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 having an excellent analgesic and anti-inflammatory effect. More specifically, by containing a specific active ingredient in loxoprofen, the present invention relates to a topical preparation with significantly improved percutaneous absorption compared to conventional loxoprofen topical preparations and their formulation technologies.

Background Art

[0002] Loxoprofen, which is a propionic acid-based non-steroidal anti-inflammatory drug (NSAIDs), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis, similar to other NSAIDs. In addition, loxoprofen is known to be a prodrug that is absorbed from the digestive tract as an unchanged form with a weak gastric mucosal irritation effect after oral administration and becomes an active form in the body, and thus has a feature of causing less gastric mucosal damage than the active form (see, for example, Non-Patent Document 1).

[0003] In recent years, as a topical anti-inflammatory and analgesic agent, loxoprofen has been commercially available as a patch, a tape, and a gel and has been used clinically (see, for example, Non-Patent Document 2). It is also known that loxoprofen is converted into a 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, pruritus, drug eruption). l-menthol is used as a blood circulation promoting ingredient in topical preparations, and as a cooling agent and fragrance in pharmaceutical excipients. Glycyrrhetinic acid is used as an anti-inflammatory ingredient in topical preparations. Vanillyl nonanoate is used as a warming and blood circulation improving ingredient in topical preparations. Benzyl nicotinate is used as a blood circulation improving ingredient in topical preparations, and as a solubilizing agent in pharmaceutical excipients. Vitamin E is used as a blood circulation improving ingredient in topical preparations, and as a stabilizer and antioxidant in pharmaceutical excipients.

[0005] To date, it has been disclosed that topical preparations containing loxoprofen have been enhanced by incorporating carboxyvinyl polymer to improve the transdermal absorption of loxoprofen (see Patent Document 2), and by incorporating propylene glycol and propylene glycol fatty acid ester as additives to improve the transdermal absorption of loxoprofen (see Patent Document 3). Furthermore, polyhydric alcohols such as propylene glycol, butylene glycol, and glycerin are often added to improve the feel of topical liquid preparations, and it is known that these polyhydric alcohols are used as transdermal absorption enhancers of the active ingredient (see Patent Document 4).

[0006] Furthermore, it is known that antihistamines enhance the skin permeability of nonsteroidal anti-inflammatory drugs and improve the pharmacological effect of the main ingredient (see Patent Document 5). In addition, liquid formulations containing loxoprofen and isopropanol to improve storage stability are also known, in which glycyrrhetinic acid, vanillyl nonanoate, chlorpheniramine maleate, etc., are further added (Patent Document 6).

[0007] However, it is not known that adding one or more ingredients selected from glycyrrhetinic acid, benzyl nicotinate, vanillylamide nonanoate, and vitamin E to a topical preparation containing loxoprofen and l-menthol reduces the skin permeability of loxoprofen sodium. Furthermore, it is completely unknown how chlorpheniramine maleate affects the transdermal absorption of loxoprofen in such topical preparations. [Prior art documents] [Patent Documents]

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

[0009] [Non-Patent Document 1] Pharmacology and Therapeutics Vol.16 No.2 1988 pp.611-619 [Non-Patent Document 2] JAPIC Medical Drug Compendium 2013, Maruzen, 2012 [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of the present invention is to find a component that further enhances the transdermal absorption of loxoprofen in a topical skin preparation (combination preparation) containing loxoprofen and other active ingredients. [Means for solving the problem]

[0011] The present inventors investigated the transdermal absorption of topical preparations containing loxoprofen, l-menthol, and ethanol in order to develop a topical preparation (combination preparation) that further contains components such as glycyrrhetinic acid, benzyl nicotinate, vanillylamide nonanoate, 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 absorption of loxoprofen decreased when one or more selected components from glycyrrhetinic acid, vanillylamide nonanoate, benzyl nicotinate, and vitamin E were added to a topical preparation containing loxoprofen, l-menthol, and ethanol. Furthermore, they found that the transdermal absorption of loxoprofen was significantly improved when chlorpheniramine maleate was added to these topical preparations, thus completing the present invention.

