Method for preparing azelaic acid particles and external preparation for skin

Abstract

The present invention provides a method for preparing azelaic acid particles, the method comprising: a solution preparation step: preparing an azelaic acid solution in which azelaic acid is dissolved in a good solvent; a crystallization step of mixing the azelaic acid solution prepared in the solution preparation step with purified water as a poor solvent to precipitate crystals; and a drying step: drying the product obtained in the crystallization step in a standing state.

Description

Technical Field

[0001] This invention relates to a method for preparing azelaic acid granules and a topical skin preparation. More specifically, this invention relates to a method for preparing azelaic acid granules with a specific shape, and a topical skin preparation comprising the azelaic acid granules. Background Technology

[0002] Azelaic acid is a saturated dicarboxylic acid, a white, fine powder.

[0003] Azelaic acid is known to inhibit excessive sebum secretion and has anti-inflammatory effects, making it an effective ingredient for treating acne. It is also known to inhibit melanocyte activity, activate skin metabolism, possess antioxidant properties, and be an effective ingredient for treating skin pigmentation.

[0004] Therefore, compositions containing azelaic acid are used as topical preparations applied to the skin (topical skin preparations).

[0005] For example, Patent Document (PTL) 1 discloses a reagent for treating acne, the reagent comprising azelaic acid in a pharmaceutically acceptable carrier, wherein the carrier is selected from creams, ointments, or lotions.

[0006] Patent document 2 discloses a topical skin preparation comprising azelaic acid, a liquid oil having polar groups in its molecule, water, and an emulsion stabilizing component, wherein at least the liquid oil is dispersed in water for emulsification.

[0007] List of cited references Patent documents Patent Document 1: Japanese Patent Application Publication No. 57-134416 Patent Document 2: Japanese Patent Application Publication No. 2015-078167 Summary of the Invention

[0008] Technical issues As described in Patent Documents 1 and 2, when preparing compositions containing azelaic acid for use in various products, the conventional practice is to disperse the azelaic acid in various matrices containing oil and / or water.

[0009] In addition, azelaic acid is known not only to treat skin lesions but also to have skin-beautifying effects (such as whitening); therefore, azelaic acid is a very useful cosmetic ingredient.

[0010] Azelaic acid is known to exert its various effects and functions through skin contact or penetration. It is also known to be a highly safe substance for human use. In formulations containing azelaic acid as an active ingredient, it needs to be incorporated in a relatively high proportion (approximately 5% to 20% by weight).

[0011] Azelaic acid is known to have low water solubility. Containing large amounts of azelaic acid in topical skin formulations raises concerns that it may adversely affect the quality of the makeup effect when applied to the skin, as well as the handleability (processability) of the product during preparation and use. Specifically, for example, it may cause a whitening effect, disrupt skin tone evenness, or result in a noticeably powdery texture, leading to an unnatural overall makeup look. Furthermore, there are concerns that the smoothness or adhesion of azelaic acid to the skin may be reduced when applied to the skin surface. Additionally, when azelaic acid is dispersed in a liquid, it is likely to aggregate and is unlikely to be evenly dispersed, and the azelaic acid particles are likely to adhere to the container walls. Therefore, for example, when azelaic acid is incorporated into a topical skin formulation, the supply of powder material is difficult to transport smoothly, resulting in poor handleability during product preparation.

[0012] Therefore, azelaic acid, as a compound for use in topical skin preparations, is required to improve its contact efficiency with the skin during application, while also exerting positive properties on the quality of the makeup and the manageability of the product during preparation and / or use.

[0013] The purpose of this invention is to provide a method for preparing azelaic acid granules suitable for application to the skin, and also to provide a topical skin preparation that uses azelaic acid granules to fully exert the various effects and functions of azelaic acid without compromising the quality of the cosmetic effect or the processability of the product preparation and / or use.

[0014] Solution The inventors of this invention conducted in-depth research to achieve the above objectives and discovered that by using azelaic acid (azelaic acid solution) as a raw material and crystallizing and drying it under specific conditions, azelaic acid particles with a controlled shape suitable for application to the skin can be obtained. Furthermore, the above problems can be solved by mixing azelaic acid particles with a controlled particle shape into topical skin preparations, thus completing this invention.

[0015] That is, the present invention includes the subject schemes of the method for preparing azelaic acid granules and the topical preparations for skin use as described in the following items.

[0016] Item 1. A method for preparing azelaic acid granules, the method comprising: Solution preparation steps: Prepare an azelaic acid solution, wherein the azelaic acid is dissolved in a good solvent; Crystallization step: The azelaic acid solution obtained in the solution preparation step is mixed with purified water, which is a poor solvent, to precipitate crystals; and Drying step: The product obtained in the crystallization step is dried under static conditions.

[0017] Item 2. The method for preparing azelaic acid particles according to Item 1, wherein the temperature of the undesirable solvent is 0°C or higher and 25°C or lower.

[0018] Item 3. The method for preparing azelaic acid particles according to Item 1 or 2, wherein the crystallization step comprises, after mixing the azelaic acid solution with the unsuitable solvent, allowing the mixture to stand for 6 hours or longer.

[0019] Item 4. A topical skin preparation containing azelaic acid particles, wherein the azelaic acid particles are prepared by the method for preparing azelaic acid particles according to Item 1 or 2.

[0020] Item 5. The method according to Item 4, wherein the form of the topical skin preparation is such that the azelaic acid particles are insoluble in water.

[0021] Item 6. A topical skin preparation comprising azelaic acid particles having a flake-like structure, said azelaic acid particles having a median particle size of 10 μm or higher as measured by a particle size analyzer based on laser diffraction scattering.

[0022] Beneficial effects of the present invention This invention provides a method for preparing azelaic acid granules suitable for application to the skin, and also provides a topical skin preparation that uses azelaic acid granules to fully exert the various effects and functions of azelaic acid without compromising the quality of the cosmetic effect or the processability of the product preparation and / or use. Attached Figure Description

[0023] Figure 1 The images show scanning electron microscope (SEM) images of commercially available azelaic acid. A. Magnification: 500x; and B. Magnification: 1000x.

[0024] Figure 2 This is a flowchart of a method for preparing azelaic acid particles according to the present invention.

