Composition for external use containing azelaic acid and method for producing same

Abstract

Provided is a composition for external use containing azelaic acid at a high concentration (for example, exceeding 10 mass%), the composition exhibiting excellent long-term dispersibility (long-term stability) of azelaic acid.　This composition for external use contains azelaic acid in an amount exceeding 10 mass%, an emulsifier, and a higher alcohol. The azelaic acid has an average particle diameter of 100 μm or smaller.

Description

Composition for external use containing azelaic acid and method for producing the same

[0001] The present invention relates to a topical composition containing azelaic acid and a method for producing the same.

[0002] Azelaic acid (heptane-1,7-dicarboxylic acid: C ９ H １６ O ４ Azelaic acid is a saturated dicarboxylic acid found in grains such as wheat flour and rye. Azelaic acid is widely known overseas as an active ingredient in acne treatments.

[0003] Azelaic acid is difficult to dissolve in a base, so it is usually included in the formulation in a dispersed state.

[0004] Patent Document 1 (JP 2012-232970 A) and Patent Document 2 (JP 2013-170124 A) disclose topical compositions containing 0.1 to 10% by mass of azelaic acid. From the viewpoint of suppressing sebum secretion and abnormal keratinization, it is desirable to provide a topical composition containing azelaic acid at a higher concentration.

[0005] Preparations such as creams and gels containing azelaic acid at a high concentration of, for example, 20% by mass are already known, and for example, Patent Document 3 (JP 2012-162461 A) discloses a composition for external use on the skin that can contain azelaic acid at a high concentration.

[0006] JP 2012-232970 A JP 2013-170124 A JP 2012-162461 A

[0007] However, the topical composition described in Patent Document 3 contains a high concentration of azelaic acid, but also contains an acrylic polymer. Given the recent consumer trend toward preparations that do not contain synthetic polymers such as acrylic polymers, it is desirable to provide a topical composition that contains a high concentration of azelaic acid without containing an acrylic polymer.

[0008] Here, the "AZ Series Azefit Spots" sold by Niki Pitta contains a high concentration (20% by weight) of azelaic acid but does not contain any acrylic polymers. The product's ingredients are listed as follows: "Water, Glycerin, Triethylhexanoin, Azelaic Acid, Sodium Hyaluronate, Water-Soluble Collagen, Dipotassium Glycyrrhizate, Salicylic Acid, Soybean Sterols, Basil Flower / Leaf Extract, Honeysuckle Flower Extract, Illicium Verum Fruit Extract, Usnea Barbata Extract, Caprylic / Capric Triglyceride, Isononyl Isononanoate, Dimethicone, Glyceryl Stearate, Glyceryl Stearate SE, PEG-10 Stearate, Behenic Acid, Hydrogenated Lecithin, Tocopherol." Here, hydrogenated lecithin is contained as an emulsifier, but the emulsifying action is unstable when a single emulsifier is used alone, so there is a possibility that sufficient dispersibility of azelaic acid may not be maintained for a long period of time.

[0009] The present invention aims to provide a topical composition containing azelaic acid at a high concentration (e.g., more than 10% by mass), which has excellent dispersibility of azelaic acid over a long period of time (long-term stability).

[0010] (1) A composition for external use, comprising more than 10% by mass of azelaic acid, an emulsifier, and a higher alcohol, wherein the average particle size of the azelaic acid is 100 μm or less.

[0011] (2) The topical composition according to (1), which does not contain a lower alcohol.

[0012] (3) The topical composition according to (1) or (2), wherein the content of the higher alcohol relative to the total amount of the topical composition is 0.5 to 5.0% by mass.

[0013] (4) The topical composition according to any one of (1) to (3), wherein the higher alcohol has 10 to 30 carbon atoms.

[0014] (5) The topical composition according to any one of (1) to (4), wherein the emulsifier is at least one selected from the group consisting of plant-derived emulsifiers, nonionic surfactants, and synthetic emulsifiers.

[0015] (6) The topical composition according to any one of (1) to (5), further comprising a polyhydric alcohol.

[0016] (7) The composition for external use according to any one of (1) to (6), having a pH of 3.0 to 5.0.