[0012] In other words, the present invention is as follows: (1) A topical skin preparation containing the following ingredients (a) through (e). (a) Loxoprofen (b) l-menthol (c) Ethanol (d) One or more selected from nonanoic acid vanillylamide, glycyrrhetinic acid, benzyl nicotinate, and vitamin E derivatives. (e) Chlorpheniramine maleate (2) The topical skin preparation according to (1), comprising vanillylamide nonanoate as component (d). (3) A topical skin preparation according to (1) or (2), comprising glycyrrhetinic acid as component (d). (4) A topical skin preparation according to any one of items (1) to (3), comprising benzyl nicotinate as component (d). (5) A topical skin preparation according to any one of items (1) to (4), comprising vitamin E as component (d). The external preparation for skin according to any one of (1) to (5), which contains vanillylamide nonanoate and benzyl nicotinate as the component (d). (7) The external preparation for skin according to any one of (1) to (6), which further contains a polyhydric alcohol. (8) The external preparation for skin according to (7), wherein the polyhydric alcohol is propylene glycol or 1,3 - butylene glycol. (9) The external preparation for skin according to any one of (1) to (8), wherein the formulation pH is 5.0 to 7.5. (10) The external preparation for skin according to any one of (1) to (9), which is for analgesic and anti - inflammatory use. (11) The external preparation for skin according to any one of (1) to (10), wherein the dosage form is an external liquid preparation, an ointment, a cream, a spray, a gel, a patch or a solid external preparation. (12) The external preparation for skin according to any one of (1) to (10), wherein the dosage form is an external liquid preparation. It is.

Advantages of the Invention

[0013] The external preparation for skin of the present invention has excellent usability, suppresses the decrease in the transdermal absorption of loxoprofen due to the compounding components, maintains the anti - inflammatory and analgesic effects, and enhances or imparts a warming - sensation stimulating effect, a blood - circulation promoting effect, an anti - histamine effect, etc., and is extremely useful clinically. <000009​​​​​​​​​​​​​The l-menthol used in this invention is listed in the 17th edition of the Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives.

[0017] The ethanol (also called ethyl alcohol or alcohol) used in this invention is listed in the 2016 Dictionary of Pharmaceutical Additives (Yakuji Nippo Co., Ltd., 2016) and is used in topical preparations as a solubilizer, base, preservative, solvent, and solubilizer. 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 used in this invention.

[0018] The nonanoic acid vanillylamide (also known as nonyl vanillylamide) used in this invention is listed in the Pharmaceutical Additives Dictionary 2016 (Yakuji Nippo Co., Ltd., 2016).

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

[0020] The benzyl nicotinate ester (also known as benzyl nicotinate) used in this invention is listed in the Japanese Pharmacopoeia Non-Official Drug Standards 2002.

[0021] In this invention, vitamin E compounds refer to vitamin E or its derivatives, specifically tocopherol, d-σ-tocopherol, calcium tocopherol succinate, tocopherol acetate, tocopherol nicotinate, etc. These are listed in the 17th edition of the Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives.

[0022] The chlorpheniramine maleate used in this invention is listed in the 17th edition of the Japanese Pharmacopoeia.

[0023] In this invention, polyhydric alcohols are alcohols with two or more hydroxyl groups in their molecule that are used in topical preparations as solubilizers, bases, wetting agents, viscosity enhancers, solvents, or solubilizers. Examples include propylene glycol, 1,3-butylene glycol, macrogol (also known as polyethylene glycol), and D-sorbitol, which are listed in the 2016 Dictionary of Pharmaceutical Additives. Preferably, propylene glycol, 1,3-butylene glycol, or a combination thereof.

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

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

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

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

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

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

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

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

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

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

[0034] In the present invention, lower alcohols other than ethanol can be added. The lower alcohols in the present invention are aliphatic alcohols having 1 to 4 carbon atoms that are used in topical preparations for purposes such as solubilizers, bases, preservatives, solvents, and solubilizers, such as methanol, propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol.

[0035] Furthermore, in the topical preparation of the present invention, drugs and pharmaceutical additives that are commonly used in topical skin preparations for analgesia and anti-inflammatory purposes, other than the above-mentioned components, may be added.

[0036] Examples of such drugs include anti-inflammatory agents such as glycyrrhizic acid, antihistamines such as diphenhydramine, antipruritic agents such as crotamiton, local irritants such as capsicum extract, and herbal ingredients such as arnica tincture. These drugs can be incorporated in amounts that do not impair the effects of the present invention.

[0037] Pharmaceutical additives other than those listed above are added as needed, for example, to improve content stability over time or to further enhance the feel of the product. Examples include bases, viscosity enhancers, solvents, wetting agents, adhesives, pH adjusters, antioxidants, and cooling agents.

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

[0039] Examples of viscosity-enhancing agents that can be added in the present invention include carmellose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, xanthan gum, macrogol, glycerin, carboxyvinyl polymer, and the like.

