Loxoprofen-containing topical skin preparation

Abstract

To provide a topical skin preparation containing loxoprofen and 60% by mass or more of lower alcohol based on the total amount of the topical skin preparation, with improved storage stability. [Solution] A topical skin preparation containing loxoprofen or a salt thereof, and one or more pH adjusting agents selected from hydrochloric acid or malic acid and their salts, at a concentration of 60% by mass or more based on the total amount of the topical skin preparation.

Description

Technical Field

[0001] The present invention relates to a topical skin preparation containing loxoprofen having excellent analgesic and anti-inflammatory effects and a good feeling of use. More specifically, the present invention relates to a topical skin preparation containing loxoprofen, in which a specific pH regulator is contained in a topical skin preparation containing 60% by mass or more of a lower alcohol based on the total amount of the topical skin preparation, thereby improving the storage stability.

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, like other NSAIDs. In addition, since loxoprofen is 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, it is also known to have 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 preparation, and a gel preparation 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] When manufacturing a liquid or semi-solid preparation containing NSAIDs, lower alcohols or purified water are often used as solvents for dissolution or dispersion. Since sodium loxoprofen has high solubility in ethanol, isopropanol, water, and mixtures thereof, these components are often used as solvents.

[0005] Furthermore, liquid or semi-solid formulations of NSAIDs may contain additional ingredients that enhance or provide auxiliary effects to their anti-inflammatory and analgesic properties. Some of these ingredients, such as menthol and tocopherol, are poorly soluble in water, and in such cases, it was necessary to either add a large amount of a solvent other than water or an appropriate surfactant.

[0006] When manufacturing topical preparations containing loxoprofen, pH adjusters are added to adjust the pH to near neutral. Known pH adjusters include hydrochloric acid, lactic acid, phosphoric acid, malic acid, triethanolamine, and diisopropanolamine. (See Patent Documents 2 and 3)

[0007] Patent Document 2 describes an external composition containing (A) one or more selected from diclofenac, felbinac, loxoprofen, and salts thereof, (B) one or more selected from malic acid and salts thereof, and (C) water, with a pH of 6 to 8, and further states that (D) it may contain 30 to 80% by mass of ethanol. However, Patent Document 2 does not describe any examples of an external composition containing loxoprofen. In other words, there are no examples of an external composition containing loxoprofen and containing 60% by mass or more of ethanol based on the total amount of the external composition, and no specific disclosure is provided.

[0008] Furthermore, the topical preparation described in Patent Document 3 is a preparation in which the concentration of ethanol contained is less than 60% by mass based on the total amount of the topical preparation. For topical preparations in which the concentration of ethanol is 60% by mass or more based on the total amount of the topical preparation, a topical pharmaceutical composition containing loxoprofen and / or its salt and tocopherol acetate, and also containing lactic acid and N-methyl-2-pyrrolidone, has been disclosed. (Patent Documents 4 and 5) [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2008-074873 [Patent Document 2] Japanese Patent Publication No. 2014-172857 [Patent Document 3] Japanese Patent Publication No. 2018-188429 [Patent Document 4] Japanese Patent Publication No. 2019-206498 [Patent Document 5] Japanese Patent Publication No. 2019-206499 [Non-patent literature]

[0010] [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 Initiative] [Problems that the invention aims to solve]

[0011] The object of the present invention is to provide a topical skin preparation containing loxoprofen and 60% by mass or more of lower alcohol based on the total amount of the topical skin preparation, with improved storage stability. [Means for solving the problem]

[0012] The inventors of the present invention investigated formulations containing high concentrations of lower alcohol to solubilize the active ingredients in order to develop a topical skin preparation (combined preparation) containing loxoprofen that further contains oil-soluble components such as tocopherol acetate and l-menthol, with the aim of imparting effects such as promoting blood circulation. As a result, when pH adjusters such as phosphoric acid and citric acid were added to a topical skin preparation containing 60% or more by mass of lower alcohol based on the total amount of loxoprofen and topical skin preparation, the storage stability was significantly reduced immediately after manufacture and under low-temperature storage. Therefore, the inventors found that the storage stability was improved by adding hydrochloric acid or DL-malic acid instead of phosphoric acid and citric acid, and thus completed the present invention.

