JP2024159327A - Composition for external use on skin, skin permeation enhancer for hyaluronic acid, and method for enhancing skin permeation of hyaluronic acid - Google Patents

Abstract

To improve the skin permeability of hyaluronic acid, specifically, to provide a topical composition for skin with improved skin permeability of hyaluronic acid, and further to provide a topical composition for skin that facilitates the deeper penetration of hyaluronic acid into the skin, offering an improved user experience such as enhanced skin softness and enriched hydration.SOLUTION: A topical composition for skin contains (A) a hyaluronic acid fermented product and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof with a weight average molecular weight of 1,200,000 or less.SELECTED DRAWING: None

Description

The present invention relates to a composition for topical application to the skin, a skin penetration enhancer for hyaluronic acid, and a method for enhancing skin penetration of hyaluronic acid.

Hyaluronic acid is a mucopolysaccharide with a linear structure of disaccharide units composed of D-glucuronic acid and N-acetylglucosamine. In the body, it exists in large quantities in the dermis as a bonding substance that fills the gaps between cells and fibers, and is also present in the epidermis. Hyaluronic acid has high water retention and viscoelasticity, so it is widely used as a moisturizer and ingredient in pharmaceuticals and cosmetics.

However, because hyaluronic acid has an extremely high molecular weight, when used as an ingredient in a skin topical agent, it is difficult for it to penetrate the skin, and in some cases, it may not be able to fully exert its function in practical use. Therefore, in an attempt to improve the percutaneous absorption of hyaluronic acid, an attempt has been made to reduce the molecular weight of hyaluronic acid (Patent Document 1: JP 2002-533376 A), an attempt to combine amphoteric surfactants with hyaluronic acid (Patent Document 2: WO 2022/259901), and an attempt to suppress the spread of hyaluronic acid molecules and form them into fine particles by apparently neutralizing the negative charge of hyaluronic acid using electrolytes such as sodium chloride and predominating hydrogen bonds (Patent Document 3: WO 2021/033725). However, the effects of these attempts are not sufficient.

Special Publication No. 2002-533376 International Publication No. 2022/259901 International Publication No. 2021/033725

In this situation, the present invention aims to improve the skin permeability of hyaluronic acid, and specifically aims to provide a composition for external use on the skin in which the skin permeability of hyaluronic acid is improved. Furthermore, it also aims to provide a composition for external use on the skin that is excellent in terms of usability, such as softness and moisturization, by allowing hyaluronic acid to penetrate deeper into the skin.

The inventors conducted extensive research to solve the above problems, and discovered that a topical skin composition containing a hyaluronic acid fermentation product by microorganisms and hyaluronic acid, a hyaluronic acid derivative, or a salt thereof (hereinafter also referred to as "hyaluronic acids") of a specific size is able to significantly enhance the permeability of the hyaluronic acids when applied to the skin, and also provides an excellent feel when used, such as softness and moisturization of the skin, and thus completed the present invention. In other words, the gist of the present invention for solving the above problems is as follows.

[1] A composition for external skin application containing (A) a hyaluronic acid fermentation product and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less.
[2] (A) The topical skin composition described in [1], wherein the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactic acid bacteria.
[3] The topical skin composition described in [1] or [2], which contains at least hydrolyzed alkyl (C12-13) glyceryl hyaluronate, hydroxypropyltrimonium hyaluronate, and sodium acetylated hyaluronate as component (B).
[4] A skin penetration enhancer for hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, comprising (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less.
[5] (A) The skin penetration enhancer described in [4], wherein the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactic acid bacteria.
[6] A method for promoting skin penetration of hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, comprising using (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less.
[7] The method for promoting skin penetration described in [6], wherein (A) the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactic acid bacteria.
[8] (A) A skin penetration enhancer for hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, comprising a hyaluronic acid fermentation product.
[9] (A) The skin penetration enhancer described in [8], wherein the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactic acid bacteria.
[10] (A) A method for promoting skin penetration of hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, characterized by using a hyaluronic acid fermentation product.
[11] The method for promoting skin penetration described in [10], wherein (A) the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactic acid bacteria.

The composition for external use on the skin of the present invention contains (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less, and thus can significantly promote the permeability of hyaluronic acid, a hyaluronic acid derivative, and/or a salt thereof into the skin, and also provides an excellent feeling of use, such as softness and moisturization of the skin.

FIG. 1-1 is a fluorescence microscope image of a skin tissue fragment after test solution 1-1 containing fluorescently labeled hydrolyzed hyaluronic acid (weight average molecular weight: 10,000) was applied to a three-dimensional cultured skin model. FIG. 1-2 is a fluorescence microscope image of a skin tissue fragment after test solution 1-2 containing fluorescently labeled hydrolyzed hyaluronic acid (weight average molecular weight 10,000) as well as hyaluronic acid fermentation product was applied to a three-dimensional cultured skin model. FIG. 2-1 is a fluorescence microscope image of a skin tissue fragment after test solution 2-1 containing fluorescently labeled hydrolyzed hyaluronate alkyl (C12-13) glyceryl (weight average molecular weight 10,000) was applied to a three-dimensional cultured skin model. Figure 2-2 is a fluorescence microscope image of a skin tissue fragment after test solution 2-2 containing fluorescently labeled hydrolyzed hyaluronate alkyl (C12-13) glyceryl (weight average molecular weight 10,000) as well as hyaluronic acid fermentation product was applied to a three-dimensional cultured skin model. FIG. 3-1 is a fluorescence microscope image of a skin tissue fragment after applying test solution 3-1 containing fluorescently labeled sodium hyaluronate (weight average molecular weight: 1.2 million) to a three-dimensional cultured skin model. FIG. 3-2 is a fluorescence microscope image of a skin tissue fragment after test solution 3-2 containing fluorescently labeled sodium hyaluronate (weight average molecular weight 1.2 million) as well as hyaluronic acid fermentation product was applied to a three-dimensional cultured skin model.

The present invention will be described in detail below.

<Composition for external use on skin>
The skin topical composition of the present invention is a skin topical composition containing (A) hyaluronic acid fermentation product and (B) hyaluronic acid, hyaluronic acid derivatives, or their salts having a weight-average molecular weight of 1.2 million or less ("(B) hyaluronic acids"). The skin topical composition of the present invention contains (A) hyaluronic acid fermentation product and (B) hyaluronic acids, which can significantly promote the permeability of hyaluronic acid, hyaluronic acid derivatives, and/or their salts into the skin, and can also provide excellent skin softness, moisturizing, and other usability. In addition to (A) hyaluronic acid fermentation product and (B) hyaluronic acids, the skin topical composition of the present invention may contain various optional components within a range that does not impair the effects of the present invention and for the purpose of improving the effects of the present invention. Each component contained in the skin topical composition of the present invention will be described in detail below.

The topical skin composition of the present invention can also be said to be a blend of (A) hyaluronic acid fermentation product and (B) hyaluronic acids.

In the present invention, hyaluronic acid refers to a mucopolysaccharide in which disaccharides consisting of N-acetylglucosamine and D-glucuronic acid (GlcNAcβ1-4GlcAβ1-3) are linked in a linear chain, and is distinguished from salts thereof.

In the present invention, the salt of hyaluronic acid may be any salt that is pharmacologically or physiologically acceptable, and examples thereof include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; ammonium salts; basic amino acid salts; and amine salts such as triethanolamine. Among these, sodium salts, potassium salts, zinc salts, and ammonium salts are preferred, and sodium salts and ammonium salts are more preferred.

In the present invention, a hyaluronic acid derivative refers to a compound that has been modified to such an extent that it does not significantly change the structure or properties of hyaluronic acid as the parent, such as by introducing functional groups, oxidizing, reducing, or substituting atoms. Examples of hyaluronic acid derivatives include acetylated hyaluronic acid, sulfated hyaluronic acid, hydrophobized hydrolyzed hyaluronic acid (hydrolyzed alkyl hyaluronate, hydrolyzed glyceryl hyaluronate, etc.), crosslinked hyaluronic acid, carboxymethyl hyaluronic acid, alkylene glycol hyaluronate, silanol hyaluronate, and cationized hyaluronic acid.

In the present invention, the salt of the hyaluronic acid derivative may be any salt that is pharmacologically or physiologically acceptable, and examples thereof include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; ammonium salts; basic amino acid salts; and amine salts such as triethanolamine. Among these, sodium salts, potassium salts, zinc salts, and ammonium salts are preferred, and sodium salts and ammonium salts are more preferred.

In the present invention, hyaluronic acid, salts of hyaluronic acid, hyaluronic acid derivatives, and salts of hyaluronic acid derivatives are sometimes referred to as "hyaluronic acids."

[(A) Hyaluronic acid fermentation product]
The hyaluronic acid fermentation product (A) contained in the composition for external skin application of the present invention refers to a product obtained by fermenting hyaluronic acid, a hyaluronic acid derivative, and/or a salt thereof with a microorganism.