[0040] Examples of solvents that can be added in the present invention include diisopropyl adipate, polyoxyethylene hydrogenated castor oil, and polysorbate.

[0041] In the present invention, for example, sodium dl-pyrrolidone carboxylate, polysorbate 40 solution, etc., can be added as wetting agents.

[0042] Examples of adhesives that can be added in the present invention include dibutylhydroxytoluene and hydrogen rosin glycerol ester.

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

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

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

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

[0047] Furthermore, the preparations for topical skin application of the present invention can be housed in metal containers or packaging made of aluminum or other metals, or in containers or packaging made of olefin resins such as polyethylene or polypropylene.

[0048] The topical skin preparation of the present invention can be used for analgesic and anti-inflammatory purposes in patients with pain or inflammation, such as those with lower back pain, bruises, sprains, shoulder pain associated with stiff shoulders, tenosynovitis, elbow pain, joint pain, etc. The topical skin preparation of the present invention is applied, sprayed, or patched to the affected area in an appropriate amount one to several times a day to the patient.

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

[0050] (Example of formulation)

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] [Table 4]

[0055] After stirring and mixing the ingredients listed in Tables 1-4 above and dissolving them, topical skin preparations for formulations 1-23 can be obtained.

[0056] As for the manufacturing method, the above ingredients and quantities can be used, and the product can be manufactured in accordance with the sections on "Topical Liquid Preparations," "Topical Solid Preparations," and "Gels" in the General Provisions of the Japanese Pharmacopoeia.

[0057] (Test Example 1) Skin permeability test of topical skin preparation containing loxoprofen 1 (1) Test materials The following ingredients were used: loxoprofen sodium dihydrate manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd., glycyrrhetinic acid, chlorpheniramine maleate, benzyl nicotinate, and vanillylamide nonanoate manufactured by Tokyo Chemical Industry Co., Ltd., tocopherol acetate manufactured by Riken Vitamin Co., Ltd., l-menthol manufactured by Suzuki Peppermint Co., Ltd., hydrochloric acid manufactured by Kanto Chemical Co., Ltd., propylene glycol manufactured by Maruishi Pharmaceutical Co., Ltd., anhydrous ethanol manufactured by Imazu Pharmaceutical Industry Co., Ltd., polyoxyethylene hydrogenated castor oil 40 manufactured by Nikko Chemicals Co., Ltd., and polysorbate 80 manufactured by Nikko Chemicals Co., Ltd.

[0058] (2) Preparation of specimens The components listed in Table 5 below were mixed and dissolved to obtain the liquid preparations for samples 1 to 9.

[0059] (3) Test method Regenerated human epidermis model (EPISKIN large, effective diffusion area 1.07 cm²) 2Lot number #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, the lid of the tissue culture plate was placed over it, and the plate was left standing in a 32°C incubator to perform a skin permeability 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 to 100.

[0060] The quantitative determination of loxoprofen sodium was performed by liquid chromatography, under the following conditions. Detector: UV absorbance spectrophotometer (measurement wavelength: 210 nm), Column: 4.6 mm inner diameter, 15 cm long stainless steel column packed with 5 μm octadecylsilylated silica gel for liquid chromatography, Column temperature: 40°C, Mobile phase: methanol / water / phosphoric acid (550:45 0:1)

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

[0062] [Table 5]

[0063] A comparison of Sample 1 and Sample 2 in Table 5 revealed that in topical preparations (combination preparations) containing loxoprofen, l-menthol, and ethanol, the addition of glycyrrhetinic acid, benzyl nicotinate, and vanillylamide nonanoate reduced the transdermal absorption of loxoprofen. On the other hand, a comparison of Sample 1, Sample 2, and Sample 3 revealed that in topical preparations containing loxoprofen, l-menthol, glycyrrhetinic acid, benzyl nicotinate, and vanillylamide nonanoate, the addition of chlorpheniramine maleate restored the reduced transdermal absorption of loxoprofen, and further increased transdermal absorption compared to topical preparations containing only loxoprofen, l-menthol, and ethanol.

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

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

[0066] Furthermore, a comparison of sample 1 and sample 8 revealed that in topical preparations (combination preparations) containing loxoprofen, l-menthol, and ethanol, the addition of glycyrrhetinic acid, benzyl nicotinate, vanillyl nonanoate, and tocopherol acetate reduced the transdermal absorption of loxoprofen. On the other hand, a comparison of sample 8 and sample 9 revealed that in topical preparations containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, benzyl nicotinate, vanillyl nonanoate, and tocopherol acetate, the addition of chlorpheniramine maleate restored the reduced transdermal absorption of loxoprofen.

