JPH01163110A - Preventive for aging of skin - Google Patents

Abstract

PURPOSE:To provide a skin-aging preventing agent having excellent stability, safety and applicability and containing a compound selected from sialic acid and its derivative such as N-acetylneuraminic acid extracted from milk. CONSTITUTION:The objective skin-aging preventing agent contains 0.001-5wt.% of one or more compounds selected from sialic acid (e.g., N-acetylneuraminic acid) and sialic acid derivative (e.g., oligosaccharide bonded with sialic acid, protein bonded with sialic acid, lipid bonded with sialic acid or sialic acid salt). The sialic acid and its derivative are preferably extracted at a low cost from cow's milk, sheep milk, human milk, etc. The purification degree is selected according to the method of application, use, type of the agent and other purposes since the concentration of sialic acid can be freely controlled by the degree of purification.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a skin aging prevention agent (used for skin aging prevention).
Regarding. In detail, the skin aging prevention effect (improving rough skin, keratin improvement effect, speeding up skin turnover rate, improving skin dullness, sagging, firmness, luster, hardening, etc., skin revitalizing effect, moisturizing effect, etc.) ).

[Conventional technology]

Regarding the aging phenomenon of skin Y9 (a phenomenon often seen in the elderly) due to aging, the appearance of dullness, wrinkles, and spots increase macroscopically at -1m, and the skin becomes dry, and as a result, the so-called skin moisture, luster, It is known to cause functional changes such as a decrease in smoothness, softness, firmness, etc. In addition, skin diseases that are frequently seen in the elderly (diseases that are often seen in the elderly) include senile pigment spots, senile xeroderma, senile vitiligo,
Examples include senile warts, senile neurofibroma, senile acne, and senile sebaceous gland hyperplasia. Furthermore, it is known that cancer precursors (actinic keratosis, skin horns, Bowen's disease, lentigo maligna), skin irritation, and malignant tumors such as malignant melanoma may occur.

The causes of these aging phenomena are ■Internal factors include decreased sebaceous gland function, decreased sweat gland function, coarse glycation of the stratum corneum, non-thinning of the epidermis, increased collagen cross-linking, increased insoluble collagen, decreased connective tissue matrix, and decreased capillary function. , decreased metabolic function, abnormal pigment metabolism, etc. External factors include ultraviolet rays, low temperature, low humidity conditions, etc.

Dry, unsmooth, rough skin, which is a typical characteristic of aging skin, is due to a decline in the function of corneocytes, a decrease in sebum secretion due to aging, and a quantitative decrease in water-binding substances in the epidermis (especially in the stratum corneum). This is a symptom caused by a lack of water. In the case of elderly people, it is likely to occur when the water content of the stratum corneum is about 10% or less of the saturated water content. This symptom worsens especially when the air is dry in winter, and a suitable example is senile xeroderma.

To deal with this phenomenon of dry skin,
Increases skin turnover (the rate at which the epidermis changes into the stratum corneum and peels off; aging skin has a slower rate of cell division, so turnover slows down) and normalizes the skin's ability to function. It is necessary to maintain
Various drugs have been developed in the medical and cosmetic fields.

-I methods include capillary dilators such as vitamin E preparations and respiratory stimulants such as placenta liquid, which promote improvement by promoting blood circulation in the skin and increasing metabolism. There is also a method of applying a sebum-like composition or a moisturizing agent to the skin surface and covering the skin to prevent dryness.

[Problem that the invention seeks to solve]

However, the above-mentioned improvement effects due to the telangiectatic effect or the skin respiration promoting effect are slow-acting, and the effect appears quickly in the case of a cream (1 week for both, and 2 weeks for a lotion), so it is difficult to obtain sufficient effects. However, sebum-like compositions and moisturizers sometimes help retain moisture in the stratum corneum, but they are not easy to use and tend to be oily or sticky. Moreover, in order to increase the durability of the effect, the amount used (the amount of application) must be increased.

In addition, drugs for dealing with aging phenomena other than those mentioned above (e.g., wrinkles, sagging, age spots, etc.) have yet to be found in the medical and cosmetic fields, with satisfactory efficacy and safety. do not have.

In view of the above circumstances, the present inventors have conducted intensive research to obtain a drug that is effective against aging phenomena and has a high degree of safety. As a result, the present inventors have found that sialic acid and sialic acid derivatives have excellent anti-aging effects. They discovered this and completed the present invention.