The microorganisms used in the above fermentation are not particularly limited, but examples include lactic acid bacteria, yeast, koji mold, and Bacillus subtilis.

Examples of the lactic acid bacteria include lactic acid cocci and lactic acid bacilli, and more specifically, for example, lactic acid bacteria of the genus Leuconostoc, such as Leuconostoc mesenteroides, Leuconostoc lactis, and Leuconostoc citreum; Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus casei, and Lactobacillus delbrueckii. Lactic acid bacteria of the genus Lactobacillus such as Lactobacillus delbrueckii; Lactic acid bacteria of the genus Carnobacterium such as Carnobacterium divergens and Carnobacterium pisicola; Lactic acid bacteria of the genus Streptococcus such as Streptococcus faecalis and Streptococcus pyogenes; Enterococcus caseiflavus Lactic acid bacteria of the genus Enterococcus, such as Enterococcus caseliflavus and Enterococcus sulfureus; lactic acid bacteria of the genus Lactococcus, such as Lactococcus plantarum, Lactococcus lactis, and Lactococcus rafinolactis; lactic acid bacteria of the genus Veissella, such as Weissella confusa and Weissella kandleri; Atopobium minutum Examples of lactic acid bacteria include lactic acid bacteria of the genus Atopobium, such as Atopobium parvulus and Atopobium minutum; lactic acid bacteria of the genus Vagococcus, such as Vagococcus fluvialis and Vagococcus salmoninarum; and lactic acid bacteria of the genus Pediococcus, such as Pediococcus damnosus and Pediococcus pentosaceus.

Examples of the yeast include yeasts of the genus Saccharomyces, such as Saccharomyces cerevisiae, Saccharomyces awamori, Saccharomyces chevalieri, Saccharomyces carlsbergensis, and Saccharomyces bayonus; yeasts of the genus Galactomyces; Torulaspora delbruekii, Torulaspora fermentatii, and the like; yeasts of the genus Torulaspora, such as Torulaspora rosei, Torulaspora fermentati, Torulaspora rosei, etc.; yeasts of the genus Zygosaccharomyces, such as Zygosaccharomyces rouxii, Zygosaccharomyces soya, Zygosaccharomyces sake, Zygosaccharomyces miso, Zygosaccharomyces lactis, etc.; yeasts of the genus Zygosaccharomyces, such as Candida versatilis, Candida Examples of yeasts of the genus Candida include yeasts of the genus Candida, such as Candida etchellsii, Candida kefir, Candida sake, and Candida scottii; yeasts of the genus Aureobasidium, such as Aureobasidium pullulans, Aureobasidium mansonii, and Aureobasidium microstictum. The yeast according to the present invention may be any of sake yeast, wine yeast, brewer's yeast, yeast derived from plant flowers (rose, plum, cherry, camellia, lily, etc.), and yeast derived from the sea.

Examples of the koji mold include yellow koji molds such as Aspergillus oryzae, Aspergillus flavus, Aspergillus polyoxogenes, and Aspergillus sojae; black koji molds such as Aspergillus awamori, Aspergillus kawauchii, Aspergillus usami, and Aspergillus niger; Monascus Examples of red koji mold include Monascus anka and Monascus pilosus.

Examples of the Bacillus subtilis include Bacillus natto, Bacillus subtilis, and Bacillus circulans.

In the present invention, the microorganisms used in the fermentation are preferably lactic acid bacteria and yeast, more preferably lactic acid bacteria, and even more preferably lactococci.

When preparing the hyaluronic acid fermentation product (A) of the present invention, it is desirable to sterilize the hyaluronic acid, hyaluronic acid derivatives, and/or salts thereof before the fermentation step in which the hyaluronic acid, hyaluronic acid derivatives, and/or salts thereof are fermented by microorganisms to remove unwanted bacteria that hinder fermentation. The method for sterilizing and removing the unwanted bacteria is not particularly limited, and the fermentation material may be sterilized by heat sterilization or the like. As the heat sterilization treatment, heat sterilization methods such as autoclave sterilization, in which the fermentation material is heated at 120 to 130°C for 10 to 20 minutes, and intermittent sterilization, in which the fermentation material is kept at 80 to 90°C for 60 to 120 minutes and repeated once a day for 2 to 3 days, are generally used.

During the above fermentation, sugars such as glucose, galactose, fructose, sucrose, maltose, and lactose may be added as a carbon source.

The fermentation material and medium that have been sterilized and freed of unwanted bacteria as described above are placed in a fermentation tank or the like, and the above-mentioned microorganisms are inoculated therein to cause fermentation. The amount of microorganism to be inoculated can be adjusted as appropriate, but is usually 10 ⁶ to 10 ⁹ cells/mL, and preferably 10 ⁷ to 10 ⁸ cells/mL. Even if the amount of inoculation is greater than the above range, the progress time of fermentation is almost unchanged, while if the amount of inoculation is less than the above range, it takes a long time to complete fermentation, which is not preferable.

The temperature during the fermentation may be within the range of the optimum temperature for growth of each microorganism, and is generally in the range of 5 to 50°C. The number of days for fermentation at the optimum temperature is usually 1 to 10 days, and preferably in the range of 2 to 5 days. If the number of days for fermentation is shorter than the above general range, the fermentation does not proceed sufficiently and the effectiveness of the fermented product tends to decrease, while if the number of days is longer than 10 days, not only is there no increase in effectiveness, but coloring and an increase in the fermentation odor occur, which is not preferable.

As the hyaluronic acid fermentation product (A) of the present invention, the fermentation product recovered from the fermentation tank or the like after the above-mentioned fermentation step may be used as it is, or the fermentation liquid from which microorganisms and other contaminants have been removed by a method such as centrifugation may be used, but the fermentation liquid from which the above-mentioned microorganisms and other contaminants have been removed is preferred. In addition, the form of the hyaluronic acid fermentation product (A) may be liquid, or may be a liquid that has been dried to a solid.

(A) The hyaluronic acid, hyaluronic acid derivatives, or salts thereof used as fermentation materials in preparing the hyaluronic acid fermentation product may be natural hyaluronic acid extracted and recovered from animal tissues such as cockscombs, shark skin, umbilical cords, eyeballs, skin, cartilage, etc., hyaluronic acid-producing microorganisms such as Streptococcus genus microorganisms, animal cells, or plant cell cultures, or may be decomposed hyaluronic acid obtained by decomposing the natural hyaluronic acid. The decomposed hyaluronic acid may be prepared, for example, by hydrolysis in the presence of acid or alkali, enzyme treatment with hyaluronidase, or physical cutting such as ultrasonic waves or shearing. The fermentation material may be various hyaluronic acid derivatives derived from the natural hyaluronic acid or decomposed hyaluronic acid, or may be a salt thereof.

(A) Hyaluronic acid fermentation products are obtained by fermenting the fermentation materials, hyaluronic acid, hyaluronic acid derivatives and/or their salts, with microorganisms, and are therefore considered to contain decomposed hyaluronic acid of various sizes.

The content of the hyaluronic acid fermentation product (A) in the topical skin composition of the present invention is 0.0001% by mass or more, preferably 0.0005% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.05% by mass or more, and particularly preferably 0.1% by mass or more, based on the total amount of the topical skin composition. The content of the hyaluronic acid fermentation product (A) is 10% by mass or less, preferably 5.0% by mass or less, more preferably 3.0% by mass or less, even more preferably 1.0% by mass or less, and particularly preferably 0.8% by mass or less, based on the total amount of the topical skin composition. The content of the hyaluronic acid fermentation product (A) in the topical skin composition of the present invention is from 0.0001% to 10% by mass, preferably from 0.0005% to 10% by mass, more preferably from 0.05% to 5.0% by mass, even more preferably from 0.1% to 3.0% by mass, and particularly preferably from 0.1% to 1.0% by mass. By setting the content of the hyaluronic acid fermentation product (A) within the above range, the permeability of the hyaluronic acids contained in the topical skin composition of the present invention into the skin can be significantly improved.

[(B) Hyaluronic acid, hyaluronic acid derivative, or salt thereof having a weight-average molecular weight of 1.2 million or less]
The skin external composition of the present invention contains (A) hyaluronic acid fermentation product as described above, and (B) hyaluronic acid, hyaluronic acid derivative, or their salts with weight-average molecular weight of 1.2 million or less.By blending (B) the above-mentioned hyaluronic acids together with (A) hyaluronic acid fermentation product, the skin external composition of the present invention can significantly improve the permeability of hyaluronic acids into the skin.

