Topical skin components

Abstract

This invention provides a technology to suppress the decrease in the content of betamethasone esters and pantothenic acids during long-term storage when they are present together. [Solution] A topical skin composition comprising the following components: (A) betamethasone ester and (B) one or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof, wherein the composition has at least one of the following configurations: Embodiment 1: The pH at 25°C of a mixture of 1 g of the topical skin composition and 30 mL of water after storage at 40°C for 1 month is 4.0 or higher and 5.3 or lower; and Embodiment 2: The residual rate of component (A) after storage at 40°C for 3 months, as measured by high-performance liquid chromatography, is 95% or higher, and the residual rate of component (B) after storage at 40°C for 3 months, as measured by high-performance liquid chromatography, is 95% or higher.

Description

Technical Field

[0001] The present invention relates to an external skin composition.

Background Art

[0002] Techniques for formulating betamethasone ester in a composition include those described in Patent Documents 1 to 3. Patent Document 1 (Japanese Unexamined Patent Application Publication No. 2024-48695) describes an external skin application agent for suppressing the deterioration of skin barrier function associated with dermatitis, which contains a steroidal anti-inflammatory agent and panthenol or a panthenol analog (Claim 1), and betamethasone or an ester thereof is exemplified as the steroidal anti-inflammatory agent (Claim 3, etc.).

[0003] Patent Document 2 (Japanese Unexamined Patent Application Publication No. 2023-145400) describes a liquid or semi-solid composition containing: a betamethasone ester; a lower alcohol; and one or more selected from the group consisting of a local anesthetic component, an antihistamine component, terpenes, crotamiton and a salt thereof, and solvates thereof, and one or more selected from the group consisting of panthenols and salicylic acids (Claim 1), and it is stated that this makes it possible to provide a liquid or semi-solid composition in which crystal precipitation is suppressed even while containing a lower alcohol together with the betamethasone ester (Paragraph 0012).

[0004] Further, Patent Document 3 (Japanese Unexamined Patent Application Publication No. 2024-104741) addresses the problem of providing an external pharmaceutical composition in which the decomposition of betamethasone valerate is suppressed (Paragraph 0006). This document describes an external pharmaceutical composition containing betamethasone valerate, zinc oxide and / or panthenol, a liquid oily component, and a thickener (Claim 1).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] Through the inventors' research, it was newly discovered that when betamethasone ester and pantothenic acid compounds are combined in a composition, the content of both betamethasone ester and pantothenic acid compounds decreases during long-term storage. The technology described in the aforementioned patent document had room for improvement in suppressing both of these content decreases.

[0007] Therefore, the present invention provides a technology to suppress the decrease in the content of betamethasone esters and pantothenic acids due to long-term storage when they are present together. [Means for solving the problem]

[0008] The embodiments of the present invention are as follows. [1] A topical skin composition containing the following components (A) and (B), A topical skin composition in which a mixture of 1 g of the topical skin composition and 30 mL of water, after being stored at 40°C for one month, has a pH of 4.0 to 5.3 at 25°C. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof. [2] A topical skin composition containing the following components (A) and (B): The residual rate of component (A) after storage at 40°C for 3 months, as measured by high-performance liquid chromatography using the following methods 1-2, is 95% or higher. A topical skin composition in which the residual rate of component (B) after storage at 40°C for 3 months is 95% or more, as measured by high-performance liquid chromatography using the following method 2. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof. (Method 1-2) Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 2.7 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and phosphoric acid diluted 1000 times with purified water. (Method 2) Detector: UV absorbance spectrophotometer, Wavelength: 210 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile / ammonium formate (1.26 g) and formic acid (2.5 mL) dissolved in water to make a total volume of 1000 mL. [3] The topical skin composition according to [2], wherein the pH of a mixture of 1 g of the topical skin composition and 30 mL of water at 25°C after being stored at 40°C for one month is 4.0 or higher and 5.3 or lower. [4] A topical skin composition according to any one of [1] to [3], further comprising the following component (C). (C) One or more selected from the group consisting of benzethonium, its salts and their hydrates. [5] The topical skin composition according to any one of [1] to [4], wherein component (B) is at least one selected from the group consisting of panthenol and pantothenyl ethyl ether. [6] Further containing a pH adjuster, The topical skin composition according to any one of [1] to [5], wherein the pH adjusting agent comprises an acidic compound. [7] The topical skin composition according to [6], further comprising a basic compound as the pH adjusting agent. [8] The content of the pH adjusting agent in the topical skin composition is 0.06% by mass or more and 1.1% by mass or less of the total amount of the topical skin composition, The topical skin composition according to [7], wherein the mass ratio of the content of the acidic compound to the content of the basic compound in the topical skin composition (acidic compound / basic compound) is 0.4 or more and 5 or less. [9] A dermal composition according to any one of [1] to [8], which is an emulsified composition.

