Loxoprofen-containing topical skin preparation

Abstract

To provide an external preparation (compound) for skin containing loxoprofen and menthol, and having a good refreshing feel.SOLUTION: An external preparation for skin contains loxoprofen or a salt thereof, l-menthol, a carboxyvinyl polymer, ethanol, and at least one nonionic surfactant of polyoxyethylene hardened castor oil or polysorbate.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a loxoprofen-containing topical skin preparation that has excellent analgesic and anti-inflammatory effects and a pleasant feel when used. More specifically, the present invention relates to a loxoprofen-containing topical skin preparation that contains loxoprofen, l-menthol, a carboxyvinyl polymer, and ethanol, and further contains a specific solubilizing agent to improve the refreshing feeling when applied. [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] L-menthol is used as a blood circulation promoting ingredient in topical preparations, and as a cooling agent and fragrance in pharmaceutical additives.

[0005] Carboxyvinyl polymers are used as pharmaceutical additives in external preparations, such as thickeners and bases.

[0006] It has been disclosed that the percutaneous absorption of loxoprofen in topical preparations has been improved by incorporating a carboxyvinyl polymer (see Patent Document 2). It is also known that the addition of polyoxyethylene hydrogenated castor oil to topical preparations containing loxoprofen prevents precipitation or sedimentation under acidic conditions (see Patent Document 3). Furthermore, topical skin preparations containing loxoprofen, l-menthol, ethanol, and one or more selected from nonanoic acid vanillylamide, glycyrrhetinic acid, nicotinic acid benzyl ester, and vitamin E, plus chlorpheniramine maleate (see Patent Document 4), and topical skin preparations containing loxoprofen or its salt, l-menthol, ethanol, tocopherol or its derivative, and polysorbate (see Patent Document 5) are known to improve percutaneous absorption.

[0007] However, in topical preparations containing loxoprofen, l-menthol, carboxyvinyl polymer, and ethanol, it is not known at all how the solubilizer affects the cooling sensation of the preparation. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] JP 2008-074873 A [Patent Document 2] Patent No. 4195178 [Patent Document 3] Patent No. 6131522 [Patent Document 4] JP 2019-142856 A [Patent Document 5] Patent Publication No. 2020-158501 [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 provide an external skin preparation containing loxoprofen, l-menthol, a carboxyvinyl polymer, ethanol, and a nonionic surfactant, which has an improved cooling sensation. [Means for solving the problem]

[0011] The present inventors investigated ingredients to be added to solubilize the active ingredients of a topical preparation containing loxoprofen, in order to develop a topical preparation (combined preparation) that further contains ingredients such as l-menthol for the purpose of promoting blood circulation, etc. As a result, they found that when a topical preparation containing loxoprofen, l-menthol, carboxyvinyl polymer, and ethanol is combined with one or more nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate, it provides an excellent cooling sensation after application, leading to the completion of the present invention.

[0012] That is, the present invention provides the following inventions. (1) A topical skin preparation containing the following [a], [b], [c], [d], and [e]. [a] Loxoprofen or its salt [b]l-Menthol [c] Carboxyvinyl polymer [d] Ethanol [e] One or more nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate. (2) [e] The topical skin preparation according to (1), wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil or polysorbate. (3) The external skin preparation according to (1) or (2), wherein the ethanol content is 10 to 30% by weight. (4) An external skin preparation according to any one of (1) to (3), wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60. (5) The topical skin preparation according to any one of (1) to (4), wherein the polysorbate is polysorbate 60 or polysorbate 80. (6) The topical skin preparation according to any one of (1) to (5), wherein the content of the nonionic surfactant [e] in the topical skin preparation is 0.2 to 15 wt %. (7) The topical skin preparation according to any one of (1) to (6), wherein the pH of the topical skin preparation is 5.0 to 8.0. (8) The topical skin preparation according to any one of (1) to (7), which is for analgesic and anti-inflammatory purposes. (9) The topical skin preparation according to any one of (1) to (8), which is in the form of a topical liquid, cream, or gel. (10) The topical skin preparation according to any one of (1) to (9), which is in the form of a gel. [Effects of the Invention]

[0013] The topical skin preparation of the present invention, which contains loxoprofen or a salt thereof; l-menthol; a carboxyvinyl polymer; ethanol; and one or more nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate, is extremely useful because it provides an excellent cooling sensation after application. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a graph showing the effect of each sample on activation of TRPM8 (Transient Receptor Potential Melastatin 8). DETAILED DESCRIPTION OF THE INVENTION

[0015] In the present invention, "loxoprofen or a salt thereof" refers to either loxoprofen or a salt thereof, or a hydrate thereof. A pharmacologically acceptable salt of loxoprofen is preferred, more preferably loxoprofen sodium or loxoprofen sodium dihydrate, and even more preferably loxoprofen sodium dihydrate. In this specification, the term "loxoprofen" includes loxoprofen or a salt thereof, as well as a hydrate thereof.