[0025] Figure 3 SEM images (observation magnification: low) of azelaic acid particles prepared by the method of the present invention are shown. A. Example 1, observation magnification: 25x; B. Example 2, observation magnification: 25x; C. Example 3, observation magnification: 25x; D. Example 4, observation magnification: 50x; E. Example 5, observation magnification: 25x; and F. Comparative Example 1, observation magnification: 50x.

[0026] Figure 4SEM images (magnification: high) of azelaic acid particles prepared by the method of the present invention are shown. A. Example 1, magnification: 200x; B. Example 2, magnification: 200x; C. Example 3, magnification: 250x; D. Example 4, magnification: 250x; E. Example 5, magnification: 250x; and F. Comparative Example 1, magnification: 300x.

[0027] Figure 5 Images showing the dispersibility of azelaic acid particles in water according to various embodiments. A. Azelaic acid particles prepared by the method for preparing azelaic acid particles according to the present invention (Example 4); and B. Azelaic acid as a comparative example (Comparative Example 2).

[0028] Figure 6 Images showing the cosmetic effect quality of the mixtures containing azelaic acid particles from various embodiments after application. Left: A mixture of petrolatum and azelaic acid (Comparative Example 2); and right: A mixture of petrolatum and azelaic acid particles prepared by the method of the present invention (Example 4). Detailed Implementation

[0029] In this specification, unless otherwise expressly stated or there is a clear contradiction in the context, the singular form encompasses both singular and plural meanings.

[0030] In this specification, the terms “comprising” and “including” include the meanings of “consistent with” and “comprises from”.

[0031] The following describes the method for preparing azelaic acid granules and embodiments of topical skin preparations according to the present invention, including preferred modes.

[0032] [Preparation of Azelaic Acid Granules] The azelaic acid granules of the present invention refer to substances obtained by converting azelaic acid into granules or granulating azelaic acid.

[0033] Azelaic acid First, let's explain azelaic acid.

[0034] Azelaic acid (chemical formula: C9H) 16 Azelaic acid (O4) is a saturated dicarboxylic acid, a substance composed of a white fine powder. The main industrial preparation method for azelaic acid is known to be the ozonolysis of oleic acid.

[0035] Azelaic acid solution dissolved in a good solvent is used as the raw material for the azelaic acid particles of the present invention. There are no particular limitations on the method for obtaining the azelaic acid itself. Commercially available azelaic acid products can be used, or azelaic acid obtained by conventional synthesis methods can be used. Furthermore, the solution containing azelaic acid obtained during conventional synthesis can be used as is as the raw material for the azelaic acid particles of the present invention.

[0036] Figure 1 The image shows a scanning electron microscope (SEM) image of commercially available azelaic acid obtained by conventional methods. Figure 1 Image A in the image is taken at a magnification of 500x. Figure 1 Image B in the image is taken at a magnification of 1000x.

[0037] Figure 1 The SEM images were obtained by using azelaic acid manufactured by CORUM Corporation and a "TM4000Plus" manufactured by Hitachi High Technology Corporation as a scanning electron microscope, under an accelerating voltage of 15 kV.

[0038] Figure 1 Commercially available azelaic acid contains needle-like, rod-like, spindle-like, and amorphous crystal structures, mainly composed of fine powder crystals with needle-like structures ranging from about 1 μm to 30 μm in length and 10 μm or less in width. The needle-like, rod-like, spindle-like, and amorphous crystal structures of azelaic acid will be collectively referred to as "needle-like structures" below.

[0039] The particle size distribution of the azelaic acid crystals was determined by dry method using a particle size analyzer based on laser diffraction scattering (PSA1190 model manufactured by Anton Paar). The particle size (D50) of the azelaic acid was approximately 5.4 μm.

[0040] The inventors of this invention have determined that azelaic acid obtained by conventional methods has a needle-like structure or similar structure (e.g., Figure 1 Based on the fine powder of azelaic acid (as shown), it was found that when azelaic acid is used as an active ingredient in topical skin preparations, there is a negative association between the structure of azelaic acid as a fine powder and having a needle-like structure, and the negative impact on the quality of the makeup effect when applied to the skin and the manageability of the product preparation and / or use.

[0041] The inventors of this invention have discovered that by using azelaic acid (azelaic acid solution) as a raw material and preparing azelaic acid particles under specific conditions, the shape of the azelaic acid particles can be controlled, thereby obtaining azelaic acid particles suitable for application to the skin, thus realizing the structure of this invention.

[0042] <Method for preparing azelaic acid granules> In the method for preparing azelaic acid particles according to the present invention, an azelaic acid solution is used as a starting material, and the azelaic acid is granulated under specific conditions and process steps.

[0043] Figure 2 This is a flowchart of the process steps for preparing azelaic acid particles according to the present invention. Figure 2 As shown, the method for preparing azelaic acid particles according to the present invention includes a solution preparation step 10 for preparing an azelaic acid solution, a crystallization step 20 for precipitating crystals from the azelaic acid solution obtained in the solution preparation step, and a drying step 30 for drying the product obtained by the crystallization step.

[0044] The steps are described below.

[0045] Perform solution preparation step 10 to obtain an azelaic acid solution as a raw material, more specifically, to prepare an azelaic acid solution in which azelaic acid 14 is dissolved in a good solvent 12.

[0046] The good solvent 12 can be any solvent, as long as a predetermined amount of azelaic acid 14 can be dissolved in the solution and an azelaic acid solution can be prepared. Specific examples of the good solvent include polar organic solvents, including: alcohols such as ethanol and methanol; glycols such as propylene glycol and butanediol; and acetone.

[0047] In one example of the solution preparation step, such as Figure 2 As shown, finely powdered azelaic acid 14 with a needle-like structure is added to a container containing a good solvent 12 at room temperature or a good solvent 12 under heating, and further heated and stirred to form a solution (reference numeral 16), thereby obtaining an azelaic acid solution 18. Hereinafter, the "finely powdered azelaic acid with a needle-like structure" refers to, for example... Figure 1 The commercially available azelaic acid shown is also known as "undissolved azelaic acid" or "azelaic acid (powder)".

[0048] Solution preparation step 10 is not limited to Figure 2 The steps are shown. Other examples of solution preparation step 10 include using the azelaic acid-containing solution generated during the synthesis of azelaic acid as is, as the azelaic acid solution.

[0049] In crystallization step 20, the azelaic acid solution 18 obtained in solution preparation step 10 is mixed with purified water 22, which is a poor solvent, to precipitate crystals.