[0013] In other words, the present invention provides the following invention. (1) A topical skin preparation containing the following [a] to [c]. [a] Loxoprofen or a salt thereof; [b] Lower alcohols in an amount of 60% by mass or more based on the total amount of the topical skin preparation; and [c] One or more pH adjusters selected from hydrochloric acid or malic acid and their salts. (2) The topical skin preparation described in (1), wherein the lower alcohol content is 60 to 80% by mass based on the total amount of the topical skin preparation. (3) The topical skin preparation according to (1) or (2), wherein the malic acid and its salt are DL-malic acid or its salt. (4) A topical skin preparation according to any one of (1) to (3), further containing an oil-soluble component. (5) The topical skin preparation according to (4), wherein the oil-soluble component is one or more selected from l-menthol and tocopherol or its derivatives. (6) A topical skin preparation according to any one of (1) to (5), further containing a polyhydric alcohol. (7) A topical skin preparation according to any one of (1) to (6), which does not contain a surfactant as an additive. (8) A topical skin preparation according to any one of (1) to (7), having a pH of 5.5 to 7.5. (9) A topical skin preparation for analgesia and anti-inflammatory purposes, as described in any one of (1) to (8). (10) A topical skin preparation according to any one of (1) to (9), wherein the dosage form is a topical liquid, ointment, spray, gel, aerosol, or topical solid preparation. [Effects of the Invention]

[0014] The present invention provides a topical skin preparation containing loxoprofen or a salt thereof, 60% by mass or more of a lower alcohol based on the total amount of the topical skin preparation, and one or more pH adjusting agents selected from hydrochloric acid or malic acid and their salts. This preparation offers excellent usability, improved storage stability, and is extremely useful clinically.

Mode for Carrying Out the Invention

[0015] The external preparation for skin in the present invention contains the following [a] to [c]. [a] Loxoprofen or a salt thereof; [b] A lower alcohol of 60% by mass or more based on the total amount of the external preparation for skin; and [c] One or more pH adjusters selected from hydrochloric acid or malic acid and salts thereof.

[0016] In the present invention, as the "loxoprofen or a salt thereof", loxoprofen or a salt thereof, or a hydrate thereof can be used. As the salt of loxoprofen, a pharmacologically acceptable salt is preferable, more preferably loxoprofen sodium or loxoprofen sodium dihydrate, and still more preferably loxoprofen sodium dihydrate.

[0017] Loxoprofen sodium dihydrate in the present invention is listed in the 17th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0018] The lower alcohol in the present invention is an aliphatic alcohol having 1 to 4 carbon atoms used in the external preparation for uses such as solubilizer, base, preservative, solvent, solubilizing aid, etc. For example, it is one or more selected from the group consisting of methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol, and preferably one or two selected from the group consisting of ethanol and isopropanol. Those having an ethanol content of 99.5% by volume or more are also called absolute ethanol.

[0019] Hydrochloric acid in the present invention can include hydrochloric acid, dilute hydrochloric acid, etc. used in the external preparation for uses such as stabilizer, solubilizer, flavoring agent, solvent, solubilizing aid, pH adjuster. Hydrochloric acid in the present invention is listed in the 17th revised Japanese Pharmacopoeia and the Pharmaceutical Additives Dictionary 2016 (Yakujutsu Shimbunsha, 2016).

[0020] In this invention, malic acid can be D-malic acid, L-malic acid, or DL-malic acid, with DL-malic acid being preferred. DL-malic acid is a pharmaceutical additive used in topical preparations as a stabilizer, buffer, flavoring agent, excipient, and pH adjuster, and is listed in the 2016 Dictionary of Pharmaceutical Additives. Examples of malate salts include sodium malate and potassium malate.

