JP6649866B2 - Cosmetic or external preparation for skin with excellent collagen production promoting effect - Google Patents

Description

  The present invention relates to a cosmetic or a skin external preparation which contains an ascorbic acid derivative having a specific structure as an active ingredient and has an excellent collagen production promoting effect.

  Ascorbic acid is a safe and useful antioxidant, is known as a compound having an excellent whitening effect and the like, and is also known as a compound having a high ability to promote collagen production. On the other hand, it is unstable against light, heat and oxidation, and has been hindered from being used in the cosmetics field. Therefore, various ascorbic acid derivatives or salts thereof have been proposed as compounds having the above-mentioned excellent effects of ascorbic acid and improved stability against light, heat and oxidation. Further, Patent Document 1 proposes the incorporation of the above ascorbic acid derivative or a salt thereof into a skin whitening agent for whitening, and Patent Document 2 proposes the incorporation of the ascorbic acid derivative or a salt thereof into cosmetics.

  However, many of the above-mentioned ascorbic acid derivatives and salts thereof have problems such as generation of coloring and odor with the passage of time, and their stability over time is still insufficient. Is desired.

  Patent Document 3 discloses various ascorbic acid derivatives and salts thereof as those having excellent temporal stability and excellent melanin production inhibitory effect, and further, these are used as skin externalizing agents for whitening. Formulation, formulation as a humectant, and formulation into cosmetics for the purpose of collagen production promoter and the like have been proposed. However, these ascorbic acid derivatives and salts thereof have poor solubility in oils, and when used as cosmetics, have a problem that they are not well-adapted to the stratum corneum and do not have sufficient permeability. Further, the collagen production promoting effect was not sufficiently satisfactory.

  As ascorbic acid derivatives having excellent solubility in oils, tri / tetrapivaloyl ascorbic acid (Patent Documents 4 and 5) and ascorbic acid tetrabranched fatty acid esters (Patent Documents 6 to 9) are disclosed. Patent Documents 4, 5, 6, and 7 disclose a whitening effect and a skin roughness improving effect, but do not disclose a collagen production promoting effect. Patent Documents 8 and 9 disclose the collagen production promoting effect. However, the collagen production promoting effect by using ascorbic acid tetrabranched fatty acid ester alone was not sufficiently satisfactory.

  In recent years, demands for cosmetics and external preparations for the skin have become more sophisticated, and more excellent functions are required. In particular, cosmetics and external preparations for skin having a more excellent collagen production promoting effect are desired.

JP-A-62-221611 JP-A-1-228978 Patent No. 4681670 JP-A-61-85308 Japanese Patent Publication No. 6-78223 JP 2003-238380 A JP 2003-306419 A JP 2003-342159 A Patent No. 4574384

  An object of the present invention is to provide a cosmetic and a skin external preparation using an ascorbic acid derivative as an active ingredient, which has an even more excellent collagen production promoting effect than before and also has excellent solubility in oils.

  The present inventors have conducted intensive studies in view of the above circumstances, and as a result, have found that an acylated ascorbic acid derivative having a specific structure is excellent in collagen production promoting effect and solubility in an oil agent, and completed the present invention.

  The present invention provides a cosmetic or external preparation for the skin (claim 1), which comprises an ascorbic acid derivative represented by the following general formula (I) as an active ingredient.

[Wherein, R ¹ , R ² , R ³ and R ⁴ each independently represent an alkyl group having 1 to 3 carbon atoms, or a linear or branched alkyl group or alkenyl group having 7 to 21 carbon atoms. It is. ^However, at least one of the groups R ^1, R ^2, R 3, ^{R 4} is an alkyl group having 1 to 3 carbon ^atoms, R ^1, R ^2, R 3, at least one group ^{R 4} is a straight-chain Alternatively, it is a branched alkyl group or alkenyl group having 7 to 21 carbon atoms. ]
When the alkyl group or alkenyl group having 7 to 21 carbon atoms represented by R ¹ , R ² , R ³ or R ⁴ is branched, it is preferable that the branch is located at a position other than the α-position.

In the invention according to claim 2, R ¹ in the general formula (I) is a linear or branched alkyl group or alkenyl group having 7 to 19 carbon atoms, R ² is a methyl group, A cosmetic or skin external preparation which contains as an active ingredient an ascorbic acid derivative in which R ³ and R ⁴ are a methyl group or a linear or branched alkyl group or alkenyl group having 7 to 19 carbon atoms. It is. Since this ascorbic acid derivative has a better collagen production promoting effect, a cosmetic or skin external preparation exhibiting a better collagen production promoting effect is provided.

The invention according to claim 3 is that, in the general formula (I), R ¹ is a linear or branched alkyl group having 11 to 17 carbon atoms, R ² is a methyl group, R ³ and An object of the present invention is to provide a cosmetic or skin external preparation containing as an active ingredient an ascorbic acid derivative wherein R ⁴ is a methyl group or a linear alkyl group having 11 to 17 carbon atoms. Since this ascorbic acid derivative is more excellent in solubility in oils and stability over time, it has a better collagen promoting effect and provides a cosmetic or skin external preparation excellent in solubility in oils and stability over time. Is done.

  Among them, the ascorbic acid derivative represented by the following structural formula (A) or (B) is particularly excellent in collagen production promoting effect and stability to an oil agent. The invention according to claim 4 is a cosmetic or external preparation for skin containing an ascorbic acid derivative represented by the following structural formula (A) or (B) as an active ingredient, and has an effect of promoting collagen production and stabilizing an oil agent. The present invention provides a cosmetic or skin external preparation particularly excellent in properties.

[Wherein, R ⁶ is a linear alkyl group having 13 to 17 carbon atoms. ]

  Furthermore, the present invention relates to the cosmetic or external preparation for skin according to any one of claims 1 to 4, wherein the ascorbic acid derivative contains 0.001 to 30% by mass of the cosmetic or external preparation. An agent (claim 5) is provided.

  The present invention further provides a method for promoting collagen production, which comprises applying the cosmetic or external preparation for skin according to claim 5 to the skin (claim 6).