[Means for solving problems]

That is, the present invention provides a skin aging preventive agent containing one or more selected from the group consisting of sialic acid and sialic acid derivatives.

Hereinafter, the configuration of the present invention will be explained in detail.

The sialic acid used in the present invention is a known substance, and the N of polyhydroxymonoaminocarboxylic acid (neuraminic acid)
It is a general term for -acyl, N-acyl, and O-acyl derivatives, and is also called sialic acid.

Sialic acid is contained in various living organisms, and usually constitutes cell surface carbohydrates and exists in glycosidic bonds at the terminal ends of glycoproteins, cosmetics, and lipids. Particularly, it exists in large quantities in the brain, nerves, blood, thyroid glands, mucin, and colostrum, but it also exists free in serum, body fluids, and urine. The most typical sialic acid found in the living world is N-acedelneuraminic acid (NANA: molecular lit. 309), with a melting point of 185-187°, [α]
It is a white powder with an angle of -32°±2°.

The biological and pharmacological actions of sialic acid and sialic acid derivatives are known to contribute to the negative charge on the cell surface, to participate in specific recognition mechanisms of cells, to cause hemagglutination reactions caused by viruses, and to the homing phenomenon of blood proteins. ing. Recently, sialic acid has been studied for its expectorant activity (Japanese Patent Application Laid-Open No. 61-684
18), anti-inflammatory effect (Japanese Patent Application Laid-Open No. 145015/1983)
and nutritional effects of sialic acid-bonded oligosaccharides (Unexamined Japanese Patent Publication No. 1986-
152233) etc. have been reported.

However, it is not yet known that it has anti-aging effects on the skin. Methods for producing sialic acid and sialic acid derivatives include synthetic methods and natural extraction methods (raw materials: egg white, submandibular gland mucin, placenta extract, colominic acid obtained from Escherichia coli, etc.), but milk raw material extraction is preferred due to its low cost. Law (Patent No. 1) 912
12, Patent No. 1253988, JP-A-59-1841
97 etc.) is particularly preferred.

An example of producing the compound according to the present invention using a milk extract is shown below. The milk used in the milk extraction method can be selected from cow's milk, milk, breast milk (human), and others as appropriate. Furthermore, the concentration of sialic acid can be freely controlled depending on the degree of purification, so the purification can be done according to usage, application, dosage form, and other purposes. Note that the manufacturing method is not limited to this.

(Production Example 1) Add 28 kg of hydrochloric acid to 10 tons of sialic acid cheese whey to adjust the pH to 2.
After adjusting the temperature, the mixture was heated at 92° C. for 60 minutes to perform hydrolysis. Proteins coagulated by heating were removed from the resulting whey hydrolysis solution using a screw decanter to obtain a sialic acid-containing solution. Next, the sialic acid-containing solution was placed in a desalination tank of an electrodialysis machine, and the acid was desalted to a conductivity of 2 mS/cm.Once the sialic acid-containing solution was desalted, the dialysis was stopped and the concentration tank liquid was discarded. Next, add 30β of distilled water to the concentration tank and increase the conductivity to 50 μS again.
Dialysis was performed to /cm. After the dialysis was completed, the concentration tank liquid was concentrated and dried to obtain 600 g of white powder. The purity of the M-released sialic acid of the powder thus obtained was about 97%.

(Production Example 2) Sialic acid salt The free sialic acid mentioned above was adjusted with caustic soda, and sialic acid N
get a. In addition, Mg salts, k salts, phosphates, amine salts, etc. can be produced depending on the purpose.

(!1idJ Preparation Example 3) The filtrate prepared by ultrafiltration of sialic acid-bonded oligosaccharide milk or cheese whey was
It was concentrated under reduced pressure to 0%. After electrodialyzing 25 kg of this liquid until the electrical conductivity reached 20 μS/cm, it was passed through a column packed with DOWEX IX2 (2 kg) to adsorb oligosaccharides. Next, 20 kg of water was passed through the column to remove neutral sugars, and then the oligosaccharides adsorbed on the column were eluted with 0.5M hydrochloric acid. The pH of the obtained eluate was adjusted to pH 7.0 with 30% caustic soda, and then electrodialyzed again until the electrical conductivity reached 150 μS/cm. The obtained dialysate was concentrated and dried to obtain 100 g of white powder. The purity of the sialic acid-bonded oligosaccharide of the powder thus obtained was 90.
It is −′ one in %.

