol. They also found that the transdermal absorbability of loxoprofen was significantly improved by adding chlorpheniramine maleate to these topical skin preparations, thereby completing the present invention.

[0012] That is, the present invention is as follows. (1) A topical skin preparation containing the following ingredients (a) to (e): (a) Loxoprofen (b) l-menthol (c) Ethanol (d) one or more selected from nonanoic acid vanillylamide, glycyrrhetinic acid, nicotinic acid benzyl ester, and vitamin E compounds (e) Chlorpheniramine maleate (2) A topical skin preparation according to (1), which contains nonanoic acid vanillylamide as component (d). (3) A topical skin preparation according to (1) or (2), which contains glycyrrhetinic acid as component (d). (4) The topical skin preparation according to any one of (1) to (3), which contains nicotinic acid benzyl ester as component (d). (5) The topical skin preparation according to any one of (1) to (4), which contains vitamin E as component (d). (6) A topical skin preparation according to any one of (1) to (5), which contains nonanoic acid vanillylamide and nicotinic acid benzyl ester as component (d). (7) The topical skin preparation according to any one of (1) to (6), further comprising a polyhydric alcohol. (8) The topical skin preparation according to (7), wherein the polyhydric alcohol is propylene glycol or 1,3-butylene glycol. (9) The topical skin preparation according to any one of (1) to (8), wherein the pH of the preparation is 5.0 to 7.5. (10) The topical skin preparation according to any one of (1) to (9), which is for analgesic and anti-inflammatory purposes. (11) The topical skin preparation according to any one of (1) to (10), which is in the form of a liquid for topical application, an ointment, a cream, a spray, a gel, a patch, or a solid for topical application. (12) The topical skin preparation according to any one of (1) to (10), which is in the form of a liquid preparation for topical application. is. [Effects of the Invention]

[0013] The topical skin preparation of the present invention has an excellent feel when used, prevents the reduction in the transdermal absorption of loxoprofen due to the ingredients contained therein, maintains its anti-inflammatory and analgesic effects, and enhances or imparts warming stimulating effects, blood circulation promoting effects, antihistamine effects, etc., making it extremely useful in clinical practice. DETAILED DESCRIPTION OF THE INVENTION

[0014] In the present invention, "loxoprofen" refers to loxoprofen or a salt thereof (including a hydrate salt), preferably loxoprofen sodium or loxoprofen sodium dihydrate, more preferably loxoprofen sodium dihydrate.

[0015] The loxoprofen of the present invention is listed in the 17th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0016] The l-menthol used in the present invention is listed in the 17th revised Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives.

[0017] The ethanol (also referred to as ethyl alcohol or alcohol) in the present invention is listed in the Pharmaceutical Additives Dictionary 2016 (Yakuji Nipposha, 2016) and is used in external preparations as a solubilizer, base, preservative, solvent, solubilizer, etc. Ethanol with an ethanol content of 99.5% by volume or more is also called absolute ethanol, and this is also included in the ethanol in the present invention.

[0018] The nonanoic acid vanillylamide (also called nonylic acid vanillylamide) of the present invention is listed in the Pharmaceutical Additives Dictionary 2016 (Yakuji Nipposha, 2016).

[0019] The glycyrrhetinic acid used in the present invention is listed in the Japanese Pharmacopoeia Non-Drug Standards 2002.

[0020] The nicotinic acid benzyl ester (also referred to as benzyl nicotinate) of the present invention is listed in the Japanese Pharmacopoeia Non-prescription Drug Standards 2002.

[0021] The vitamin E compounds in the present invention refer to vitamin E or derivatives thereof, and specific examples thereof include tocopherol, d-σ-tocopherol, tocopherol calcium succinate, tocopherol acetate, and tocopherol nicotinate, which are listed in the 17th revised Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives.

[0022] Chlorpheniramine maleate in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia.

[0023] The polyhydric alcohol in the present invention refers to an alcohol having two or more hydroxyl groups in the molecule, which is used in topical preparations as a solubilizer, base, humectant, thickener, solvent, solubilizer, etc., and is listed in the Pharmaceutical Additives Dictionary 2016, for example, propylene glycol, 1,3-butylene glycol, macrogol (also known as polyethylene glycol), and D-sorbitol. Preferred are propylene glycol, 1,3-butylene glycol, or a combination thereof.

[0024] The content of loxoprofen in the topical preparation of the present invention is preferably 0.1 to 10% by weight, more preferably 0.5 to 8.5% by weight, in terms of loxoprofen sodium dihydrate.

[0025] The content of l-menthol in the topical preparation of the present invention is preferably 0.01 to 10% by weight, more preferably 0.5 to 7.5% by weight.