[10] A topical skin composition according to any one of [1] to [9], which is a cream.

[11] A method for improving the storage stability of a composition containing the following components (A) and (B), comprising adjusting the pH at 25°C of a mixture of 1 g of the composition and 30 mL of water after storage at 40°C for one month to be between 4.0 and 5.3. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof.

[12] A topical skin composition containing the following components (A) and (B): The residual rate of component (A) after storage at 40°C for 3 months, as measured by high-performance liquid chromatography using the following method 1-1, is 95% or higher. A topical skin composition in which the residual rate of component (B) after storage at 40°C for 3 months is 95% or more, as measured by high-performance liquid chromatography using the following method 2. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof. (Method 1-1) Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and formic acid diluted 1000 times with purified water. (Method 2) Detector: Ultraviolet absorption photometer, Wavelength: 210 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm Column temperature: 40°C Mobile phase: A mixed solution of acetonitrile and a solution prepared by dissolving 1.26 g of ammonium formate and 2.5 mL of formic acid in water to make 1000 mL

[0009] Note that any arbitrary combination of these respective configurations, or any transformation of the expression of the present invention into a method, apparatus or the like, is also effective as an aspect of the present invention. [Effects of the Invention]

[0010] According to the present invention, it is possible to suppress the decrease in the content of betamethasone ester and pantothenic acids due to long-term storage when they coexist. [Modes for Carrying Out the Invention]

[0011] Hereinafter, embodiments of the present invention will be described. In the present embodiment, the composition may contain each component alone or in combination of two or more. As each component, for example, a commercially available product may be used, or it may be produced by a known method and used. In addition, the salt of the compound can be, for example, a pharmaceutically or physiologically acceptable salt. In the present specification, "~" indicating a numerical range means no less than and no more than, and includes both numerical values at both ends.

[0012] (External skin composition) In the present embodiment, the external skin composition contains the following components (A) and (B), and has at least one of the configurations according to the following aspects 1 and 2. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, derivatives thereof, and salts thereof (Pattern 1) The pH of a mixture of 1 g of the topical skin composition and 30 mL of water, after being stored at 40°C for one month, is between 4.0 and 5.3 at 25°C. (Aspect 2) The component (A) measured by high-performance liquid chromatography using Method 1-1 or Method 1-2 below has a remaining percentage of 95% or more after storage at 40°C for 3 months, and the component (B) measured by high-performance liquid chromatography using Method 2 below has a remaining percentage of 95% or more after storage at 40°C for 3 months. (Method 1-1) Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and formic acid diluted 1000 times with purified water. (Method 1-2) Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 2.7 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and phosphoric acid diluted 1000 times with purified water. (Method 2) Detector: UV absorbance spectrophotometer, Wavelength: 210 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile / ammonium formate (1.26 g) and formic acid (2.5 mL) dissolved in water to make a total volume of 1000 mL.

[0013] In this embodiment, since the topical skin composition containing components (A) and (B) in combination has at least one of the configurations of Embodiments 1 and 2, the decrease in the content of components (A) and (B) due to long-term storage can be suitably suppressed. Therefore, according to this embodiment, a topical skin composition with an excellent trade-off balance for the storage stability of components (A) and (B) can be obtained. Furthermore, according to this embodiment, it is possible to suppress the decrease in the content of components (A) and (B) during long-term storage of 3 years or more at a temperature of 1 to 30°C. In addition, according to this embodiment, it is possible to suppress deterioration that cannot be detected by visual inspection of the appearance of the topical skin composition.

[0014] The topical skin composition has at least one of the configurations of Embodiments 1 and 2, and preferably both configurations of Embodiments 1 and 2. This further stabilizes the reduction in the content of components (A) and (B) due to long-term storage. The following describes embodiments 1 and 2.

[0015] (Aspect 1) The pH of a mixture of 1 g of the topical skin composition and 30 mL of water, after being stored at 40°C for one month, at 25°C is preferably 4.0 or higher, more preferably 4.2 or higher, even more preferably 4.4 or higher, and even more preferably 4.5 or higher. This allows for a more favorable suppression of the decrease in the content of component (B). Furthermore, the pH is preferably 5.3 or lower, more preferably 5.1 or lower, and even more preferably 4.9 or lower. This allows for a more favorable suppression of the decrease in the content of component (A).

[0016] For pH measurement, the topical skin composition is stored at 40°C for one month, then 1 g is weighed out at 25°C and mixed with 30 mL of water to obtain a mixture. Alternatively, it is preferable to heat the mixture to 60°C to completely suspend it, then return it to 25°C before subjecting it to pH measurement. This improves the handling of the mixture and allows for more stable pH measurement. The pH of the mixture is measured at 25°C using a commercially available pH meter (for example, F-73, manufactured by Horiba, Ltd.).

