JP3826132B2 - Wrinkle improving agent - Google Patents

Description

  The present invention relates to a wrinkle-improving agent containing farnesyl acetate having an effect of improving wrinkles generated at an exposed site with aging, and having an effect of keeping the skin in a dermatological and cosmetically healthy state.

  Organs of all living organisms including humans are born and grow, then gradually decline with age, eventually stop functioning, and die when a certain part of the function is stopped. A state in which the function gradually declines is called aging. The skin is directly affected by the surrounding environment, and since it has an important function to maintain the environment inside the living body, it is unlikely that everything will stop functioning, but aging such as wrinkles, spots, dullness, tarmi, etc. This is an organ in which signs are easily manifested, and is particularly prominent in exposed areas exposed to sunlight.

  As skin aging progresses, defense against stimuli such as oxidative stress is weakened, causing the internal environment of the skin to be disturbed and further aging. In particular, since the exposed part is constantly exposed to strong oxidative stress caused by ultraviolet irradiation or the like, the progress of aging is remarkable. Such skin changes are called photoaging. In such skin, the epidermis is thickened, and the collagen, which is the major component in the dermis, decreases, causing wrinkles deeper and larger on the skin surface. This is also unfavorable for cosmetic purposes.

In the United States, retinoic acid is used as a prescription drug as a substance that has an improvement effect on wrinkles caused by the progress of photoaging, but it has not been approved in Japan because of its side effects and safety issues. . In addition, retinol (vitamin A), which is said to be converted into retinoic acid after being absorbed into the body and exert its effect, ascorbic acid (vitamin C) having an antioxidant and collagen synthesis promoting effect, and tocopherol having a strong antioxidant effect ( Vitamin E) and the like have been proposed as wrinkle-improving substances (see, for example, Patent Document 1 and Patent Document 2), but these have a drawback that a sufficiently satisfactory effect cannot be obtained. Therefore, there has been no substance that has a sufficiently satisfactory effect and safety as a substance for improving wrinkles so far.
JP 7-165567 A JP 62-164609 A

  An object of the present invention is to provide a wrinkle characterized by blending farnesyl acetate, which has an excellent effect of improving wrinkles that are noticeably manifested by aging, and has an effect of maintaining cosmetically healthy skin. It is to provide an improving agent.

（但し、式中Ｒは炭素原子数１〜９の直鎖又は分岐鎖状の、飽和又は不飽和炭化水素基を示す）で表されるファルネシル酢酸エステルの少なくとも一種以上を配合することを特徴とするシワ改善剤にある。 As a result of intensive studies in view of the above circumstances, the present inventors have improved the wrinkle that appears prominently at the exposed site due to aging, and the effect of keeping the skin healthy cosmetically. And it was confirmed that it was excellent in safety, and the present invention was completed. That is, the present invention provides the following general formula (1)

(Wherein R represents a straight-chain or branched, saturated or unsaturated hydrocarbon group having 1 to 9 carbon atoms) and at least one kind of farnesyl acetate represented by: It is in the wrinkle improving agent.

  INDUSTRIAL APPLICABILITY The present invention can provide a wrinkle improving agent that is excellent in improving wrinkles that occur particularly in exposed areas with aging and that keeps the skin in a dermatological and cosmetically healthy state.

  Hereinafter, embodiments of the present invention will be described in detail. Farnesyl acetate is an ester of farnesyl acetic acid (5,9,13-trimethyl-4,8,12-tetradecatrienoic acid) and a linear or branched saturated or unsaturated alcohol having 1 to 9 carbon atoms. . Examples of linear or branched saturated or unsaturated alcohols having 1 to 9 carbon atoms include methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, pentanol, 2-pentanol, and 3-pen. Tanol, 2-methylbutanol, dimethylpropanol, hexanol, heptanol, octanol, 2-ethylhexanol, 4-ethylhexanol, nonanol, allyl alcohol, crotyl alcohol, 2-butenol, 2-pentenol, 3-hexenol, 2- Examples include heptenol, phenol and benzyl alcohol.

  In the general formula (1), the hydrocarbon group represented by R has 1 to 9 carbon atoms, and more preferably the hydrocarbon group has 1 to 5 carbon atoms. When the number of carbon atoms of the hydrocarbon group exceeds 9, the solubility is poor and it is not preferable from the viewpoint of use. These farnesyl acetates can be used as they are commercially available as they are or after being purified by a conventional method such as distillation, and can be used from farnesyl acetate and various alcohols by a known esterification method or commercially available. It can be easily synthesized by a transesterification reaction from farnesyl acetic acid geranyl ester.

  These farnesyl acetates may be blended singly or in combination of two or more. Further, the blending amount of these farnesyl acetates is preferably 0.001 to 10.0% by mass (hereinafter simply referred to as%) based on the total amount of the wrinkle improving agent. If the blended amount of farnesyl acetate is less than 0.001%, the intended effect of the present invention may not be sufficiently obtained. Even if the blended amount exceeds 10.0%, the effect commensurate with the increased amount. In some cases, improvement cannot be expected, and the feeling during use tends to be poor and the formulation tends to be hindered.