In the present invention, the weight average molecular weight is a value measured by size exclusion chromatography.
The conditions are as follows:
Column: TSKgel GMPWXL 7.8 mm x 30 cm (Tosoh Corporation)
Column temperature: constant temperature around 40°C Detector: differential refractometer Mobile phase: 0.2 mol/L NaCl
Flow rate: 0.3mL/min Injection volume: 100μL
Standard substance: pullulan standard (STANDARD P-82, Showa Denko K.K.)

(B) Hyaluronic acids are explained below by dividing them into high molecular weight hyaluronic acid (weight average molecular weight of 50,000 or more) or its salts, low molecular weight hyaluronic acid (weight average molecular weight of less than 50,000) or its salts, and hyaluronic acid derivatives or its salts.

(High molecular weight hyaluronic acid or its salt)
Hyaluronic acid is a kind of acidic mucopolysaccharide, and is a polysaccharide containing disaccharide of glucuronic acid and N-acetylglucosamine as a constituent unit. Hyaluronic acid can be extracted and collected from animal tissues such as cockscomb, shark skin, umbilical cord, eyeball, skin, cartilage, etc., and from cultures of hyaluronic acid-producing microorganisms such as Streptococcus genus microorganisms, animal cells, and plant cells. It can also be purchased commercially. As the polymeric hyaluronic acid having a weight-average molecular weight of 50,000 or more and 1,200,000 or less, such natural hyaluronic acid can be used. The weight-average molecular weight of natural hyaluronic acid is about 500,000 to 7,000,000, so that one having the above-mentioned size range can be used from that.

Decomposed hyaluronic acid obtained by decomposing natural hyaluronic acid can also be used as long as it has a weight-average molecular weight of 50,000 or more and 1,200,000 or less. Decomposed hyaluronic acid can be prepared, for example, by hydrolysis in the presence of acid or alkali, enzyme treatment with hyaluronidase or the like, physical cutting such as ultrasonic waves or shearing, or fermentation by microorganisms. Commercially available products can also be used.

In the present invention, the weight-average molecular weight of the polymeric hyaluronic acid or its salt is 50,000 or more, preferably 100,000 or more, more preferably 200,000 or more, even more preferably 300,000 or more, and even more preferably 500,000 or more. The weight-average molecular weight of the polymeric hyaluronic acid or its salt can be, for example, 1,600,000 or less, preferably 1,200,000 or less, and more preferably 800,000 or less. Furthermore, the weight-average molecular weight of the polymeric hyaluronic acid or its salt is 50,000 or more and 1,600,000 or less, preferably 100,000 or more and 1,400,000 or less, more preferably 200,000 or more and 1,200,000 or less, and even more preferably 300,000 or more and 1,200,000 or less. Within this range, when the skin topical composition of the present invention is applied to the skin, the permeability of hyaluronic acids is significantly promoted, and the skin is excellent in terms of softness, moisturizing feeling, and other usability.

Examples of commercially available polymeric hyaluronic acid include sodium hyaluronate HA12N (trade name) (Shiseido Co., Ltd.; weight average molecular weight 1.1 to 1.6 million), sodium biohyaluronate SZE (trade name) (Shiseido Co., Ltd.; weight average molecular weight 1.1 to 1.6 million), hyaluronic acid FCH-120 (trade name) (Kikkoman Biochemifa Corporation; weight average molecular weight 1.0 to 1.4 million), hyaluronic acid HA-LQ (trade name) (Kewpie Corporation; weight average molecular weight 850,000 to 1.6 million), hyaluronic acid FCH-80 (trade name) (Kikkoman Biochemifa Corporation; weight average molecular weight 600,000 to 1 million), hyaluronic acid FCH-60 (trade name) (Kikkoman Biochemifa Corporation; weight average molecular weight 500,000 to 700,000), and hyaluronic acid FCH-SU (trade name) (Kikkoman Biochemifa Corporation; weight average molecular weight 500,000 to 110,000).

The salt of polymeric hyaluronic acid may be any salt that is pharmacologically or physiologically acceptable, and examples thereof include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; ammonium salts; basic amino acid salts; and amine salts such as triethanolamine. Among these, alkali metal salts and metal salts are preferred, with sodium salts, potassium salts, and zinc salts being particularly preferred. In addition, when it comes to polymeric hyaluronic acid, it is preferred to use hyaluronic acid in a salt state, as this is more stable than hyaluronic acid.

One or more types of polymeric hyaluronic acid or its salt can be used.

The content of the polymeric hyaluronic acid or its salt is preferably 0.001% by mass or more, more preferably 0.005% by mass or more, even more preferably 0.01% by mass or more, and even more preferably 0.02% by mass or more, based on the total amount of the composition for external use on the skin. The content of the polymeric hyaluronic acid or its salt is preferably 10% by mass or less, more preferably 1.0% by mass or less, even more preferably 0.5% by mass or less, and even more preferably 0.3% by mass or less, based on the total amount of the composition for external use on the skin. The content of the polymeric hyaluronic acid or its salt is preferably 0.001% by mass or more and 10% by mass or less, more preferably 0.005% by mass or more and 1% by mass or less, even more preferably 0.01% by mass or more and 0.5% by mass or less, and even more preferably 0.02% by mass or more and 0.3% by mass or less. Within this range, when the topical skin composition of the present invention is applied to the skin, the permeability of hyaluronic acid is significantly promoted, and the skin feels soft and moisturized when used. When multiple types of polymeric hyaluronic acid or salts thereof are included, the content of polymeric hyaluronic acid or salts thereof refers to the total content of the polymeric hyaluronic acid or salts thereof.

(Low molecular weight hyaluronic acid or its salt)
As the low molecular weight hyaluronic acid having a weight average molecular weight of less than 50,000, a decomposition product of high molecular weight hyaluronic acid can be used. The low molecular weight hyaluronic acid can be obtained by hydrolyzing high molecular weight hyaluronic acid in the presence of an acid such as hydrochloric acid or an alkali, treating with an enzyme such as hyaluronidase, physically cutting the high molecular weight hyaluronic acid by ultrasonic waves or shearing, or fermenting with a microorganism. When using hyaluronic acid oligosaccharides and/or salts thereof as the low molecular weight hyaluronic acid, it is preferable to use 2 to 16 sugars, and either saturated or unsaturated type can be used. For example, there can be mentioned unsaturated hyaluronic acid in which a double bond is formed between the 4th and 5th positions of some or all of the D-glucuronic acids.

In the present invention, the weight-average molecular weight of the low molecular weight hyaluronic acid or its salt is less than 50,000, preferably 40,000 or less, more preferably 30,000 or less, and even more preferably 20,000 or less. The weight-average molecular weight of the low molecular weight hyaluronic acid or its salt is preferably 100 or more, more preferably 200 or more, even more preferably 500 or more, and even more preferably 1,000 or more. The weight-average molecular weight of the low molecular weight hyaluronic acid or its salt is preferably 100 or more and less than 50,000, more preferably 200 or more and 40,000 or less, even more preferably 500 or more and 30,000 or less, and even more preferably 1,000 or more and 20,000 or less. Within this range, when the skin topical composition of the present invention is applied to the skin, the permeability of the hyaluronic acid is significantly promoted, and the skin is excellent in terms of softness, moisturizing feeling, and other usability.

In the present invention, commercially available low molecular weight hyaluronic acid can be purchased and used. Commercially available low molecular weight hyaluronic acid products include Hyalo Oligo (trade name) (Kewpie Corporation; weight average molecular weight 10,000 or less), Hyaluronic Acid (SL) (trade name) (FAP Japan Co., Ltd.; weight average molecular weight 10,000 or less), Micro Hyaluronic Acid FCH (trade name) (Kikkoman Biochemifa Corporation; weight average molecular weight 5,000 or less), and HA Booster (trade name) (Kewpie Corporation; weight average molecular weight 2,000).

The salt of low molecular weight hyaluronic acid may be any salt that is pharmacologically or physiologically acceptable, and examples thereof include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; ammonium salts; basic amino acid salts; and amine salts such as triethanolamine. Among these, alkali metal salts and metal salts are preferred, sodium salts, potassium salts, and zinc salts are more preferred, and sodium salts are even more preferred.

One or more types of low molecular weight hyaluronic acid or its salt can be used.

The content of low molecular weight hyaluronic acid or its salt is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.005% by mass or more, and even more preferably 0.01% by mass or more, based on the total amount of the skin topical composition. The content of low molecular weight hyaluronic acid or its salt is preferably 20.0% by mass or less, more preferably 10.0% by mass or less, even more preferably 5.0% by mass or less, and even more preferably 3.0% by mass or less, based on the total amount of the skin topical composition. The content of low molecular weight hyaluronic acid or its salt in the skin topical composition of the present invention is 0.0001% by mass or more and 20.0% by mass or less, preferably 0.001% by mass or more and 10.0% by mass or less, more preferably 0.005% by mass or more and 5.0% by mass or less, and particularly preferably 0.01% by mass or more and 3.0% by mass or less, based on the total amount of the skin topical composition. By setting the content of low molecular weight hyaluronic acid or its salt within the above range, the permeability of the hyaluronic acids contained in the topical skin composition of the present invention into the skin can be significantly improved. Note that, when multiple types of low molecular weight hyaluronic acid or its salt are contained, the content of low molecular weight hyaluronic acid or its salt refers to the total content of them.

