KR101526592B1 - Anti-wrinkle composition - Google Patents

Abstract

The present invention relates to a composition for improving skin wrinkles, and more particularly, to a composition for improving skin wrinkles, which comprises 2- (hydroxymethyl) piperidine-3,4,5-triol having an excellent collagen synthesis promoting activity and collagenase inhibiting activity, (hydroxymethyl) piperidine-3,4,5-triol].

2- (hydroxymethyl) piperidine-3,4,5-triol, 2- (hydroxymethyl) piperidine-3,4,5-triol, collagen synthesis, collagenase inhibition, wrinkles,

Description

Anti-wrinkle composition [0002]

The present invention relates to a composition for improving skin wrinkles, and more particularly, to a composition for improving skin wrinkles, which comprises 2- (hydroxymethyl) piperidine-3,4,5-triol having an excellent collagen synthesis promoting activity and collagenase inhibiting activity, (hydroxymethyl) piperidine-3,4,5-triol].

Collagen is present in extracellular epilepsy as a major substrate protein produced in the fibroblasts of the skin, and its important functions are mechanical durability of the skin, resistance of connective tissues, binding of tissues, and support of cell adhesion (van der Rest et al., 1990). Such collagen is reduced by aging and photoaging by ultraviolet irradiation, which is known to be closely related to the wrinkling of the skin (Arthur K. Balin et al., "Aging and the skin ", 1989). In recent years, extensive research into skin aging has been developed and the important functions of collagen in the skin have been revealed.

In the prior art, there have been products in which collagen is formulated into cosmetics from the skin moisturizing effect of collagen. However, since these cosmetics are not coated with collagen on the skin surface and can not be expected to have a moisturizing effect due to transdermal absorption of collagen as a polymer, Improvement can not be said.

On the other hand, there are known effective substances that promote collagen synthesis and exhibit wrinkle-reducing effects. For example, retinoic acid, transforming growth factor (TGF) (Cardinale G. et al, Adv. Enzymol., 41, p. 425, 1974), animal placenta- (JP-A No. 231370), betulinic acid (Japanese Patent Laid-Open No. 1996-208424), chlorella extract (Japanese Patent Laid-Open No. 1997-40523, Japanese Patent Laid-Open No. 1998-36283) have. However, the above-mentioned effective ingredients are limited in the use amount due to safety problems such as irritation and reddening when applied to the skin, or have insufficient effect, so that there is a problem that the effect of improving skin function by promoting collagen synthesis of skin substantially can not be expected.

Therefore, it is safe for skin even when used for a long period of time, has stable physicochemical properties such as solubility suitable for making various formulations without breaking the active ingredient due to heat, light, and elapsed time during production and storage of the product, Above all, the development of an active ingredient capable of providing a wrinkle-improving effect superior to that of a conventional collagen synthesis promoting substance is urgently required.

Accordingly, the present inventors have found that, in the course of screening active ingredients that have strong collagen synthesis promoting activity and collagenase inhibiting activity, are safe for skin, easy to formulate, and have stability in cosmetic preparation and storage, Methyl) piperidin-3, 4, 5-triol have such properties, thereby completing the present invention.

It is an object of the present invention to provide a pharmaceutical composition containing 2- (hydroxymethyl) piperidine-1-sulfonic acid having strong collagen synthesis promoting activity and collagenase inhibiting activity and being safe for skin, The present invention provides a composition for improving skin wrinkles, which has no toxicity, is excellent in stability, and has an excellent effect of improving skin wrinkles by containing 3,4,5-triol as an active ingredient.

In order to achieve the above object, the present invention provides, as one embodiment, a composition for improving skin wrinkles containing 2- (hydroxymethyl) piperidine-3,4,5-triol represented by the following general formula .

In the present invention, the compound of formula I is represented by the formula (2) to the (2 R, 3 R, 4 R, 5 R) -2- ( hydroxymethyl) piperidine -3,4,5-triol Lt; / RTI >

In the present invention, the 2- (hydroxymethyl) piperidine-3,4,5-triol has strong collagen synthesis promoting activity and collagenase inhibiting activity as a collagen synthesis promoter.