[0017] (8) The composition for external use according to any one of (1) to (7), which is a cream formulation.

[0018] (9) A method for producing a topical composition containing more than 10% by mass of azelaic acid, the method comprising: a heating step of heating a first raw material mixture containing water and a second raw material mixture containing an emulsifier and a higher alcohol; a first mixing step of mixing the heated first raw material mixture with the second raw material mixture to obtain an emulsified dispersion; and a second mixing step of lowering the emulsified dispersion to a predetermined temperature and then mixing a third raw material mixture containing azelaic acid into the emulsified dispersion, wherein the azelaic acid is a powder having an average particle size of 100 μm or less.

[0019] (10) The production method according to (9), wherein the third raw material mixture does not contain a lower alcohol.

[0020] (11) The production method according to (9) or (10), wherein the first raw material mixture further contains a polyhydric alcohol, and the second raw material mixture further contains an oil or fat.

[0021] (12) The manufacturing method according to any one of (9) to (11), wherein in the heating step, the first raw material mixture and the second raw material mixture are heated to 60 to 90°C, and in the second mixing step, the predetermined temperature is 35 to 55°C.

[0022] According to the present invention, a topical composition containing azelaic acid at a high concentration (e.g., more than 10% by mass) can be provided, which has excellent dispersibility (long-term stability) of the azelaic acid over a long period of time. That is, the topical composition containing azelaic acid of the present invention is less likely to undergo syneresis or separation of components over a long period of time.

[0023] In the present invention, by incorporating a higher alcohol as an emulsifying aid in addition to an emulsifier into the azelaic acid-containing composition, it is possible to maintain a stable emulsion dispersion and improve the stability of the topical composition containing azelaic acid.

[0024] 1 is a photograph of Example 1 after storage at 40°C for one month. 2 is another photograph of Example 1 after storage at 40°C for one month. 3 is a photograph of Comparative Example 1 after storage at 40°C for one month. 4 is another photograph of Comparative Example 1 after storage at 40°C for one month. 5 is a photograph of Comparative Example 2 after storage at 40°C for one month. 6 is another photograph of Comparative Example 2 after storage at 40°C for one month. 7 is a photograph of Comparative Example 3 after storage at 40°C for one month. 8 is a photograph of Comparative Example 4 after storage at 40°C for one month. 9 is a photograph of Example 2 after storage at 40°C for one month. 10 is a photograph of Comparative Example 5 after storage at 40°C for one month. 11 is a photograph showing the state of Comparative Example 5 after the second mixing step. 12 is a photograph of Example 1 after storage at 40°C for four months. 13 is a photograph of Example 2 after storage at 40°C for 50 days. 14 is a photograph of Example 2 after storage at 40°C for 50 days.

[0025] <Composition for External Use (Azelaic Acid-Containing Composition)> The composition for external use of the present invention is a composition for external use containing azelaic acid (azelaic acid-containing composition). The composition for external use is preferably a composition for external use on skin.

[0026] (Azelaic acid) The content of azelaic acid in the total amount of the topical composition is more than 10% by mass, preferably 15% by mass or more, more preferably 18% by mass or more, even more preferably 19% by mass or more, and even more preferably 20% by mass or more.Within this range, it is possible to obtain a higher inhibitory effect on sebum secretion and abnormal keratinization than conventionally.The upper limit of the blending rate of azelaic acid is not particularly limited, but is preferably 35% by mass or less, more preferably 30% by mass or less, and even more preferably 25% by mass or less.Within this range, the dispersion stability of azelaic acid is likely to be maintained for a long period of time.

[0027] The average particle size of the azelaic acid used in the present invention is 100 μm or less, preferably 70 μm or less, more preferably 50 μm or less, even more preferably 30 μm or less, and even more preferably 20 μm or less. Within this range, the dispersion stability of the azelaic acid can be maintained for a long period of time. Furthermore, an azelaic acid-containing composition that is smooth and comfortable to use can be obtained. The lower limit of the average particle size of the azelaic acid is not particularly limited, but is preferably 0.5 μm or more, more preferably 1 μm or more, and even more preferably 2 μm or more. Within this range, the raw material powder of azelaic acid generates little dust and is easy to handle during production.