[0050] The purified water used as the undesirable solvent 22 can be any type of water, as long as the content of impurities in the water is reduced. Examples of purified water include water referred to as ultrapure water and pure water. From the perspective of manufacturing cost, specific examples of purified water preferably include ion-exchanged water, RO water, and distilled water.

[0051] In an example of crystallization step 20, a poor solvent (i.e., purified water 22) is added to the container storing the azelaic acid solution at a predetermined amount and rate, and the resulting product is stirred or allowed to stand for a predetermined time to precipitate crystals (reference numeral 24). In another example of crystallization step 20, an azelaic acid solution is added to the container storing the poor solvent (i.e., purified water 22) at a predetermined amount and rate, and the resulting product is stirred or allowed to stand for a predetermined time to precipitate crystals (reference numeral 24).

[0052] Thus, the azelaic acid solution becomes a slurry containing azelaic acid crystals.

[0053] The shape of the resulting azelaic acid particles can be controlled by selecting various conditions (including operational details) in crystallization step 20. The conditions for controlling the shape of the azelaic acid particles in crystallization step 20 of the present invention will be described below by example.

[0054] There are no particular limitations on the temperature in the crystallization step 20 of this invention. However, as described in the examples below, the shape of the azelaic acid particles can be controlled, particularly when the unsuitable solvent is within a specific temperature range, and azelaic acid particles more suitable for skin application can be obtained.

[0055] Specifically, when the temperature of the unsuitable solvent used in crystallization step 20 is 0°C or higher and 25°C or lower, the ratio of the long side to the short side in the lamellar structure (hereinafter referred to as "aspect ratio") decreases. In particular, when the temperature of the unsuitable solvent 22 used in crystallization step 20 is 10°C or higher and 20°C or lower, the content of azelaic acid particles with a needle-like structure or a large aspect ratio is significantly reduced, and azelaic acid particles more suitable for skin application can be obtained in high yield; more specifically, azelaic acid particles with a lamellar structure and a small aspect ratio can be obtained. In this case, the temperature of the unsuitable solvent 22 can be selected such that the aspect ratio of the obtained azelaic acid particles is 10 or less, more preferably 5 or less. The aspect ratio preferably represents the average aspect ratio. The average aspect ratio can be obtained by observing multiple (preferably 20 or more, more preferably 50 or more) azelaic acid particles under a microscope, measuring their long and short sides, calculating the aspect ratio of each azelaic acid particle, and obtaining the average aspect ratio. Therefore, azelaic acid particles can be obtained that further enhance smoothness when applied to the skin, and further improve the quality of the makeup effect, such as skin adhesion and reducing whitening.

[0056] The crystallization step 20 of this invention involves mixing an azelaic acid solution 18 with purified water, then stirring or allowing the mixture to stand to precipitate crystals (reference numeral 24). The operation and time for crystal precipitation are not particularly limited. However, as described in the embodiments below, by employing specific operations and durations, the shape of the azelaic acid particles can be controlled, resulting in azelaic acid particles more suitable for skin application. Specifically, when crystallization step 20 includes a process step of allowing the mixture to stand for 6 hours or longer, more preferably 12 hours or longer, after mixing the azelaic acid solution 18 with purified water, the surface of the sheet-like structure becomes flattened. Consequently, the azelaic acid particles can further enhance smoothness when applied to the skin and can have a glossy appearance as a cosmetic effect.

[0057] In crystallization step 20, there is no particular limitation on the amount (addition ratio) of the undesirable solvent 22 to be added to the azelaic acid solution 18. However, for example, the amount of undesirable solvent 22 to be added may be 2 times or more the amount of the azelaic acid solution 18, and more preferably 3 times or more the amount of the azelaic acid solution 18. There is no particular limitation on the mixing speed (time required for mixing) of the azelaic acid solution 18 and the undesirable solvent 22. However, for example, the speed may be 60 minutes or less, more preferably 30 minutes or less. Therefore, high-yield production and production with stable quality can be carried out.

[0058] Drying step 30 includes drying the product obtained in crystallization step 20 under static conditions (reference numeral 36). This causes azelaic acid to aggregate and granulate, yielding azelaic acid particles 38. Drying the product obtained in crystallization step 20 can be either direct drying or drying after further treatment of the product.

[0059] In the drying step 30 of this invention, the object to be dried can remain unchanged during drying. The slurry 26 obtained in the crystallization step 20 can be directly dried. However, as... Figure 2 As shown, from the perspective of drying efficiency, it is preferable to dry the solid components obtained by solid-liquid separation (reference numeral 32) of slurry 26 (reference numeral 34).

[0060] In the drying step 30 of the present invention, there are no particular limitations on the method of drying the object in a static state. For example, the object to be dried (slurry or solid component) contained in a tray can be dried using a known drying apparatus. Examples of known drying apparatus in this case include cold air dryers, hot air dryers, and vacuum dryers. From the perspective of drying efficiency and inhibition of azelaic acid denaturation, a vacuum dryer is preferred. More specifically, a vacuum tray dryer is preferred.

[0061] In the drying step 30 of the present invention, there are no special restrictions on drying conditions such as drying temperature and drying time. However, for example, when a vacuum dryer is used, the drying is carried out at a temperature of 100°C or lower for 36 hours or less.

[0062] In the drying step of this invention, the obtained particle size can be controlled by selecting and adjusting drying conditions (such as drying temperature and drying time) and the content of azelaic acid in the object to be dried.

[0063] The amount of azelaic acid in the azelaic acid particles obtained by the method for preparing azelaic acid particles according to the present invention is, but not particularly limited to, preferably 90% by mass or more, more preferably 95% by mass or more, even more preferably 98% by mass or more, and particularly preferably 99% by mass or more, and is, for example, about 100% by mass.

[0064] The azelaic acid particles obtained by the method for preparing azelaic acid particles according to the present invention mainly have a lamellar structure. In the present invention, particles having a "lamellar structure" can be particles with a thin and flat shape, examples of which include particles having a flat, flaky, or scale-like shape. The proportion of the number of azelaic acid particles having a lamellar structure relative to the total number of azelaic acid particles is, for example, 30% or more, 50% or more, 80% or more, or 90% or more.