In the present invention, the content of the 2- (hydroxymethyl) piperidine-3,4,5-triol is preferably 0.0001-10% by weight in the total composition.

In a preferred embodiment of the present invention, the composition of the present invention may be a cosmetic composition.

In a preferred embodiment of the present invention, the composition of the present invention may be a pharmaceutical composition.

In addition, as a preferred embodiment of the present invention, the composition for improving skin wrinkles of the present invention may further comprise a known wrinkle-improving component in addition to the compound of formula (1).

In one embodiment of the present invention, the wrinkle-improving composition is a wrinkle-improving ingredient known in the art and includes at least one wrinkle selected from the group consisting of retinoic acid, TGF, protein from animal placenta, betulinic acid, and chlorella extract May further comprise an improving component.

In the present invention, the additional wrinkle-improving component may be included in an amount of 0.0001 to 10% by weight based on the total weight of the composition, wherein the weight% is selected from the group consisting of collagen synthesis promoting or collagenase inhibiting activity, skin safety, And the ease of formulation of the drug.

Hereinafter, the present invention will be described in detail.

The active ingredient 2- (hydroxymethyl) piperidine-3,4,5-triol of the present invention has a structure represented by the following formula (1).

[Chemical Formula 1]

The compound of formula (I) may be in the form of (2 R, 3 R, 4 R, 5 R) -2- ( hydroxymethyl) -3,4,5-piperidin-triol represented by the following formula (2) to .

(2)

In order to exhibit an excellent wrinkle-improving effect when the wrinkle-improving component is applied to the actual skin, it exhibits a high active wrinkle-reducing activity at a low concentration, has an excellent ability to permeate and absorb the skin and can stay for a sufficient time to exhibit a wrinkle- It is preferable to be low in volatility, to stably maintain the active ingredient on the composition or on the skin, to be easily formulated into medicines or cosmetics, and to be safe for the skin.

However, among the known wrinkle reducing components, wrinkle reducing components that satisfy all of the above characteristics are not common. For example, some wrinkle-improving ingredients have excellent wrinkle-reducing activity even at low concentrations in vitro, but they are difficult to apply to real skin because of their ability to permeate through the skin. Other wrinkle-reducing ingredients have low hydrophilicity and are difficult to formulate into medicines or cosmetics. In addition, some wrinkle-reducing ingredients may be degraded or transformed into other compounds when exposed to heat, light, or oxygen, which may already wrinkle the skin before application to the skin.

As can be seen in the following examples, the compound of formula (I) exhibits superior collagenase activity at a low concentration as compared with retinoic acid, which is a known wrinkle improving ingredient, and exhibits excellent collagen synthesis promoting effect. In addition, it has high solubility in a hydrophilic solvent, exhibits low volatility when applied to a product, excellent skin permeability, easy formability, and excellent stability in light, heat, or time. Furthermore, since the wrinkle improving effect is sufficiently exhibited at a low concentration, it has been shown to be very safe for the skin.

Therefore, the compound of Chemical Formula 1 can be used as an active ingredient exhibiting wrinkle-reducing effect in pharmaceuticals or cosmetics.

Therefore, the present invention also provides a wrinkle-improving method comprising the use of the compound of Chemical Formula 1 for the preparation of a wrinkle-improving pharmaceutical composition or a wrinkle-improving cosmetic composition and the effective amount of the compound of Chemical Formula 1 applied to the skin.

The compound of formula (1) may be synthesized as a known compound or a commercially available compound may be used.

In the present invention, "wrinkle improvement" refers to inhibiting or inhibiting the generation of wrinkles on the skin, or alleviating the wrinkles already generated.