[0028] The average particle size of the raw material powder of azelaic acid is the median value (median diameter: D50) in the volume-based particle size distribution, and can be measured using a laser diffraction particle size distribution measuring device (Malvern Panalytical's "Mastersizer 3000E").

[0029] The particle size peak of azelaic acid is preferably 0.5 to 100 μm, more preferably 1 to 50 μm, and even more preferably 2 to 30 μm. The particle size peak of the raw material powder of azelaic acid is the mode diameter (mode value) in the volume-based particle size distribution, and can be measured using a laser diffraction particle size analyzer (Malvern Panalytical's "Mastersizer 3000E"). In the particle size distribution of azelaic acid measured using the laser diffraction particle size analyzer (Malvern Panalytical's "Mastersizer 3000E"), it is preferable that 90% by mass or more (preferably 95% by mass or more) of the azelaic acid particles have a particle size within the range of 2 to 15 μm.

[0030] In the topical composition, azelaic acid is basically present in a dispersed state (as a dispersoid), but may be partially dissolved in the base. The average particle size of the azelaic acid contained in the topical composition is basically the same as the average particle size of the raw material powder of azelaic acid.

[0031] Azelaic acid may be used in the form of a physiologically acceptable salt. That is, in this specification, "azelaic acid" means at least one of azelaic acid and azelaic acid salts. Physiologically acceptable salts of azelaic acid include sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ammonium salt, methylamine salt, pyridine salt, trimethylamine salt, triethanolamine salt, and diethanolamine salt. Even if azelaic acid is incorporated as azelaic acid during the preparation of a topical composition, one or more azelaic acid salts may be generated in the resulting composition.

[0032] In this specification, "azelaic acid" does not include azelaic acid derivatives such as azeloylglycine K. The topical composition of this embodiment may further contain an azelaic acid derivative in addition to azelaic acid. However, from the viewpoint of reducing skin irritation, it is preferable not to contain an azelaic acid derivative.

[0033] (Emulsifier) ​​The emulsifier may be any of various known emulsifiers used in cosmetics, quasi-drugs, topical pharmaceuticals, etc. Examples of the emulsifier include plant-derived emulsifiers, fatty acid monoglycerides, nonionic surfactants, synthetic emulsifiers, hydrogenated lecithin, lecithin, hydrogenated lysolecithin, sodium dilauramidoglutamide lysine, glyceryl stearate, glyceryl stearate (SE), glyceryl myristate, glyceryl isostearate, glyceryl oleate, sorbitan stearate, sorbitan isostearate, hydrogenated castor oil stearate, polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, and PEG-100 hydrogenated castor oil.

[0034] The emulsifier is preferably at least one selected from the group consisting of plant-derived emulsifiers, fatty acid monoglycerides, nonionic surfactants, and synthetic emulsifiers. The emulsifier is more preferably at least one selected from the group consisting of plant-derived emulsifiers, fatty acid monoglycerides, and nonionic surfactants. In these cases, the effect of maintaining the dispersibility of the azelaic acid-containing composition over a long period of time (the effect of improving long-term stability) can be more reliably obtained.

[0035] Examples of plant-derived emulsifiers include lecithin-based emulsifiers (hydrogenated lecithin, lecithin, hydrogenated lysolecithin, sodium dilauramidoglutamide lysine, etc.), fatty acid monoglycerides (glyceryl stearate, glyceryl behenate, glyceryl stearate (SE), glyceryl myristate, glyceryl isostearate, glyceryl oleate, etc.), etc. Examples of nonionic surfactants include sorbitan stearate, sorbitan isostearate, hydrogenated castor oil stearate, polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, polyglyceryl-6 octastearate, polyglycerin fatty acid esters, etc. Examples of synthetic emulsifiers include ceteth-2, ceteth-6, ceteth-7, ceteth-10, ceteth-15, ceteth-20, ceteareth-2, ceteareth-4, ceteareth-20, oleth-7, oleth-10, oleth-15, and oleth-20.