(Production Example 4) Sialic acid-bound protein Rennet Casein Card waste liquid 3001 was heat sterilized at 75°C for 30 minutes in a Fordora tank, then cooled to 40°C, and the pH was adjusted to 4.6 with concentrated hydrochloric acid. Let stand for about 30 minutes to form a precipitate, then pass the solution through a tallifier.
After returning H to 7.0, the clear liquid was concentrated and desalted using an RO membrane. After concentrating to 10 times, it was added to the concentrate and concentrated again to 10 times. The purity of the sialic acid-bound protein in the powder obtained was about 80%.

(!!!Preparation Example 5) To 15 kg of sialic acid lipid buttermilk powder was added 1,001 liters of a chloroform-methanol mixture (1:1), and the mixture was stirred at room temperature for 30 minutes for extraction. Next, the chloroform-methanol mixture was collected and passed through an ion exchange resin (D [EAE-Toyopearl acetate type) 1j2 to adsorb sialic acid-bound lipids, and then a chloroform-methanol mixture (1:1) 2N
After washing the resin with 0.5M sodium acetate-methanol solution (1:1) 2j2,
．． Sialic acid-bound lipids were eluted with sodium nail acetate-methanol solution 41. After concentrating the eluate to remove methanol, 5 g of water was added and ultrafiltration was performed to desalt and concentrate the sialic acid-bound lipids.

After the concentrated solution containing sialic acid-bound lipids was dried in an evaporator, it was passed through a silica gel column (4, OX 50cm) to adsorb the sialic acid-bound lipids, and then chloroform 1β
After sequentially washing with chloroform-methanol mixture (4:1) IA, the sialic acid-bound lipid was eluted with chloroform-methanol (2:8) mixture 2I2. The eluate was evaporated to dryness using an evaporator to obtain 15 g of white powder.

The purity of the sialic acid-bound lipid in the powder thus obtained was 90% or more (resorcinol method) as determined by thin layer chromatography.

Next, safety tests were conducted on sialic acid and sialic acid derivatives, and the results are shown below.

Acute toxicity test Sialic acid produced in Production Examples 1 to 5, sialic acid Na%
Sialic acid-bound oligosaccharides, sialic acid-bound proteins, and sialic acid-bound lipids were each used as test substances in ICR female mice (6 weeks old, 5 mice per group), and 0.5% was administered intraperitoneally.
Each test substance was suspended in sodium carboxymethylcellulose/physiological saline solution at a concentration of 2% by weight.
For oral administration, each test substance was suspended in olive oil at a concentration of 5% by weight and administered intraperitoneally using an oral needle (60 mff/kg).
, given orally (30++!?/kg). As a result, no deaths, no decreases in body weight, and no noteworthy toxic symptoms were observed for any of the test substances during the 7-day observation period, and no signs of toxicity were observed in the autopsy conducted on the 7th day.

As is clear from this result, the acute toxicity value (LD50) of sialic acid and sialic acid derivatives is 12
00mg/kg or more, orally 1500mg/k
g or more, indicating high safety.

Next, we will describe formulations for applying sialic acid and sialic acid derivatives as skin aging preventive agents.

The skin aging preventive agent of the present invention can be used in the form of a mixture containing pharmaceutically acceptable additives and other drugs in addition to sialic acid and sialic acid derivatives. However, since sialic acid has poor stability against light, acids, and alkalis, there is a problem in long-term storage, and from the viewpoint of stability, it is preferable to use sialic acid derivatives.