The wrinkle-improving composition of the present invention can provide a desirable wrinkle-improving effect when an effective amount of the compound of formula (1) is contained. In the present invention, the term "effective amount" refers to the amount of a compound capable of inhibiting or inhibiting the generation of wrinkles of the skin or alleviating the wrinkles already formed. The effective amount of the compound contained in the wrinkle-improving composition of the present invention will vary depending on the form in which the composition for improving wrinkles is commercialized, the method in which the compound is applied to the skin, and the time on the skin. For example, when the wrinkle-improving composition is commercialized as a medicament for dermatological treatment due to the formation of wrinkles of the skin, it may contain a compound of the formula (1) at a higher concentration than the case where it is commercialized as a cosmetic product, There will be. In the case of a wash-off type cosmetic such as a make-up removing agent, a detergent and the like in which the active ingredient remains on the skin in a short period of time even when it is commercialized as a cosmetic product, it may contain a relatively high concentration of the compound of the formula . On the other hand, in the case of leave-on type cosmetics such as lotion, cream, essence and the like in which the active ingredient remains on the skin for a long period of time, a low concentration of the compound of the formula (1) It will be acceptable. In one embodiment of the present invention, the composition for improving wrinkles may contain 0.0001% by weight to 10% by weight of the compound of formula (1) based on the total weight of the composition. When the wrinkle-improving composition of the present invention contains less than 0.0001% by weight of the compound of the formula (I), sufficient wrinkle-improving effect can not be expected. When the wrinkle-improving composition is contained in an amount exceeding 10% by weight, To prevent such a problem.

The composition for improving wrinkles of the present invention may further contain a known wrinkle improving component in addition to the compound of the above formula (1). The wrinkle-improving effect of the composition of the present invention may be further enhanced by including an additional wrinkle-improving ingredient. When the wrinkle-improving ingredient is added, skin safety, easiness of formulation, and stability of effective ingredients can be taken into consideration in combination use. In one embodiment of the present invention, the wrinkle-improving composition is a wrinkle-improving ingredient known in the art and includes at least one wrinkle selected from the group consisting of retinoic acid, TGF, protein from animal placenta, betulinic acid, and chlorella extract May further comprise an improving component. The additional wrinkle improving ingredient may be included in an amount of 0.0001% to 10% by weight based on the total weight of the composition, wherein the weight% is selected from the group consisting of collagen synthesis promoting or collagenase inhibiting activity, skin safety, And the ease of poetry and the like.

In the present invention, the composition for improving wrinkles may be a pharmaceutical composition or a cosmetic composition. When formulating the wrinkle-improving composition into a medicament or cosmetic preparation, it may contain known dermatologically acceptable excipients that act as carriers for the active ingredient. When formulated as a medicament, the contents disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be referred to. When formulating into cosmetics, International cosmetic ingredient dictionary, 6th ed., The cosmetic, Toiletry and Fragrance Association , Inc., Washington, 1995, which is incorporated herein by reference in its entirety. Which are incorporated herein by reference.

When the composition for improving wrinkles of the present invention is a cosmetic composition, the composition may include, but is not limited to, emulsions such as lotion, facial lotion, body lotion, Makeup remover, cleansing foam, soap such as foundation, powder, cleansing lotion, cleansing oil such as cream, essence, cosmetic lotion, spray, gel, pack, sunscreen, makeup base, liquid type, solid type or spray type , A body wash, and the like. In this case, the cosmetic composition may contain a surfactant, an emulsifier, a soap acid, a solvent, a coloring agent, a preservative, an antioxidant, a defoamer, an antibacterial agent, an anticorrosion agent, an enzyme, a plant or mineral oil, a fat, a fluorescent substance, a fungicide, Preservatives, proteins, silicones, solubilizers, sugar derivatives, sunscreens, vitamins, plant extracts, waxes, and the like.

When the composition for improving wrinkles of the present invention is a pharmaceutical composition, the composition may have external formulations such as ointment and cream, though not limited thereto. In this case, the pharmaceutical composition may be prepared in unit dosage form by formulating it with a pharmaceutically acceptable carrier and / or excipient, or may be prepared by inserting it into a multi-dose container, and may further include a dispersant or a stabilizer .

The pharmaceutical composition of the present invention can be applied by a transdermal route during parenteral administration, more preferably by a topical application route by application, though it is not limited thereto.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dosage of the pharmaceutical composition of the present invention is preferably 0.5 to 5.0 ml per day on an adult basis, once or twice a day, and continued for at least one month.