The content of hyaluronic acid or a salt thereof in the topical skin composition of the present invention (the total content of high molecular weight hyaluronic acid or a salt thereof and low molecular weight hyaluronic acid or a salt thereof) is preferably 0.0001% by mass or more, more preferably 0.005% by mass or more, even more preferably 0.01% by mass or more, and even more preferably 0.05% by mass or more, based on the total amount of the topical skin composition. The content of hyaluronic acid or a salt thereof is preferably 30% by mass or less, more preferably 20% by mass or less, even more preferably 10% by mass or less, and even more preferably 5.0% by mass or less, based on the total amount of the topical skin composition. Furthermore, the content of hyaluronic acid or a salt thereof in the topical skin composition of the present invention is from 0.0001% to 30.0% by mass, preferably from 0.005% to 20.0% by mass, more preferably from 0.01% to 10% by mass, and even more preferably from 0.05% to 5.0% by mass, based on the total amount of the topical skin composition. Within this range, when the topical skin composition of the present invention is applied to the skin, the permeability of hyaluronic acid is significantly promoted, and the skin is also excellent in terms of softness, moisturization, and other usability.

The content ratio of high molecular weight hyaluronic acid or its salt to low molecular weight hyaluronic acid or its salt in the skin topical composition of the present invention can be 0.0001 parts by mass or more, 0.001 parts by mass or more, 0.01 parts by mass or more, 0.1 parts by mass or more, or 0.3 parts by mass or more of low molecular weight hyaluronic acid or its salt per 1 part by mass of high molecular weight hyaluronic acid or its salt. It can also be 1000 parts by mass or less, 50 parts by mass or less, 10 parts by mass or less, or 5 parts by mass or less. Within this range, when the skin topical composition of the present invention is applied to the skin, the permeability of hyaluronic acid is significantly promoted, and the skin is excellent in terms of softness, moisturizing feeling, and other usability.

(Hyaluronic acid derivative or its salt)
The hyaluronic acid derivative in the present invention is not particularly limited as long as it has a weight-average molecular weight of 1,200,000 or less among hyaluronic acid derivatives, and examples thereof include acetylated hyaluronic acid, sulfated hyaluronic acid, hydrophobized hydrolyzed hyaluronic acid (hydrolyzed alkyl hyaluronate, hydrolyzed glyceryl hyaluronate, etc.), crosslinked hyaluronic acid, carboxymethyl hyaluronic acid, alkylene glycol hyaluronate, silanol hyaluronate, cationized hyaluronic acid, and salts thereof.

Of these, acetylated hyaluronic acid, hydroxypropyltrimonium hyaluronate, hydrolyzed alkyl hyaluronate (alkyl group having 12 to 13 carbon atoms; C12-13) glyceryl, crosslinked hyaluronic acid, carboxymethyl hyaluronic acid, propylene glycol hyaluronate, dimethylsilanol hyaluronate, and salts thereof are preferred, and acetylated hyaluronic acid, hydroxypropyltrimonium hyaluronate, hydrolyzed alkyl hyaluronate (C12-13) glyceryl, crosslinked hyaluronic acid, propylene glycol hyaluronate, dimethylsilanol hyaluronate, and salts thereof are more preferred.

Acetylated hyaluronic acid is preferably hyaluronic acid in which the hydroxyl groups have been acetylated. Hyaluronic acid has four hydroxyl groups per structural unit (disaccharide), and acetylated hyaluronic acid in which two to four hydroxyl groups have been acetylated is preferred.

Commercially available hyaluronic acid derivatives include acetylated sodium hyaluronate (trade name) (Shiseido Co., Ltd.; weight average molecular weight 10,000 to 100,000), Hyalobell (trade name) (Kewpie Corporation; weight average molecular weight 500,000 to 800,000), HyaloRepea (trade name) (Kewpie Corporation; weight average molecular weight 10,000 or less), Hyalocatch (trade name) (Kewpie Corporation; weight average molecular weight 800,000 to 1,200,000), Hyalujon (trade name) (Kikkoman Biochemifa Corporation; propylene glycol hyaluronate), D.S.H.CN6 (trade name) (EXSYMOL S.A.M; dimethylsilanol hyaluronate), and D.S.H.CN (trade name) (EXSYMOL S.A.M; dimethylsilanol hyaluronate).

The salt of the hyaluronic acid derivative may be any salt that is pharmacologically or physiologically acceptable, and examples thereof include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as zinc and aluminum; ammonium salts; basic amino acid salts; and amine salts such as triethanolamine. Among these, sodium salts, potassium salts, zinc salts, and ammonium salts are preferred, and sodium salts and ammonium salts are more preferred. Examples of salts of hyaluronic acid derivatives include sodium acetylated hyaluronate, potassium acetylated hyaluronate, calcium acetylated hyaluronate, magnesium acetylated hyaluronate, zinc acetylated hyaluronate, ammonium acetylated hyaluronate, sodium hyaluronate crosspolymer, and hydroxypropyltrimonium hyaluronate.

One or more types of hyaluronic acid derivatives can be used.

The content of hyaluronic acid derivative or its salt in the skin external composition of the present invention is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, more preferably 0.01% by mass or more, and even more preferably 0.1% by mass or more, based on the total amount of the skin external composition.In addition, the content of hyaluronic acid derivative or its salt is preferably 20.0% by mass or less, more preferably 10.0% by mass or less, more preferably 5.0% by mass or less, and even more preferably 3.0% by mass or less, based on the total amount of the skin external composition.In addition, the content of hyaluronic acid derivative or its salt in the skin external composition of the present invention is 0.0001% by mass or more and 20.0% by mass or less, preferably 0.001% by mass or more and 10.0% by mass or less, more preferably 0.01% by mass or more and 5.0% by mass or less, and particularly preferably 0.1% by mass or more and 3.0% by mass or less, based on the total amount of the skin external composition. By making the content of hyaluronic acid derivative or its salt within the above-mentioned range, the skin permeability of the hyaluronic acid, hyaluronic acid derivative and/or their salt contained in the skin external composition of the present invention can be significantly improved.Note that, when containing multiple kinds of hyaluronic acid derivative or its salt, the content of hyaluronic acid derivative or its salt refers to the total content of them.

In the skin topical composition of the present invention, the hyaluronic acid (B) contains at least three types selected from the group consisting of the hyaluronic acids listed above, preferably at least four types, more preferably at least five types, and even more preferably at least six types. The combination of hyaluronic acids (B) contained in the skin topical composition of the present invention is not particularly limited, but preferred combinations include, for example, a combination of hydrolyzed alkyl (C12-13) glyceryl hyaluronate, hydroxypropyltrimonium hyaluronate, and acetylated sodium hyaluronate, and a combination of sodium hyaluronate (weight average molecular weight 1,200,000), hydrolyzed sodium hyaluronate (weight average molecular weight 10,000), and hydrolyzed alkyl (C12-13) glyceryl hyaluronate (weight average molecular weight 10,000).

The content of (B) hyaluronic acid in the skin topical composition of the present invention is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.01% by mass or more, and even more preferably 0.1% by mass or more, based on the total amount of the skin topical composition. The content of (B) hyaluronic acid is preferably 30.0% by mass or less, more preferably 20.0% by mass or less, even more preferably 10.0% by mass or less, and even more preferably 5.0% by mass or less, based on the total amount of the skin topical composition. The content of (B) hyaluronic acid in the skin topical composition of the present invention is 0.0001% by mass or more and 30.0% by mass or less, preferably 0.001% by mass or more and 20.0% by mass or less, more preferably 0.01% by mass or more and 10.0% by mass or less, and particularly preferably 0.05% by mass or more and 5.0% by mass or less, based on the total amount of the skin topical composition. By setting the content of (B) hyaluronic acids within the above range, the skin permeability of the hyaluronic acid, hyaluronic acid derivatives and/or salts thereof contained in the topical skin composition of the present invention can be significantly improved. Note that, when multiple types of (B) hyaluronic acids are contained, the content of (B) hyaluronic acids refers to the total content of them.

[solvent]
The composition for external use on the skin of the present invention contains water, alcohol, a hydrophilic organic solvent, a fatty acid, a higher fatty acid ester, a glyceride, or a hydrophobic organic solvent, or a miscible mixture thereof.