[0017] (Aspect 2) In this embodiment, the residual rate of component (A) after storage at 40°C for 3 months is measured by either method 1-1 or 1-2 described above, and the inventors have confirmed that equivalent results can be obtained with these methods. The residual rate of component (A) after storage at 40°C for 3 months may be measured, for example, by method 1-2. In this case, component (A) is preferably at least one selected from the group consisting of betamethasone valerate and betamethasone butyrate propionate. Furthermore, the residual rate of component (A) after storage at 40°C for 3 months may be measured by method 1-1, in which case component (A) is preferably betamethasone valerate. The residual rate of component (A) after 3 months of storage at 40°C is preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, and even more preferably 98% or more. This improves the long-term storage stability of the topical skin composition. Furthermore, the above-mentioned residual rate of component (A) may be, for example, 100% or less.

[0018] The residual rate of component (B) after 3 months of storage at 40°C is preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, and even more preferably 98% or more. This improves the long-term storage stability of the topical skin composition. Furthermore, the remaining percentage of component (B) may be, for example, 100% or less.

[0019] The remaining percentages of components (A) and (B) are measured by high-performance liquid chromatography (HPLC) using Method 1-1 or Method 1-2 and Method 2, respectively. In Methods 1-1, 1-2, and 2, the skin topical compositions shall be stored in a container in an airtight condition. The container shall be, for example, airtight and may be appropriately selected from aluminum tubes, polyolefin containers (laminated tubes, aluminum laminate tubes, jar containers, etc.), metal containers, and glass containers. Furthermore, in methods 1-1, 1-2, and 2, if the measured content of components (A) and (B) after storage is greater than 100% of the measured content before storage, the reduction rate can be set to 0% (remaining amount 100%). Next, we will explain the ingredients contained in the topical skin composition.

[0020] (Component (A)) Component (A) is betamethasone ester. Component (A) is one or more selected from the group consisting of betamethasone carboxylic acid esters such as betamethasone valerate, betamethasone dipropionate, and betamethasone butyrate propionate; and betamethasone inorganic acid esters such as betamethasone sodium phosphate and their salts, preferably betamethasone carboxylic acid ester, and more preferably betamethasone valerate. This makes it possible to more reliably suppress the decrease in the content of component (A) in the topical skin composition. Betamethasone valerate, one of the betamethasone carboxylic acid esters, is specifically a halogenated corticosteroid with a valerate ester at the 17th hydroxyl group. Component (A) is listed in the 18th edition of the Japanese Pharmacopoeia. Betamethasone valerate is a topical corticosteroid with anti-inflammatory effects, showing excellent efficacy against many skin diseases such as eczema, dermatitis, heat rash, contact dermatitis, itching, chilblains, insect bites, and hives, and is widely used as a topical agent. Betamethasone butyrate propionate is a compound in which the 17th hydroxyl group of betamethasone is replaced with butyrate and the 21st hydroxyl group is replaced with propionate.

[0021] The content of component (A) in the topical skin composition is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, even more preferably 0.1% by mass or more, and even more preferably 0.12% by mass or more, relative to the total amount of the topical skin composition. This makes it possible to more reliably impart the desired pharmacological effects to the topical skin composition. Furthermore, the content of component (A) in the topical skin composition is preferably 1.0% by mass or less, more preferably 0.5% by mass or less, even more preferably 0.3% by mass or less, even more preferably 0.25% by mass or less, and may also be, for example, 0.1% by mass or less, relative to the total amount of the topical skin composition. This makes it possible to impart the desired pharmacological effects to the topical skin composition while suppressing the amount of component (A) used.

[0022] (Component (B)) Component (B) is one or more selected from the group consisting of pantothenic acid, its derivatives, and salts thereof. Component (B) is, for example, at least one selected from the group consisting of pantothenic acid, calcium pantothenate, panthenol, D-panthesine, D-pantethine, coenzyme A, and pantothenyl ethyl ether, preferably at least one selected from the group consisting of panthenol and pantothenyl ethyl ether, and more preferably panthenol. This makes it possible to more reliably suppress the decrease in the content of component (B) in the topical skin composition.

[0023] Component (B) is a water-soluble provitamin, also known as provitamin B5, which is converted to vitamin B5 (pantothenic acid) in the body and is known to exhibit moisturizing, tissue repair promoting, and anti-inflammatory effects. Panthenol (also known as pantothenyl alcohol or D-pantothenyl alcohol) and pantothenyl ethyl ether (also known as pantothenyl ethyl ether) are listed in the Japanese Pharmacopoeia Non-Official Drug Standards (2002), and for example, a substance conforming to these standards may be used.