[0036] (Higher Alcohol) In this specification, a higher alcohol refers to a monohydric alcohol (R—OH) having 6 or more carbon atoms. The higher alcohol is preferably a straight-chain alcohol. The straight-chain alcohol is preferably a saturated aliphatic alcohol, but may also be an unsaturated aliphatic alcohol. The number of carbon atoms of the higher alcohol used in the present invention is preferably 10 to 30, more preferably 16 to 26, and even more preferably 18 to 24. Within this range, the effect of maintaining the dispersibility of the azelaic acid-containing composition over a long period of time (the effect of improving long-term stability) can be more reliably obtained.

[0037] Examples of saturated fatty alcohols include behenyl alcohol (C ２２ H ４６ O), arachidyl alcohol (C ２０ H ４２ O), stearyl alcohol (C １８ H ３８ O), Cetyl alcohol (C １６ H ３４ These saturated aliphatic alcohols may be used alone or in combination of two or more.

[0038] The content of the higher alcohol relative to the total amount of the topical composition (the ratio of the amount of higher alcohol contained in the topical composition to the total amount of the topical composition) is preferably 0.2 to 5.0% by mass, more preferably 0.5 to 3.0% by mass, and even more preferably 1.0 to 2.5% by mass. Within this range, the effect of maintaining the dispersibility of the azelaic acid-containing composition over a long period of time (the effect of improving long-term stability) can be more reliably achieved.

[0039] From the viewpoint of improving the dispersibility (preparation stability) of azelaic acid, it is preferable that the topical composition of this embodiment does not contain a lower alcohol (a monohydric alcohol having 5 or less carbon atoms) such as ethanol.

[0040] (pH) The pH of the topical composition of this embodiment is preferably 3.0 to 5.0, more preferably 3.0 to 4.5, and even more preferably 3.5 to 4.0. Within this range, dispersion stability can be more reliably achieved over a long period of time. Furthermore, the skin irritation of the topical composition can be kept low.

[0041] The pH may be adjusted using various bases, acids, etc. Examples of bases include inorganic bases such as potassium hydroxide and sodium hydroxide, and organic bases such as triethanolamine, diisopropanolamine, and triisopropanolamine. Examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, and sodium succinate. The acids and bases may be used alone or in combination of two or more.

[0042] (Polyhydric Alcohol) The azelaic acid-containing composition of the present embodiment may contain a polyhydric alcohol. As the polyhydric alcohol, various known polyhydric alcohols used in cosmetics, quasi-drugs, topical pharmaceutical preparations, etc. can be used. Specific examples of polyhydric alcohols include dihydric alcohols such as ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, 1,4-butanediol (tetramethylene glycol), 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol (pentylene glycol), isoprene glycol (isopentyl diol), hexylene glycol, dipropylene glycol, polyethylene glycols (polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, and polyethylene glycol 35000), and polypropylene glycols (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, and the like); Examples include trihydric alcohols such as glycerin and trimethylolpropane; diglycerin; and polyglycerin.

[0043] Among these, 1,3-butylene glycol and 1,2-pentanediol are preferably used.

[0044] When the composition contains a polyhydric alcohol, the content of the polyhydric alcohol (ratio to the total amount of the composition) is preferably 1% by mass or more, more preferably 3% by mass or more, and even more preferably 5% by mass or more.Within this range, the effect of maintaining the dispersibility of the azelaic acid-containing composition for a long period of time (the effect of improving long-term stability) can be obtained.Furthermore, when the composition contains a polyhydric alcohol, the content of the polyhydric alcohol is preferably 50% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less.Within this range, a good, non-sticky feel can be obtained.

[0045] (Base or Carrier) The topical composition may contain a base or carrier other than the polyhydric alcohol. As the base or carrier, those known as bases or carriers for cosmetics, quasi-drugs, or pharmaceuticals can be used.

[0046] Examples of such known bases or carriers include hydrocarbons such as squalane, dodecane, liquid paraffin, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, and light liquid paraffin; silicone oils such as methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl-modified silicone, crosslinked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, crosslinked polyether-modified silicone, crosslinked alkyl polyether-modified silicone, silicone / alkyl chain co-modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; higher alcohols such as cetyl alcohol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; Vegetable oils such as medfoam oil, sunflower oil, grape seed oil, camellia oil, squalane, shea butter, and rice germ oil; animal oils such as lanolin, orange roughy oil, squalane, and horse oil; natural polymer derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, cationized guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and acrylic acid / alkyl methacrylate copolymer; carrageenan, alginic acid, cellulose, guar gum, quinone Examples of suitable oil-soluble surfactants include natural polymers such as sesame seeds, dextran, gellan gum, and hyaluronic acid; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, methylheptyl laurate, pentaerythrityl tetra-2-ethylhexanoate, jojoba oil, and caprylic / capric triglyceride; polysaccharides such as dextrin and maltodextrin; organic acids such as succinic acid, glycolic acid, gluconic acid, and citric acid; and aqueous bases such as water.