[0021] In the topical skin preparation according to the present invention, one or more pH adjusting agents selected from hydrochloric acid or malic acid and its salts are used. In the topical skin preparation according to the present invention, for example, hydrochloric acid and malic acid and its salts may be used as pH adjusting agents. In the topical skin preparation according to the present invention, for example, malic acid and its salts (e.g., DL-malic acid) may be used as pH adjusting agents. Furthermore, in the topical skin preparation according to the present invention, it is preferable to use hydrochloric acid as a pH adjusting agent, for example, from the viewpoint that it is more easily soluble in water and ethanol.

[0022] The topical skin preparation according to the present invention may contain an oil-soluble component. In the present invention, oil-soluble components are components that are poorly soluble in water and readily soluble in oil, and can be incorporated into topical skin preparations. Examples include l-menthol, tocopherol or its derivatives, and nonyl vanillylamide. In the topical skin preparation according to the present invention, the oil-soluble component may be one or more selected from l-menthol and tocopherol or their derivatives. The l-menthol used in this invention is listed in the 17th edition of the Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives (Yakuji Nippo Co., Ltd., 2016).

[0023] Examples of tocopherol or its derivatives in the present invention include tocopherol, d-δ-tocopherol, and tocopherol acetate, with tocopherol acetate being preferred. Tocopherol, d-δ-tocopherol, and tocopherol acetate are listed in the 17th edition of the Japanese Pharmacopoeia and the 2016 Dictionary of Pharmaceutical Additives.

[0024] The topical skin preparation of the present invention may contain a polyhydric alcohol. In the present invention, a polyhydric alcohol is an alcohol having two or more hydroxyl groups in its molecule that is used in topical preparations for purposes such as solubilizer, base, wetting agent, viscosity agent, solvent, or solubilizer. Examples include propylene glycol, 1,3-butylene glycol, macrogol (also called polyethylene glycol), glycerin, and D-sorbitol, which are listed in the 2016 Dictionary of Pharmaceutical Additives.

[0025] In the present invention, the loxoprofen content is preferably 0.1 to 10% by mass, and more preferably 0.5 to 5% by mass, based on the total amount of the topical skin preparation, as loxoprofen sodium dihydrate.

[0026] The lower alcohol content in the present invention (total amount of added alcohol if two or more types of alcohol are included) is 60% by mass or more, preferably 60-80% by mass, more preferably 60-73% by mass, and even more preferably 60-71% by mass, based on the total amount of the topical skin preparation. The lower alcohol content may also be 61% by mass or more, 62% by mass or more, 63% by mass or more, 64% by mass or more, or 65% by mass or more, based on the total amount of the topical skin preparation. The lower alcohol content may also be 70% by mass or less, 69% by mass or less, 68% by mass or less, 67% by mass or less, or 66% by mass or less, based on the total amount of the topical skin preparation. If the concentration of the lower alcohol is less than 60% by mass, based on the total amount of the topical skin preparation, for example, it will be necessary to add a surfactant when incorporating poorly soluble oil-soluble components. Furthermore, when the concentration of lower alcohol is high, extra caution is required regarding fire and temperature during the storage and transportation of bulk materials and products containing the ingredients. Therefore, it is preferable that the lower alcohol content be 80% by mass or less, based on the total amount of topical skin preparations.

[0027] The content of one or more pH adjusting agents selected from hydrochloric acid or malic acid and its salts in the present invention is preferably 0.01 to 5% by mass, and more preferably 0.05 to 3% by mass, based on the total amount of the topical skin preparation.

[0028] When the topical skin preparation of the present invention contains l-menthol, the l-menthol content is preferably 0.01 to 10% by mass, and more preferably 0.5 to 7.5% by mass, based on the total amount of the topical skin preparation.

[0029] When the topical skin preparation of the present invention contains tocopherol or a derivative thereof, the content of tocopherol or a derivative thereof is usually 0.001 to 5% by mass, preferably 0.05 to 3% by mass, and more preferably 0.1 to 1% by mass, based on the total amount of the topical skin preparation.

