JP7659849B2 - Composition for external use containing azelaic acid and its manufacturing method - Google Patents

Description

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

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

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

Patent Document 1 (JP 2012-232970 A) and Patent Document 2 (JP 2013-170124 A) disclose compositions for external use that contain 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 a higher concentration of azelaic acid.

Preparations such as creams and gels that contain azelaic acid at high concentrations (e.g., 20% by mass) are already known. For example, Patent Document 3 (JP Patent Publication 2012-162461 A) discloses a skin topical composition that can contain azelaic acid at a high concentration.

JP 2012-232970 A JP 2013-170124 A JP 2012-162461 A

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 of preferring formulations 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.

Here, "AZ Series Azefit Spots" sold by NIKIPITA contains a high concentration (20% by weight) of azelaic acid and does not contain acrylic polymers. The product's ingredients are listed as "Water, Glycerin, Triethylhexanoin, Azelaic Acid, Sodium Hyaluronate, Water-Soluble Collagen, Dipotassium Glycyrrhizinate, Salicylic Acid, Soybean Sterol, 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 included as an emulsifier, but the emulsifying effect is unstable when using only one emulsifier, so there is a possibility that sufficient dispersibility of azelaic acid may not be maintained for a long period of time.

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

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

(2) The composition for external use according to (1) does not contain a lower alcohol.

(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.

(4) The composition for external use according to any one of (1) to (3), wherein the number of carbon atoms of the higher alcohol is 10 to 30.

(5) The composition for external use 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.

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

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

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

(9) A method for producing a composition for external use 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 heated second raw material mixture to obtain an emulsified dispersion;
a second mixing step of mixing a third raw material mixture containing azelaic acid into the emulsified dispersion after lowering the temperature of the emulsified dispersion to a predetermined temperature,
The method for producing the azelaic acid is a powder having an average particle size of 100 μm or less.

(10) The manufacturing method described in (9), wherein the third raw material mixture does not contain a lower alcohol.

(11) The first raw material mixture further contains a polyhydric alcohol,
The method for producing a food product according to claim 9 or 10, wherein the second raw material mixture further contains a fat or oil.

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

According to the present invention, it is possible to provide a topical composition containing azelaic acid at a high concentration (e.g., more than 10% by mass) and having excellent dispersibility (long-term stability) of azelaic acid over a long period of time. In other words, the topical composition containing azelaic acid of the present invention is less susceptible to syneresis or separation of components over a long period of time.

In the present invention, by blending a higher alcohol as an emulsifier in addition to an emulsifier in the azelaic acid-containing composition, it is possible to stably maintain the emulsion dispersion and improve the stability of the topical composition containing azelaic acid.

This is a photograph of Example 1 after storage at 40° C. for one month. 13 is another photograph of Example 1 after storage at 40° C. for one month. This is a photograph of Comparative Example 1 after storage at 40° C. for one month. 13 is another photograph of Comparative Example 1 after storage at 40° C. for one month. This is a photograph of Comparative Example 2 after storage at 40° C. for one month. 13 is another photograph of Comparative Example 2 after storage at 40° C. for one month. This is a photograph of Comparative Example 3 after storage at 40° C. for one month. This is a photograph of Comparative Example 4 after storage at 40° C. for one month. This is a photograph of Example 2 after storage at 40° C. for one month. This is a photograph of Comparative Example 5 after storage at 40° C. for one month. 13 is a photograph showing the state after the second mixing step for Comparative Example 5. This is a photograph of Example 1 after storage at 40° C. for 4 months. This is a photograph of Example 2 after storage at 40° C. for 50 days. This is a photograph of Example 2 after storage at 40° C. for 50 days.

<External composition (azelaic acid-containing composition)>
The topical composition of the present invention is a topical composition containing azelaic acid (azelaic acid-containing composition). The topical composition is preferably a topical composition for skin.

(Azelaic acid)
The content of azelaic acid in the total amount of the composition for external use 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, a higher inhibitory effect on sebum secretion and abnormal keratinization than conventional ones can be obtained.
The upper limit of the blending ratio 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.