[0026] The content of ethanol in the topical preparation of the present invention is preferably 10.0 to 70.0% by weight, more preferably 30.0 to 60.0% by weight.

[0027] The content of nonanoic acid vanillylamide in the topical preparation of the present invention is preferably 0.001 to 0.1% by weight, more preferably 0.005 to 0.05% by weight.

[0028] The content of glycyrrhetinic acid in the topical preparation of the present invention is preferably 0.01 to 1.0% by weight, more preferably 0.02 to 0.75% by weight.

[0029] The content of benzyl nicotinate in the topical preparation of the present invention is preferably 0.001 to 0.15% by weight, more preferably 0.005 to 0.05% by weight.

[0030] The content of vitamin E in the topical preparation of the present invention is preferably 0.001 to 5% by weight, more preferably 0.05 to 1% by weight.

[0031] The content of chlorpheniramine maleate in the topical preparation of the present invention is preferably 0.01 to 1% by weight, more preferably 0.05 to 1% by weight.

[0032] In the topical preparation of the present invention, when a polyhydric alcohol is contained, the content of the polyhydric alcohol is not particularly limited, but is preferably 0.5 to 20% by weight, more preferably 1.0 to 15% by weight.

[0033] The pH range of the topical agent of the present invention is preferably 5.0 to 7.5, and more preferably 6.0 to 7.5.

[0034] In the present invention, a lower alcohol other than ethanol can be added. The lower alcohol in the present invention refers to an aliphatic alcohol having 1 to 4 carbon atoms that is used in external preparations as a solubilizer, base, preservative, solvent, solubilizer, etc., such as methanol, propanol, isopropanol (also known as isopropyl alcohol), and butyl alcohol.

[0035] Furthermore, the topical preparation of the present invention may contain drugs and pharmaceutical additives other than the above-mentioned ingredients that are commonly used in topical analgesic and anti-inflammatory skin preparations.

[0036] Examples of such drugs include anti-inflammatory agents such as glycyrrhizinic acid, antihistamines such as diphenhydramine, antipruritics such as crotamiton, local irritant ingredients such as chili pepper extract, and herbal ingredients such as arnica tincture, and these drugs can be incorporated within a range that does not impair the effects of the present invention.

[0037] Pharmaceutical additives other than the above-mentioned components are added as needed, for example, for the purpose of further improving the stability of the content over time and the feel when used, and examples thereof include bases, thickeners, solubilizers, humectants, adhesives, pH adjusters, antioxidants, and cooling agents.

[0038] Examples of the base in the present invention include styrene-isoprene-styrene copolymer, polyisobutylene, liquid paraffin, partially neutralized polyacrylic acid, and partially saponified polyvinyl alcohol.

[0039] Examples of thickening agents that can be added in the present invention include carmellose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, xanthan gum, macrogol, glycerin, and carboxyvinyl polymer.

[0040] As the solubilizer in the present invention, for example, diisopropyl adipate, polyoxyethylene hydrogenated castor oil, polysorbate, etc. can be added.

[0041] As the wetting agent in the present invention, for example, sodium dl-pyrrolidone carboxylate, polysorbate 40 liquid, etc. may be added.

[0042] As the adhesive in the present invention, for example, dibutylhydroxytoluene, hydrogenated rosin glycerin ester, etc. may be added.

[0043] Examples of pH adjusters that can be used in the present invention include hydrochloric acid, sodium hydroxide, potassium hydroxide, lactic acid, organic acids, organic amines, and phosphoric acid.

[0044] Examples of antioxidants that can be used in the present invention include ascorbic acid, ascorbic acid palmitate, sodium hydrogen sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, and propyl gallate.

[0045] Examples of the cooling agent in the present invention include camphor, dl-camphor, peppermint oil, eucalyptus oil, and the like.

[0046] Examples of dosage forms of the topical skin preparation of the present invention include topical liquid preparations, creams, gels, sprays (pump sprays, topical aerosols), ointments, patches (tapes, poultices), topical solid preparations, etc. These dosage forms can be produced using appropriate additives according to the usual methods described in the 17th edition of the Japanese Pharmacopoeia, etc.

[0047] Furthermore, the preparation of the external skin preparation of the present invention can be housed in a container or package made of a metal such as aluminum, or an olefin resin such as polyethylene or polypropylene.

[0048] The topical skin preparation of the present invention can be used as an analgesic and anti-inflammatory agent for patients suffering from pain or inflammation, such as lower back pain, bruises, sprains, shoulder pain associated with stiff shoulders, tendonitis, elbow pain, joint pain, etc. An appropriate amount of the topical skin preparation of the present invention is applied, sprayed, or pasted onto the affected area by the patient once to several times a day.