  The ascorbic acid derivative having a specific structure contained as an active ingredient in the cosmetic or external preparation for skin of the present invention has an excellent collagen production promoting effect, and is also excellent in stability and solubility in oils. Therefore, the cosmetic or external preparation for skin of the present invention containing the ascorbic acid derivative having this specific structure as an active ingredient is excellent in collagen production promoting effect, and also excellent in stability and solubility in oils, and According to the method of applying a cosmetic or a skin external preparation to the skin, collagen production can be further promoted as compared with a conventional cosmetic or skin external preparation.

  Hereinafter, embodiments of the present invention will be described, but the scope of the present invention is not limited to these embodiments.

Specific examples of the ascorbic acid derivative of the present invention include, for example, the following compounds.
2,3,5-tri-O-acetyl-6-O-alkanoyl ascorbic acid, 2,3,5-tri-O-acetyl-6-O-alkenoyl ascorbic acid, 2,3,6-tri-O -Acetyl-5-O-alkanoyl ascorbic acid, 2,3,6-tri-O-acetyl-5-O-alkenoyl ascorbic acid, 2,5,6-tri-O-acetyl-3-O-alkanoyl ascorbic acid Acid, 2,5,6-tri-O-acetyl-3-O-alkenoyl ascorbic acid, 3,5,6-tri-O-acetyl-2-O-alkanoyl ascorbic acid, 3,5,6-triacid Triacetyl monoester ascorbic acid derivatives such as -O-acetyl-2-O-alkenoyl ascorbic acid;

  5,6-di-O-acetyl-2,3-di-O-alkanoyl ascorbic acid, 5,6-di-O-acetyl-2,3-di-O-alkenoyl ascorbic acid, 5,6-di -O-acetyl-2-O-alkanoyl-3-O-alkenoyl ascorbic acid, 5,6-di-O-acetyl-2-O-alkenoyl-3-O-alkanoyl ascorbic acid, 3,6-di- O-acetyl-2,5-di-O-alkanoyl ascorbic acid, 3,6-di-O-acetyl-2,5-di-O-alkenoyl ascorbic acid, 3,6-di-O-acetyl-2 -O-alkanoyl-5-O-alkenoyl ascorbic acid, 3,6-di-O-acetyl-2-O-alkenoyl-5-O-alkanoyl ascorbic acid, 2,6-di-O-acetyl-3, 5-di-O-alkano Ruascorbic acid, 2,6-di-O-acetyl-3,5-di-O-alkenoyl ascorbic acid, 2,6-di-O-acetyl-3-O-alkanoyl-5-O-alkenoyl ascorbin Acid, 2,6-di-O-acetyl-3-O-alkenoyl-5-O-alkanoyl ascorbic acid, 3,5-di-O-acetyl-2,6-di-O-alkanoyl ascorbic acid, 3, 5-di-O-acetyl-2,6-di-O-alkenoyl ascorbic acid, 3,5-di-O-acetyl-2-O-alkanoyl-6-O-alkenoyl ascorbic acid, 3,5- Di-O-acetyl-2-O-alkenoyl-6-O-alkanoyl ascorbic acid, 2,5-di-O-acetyl-3,6-di-O-alkanoyl ascorbic acid, 2,5-di-O- Acetyl-3, -Di-O-alkenoyl ascorbic acid, 2,5-di-O-acetyl-3-O-alkanoyl-6-O-alkenoyl ascorbic acid, 2,5-di-O-acetyl-3-O-alkenoyl -6-O-alkanoyl ascorbic acid, 2,3-di-O-acetyl-5,6-di-O-alkanoyl ascorbic acid, 2,3-di-O-acetyl-5,6-di-O-alk Noyl ascorbic acid, 2,3-di-O-acetyl-5-O-alkanoyl-6-O-alkenoyl ascorbic acid, 2,3-di-O-acetyl-5-O-alkenoyl-6-O-alkanoyl Diacetyl ascorbic acid derivatives such as ascorbic acid,

  2,3,5-tri-O-alkanoyl-6-O-acetylascorbic acid, 2,3,5-tri-O-alkenoyl-6-O-acetylascorbic acid, 2,3,6-tri-O- Alkanoyl-5-O-acetylascorbic acid, 2,3,6-tri-O-alkenoyl-5-O-acetylascorbic acid, 2,5,6-tri-O-alkanoyl-3-O-acetylascorbic acid, 2,5,6-tri-O-alkenoyl-3-O-acetylascorbic acid, 3,5,6-tri-O-alkanoyl-2-O-acetylascorbic acid, 3,5,6-tri-O- Alkenoyl-2-O-acetylascorbic acid,

  2,3,5-tri-O-propanoyl-6-O-alkanoyl ascorbic acid, 3,5-di-O-propanoyl-2,6-di-O-alkanoyl ascorbic acid, 2,3,5-tri- Propanoyl alkanoyl ascorbic acid such as O-alkanoyl-6-O-propanoyl ascorbic acid, 2,3,5-tri-O-butanoyl-6-O-alkanoyl ascorbic acid, 3,5-di-O-butanoyl- Butanoylalkanoyl ascorbic acid such as 2,6-di-O-alkanoyl ascorbic acid and 2,5,6-tri-O-alkanoyl-3-O-butanoyl ascorbic acid can be mentioned.

In the above examples, the alkanoyl group refers to R ⁵ —CO— (R ⁵ represents an alkyl group or an alkenyl group having 7 to 21 carbon atoms), for example, an octanoyl group, a nonanoyl group, a decanoyl group, and an undecanoyl group. Group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanoyl group, octadecanoyl group, nonadecanoyl group, eicosanoyl group, henicosanoyl group, docosanoyl group, and other linear alkanoyl groups Group,
2-ethylhexanoyl group, 3-ethylhexanoyl group, isooctanoyl group such as 5-methylheptanoyl group, 2-octyldecanoyl group, isooctadecanoyl group such as 17-methylheptadecanoyl group, isononanoyl group, Isodecanoyl group, isoundecanoyl group, isododecanoyl group, isotridecanoyl group, isotetradecanoyl group, isopentadecanoyl group, isohexadecanoyl group, isoheptadecanoyl group, isononanodecanoyl group, isoeicosa Noyl group, isohenicosanoyl group, branched alkanoyl group such as isodocosanoyl group,
Octenoyl group, nonyl group, decenoyl group, undecenoyl group, dodecenoyl group, tridecenoyl group, tetradecenoyl group, pentadecenoyl group, hexadecenoyl group, heptadecenoyl group, octadecenoyl group, nonadecenoyl group, eicosenoyl group, etc. And the like.