[0067] (Test Example 2) Skin Permeability Test of Loxoprofen-Containing Topical Skin Preparation 2 (1) Test materials The following ingredients were used: loxoprofen sodium dihydrate manufactured by Daiichi Sankyo Chemical Pharma Co., Ltd.; glycyrrhetinic acid, chlorpheniramine maleate, benzyl nicotinate, and vanillylamide nonanoate manufactured by Tokyo Chemical Industry Co., Ltd.; tocopherol acetate manufactured by Riken Vitamin Co., Ltd.; l-menthol manufactured by Suzuki Peppermint Co., Ltd.; hydrochloric acid manufactured by Kanto Chemical Co., Ltd.; propylene glycol manufactured by Maruishi Pharmaceutical Co., Ltd.; and anhydrous ethanol manufactured by Imazu Pharmaceutical Industry Co., Ltd.

[0068] (2) Preparation of specimens The components listed in Table 6 below were mixed and dissolved to obtain the liquid preparations for samples 10-14.

[0069] (3) Test method Regenerated human epidermis model (EPISKIN large, effective diffusion area 1.07 cm²) 2The sample (lot number #17EPIS028, Nicoderm Research Co., Ltd.) was placed in a 12-well tissue culture plate (IWAKI, Asahi Glass Co., Ltd.), and the test was conducted in the same manner as in Skin Permeability Test 1 above. The receiver fluid was collected after permeation, and the concentration of loxoprofen sodium in the receiver fluid 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 10) after 2 hours of permeation set to 100.

[0070] The quantitative determination of loxoprofen sodium was performed by liquid chromatography, under the same conditions as in the skin permeability test 1 described above.

[0071] [Table 6]

[0072] A comparison of samples 10 and 12 in Table 6 revealed that adding glycyrrhetinic acid and vanillyl nonanoate to a topical preparation (combination) containing loxoprofen, l-menthol, and ethanol reduced the transdermal absorption of loxoprofen. On the other hand, a comparison of samples 10, 11, and 12 revealed that adding chlorpheniramine maleate to a topical preparation containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, and vanillyl nonanoate restored the reduced transdermal absorption of loxoprofen.

[0073] Furthermore, a comparison of sample 10 and sample 14 revealed that in topical preparations (combination preparations) containing loxoprofen, l-menthol, and ethanol, the addition of glycyrrhetinic acid and benzyl nicotinate reduced the transdermal absorption of loxoprofen. On the other hand, a comparison of sample 13 and sample 14 revealed that in topical preparations containing loxoprofen, l-menthol, ethanol, glycyrrhetinic acid, and benzyl nicotinate, the addition of chlorpheniramine maleate restored the reduced transdermal absorption of loxoprofen. [Industrial applicability]

[0074] The topical skin preparation containing loxoprofen of the present invention has excellent usability, suppresses the reduction in transdermal absorption of loxoprofen due to the ingredients, maintains its anti-inflammatory and analgesic effects, and enhances or imparts warming stimuli, blood circulation promoting effects, antihistamine effects, etc., making it extremely useful.

Claims

1. A topical skin preparation containing the components (a) to (e) below, and further containing a solvent, wherein the solvent is one or more selected from diisopropyl adipate, polyoxyethylene hydrogenated castor oil, and polysorbate. (a) Loxoprofen (b) l-menthol (c) Ethanol (d) Vitamin E compounds, one or more selected from tocopherol, d-σ-tocopherol, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate. (e) Chlorpheniramine maleate

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

3. The topical skin preparation according to claim 1 or 2, further comprising glycyrrhetinic acid.

4. Furthermore, the topical skin preparation according to any one of claims 1 to 3, further comprising benzyl nicotinate.

5. The topical skin preparation according to claim 1, further comprising vanillylamide nonanoate and benzyl nicotinate.

6. Furthermore, the topical skin preparation according to any one of claims 1 to 5, further containing a polyhydric alcohol.

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

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

5.

9. A topical skin preparation according to any one of claims 1 to 8, for analgesic and anti-inflammatory purposes.

10. A topical skin preparation according to any one of claims 1 to 9, wherein the dosage form is an ointment, cream, spray, gel, patch, or topical solid preparation.

11. A topical skin preparation according to any one of claims 1 to 10, wherein the vitamin E content is 0.05% by weight or more.

12. (b) l-menthol or (d) vitamin E derivatives as a blood circulation improving ingredient, a topical skin preparation according to any one of claims 1 to 11 for promoting blood circulation.

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