In addition to the above-mentioned essential ingredients, the skin aging prevention agent of the present invention may contain other ingredients commonly used in cosmetics and pharmaceuticals, such as avocado oil, palm oil, peanut oil, beef tallow, rice bran oil,
Jojoba oil, carnauba wax, lanolin, liquid paraffin,
Oils such as oxystearic acid, isostearyl palmitate, isostearyl alcohol, glycerin, sorbitol, polyethylene glycol, collagen, hyaluronic acid, humectants such as chondroitin sulfate, amyl paradimethylaminobenzoate, urocanic acid, diisobrobyl cinnamic acid UV absorbers such as ethyl, sodium erythorbate, sage extract, vitamin E, antioxidants such as parahydroxyanisole, sodium stearyl sulfate,
Surfactants such as cetyl sulfate jetanolamine, cetyl trimethylammonium saccharin, polyethylene glycol isostearate, and glyceryl arachate, preservatives such as ethyl paraben and butyl paraben, and antiseptics such as sucrose, orensis, chicon, peony, Japanese japonica, birch, loquat, etc. Extracts, anti-inflammatory agents such as glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, whitening agents such as fetal rock extract, glutathione, saxifrage extract, ascorbic acid derivatives, carrots, aloe, mallow, Extracts of iris, grape, lily, loofah, lily, etc., royal jelly, photosensor, cholesterol derivatives, various amino acids,
Activators of various vitamins and derivatives such as biotin and pantothenic acid derivatives, extracts of saffron, nebula, ginger, hypericum, ononis, rosemary, garlic, etc., T-oryzanol, dextran sodium sulfate, vitamin E derivatives, nicotinic acid Derivatives, blood circulation promoters such as nicotinic acid derivatives, antiseborrheic agents such as sulfur and thianthol, fragrances, water, alcohol, thickeners such as carboxyvinyl polymer, and coloring agents such as titanium yellow, cursamine, and henibana red are required. It can be blended as appropriate.

The dosage form of the present invention can be used in any form as long as it achieves medicinal effects, such as external preparations, powders, granules, powders, etc.
Examples include tablets, capsules, syrups, physiological preparations, and injections. Among these, external preparations are preferred from the standpoint of both prevention and treatment as they are easy to use, and may be in any form as long as they can be applied externally.

Examples include external liquid preparations such as lotions, liniments, and emulsions, and external semi-solid preparations such as creams, ointments, baths, jellies, and sprays, and are administered by transdermal administration by directly applying or spraying on the skin.

The amount of one or more types of sialic acid and sialic acid derivatives as active ingredients in the skin aging prevention agent of the present invention is as follows:
The amount is 0.0001 to 50% by weight, preferably 0.001 to 5% by weight, based on the total weight of the composition.

If it is less than 0.0001% by weight, the effect tends to be poor, and even if it is added in excess of 50ffiJi%, it is difficult to expect a significant increase in the effect.

The dosage of the skin aging preventive agent of the present invention cannot be clearly defined because the amount may be outside the following range depending on age, individual differences, symptoms, etc. Oral and transdermal administration of one or more of
g, preferably 0.001 to 200 mg, and this amount can be administered once a day or in divided doses.

Furthermore, depending on the blending concentration of sialic acid and sialic acid derivatives and the degree of desired effect, it can be applied to pharmaceuticals, quasi-drugs, cosmetics, and even foods for the purpose of preventing aging.

[Example] In order to clarify the excellent effects of the present invention, evaluation tests were conducted using Examples and Comparative Examples.

Note that the present invention is not limited to this.

(Test method) (1) Epidermal turnover using guinea pig skin Alpino guinea pigs were divided into 6 groups of 5 animals per group and used for evaluation. After pricking the abdominal skin of the guinea pig, a white petrolatum ointment containing 5% by weight of the fluorescent dye danzyl chloride was applied in an occluded manner at 0.1 J/cn for 24 hours. The test substance was 0.3% of Examples 1 to 5 and Comparative Example 1 once a day.
mff was applied onto the area to which Danzyl chloride was applied, and the turnover rate of the stratum corneum of the skin was evaluated by the number of applications until Danzyl chloride disappeared.

(2) Method for measuring the therapeutic effect of dryness disease Example 1: 30 female patients aged 40 to 60 years old with senile xeroderma were divided into 6 groups of 5 people per group, and the drug was administered on the right cheek.
5 or Comparative Example 1, and as a control, Comparative Example 2 containing no drug was applied to Hitoyori.

The test period was one month in winter, and 100% of each test substance was used.
It was applied twice, 2 ml each in the morning and at night. At the end of 30 days of application, a doctor evaluated the improvement effect on the right cheek compared to Hitoyori.