The composition for improving skin wrinkles of the present invention is a composition for promoting skin collagen synthesis, which has a strong collagen synthesis promoting activity and collagenase inhibitory activity, and which is stable in cosmetics manufacturing and storage, 2- (hydroxymethyl) piperidine-3,4,5-triol As an active ingredient, it is free of toxicity, has good stability, is easy to make a formulation, and has excellent wrinkle improving effect on skin, so that it can be usefully used in cosmetics industry and pharmaceutical industry.

Hereinafter, advantages and features of the present invention and methods of achieving the same will be apparent from the following detailed description. The present invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Is provided to fully convey the scope of the invention to those skilled in the art, and the invention is only defined by the scope of the claims.

Example 1 Confirmation of Inhibitory Effect of Compound of Formula 2 on Collagenase Activity

Commercially available substrate, Dabcyl-r-Abu-Pro- GLu-Gly-Leu-Glu (EDANS) -Ala-Lys-NH 2 for Gly-Leu combining collagenase C-terminus of the N-terminal and EDNAS of Dabcyl group by decomposition I Using the mechanism of this quencher, the inhibitory effect of the compound of formula (2) on collagenase activity was confirmed as follows.

(Chromadex, USA, Product No. ASB-00004239) was added to a 96-well 96-well plate by concentration (0.001 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt% -010) was added, and 50 mM Tris buffer (pH 7.6) and the commercially available substrate and collagenase were added thereto. The mixture was reacted at 37 ° C for 1 hour and then 5 μl of EDTA was added to terminate the reaction. The degree of color development was measured by measuring the absorbance at 340 nm / 520 nm using a flurometer (Bob Beekman et al., FEBS, 390, 221-225, 1996). As a negative control group, a group to which the compound of formula (1) was not added was used. The inhibition rate of collagenase activity was calculated by the following formula (1), and the results are shown in Table 1.

Collagenase activity inhibition rate (%) = {1- (reaction absorbance of sample and substrate / reaction absorbance of control group)} × 100

Inhibition of collagenase activity by concentration sample Inhibition rate of collagenase activity (%) 1% by weight of the compound of formula (1) 84 0.5% by weight of the compound of formula (1) 50 0.1% by weight of the compound of formula (1) 24 0.05% by weight of the compound of formula (1) 18 0.001 wt% of the compound of formula (1) 2 Negative control (no treatment) 0

As can be seen from Table 1, it was found that the collagenase activity inhibitory effect was excellent in a large number of samples.

Example 2 Confirmation of Collagen Synthesis Promotion Effect of Compound of Chemical Formula 2

The compound of formula (2) was added to the culture medium of human-derived fibroblasts to examine the promoting effect of collagen synthesis at the cellular level. The biocompatible collagen was quantitated using a PICP EIA kit (Procollagen Type I C-Peptide Enzyme Immunoassay Kit).

The compound of formula (2) was added to the culture medium of human fibroblasts to a final concentration of 0.5 ug / ml, 1 ug / ml, 2 ug / ml, 5 ug / ml, 10 ug / ml and 50 ug / ml respectively and cultured for 1 day. As a negative control group, a group not treated with the compound of formula (2) was used, and as a positive control, a final concentration of 52.8 mg / ml Vit. C treated group. After culturing, the culture broth was taken and the degree of collagen biosynthesis at each concentration was measured with a PICP EIA Kit using a spectrophotometer at 450 nm. The collagen biosynthesis performance was calculated as the sum of the relative abundance of the negative control to which no collagen synthesis promoter was added. The results are shown in Table 2.

Effect of collagen biosynthesis at the cellular level by concentration sample Amount of collagen production ^* Growth rate (%) ^* Negative control group (no addition) 1.472 + 0.074 - The compound of formula 2 (final concentration 0.5 ug / ml) 1.550 + 0.060 105.30% The compound of formula 2 (final concentration 1 ug / ml) 1.656 + - 0.052 112.50% The compound of formula 2 (final concentration 2 ug / ml) 1.777 + 0.063 120.70% The compound of formula 2 (final concentration 5 ug / ml) 1.887 + 0.088 128.20% The compound of formula 2 (final concentration 10 ug / ml) 1.987 + 0.067 135.00% The compound of formula 2 (final concentration 50 ug / ml) 2.101 + 0.043 142.70% Positive control (Vit. C, final concentration 52.8 ug / ml) 1.858 + 0.066 126.20% [Note] * number of repetitions = 6

As can be seen from the results shown in Table 2, the compound of Chemical Formula 2 has excellent collagen biosynthesis ability against human-derived fibroblasts.