  The wrinkle improving agent of the present invention can be applied as a skin cosmetic or an external preparation to pharmaceuticals, bathing agents, etc., and the dosage form can be, for example, lotions, emulsions, creams, packs and the like. In addition to the above, a coloring matter, a fragrance, a preservative, a surfactant, a pigment, an antioxidant and the like can be appropriately blended with the wrinkle improving agent of the present invention as long as the object of the present invention is achieved.

  Hereinafter, the present invention will be described in detail based on examples and comparative examples.

Production Example 1 (farnesyl acetate methyl ester)
Sodium metal (252 mg) was added to methanol (150 mL), and the mixture was stirred at room temperature for 30 minutes to prepare sodium ethoxide. A methanol solution (50 mL) of farnesyl acetic acid geranyl ester (3.01 g) was added thereto, and the mixture was stirred for 15 hours while heating under reflux. After cooling to room temperature, the mixture was neutralized by adding acetic acid (0.70 mL). The residue obtained by concentration under reduced pressure was diluted with ethyl acetate, and this was filtered to remove precipitated sodium acetate. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (hexane: ethyl acetate = 50: 1) and distillation under reduced pressure to obtain 1.15 g of farnesyl acetate methyl ester as a colorless oil.

Production Example 2 (farnesyl acetic acid butyl ester)
Sodium metal (246 mg) was added to butanol (150 mL), and the mixture was stirred at room temperature for 60 minutes to prepare sodium butoxide. A butanol solution (50 mL) of farnesyl acetic acid geranyl ester (3.01 g) was added thereto and stirred at 110 ° C. for 15 hours. After cooling to room temperature, the mixture was neutralized by adding acetic acid (0.70 mL). The residue obtained by concentration under reduced pressure was diluted with diethyl ether, and this was filtered to remove precipitated sodium acetate. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (hexane: ethyl acetate = 50: 1) and distillation under reduced pressure to obtain 1.00 g of farnesyl acetate butyl ester as a colorless oil.

Example 1 (Farnesyl acetate methyl ester-containing wrinkle improving agent)
The wrinkle improving agent blended with farnesyl acetic acid methyl ester of Production Example 1 was applied to photoaged skin, and the wrinkle improving effect was examined by the following test method.

(Test method)
1. Experimental animals One group of 10 hairless mice aged 10 weeks at the start of the test was used.

2. 2. Measurement of wrinkle improvement effect 2-1. Photoaging conditions Photoaging was induced by irradiating UVA and UVB once a day, 5 times a week for 8 weeks. Irradiation dose, UVA is increased with ^{20J / cm 2, 25J / cm} 2, 30J / cm 2, UVB is ^{20mJ / cm 2, 30mJ / cm} 2, 40mJ / cm 2, an irradiation amount for each 1 week, 3 After week, the maximum dose was irradiated.

2-2. Evaluation method of wrinkle improvement effect The wrinkle improvement effect was evaluated by the wrinkle score and skin thickness. The wrinkle score was scored according to the method of Bissett et al. (Photochem. Photobiol. 46: 367-378, 1987). That is, the size and depth of the wrinkle are comprehensively evaluated with the naked eye, 3 indicating that “a large and deep wrinkle can be confirmed”, 2 indicating “a wrinkle can be confirmed”, 1 indicating “a wrinkle cannot be confirmed”, and “normal” “The texture is observed” was scored on a scale of 0. The skin thickness was measured by collecting the skin of all layers and preparing a skin slice sample according to a standard method, then staining with hematoxylin and eosin, and measuring the thickness of the epidermis with image analysis software (Microanalyzer, manufactured by Pola Digital Japan). .

2-3. Sample and Operation A sample was prepared by blending the 50% ethanol aqueous solution (base) with 1.0% farnesyl acetate obtained in Production Example 1 (Example 1). A sample containing only the base was used as Comparative Example 1.
First, 0.1 mL of these samples were applied to the back skin of a hairless mouse (diameter: about 2.5 cm) once a day at a frequency of 5 times a week from the fifth week after the start of UV irradiation to the fourth week after the end of irradiation. Applied. And after completion | finish of application | coating, the wrinkle score was scored, after slaughtering, the skin was extract | collected and epidermis thickness was measured. Both the wrinkle score and the skin thickness were compared using the base (Comparative Example 1) application group as a control.

(Wrinkle score evaluation result)
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Group Wrinkle score (value is mean ± SE)
-------------------------
Example 1 application group 2.15 ± 0.09
Comparative Example 1 application group 2.55 ± 0.11
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  The wrinkle improving agent application group of Example 1 showed a significantly lower wrinkle score value compared to the Comparative Example 1 application group, indicating that farnesyl acetate was effective against wrinkles induced by photoaging.

(Skin thickness measurement result)
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Group skin thickness (μm, values are mean ± SE)
-------------------------
Example 1 application group 36.88 ± 3.14
Comparative Example 1 Application Group 41.16 ± 2.60
-------------------------

  In the wrinkle improving agent application group of Example 1, the skin thickness is significantly thinner than that in the Comparative Example 1 application group, and farnesyl acetate has an effect of reducing the thickness on the skin thickened by photoaging. Indicated. In addition, when retinoic acid is applied to this test system, it is effective for the wrinkle score and collagen content, but the skin thickness works in the direction of increasing thickening, and this action is one factor that raises safety concerns. It was. In comparison, farnesyl acetic acid methyl ester had no such effect, and there was no problem in normal safety tests.