The solvent is preferably one that functions as a base or carrier in the topical skin composition of the present invention, and includes aqueous solvents such as water, liquid paraffin, squalane, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, and hydrocarbons such as light liquid paraffin; methyl polysiloxanes such as polymethylsilsesquioxane, crosslinked methyl polysiloxanes, highly polymerized methyl polysiloxanes, cyclic silicones, alkyl-modified silicones, crosslinked alkyl-modified silicones, amino-modified silicones, polyether-modified silicones, polyglycerin-modified silicones such as lauryl dimethicone polyglycerin-3 crosspolymer, crosslinked polyether-modified silicones, crosslinked alkyl polyether-modified silicones, silicone/alkyl chain co-modified polyether-modified silicones, silicone/alkyl chain co-modified polyglycerin-modified silicones, polyether-modified branched silicones, and polyglycerin-modified branched silicones. Examples of suitable solvents include silicone oils such as silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, octyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, glyceryl tri-2-ethylhexanoate, and jojoba oil; polysaccharides such as dextrin and maltodextrin; and alcohols such as ethanol and isopropanol. Of these, aqueous solvents are preferred, and water is particularly preferred. When the topical skin composition of the present invention contains water, the amount of water can be appropriately selected taking into consideration the feel on the skin when used and the effects of the present invention, but is, for example, 0.001% to 99.99% by mass, preferably 0.01% to 99.9% by mass, more preferably 0.1% to 95% by mass, and most preferably 1% to 90% by mass, based on the total amount of the topical skin composition of the present invention.

[Oil content]
The skin external composition of the present invention does not contain oil, or its content is 10% by mass or less based on the total amount of the skin external composition.The oil content is preferably 5% by mass or less based on the total amount of the skin external composition, more preferably 3% by mass or less, even more preferably 2% by mass or less, and even more preferably 1% by mass or less.This range is also preferable from the viewpoint of the permeability of the hyaluronic acid contained in the skin external composition of the present invention into the skin.

In the present invention, the oil is an oily substance that is liquid or fluid at 25°C. The oil in the present invention is preferably an oily substance that is liquid, fluid, or semi-solid at 25°C, and more preferably a liquid, fluid, semi-solid, or solid oily substance at 25°C. Solid means that it has no fluidity at 25°C, semi-solid means that it has a melting point of 25°C to 45°C, and liquid means that it has fluidity at 25°C. Examples of oily substances include hydrocarbons, waxes, silicones, higher alcohols, higher fatty acids, oils and fats, and esters. These oily substances are blended for purposes different from those of the above-mentioned solvents.

Examples of hydrocarbons include liquid paraffin, liquid isoparaffin, squalane, petrolatum, paraffin, microcrystalline wax, polybutene, polyethylene powder, gelled hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, light liquid paraffin, light iso liquid paraffin, isododecane, isohexadecane, etc. Among these, liquid paraffin, liquid isoparaffin, squalane, petrolatum, gelled hydrocarbons (such as Plastibase), α-olefin oligomers, light liquid paraffin, and light iso liquid paraffin are preferred, and liquid paraffin, liquid isoparaffin, squalane, α-olefin oligomers, light liquid paraffin, and light iso liquid paraffin are more preferred.

Examples of waxes include jojoba oil, beeswax, candelilla wax, rice bran wax, cotton wax, carnauba wax, lanolin, liquid lanolin, reduced lanolin, etc. Among these, jojoba oil, beeswax, candelilla wax, and rice bran wax are preferred, with jojoba oil being particularly preferred.

Examples of silicones include methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, phenyl modified silicones such as methylphenyl polysiloxane, cyclic silicones such as decamethylcyclopentasiloxane, alkyl modified silicones such as methyl hydrogen polysiloxane, methyl trimethicone, dimethiconol, dimethiconol crosspolymer, and caprylyl methicone, crosslinked alkyl modified silicones, amino modified silicones, polyether modified silicones, polyglycerin modified silicones, crosslinked polyether modified silicones, crosslinked alkyl polyether modified silicones, silicone/alkyl chain co-modified polyether modified silicones, silicone/alkyl chain co-modified polyglycerin modified silicones, polyether modified branched silicones, polyglycerin modified branched silicones, acrylic silicones, phenyl modified silicones, and silicone resins. Among these, methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, methylphenyl polysiloxane, and decamethylcyclopentasiloxane are preferred.

Examples of higher alcohols include saturated or unsaturated, straight-chain or branched higher alcohols having 8 to 22 carbon atoms. Specific examples include capryl alcohol, lauryl alcohol, myristyl alcohol, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol, oleyl alcohol, etc. Among these, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, and isostearyl alcohol are preferred, and octyldodecanol and isostearyl alcohol are more preferred.

Higher fatty acids include saturated or unsaturated, straight-chain or branched higher alcohols having 8 to 22 carbon atoms. Specific examples include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and behenic acid. Among these, isostearic acid, stearic acid, and behenic acid are preferred, and isostearic acid is more preferred.

Examples of oils and fats include avocado oil, linseed oil, camellia oil, macadamia nut oil, kukui nut oil, hazelnut oil, corn oil, olive oil, safflower oil, apricot kernel oil, cinnamon oil, jojoba oil, grape seed oil, sunflower oil, almond oil, meadowfoam oil, camellia oil, rapeseed oil, sesame oil, cocoa butter, coconut oil, hardened coconut oil, palm oil, palm kernel oil, Japan wax kernel oil, Japan wax, wheat germ oil, rice germ oil, rice bran oil, cottonseed oil, soybean oil, peanut oil, tea seed oil, evening primrose oil, shea butter, hardened oil, orange roughy oil, and horse oil. Among these, avocado oil, macadamia nut oil, olive oil, grape seed oil, sunflower oil, almond oil, meadowfoam oil, sesame oil, palm oil, palm kernel oil, rice germ oil, rice bran oil, soybean oil, evening primrose oil, shea butter, and orange roughy oil are preferred.

Esters include isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, diisopropyl adipate, decyl oleate, oleyl oleate, isodecyl oleate, hexyldecyl dimethyloctanoate, diisopropyl sebacate, di-2-ethylhexyl sebacate, 2-hexyldecyl myristate, 2-ethylhexyl palmitate, diisopropyl adipate, isotridecyl isononanoate, Cetyl lactate, isostearyl isostearate, cholesteryl 12-hydroxystearate, cholesteryl stearate, cholesteryl oleate, phytosteryl macadamiate, phytosteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, neopentyl glycol dicaprate, tri-2-ethylhexyl trimellitate, tridecyl trimellitate , trimethylolpropane tri-2-ethylhexyl acid, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane triisostearate, polyglyceryl diisostearate, polyglyceryl monoisostearate, caprylic/capric triglyceride, caprylic/capric/myristic/stearic triglyceride, oleyl oleate, lauroyl Examples of suitable glyceryl/isostearyl/cetyl/behenyl dimer dilinoleate include phytosteryl/octyldodecyl glutamate, octyldodecyl/phytosteryl/behenyl lauroyl glutamate, triethyl citrate, phytosteryl/isostearyl/cetyl/stearyl/behenyl dimer dilinoleate, dimer dilinoleyl dimer dilinoleate, dipentaerythrityl tri-polyhydroxystearate, glyceryl tri(behenate/isostearate/eicosadioate), diisostearyl malate, and triethyl citrate. Among them, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, isononyl isononanoate, oleyl oleate, diisopropyl sebacate, di-2-ethylhexyl sebacate, 2-ethylhexyl palmitate, diisopropyl adipate, isotridecyl isononanoate, isostearyl isostearate, cholesteryl 12-hydroxystearate, cholesteryl stearate, cholesteryl oleate, phytosteryl macadamiate, phytosteryl oleate, dextrin palmitate, inulin stearate, hydrogenated jojoba oil, ethylene glycol di-2-ethylhexylate, dipentaerythritol fatty acid ester, neopentyl glycol dicaprate, tri-2-ethylhexyl trimellitate, tritridecyl trimellitate, trimethylolpropane tri-2-ethylhexylate, triisostearate, Trimethylolpropane tearic acid, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane triisostearate, polyglyceryl diisostearate, polyglyceryl monoisostearate, tri(caprylic acid/capric acid), tri(caprylic acid/capric acid/myristic acid/stearic acid), oleyl oleate, di(phytosteryl/octyldodecyl) lauroyl glutamate, di(octyldodecyl/phytosteryl/behenyl) lauroyl glutamate, triethyl citrate, dimer dilinoleate (phytosteryl/isostearyl/cetyl/stearyl/behenyl), dimer dilinoleyl dimer dilinoleate, dipentaerythrityl tripolyhydroxystearate, and tri(behenic acid/isostearic acid/eicosandioic acid)glyceryl are preferred.

In the skin topical composition of the present invention, one or more oils can be used.