[0065] The inventors of this invention have discovered that when azelaic acid particles have a specific shape and primarily a lamellar structure, compared to finely powdered azelaic acid with a needle-like structure, the azelaic acid particles can be expected to enhance the smoothness of the skin surface, and further, for example, enhance the skin adhesion of the azelaic acid particles and reduce the whitening sensation caused by adhering to the skin ridges. That is, azelaic acid particles suitable for application to the skin can be obtained by the method for preparing azelaic acid particles according to this invention.

[0066] In the case of azelaic acid particles obtained using the method for preparing azelaic acid particles according to the present invention, the evaluation results of the cosmetic effect quality when applied to the skin and the processability of the product in preparation and / or use will be described in the following examples.

[0067] [Topical skin preparations] The topical skin formulation of the present invention is a topical skin formulation containing azelaic acid particles, wherein the azelaic acid particles obtained by the above-described method for preparing azelaic acid particles are incorporated into the topical skin formulation. Therefore, a topical skin formulation can be provided that, compared to a topical skin formulation incorporating finely powdered azelaic acid with a needle-like structure, is expected to enhance the smoothness of the skin surface and, for example, enhance the skin adhesion of the azelaic acid particles and reduce the whitening sensation caused by adhering to the skin ridges. That is, a topical skin formulation can be provided that, when used, allows the azelaic acid to exert one or more of its effects and benefits selected from the following without compromising makeup quality and workability: sebum suppression, anti-inflammatory effect, whitening effect, acne improvement effect, melanocyte activity inhibition, skin metabolism promotion, antioxidant effect, and skin pigmentation inhibition. In addition, a topical skin formulation may be provided in which azelaic acid particles, which have excellent dispersibility in water (in other words, low aggregation), are used as a powder raw material, and exhibit excellent processability in the preparation of the product.

[0068] The particle size of the azelaic acid particles incorporated into the topical skin formulations according to the present invention is not particularly limited, as long as the azelaic acid particles have a specific shape, specifically a plate-like structure. Examples of particle size include the particle size of raw materials commonly used in general powder cosmetics (median particle size D50 of about 5 μm to 20 μm), and particle sizes larger than such fine azelaic acid powder particle sizes, such as... Figure 1 As shown.

[0069] The particle size of the azelaic acid particles of the present invention, for example, with respect to the median particle size (D50) obtained by a particle size analyzer based on laser diffraction scattering, is preferably 10 μm or greater, more preferably 25 μm or greater. There is no particular upper limit to the particle size of the azelaic acid particles; for example, with respect to the median particle size (D50), it is preferably 300 μm or less, more preferably 150 μm or less.

[0070] By setting the median particle size of the azelaic acid particles within the aforementioned range, when applied to the skin, the azelaic acid particles can be embedded in and retained within the skin texture, thereby achieving the effect of easily maintaining the azelaic acid particles in close contact with the skin surface without them falling off.

[0071] This ensures excellent makeup results when the azelaic acid particles are applied to the skin, while fully showcasing the various effects and benefits of azelaic acid.

[0072] In this invention, there are no particular limitations on the method used to adjust the particle size of the azelaic acid particles. Examples include selecting preparation conditions (solvent, processing time, processing temperature, etc.) when preparing azelaic acid particles from azelaic acid as a raw material; and subjecting the obtained azelaic acid particles to pulverization and grading (e.g., sieving). Therefore, those skilled in the art can obtain azelaic acid particles with the specified particle size using conventional techniques.

[0073] Furthermore, there are no particular limitations on the means used to confirm (determine) the particle size of azelaic acid particles in this invention, and measuring devices and methods known in the art can be used. Examples include measurements using a particle size analyzer, measurements using image data analysis (calculation), etc. More specifically, in addition to the median particle size measured using a particle size analyzer based on laser diffraction scattering, for example, the average particle size (diameter, or the combination of the longest and shortest diameters) of a plurality of randomly selected particles (e.g., 20 particles) from SEM images of azelaic acid particles can be regarded as the particle size of azelaic acid particles in this invention.

[0074] In the topical skin formulation of the present invention, the content of the azelaic acid particles is not particularly limited, but is preferably from 0.001% by mass to 100.0% by mass. The lower limit is more preferably 0.1% by mass or higher, further preferably 1.0% by mass or higher, and particularly preferably 5.0% by mass or higher. The upper limit is more preferably 50.0% by mass or less, further preferably 30.0% by mass or less, and particularly preferably 20.0% by mass or less.

[0075] Since the content of the azelaic acid particles is within the above-mentioned range, the various effects and functions of azelaic acid can be fully exerted, such as sebum suppression, anti-inflammatory effects, and whitening effects. Furthermore, from the perspective of fully demonstrating the various effects and functions of azelaic acid when mixed into topical skin preparations and achieving excellent cosmetic effects when applied to the skin, the content of the azelaic acid particles is particularly preferably 5.0% by mass or higher.

[0076] <Other Ingredients> Depending on their intended use, the topical skin formulations of the present invention may include one or more other ingredients commonly used in conventional topical skin formulations that comprise cosmetics and therapeutic agents. Examples include inorganic pigments, polymer powders, oil-based ingredients, surfactants, humectants, thickeners, polymers, UV protectants, antioxidants, antioxidant auxiliaries, chelating agents, metal soaps (such as magnesium stearate), whitening agents, anti-wrinkle agents, agents for improving skin roughness, acne medications, deodorants, cooling agents, astringents, antibacterial agents, preservatives, pH adjusters, organic pigments, natural colorants, fragrances, vitamins, emollients, etc.

[0077] Examples of inorganic pigments include extender pigments, colored pigments, and white pigments.

[0078] Extender pigments are used to maintain the shape of a product and allow for adjustments to its usability (spreadability, adhesion), gloss, etc. Specific examples include mica, sericite, talc, kaolin, synthetic phlogopite, calcium carbonate, magnesium carbonate, anhydrous silica, alumina, barium sulfate, etc.

[0079] Colored pigments are used to adjust the color tone of products. Specific examples include iron oxide red, iron oxide yellow, iron oxide black, chromium oxide, ultramarine, Prussian blue, carbon black, etc.

[0080] White pigments can not only adjust the color tone of a product, but also enhance its concealing power. Specific examples include titanium dioxide and zinc oxide.

[0081] Specific examples of polymer powders include polyethylene powder, polymethyl methacrylate powder, polyethylene terephthalate-polymethyl methacrylate composite powder, nylon powder, polyurethane powder, siloxane powder, etc.