[0016] The loxoprofen used in the present invention is listed in the 17th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0017] The l-menthol used in the present invention is listed in the 17th revised Japanese Pharmacopoeia and the Pharmaceutical Additives Dictionary 2016 (Yakuji Nipposha, 2016).

[0018] The carboxyvinyl polymer (also called carboxypolymethylene) in the present invention is a pharmaceutical additive used in external preparations as a thickener, adhesive, dispersant, stabilizer, base, etc., and is listed in the Pharmaceutical Additives Encyclopedia 2016.

[0019] The ethanol (also called ethyl alcohol) in the present invention is used in external preparations as a solubilizer, base, solvent, or solubilizer, and examples thereof include ethanol, absolute ethanol, etc. The ethanol and absolute ethanol in the present invention are listed in the Pharmaceutical Additives Dictionary 2016.

[0020] The nonionic surfactant in the present invention is one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate. As the nonionic surfactant, polyoxyethylene hydrogenated castor oil or polysorbate may be blended alone or in combination of two or more thereof, but a combination of polyoxyethylene hydrogenated castor oil and polysorbate is preferred.

[0021] Examples of the polyoxyethylene hydrogenated castor oil in the present invention include polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, with polyoxyethylene hydrogenated castor oil 60 being preferred.

[0022] Examples of the polysorbate in the present invention include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc., with polysorbate 60 or polysorbate 80 being preferred. The nonionic surfactants used in the present invention are listed in the Pharmaceutical Additives Encyclopedia 2016. In the present invention, it is particularly preferable to use polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 in combination.

[0023] The topical skin preparation of the present invention may contain a polyhydric alcohol. 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 Encyclopedia 2016. Examples of polyhydric alcohols include propylene glycol, 1,3-butylene glycol, macrogol (also known as polyethylene glycol) (e.g., macrogol 400), glycerin, and D-sorbitol.

[0024] In the present invention, the content of loxoprofen, calculated as loxoprofen sodium dihydrate, is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight.

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

[0026] The content of the carboxyvinyl polymer in the present invention is preferably 0.1 to 5.0% by weight, more preferably 0.5 to 3.0% by weight.

[0027] Furthermore, the content of the nonionic surfactant in the present invention (the total content when two or more types of nonionic surfactants are contained) is preferably 0.2 to 15 wt%, more preferably 0.5 to 15 wt%, and even more preferably 1.0 to 12 wt%. When the nonionic surfactant in the present invention is polyoxyethylene hydrogenated castor oil, the content of polyoxyethylene hydrogenated castor oil is preferably 0.5 to 15 wt%, more preferably 1.0 to 6.0 wt%. When the nonionic surfactant in the present invention is polysorbate, the content of polysorbate is preferably 0.5 to 15 wt%, more preferably 1.0 to 10 wt%.

[0028] Furthermore, the range of the amount of ethanol added to the topical skin preparation of the present invention is not particularly limited, but is preferably 5.0 to 50.0% by weight, more preferably 10.0 to 30.0% by weight, even more preferably 10.0 to 25.0% by weight, and particularly preferably 10.0 to 20.0% by weight.

[0029] Furthermore, when a polyhydric alcohol is added, the amount of the polyhydric alcohol added is not particularly limited, but is preferably 0.5 to 20%, more preferably 1.0 to 15%.

[0030] The pH range of the external skin preparation is preferably 5.0 to 8.0, more preferably 5.5 to 7.5.