(3) Method for measuring the revitalizing effect on tired human skin Lack of sleep causes skin roughness, darkening of the skin, and loss of skin luster and firmness. We evaluated the immediate skin revitalizing effect of the test substance on tired skin, especially in the winter when these symptoms are most noticeable. 1 with 30 women in their 30s as subjects.
There were 5 people in the group, divided into 6 groups, and Examples 1 to 5 or Comparative Example 1 were applied to the right cheek, while Hitoyori was left unapplied. The test period was 2 days in winter, and 2 doses of each test substance were applied twice a day for 2 days in the morning and before going to bed.After the test, the condition of the skin after the test was compared to the skin before the test. Subjects were asked to self-score.

However, during the 20 tests, the test subjects were to go to bed at 4am in the morning and wake up at 7am (sleep time 3 hours), and take no other naps.

-Measurement items 1 ■ Degree of skin roughness, ■ Skin dullness, ■ Skin texture, ■ Makeup paste, ■ Skin gloss, firmness, and sagging - Scoring - 5 points: Significantly improved compared to before the test.

4 points: Slightly improved.

3 points: No change.

2 points: Slightly worsened.

1 point: Significantly worsened.

(4) Method 2 for determining anti-aging effects on human skin
The subjects were 30 women aged 5 to 50, with 5 women per group and 6
They were divided into groups, and Examples 1 to 5 and Comparative Example 1 were used on the right cheek, while Comparative Example 2, which did not contain any drug, was used on the right cheek. The test period was two months of winter, with continuous application twice a day in the morning and evening.
The effects were evaluated in a) to (e).

(Ill) Evaluation of skin 19 surface morphology The skin 19 surface morphology was evaluated by visually determining the degree of skin dryness according to the following criteria.

-Judgment method- Remarkable effect: Compared to Comparative Example 2, there is almost no drying or flaking.

Effective: Less drying and peeling than Comparative Example 2.

Slightly effective: Drying is the same as in Comparative Example 2, but it is not easy to remove.

Ineffective: There is no difference in drying and peeling compared to Comparative Example 2.

Deterioration: Compared to Comparative Example 2, dryness and flaking are significant.

(b) Observation of skin appearance The beauty of the skin appearance was evaluated by collecting skin replicas of the above subjects using silicone resin and observing them with a stereoscopic microscope.

1. Judgment method 1. Remarkable effectiveness: Compared to Comparative Example 2, the skin grooves and skin mounds are significantly clearer and more regular.

Effective: Compared to Comparative Example 2, the skin grooves and skin mounds are slightly more clearly arranged.

Invalid: No difference compared to Comparative Example 2.

Deterioration: Compared to Comparative Example 2, skin grooves and skin mounds are unclear.

(Evaluation of the function of the C1 stratum corneum TWL
The function of the stratum corneum was evaluated by measuring rLoss (transepidermal water loss). TWL was measured using Evapolymeter EPL (manufactured by Sernuo Med, Sweden).

1. Judgment method 1. Significant effect: TWL decreased by 30% or more compared to Comparative Example 2.

Soothing effect: TWL decreased by 10% or more compared to Comparative Example 2.

Ineffective: TWL is less than 10% compared to Comparative Example 2.

Deterioration: TWL increased by 10% or more compared to Comparative Example 2.

(dl Evaluation of exfoliated keratinocytes) Apply Scotch tape to Tiban mending tape to the skin of the test subject before and after the evaluation test. After peeling off the tape, the keratinocytes attached to the tape are stained with HE and the presence or absence of nuclei within the cells is examined using a microscope. Judgment was made.

-Judgment method- Normal: No nuclei are observed and normal keratinization occurs.

Abnormal: Nuclei are observed and abnormal keratinization occurs.

(e) After the sensory evaluation test was completed, the subjects were asked to self-rate the skin condition of Uyori compared to Hitoyori (Comparative Example 2).

-Measurement items 1 ■Fine wrinkles, ■Skin texture, ■Skin dullness, ■Skin sagging, luster, firmness, ■Makeup paste1 Score- 5 points: Significantly improved compared to Comparative Example 2.

4 points: Slightly improved.

3 points: No change.

2 points: Slightly worsened.

1 point: Significantly worsened.

Comparative Example 2 is a drug-free formulation in which vitamin E acetate was replaced with purified water from Comparative Example 1.