[0082] Examples of oil-based raw materials include fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, and silicone oils. Specific examples of fats and oils include olive oil, camellia seed oil, macadamia nut oil, and castor oil. Specific examples of waxes include carnauba wax, candelilla wax, jojoba oil, beeswax, and lanolin. Specific examples of hydrocarbons include liquid paraffin, paraffin wax, petrolatum, mineral wax, microcrystalline wax, and squalane. Specific examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, and isostearic acid. Specific examples of higher alcohols include cetyl alcohol, stearyl alcohol, isostearyl alcohol, and 2-octyldodecyl alcohol. Specific examples of esters include isopropyl myristate, 2-octyldodecyl myristate, cetyl 2-ethylhexanoate, and diisostearyl malate. Specific examples of silicone oils include methyl polysiloxane, methylphenyl polysiloxane, decamethylcyclopentasiloxane, and highly polymerized methyl polysiloxane.

[0083] Examples of surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants. Specific examples of anionic surfactants include higher fatty acid soaps, alkyl sulfate salts, polyoxyalkyl ether sulfates, acyl N-methyl taurate, alkyl ether phosphate salts, and N-acyl amino acid salts. Specific examples of cationic surfactants include alkyl trimethylammonium chloride, dialkyl dimethylammonium chloride, and benzalkonium chloride. Specific examples of amphoteric surfactants include alkyl dimethylaminoacetic acid betaine, alkylamidopropyl dimethylaminoacetic acid betaine, and 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazoline betaine. Specific examples of nonionic surfactants include polyoxyethylene surfactants, polyol ester surfactants, and ethylene oxide-propylene oxide block copolymers.

[0084] Examples of moisturizers include glycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, polyethylene glycol, sorbitol, sodium lactate, sodium 2-pyrrolidone-5-carboxylate, sodium hyaluronate, hydrolyzed hyaluronic acid, hydroxypropyltrimethylammonium hyaluronate, sodium carboxymethyl hyaluronate, ceramides (ceramide-like substances, human ceramides, and natural human ceramides), etc.

[0085] Examples of thickeners include papaya seed gum, xanthan gum, sodium carboxymethyl cellulose, and carboxyvinyl polymers.

[0086] Examples of polymers include polyvinyl alcohol, polyvinylpyrrolidone, nitrocellulose, and polysiloxanes.

[0087] Examples of UV protectants include: UV absorbers, such as benzophenone derivatives, para-aminobenzoic acid derivatives, methoxycinnamic acid derivatives, and salicylic acid derivatives; and UV scattering agents, such as fine-grained titanium dioxide, fine-grained zinc oxide, and fine-grained iron oxide.

[0088] Examples of antioxidants include tocopherol, butylated hydroxytoluene (BHT), and gallic acid esters.

[0089] Examples of antioxidant auxiliaries include phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phospholipids, sodium hexametaphosphate, phytic acid, ethylenediaminetetraacetic acid (EDTA), etc.

[0090] Examples of chelating agents include sodium ethylenediaminetetraacetate, phosphoric acid, citric acid, ascorbic acid, succinic acid, gluconic acid, sodium polyphosphate, sodium metaphosphate, etc.

[0091] Examples of skin whitening agents include vitamin C, arbutin, kojic acid, ellagic acid, and 4-n-butylresorcinol (Rucinol).

[0092] Examples of anti-wrinkle agents include retinoic acid (vitamin A), alpha-hydroxy acids, various peptides, and amino acids.

[0093] Examples of agents that improve skin roughness include anti-inflammatory agents such as β-glycyrrhetinic acid, glycyrrhizic acid derivatives, allantoin, azulen, hydrocortisone, and protease inhibitors.

[0094] Examples of acne medications include sebum-suppressing ingredients such as estradiol, estrone, ethinylestradiol, and vitamin B6; exfoliating and / or keratolytic ingredients such as sulfur, salicylic acid, and resorcinol; antibacterial ingredients such as benzalkonium chloride, benzyl chloride, halocarban, and 2,4,4-trichloro-2-hydroxyphenol; anti-inflammatory ingredients such as glycyrrhizic acid and glycyrrhetinic acid; and so on.

[0095] Examples of deodorants include antiperspirant ingredients such as aluminum hydroxychloride, aluminum chloride, allantoin basic aluminum chloride, zinc oxide, zinc p-phenol sulfonate, and silver-containing zeolite; antibacterial ingredients such as benzalkonium chloride, isopropyl methylphenol, benzyl chloride, halocarban, and chlorhexidine hydrochloride; deodorizing ingredients such as polyphenolic persimmon tannin and tea catechin; antioxidant ingredients such as thiotaurine, taurine, and tocopherol; and so on.

[0096] Examples of cooling agents include menthol and camphor.

[0097] Examples of astringents include zinc oxide, zinc sulfate, allantoin, basic aluminum chloride, aluminum chloride, zinc phenolsulfonate, tannic acid, citric acid, lactic acid, etc.

[0098] Examples of antibacterial agents include benzoic acid and its salts, salicylic acid and its salts, phenol, sorbic acid and its salts, dehydroacetic acid and its salts, p-hydroxybenzoic acid esters, chlorocresol, hexachlorophenol, resorcinol, isopropylmethylphenol, o-phenylphenol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyl isoquinoline bromide, triclocarban, halocarban, photosensitive dye No. 201, phenoxyethanol, triclosan, methylchloroisothiazolinone / methylisothiazolinone liquids, bisabolol, alkyl diaminoethyl glycine hydrochloride, trichlorosalinomyline, tribromosalinomyline, mercury compounds, formalin, ammonium mercury chloride, thiobis(dichlorophenol), boric acid, borax, dichlorophenol, hexachlorophenol, halosalicylaniline, etc.

[0099] Examples of preservatives include methylparaben, ethylparaben, butylparaben, phenoxyethanol, etc.

[0100] Examples of pH adjusters include acids such as citric acid and tartaric acid; bases such as sodium hydroxide and potassium hydroxide; and buffers such as lactate-sodium lactate, citric acid-sodium citrate, and succinate-sodium succinate.

[0101] Furthermore, topical skin preparations may include ingredients that provide particularly beneficial functions as other ingredients. Examples include ingredients containing growth factors and / or cytokines that inhibit skin aging and damage and promote the production of skin tissue (e.g., human stem cell culture medium (supernatant)), and ingredients that promote collagen production (exosomes, hydroxyapatite, etc.).