  The ascorbic acid derivative represented by the above formula (I) of the present invention can be produced by various known methods for acylating a mixture of ascorbic acid and an acylating agent. Examples include a method of mixing ascorbic acid and various acid chlorides, a method of mixing ascorbic acid and various acid anhydrides, and a method of mixing and acylating ascorbic acid and various carboxylic acids in concentrated sulfuric acid. it can. Further, it can be obtained by acylating a commercially available acylated ascorbic acid.

  For example, examples of the acid chloride include acetyl chloride, propionyl chloride, butanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride, dodecanoyl chloride, tridecanoyl chloride, tetradecanoyl chloride, and pentachloride. Decanoyl chloride, hexadecanoyl chloride, heptadecanoyl chloride, octadecanoyl chloride, nonadecanoyl chloride, eicosanoyl chloride, henicosanoyl chloride, docosanoyl chloride, 2-ethylhexanoyl chloride, 3-ethylhexanoyl Chloride, 5-methylheptanoyl chloride, 2-octyldecanoyl chloride, 17-methylheptadecanoyl chloride, isononanoyl chloride, isodecanoyl chloride, i Undecanoyl chloride, isododecanoyl chloride, isotridecanoyl chloride, isotetradecanoyl chloride, isopentadecanoyl chloride, isohexadecanoyl chloride, isoheptadecanoyl chloride, isononadecanoyl chloride, isoeicosa Noyl chloride, isohenicosanoyl chloride, isodocosanoyl chloride and the like can be used.

  Ascorbic acid used in the production of the ascorbic acid derivative or a salt thereof of the present invention may have either a S-configuration or an R-configuration in the configuration of carbon at the 4-position and 5-position.

  The type of solvent that can be used in the above reaction is not particularly limited. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), dioxane, and the like. Examples thereof include a solvent selected from acetonitrile, tetrahydrofuran (THF), pyridine and the like, or a mixed solvent thereof. Among them, aprotic solvents such as DMSO, DMF, dioxane, acetonitrile, THF and the like can be suitably used as solvents in which generation of by-products is small.

  In the ascorbic acid derivative produced as described above, when an acyl group having a different carbon chain is bonded to the hydroxyl group of ascorbic acid, column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, Purification by means of activated carbon treatment, extraction, distillation, crystallization, etc., and the resulting derivative is further reacted with an acylating agent having a different carbon chain to introduce an acyl group having a different carbon chain into ascorbic acid. . Also, the ascorbic acid derivative obtained by this method can be purified by the above-mentioned purification method.

  The amount of the ascorbic acid derivative to be added to the cosmetic or external preparation for skin of the present invention is not particularly limited, and the preferable range varies depending on the type of the cosmetic and external preparation for skin, but usually, the preferable range is, It is in the range of 0.001% by mass to 30.0% by mass. When the content is 0.001% by mass or less, the effect of promoting collagen production cannot often be sufficiently exhibited. On the other hand, if it exceeds 30.0% by mass, the dosage form may be broken. Further, when the ascorbic acid derivative is blended in the range of 0.01% by mass to 10.0% by mass, it is preferable to obtain an effect corresponding to the blending amount, and more preferably, 0.1% by mass to 5.0% by mass. % Range.

  In the cosmetic of the present invention, in addition to the ascorbic acid derivative which is an essential component (active ingredient), components commonly used in cosmetics and skin external preparations, for example, oily raw materials, surfactants, humectants, and polymers Compounds, antioxidants, whitening agents, ultraviolet absorbers, sequestering agents, protein hydrolysates, amino acids or their derivatives, pH adjusters, preservatives, thickeners, dyes and other agents are appropriately compounded. You.

  The agent system of the cosmetic or external preparation for skin of the present invention is optional, and any of a solution system, a solubilizing system, an emulsifying system, a gel system, a powder dispersion system, a water-oil two-layer system, and the like are possible, and The ascorbic acid derivative represented by the above general formula (I) and the above other components can be blended by a known method according to the type of the product to produce the compound.

  Next, specific embodiments for carrying out the present invention will be described with reference to examples, but the scope of the present invention is not limited to the following examples.

  First, a synthesis example of an ascorbic acid derivative used in a comparative example and a production example of an ascorbic acid derivative used in an example will be described. 2,6-Di-O-palmitoyl L-ascorbic acid, 6-O-palmitoyl L-ascorbic acid, 6-O-stearoyl L-ascorbic acid, phosphorus L-ascorbate used in Synthesis Examples, Production Examples and Test Examples Magnesium acid, 2-O-α-D-glucopyranosyl ascorbic acid and glyceryl ascorbic acid are reagents manufactured by Tokyo Chemical Industry Co., Ltd. 16-methylheptadecanoic acid is a reagent manufactured by Wako Pure Chemical Industries. Reagents were also used for other drugs except those described in the table.

Synthesis Example 1
Under argon atmosphere, DMSO (10 mL) was added to L-ascorbic acid (3.00 g) and stirred. Triethylamine (9.47 g) and acetic anhydride (9.56 g) were added with stirring, heated to 60 ° C., stirred for 3 hours, and extracted with ethyl acetate. And washed with water (the above is referred to as “synthesis step”). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 2.87 g of the obtained residue was subjected to silica gel column chromatography. Elution is performed with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → 1/5), and the mixture is concentrated under reduced pressure. 1.72 g of product was obtained.

This product was subjected to mass spectrometry under the following MASS analysis conditions, and the following peak was detected from the ESI mass spectrum.
Positive ion: 362 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5,6-tetra-O-acetylascorbic acid represented by the following structural formula.