(Left below) (Test results) (1) As is clear from the results in Table 2, the evaluation using guinea pigs showed that Examples 1 to 5 containing sialic acid or sialic acid derivatives were superior to Comparative Example 1. It was observed that epidermal turnover was accelerated for 2 to 3 days, and furthermore, it was found that a synergistic effect can be obtained by combining two or more types.

Table-2 Epidermal turnover speed test results (2) Table-3
From the results, Examples 1 to 5 were found to be more effective against senile xeroderma than Comparative Example 1. Furthermore, it has been found that a synergistic effect can be obtained by combining two or more types of sialic acid and sialic acid derivatives.

Table 3 Results of senile xeroderma therapeutic efficacy test (3) From the results in Table 4, Examples 1 to 5 have an immediate skin revitalizing effect on tired skin compared to Comparative Example 1. It has also been found that a synergistic effect can be obtained by combining two or more types of sialic acid and sialic acid derivatives.

Table 4 Skin revitalization effect test results for fatigued skin (4) From the results in Table 5, the Example is more effective than Comparative Example 1 in any of the macroscopic, replica, TWL, and sensory evaluations. It has been found that the combination of sialic acid and sialic acid derivatives has a synergistic effect. (The dl results show that the promotion of epidermal turnover is not caused by abnormal keratinization.

Table 5 Results of anti-aging effect test on human skin Next, various embodiments are shown. Hereinafter, the blending amount is expressed as weight %.

Example 6 Emulsion A milky lotion was produced by a conventional method according to the following recipe.

Stearic acid 2.0 (%)
Cefnol 1.0 Vaseline 3.0 Lanolin Alcohol 2.0 Liquid Paraffin
8.0 Squalane
3.0 Escarole 507
2.0 Sodium sialate 0
．． 001POE (10) Monooleate
2.5 Triethanolamine 1
．． 0 Propylene Glycol 5.0 Preservatives Percent Fragrance
I Distilled water Remaining Example 7
Nutritional Cream A nutritional cream was prepared by a conventional method according to the following recipe.

Stearic acid 2.0 (% stearyl alcohol 7.0 reduced lanolin 2.0 squalane
5.0 octyldodecanol
6.0POE(25) Cetyl ether
3.0 Glyceryl monostearate 2.0 Propylene glycol 5.0 Sialic acid-bound oligosaccharide 1.0 Sialic acid-bound protein 1.0 Preservative
Percentage fragrance Percentage distilled water Remaining Example 8
Punctures were manufactured by a conventional method according to the following recipe.

Kaolin 67.5 (
%) Talc 19.0 Propylene glycol 7.5 Calcium acetate 0.01) Urea
0.5 Sialic acid-bound lipid 5.0 Flavor
0.49 Example 9 Lip Treatment A lip 1-treatment having the following formulation was manufactured according to a conventional method.

Candelilla Row 9.0 (O
A) Solid paraffin 8.0 Beeswax 5.0 Carnauba wax 5.0 Lanolin
1). 0 sialic acid-linked oligosaccharide
0.2 isopropyl myristate 1-
10.0 Fragrance Appropriate amount Antioxidant Appropriate amount Castor oil
Remaining Example 10 Ointment An ointment having the following formulation was manufactured according to a conventional method.

Stearyl alcohol 18.0 Japanese blackberry 20.0 Sialic acid-bonded protein 0.5 Polyoxyethylene monooleate 0.25 Glycerin monostearate 0.25 Vaseline
40.0 Purified water
Residual [Effects of the Invention] Skin 1 of the present invention Anti-aging agent has skin anti-aging effects (improving rough skin, improving keratin, promoting epidermal turnover, improving skin dullness, sagging, firmness, luster, and hardening, and revitalizing the skin. effect,
It has excellent moisturizing effect), stability, safety and usability.

Claims (4)

[Claims] (1) A skin aging prevention agent containing one or more selected from the group consisting of sialic acid and sialic acid derivatives. (2) The skin aging prevention agent according to claim (1), wherein the sialic acid derivative is a sialic acid-bonded oligosaccharide, a sialic acid-bonded protein, a sialic acid-bound lipid, or a sialic acid salt. (3) The skin aging prevention agent according to claim (1) or (2), which uses sialic acid or a sialic acid derivative obtained by extraction from milk. (4) The skin aging preventive agent according to claim (1), (2) or (3), wherein the sialic acid is N-acetylneuraminic acid.