[0102] Furthermore, depending on the form and product type of the topical skin preparation described below, the topical skin preparation may contain commonly used ingredients as other ingredients. For example, in the case where the topical skin preparation is a product with a cleansing function, examples of the other ingredients include not only ingredients known as detergents, but also rubs, water-soluble polymers, chelating agents, etc. In the case where the topical skin preparation is a product that forms an emulsion, examples of the other ingredients include ingredients known as emulsifiers.

[0103] <Forms and Types of Topical Skin Preparations> There are no particular limitations on the form of the topical skin preparation according to the present invention, but the azelaic acid particles according to this embodiment are preferably blended in a manner that maintains their shape. In other words, the azelaic acid particles are preferably insoluble in water as the form of the topical skin preparation according to the present invention. Examples of the form of the topical skin preparation according to the present invention include forms in which all components of the topical skin preparation are formed from solids, and more specifically, solid forms in which all components are compacted (such as powder cakes) and powder forms in which the components are used in a powder state (such as loose powder). Other examples of the form include forms in which the azelaic acid particles are insoluble and dispersed in various dispersion media in the components forming the topical skin preparation, and more specifically, gas-solid forms (formed by spray gas and powder: aerosols, etc.), liquid-solid forms (formed by liquid layers and powder layers), water-in-oil (W / O) forms, oil-in-water (O / W) forms, and multilayer (W / O / W, O / W / O) forms. From the viewpoint of maintaining the shape of the azelaic acid particles, the form of the topical skin preparation according to the present invention is particularly preferred to be a solid form or a powder form.

[0104] When the topical skin formulation according to the invention is in the form of an emulsion, such as a water-in-oil (W / O), oil-in-water (O / W), or multilayer (W / O / W, O / W / O) form, the emulsification method used to generate the emulsion is not particularly limited. Examples of such emulsification methods include surface chemical methods using emulsifiers (surfactants), mechanical methods by stirring, phase inversion emulsification, liquid crystal emulsification, amino acid gel emulsification, D-phase emulsification, and three-phase emulsification.

[0105] There are no particular limitations on the product types of the topical skin preparations of this invention. Examples of such types include foundations (powder, liquid, cream, cushion), skin tone correctors (powder, liquid, cream), primers, setting powders (loose powder), carmine lotions, BB creams, CC creams, lotions (moisturizing lotions, massage lotions, etc.), moisturizing creams, massage creams, spray lotions, sunscreens, antiperspirants (roll-on, stick, aerosol), facial cleansers, shower gels, hand soaps, solid soaps, shampoos (including dry shampoo), conditioners, hair masks, and scalp cosmetics (liquid, cream, aerosol).

[0106] The topical skin preparations according to the present invention are preferably in a form and product type suitable for direct application to the skin. In other words, the topical skin preparations according to the present invention are preferably in a form and product type suitable for application to the skin before using another topical skin preparation (e.g., other cosmetics) or after washing or cleansing the face. This allows the beneficial effects and functions of azelaic acid contained in the topical skin preparations according to the present invention to be exerted more effectively. In particular, by using azelaic acid in topical skin preparations (powder cosmetics, etc.) where the main component is formed of powder, it is expected to increase the contact efficiency of azelaic acid in direct contact with the skin, thereby enabling the beneficial effects and functions of azelaic acid as a cosmetic ingredient to be exerted more effectively.

[0107] [Preparation methods for topical skin preparations] The powder cosmetic of the present invention can be prepared by conventional methods by filling or molding a mixture (cosmetic composition) of azelaic acid particles with one or more other ingredients into a container.

[0108] For example, in the case of cosmetics where the topical skin preparation is in solid or powder form (powder cosmetics), a mixture (cosmetic composition) comprising azelaic acid and one or more other ingredients, prepared by conventional methods, is directly packaged into a container and provided as loose powder. As another example, the cosmetic composition is packaged into a container and then supplied as a pressed powder using equipment commonly used in the production of topical skin preparations (such as a powder press or dryer).

[0109] In the case of a topical skin preparation that is an aerosol-solid or liquid-solid cosmetic, for example, the mixture (cosmetic composition) formed by the azelaic acid particles and other ingredients is mixed with each dispersion medium (spray gas or a poor solvent as a liquid layer) by conventional methods and filled into a container, thereby providing it as an aerosol cosmetic or a two-layer (liquid layer and powder layer) cosmetic.

[0110] For example, in the case of a topical skin formulation that is a water-in-oil (W / O), oil-in-water (O / W), or multi-layered (W / O / W, O / W / O) cosmetic, the azelaic acid particles are dispersed in an aqueous or oil phase, mixed and emulsified with other ingredients using conventional methods, and the resulting product is filled into a container to provide it as a product. More specifically, for example, a stabilizer and an oil phase component are added to an aqueous phase component in which the azelaic acid particles are dispersed, and the resulting product is emulsified by homogenization and filled into a container, thereby providing the resulting product as a water-in-oil (W / O) cosmetic (cream foundation, lotion, etc.).

[0111] The topical skin preparations according to the present invention can be used in various cosmetics, quasi-medicines, and pharmaceuticals.

[0112] Example The present invention will be described in more detail below with reference to the embodiments; however, the technical scope of the present invention is not limited to these embodiments.

[0113] [Preparation of Azelaic Acid Granules] First, the preparation of azelaic acid particles in the examples is described.

[0114] In the solution preparation step, finely powdered azelaic acid (produced by CORUM) with a needle-like structure is used. Figure 1 Azelaic acid solution is prepared by dissolving azelaic acid in 99% ethanol. In this case, the amount of good solvent (ethanol) relative to azelaic acid is 3 or 8 times the amount of azelaic acid.

[0115] Subsequently, in the crystallization step, purified water (ion-exchanged water) as a poor solvent is added to the azelaic acid solution to precipitate crystals, thereby obtaining a slurry containing azelaic acid. During the crystal precipitation process, the azelaic acid solution and the poor solvent are stirred for 1 hour, then allowed to stand for 12 hours or longer, or continuously stirred for 12 hours or longer. During this process, the amount of the poor solvent added to the azelaic acid solution is 3 or 4 times the amount of the good solvent, and the rate at which the poor solvent is added to the azelaic acid solution (the time required for mixing) is 1 minute or less.

[0116] In the drying step, the slurry is subjected to solid-liquid separation. The resulting solid components are placed in a stainless steel tray and dried in a vacuum dryer for 6 hours to obtain azelaic acid granules.