[MASS analysis conditions]
Mobile phase:
5 mmol / L aqueous ammonium acetate solution: acetonitrile = 50:50
Flow rate: 0.2 mL / min
Detector voltage: 1.15 kV
Interface voltage: 4.5 kV
Heat block temperature: 200 ° C
Interface temperature: 300 ℃
Nebulizer gas: 1.5 L / min
Drying gas: 15 L / min
Ionization mode: ESI-positive or negative Measurement mode: Scan mode Sample introduction method: FID (direct sample introduction)

Synthesis Example 2
A synthesis step and a purification step were carried out in the same manner as in Synthesis Example 1 except that 9.56 g of acetic anhydride was replaced with 14.8 g of butanoic anhydride to obtain 5.18 g of a product. When this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 470 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5,6-tetra-O-butanoyl ascorbic acid represented by the following structural formula.

Synthesis Example 3
A synthesis step and a purification step were carried out in the same manner as in Synthesis Example 1 except that 9.56 g of acetic anhydride was replaced with 25.4 g of octanoic anhydride to obtain 5.52 g of a product. When this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 698 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5,6-tetra-O-octanoyl ascorbic acid represented by the following structural formula.

Synthesis Example 4
Synthetic process and purification were performed in the same manner as in Synthetic Example 1, except that 9.56 g of acetic anhydride was replaced with 17.4 g of pivalic anhydride, and the heating time at 60 ° C. was changed to 3 hours to 8 hours. The steps were performed to give 1.12 g of product. When this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 530 (equivalent to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5,6-tetra-O-pivaloyl ascorbic acid represented by the following structural formula.

Synthesis Example 5
Under an argon atmosphere, 10 mL of DMSO, 0.1 mL of water and 0.75 g of sodium hydroxide were added to 3.00 g of L-ascorbic acid and stirred, and 5.15 g of triethylamine and 9.49 g of pivalic anhydride were added with stirring. After warming to ℃ and stirring for 8 hours, the mixture was extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 4.86 g of the obtained residue was subjected to silica gel chromatography. The mixture was eluted with a mixed solution of chloroform / methanol / water (chloroform / methanol / water = 30/3 / 0.3 → 10/3 / 0.3) and concentrated under reduced pressure to obtain 1.05 g of the first product. I got

The same as in Synthesis Example 1 except that 1.05 g of the first product was used instead of 3.00 g of L-ascorbic acid, and the amount of triethylamine was changed to 0.77 g and the amount of acetic anhydride was changed to 0.78 g. Under the same conditions, the synthesis step and the purification step were performed in the same manner to obtain 0.31 g of a second product. This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 446 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 3,5-di-O-acetyl-2,6-pivaloyl ascorbic acid represented by the following structural formula.

Synthesis Example 6
The first product in Synthesis Example 5 except that 9.49 g of pivalic anhydride was replaced with 8.08 g of butanoic anhydride, the amount of triethylamine was changed to 5.13 g, and the stirring time at 60 ° C. was changed to 3 hours. 1.18 g of the first product was obtained in the same manner under the same conditions as when Same as Synthesis Example 1 except that 1.18 g of the first product was used in place of 3.00 g of L-ascorbic acid, and the amount of triethylamine was changed to 0.94 g and the amount of acetic anhydride was changed to 0.95 g. Under the same conditions, the synthesis step and the purification step were performed in the same manner to obtain 0.36 g of a second product. This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 418 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 3,5-di-O-acetyl-2,6-butanoyl ascorbic acid represented by the following structural formula.

Synthesis Example 7 (2,3,5,6-tetra-O-hexadecanoyl ascorbic acid)
Under an argon atmosphere, 10 mL of DMSO was added to 2,6-dipalmitoyl ascorbic acid (1.00 g), and the mixture was stirred. Triethylamine (0.30 g) and palmitic anhydride (1.47 g) were added with stirring. After heating and stirring for 3 hours, the mixture was extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 2.10 g of the obtained residue was subjected to silica gel column chromatography. Elution with a hexane / ethyl acetate mixture (hexane / ethyl acetate = 5/1 → 1/1 → 1/5), concentration under reduced pressure, and 2,3,5,6-tetra-O-hexadeca Noyl ascorbic acid (0.39 g) was obtained.

  The obtained product was subjected to mass spectrometry under the above-described MASS analysis conditions. As a result, the following peaks were obtained from the ESI mass spectrum. From the measurement results, it was confirmed that the product was 2,3,5,6-tetra-O-hexadecanoyl ascorbic acid represented by the following structural formula.

[ESI mass spectrum measurement result: detected peak]
Positive ion: 1146 (corresponding to [M + NH ₄ ] ⁺ )

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.88 (12 H, t), 1.25 (96 H, brs), 1.62 (8 H, m), 2.34 (4 H, t), 2. 44 (4H, t), 4.29 (1H, dd), 4.40 (1H, dd), 5.34 (1H, d), 5.49 (1H, dt-like)

Production Example 1
Under an argon atmosphere, 10 mL of DMSO was added to 3.00 g of 2,6-di-O-palmitoyl L-ascorbic acid and stirred, and while stirring, 1.39 g of triethylamine and 1.40 g of acetic anhydride were added, and the mixture was heated to 60 ° C. After stirring for 3 hours, the mixture was extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 3.15 g of the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → 1/5), and concentrated under reduced pressure to obtain 1.05 g of a product.

When 1.05 g of the obtained product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 754 (corresponding to [M + NH ₄ ] ⁺ )
In addition, ¹ H-NMR, ¹³ C-NMR measurement and infrared absorption spectrum measurement (IR measurement) were performed, and the following results were obtained. From these measurement results, it was confirmed that the product was 3,5-di-O-acetyl-2,6-di-O-hexadecanoyl ascorbic acid represented by the following structural formula.