[0047] However, due to recent consumer trends, there is a tendency for preparations that do not contain synthetic polymers such as acrylic polymers to be preferred, so it is preferable that the topical composition of the present invention does not contain acrylic polymers, acrylic copolymers, etc.

[0048] (Additives) Known additives added to cosmetics, quasi-drugs, or pharmaceuticals can be added to the topical composition as long as they do not impair the effects of the present invention. Examples of additives include antioxidants, surfactants, thickeners (e.g., hydroxyethyl cellulose), preservatives, pH adjusters, stabilizers, irritation reducers, antiseptics, colorants, fragrances, and pearlescent agents. It is preferable that the topical composition of this embodiment does not contain any additives or contains only a small amount of additives.

[0049] (Other Active Ingredients) The topical composition of the present invention may contain other active ingredients to the extent that the effects of the present invention are not impaired. Specific examples of active ingredients include moisturizing ingredients (e.g., sodium hyaluronate), anti-inflammatory ingredients (e.g., dipotassium glycyrrhizinate), antibacterial or bactericidal ingredients, vitamins, peptides or derivatives thereof, cell activating ingredients, anti-aging ingredients, blood circulation promoting ingredients, keratin softening ingredients, whitening ingredients, astringent ingredients, and UV protection ingredients.

[0050] (Form of Preparation) The topical composition of the present invention can be prepared as a cosmetic, quasi-drug, or pharmaceutical preparation.

[0051] The formulation of the topical composition is not particularly limited, and examples thereof include solutions, suspensions, emulsions, creams, ointments, gels, liniments, lotions, aerosols, sticks, and sheets of nonwoven fabric impregnated with a drug solution. These formulations can be produced, for example, according to the method described in the Japanese Pharmacopoeia General Rules for Pharmaceutical Preparations. Among these, creams are preferred from the viewpoint of dispersibility of azelastic acid. When an oily base and an aqueous base are contained, as in creams and emulsions, they may be either W / O type or O / W type, with O / W type being preferred. Specific uses of topical compositions include, for example, basic cosmetics such as lotions, emulsions, gels, creams, serums, sunscreens, packs, masks, hand creams, body lotions, and body creams; cleansing cosmetics such as facial cleansers, makeup removers, shaving products, body shampoos, shampoos, rinses, and treatments; lip cosmetics such as lip balms and lipsticks; hair removers; and bath additives.

[0052] <Production Method> The present invention also relates to a method for producing a topical composition containing more than 10% by mass of azelaic acid. The production method of this embodiment includes: a heating step of heating a first raw material mixture containing water and a second raw material mixture containing an emulsifier and a higher alcohol; a first mixing step of mixing the heated first raw material mixture with the second raw material mixture to obtain an emulsified dispersion; and a second mixing step of cooling the emulsified dispersion to a predetermined temperature and then mixing the emulsified dispersion with a third raw material mixture containing azelaic acid.

[0053] In the manufacturing method of this embodiment, it is preferable to use azelaic acid powder having the above-mentioned average particle size (100 μm or less) as the azelaic acid, which makes it possible to more reliably obtain an azelaic acid-containing composition that can maintain dispersibility for a long period of time (high long-term stability).

[0054] It is preferable that the third raw material mixture does not contain a lower alcohol. Generally, lower alcohols are thought to aid in the dispersion of azelaic acid, and when the concentration of azelaic acid is low, the incorporation of a lower alcohol is thought to improve the dispersibility of azelastic acid. However, the inventors' studies have found that when the concentration of azelaic acid is high, the incorporation of a lower alcohol actually reduces the dispersibility of azelaic acid. While the details of this mechanism are unclear, it is thought that, for example, the lower alcohol destroys the formulation system (emulsion system), thereby reducing the dispersibility of azelaic acid.