[0117] Table 1 shows details of the procedures and conditions for preparing azelaic acid particles according to the examples. Table 1 also shows those of Comparative Example 1 (tap water was used as a poor solvent).

[0118] The particle size distribution of azelaic acid particles obtained in each example and comparative example was determined by dry method using a particle size analyzer based on laser diffraction scattering (PSA1190 model manufactured by Anton Paar). The particle size distribution is shown as median particle size (D50) in Table 1.

[0119] [Table 1] Figure 3 and Figure 4 Showing in relation to Figure 1 SEM images of azelaic acid particles from Examples 1 to 5 and Comparative Example 1, obtained under the same observation conditions. Figure 3 The images shown are SEM images obtained at low observation magnification (25x or 50x). Figure 4 The image shows SEM images obtained at high magnification (200x to 300x).

[0120] Figure 3 and Figure 4 This indicates that in Examples 1 to 5 and Comparative Example 1, with undissolved azelaic acid (see...) Figure 1 In contrast, azelaic acid aggregates or granulates to obtain azelaic acid particles with a predominantly lamellar structure.

[0121] A comparison between Examples 1 to 5 and Comparative Example 1 shows that the shape and size of the azelaic acid particles in Comparative Example 1 are significantly different. Figure 3 In Examples 1 to 5, the azelaic acid particles had relatively uniform shape and size (within a certain range). Figure 3 (AE in the text).

[0122] In particular, based on Figure 4 Example 1 ( Figure 4 A) and Example 2 ( Figure 4 The comparison between B) shows that, compared with the case where the azelaic acid solution and the unsuitable solvent were continuously stirred and not allowed to stand during the crystallization process (Example 2), the surface of the sheet-like structure is flat when the crystallization process includes a step of allowing the azelaic acid solution and the unsuitable solvent to stand (Example 1).

[0123] Based on Table 1 and Figure 4 Examples 3 to 5 ( Figure 4 The comparison between C to E in the examples shows that the lower the temperature of the poor solvent below 25°C, the smaller the aspect ratio of the lamellar structure and the higher the yield. (See Examples 4 and 5). Figure 4As shown in D and E), when the temperature of the unsuitable solvent is 20°C or lower, the content of azelaic acid particles with needle-like structures and azelaic acid particles with large aspect ratios is significantly reduced, and only azelaic acid particles (with plate-like structures and small aspect ratios) that are more suitable for skin application are obtained in high yield.

[0124] Examples 4 and 5 show that, based on the lamellar structure of azelaic acid particles (small aspect ratio and flat surface), light is reflected from the particle surface.

[0125] [Evaluation of Azelaic Acid Granules] First, the cosmetic effect of the obtained azelaic acid granules was evaluated when applied to the skin. The example used for evaluation was the azelaic acid granules of Example 4. For this evaluation, azelaic acid that had not yet formed granules (undissolved azelaic acid; see [link to example]) was used. Figure 1 ) as a comparative example (Comparative Example 2).

[0126] The evaluation method is as follows.

[0127] Ten team members applied azelaic acid particles from Example 4 and azelaic acid from Comparative Example 2 to portions of their skin (inner forearm), respectively. Visual evaluation tests were conducted from the perspectives of "skin adhesion," "powdery texture of the makeup effect," "whitening effect after application," and "transparency of the makeup effect." The evaluation tests were performed by relatively evaluating the Examples against the Comparative Example, which was set to "0 (reference)."

[0128] The evaluation criteria and results from each perspective are as follows.

[0129] (Skin fit) Compared to the comparative example, the skin adhesion of the particles in the comparative example was visually evaluated upon application.

[0130] The evaluation criteria are as follows.

[0131] 2 points: Very high (compared to the average skin fit) 1 point: High 0 points: Average (comparable to the comparison) -1 point: low -2 points: Very low Based on the above evaluation criteria, each group member conducted an evaluation test, and the average score of the evaluation results was 2.00. That is, it was found that the skin adhesion of the embodiment (azelaic acid particles with a specific shape) was better than that of the comparative example.

[0132] (The powdery texture of the makeup) Compared to the comparative example, the powdery texture of the particles in the example was visually evaluated when applied.

[0133] The evaluation criteria are as follows.

[0134] 2 points: Absolutely no powdery texture (compared to the comparison ratio) 1 point: No powdery texture 0 points: Average (comparable to the comparison) -1 point: Has a powdery texture -2 points: Very powdery texture Based on the above evaluation criteria, each group member conducted an evaluation test, and the average score of the evaluation results was 2.00. That is, it was found that compared with the comparative example, the embodiment did not exhibit a powdery texture in the makeup effect and achieved an excellent makeup effect.

[0135] (Whitening effect after application) Compared to the comparative example, the whitening effect of the particles in the example compared to skin color was visually evaluated when applied.

[0136] The evaluation criteria are as follows.

[0137] 2 points: No whitening at all (compared to the comparison). 1 point: No whitening 0 points: Average (comparable to the comparison) -1 point: Pale -2 points: The whitening effect is very obvious. Based on the above evaluation criteria, each group member conducted an evaluation test, and the average score of the results was 2.00. That is, it was found that compared to the comparative example, the embodiment showed no whitening effect when applied to the skin, achieving an excellent makeup effect.

[0138] (The transparency of the makeup effect) Compared to the comparative example, the transparency of the makeup effect of the particles in the example was visually evaluated when applied.

[0139] The evaluation criteria are as follows.

[0140] 2 points: Very transparent (compared to the comparison). 1 point: Has a sense of transparency 0 points: Average (comparable to the comparison) -1 point: No transparency -2 points: Completely lacking transparency Based on the above evaluation criteria, each group member conducted an evaluation test, and the average score of the evaluation results was 2.00. That is, it was found that compared to the comparative example, the embodiment exhibited a high degree of transparency after application to the skin, achieving an excellent makeup effect.

[0141] The above evaluation results show that, compared with the comparative example of azelaic acid having a needle-like structure, the azelaic acid particles of the embodiment with a specific shape, when applied to the skin, enable, for example, improved adherence and reduced whitening. Therefore, even when used as an active ingredient in high concentrations (dosage) in topical skin formulations, the azelaic acid particles of the embodiment do not disrupt the makeup effect during application. Furthermore, the azelaic acid particles of the embodiment retain the properties of azelaic acid, thereby fully demonstrating the various effects and functions of azelaic acid.