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.85 (6H, t), 1.23 (48H, brs), 1.62 (4H, m), 2.03 (3H, s), 2. 24 (3H, s), 2.30 (2H, t), 2.49 (2H, t), 4.28 (1H, dd), 4.37 (1H, dd), 5.35 (1H, d) ), 5.45 (1H, dt-like),
¹³ C-NMR (100 MHz, CDCl ₃ ): δ ppm 14.1, 20.3, 20.4, 22.7, 24.5, 24.8, 28.9, 29.07, 29.15, 29. 2, 29.3, 29.4, 29.6, 31.9, 33.3, 34.0, 61.8, 66.4, 74.9, 122.1, 149.6, 164.7, 165.2, 169.1, 170.0, 173.1

[IR measurement result]
ATR (wave number cm ^-1 ) 2916,2849,1782,1557,1742,1231,1152,1099

Production Example 2
Except that 2,6-di-O-palmitoyl L-ascorbic acid was replaced with 3.00 g of 6-O-palmitoyl L-ascorbic acid, the amount of triethylamine was changed to 3.29 g, and the amount of acetic anhydride was changed to 3.33 g. In the same manner as in Production Example 1, the respective steps were carried out in the same manner to obtain 1.09 g of a product. When 1.09 g of this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 558 (corresponding to [M + NH ₄ ] ⁺ )
In addition, ¹ H-NMR, ¹³ C-NMR measurement and infrared absorption spectrum measurement (IR measurement) were performed, and the following results were obtained. From these measurement results, it was confirmed that the product was 2,3,5-tri-O-acetyl-6-O-hexadecanoyl ascorbic acid represented by the following structural formula.

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.85 (3H, t), 1.23 (24H, brs), 1.59 (2H, m), 2.02 (3H, s), 2. 23 (3H, s), 2.25 (3H, s), 2.30 (2H, t), 4.28 (1H, dd), 4.37 (1H, dd), 5.35 (1H, d) ), 5.46 (1H, dt-like)
¹³ C-NMR (100 MHz, CDCl ₃ ): δ ppm 14.1, 20.3, 20.4, 22.7, 24.8, 29.1, 29.2, 29.3, 29.4, 29. 6, 29.7, 31.9, 33.9, 61.8, 66.4, 74.9, 122.0, 149.8, 164.7, 165.1, 166.1, 170.0, 173.1

[IR measurement result]
ATR (wave number cm ^-1 ) 2916, 2851, 1771, 1738, 1240, 1219, 1150, 1093, 1057

Production Example 3
Under an argon atmosphere, 10 mL of DMSO, 0.1 mL of water and 0.75 g of sodium hydroxide were added to 3.00 g of 6-O-stearoyl L-ascorbic acid, and the mixture was stirred, and 5.15 g of triethylamine and stearic anhydride were added with stirring. After adding 37 g, the mixture was heated to 60 ° C., stirred for 8 hours, extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue (12.3 g) was subjected to silica gel chromatography. The mixture was eluted with a mixed solution of chloroform / methanol / water (chloroform / methanol / water = 30/3 / 0.3 → 10/3 / 0.3) and concentrated under reduced pressure to obtain 4.34 g of the first product. Was obtained (the step of obtaining the first product is referred to as reaction step 1).

  To the obtained 4.34 g of the first product, 15 mL of DMSO was added and stirred. Triethylamine (1.55 g) and acetic anhydride (1.56 g) were added with stirring, and the mixture was heated to 60 ° C. and stirred for 3 hours. , Extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → 1/5), and concentrated under reduced pressure to obtain 0.73 g of a second product (first product). The step of obtaining the second product from the product is referred to as reaction step 2).

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 810 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 3,5-di-O-acetyl-2,6-di-O-octadecanoyl ascorbic acid represented by the following structural formula.

Production Example 4
Except that 3.00 g of 6-O-palmitoyl L-ascorbic acid was used instead of 6-O-stearoyl L-ascorbic acid, the amount of triethylamine was changed to 1.10 g, and the amount of stearic anhydride was changed to 5.99 g. In the same manner, the reaction step 1 was performed under the same conditions as in Production Example 3 to obtain 1.53 g of a first product.
DMSO (10 mL) was added to the 1.53 g of the first product, followed by stirring. Thereafter, the same conditions as in Production Example 3 were used except that the amount of triethylamine was changed to 0.57 g and the amount of acetic anhydride was changed to 0.57 g. Reaction step 2 was performed in the same manner to obtain 0.31 g of a second product.
When this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 782 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 3,5-di-O-acetyl-6-O-hexadecanoyl-2-O-octadecanoyl ascorbic acid represented by the following structural formula.

Production Example 5
Same as Production Example 3 except that 3.00 g of L-ascorbic acid was used instead of 3.00 g of 6-O-stearoyl L-ascorbic acid and 19.5 g of lauric anhydride was used instead of stearic anhydride. Reaction step 1 was carried out under the same conditions and conditions to obtain 2.75 g of a first product. DMSO (10 mL) was added to this 2.75 g of the first product, and the mixture was stirred. Thereafter, the same conditions as in Production Example 3 were used except that the amount of triethylamine was changed to 1.29 g, and the amount of acetic anhydride was changed to 1.31 g. Reaction step 2 was performed in the same manner to obtain 0.64 g of a second product. When this product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, the following peaks were detected from the ESI mass spectrum.
Positive ion: 642 (equivalent to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 3,5-di-O-acetyl-2,6-di-O-dodecanoyl ascorbic acid represented by the following structural formula.

Production Example 6
Under an argon atmosphere, 10 mL of DMSO was added to 3.00 g of 6-O-palmitoyl L-ascorbic acid and stirred. 1.61 g of triethylamine and 1.63 g of acetic anhydride were added with stirring, and the mixture was heated to 60 ° C. and stirred for 8 hours. Then, the mixture was extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a mixed solution of chloroform / methanol / water (chloroform / methanol / water = 30/3 / 0.3 → 10/3 / 0.3) and concentrated under reduced pressure to obtain 1.18 g of the first product. Was obtained (the step of obtaining the first product is referred to as reaction step 1).

To the obtained 1.18 g of the first product, 10 mL of DMSO is added and stirred. Triethylamine (0.26 g) and palmitic anhydride (1.29 g) are added with stirring, and the mixture is heated to 60 ° C. and stirred for 3 hours. Then, the mixture was extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography. The mixture was eluted with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → 1/5), and concentrated under reduced pressure to obtain 0.47 g of a second product (first product). The step of obtaining the second product from the product is referred to as reaction step 2). This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 754 (corresponding to [M + NH ₄ ] ⁺ )
In addition, ¹ H-NMR and ¹³ C-NMR measurements were performed, and the following results were obtained. From these measurement results, it was confirmed that the product was 2,5-di-O-acetyl-3,6-di-O-hexadecanoyl ascorbic acid represented by the following structural formula.