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. If it is within this range, the effect of maintaining the dispersion stability of the azelaic acid for a long period of time can be obtained. In addition, it is possible to obtain an azelaic acid-containing composition that is not rough and has a good feel when used.
The lower limit of the average particle size of azelaic acid is not particularly limited, but is preferably 0.5 μm or more, more preferably 1 μm or more, and further preferably 2 μm or more. Within this range, the raw material powder of azelaic acid generates little dust, etc., and the handling during production is good.

The average particle size of the raw 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").

The peak particle size 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 (the most frequent value) 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").
In the particle size distribution of azelaic acid measured using a laser diffraction particle size distribution measuring device (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.

In addition, azelaic acid is basically present in a dispersed state (as a dispersoid) in the topical composition, 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.

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 a salt of azelaic acid.
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, diethanolamine salt, etc. Even if azelaic acid is incorporated during preparation of a topical composition, one or more azelaic acid salts may be generated in the resulting composition.

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 suppressing skin irritation, it is preferable not to contain an azelaic acid derivative.

(emulsifier)
As the emulsifier, various known emulsifiers used in cosmetics, quasi-drugs, external medicines, etc. can be used.
Examples of emulsifiers include plant-derived emulsifiers, fatty acid monoglycerides, nonionic surfactants, synthetic emulsifiers, hydrogenated lecithin, lecithin, hydrogenated lysolecithin, sodium dilauroyl glutamate 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.

The emulsifier is preferably at least one selected from the group consisting of plant-derived emulsifiers, fatty acid monoglycerides, nonionic surfactants, and synthetic emulsifiers. It is more preferable that the emulsifier is at least one selected from the group consisting of plant-derived emulsifiers, fatty acid monoglycerides, and nonionic surfactants. In these cases, it is possible to more reliably obtain 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).

Examples of plant-derived emulsifiers include lecithin-based emulsifiers (hydrogenated lecithin, lecithin, hydrogenated lysolecithin, sodium dilauroyl glutamate 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.

(Higher alcohol)
In this specification, a higher alcohol is 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 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 further preferably 18 to 24. 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 more reliably.

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

The content of 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 for a long period of time (the effect of improving long-term stability) can be obtained more reliably.

From the viewpoint of improving the dispersibility (formulation 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.

(pH)
The pH of the topical composition of the present 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 obtained over a long period of time. In addition, the skin irritation of the topical composition can be kept low.

The pH can be adjusted using various bases and acids. 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.

(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, external medicines and the like 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 glycol (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 glycol (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, and the like);
Trihydric alcohols such as glycerin and trimethylolpropane;
diglycerol; and polyglycerol.

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

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.
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 feeling of use without stickiness can be obtained.

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

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 cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; jojoba oils such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; 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, hydroxypropyl methylcellulose, cationic guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymers, and alkyl acrylate/methacrylate copolymers; carrageenan, alginic acid, cellulose, guar gum, quinone, etc. Natural polymers such as sucrose, dextran, gellan gum, and hyaluronic acid; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, methylheptyl laurate, pentaerythritol tetra 2-ethylhexanoate, jojoba oil, and tri(caprylic/capric acid)glyceryl; 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.

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

(Additives)
The topical composition may contain known additives that are added to cosmetics, quasi-drugs, or pharmaceuticals, 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, preservatives, colorants, fragrances, and pearlescent agents. It is preferable that the topical composition of the present embodiment does not contain any additives or contains only a small amount of additives.

(Other active ingredients)
The topical composition of the present invention may contain other active ingredients within the scope of not impairing the effects of the present invention. 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.

(Form of preparation)
The composition for external use of the present invention may be in the form of a cosmetic, quasi-drug, or pharmaceutical preparation.

The formulation of the external composition is not particularly limited, and examples thereof include liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, aerosols, sticks, and sheets in which nonwoven fabric is impregnated with a drug solution. These formulations can be produced, for example, according to the method described in the General Provisions of Preparations in the Japanese Pharmacopoeia for Pharmaceuticals. Among these, creams are preferred from the viewpoint of dispersibility of azelastic acid.
When an oily base and an aqueous base are contained, such as in creams and emulsions, they may be of the W/O type or the O/W type, with the O/W type being preferred.
Specific uses of the topical compositions include, for example, basic cosmetics such as lotions, milky lotions, gels, creams, beauty 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 products.