[0049] The present invention will be explained in more detail below with reference to examples. [Example]

[0050] (Formulation example)

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] [Table 4]

[0055] After dissolving the ingredients listed in Tables 1 to 4 above by stirring and mixing, the external preparations for skin of Formulation Examples 1 to 23 can be obtained.

[0056] The preparation can be carried out by using the above ingredients and amounts in accordance with the Japanese Pharmacopoeia General Provisions for Preparations, sections on "external liquid preparations," "external solid preparations," and "gel preparations."

[0057] (Test Example 1) Skin permeability test 1 of topical skin preparation containing loxoprofen (1) Test materials Loxoprofen sodium dihydrate was from Daiichi Sankyo Chemical Pharma Co., Ltd.; glycyrrhetinic acid, chlorpheniramine maleate, nicotinic acid benzyl ester, and nonanoic acid vanillylamide were from Tokyo Chemical Industry Co., Ltd.; tocopherol acetate was from Riken Vitamin Co., Ltd.; l-menthol was from Suzuki Menthol Co., Ltd.; hydrochloric acid was from Kanto Chemical Co., Ltd.; propylene glycol was from Maruishi Pharmaceutical Co., Ltd.; absolute ethanol was from Imazu Pharmaceutical Co., Ltd.; polyoxyethylene hydrogenated castor oil 40 was from Nikko Chemicals Co., Ltd.; and polysorbate 80 was from Nikko Chemicals Co., Ltd.

[0058] (2) Sample preparation The components shown in Table 5 below were mixed and dissolved to obtain liquid preparations of samples 1 to 9.

[0059] (3) Test method Reconstructed human epidermis model (EPISKIN large, effective diffusion area 1.07cm) 2(Lot No. #17EPIS002, Nicoderm Research Co., Ltd.) was placed in a 12-well tissue culture plate (IWAKI, Asahi Glass Co., Ltd.), and 2 mL of 1 / 15 M phosphate-buffered saline (pH 7.4) (PBS) was dispensed into each well to serve as the receiver solution. 200 μL of each sample was placed in the donor side, and the tissue culture plate was covered with a lid and placed in an incubator at 32°C for the skin permeation test. The receiver solution was collected after permeation, and the concentration of loxoprofen sodium in the receiver solution was measured by high-performance liquid chromatography (HPLC) to calculate the amount of loxoprofen sodium permeated per unit area. The test was performed three times for each sample, and the average value was calculated. From this value, the relative permeation amount was calculated, with the cumulative amount of loxoprofen sodium permeated per unit area of ​​the control (sample 1) after 2 hours of permeation set at 100.

[0060] The quantity of loxoprofen sodium was determined by liquid chromatography under the following conditions. Detector: ultraviolet absorption photometer (measurement wavelength: 210 nm), column: 4.6 mm inner diameter, 15 cm long stainless steel column packed with 5 μm octadecylsilanized silica gel for liquid chromatography, column temperature: 40°C, mobile phase: methanol / water / phosphoric acid (550:450:1)

[0061] (4) Test results The results are shown in Table 5.

[0062] [Table 5]

[0063] A comparison of Samples 1 and 2 in Table 5 revealed that the percutaneous absorption of loxoprofen was reduced by further adding glycyrrhetinic acid, nicotinic acid benzyl ester, and nonanoic acid vanillylamide to a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol. On the other hand, a comparison of Samples 1, 2, and 3 revealed that the percutaneous absorption of loxoprofen was restored by further adding chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, glycyrrhetinic acid, nicotinic acid benzyl ester, and nonanoic acid vanillylamide, and further revealed that the percutaneous absorption was increased compared to a topical preparation containing only loxoprofen, l-menthol, and ethanol.

[0064] Furthermore, a comparison of Sample 1 and Sample 5 revealed that the further incorporation of nonanoic acid vanillylamide in a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol reduced the percutaneous absorption of loxoprofen. On the other hand, a comparison of Sample 1, Sample 4, and Sample 5 revealed that the further incorporation of chlorpheniramine maleate in a topical preparation containing loxoprofen, l-menthol, ethanol, and nonanoic acid vanillylamide restored the reduced percutaneous absorption of loxoprofen.

[0065] Furthermore, a comparison of Samples 1 and 6 revealed that the addition of tocopherol acetate to a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol reduced the percutaneous absorption of loxoprofen. On the other hand, a comparison of Samples 6 and 7 revealed that the addition of chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, ethanol, and tocopherol acetate restored the reduced percutaneous absorption of loxoprofen.