Example 3 Evaluation of wrinkle-improving effect of compound of formula (2) in vivo

Using a 6-week-old hairless mouse, the wrinkle-improving effect of the compound of formula (2) on the wrinkles induced by light was tested. The compound of formula (2) was dissolved in 1,3-butylene glycol at 0.5% and used as a sample. The test method was as follows.

The hairless mouse was irradiated with 2MED for 3 weeks and 10 weeks using a solar simulator to form wrinkles. A control group treated with 1,3-butylene glycol to which no sample was added and a control group treated with 0.5 wt% (10 mice) treated with 0.5 ml / cm ² of the compound of formula ( ² ) twice per day (2.5 mg / cm ² by the compound of formula ( ² )) for 6 weeks were qualitatively evaluated.

The degree of wrinkle improvement was judged by naked eyes through visual observation and photographing, and the judgment criteria were three stages of no improvement, little improvement, and considerable improvement compared with those before the sample treatment in the sample treatment group and the control group Table 3 shows the results.

Wrinkle improvement effect on mouse sample Population
(Marie) No improvement Slight improvement A significant improvement Control group 10 7 3 0 The compound of the formula (2) 10 2 3 5

Production Example 1 and Comparative Example 1

Skin ointments containing the compound of formula (2) as in the composition of Table 4 were prepared according to the conventional method. In addition, a skin external ointment made from the components other than the compound of Chemical Formula 2 was prepared in Comparative Example 1.

Composition Production Example 1 (% by weight) Comparative Example 1 (% by weight) - The compound of formula 2
- diethyl sebacate
- Writers
- polyoxyethylene oleyl ether
Phosphate
- Sodium benzoate
-vaseline 2
8
5
6

Suitable amount
to 100 -
8
5
6

Suitable amount
to 100

Production Example 2 and Comparative Example 2

Creams containing the compound of formula (2) as in the composition of Table 5 below were prepared according to conventional methods. In addition, a cream prepared from the components other than the compound of the formula (2) was prepared in Comparative Example 2.

Composition Production Example 2 (% by weight) Comparative Example 2 (% by weight) - The compound of formula 2
- Stearic acid
- Cetanol
- potassium hydroxide
-glycerin
- propylene glycol
-antiseptic
-incense
-Purified water 0.5
15.0
1.0
0.7
5.0
3.0
Suitable amount
Suitable amount
to 100 -
15.0
1.0
0.7
5.0
3.0
Suitable amount
Suitable amount
to 100

Production Example 3 and Comparative Example 3

A flexible lotion comprising the compound of formula (2) as in the composition of Table 6 below was prepared according to the conventional method. In addition, a soft lotion prepared from the components other than the compound of the formula (2) was prepared in Comparative Example 3.

Composition Production Example 3 (% by weight) Comparative Example 3 (% by weight) - The compound of formula 2
-ethanol
- Polyoxyethylene polylauric acid
Sorbitan
- Paraoxybenzoic acid methyl
-glycerin
-1,3-butylene glycol
-incense
- Pigment
-Purified water 0.2
10.0
1.0

0.2
5.0
6.0
Suitable amount
Suitable amount
to 100 -
10.0
1.0

0.2
5.0
6.0
Suitable amount
Suitable amount
to 100

Production Example 4 and Comparative Example 4

A nutritional lotion comprising the compound of formula (2) as in the composition of Table 7 below was prepared according to conventional methods. In addition, a nutritional lotion made from the components other than the compound of Formula 2 was prepared in Comparative Example 4.