<Production Method>
The present invention also relates to a method for preparing a topical composition containing more than 10% by weight of azelaic acid.
The manufacturing method of this embodiment is as follows:
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 heated second raw material mixture to obtain an emulsified dispersion;
and a second mixing step of mixing the emulsified dispersion with a third raw material mixture containing azelaic acid after lowering the temperature of the emulsified dispersion to a predetermined temperature.

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. This makes it possible to obtain an azelaic acid-containing composition that can more reliably maintain dispersibility over a long period of time (high long-term stability).

The third raw material mixture preferably does not contain a lower alcohol.
Usually, it is considered that lower alcohol acts to assist the dispersion of azelaic acid, and when the concentration of azelaic acid is low, it is considered that the dispersibility of azelastic acid is improved by adding lower alcohol.However, the present inventors have found that when the concentration of azelaic acid is high, the addition of lower alcohol reduces the dispersibility of azelaic acid.The details of this mechanism are unclear, but it is considered that, for example, lower alcohol destroys the formulation system (emulsion system), thereby reducing the dispersibility of azelaic acid.

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 for a long period of time (high long-term stability).
The first raw material mixture may further contain a thickener (such as hydroxyethyl cellulose).

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 obtain an azelaic acid-containing composition that can more reliably maintain dispersibility over a long period of time (high long-term stability). Examples of fat or oil include esters (methylheptyl laurate, etc.).
The second raw material mixture may further contain a hydrocarbon, such as squalane or dodecane.

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 temperatures, it is possible to more reliably obtain an azelaic acid-containing composition that can maintain dispersibility over a long period of time (having high long-term stability).

The following describes examples of the present invention, but the present invention is not limited to these.

Example 1
As Example 1, a composition for external use containing 20% by mass of azelaic acid, an emulsifier, a higher alcohol, etc. was prepared.
Specifically, each of the mixture of component A (first mixture) and the mixture of component B (second mixture) shown in Table 1 below was heated to a temperature in the range of 70 to 80° C. [Heating step]
Thereafter, component A was added to the heated component B, and the components were emulsified and dispersed by mixing for 5 to 10 minutes at 3,000 to 5,000 rpm using a homomixer MARK II manufactured by Primix Corporation.
The resulting emulsion dispersion was then cooled. When the temperature of the emulsion dispersion had dropped to a temperature within the range of 50 to 40°C, the mixture of component C (third raw material mixture) was added to the emulsion dispersion, and each component was dispersed by the same mixing operation as above. The components were thoroughly dispersed and the process was completed at 30°C or less. [Second mixing process]
By the above operations, the topical composition (cream preparation) of Example 1 was prepared.

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 Acid HA-LQ" (Kewpie Corporation)
・Dipotassium glycyrrhizinate・1,3-butylene glycol: "BRONTIDE SKY" (Genomatica)
・1,2-Pentanediol: "GREEN PENTANE DIOR" (GSI Creos Co., Ltd.)
<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 Lecithinol 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.) (Plant-based 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" (Gattefosse)
Herbal Blend: "MultiEX BSASM (ECO)" (a blend of seven anti-inflammatory herbs including chamomile, Japanese knotweed, tea plant, Centella asiatica, Scutellaria, rosemary, and Spanish licorice) (GSI Creos Co., Ltd.)

The "dodecane" in component B above is a saturated linear alkane represented by the following formula:

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

(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 the above, the topical compositions of 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 contains ethanol.
Comparative Example 4 differs from Example 1 in that it does not contain behenyl alcohol and contains ethanol and diethylene glycol monoethyl ether.

(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 the above, the topical compositions of Example 2 and Comparative Example 5 were prepared in the same manner as in Example 1.