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.88 (6H, t), 1.25 (48H, brs), 1.63 (4H, m), 2.04 (3H, s), 2. 25 (3H, s), 2.35 (2H, t), 2.52 (2H, t), 4.31 (1H, dd), 4.39 (1H, dd), 5.37 (1H, d) ), 5.47 (1H, dt-like),
¹³ C-NMR (100 MHz, CDCl ₃ ): δ ppm 14.1, 20.1, 20.4, 22.7, 24.2, 24.7, 24.8, 28.81, 28.88, 29. 06, 29.10, 29.17, 29.20, 29.25, 29.38, 29.44, 29.59, 29.67, 29.70, 31.9, 33.5, 33.97, 34.03, 35.3, 61.8, 66.4, 75.0, 121.8, 150.0, 165.3, 166.1, 167.8, 169.9, 173.1, 179. 9

Production Example 7
Under an argon atmosphere, 3.00 g (17.0 mmol) of L-ascorbic acid and 7.24 g of stearic acid were added to 30 g of concentrated sulfuric acid, and the mixture was stirred at room temperature for 2 hours. Then, the reaction solution was slowly stirred in 500 mL of water. After addition, the aqueous phase was removed and extracted with ethyl acetate and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 8.70 g of the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a mixed solution of chloroform / methanol / water (chloroform / methanol / water = 30/3 / 0.3 → 10/3 / 0.3) and concentrated under reduced pressure to obtain 1.88 g of the first product. Was obtained (the step of obtaining the first product is referred to as reaction step 1).

  To the obtained first product (1.88 g) was added 10 mL of DMSO, and the mixture was stirred. 1.93 g of acetic anhydride and 1.92 g of triethylamine were added with stirring, and the mixture was heated to 60 ° C. and stirred for 3 hours, and then ethyl acetate was added. And extracted and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 2.91 g of the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → /), and concentrated under reduced pressure to obtain 0.51 g of a second product (first product). The step of obtaining the second product from the product is referred to as reaction step 2).

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 586 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5-tri-O-acetyl-6-O-octadecanoyl ascorbic acid represented by the following structural formula.

Production Example 8
Reaction step 1 was carried out in the same manner as in Production Example 7 except that 5.1 g of lauric acid was used instead of 7.24 g of stearic acid, to obtain 2.29 g of a first product. After adding 10 mL of DMSO to 2.29 g of the obtained first product and stirring, the same conditions as in Production Example 7 were used except that the amount of acetic anhydride was changed to 2.11 g and the amount of triethylamine was changed to 2.09 g. Reaction step 2 was performed in the same manner to obtain 0.57 g of a second product.

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 516 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5-tri-O-acetyl-6-O-dodecanoyl ascorbic acid represented by the following structural formula.

Production Example 9
Except that 7.25 g of 16-methylheptadecanoic acid (isostearic acid) was used instead of stearic acid, reaction step 1 was performed in the same manner as in Production Example 7 under the same conditions to obtain 1.80 g of a first product. . After adding 10 mL of DMSO to the obtained 1.80 g of the first product and stirring, the same conditions as in Production Example 7 were used except that the amount of acetic anhydride was changed to 1.87 g and the amount of triethylamine was changed to 1.85 g. Reaction step 2 was performed in the same manner to obtain 0.47 g of a second product.

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 586 (corresponding to [M + NH ₄ ] ⁺ )
From this measurement result, it was confirmed that the product was 2,3,5-tri-O-acetyl-6-O- (16-methylheptadecanoyl) ascorbic acid represented by the following structural formula.

Production Example 10
Instead of 3.00 g of 6-O-palmitoyl L-ascorbic acid, 3.00 g of 2,6-di-O-palmitoyl L-ascorbic acid was used, the amount of triethylamine was 0.51 g, and the amount of acetic anhydride was 0.1 g. Reaction step 1 was carried out in the same manner as in Production Example 6 except that the amount was changed to 47 g, to obtain 1.28 g of a first product. After adding 10 mL of DMSO to the obtained 1.28 g of the first product and stirring, the same as in Production Example 6 except that the amount of triethylamine was changed to 0.18 g and the amount of palmitic anhydride to 0.95 g. Under the same conditions, the reaction step 2 was carried out in the same manner to obtain 0.34 g of a second product.

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 950 (corresponding to [M + NH ₄ ] ⁺ )
In addition, ¹ H-NMR and ¹³ C-NMR measurements were performed, and the following results were obtained. From these measurement results, it was confirmed that the product was 5-O-acetyl-2,3,6-tri-O-hexadecanoyl ascorbic acid represented by the following structural formula.

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.88 (9H, t), 1.26 (72H, brs), 1.63 (6H, m), 2.02 (3H, s), 2. 35 (4H, s), 2.51 (2H, s), 4.30 (1H, dd), 4.39 (1H, dd), 5.36 (1H, m), 5.48 (1H, m) )
¹³ C-NMR (100 MHz, CDCl ₃ ): δ ppm 14.1, 0.3, 22.7, 24.2, 24.6, 24.7, 24.8, 24.85, 28.91, 29. 06, 29.10, 29.25, 29.38, 29.44, 29.60, 29.68, 29.70, 31.9, 33.3, 33.5, 34.0, 61.8, 66.4, 74.9, 121.9, 149.8, 165.3, 167.8, 169.1, 169.9, 173.1, 179.7

Production Example 11
Under an argon atmosphere, 10 mL of DMSO was added to 3.00 g of L-ascorbic acid, and the mixture was stirred. 2.58 g of triethylamine and 10.4 g of oleic anhydride were added with stirring, and the mixture was heated to 60 ° C. and stirred for 3 hours. Extracted with ethyl and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. Elution with a mixed solution of chloroform / methanol / water (chloroform / methanol / water = 30/3 / 0.3 → 10/3 / 0.3), concentration under reduced pressure, and 1.84 g of the first product I got

  To the obtained 1.84 g of the first product, 10 mL of DMSO was added and stirred, and 1.39 g of triethylamine was added with stirring, 1.49 g of acetic anhydride was added, and the mixture was heated to 60 ° C. and stirred for 3 hours. Extracted with ethyl and washed with water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The mixture was eluted with a hexane / ethyl acetate mixed solution (hexane / ethyl acetate = 5/1 → 1/1 → 1/5) and concentrated under reduced pressure to obtain 0.49 g of a second product.