[0024] The content of component (B) in the topical skin composition is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, more preferably 0.8% by mass or more, and even more preferably 1% by mass or more, relative to the total amount of the topical skin composition. This is expected to help the normal function of the skin and to have a skin repair effect. Furthermore, the content of component (B) in the topical skin composition is preferably 10% by mass or less, more preferably 8% by mass or less, and even more preferably 5% by mass or less, and may also be, for example, 3% by mass or less, 2% by mass or less, or 1% by mass or less. This makes it possible to obtain the above-mentioned effects while suppressing the amount of component (B) used.

[0025] The mass ratio ((A) / (B)) of the content of component (A) to the content of component (B) in the topical skin composition is preferably 0.02 or higher, more preferably 0.04 or higher, even more preferably 0.1 or higher, and may also be, for example, 0.3 or higher or 0.5 or higher, and preferably 1 or lower, more preferably 0.8 or lower, even more preferably 0.5 or lower, even more preferably 0.3 or lower, and may also be, for example, 0.1 or lower. This further stably suppresses the decrease in the content of components (A) and (B) during long-term storage.

[0026] In this embodiment, the topical skin composition may contain components other than those described above. Other components can be selected, for example, depending on the dosage form of the topical skin composition and the efficacy to be imparted to the topical skin composition.

[0027] (Component (C)) The topical skin composition preferably further comprises one or more elements selected from the group consisting of component (C): benzethonium, its salts, and their hydrates. Component (C) is preferably a benzethonium salt, and more preferably benzethonium chloride. Benzethonium chloride is listed in the 18th edition of the Japanese Pharmacopoeia. Benzethonium chloride is a quaternary ammonium salt classified as a reverse soap, and has broad antibacterial activity against non-spore-forming bacteria and fungi, showing efficacy against Gram-positive bacteria at lower concentrations than against Gram-negative bacteria.

[0028] The content of component (C) in the topical skin composition is preferably 0.001% by mass or more, more preferably 0.005% by mass or more, and even more preferably 0.01% by mass or more, and may also be, for example, 0.05% by mass or more, relative to the total amount of the topical skin composition. This allows for a more reliable expectation that the medicinal effects of component (C) will be added to the medicinal effects of component (A), thereby soothing skin inflammation and preventing the worsening of symptoms caused by infection through its bactericidal effect on the skin. Furthermore, the content of component (C) in the topical skin composition is preferably 0.5% by mass or less, more preferably 0.3% by mass or less, even more preferably 0.2% by mass or less, and even more preferably 0.1% by mass or less, or for example, 0.05% by mass or less, 0.03% by mass or less, or 0.02% by mass or less. This makes it possible to impart the desired efficacy to the topical skin composition while suppressing the amount of component (C) added.

[0029] (pH adjuster) By further including a pH adjuster in the topical skin composition, the decrease in the content of components (A) and (B) during long-term storage can be more stably suppressed.

[0030] Specific examples of pH adjusters include inorganic acids and their salts such as hydrochloric acid, phosphoric acid, sodium dihydrogen phosphate (acidic compound), and disodium hydrogen phosphate (basic compound); organic acids and their salts such as citric acid, sodium citrate (basic compound), malic acid, tartaric acid, sodium tartrate (basic compound), gluconic acid, lactic acid, and sodium lactate (basic compound); inorganic bases such as sodium hydroxide and potassium hydroxide; and organic bases such as organic amines (triethanolamine, diisopropanolamine, etc.). One or more of these can be selected from this group. pH adjusters may also be in hydrate form. Specific examples of the salts include monovalent metal salts (alkali metal salts, etc.) such as sodium and potassium; and divalent metal salts (alkaline earth metal salts, etc.) such as calcium and magnesium.

[0031] The pH adjusting agent preferably contains an acidic compound, and more preferably further contains a basic compound. This further stabilizes the reduction in the content of components (A) and (B) during long-term storage. Specifically, the acidic compounds can be selected from the inorganic acids, organic acids, and salts thereof that are water-soluble and function as acids. Furthermore, the basic compound can be specifically selected from the inorganic bases, organic bases, and salts thereof that are water-soluble and function as a base. Specifically, a water-soluble compound refers to a compound that has a solubility of 0.5% by mass or more in water at 25°C and atmospheric pressure (760 mmHg).

[0032] The pH adjusting agent content in the topical skin composition is preferably 0.06% by mass or more, more preferably 0.08% by mass or more, and even more preferably 0.10% by mass or more, and may also be, for example, 0.3% by mass or more, 0.5% by mass or more, or 0.7% by mass or more. This allows for more favorable suppression of pH fluctuations during storage of the topical skin composition and favorable suppression of the decrease in the content of components (A) and (B). Similarly, the content of the pH adjusting agent in the topical skin composition is preferably 1.1% by mass or less, more preferably 1.0% by mass or less, and even more preferably 0.90% by mass or less.