[0055] The first raw material mixture preferably further contains a polyhydric alcohol. That is, the first raw material mixture preferably contains water and a polyhydric alcohol. This makes it possible to more reliably obtain an azelaic acid-containing composition that can maintain dispersibility over a long period of time (high long-term stability). The first raw material mixture may further contain a thickener (e.g., hydroxyethyl cellulose).

[0056] The second raw material mixture preferably further contains a fat or oil. That is, the second raw material mixture preferably contains an emulsifier, a higher alcohol, and a fat or oil. This makes it possible to more reliably obtain an azelaic acid-containing composition that can maintain dispersibility over a long period of time (high long-term stability). Examples of fat or oil include esters (e.g., methylheptyl laurate). The second raw material mixture may further contain a hydrocarbon. Examples of hydrocarbons include squalane and dodecane.

[0057] In the heating step, the first raw material mixture and the second raw material mixture are preferably heated to 60 to 90° C. In the second mixing step, the predetermined temperature is preferably 35 to 55° C. By carrying out the heating step and the second mixing step at such a temperature, an azelaic acid-containing composition that can more reliably maintain dispersibility over a long period of time (high long-term stability) can be obtained.

[0058] Examples of the present invention will be described below, but the present invention is not limited to these examples.

[0059] Example 1: In Example 1, a topical composition containing 20% ​​by weight of azelaic acid, an emulsifier, a higher alcohol, and the like was prepared. Specifically, the mixture of component A (first mixture) and the mixture of component B (second mixture) shown in Table 1 below were each heated to a temperature within the range of 70-80°C. [Heating Step]: Component A was then added to the heated component B, and the components were emulsified and dispersed by mixing for 5-10 minutes at 3000-5000 rpm using a PRIMIX Corporation MARK II homomixer. [First Mixing Step]: The resulting emulsion dispersion was then cooled. When the temperature of the emulsion dispersion had dropped to a temperature within the range of 50-40°C, the mixture of component C (third raw material mixture) was added to the emulsion dispersion, and the components were dispersed by the same mixing procedure as above. The mixture was thoroughly dispersed and the temperature was then cooled to below 30°C. [Second Mixing Step] By the above operations, the topical composition (cream preparation) of Example 1 was prepared.

[0060] The details of each component shown in Table 1 are as follows: The numerical values ​​in the table indicate the content (mass%) of each component in the topical composition. <Component A> ・Purified water ・Ag-P water: "Ag-P water" (Shin-ei Chemical Co., Ltd.) ・Hydroxyethyl cellulose: "SANHEC HH" (Sansho Co., Ltd.) ・Sodium hyaluronate: "Hyaluronic San HA-LQ" (Kewpie Corporation) ・Dipotassium glycyrrhizinate ・1,3-butylene glycol: "BRONTIDE SKY" (Genomatica) ・1,2-pentanediol: "GREEN PENTANE DIOR" (GSI Creos Corporation) <Component B> ・1,3-butylene glycol: "BRONTIDE SKY" (Genomatica) ・Squalane: "Sugar Squalane (registered trademark)" (Nikko Chemicals Co., Ltd.) ・Methylheptyl laurate: "NIKKOL GS-MHL" (Nikko Chemicals Co., Ltd.) ・Dodecane: "PARAFOL (registered trademark) 12 RSPO-MB" (SASOL Germany GmbH)・Hydrogenated lecithin (emulsifier): "NIKKOL Resinol S-10E" (Nikko Chemicals Co., Ltd.) ・Glyceryl stearate (emulsifier): "NIKKOL MGS-BV2" (Nikko Chemicals Co., Ltd.) ・Glyceryl behenate (emulsifier), polyglyceryl-6 octastearate (emulsifier): "TAISET 50-C" (Taiyo Kagaku Co., Ltd.) (vegetable gelling agent) ・Behenyl alcohol (higher alcohol) <Component C> Azelaic acid: "Azelaic Acid" (H. Holstein Co., Ltd.) Ethanol: Absolute ethanol Diethylene glycol monoethyl ether: "TRANSCUTOL CG" (Gatefosse Co., Ltd.) Herbal blend: "MultiEX BSASM (ECO)" (a blend of seven anti-inflammatory herbs: chamomile, knotweed, tea plant, centella asiatica, scutellaria, rosemary, and Spanish licorice) (GSI Creos Co., Ltd.)