<Confirmation test for dispersion stability>
Tests were carried out to confirm the stability of dispersibility of the topical compositions containing azelaic acid obtained in Examples 1 and 2 and Comparative Examples 1 to 5 above.
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 separation of components was visually confirmed after storage at room temperature for one month, after storage at 40° C. for two weeks, and after storage at 40° C. for one month. For the topical composition of Example 1, the presence or absence of syneresis and separation of components 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 separation of components 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 have the following meanings:
○: No release 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.

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 at 40°C for one month.
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 were observed when stored at 40°C for one month.
Therefore, it is believed that the dispersion stability of a topical composition containing azelaic acid can be improved by incorporating a higher alcohol in addition to an emulsifier, etc.

In addition, in the topical composition of Comparative Example 1, which contained a higher alcohol as well as a lower alcohol, slight syneresis and separation were observed when stored at 40° C. for one month.
From this, it is considered that in an azelaic acid-containing composition in which a higher alcohol is blended in addition to an emulsifier, etc., the dispersion stability of the composition is improved by not blending a lower alcohol.

In addition, in 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 obvious syneresis and separation than Comparative Example 2 when stored at 40°C for one month.
These results show that the effect of improving dispersion stability in the topical composition of Example 1, which contains a higher alcohol in addition to an emulsifier, etc., is achieved by the inclusion of the higher alcohol, and that even if lower alcohols or glycol ethers, which are sometimes used as solubilizers, are added, the same effect of improving dispersion stability as in Example 1 cannot be obtained.

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 the cases of 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.

<Skin irritation confirmation test>
A confirmation test for skin irritation (safety) was carried out for the topical composition (azelaic acid-containing composition) of Example 1. For reference, the same test was also carried out for 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 of the 20 subjects based on the evaluation criteria below was used as the skin irritation index. The classification based on the skin irritation index is shown in Table 4.
The test results are shown in Table 5.

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. Furthermore, while a composition with a skin irritation index of 15.0 or less (safe and acceptable products in the classification of Table 4) is acceptable as a product, the topical composition of Example 1 has a skin irritation index of 2.5, making it extremely safe.

It was confirmed that the topical composition of Example 2 (the composition containing azelaic acid) had no roughness and was pleasant to use.
On the other hand, although the topical composition of Comparative Example 5 could be prepared as a mixture, it was confirmed that granules remained, the mixture was rough, and the feel of use was poor, as shown in the photograph of FIG.

Claims (12)

Contains more than 10% by mass and not more than 20% by mass of azelaic acid, an emulsifier, and a higher alcohol;
The average particle size of the azelaic acid is 100 μm or less,
The pH is 3.0 to 5.0,
The emulsifier includes a lecithin-based emulsifier and a fatty acid monoglyceride,
A topical composition , wherein the higher alcohol comprises behenyl alcohol . The composition for external use according to claim 1, which does not contain a lower alcohol. 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% by mass. The topical composition according to claim 1, wherein the higher alcohol has 10 to 30 carbon atoms. The composition for external use 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. The topical composition according to claim 1, further comprising a polyhydric alcohol. The topical composition of claim 1 , which does not contain any surfactants (other than the emulsifier) . The composition for external use according to claim 1, which is a cream formulation. A method for producing a composition for external use containing more than 10% by mass and not more than 20% 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 heated second raw material mixture to obtain an emulsified dispersion;
a second mixing step of mixing a third raw material mixture containing azelaic acid into the emulsified dispersion after lowering the temperature of the emulsified dispersion to a predetermined temperature,
The azelaic acid is a powder having an average particle size of 100 μm or less,
The emulsifier includes a lecithin-based emulsifier and a fatty acid monoglyceride,
The method for producing said higher alcohol comprises behenyl alcohol . The manufacturing method according to claim 9, wherein the third raw material mixture does not contain a lower alcohol. The first raw material mixture further contains a polyhydric alcohol,
The method according to claim 9 , wherein the second raw material mixture further contains an oil or fat. In the heating step,
The first raw material mixture and the second raw material mixture are heated to 60 to 90° C.,
The method according to claim 9, wherein in the second mixing step, the predetermined temperature is 35 to 55°C.