This second product was subjected to mass spectrometry under the same MASS analysis conditions as in Synthesis Example 1, and the following peaks were detected from the ESI mass spectrum.
Positive ion: 566 (equivalent to [M + NH ₄ ] ⁺ )
In addition, ¹ H-NMR and ¹³ C-NMR measurements were performed, and the following results were obtained. From these measurement results, it was confirmed that the product was 2,3,5-tri-O-acetyl-6-O- (9,10-octadecenoyl) ascorbic acid represented by the following structural formula.

[Analysis result by NMR]
¹ H-NMR (400 MHz, CDCl ₃ ): δ ppm 0.88 (3H, t), 1.27 / 1.31 (72H, brs), 1.68 (2H, m), 2.02 (2H, m) ), 2.06 (3H, s), 2.09 (3H, s), 2.26 (3H, s), 2.52 (2H, t), 4.31 (1H, dd), 4.41 (1H, dd), 5.34 (2H, m) 5.38 (1H, m), 5.49 (1H, dt-like)
¹³ C-NMR (100 MHz, CDCl ₃ ): δ ppm 14.1, 20.36, 20.40, 20.67, 22.7, 24.5, 27.15, 27.22, 28.8, 29. 1,9.3,29.5,29.7,29.8,31.9,33.3,62.1,66.4,74.9,122.1,129.7,130.1, 130.3, 149.6, 164.7, 165.2, 169.1, 170.1, 170.3

Test Example 1: Collagen production promotion evaluation test The ascorbic acid derivatives of Synthesis Examples 1 to 7 are Comparative Examples 1 to 7, the ascorbic acid derivatives of Production Examples 1 to 11 are Examples 1 to 11, and a commercially available ascorbic acid The derivatives L-ascorbic acid, magnesium phosphate L-ascorbate, 2-O-α-D-glucopyranosyl ascorbic acid, glyceryl ascorbic acid and 6-O-palmitoyl L-ascorbic acid were compared with Comparative Examples 8 to The collagen production promoting effect of each was evaluated by the following method.

[Collagen production promotion evaluation test method]
Normal human dermal fibroblasts were seeded at 2.5 × 10 ⁴ cells / well in a 96-well plate using a D-MEM medium containing 5% fetal bovine serum (hereinafter referred to as FBS). Culture was performed for 24 hours under% CO ₂ , and after the culture, the medium was removed. D-MEM medium, which was added and adjusted so that the sample had a predetermined concentration, was added to each well, and the cells were further cultured for 48 hours. After completion of the culture, the type I collagen in the culture supernatant was measured by ELISA assay. The group in which the ascorbic acid derivative was not used was taken as a control group, and the collagen production promotion rate of each test culture solution was calculated, assuming that the collagen production promotion amount of the control group was 100%. The collagen production promotion rate is shown in parentheses in the column of “Judgment” in Tables 1 and 2.

The collagen production promotion rate when the test sample was applied at 0.1 μmol / L or 1 μmol / L was determined based on the following, and the results are shown in Tables 1 and 2.
Less than 200%: ±
200% or more and less than -350%: +
350% or more and less than -500%: ++
500% or more: +++

  The ascorbic acid derivatives used in Example 1 and Examples 3 to 6 are ascorbic acid derivatives having two acetyl groups in the molecule and having an alkanoyl group having 12 to 18 carbon atoms. Examples 2 and 7 9 to 11 are ascorbic acid derivatives having three acetyl groups in the molecule and having an alkanoyl group or an oleinoyl group having 12 to 18 carbon atoms (Example 11), and Example 10 has one acetyl group in the molecule. This is an ascorbic acid derivative having three hexadecanoyl groups each having 17 carbon atoms. All of these ascorbic acid derivatives show excellent collagen production promoting effects, and among them, ascorbic acid derivatives having an acyl group (alkanoyl group or alkenoyl group) having 16 or 18 carbon atoms (Examples 1 to 4, In Example 7, Example 9, and Example 11), the collagen production promoting effect was particularly excellent.

  On the other hand, the ascorbic acid derivatives used in Comparative Examples 1, 5, and 6 have an acetyl group in the molecule but do not have an alkanoyl group having 7 or more carbon atoms. The ascorbic acid derivatives used in Comparative Examples 2 to 4 and 7 have no acetyl group in the molecule. These ascorbic acid derivatives and commercially available ascorbic acid derivatives (Comparative Examples 8 to 12) did not have an excellent collagen-producing effect at the low concentrations performed in this test. From these facts, an ascorbic acid derivative having an acetyl group in the molecule and having an alkanoyl group or an alkenoyl group having 7 or more carbon atoms has an excellent collagen production promoting effect, and has an excellent collagen production promoting agent ( Cosmetics, external preparations for skin).

Test Example 2: Actual use test (emulsion)
Emulsions having the compositions shown in Table 3 (the numbers in the table are represented by mass%) were prepared and evaluated for wrinkles, skin abrasions, elasticity, and low bulk after continuous use for 2 months. In Example 12, the ascorbic acid derivative of Production Example 1 was used, and in Comparative Example 13, a commercially available L-ascorbic acid was used.

  In the test using the above-mentioned emulsion, the emulsions A and B were applied twice a day (morning and evening) to the right and left sides of the face twice as emulsions A and B, respectively, without revealing the examples and comparative examples to 10 subjects. 2 g was applied (the coated surface of A and the coated surface of B were always the same), and the continuous use test was continued for 2 months. After the end of the two-month continuous use test, each subject was allowed to self-evaluate wrinkles, beams, elasticity, and lack of stiffness of each item based on the following criteria.