[0033] Furthermore, it is more preferable that the pH adjusting agent content in the topical skin composition is within the above-mentioned range, and that the mass ratio of the acidic compound content to the basic compound content in the topical skin composition (acidic compound / basic compound) is 0.4 or more and 5 or less. This further stabilizes the reduction in the content of components (A) and (B) during long-term storage. Similarly, the above mass ratio (acidic compound / basic compound) is preferably 0.4 or higher, more preferably 0.45 or higher, even more preferably 0.5 or higher, and also preferably 5 or lower, more preferably 2 or lower, and even more preferably 1.3 or lower.

[0034] Furthermore, it is preferable that the pH adjusting agent includes at least one selected from the group consisting of citric acids, i.e., citric acid, its salts, and their hydrates; more preferably, it includes two or more of these; and even more preferably, it includes a combination of citric acid or its hydrate and a citrate (such as sodium citrate) or its hydrate. This further stabilizes the reduction in the content of components (A) and (B) during long-term storage. The salts in citrates are, for example, monovalent metal salts such as potassium and sodium.

[0035] Furthermore, the topical skin composition may also contain other drugs or pharmaceutical additives, such as those commonly used in topical skin preparations for antipruritic and anti-inflammatory purposes.

[0036] The above drugs include, for example, steroids other than component (A) such as cortisone acetate, dexamethasone acetate, dexamethasone, hydrocortisone acetate, hydrocortisone, prednisolone acetate, prednisolone, hydrocortisone butyrate, and prednisolone valerate acetate; antihistamines such as isotipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, and diphenhydramine hydrochloride; crotamiton; glycyrrhizic acid and its salts, and glycyrrhetinic acid derivatives such as glycyrrhetinic acid; and salicylic acid derivatives such as glycol salicylate and methyl salicylate. Examples include allantoin; disinfectants other than component (C), such as isopropylmethylphenol and benzalkonium chloride; astringents such as calamine and zinc oxide; local anesthetics such as ethyl aminobenzoate, oxypolyethoxide dodecane, dibucaine, dibucaine hydrochloride, lidocaine, and lidocaine hydrochloride; cooling agents such as d-camphor, dl-camphor, peppermint oil, dl-menthol, l-menthol, and d-borneol; ammonia water; tannic acid; gamma-oryzanol; and one or more selected from the group consisting of vitamins other than component (B), such as tocopherol, tocopherol acetate, vitamin A oil, and retinol palmitate. Examples of glycyrrhizic acid and its salts, as well as glycyrrhetinic acid derivatives such as glycyrrhetinic acid, include glycyrrhetinic acid, glycyrrhizic acid, and dipotassium glycyrrhizinate.

[0037] Furthermore, pharmaceutical additives may include those added as needed to further improve, for example, the stability of content or appearance over time, or the feel of use. Specific examples of pharmaceutical additives include, in addition to the pH adjusters mentioned above, one or more selected from the group consisting of bases, humectants, adhesives, antioxidants, cooling agents, surfactants, stabilizers, preservatives, viscosities, or thickening agents.

[0038] Examples of bases include water; oily bases; partially neutralized polyacrylic acid; polyhydric alcohols such as polyvinyl alcohol (partially saponified), propylene glycol, dipropylene glycol, macrogol, 1,3-butylene glycol, glycerin (e.g., concentrated glycerin), and D-sorbitol.

[0039] When a topical skin composition contains water, the water content may be, for example, the remainder after removing components other than water from the topical skin composition. Furthermore, the water content in the topical skin composition is preferably 40% by mass or more, more preferably 50% by mass or more, and even more preferably 60% by mass or more, relative to the total amount of the topical skin composition. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B). Similarly, the water content in the topical skin composition is preferably 85% by mass or less, more preferably 80% by mass or less, and even more preferably 75% by mass or less, relative to the entire topical skin composition.

[0040] As an oily base, one or more selected from the group consisting of styrene-isoprene-styrene copolymer; hydrocarbons such as petrolatum, paraffin, liquid paraffin, light isoparaffin, liquid isoparaffin, ozokerite, ceresin, hard fat, microcrystalline wax, squalane, α-olefin oligomer, polyethylene powder, and polyisobutylene; higher alcohols such as stearyl alcohol, cetanol, behenyl alcohol, cetostearyl alcohol, hexyldecanol, isostearyl alcohol, octyldodecanol, oleyl alcohol, decyltetradecanol, and myristyl alcohol; ester oils such as isopropyl palmitate, isopropyl myristate, octyldodecyl myristate, cetyl palmitate, glyceryl tri-2-ethylhexylate (glyceryl triisooctanoate), and medium-chain triglyceride; polymerized silicones such as dimethylpolysiloxane and dimethylsiloxane; and vegetable oils such as olive oil. The content of the oily base in the topical skin composition is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, and also preferably 30% by mass or less, more preferably 25% by mass or less, and even more preferably 20% by mass or less, relative to the total amount of the topical skin composition. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B).