[0066] Furthermore, a comparison of Samples 1 and 8 revealed that the percutaneous absorption of loxoprofen was reduced by further adding glycyrrhetinic acid, nicotinic acid benzyl ester, nonanoic acid vanillylamide, and tocopherol acetate to a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol. On the other hand, a comparison of Samples 8 and 9 revealed that the reduced percutaneous absorption of loxoprofen was restored by further adding chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, nicotinic acid benzyl ester, nonanoic acid vanillylamide, and tocopherol acetate.

[0067] (Test Example 2) Skin permeability test 2 of topical skin preparation containing loxoprofen (1) Test materials Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd.; glycyrrhetinic acid, chlorpheniramine maleate, nicotinic acid benzyl ester, and nonanoic acid vanillylamide were manufactured by Tokyo Chemical Industry Co., Ltd.; tocopherol acetate was manufactured by Riken Vitamin Co., Ltd.; l-menthol was manufactured by Suzuki Menthol Co., Ltd.; hydrochloric acid was manufactured by Kanto Chemical Co., Ltd.; propylene glycol was manufactured by Maruishi Pharmaceutical Co., Ltd.; and absolute ethanol was manufactured by Imazu Pharmaceutical Co., Ltd.

[0068] (2) Sample preparation The components shown in Table 6 below were mixed and dissolved to obtain liquid preparations of samples 10 to 14.

[0069] (3) Test method Reconstructed human epidermis model (EPISKIN large, effective diffusion area 1.07cm) 2(Lot No. #17EPIS028, Nicoderm Research Co., Ltd.) was placed in a 12-well tissue culture plate (IWAKI, Asahi Glass Co., Ltd.), and the same procedure as in Skin Permeation Test 1 above was carried out. After permeation, the receiver solution was collected, and the concentration of loxoprofen sodium in the receiver solution was measured by high-performance liquid chromatography (HPLC) to calculate the amount of loxoprofen sodium permeated through the skin per unit area. The test was carried out three times for each sample, and the average value was calculated. From this value, the relative permeation amount was calculated, assuming that the cumulative amount of loxoprofen sodium permeated through the skin per unit area of ​​the control (sample 10) two hours after permeation was 100.

[0070] The quantity of loxoprofen sodium was determined by liquid chromatography under the same conditions as in Skin Permeability Test 1 above.

[0071] [Table 6]

[0072] A comparison of Samples 10 and 12 in Table 6 revealed that the percutaneous absorption of loxoprofen was reduced by further adding glycyrrhetinic acid and nonanoic acid vanillylamide to a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol. On the other hand, a comparison of Samples 10, 11, and 12 revealed that the reduced percutaneous absorption of loxoprofen was restored by further adding chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, and nonanoic acid vanillylamide.

[0073] Furthermore, a comparison of Samples 10 and 14 revealed that the percutaneous absorption of loxoprofen was reduced by further adding glycyrrhetinic acid and nicotinic acid benzyl ester to a topical preparation (combination preparation) containing loxoprofen, l-menthol, and ethanol. On the other hand, a comparison of Samples 13 and 14 revealed that the reduced percutaneous absorption of loxoprofen was restored by further adding chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, and nicotinic acid benzyl ester. [Industrial Applicability]

[0074] The topical skin preparation containing loxoprofen of the present invention is extremely useful because it has an excellent feel when used, prevents the reduction in the transdermal absorption of loxoprofen due to the ingredients contained in the preparation, maintains its anti-inflammatory and analgesic effects, and enhances or imparts warming, stimulating, blood circulation-promoting, and antihistamine effects.

Claims

1. An external skin preparation comprising the following components (a) to (e), and further comprising polyoxyethylene hydrogenated castor oil and / or polysorbate, and in the form of an external liquid preparation: (a) loxoprofen (b) l-menthol (c) ethanol (d) Vitamin E compounds, which are one or more selected from tocopherol, d-σ-tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate. (e) chlorpheniramine maleate

2. 2. The topical skin preparation according to claim 1, further comprising nonanoic acid vanillylamide.

3. 3. The external skin preparation according to claim 1, further comprising glycyrrhetinic acid.

4. The external skin preparation according to any one of claims 1 to 3, further comprising nicotinic acid benzyl ester.

5. 2. The topical skin preparation according to claim 1, further comprising nonanoic acid vanillylamide and nicotinic acid benzyl ester.

6. The external skin preparation according to claim 1 , further comprising a polyhydric alcohol.

7. 7. The external skin preparation according to claim 6, wherein the polyhydric alcohol is propylene glycol or 1,3-butylene glycol.

8. The external skin preparation according to any one of claims 1 to 7, wherein the pH of the preparation is 5.0 to 7.

5.

9. The external skin preparation according to any one of claims 1 to 8, which is for analgesic and anti-inflammatory purposes.

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