[0031] The topical skin preparation of the present invention may contain drugs and pharmaceutical additives other than the above-mentioned ingredients that are commonly used in topical skin preparations for analgesia and anti-inflammatory purposes. Examples of such drugs include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, blood circulation improving ingredients such as nicotinic acid benzyl ester, tocopherol or its derivatives (e.g., tocopherol esters such as tocopherol acetate), local stimulating ingredients such as chili pepper extract, nonanoic acid vanillylamide, capsaicin, 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. Note that the topical skin preparation of the present invention may or may not contain tocopherol or its derivatives (e.g., tocopherol esters such as tocopherol acetate), but it is preferable that it does not contain. Note that the topical skin preparation of the present invention may or may not contain nonanoic acid vanillylamide, but it is preferable that it does not contain.

[0032] 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 humectants, pH adjusters, antioxidants, cooling agents, thickeners, etc. As such moisturizing agents, for example, propylene glycol, 1,3-butylene glycol, glycerin, macrogol, hydroxypropyl cellulose, sodium dl-pyrrolidone carboxylate, hyaluronic acid, etc. may be added. Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, lactic acid, organic acids, organic amines (such as triethanolamine), and phosphoric acid. Examples of antioxidants that can be used 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. Examples of the cooling agent include camphor, dl-camphor, peppermint oil, and eucalyptus oil. Examples of thickeners include polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, carrageenan, locust bean gum, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hypromellose (short for hydroxypropylmethyl cellulose).

[0033] An example of the topical skin preparation of the present invention is a topical skin preparation containing loxoprofen sodium hydrate, l-menthol, carboxyvinyl polymer, hypromellose, triethanolamine, absolute ethanol, macrogol, polyoxyethylene hydrogenated castor oil, polysorbate, and water. An example of an external skin preparation of the present invention is an external skin preparation consisting only of loxoprofen sodium hydrate, l-menthol, carboxyvinyl polymer, hypromellose, triethanolamine, absolute ethanol, macrogol, polyoxyethylene hydrogenated castor oil, polysorbate, and water. An example of an external skin preparation of the present invention is an external skin preparation containing loxoprofen sodium hydrate, l-menthol, carboxyvinyl polymer, hypromellose, triethanolamine, absolute ethanol, macrogol, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and water. An example of an external skin preparation of the present invention is an external skin preparation consisting only of loxoprofen sodium hydrate, l-menthol, carboxyvinyl polymer, hypromellose, triethanolamine, absolute ethanol, macrogol, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and water.

[0034] Specific dosage forms of the topical skin preparation of the present invention include, for example, topical liquid preparations, creams, sprays (topical aerosols, pump sprays), gels, etc., and these can be produced by appropriately using additives and bases suitable for each dosage form, according to standard methods described in the 17th edition of the Japanese Pharmacopoeia, etc. Gels are particularly preferred as the dosage form of the topical skin preparation of the present invention. Furthermore, the formulation of the topical skin preparation of the present invention can be contained and sealed in a container or package made of metal such as aluminum, or a container or package made of an olefin resin such as polyethylene or polypropylene, a container or package made of a resin such as polyethylene terephthalate, or a container or package made of an aluminum laminate film formed by laminating polyethylene and aluminum, polyethylene, aluminum and polyethylene terephthalate, or the like.

[0035] 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 or sprayed onto the affected area of ​​the patient once to several times a day. The present invention will be explained in more detail below with reference to examples. [Example]

[0036] <Test Example 1> Evaluation test of the cooling sensation of topical skin preparations containing loxoprofen (1) Preparation of test materials and specimens Loxoprofen sodium dihydrate was manufactured by KOLON LIFE SCIENCE, Inc.; l-menthol was manufactured by Suzuki Mint Co., Ltd.; carboxyvinyl polymer was manufactured by Sumitomo Seika Chemicals, Inc.; hypromellose was manufactured by Shin-Etsu Chemical Co., Ltd.; triethanolamine was manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.; absolute ethanol was manufactured by Imazu Pharmaceutical Industry Co., Ltd.; macrogol 400 was manufactured by NOF Corporation; polyoxyethylene hydrogenated castor oil 60, polysorbate 60, polysorbate 80, polyoxyethylene (20) polyoxypropylene (8) cetyl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, and polyoxyethylene oleyl ether were manufactured by Nikko Chemicals Co., Ltd. The ingredients listed in Table 1 below were mixed and dissolved to obtain gels (Samples 1 to 6).