[0041] The polyhydric alcohol content in the topical skin composition is preferably 1% by mass or more, more preferably 2% by mass or more, even more preferably 3% by mass or more, and also preferably 20% by mass or less, more preferably 15% by mass or less, even more preferably 12% by mass or less, and even more preferably 8% by mass or less, relative to the total amount of the topical skin composition. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B).

[0042] Examples of wetting agents include at least one selected from the group consisting of dl-pyrrolidone carboxylate sodium and polysorbate 40 solution.

[0043] Examples of adhesives include at least one selected from the group consisting of dibutylhydroxytoluene and hydrogen rosin glycerol esters.

[0044] As antioxidants, in addition to the aforementioned citric acid hydrate and anhydrous citric acid used as pH adjusters, one or more selected from the group consisting of, for example, ascorbic acid, ascorbic palmitate, sodium bisulfite, sodium pyrosulfite, sodium edetate, dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, and propyl gallate may be used.

[0045] Examples of cooling agents include one or more selected from the group consisting of menthol such as l-menthol, terpenes such as camphor, peppermint oil, eucalyptus oil, and the like.

[0046] As the surfactant, a nonionic surfactant or an ionic surfactant may be used. Furthermore, the surfactant may also be an emulsifier. Nonionic surfactants include, for example, polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol monofatty acid esters, ethylene glycol monofatty acid esters, glycerin monofatty acid esters (e.g., glyceryl monostearate), glycerin polyfatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, alkyl polyglucosides, polyethylene glycol fatty acid esters; polyoxyethylene ethers such as polyoxyethylene alkyl ethers (e.g., polyoxyethylene behenyl ether), polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl ether; and polyoxyethylene One or more of the following are selected from the group consisting of polyoxyethylene mono fatty acid esters, polyethylene glycol di fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid esters, and ether esters such as polyoxyethylene polyoxypropylene glycol. Specifically, polyoxyethylene alkyl ether refers to a nonionic surfactant in which only ethylene oxide is added to an alkyl group, and does not include those containing propylene oxide. The nonionic surfactant preferably comprises at least one selected from the group consisting of glycerol monofatty acid esters and polyoxyethylene alkyl ethers, and more preferably comprises glycerol monofatty acid esters and polyoxyethylene alkyl ethers. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B). The content of the nonionic surfactant in the topical skin composition is preferably 0.1% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, even more preferably 3% by mass or more, and also preferably 15% by mass or less, more preferably 10% by mass or less, even more preferably 8% by mass or less, and may also be, for example, 5% by mass or less. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B). Furthermore, specific examples of ionic surfactants include anionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate.

[0047] Examples of stabilizers include at least one selected from the group consisting of the aforementioned antioxidants and ionic surfactants.

[0048] Examples of preservatives include one or more selected from the group consisting of benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol. The preservative content in the topical skin composition is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, even more preferably 0.1% by mass or more, and also preferably 1% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.3% by mass or less, relative to the total amount of the topical skin composition. This makes it possible to more reliably obtain the effect of suppressing the decrease in the content of components (A) and (B).

[0049] Examples of thickening agents include one or more selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and hydroxyethylcellulose; thickening polysaccharides such as magnesium aluminum silicate, carboxyvinyl polymer, sodium alginate, xanthan gum, carrageenan, guar gum, gelatin, dextrin, cyclodextrin, and pectin; and carboxylate sodium, polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, and light anhydrous silicic acid.

[0050] A topical skin composition can be manufactured, for example, by combining components (A), (B), and other components as appropriate, using known manufacturing methods. For example, a topical skin composition can also be manufactured according to the usual methods described in the 18th edition of the Japanese Pharmacopoeia, etc.

[0051] In order to obtain a topical skin composition having at least one of the configurations of Embodiments 1 and 2, it is important to appropriately select, for example, the components and their proportions contained in the topical skin composition, as well as to appropriately select the manufacturing process of the topical skin composition. For example, it is important to appropriately select and combine the types and amounts of components contained in the topical skin composition to design the formulation. It is preferable that the topical skin composition contains a combination of components (A) to (C), and more preferably components (A) to (C) and a pH adjuster. It is also preferable to appropriately select and combine the types and amounts of components (A), (B) and the pH adjuster to design the formulation. It is more preferable that the pH adjuster contains both an acidic compound and a basic compound, and even more preferable to appropriately set the ratio of the acidic compound and the basic compound. It is also preferable that the pH adjuster contains both citric acid or its hydrate and a citrate or its hydrate. Furthermore, it is preferable that the topical skin composition be an emulsified composition such as a cream and also contain a pH adjuster. Furthermore, it is preferable to set appropriate temperatures and rotation speeds during the emulsification process when manufacturing the topical skin composition. It is also preferable to control the pH of the topical skin composition immediately after manufacturing.