[0061] The "dodecane" of the above component B is a saturated linear alkane represented by the following formula:

[0062]

[0063] The measured average particle size (D50) of the above component C, azelaic acid ("Azelaic Acid": H. Holstein) is 11.85 μm, and the measured peak particle size (mode diameter) is 16.40 μm.

[0064] (Comparative Examples 1 to 4) Comparative Examples 1 to 4 differ from Example 1 in the composition of each component as shown in Table 1. Except for these differences, topical compositions for Comparative Examples 1 to 4 were prepared in the same manner as Example 1. Comparative Example 1 differs from Example 1 in that it contains ethanol. Comparative Example 2 differs from Example 1 in that it does not contain behenyl alcohol. Comparative Example 3 differs from Example 1 in that it does not contain behenyl alcohol and that it contains ethanol. Comparative Example 4 differs from Example 1 in that it does not contain behenyl alcohol and that it contains ethanol and diethylene glycol monoethyl ether.

[0065] (Example 2, Comparative Example 5) In Example 2, azelaic acid having an actual measured average particle size (D50) of 50 μm ("SpecKare ALA", Spec-Chem Industry Inc.) was used as the azelaic acid. In Comparative Example 5, azelaic acid having an actual measured average particle size (D50) of 160 μm (pulverized azelaic acid manufactured by Kishida Chemical Co., Ltd.) was used as the azelaic acid. Except for this, the topical compositions of Example 2 and Comparative Example 5 were prepared in the same manner as in Example 1.

[0066]

[0067] <Dispersion Stability Confirmation Test> A test was conducted to confirm the dispersibility stability of the topical compositions containing azelaic acid obtained in Examples 1 and 2 and Comparative Examples 1 to 5. Specifically, for each of the topical compositions of Examples 1 and 2 and Comparative Examples 1 to 5, the presence or absence of syneresis and component separation was visually confirmed after storage at room temperature for one month, at 40°C for two weeks, and at 40°C for one month. For the topical composition of Example 1, the presence or absence of syneresis and component separation was visually confirmed even after storage at 40°C for four months. For the topical compositions of Example 2 and Comparative Example 5, the presence or absence of syneresis and component separation was visually confirmed even after storage at 40°C for 50 days. The results of the confirmation are shown in Table 2. The symbols in the table mean the following: ◯: No syneresis or separation was observed. Δ: Slight syneresis and / or separation was observed. ×: Syneresis and / or separation was observed. 1 to 10 show photographs of the compositions of the Examples and Comparative Examples after storage at 40°C for one month. FIG. 12 shows a photograph of the composition of Example 1 after storage at 40°C for four months. FIGs. 13 and 14 show photographs of the compositions of Example 2 and Comparative Example 5 after storage at 40°C for 50 days. Syneresis or separation was observed in the areas surrounded by dotted lines in the figures.

[0068]

[0069] As shown in Table 2, in the topical compositions of Examples 1 and 2 (Comparative Example 5), which contained a higher alcohol (behenyl alcohol) but no lower alcohol (ethanol), no syneresis or separation was observed even when stored for one month at 40° C. In contrast, in the topical composition of Comparative Example 2, which was similar to Example 1 except that it did not contain a higher alcohol (behenyl alcohol), slight syneresis and separation was observed when stored for one month at 40° C. Therefore, it is believed that the incorporation of a higher alcohol in addition to an emulsifier, etc., improves the dispersion stability of topical compositions containing azelaic acid.

[0070] Furthermore, in the topical composition of Comparative Example 1, which contained both a higher alcohol and a lower alcohol, slight syneresis and separation were observed after storage for one month at 40° C. From this, it is believed that in azelaic acid-containing compositions containing a higher alcohol in addition to an emulsifier, etc., the dispersion stability of the composition is improved when the lower alcohol is not added.