[Optional ingredients]
In order to improve the effect of the present invention, the skin topical composition of the present invention may contain vitamins, alkanediols, polyhydric alcohols, glycol ethers, thickeners, etc. in addition to the above-mentioned (A) and (B) components. In addition, other components may be contained within a range that does not impair the effect of the present invention. In addition, each of these components may be used alone, or two or more may be used in any combination. In addition, when the compounds specifically exemplified as each component overlap, it is sufficient that they are contained as either component.

(Vitamins)
Examples of the vitamins include retinol derivatives such as retinol, retinol acetate, and retinol palmitate, vitamin A such as retinal, retinoic acid, methyl retinoate, ethyl retinoate, retinol retinoic acid, d-δ-tocopheryl retinoate, α-tocopheryl retinoate, and β-tocopheryl retinoate; provitamin A such as β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthin, and echinenone; δ-tocopherol, α-tocopherol, β-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, δ-tocopherol, and nicotinamide. Vitamin E such as tocopherol tartrate; vitamin B2 such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin sodium 5'-phosphate, and riboflavin tetranicotinate; nicotinic acids such as methyl nicotinate, nicotinic acid, and nicotinamide; ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetraisopalmitate (ascorbyl tetra 2-hexyldecanoate), ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbyl phosphate, and ascorbyl phosphate. Vitamin C such as magnesium, ascorbic acid glucoside, 3-O-ethyl ascorbic acid; Vitamin D such as methylhesperidin, ergocalciferol, cholecalciferol; Vitamin K such as phylloquinone, farnoquinone; dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate ester Vitamin B1 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, vitamin B12 such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, folates such as folic acid and pteroylglutamic acid, pantothenic acids such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantetheine, D-pantethine, coenzyme A, pantothenyl ethyl ether, biotins such as biocytin, and vitamin-like action factors such as carnitine, ferulic acid, α-lipoic acid, orotic acid, and γ-oryzanol. Among these, vitamin C is preferred from the viewpoint of the effect of the skin external composition of the present invention. Among vitamin C, some of the vitamin C derivatives are converted into vitamin C by enzymes in the living body and act.

When vitamins are added, the amount used can be appropriately selected taking into consideration the feel when used, but is, for example, 0.001% to 30% by mass, preferably 0.1% to 25% by mass, and more preferably 0.5 to 20% by mass, based on the total amount of the topical skin composition of the present invention.

(Alkanediol)
The composition for external use on skin of the present invention may contain an alkanediol having 5 to 10 carbon atoms. The alkanediol preferably has 5 to 10 carbon atoms, more preferably has 5 to 8 carbon atoms, and even more preferably has 5 to 6 carbon atoms. In addition, the alkanediol is preferably a 1,2-alkanediol.

Examples of alkanediols having 5 to 10 carbon atoms include 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-nonanediol, and 1,2-decanediol. Among these, 1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol are preferred, 1,2-pentanediol and 1,2-hexanediol are more preferred, and 1,2-pentanediol is even more preferred.

Commercially available alkanediols having 5 to 10 carbon atoms include HYDROLITE-5, HYDROLITE-5 Green (manufactured by Symrise Co., Ltd.), KMO-6 (manufactured by Osaka Organic Chemical Industry Co., Ltd.), Microcare Emollient PTGJ, and Microcare Emollient HXD (manufactured by THOR Co., Ltd.).

One or more types of alkanediols having 5 to 10 carbon atoms can be used.

The content of 1,2-alkanediol in the topical skin composition of the present invention is preferably 0.001% by mass to 20% by mass, more preferably 0.01% by mass to 15% by mass, and even more preferably 0.1% by mass to 10% by mass. When multiple types of alkanediols are contained, the content of alkanediol is the total content thereof.

(Polyhydric alcohol)
The skin topical composition of the present invention may further contain a polyhydric alcohol. As the polyhydric alcohol used in the skin topical composition of the present invention, any polyhydric alcohol used in cosmetics, quasi-drugs or pharmaceuticals may be used without limitation. Examples of the polyhydric alcohol include glycols (ethylene glycol, diethylene glycol, propylene glycol, isopropylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, 1,3-butylene glycol, pentylene glycol, etc.), glycerin, diglycerin, triglycerin, polyglycerin, sorbitol, alkanediols (propanediol, 3-methyl-1,3-butanediol, pentanediol, etc.), etc. Among these, from the viewpoint of formulation taking into consideration the feeling of use, etc., propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, glycerin, diglycerin, sorbitol, alkanediols (propanediol, pentanediol, hexanediol), etc. are preferred, and dipropylene glycol, 1,3-butylene glycol, and pentylene glycol are more preferred.

The content of the polyhydric alcohol in the topical skin composition of the present invention is preferably 0.01% by mass to 99.9% by mass, more preferably 0.1% by mass to 75% by mass, and even more preferably 0.5% by mass to 50% by mass. If it is within the above range, in addition to the effects of the present invention, the topical skin composition can be imparted with moisturizing power and a good feel when used.

(Glycol Ether)
The skin topical composition of the present invention may further contain glycol ether. As the glycol ether used in the skin topical composition of the present invention, any glycol ether used as a glycol ether in cosmetics, quasi-drugs or pharmaceuticals may be used without limitation. For example, ethylene glycol-based glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monopropyl ether; diethylene glycol-based glycol ethers such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and diethylene glycol monopropyl ether; propylene glycol-based glycol ethers such as propylene glycol monoethyl ether and propylene glycol monopropyl ether; and dipropylene glycol-based glycol ethers such as dipropylene glycol monoethyl ether and dipropylene glycol monopropyl ether. Among them, ethylene glycol-based and diethylene glycol-based glycol ethers are preferred, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether are more preferred, and diethylene glycol monoethyl ether is particularly preferred.

The content of glycol ether in the topical composition of the present invention is preferably 0.01% by mass to 97% by mass, more preferably 0.1% by mass to 50% by mass, and even more preferably 0.5% by mass to 30% by mass. If it is within the above range, in addition to the effects of the present invention, the topical composition can be imparted with moisturizing power and a good feel when used.

(Thickener)
The skin topical composition of the present invention may further contain a thickener. This allows the skin topical composition to have good skin compatibility and excellent usability. As such a thickener, any thickener used in cosmetics, quasi-drugs, or pharmaceuticals may be used without limitation. For example, agar, gellan gum, guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, sodium alginate, propylene glycol alginate, dextran, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, acrylic acid alkyl methacrylate copolymer, sodium polyacrylate, polyethylene glycol ... Examples of the cellulose acetate copolymer include glycol, bentonite, dextrin fatty acid ester, pectin, (hydroxyethyl acrylate/sodium acryloyldimethyl taurate) copolymer, dimethyl distearyl ammonium hectorite, (ammonium acryloyldimethyl taurate/vinyl pyrrolidone) copolymer, (ammonium acryloyldimethyl taurate/beheneth-25 methacrylate) cross copolymer, (ammonium acryloyldimethyl taurate/steareth-25 methacrylate) crosspolymer, polyethylene glycol distearate, ethylene glycol triisostearate, polyoxyethylene (20) methyl glucoside triisostearate, etc. Among these, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, xanthan gum, acrylic acid/alkyl methacrylate copolymer, (hydroxyethyl acrylate/sodium acryloyldimethyl taurate) copolymer, and (ammonium acryloyldimethyl taurate/vinyl pyrrolidone) copolymer are more preferred.

The content of the thickener in the topical composition of the present invention is preferably 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, and even more preferably 0.05% by mass to 5% by mass. If the content of the thickener is within the above range, the topical composition for skin can be made to have good compatibility with the skin and excellent usability.

(Other ingredients)
In addition to the above-mentioned components, the skin topical composition of the present invention may contain one or more of various components, such as an ultraviolet scattering component, an ultraviolet absorbing component, a component having an effect of preventing and/or repairing DNA damage, a brightening component, an anti-inflammatory component, a cell activating component, an astringent component, an antioxidant component, an anti-aging component, a moisturizing component, a keratin softening component, and a blood circulation promoting component, in order to impart other useful effects. These components are not particularly limited as long as they can be used in the fields of medicines, quasi-drugs, cosmetics, etc., and any one can be appropriately selected and used. In addition, components that fall under the following multiple components can be added as components with any of the effects.

Examples of the ultraviolet scattering component include inorganic compounds such as zinc oxide, titanium oxide, iron oxide, cerium oxide, zirconium oxide, titanium silicate, zinc silicate, anhydrous silicic acid, cerium silicate, and hydrous silicic acid, as well as inorganic compounds coated with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica, and talc, or composites with resin powders such as polyamide, polyethylene, polyester, polystyrene, and nylon, and further compounds treated with silicone oil, fatty acid aluminum salts, and the like. Among these, inorganic compounds such as zinc oxide, titanium oxide, and iron oxide, as well as inorganic compounds coated with inorganic powders such as aluminum hydroxide, hydrous silicic acid, mica, and talc, or silicone oil, are preferred.