[0030] When the topical skin preparation of the present invention contains a polyhydric alcohol, the polyhydric alcohol content is not particularly limited, but is preferably 0.5 to 20% by mass, and more preferably 1.0 to 15% by mass, based on the total amount of the topical skin preparation.

[0031] From the viewpoint of reducing skin irritation, the pH range of the topical skin preparation of the present invention is preferably 5.0 to 8.0, more preferably 5.5 to 7.5, and even more preferably 6.0 to 7.0.

[0032] In the topical skin preparation of the present invention, drugs and pharmaceutical additives commonly used in topical skin preparations for analgesia and anti-inflammatory purposes, other than the above-mentioned components, may be added. Examples of drugs include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, blood circulation improving components such as benzyl nicotinate, local irritants such as capsicum extract and capsaicin, and herbal ingredients such as arnica tincture. These drugs can be incorporated in amounts that do not impair the effects of the present invention.

[0033] Pharmaceutical additives other than those listed above are added as needed, for example, to improve content stability over time or enhance the user experience. Examples include humectants, antioxidants, and cooling agents. As a wetting agent, for example, sodium dl-pyrrolidone carboxylate can be added.

[0034] Examples of antioxidants that can be used include ascorbic acid, ascorbic palmitate, sodium bisulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, and propyl gallate. Examples of cooling agents include camphor, dl-camphor, peppermint oil, and eucalyptus oil.

[0035] The topical skin preparation of the present invention may or may not contain a surfactant, but from the viewpoint of reducing skin irritation, it is preferable that it does not contain a surfactant.

[0036] Specific dosage forms of the topical skin preparation of the present invention include, for example, topical liquids, ointments, creams, sprays (such as pump sprays), gels, aerosols (such as topical aerosols), patches (tapes, poultices), or topical solid preparations. The above dosage forms can be manufactured by appropriately using additives and bases suitable for each dosage form, in accordance with the usual methods described in the 17th edition of the Japanese Pharmacopoeia, etc. Preferred dosage forms of the topical skin preparation of the present invention are topical liquids, ointments, sprays, gels, aerosols, or topical solid preparations, with topical liquids being particularly preferred. Furthermore, the preparations of the topical skin preparation of the present invention can be housed and sealed in metal containers and packaging made of aluminum or other materials, or in containers and packaging made of olefin resins such as polyethylene or polypropylene.

[0037] 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 or patched to the affected area in an appropriate amount one to several times a day to the patient. The present invention will be described in more detail below with reference to examples. [Examples]

[0038] <Test Example 1> Test to confirm the properties of a topical skin preparation containing loxoprofen 1 (1) Preparation of test materials and specimens The following ingredients were used: loxoprofen sodium dihydrate manufactured by KOLON LIFE SCIENCE Co., Ltd., l-menthol manufactured by Suzuki Peppermint Co., Ltd., tocopherol acetate manufactured by Riken Vitamin Co., Ltd., anhydrous ethanol manufactured by Imazu Pharmaceutical Industry Co., Ltd., hydrochloric acid, phosphoric acid, and 1,3-butylene glycol manufactured by Kanto Chemical Co., Ltd., and DL-malic acid and citric acid manufactured by Tokyo Chemical Industry Co., Ltd. The components listed in Table 1 below were mixed and dissolved to obtain the topical solutions shown in the table. Appropriate amounts of each pH adjusting agent were added to adjust the pH of the formulation to 6.5.

[0039] (2) Evaluation method The properties of each obtained sample were visually inspected. The properties were evaluated based on the presence or absence of precipitation or sedimentation of insoluble matter according to the following criteria, with only ○ being considered acceptable. ○: A colorless, clear liquid with no precipitates or sediments observed. ×: A cloudy liquid or precipitates / sediments may be observed. Furthermore, the product was deemed acceptable if its properties were good immediately after manufacturing, after 24 hours at room temperature, and after 24 hours at 5°C.

[0040] (3) Test results The results are shown in Table 1.