[0142] Subsequently, the dispersibility (aggregation) of the obtained azelaic acid particles relative to water was evaluated. The example used for evaluation was the azelaic acid particles of Example 4. The comparative example used for evaluation was Comparative Example 2 (undissolved azelaic acid; see Comparative Example 2). Figure 1 ).

[0143] The evaluation method is as follows.

[0144] Add 9 g of purified water to a 100 mL beaker, and then add 1 g of azelaic acid granules from the example or azelaic acid from the comparative example to the beaker. Stir the resulting product for 120 seconds. Afterward, visually inspect the dispersion of the azelaic acid granules from the example and the azelaic acid from the comparative example relative to water.

[0145] Figure 5 Images showing the evaluation results of the dispersibility of azelaic acid particles in Example 4 and the comparative example (Comparative Example 2) relative to water are displayed.

[0146] Figure 5 In this context, "A" indicates that the azelaic acid particles in Example 4 were almost uniformly dispersed in water. Meanwhile, Figure 5 In the figure, B indicates that the azelaic acid in the comparative example (comparative example 2) aggregates in water and its dispersibility decreases.

[0147] The above evaluation results indicate that, compared to the comparative azelaic acid with structures such as needle-like structures, the azelaic acid particles of the specific shape of the embodiments exhibit excellent dispersibility in water; in other words, they have low aggregation. This demonstrates that by using the azelaic acid particles of the embodiments as a powder raw material for topical skin formulations, even when the azelaic acid particles of the embodiments are used as an active ingredient in topical skin formulations in large blending amounts (usage amounts), a topical skin formulation with excellent processability in product preparation is provided.

[0148] Subsequently, the obtained azelaic acid granules were mixed with a highly versatile petrolatum matrix, and the cosmetic effect (especially the degree of whitening) was evaluated after the resulting mixture was applied. The azelaic acid granules of Example 4 were used for evaluation. Comparative examples used for evaluation included Comparative Example 2 (undissolved azelaic acid; see Comparative Example 2). Figure 1 ).

[0149] The evaluation method is as follows.

[0150] Knead 0.4 g of azelaic acid granules from the example or the comparative example into 1.6 g of white petrolatum (“Y-445” manufactured by NIKKO RICA CORPORATION). Apply the resulting mixture of 0.4 g evenly to a surface with a predetermined area (5 × 2.7 cm). 2 On black drawing paper. After applying the azelaic acid granules of the example or the azelaic acid of the comparative example, visually inspect the finished state (whitening) of the applied mixture.

[0151] Figure 6 Images show the evaluation results of the cosmetic effect after applying the mixture of azelaic acid particles and petrolatum in Example 4 and the mixture of azelaic acid and petrolatum in Comparative Example 2.

[0152] like Figure 6 As shown on the right, the mixture of azelaic acid granules and petrolatum in Example 4 showed the background color (black) after application, indicating reduced whitening and high transparency. Meanwhile, as... Figure 6 As shown on the left, the azelaic acid mixture of the comparative example (Comparative Example 2) and petrolatum did not show through the background color (black) after application, indicating that a whitening effect was produced.

[0153] The above evaluation results indicate that, compared to azelaic acid with a needle-like structure, the azelaic acid particles of the specific shape of the embodiments can reduce whitening when applied to the skin as a mixture with petrolatum. Therefore, when the azelaic acid particles of the embodiments are used as an active ingredient in topical skin preparations in a large blending amount (usage amount), the quality of the makeup effect is not impaired during use. Furthermore, the azelaic acid particles of the embodiments retain the properties of azelaic acid, thus allowing the efficacy and effects of azelaic acid to be fully utilized.

[0154] [Formulation Examples] Formulation examples of topical skin preparations according to the present invention will be described below. However, the scope of the present invention is not limited to these formulation examples.

[0155] (Formulation Example 1) Prepare the loose powder (loose powder) according to the following formula.

[0156]

[0157] (Formulation Example 2) Prepare baby powder according to the following formula.

[0158]

[0159] (Formulation Example 3) Prepare the carmine lotion according to the following formula.

[0160]

[0161] (Formulation Example 4) Prepare an oil-in-water emulsion foundation (cream type) according to the following formula.

[0162]

[0163] (Formulation Example 5) Prepare a solid powder foundation (cake-type foundation) according to the following formula.

[0164]

[0165] (Formulation Example 6) Prepare a milky emulsion (moisturizing emulsion, water-in-oil type) according to the following formula.

[0166]

[0167] (Formulation Example 7) Prepare a moisturizing cream (oil-in-water type) according to the following formula.

[0168]

[0169] Industrial application The method for preparing azelaic acid granules according to the present invention is used to provide azelaic acid granules that enable the various effects and functions of azelaic acid to be exerted without compromising the cosmetic quality when applied to the skin or the processability of the product in preparation and / or use. Furthermore, topical skin preparations containing azelaic acid granules obtained according to the method for preparing azelaic acid granules according to the present invention can be used in various cosmetics, quasi-pharmaceuticals, and pharmaceuticals.

Claims

1. A method for preparing azelaic acid granules, the method comprising: Solution preparation steps: Prepare an azelaic acid solution, wherein the azelaic acid is dissolved in a good solvent; Crystallization step: The azelaic acid solution obtained in the solution preparation step is mixed with purified water, which is a poor solvent, to precipitate crystals; and Drying step: The product obtained in the crystallization step is dried under static conditions.

2. The method for preparing azelaic acid particles according to claim 1, wherein, The temperature of the undesirable solvent is 0°C or higher and 25°C or lower.

3. The method for preparing azelaic acid particles according to claim 1 or 2, wherein, The crystallization step includes mixing the azelaic acid solution with the unsuitable solvent and then allowing the mixture to stand for 6 hours or longer.

4. A method for preparing a topical skin formulation containing azelaic acid particles, the method comprising: The azelaic acid particles are prepared by the method for preparing azelaic acid particles according to claim 1 or 2; as well as The azelaic acid granules are added as an ingredient in the topical skin preparation.

5. The method according to claim 4, wherein, The topical skin preparation is in the form in which the azelaic acid particles are insoluble in water.

6. A topical skin preparation comprising azelaic acid particles having a flake-like structure, said azelaic acid particles having a median particle size of 10 μm or higher as measured by a particle size analyzer based on laser diffraction scattering.

Images