Examples of the ultraviolet absorbing component include 2-ethylhexyl paramethoxycinnamate, 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid hexyl ester, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, 2-ethylhexyl dimethoxybenzylideneoxoimidazolidinepropionate, 2,4-bis-[{4-(2-ethylhexyloxy)-2-hydroxy}-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, and the like.

Examples of the brightening ingredients include hydroquinone, placenta, arbutin, kojic acid, ellagic acid, phytic acid, tranexamic acid, 4-n-butylresorcinol, chamomile extract, vitamins such as vitamin A or its derivatives, pantothenic acid or its derivatives, etc. Furthermore, plant ingredients having a whitening effect may be used as the whitening ingredient. Examples of such plant ingredients include iris, almond, aloe, ginkgo, oolong tea, Chinese laurel, Scutellaria baicalensis, Coptis chinensis, Hypericum perforatum, white lamb's foot, seaweed, pueraria root, gardenia, lily of the valley, chlorella, barley, rice, rice hyacinth, oryzanol, rice bran, Chinese laurel, Japanese pepper, perilla, peony, cnidium officinalis, soybean, natto, tea, angelica tree, calendula officinalis, garlic, witch hazel, safflower, peonies, coix seed, angelica tree, amethyst, astragalus, andromeda japonica, Japanese hackberry, Japanese persimmon (Diospyros persica), and the like. kaki), catalpa, black bean, gentian, gentian root, salsa, green leopard, jūrou, sage, zenko, radish, azalea, bush clover, toshin, bitter oak, parsley, holly, hops, Japanese bush clover, clove, licorice, grapefruit, etc. Preferred are components derived from iris (iris), aloe, ginkgo, oolong tea, Chinese laurel, Scutellaria baicalensis, Coptis chinensis, Hypericum perforatum, white lamb's foot, seaweed, pueraria lobata, gardenia, kudzu, gobaishi, wheat, rice, rice bran, saishin, zanthoxylum, perilla, peony, cnidium officinalis, sohakuhi, tea, angelica tree, calendula officinalis, hamamelis, safflower, peonies, coix seed, amethyst, acacia, enoki mushroom, persimmon (Diospyros kaki), catalpa, black bean, gentian, salsa, green bean, jūro, sage, zenko, radish, azalea, bush clover, toshin, bitter gourd, parsley, holly, hops, clove, licorice, grapefruit and angelica are derived from these, and more preferred are components derived from iris (iris), aloe, ginkgo, Chinese laurel, Scutellaria, Coptis, Hypericum, gardenia, sophora jasmine, rice, rice bran, saishin, peony, cnidium, sophora rhododendron, tea, angelica, calendula, hamamelis, safflower, moutan tree, amethyst, acacia, Chinese hackberry, persimmon (Diospyros kaki), sage, radish, azalea, parsley, hops, licorice, grapefruit and coix seed. Among these, iris root extract, which is an ingredient derived from iris, and brown algae extract, Laminaria serrata extract, and aloe extract, which are ingredients derived from seaweed, are more preferred. When these plant ingredients are used in the topical composition of the present invention, the form of the plant ingredient is not particularly limited, but they can usually be used in the form of a plant extract or essential oil. Note that the parentheses in the above plant ingredients indicate the scientific name, alternative name, or herbal medicine name of the plant.

Examples of the anti-inflammatory ingredient include allantoin, calamine, tranexamic acid, glycyrrhizic acid or its derivatives or their salts, glycyrrhetinic acid or its derivatives or their salts, zinc oxide, guaiazulene, tocopherol acetate, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, salicylic acid or its derivatives, etc. Preferred are glycyrrhizic acid or its derivatives or their salts (e.g., dipotassium glycyrrhizinate, etc.), glycyrrhetinic acid or its derivatives or their salts, or zinc oxide.

The above-mentioned cell activation components include, for example, amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponin, allantoin, photosensitizer No. 301, etc.

Examples of the astringent ingredients include metal salts such as alum, chlorohydroxyaluminum, aluminum chloride, aluminum allantoin salt, zinc sulfate, and potassium aluminum sulfate; and organic acids such as tannic acid, citric acid, lactic acid, and succinic acid.

Examples of the antioxidant components include butyl hydroxyanisole, dibutyl hydroxytoluene, sodium bisulfite, sodium pyrosulfite, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, taurine, thiotaurine, hypotaurine, L-cysteine hydrochloride, and astaxanthin.

Examples of the anti-aging ingredients include pangamic acid, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, etc.

Examples of the moisturizing components include amino acids and derivatives thereof, such as alanine, serine, leucine, isoleucine, threonine, glycine, trimethylglycine, proline, hydroxyproline, glucosamine, and theanine; polyhydric alcohols, such as glycerin; sugar alcohols, such as sorbitol; phospholipids, such as lecithin and hydrogenated lecithin; NMF-derived components, such as lactic acid, sodium pyrrolidone carboxylate, and urea; and plant-derived components, such as lavender oil and Salicornia herbacea extract.

Examples of the above-mentioned keratin softening ingredients include lanolin, urea, phytic acid, lactic acid, lactate salts, glycolic acid, salicylic acid, malic acid, citric acid, etc.

The above blood circulation-promoting ingredients include, for example, ingredients derived from plants (e.g., ginseng, angelica, arnica, ginkgo, fennel, Japanese oak, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, Japanese hawthorn, shiitake mushroom, European hawthorn, European juniper, Cnidium rhizome, Swertia japonica, thyme, clove, Chinese citrus fruit, Japanese angelica, Japanese pear, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, rosemary, rose hip, Chinese citrus fruit, Japanese angelica, spruce, peach, apricot, walnut, corn); tocopherol nicotinate, glucosyl hesperidin, and hesperidin.

In addition to the above-mentioned components, the topical composition of the present invention may contain additives that are commonly used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., depending on the application or dosage form. There are no particular limitations on the additives that can be added, but examples of additives that can be added include surfactants, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, colorants, dispersants, fragrances, etc. These components can be added alone or in any combination of two or more. The amounts of these components used can be determined appropriately from the conventionally known ranges without impairing the effects of the present invention.

Examples of the above surfactants include sorbitan esters such as sorbitan stearate, PEG sorbitan stearate, sorbitan monooleate, sorbitan monoisostearate, and sorbitan monolaurate; POE-sorbitan monooleate; polyoxyethylene hydrogenated castor oil (HCO-10); glycerin fatty acid esters such as glycerin monooleate, glycerin monostearate, and glycerin monomyristate; glycerin alkyl ethers such as monoisostearyl glyceryl ether and monomyristyl glyceryl ether; various nonionic surfactants such as polyglycerin fatty acid esters such as polyglyceride stearate, polyglyceryl-10 isostearate, diglyceryl monostearate, decaglyceryl decastearate, decaglyceryl decastearate, and diglyceryl diisostearate; and naturally derived surfactants such as lecithin, hydrogenated lecithin, saponin, sodium surfactin, cholesterol, and bile acid.

Examples of the preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate, and phenoxyethanol.

Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

Examples of the chelating agent include ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetate (sodium salt (sodium edetate: Japanese Pharmacopoeia, EDTA-2Na, etc.), potassium salt, etc.), phytic acid, gluconic acid, polyphosphoric acid, metaphosphoric acid, etc. Among these, sodium edetate is preferred.

Examples of the stabilizer include magnesium sulfate, sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.

Examples of the irritation reducers include licorice extract, gum arabic, polyvinylpyrrolidone, sodium alginate, etc.

The above colorants include inorganic pigments, natural dyes, etc.

Examples of the dispersing agent include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether/maleic anhydride crosslinked copolymer, organic acids, etc.

[pH]
The composition for external use on the skin of the present invention may generally have a liquid property of pH 2.0 to 9.0, but from the viewpoints of low irritation to the skin and mucous membranes and good feel on the skin, the pH is preferably 3.0 to 8.5, and more preferably 3.5 to 8.0.

[Properties and Formulations]
The properties of the skin external composition of the present invention are not particularly limited, and can be liquid, fluid, or semi-solid.The formulation form can be, for example, liquid, suspension, emulsion, cream, milky lotion, ointment, gel, liniment, lotion, or sheet of nonwoven fabric impregnated with drug solution.Among them, emulsion, cream, milky lotion, ointment, gel, and lotion are preferred, and cream, milky lotion, ointment, and gel are particularly preferred.

The container for filling the topical skin composition of the present invention can be any container of a known shape without any restrictions. The material of the container is also not particularly limited, and the composition can be filled and provided in a container made of a material such as plastics, such as polyethylene terephthalate, polyethylene naphthalate, polyarylate, polycarbonate, polyethylene, or polypropylene, or glass.