Wrinkle:
3: Feel that the area and depth of wrinkles are improved as compared to before continuous use.
2: It is felt that the area and depth of wrinkles are slightly improved as compared to before continuous use.
1: Little change or deterioration compared to before continuous use.
Needle:
3: Feel that skin firmness around the corners of the eyes and around the cheeks was improved compared to before continuous use.
2: It feels that the tension of the skin around the corners of the eyes and around the cheeks is slightly improved as compared to before the continuous use.
1: Little change or deterioration compared to before continuous use.
Elasticity:
3: Feel that the elasticity of the skin has improved compared to before continuous use.
2: It feels that the elasticity of the skin is slightly improved compared to before the continuous use.
1: Little change or deterioration compared to before continuous use.
No bulkiness:
3: Feel that the moisture of the skin increased and improved as compared to before the continuous use.
2: Feel that the moisture of the skin was slightly improved compared to before continuous use.
1: Little change or deterioration compared to before continuous use.

The total of the evaluation results of 10 persons was classified as follows. Table 4 shows the results.
Less than 15: ±
15 or more and less than -20: +
20 or more and less than -25: ++
25 or more: +++

  As shown in Table 4, when the latex containing the ascorbic acid derivative as the collagen production promoter of the present invention was continuously used (Example 12), it was excellent in all items such as wrinkles, beams, elasticity and non-bulkness. Improvements were confirmed. On the other hand, when the collagen production promoter of the present invention was not added (Comparative Example 13), no improvement effect was observed by continuous use. Therefore, it was confirmed that the ascorbic acid derivative as the collagen production promoter of the present invention has a collagen production promotion effect that is particularly excellent as compared with existing ascorbic acid.

Test Example 3: Actual use test (cream)
A cream having the composition shown in Table 5 (the numbers in the table are% by mass) was prepared, and the wrinkles, skin swelling, elasticity, and lack of bulk after continuous use for 2 months were evaluated. In Example 13, the ascorbic acid derivative of Production Example 2 was used, and in Comparative Example 14, a commercially available glyceryl ascorbic acid was used.

  The test using the cream described above did not reveal the examples and comparative examples to 10 subjects. As creams A and B, the cream of A or B was applied to the entire right and left sides of the face twice daily (morning and evening). 2 g was applied (the coated surface of A and the coated surface of B were always the same), and the continuous use test was continued for 2 months. After completion of the continuous use test for 2 months, each subject was allowed to self-evaluate wrinkles, beams, elasticity, and non-bulkness based on the same criteria as in Test Example 2 above for each item compared to before continuous use, and the evaluation results Were classified in the same manner as in Test Example 2. Table 6 shows the results.

  As shown in Table 6, when the emulsion containing the ascorbic acid derivative which is the collagen production promoter of the present invention was continuously used (Example 13), the wrinkles, the beams, the elasticity, and the non-bulkness were all observed. Excellent improvement was confirmed. On the other hand, when the collagen production promoter of the present invention was not added (Comparative Example 14), no improvement effect was observed by continuous use. Therefore, it was confirmed that the ascorbic acid derivative as the collagen production promoter of the present invention has a collagen production promotion effect that is particularly excellent as compared with existing ascorbic acid.

Test Example 4: Oil solubility test For the ascorbic acid derivatives shown in Table 7, the solubility of squalane, liquid paraffin, and tri (caprylic / capric acid) glyceryl in various oils was confirmed. An oil agent was added so that the concentration of various ascorbic acid derivatives became 10% by mass, and the mixture was stirred at room temperature for 10 minutes. The appearance of each sample after stirring was evaluated according to the following criteria. As the ascorbic acid derivative of the comparative product, a commercial product was used as in Test Example 1.

：: Clear state, no melting left.
：: Almost dissolved, with some undissolved residue.
Δ: Slightly dissolved.
×: Remains almost undissolved.

  The collagen production promoter comprising the ascorbic acid derivative of the present invention can be used by blending it into cosmetics for the purpose of improving wrinkles, skin sticking, elasticity and bulkiness. Table 8 shows examples of oil preparations (Cosmetic Application Example 1) and Table 9 shows examples of gel preparations (Cosmetic Application Example 2) as formulation examples of cosmetics containing the collagen production promoter of the present invention.

Claims (5)

A cosmetic or external preparation for skin comprising an ascorbic acid derivative represented by the following general formula (I) as an active ingredient.

[Wherein, R ¹ , R ² , R ³ and R ⁴ each independently represent an alkyl group having 1 to 3 carbon atoms, or a linear or branched alkyl group or alkenyl group having 7 to 21 carbon atoms. It is. ^However, at least one of the groups R ^1, R ^2, R 3, ^{R 4} is an alkyl group having 1 to 3 carbon ^atoms, R ^1, R ^2, R 3, at least one group ^{R 4} is a straight-chain Alternatively, it is a branched alkyl group or alkenyl group having 7 to 21 carbon atoms. ] R ¹ in the general formula (I) is a linear or branched alkyl group or alkenyl group having 7 to 19 carbon atoms, R ² is a methyl group, and R ³ and R ⁴ are a methyl group The cosmetic or external preparation for skin according to claim 1, which contains, as an active ingredient, an ascorbic acid derivative which is a linear or branched alkyl group or alkenyl group having 7 to 19 carbon atoms. R ¹ in the general formula (I) is a linear or branched alkyl group having 11 to 17 carbon atoms, R ² is a methyl group, and R ³ and R ⁴ are a methyl group or a linear group. The cosmetic or external preparation for skin according to claim 1, comprising an ascorbic acid derivative which is an alkyl group having 11 to 17 carbon atoms as an active ingredient. Cosmetic or skin external preparation containing ascorbic acid derivative represented by the following structural formula (A) or (B) as an active ingredient

[Wherein, R ⁶ is a linear alkyl group having 13 to 17 carbon atoms. ]   The cosmetic or external preparation for skin according to any one of claims 1 to 4, wherein the external preparation contains 0.001 to 30% by mass of the ascorbic acid derivative.