[0041] [Table 1]

[0042] A comparison of Examples 1, 2, and 5 in Table 1 with Comparative Examples 1, 2, and 5 shows that in topical preparations containing loxoprofen sodium hydrate, 70% by mass of anhydrous ethanol and 1,3-butylene glycol based on the total amount of the topical preparation, the properties immediately after manufacturing and after 24 hours at room temperature were significantly improved when hydrochloric acid and DL-malic acid were added compared to when citric acid or phosphoric acid was added as a pH adjuster.

[0043] The amount of loxoprofen sodium hydrate included is equivalent to 1g of loxoprofen sodium (anhydrous basis).

[0044] A comparison of Examples 3 and 4 in Table 1 with Comparative Examples 3 and 4 shows that in topical preparations containing loxoprofen sodium hydrate, 70% by mass of anhydrous ethanol and l-menthol based on the total amount of the topical preparation, the properties immediately after manufacturing and after 24 hours at room temperature were significantly improved when hydrochloric acid and DL-malic acid were added compared to when citric acid or phosphoric acid was added as pH adjusters.

[0045] The amount of loxoprofen sodium hydrate included is equivalent to 1g of loxoprofen sodium (anhydrous basis).

[0046] <Test Example 2> Test to confirm the properties of a topical skin preparation containing loxoprofen 2 (1) Preparation of test materials and specimens The procedure was carried out in the same manner as in Test Example 1. For samples that did not contain loxoprofen sodium hydrate, the same amount of pH adjuster as for samples containing loxoprofen sodium hydrate with the same formulation was added. (2) Evaluation method The procedure was carried out in the same manner as in Test Example 1.

[0047] (3) Test results The results are shown in Table 2. [Table 2]

[0048] As shown in Reference Examples 1-5 of Table 2, topical preparations that do not contain loxoprofen sodium hydrate exhibited stable properties regardless of the type of pH adjusting agent added.

[0049] <Test Example 3> Test to confirm the properties of a topical skin preparation containing loxoprofen 3 (1) Preparation of test materials and specimens The sample was prepared in the same manner as in Test Example 1, based on the components listed in Table 3. (2) Evaluation method The procedure was carried out in the same manner as in Test Example 1.

[0050] (3) Test results The results are shown in Table 3. [Table 3]

[0051] Table 3 shows that when comparing Example 6 and Comparative Example 6, where the concentration of anhydrous ethanol is 60% by mass based on the total amount of the topical preparation, the properties deteriorated when phosphoric acid was added after 24 hours of storage at 5°C, whereas the properties remained stable when hydrochloric acid was added. In Comparative Example 7, where the concentration of anhydrous ethanol was 61% by mass based on the total amount of the topical preparation and phosphoric acid was added, the properties deteriorated both immediately after production and after 24 hours of storage at room temperature or 5°C. When comparing Example 7 and Comparative Example 8, where the concentration of anhydrous ethanol is 70% by mass based on the total amount of the topical preparation, the properties deteriorated both immediately after production and after 24 hours of storage at room temperature when phosphoric acid was added, whereas the properties remained stable in both cases when hydrochloric acid was added. From these results, it was found that when anhydrous ethanol is contained at 60% by mass or more based on the total amount of the topical preparation, using phosphoric acid as the pH adjuster leads to a decrease in the stability of the properties of the topical preparation containing loxoprofen sodium hydrate. Furthermore, it was found that the properties of the solution could be stabilized by changing the pH adjuster from phosphoric acid to hydrochloric acid.

[0052] <Test Example 4> Test to confirm the properties of a topical skin preparation containing loxoprofen 4 (1) Preparation of test materials and specimens In Test Example 1, anhydrous ethanol was replaced with isopropanol (manufactured by Kosakai Pharmaceutical Co., Ltd.), and each sample was prepared in the same manner as in Test Example 1, based on the components in Table 4. (2) Evaluation method The procedure was carried out in the same manner as in Test Example 1.