<Method of manufacturing the composition for external use on skin>
The skin external composition of the present invention can be produced by appropriately selecting and blending (A) hyaluronic acid fermentation product, (B) hyaluronic acid with weight-average molecular weight of 1.2 million or less, and other components as mentioned above.The method of producing the skin external composition of the present invention is not particularly limited, and can be produced by appropriately selecting (A) hyaluronic acid fermentation product, (B) hyaluronic acid with weight-average molecular weight of 1.2 million or less, and other components as mentioned above, and mixing them in solvent by conventional method.

The topical skin composition of the present invention contains (A) a hyaluronic acid fermentation product and (B) hyaluronic acids having a weight-average molecular weight of 1.2 million or less, thereby significantly promoting the permeability of hyaluronic acid, hyaluronic acid derivatives and/or salts thereof into the skin and providing an excellent feel when used, such as skin softness and moisturization. The topical skin composition of the present invention has excellent permeability of hyaluronic acids into the skin and also has an improved feel when used, and therefore can be suitably used in the fields of cosmetics, quasi-drugs and pharmaceuticals.

<Skin penetration enhancer>
The present invention also includes the skin permeation enhancer of hyaluronic acid, hyaluronic acid derivatives, or their salts, characterized by containing (A) hyaluronic acid fermentation product and (B) hyaluronic acids with weight-average molecular weight of 1.2 million or less.The skin permeation enhancer of the present invention contains (A) hyaluronic acid fermentation product and (B) hyaluronic acids with weight-average molecular weight of 1.2 million or less, so that it can significantly promote the permeability of hyaluronic acid, hyaluronic acid derivatives, and/or their salts (hyaluronic acids) into the skin, and can also provide excellent usability such as skin softness and moisturizing feeling.In addition, the skin permeation enhancer of the present invention may contain various optional components other than (A) hyaluronic acid fermentation product and (B) hyaluronic acids, within the scope that does not impair the effect of the present invention, and for the purpose of improving the effect of the present invention.

The skin penetration enhancer of the present invention can also be said to be a combination of (A) hyaluronic acid fermentation product and (B) hyaluronic acids.

The skin penetration enhancer of the present invention is one embodiment of the above-mentioned skin topical composition of the present invention, so the specific description in the section on skin topical composition can be applied as is.

The present invention also includes a skin penetration enhancer for hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, which contains (A) a hyaluronic acid fermentation product. When the skin penetration enhancer containing (A) a hyaluronic acid fermentation product is blended with a topical skin composition containing hyaluronic acids, the effect of significantly enhancing the skin permeability of the hyaluronic acids is achieved.

<Method for promoting skin penetration>
The present invention also relates to a method for promoting skin penetration of hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, which is characterized by using (A) a hyaluronic acid fermentation product and (B) a hyaluronic acid having a weight-average molecular weight of 1,200,000 or less. By applying a composition for external use to the skin containing (A) a hyaluronic acid fermentation product and (B) hyaluronic acids having a weight-average molecular weight of 1,200,000 or less, to the skin, hyaluronic acid, hyaluronic acid derivatives, and It is possible to significantly promote the permeability of the composition and/or salts thereof (hyaluronic acids) into the skin, and also to provide excellent sensations upon use, such as softness of the skin and a moist feeling.

The skin permeation promoting method of the present invention can be said to be a method for promoting the permeation of hyaluronic acids into the skin by using the above-mentioned skin topical composition of the present invention.

The present invention also includes a method for promoting skin penetration of hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, using (A) a hyaluronic acid fermentation product. According to the method of the present invention, by incorporating (A) a hyaluronic acid fermentation product into a skin topical composition containing hyaluronic acids, it is possible to significantly promote the skin penetration of hyaluronic acids.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

1. Hyaluronic acid permeability evaluation test 1
[Preparation of topical skin composition]
Each composition (test solution) was prepared by a conventional method according to the recipe shown in Table 1 below. The units of values in each table are mass (%). The sodium hyaluronate, hydrolyzed sodium hyaluronate, and hydrolyzed alkyl (C12-13) glyceryl hyaluronate in each test solution in Table 1 were subjected to fluorescein amine labeling treatment.

[Evaluation of hyaluronic acid permeability]
Each test solution was applied to the surface of a three-dimensional cultured skin model (LabCyte EPI-MODEL12, manufactured by Japan Tissue Engineering Co., Ltd.) and allowed to stand for 30 minutes under closed conditions, after which the surface of the skin model was washed with phosphate buffered saline to remove the test solution remaining on the surface. The tissue of the skin model was fixed with formalin for 24 hours, and images of the tissue pieces were obtained using a fluorescent microscope. The results are shown in Figures 1-1 to 3-2.

As shown in Figures 1-1 to 3-2, it was found that the skin permeability of the sodium hyaluronate, hydrolyzed hyaluronic acid, and hydrolyzed alkyl (C12-13) glyceryl hyaluronate in each test solution was significantly improved by adding hyaluronic acid fermentation product.

2. Hyaluronic acid permeability evaluation test 2
[Preparation of topical skin composition]
Each composition (test solution) was prepared by a conventional method according to the formulation shown in the following Table 2. The units of values in each table are mass (%).

[Evaluation of hyaluronic acid permeability]
A panel of six experts evaluated the survivability of each composition according to the evaluation criteria. The evaluation results are shown in Table 2.

(Assessment of Survivability)
1 g of each composition was applied to an area of 10 ^cm2 on the arm. The application was carried out for 1 minute, and the remaining properties of the composition on the surface of the applied area were evaluated. A score of 1 was given when no remaining properties were felt, and a score of 7 was given when a strong remaining property was felt. The average of the scores of the expert panel was regarded as the remaining properties of each composition.

As shown in Table 2, the composition containing sodium hyaluronate with a weight-average molecular weight of 1.2 million and hyaluronic acid fermentation product was perceived to have lower residual properties than the composition containing sodium hyaluronate with a weight-average molecular weight of 1.2 million. From this, it is believed that the sodium hyaluronate with a weight-average molecular weight of 1.2 million in the composition has improved skin permeability due to the inclusion of hyaluronic acid fermentation product.

3. Hyaluronic acid permeability evaluation test 3
[Preparation of topical skin composition]
Each composition (test solution) was prepared by a conventional method according to the recipe shown in the following Table 3. The units of values in each table are mass (%).

[Evaluation of hyaluronic acid permeability]
The penetration feeling of each composition was evaluated by three expert panelists according to the evaluation criteria. The evaluation results are shown in Table 3.

(Skin softness evaluation)
2 g of each composition was applied to the arm with a finger. After application, the applied area was pressed with a finger to evaluate the softness of the skin. In comparison with the unapplied part of the arm, the area was scored as 1 when no softness was felt at all, and 7 when the area was most soft. The average of the scores of the expert panel was taken as the softness of the skin. Evaluation was performed immediately after application and 2 minutes after application, and the results are shown in Table 3.

(Evaluation of Moisture Sensation)
1 g of each composition was applied to an area of 12 ^cm2 on the arm. The application was continued for 1 minute, and the moist feeling of the applied surface was evaluated. A score of 1 was given when no moist feeling was felt, and a score of 7 was given when a strong moist feeling was felt. The average of the scores of the expert panel was regarded as the moist feeling of each composition.

As shown in Table 3, the composition containing sodium hyaluronate with a weight-average molecular weight of 1.2 million, hydrolyzed sodium hyaluronate with a weight-average molecular weight of 10,000, hydrolyzed alkyl (C12-13) glyceryl hyaluronate with a weight-average molecular weight of 10,000, and hyaluronic acid fermentation product promoted skin softness and moisturization. From this, it is considered that sodium hyaluronate with a weight-average molecular weight of 1.2 million, hydrolyzed sodium hyaluronate with a weight-average molecular weight of 10,000, hydrolyzed alkyl (C12-13) glyceryl hyaluronate with a weight-average molecular weight of 10,000, and hyaluronic acid fermentation product in the composition have enhanced skin permeability.

The topical skin composition of the invention contains (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less, and thus can significantly promote the permeability of hyaluronic acid, a hyaluronic acid derivative, and/or a salt thereof into the skin, and can provide excellent skin feel, such as softness and moisturization.

Claims (6)

A composition for external use on the skin, comprising (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less. The composition for external use on the skin according to claim 1, wherein (A) the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactococcus. The topical skin composition according to claim 1 or 2, which contains at least hydrolyzed alkyl (C12-13) glyceryl hyaluronate, hydroxypropyltrimonium hyaluronate, and sodium acetylated hyaluronate as component (B). A skin penetration enhancer for hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, comprising (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less. The skin penetration enhancer according to claim 4, wherein (A) the hyaluronic acid fermentation product is a fermentation product of hyaluronic acid by lactobacillus. A method for promoting skin penetration of hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, comprising using (A) a hyaluronic acid fermentation product, and (B) hyaluronic acid, a hyaluronic acid derivative, or a salt thereof having a weight-average molecular weight of 1.2 million or less.