Example 2 (farnesyl butyl ester-containing wrinkle improving agent)
About the wrinkle improving agent which mix | blended farnesyl acetic acid butyl ester of manufacture example 2, when the wrinkle improvement effect was confirmed by the test similar to the said Example 1, compared with the comparative example 1 application group which is a control | contrast, it is significant in a wrinkle score value. The skin thickness was significantly lower in the skin thickness.

  From the above results, it was shown that the wrinkle improving agent containing the farnesyl acetate of Examples 1 and 2 clearly has an effect of improving wrinkles due to photoaging as compared with Comparative Example 1.

Example 3, Comparative Example 2 (skin lotion)
Skin lotions (Example 3, Comparative Example 2) having the following composition were prepared according to the following preparation method, and the wrinkle improvement effect was evaluated according to the following using the samples as samples.
Five healthy subjects with wrinkles in the corners of the eyes (female, 44-55 years old) were used as subjects, and the skin lotions of Example 3 and Comparative Example 2 were determined to be either left or right, after washing in the morning, and Twice a day after bathing in the evening for 2 months (60 days), apply about 0.2 mL of wrinkles on the corner of the eye (about 4 cm ² , 2 x 2 cm centered on the corner of each eye for each sample). It was. Then, after the final application, they were asked to answer a questionnaire regarding the condition of the skin (wrinkles) on the left and right eye corners.

(composition)
Ingredients Component Amount (%)
Component A (1) Olive oil 10.0
(2) Isopropyl myristate 1.0
(3) Monolauric acid polyoxyethylene (20) sorbitan 0.5
(4) Propylene glycol 1.0
(5) Glycerin 2.0
Component B (6) Methylparaben 0.1
(7) Ethanol 7.0
(8) Purified water remaining amount C component (9) Farnesyl acetic acid methyl ester 2.0 (Example 3)
Or 0 (Comparative Example 2)

(Manufacturing method)
The farnesyl acetic acid methyl ester of component C was added to component B and uniformly dissolved, then component A was added, mixed, stirred and dispersed, and then filled into a container. During use, the contents were uniformly shaken and dispersed.

  Based on the questionnaire results, the number of respondents who answered that the skin lotion of Example 3 is more effective than Comparative Example 2 for each item regarding the state of skin (wrinkles) is shown below.

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Item Number of people
-------------------
Wrinkles are less noticeable 5
The skin became soft 4
The skin got firmer 5
Shining on the skin 3
My skin became moist 4
-------------------

  From this test result, it can be seen that the skin lotion of Example 3 clearly improved the wrinkles as compared with Comparative Example 2, and further improved the flexibility and color tone deteriorated by photoaging. In addition, skin abnormalities such as irritation and itching due to the skin lotion of the present invention were not observed.

Example 4 (skin cream)
A skin cream blended with farnesyl acetate methyl ester of Production Example 1 was prepared by the following composition and production method.

(composition)
Ingredients Component Amount (%)
A component (1) dense wax 2.0
(2) Stearic acid 5.0
(3) Stearyl alcohol 5.0
(4) Reduced lanolin 2.0
(5) Squalene 20.0
(6) Monostearate sorbitan 3.0
(7) Monostearate Polyoxyethylene (20) Sorbitan 3.0
(8) Propylene glycol 5.0
Component B (9) Methylparaben 0.2
(10) Purified water remaining amount C component (11) farnesyl acetic acid methyl ester 2.0

(Manufacturing method)
After blending C component farnesyl acetic acid methyl ester into component B, each of components A and B was heated and dissolved at 80 ° C., mixed and stirred, and cooled to 30 ° C. to prepare a skin cream.

  Twenty healthy persons (women, 50-55 years old) who listed wrinkles in the corners of their eyes as a skin problem in a preliminary questionnaire were asked to use the skin cream for over a week. The following items were surveyed on the wrinkle condition, and the number of people who answered that they thought so after using each item compared to before using was shown below.

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Item Number of people
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Wrinkles are less noticeable 19
Wrinkle size decreased 17
Number of wrinkles decreased 5
Increased wrinkles 0
-------------------

  From this test result, the skin cream of Example 4 is almost all humans who feel that wrinkles are less noticeable than before use, and the factor is that the size of wrinkles is reduced rather than the number of wrinkles. It can be seen that wrinkles due to photoaging were improved. In addition, skin abnormalities such as irritation and itching with the skin cream of the present invention were not observed.

It can be applied to skin care cosmetics and external preparations, such as pharmaceuticals and baths, and can be formulated into lotions, milks, creams, packs, etc. Very useful.

Claims (1)

The following general formula (1)

(Wherein R represents a straight-chain or branched, saturated or unsaturated hydrocarbon group having 1 to 9 carbon atoms) and at least one kind of farnesyl acetate represented by: Wrinkle improving agent.