[0052] The pH of the topical skin composition immediately after manufacturing is preferably 3.8 or higher, more preferably 4.0 or higher, even more preferably 4.3 or higher, and also preferably 5.4 or lower, more preferably 5.2 or lower, and even more preferably 5.0 or lower. This makes it possible to more stably suppress the decrease in the content of components (A) and (B) due to long-term storage.

[0053] The dosage form of the topical skin composition can be selected from the group consisting of, for example, creams, ointments, topical solutions, gels, topical solids, sprays (aerosols or pump sprays), foams, and patches. The topical skin composition is preferably a cream or hydrophilic ointment, and more preferably a cream. This further stabilizes the reduction in the content of components (A) and (B) during long-term storage. Similarly, the topical skin composition is preferably an emulsion composition, and more preferably an oil-in-water emulsion composition. Similarly, for topical skin compositions, the aqueous phase is preferably a continuous phase.

[0054] Furthermore, since the topical skin composition contains component (A), it is suitable as a topical agent such as an antipruritic and anti-inflammatory agent. The topical skin composition may be a pharmaceutical composition. The method of applying the topical skin composition is the same as for ordinary topical compositions; for example, an appropriate amount can be applied to the target area of ​​skin once to several times a day, according to the symptoms.

[0055] (Methods to improve storage stability) In this embodiment, the method for improving storage stability is a method for improving the storage stability of a composition containing components (A) and (B), and includes setting the pH of a mixture of 1 g of the composition and 30 mL of water at 25°C to 4.0 or higher and 5.3 or lower after storage at 40°C for one month. As described above, in this embodiment, by controlling the pH of the composition containing components (A) and (B) after storage, the decrease in the content of components (A) and (B) due to long-term storage can be effectively suppressed.

[0056] The embodiments of the present invention have been described above, but these are merely examples, and various other configurations can also be adopted. [Examples]

[0057] The embodiment will be described in detail below with reference to examples, but this embodiment is not limited to these examples.

[0058] (Examples 1-10, Comparative Examples 1 and 2) Each component was prepared according to the composition shown in Table 1 or Table 2, in accordance with the section on "Creams" in the General Provisions of the 18th Revised Japanese Pharmacopoeia, and each example composition (cream) was prepared.

[0059] (pH) The compositions for each example were filled into aluminum tubes and stored in an airtight condition at 40°C for one month. The pH of each composition was measured immediately after preparation and after storage using the following method. Specifically, 1 g of the composition before or after storage was weighed at 25°C and mixed with 30 mL of water to obtain a mixture. The resulting mixture was heated to 60°C to completely suspend, then returned to 25°C for pH measurement. pH was measured at 25°C using a commercially available pH meter (F-73, Horiba, Ltd.). The results are shown in Tables 1 and 2.

[0060] (survival rate) For the examples listed in Table 1, the compositions for each example were stored in aluminum tubes in an airtight condition at 40°C for 3 months. The remaining percentages of components (A) and (B) after 1 month and 3 months of storage were measured by HPLC under the following conditions. The results are shown in Table 1. In Table 1, "-" indicates that the remaining percentage of at least one of components (A) and (B) was less than 95% after 1 month of storage at 40°C, and therefore the remaining percentage after 3 months of storage could not be measured. Furthermore, in the example shown in Table 2, the samples were stored for one month in accordance with the example shown in Table 1, and the remaining percentages of components (A) and (B) after one month of storage were measured by HPLC under the following conditions. The results are shown in Table 2. (Remaining percentage of component (A)) The examples listed in Table 1 were measured using Method 1-1 described above under the following conditions. Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and formic acid diluted 1000 times with purified water. Based on the measurement results of the composition immediately after manufacturing and after storage, the content of component (A) was calculated as a mass percentage of the total composition. The ratio of the content of component (A) after storage to the content of component (A) immediately after manufacturing in each example was calculated and defined as the residual rate.

[0061] For the examples listed in Table 2, measurements were taken using Method 1-2 described above under the following conditions. Detector: UV absorbance spectrophotometer, Wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 2.7 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile and phosphoric acid diluted 1000 times with purified water. Based on the measurement results of the composition immediately after manufacturing and after storage, the content of component (A) was calculated as a mass percentage of the total composition. The ratio of the content of component (A) after storage to the content of component (A) immediately after manufacturing in each example was calculated and defined as the residual rate.