[0071] Furthermore, for the topical compositions of Comparative Examples 2 to 4, which contained an emulsifier but no higher alcohol, Comparative Example 3, which further contained a lower alcohol, and Comparative Example 4, which further contained a lower alcohol and a glycol ether (diethylene glycol monoethyl ether), showed more pronounced syneresis and separation than Comparative Example 2 when stored at 40°C for one month. These results demonstrate that the improvement in dispersion stability of the topical composition of Example 1, which contained a higher alcohol in addition to an emulsifier, etc., is achieved by the inclusion of the higher alcohol, and that the same improvement in dispersion stability as in Example 1 cannot be achieved even if a lower alcohol or glycol ether, which is sometimes used as a solubilizer, is added.

[0072] Furthermore, the results of Examples 1 and 2 and Comparative Example 5 after storage at 40°C for 50 days (4 months for Example 1) show that in Examples 1 and 2, where the average particle size of azelaic acid is 100 μm or less, the dispersion stability of azelaic acid is maintained for a long period of time.

[0073] <Confirmation Test for Skin Irritation> A confirmation test for skin irritation (safety) was conducted on the topical composition (azelaic acid-containing composition) of Example 1 above. For reference, similar tests were also conducted on physiological saline, water for injection, and white petrolatum. Specifically, a 24-hour occlusive patch test (number of subjects: 20) was conducted as described in Tetsuro Sugai, Cosmetic Science, Vol. 19, Special Edition, 49-56 (1995). The patch test evaluation criteria are shown in Table 3. The total score for the 20 subjects, based on the following evaluation criteria, was used as the skin irritation index. Classification based on the skin irritation index is shown in Table 4. The test results are shown in Table 5.

[0074]

[0075]

[0076]

[0077] As shown in Table 5, the topical composition of Example 1 was confirmed to have low skin irritation (high safety) at the same level as water for injection. While compositions with a skin irritation index of 15.0 or less (safe and acceptable products in the classification of Table 4) are acceptable products, the topical composition of Example 1 had a skin irritation index of 2.5, making it extremely safe.

[0078] The topical composition of Example 2 (azelaic acid-containing composition) was confirmed to be free of roughness and to have a good feel when used. On the other hand, the topical composition of Comparative Example 5, although prepared as a mixture, had residual grains, was rough, and had a poor feel when used, as shown in the photograph in Figure 11.

Claims

1. A composition for external use comprising more than 10% by weight of azelaic acid, an emulsifier, and a higher alcohol, wherein the average particle size of the azelaic acid is 100 μm or less.

2. The topical composition according to claim 1, which does not contain a lower alcohol.

3. The topical composition according to claim 1, wherein the content of the higher alcohol relative to the total amount of the topical composition is 0.5 to 5.0 mass%.

4. The topical composition according to claim 1, wherein the higher alcohol has 10 to 30 carbon atoms.

5. The topical composition according to claim 1, wherein the emulsifier is at least one selected from the group consisting of plant-derived emulsifiers, nonionic surfactants, and synthetic emulsifiers.

6. The topical composition according to claim 1, further comprising a polyhydric alcohol.

7. The topical composition according to claim 1, having a pH of 3.0 to 5.

0.

8. The topical composition according to claim 1, which is a cream formulation.

9. A method for producing a topical composition containing more than 10% by mass of azelaic acid, comprising: a heating step of heating a first raw material mixture containing water, and heating a second raw material mixture containing an emulsifier and a higher alcohol; a first mixing step of mixing the heated first raw material mixture and the second raw material mixture to obtain an emulsified dispersion; and a second mixing step of lowering the emulsified dispersion to a predetermined temperature and then mixing a third raw material mixture containing azelaic acid into the emulsified dispersion, wherein the azelaic acid is a powder having an average particle size of 100 μm or less.

10. The method of claim 9, wherein the third feedstock mixture does not contain a lower alcohol.

11. The manufacturing method according to claim 9, wherein the first raw material mixture further contains a polyhydric alcohol, and the second raw material mixture further contains an oil or fat.

12. The manufacturing method according to claim 9, wherein in the heating step, the first raw material mixture and the second raw material mixture are heated to 60 to 90°C, and in the second mixing step, the predetermined temperature is 35 to 55°C.

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