[0037] (2) Evaluation method The effect of each sample on the cooling sensation was evaluated using as an index the activation of TRPM8, a receptor that responds to menthol and cold stimuli. The human TRPM8 gene was cloned into the pcDNA3.2 vector and transfected into CHO-K1 cells. After drug selection with G-418, TRPM8 expression was confirmed by Western blotting. Cells responding to menthol were selected to generate a CHO-K1 cell line stably expressing human TRPM8. The CHO-K1 cell line stably expressing human TRPM8 was seeded (10,000 cells / well) into a 384-well plate (Corning) and incubated overnight at 37°C and 5% CO2. Ham's F-12K (Kaighn's) Medium (Gibco) supplemented with 10% FBS and penicillin-streptomycin was used. A calcium probe solution (Invitrogen; Fluo-4 Direct® Calcium Assay Kit) was added, and the cells were incubated at 37°C for 30 minutes and then at room temperature for 30 minutes. The 384-well plate was then placed in a FLIPR Tetra (Molecular Devices) and fluorescence intensity (excitation wavelength 495 nm, detection wavelength 518 nm) was measured every second for approximately 2 minutes. 10 seconds after the start of measurement, a test sample (a sample diluted with ultrapure water to a final concentration of 0.2%) was added, and the change in fluorescence intensity was observed. TRPM8 activity was evaluated using the increase in fluorescence intensity, calculated by subtracting the fluorescence intensity before adding the test sample from the maximum fluorescence intensity 2 minutes after adding the test sample. Six wells were evaluated for each sample, and the average value was used.

[0038] (3) Test results The formulation of each sample is shown in Table 1. The results of the effects of each sample on TRPM8 activation are shown in Figure 1.

[0039] [Table 1]

[0040] The amount of loxoprofen sodium hydrate, 1.13 g, is equivalent to 1 g of loxoprofen sodium (anhydrous equivalent).

[0041] The results of evaluating TRPM8 activation for Samples 1 to 6 are shown in Figure 1. Comparing Samples 1 to 6, the topical preparations containing loxoprofen, l-menthol, carboxyvinyl polymer, and ethanol showed stronger TRPM8 activation in the preparations containing polyoxyethylene hydrogenated castor oil 60, polysorbate 60, or polysorbate 80 (Samples 1, 2, and 3) compared with the preparations containing polyoxyethylene (20) polyoxypropylene (8) cetyl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, or polyoxyethylene oleyl ether as a solubilizer (nonionic surfactant) (Samples 4, 5, and 6). Therefore, the inclusion of polyoxyethylene hydrogenated castor oil 60, polysorbate 60, or polysorbate 80 in the topical skin preparation containing loxoprofen, l-menthol, carboxyvinyl polymer, and ethanol appears to improve the cooling sensation upon application.

[0042] (Formulation example) After dissolving the ingredients listed in Table 2 below by stirring and mixing, the external skin preparations of Formulation Examples 1 to 12 can be obtained. 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" and "gel preparations."

[0043] [Table 2]

[0044] *Equivalent to 1g of loxoprofen sodium (anhydrous equivalent). [Industrial Applicability]

[0045] The topical skin preparation of the present invention containing loxoprofen and l-menthol has an excellent cooling sensation and is extremely useful.

Claims

1. A topical skin preparation containing the following [a], [b], [c], [d] and [e], and further containing macrogol, hypromellose and triethanolamine, and having an ethanol content of 10.0 to 25.0 wt. %. [a] Loxoprofen or a salt thereof [b] l-menthol [c] Carboxyvinyl polymer [d] Ethanol [e] One or more nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate.

2. [e] The topical skin preparation according to claim 1, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil or polysorbate.

3. 3. The external skin preparation according to claim 1, wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.

4. The external skin preparation according to claim 1 , wherein the polysorbate is polysorbate 60 or polysorbate 80.

5. The topical skin preparation according to any one of claims 1 to 4, wherein the content of the nonionic surfactant [e] in the topical skin preparation is 0.2 to 15 wt%.

6. The external skin preparation according to any one of claims 1 to 5, wherein the pH of the external skin preparation is 5.0 to 8.

0.

7. The external skin preparation according to any one of claims 1 to 6, which is for analgesic and anti-inflammatory purposes.

8. The external skin preparation according to claim 1 , which is in the form of an external liquid, cream, or gel.

9. The topical skin preparation according to claim 1 , which is in the form of a gel.

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