[0053] (3) Test results The results are shown in Table 4. [Table 4]

[0054] A comparison of Example 8 and Comparative Example 9 in Table 4 revealed that even when isopropyl alcohol was used instead of anhydrous ethanol as the lower alcohol, the properties immediately after production and after 24 hours at room temperature were significantly improved when hydrochloric acid was used as the pH adjuster, compared to when phosphoric acid was used.

[0055] (Example of formulation) After stirring and mixing the components listed in Tables 5 and 6 below and dissolving them, the topical skin preparations of Formulation Examples 1 to 18 can be obtained. 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 "External Liquid Preparations" and "Gel Preparations" in the General Provisions of the Japanese Pharmacopoeia.

[0056] [Table 5] JPEG2026110843000006.jpg17170

[0057] [Table 6] JPEG2026110843000008.jpg17170

[0058] [Table 7]

[0059] In Tables 5, 6, and 7, the amount of loxoprofen sodium hydrate used corresponds to 1 g of loxoprofen sodium (anhydrous equivalent).

[0060] <Test Example> Test 5 for confirming the properties of a topical skin preparation containing loxoprofen (1) Preparation of test materials and specimens The sample was prepared in the same manner as in Test Example 1, based on the components listed in Table 8. (2) Evaluation method The procedure was carried out in the same manner as in Test Example 1.

[0061] (3) Test results The results are shown in Table 8. [Table 8]

[0062] A comparison of Examples 9-11 and Comparative Examples 10-11 in Table 8 shows that, regardless of whether the concentration of anhydrous ethanol was 60% by mass or 80% by mass based on the total amount of the topical preparation, when phosphoric acid was added as a pH adjuster, the properties deteriorated immediately after production or after 24 hours of storage at room temperature or 5°C. In contrast, when hydrochloric acid or DL-malic acid was added, the properties improved significantly immediately after production and after 24 hours at room temperature and 5°C.

[0063] <Test Example> Test 6 for confirming the properties of a topical skin preparation containing loxoprofen (1) Preparation of test materials and specimens The sample was prepared in the same manner as in Test Example 1, based on the components listed in Table 8. (2) Evaluation method The procedure was carried out in the same manner as in Test Example 1.

[0064] (3) Test results The results are shown in Table 9. [Table 9]

[0065] A comparison of Examples 12-15 and Comparative Examples 12-15 in Table 9 shows that, regardless of whether the pH was 5.5 or 7.5, when phosphoric acid or citric acid was used as a pH adjuster, the properties deteriorated both immediately after production and after 24 hours of storage at room temperature or 5°C. In contrast, when hydrochloric acid or DL-malic acid was used, the properties improved significantly both immediately after production and after 24 hours at room temperature and 5°C.

[0066] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention. [Industrial applicability]

[0067] The topical skin preparation containing loxoprofen according to the present invention is extremely useful because it has excellent usability and superior storage stability in terms of appearance.

Claims

1. A topical skin preparation containing the following [a] to [c]. [a] Loxoprofen or a salt thereof; [b] Lower alcohols in an amount of 60% by mass or more based on the total amount of the topical skin preparation; and [c] One or more pH adjusting agents selected from hydrochloric acid or malic acid and their salts.

2. The topical skin preparation according to claim 1, wherein the content of the lower alcohol is 60 to 80% by mass based on the total amount of the topical skin preparation.

3. The topical skin preparation according to claim 1 or 2, wherein the malic acid and its salt are DL-malic acid or its salt.

4. Furthermore, the topical skin preparation according to any one of claims 1 to 3, further containing an oil-soluble component.

5. The topical skin preparation according to claim 4, wherein the oil-soluble component is one or more selected from l-menthol and tocopherol or their derivatives.

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

7. A topical skin preparation according to any one of claims 1 to 6, which does not contain a surfactant as an additive.

8. A topical skin preparation according to any one of claims 1 to 7, wherein the pH is 5.5 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 a topical liquid, ointment, spray, gel, aerosol, or topical solid preparation.

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