[0062] (Remaining percentage of component (B)) Detector: UV absorbance spectrophotometer, Wavelength: 210 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40℃ Mobile phase: A mixture of acetonitrile / ammonium formate (1.26 g) and formic acid (2.5 mL) dissolved in water to make a total volume of 1000 mL. Based on the measurement results of the composition immediately after manufacturing and after storage, the content of component (B) was calculated as a mass percentage of the total composition. The ratio of the content of component (B) after storage to the content of component (B) immediately after manufacturing in each example was calculated and defined as the residual rate.

[0063] [Table 1]

[0064] [Table 2]

[0065] In Tables 1 and 2, the unit of component amounts is mass%. Furthermore, the details of the components listed in Tables 1 and 2 are shown below. Liquid paraffin: Manufactured by Kaneda Co., Ltd. Dimethylpolysiloxane: Manufactured by Shin-Etsu Chemical Co., Ltd. Polyoxyethylene behenyl ether: Manufactured by Nikko Chemicals Co., Ltd.

[0066] Table 1 shows that in each example, the decrease in the content of components (A) and (B) was suppressed even after storage at 40°C for 3 months. Therefore, for example, the decrease in the content of components (A) and (B) during long-term storage of 3 years at 25°C can be suitably suppressed. Furthermore, it is expected that the decrease in the content of components (A) and (B) during long-term storage of 3 years at temperatures of 1 to 30°C can be suppressed, ensuring a quality suitable for distribution and sale. Furthermore, when the residual rate of component (A) was measured using Method 1-2 for each example listed in Table 1, it was confirmed that the results were equivalent to those obtained when measured using Method 1-1 (Table 1). Furthermore, in the examples shown in Table 2, the decrease in the content of components (A) and (B) after storage at 40°C for one month was suppressed.

[0067] (Examples of formulations 1-11) Table 3 shows examples of cream formulations. Each example of a cream formulation can be obtained by combining the components according to the composition shown in Table 3, for example, in accordance with the section on "Creams" in the General Provisions of the 18th Revised Japanese Pharmacopoeia.

[0068] [Table 3]

Claims

1. A topical skin composition containing the following components (A) and (B), A topical skin composition in which a mixture of 1 g of the topical skin composition and 30 mL of water, after being stored at 40°C for one month, has a pH of 4.0 to 5.3 at 25°C. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof.

2. A topical skin composition containing the following components (A) and (B), The residual rate of component (A) after storage at 40°C for 3 months, as measured by high-performance liquid chromatography using the following methods 1-2, is 95% or higher. A topical skin composition in which the residual rate of component (B) after storage at 40°C for 3 months is 95% or more, as measured by high-performance liquid chromatography in the following method 2. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof. (Method 1-2) Detector: UV absorbance spectrophotometer, wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 2.7 μm. Column temperature: 40°C Mobile phase: A mixture of acetonitrile and phosphoric acid diluted 1000 times with purified water. (Method 2) Detector: UV absorbance spectrophotometer, Wavelength: 210 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 3 μm. Column temperature: 40°C Mobile phase: A mixture of acetonitrile / ammonium formate (1.26 g) and formic acid (2.5 mL) dissolved in water to make a total volume of 1000 mL.

3. The topical skin composition according to claim 2, wherein the pH of a mixture of 1 g of the topical skin composition and 30 mL of water at 25°C after being stored at 40°C for one month is 4.0 or higher and 5.3 or lower.

4. A topical skin composition according to any one of claims 1 to 3, further comprising the following component (C). (C) One or more selected from the group consisting of benzethonium, its salts and their hydrates.

5. The topical skin composition according to any one of claims 1 to 3, wherein component (B) is at least one selected from the group consisting of panthenol and pantothenyl ethyl ether.

6. It further contains a pH adjuster, The topical skin composition according to any one of claims 1 to 3, wherein the pH adjusting agent comprises an acidic compound.

7. The topical skin composition according to claim 6, wherein the pH adjusting agent further comprises a basic compound.

8. The content of the pH adjusting agent in the topical skin composition is 0.06% by mass or more and 1.1% by mass or less relative to the entire topical skin composition. The topical skin composition according to claim 7, wherein the mass ratio of the content of the acidic compound to the content of the basic compound in the topical skin composition (acidic compound / basic compound) is 0.4 or more and 5 or less.

9. A topical skin composition according to any one of claims 1 to 3, which is an emulsified composition.

10. A topical skin composition according to any one of claims 1 to 3, which is a cream.

11. A method for improving the storage stability of a composition containing the following components (A) and (B), comprising setting the pH of a mixture of 1 g of the composition and 30 mL of water at 25°C to 4.0 or higher and 5.3 or lower after storage at 40°C for one month. (A) Betamethasone ester (B) One or more selected from the group consisting of pantothenic acid, its derivatives and salts thereof.

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