Composition Production Example 4 (% by weight) Comparative Example 4 (% by weight) - The compound of formula 2
- Vaseline
- sesquioleic acid sorbitan
- polyoxyethylene oleyl ethyl
- Paraoxybenzoic acid methyl
- propylene glycol
-ethanol
-Carboxyvinyl polymer
- potassium hydroxide
- Pigment
-incense
-Purified water 0.1
2.0
0.8
1.2
Suitable amount
5.0
3.2
18.0
0.1
Suitable amount
Suitable amount
to 100 -
2.0
0.8
1.2
Suitable amount
5.0
3.2
18.0
0.1
Suitable amount
Suitable amount
to 100

Production Example 5 and Comparative Example 5

A pack containing the compound of formula (2) as a composition of the following Table 8 was prepared according to a conventional method. In addition, a pack prepared from the components other than the compound of the formula (2) was prepared in Comparative Example 5.

Composition Production Example 5 (% by weight) Comparative Example 5 (% by weight) - The compound of formula 2
-glycerin
- propylene glycol
- Polyvinyl alcohol
-ethanol
- polyoxyethylene oleyl ether
- Paraoxybenzoic acid methyl
- Pigment
-incense
-Purified water 0.2
5.0
4.0
15.0
8.0
1.0
0.2
Suitable amount
Suitable amount
to 100 -
5.0
4.0
15.0
8.0
1.0
0.2
Suitable amount
Suitable amount
to 100

Production Example 6 and Comparative Example 6

Essences containing the compound of formula (2) as in the composition of Table 9 below were prepared according to the conventional method. In addition, an essence prepared from the components other than the compound of Formula 2 was prepared in Comparative Example 6.

Composition Production Example 6 (% by weight) Comparative Example 6 (% by weight) - The compound of formula 2
- propylene glycol
-glycerin
- aqueous solution of sodium hyaluronate (1%)
-ethanol
- Polyoxyethylene hardened castor oil
- Paraoxybenzoic acid methyl
-incense
-Purified water One
10.0
10.0
5.0
5.0
1.0
0.1
Suitable amount
to 100 -
10.0
10.0
5.0
5.0
1.0
0.1
Suitable amount
to 100

Experimental Example 1: Confirmation of wrinkle-improving effect of the compound of formula (2)

The effect of improving the wrinkles of the healthy persons 35 to 50 years old on the essences of Preparation Example 6 and Comparative Example 6 was as follows.

30 women aged 35 to 50 years were divided into two groups of 15 persons each. Group 1 contained the essence of Preparation Example 6 containing 1% by weight of the compound of Formula 2, Group 2 contained the essence of Comparative Example 6, Once a day for 2 months.

After 2 months, the improvement of wrinkles was evaluated by image analysis of questionnaires and wrinkles. The subjects' questionnaires were compared with those before use with respect to improvement of wrinkles and elasticity. No improvement, slight improvement, and significant improvement were determined in three steps. The results are shown in Table 10.

The wrinkle-improving effect (persons) of the production example according to the present invention: sample Population
(persons) No improvement Slight improvement A significant improvement Comparative Example 6 15 8 5 2 Production Example 6 15 3 5 7

As can be seen from Table 10, it was found that the effect of improving the wrinkles was excellent when the essence of Production Example 6 according to the present invention was used.

Immediately after the experiment, the replica was collected from the same area under the eye. The image was analyzed by image analysis to determine the degree of wrinkles The density of wrinkles was measured by dimensional analysis. The results of the measurement of the wrinkle density by image analysis are shown in Table 11 by averaging the reduction rates with respect to the wrinkle density before use.

The wrinkle improvement effect (image analysis) of the production example according to the present invention sample Wrinkle density reduction rate (%) Comparative Example 14% Manufacturing example 32%

As can be seen from Table 11, when the essence of Production Example 6 according to the present invention was applied, it was found that the density of wrinkles was greatly reduced before use.

Claims (8)

A composition for improving skin wrinkles, comprising a compound represented by the following formula (1) as an active ingredient. [Chemical Formula 1]

According to claim 1, (5 R 2 R, 3 R, 4 R,) represented by the formula (2) the compound of Formula 1-2- (hydroxymethyl) piperidin--3,4,5-tree Wherein the composition is in the form of an oil. (2)

The composition for improving skin wrinkles according to claim 1, wherein the compound of formula (1) has collagen synthesis promoting activity and collagenase inhibiting activity. The composition for improving skin wrinkles according to claim 1, wherein the content of the compound of Formula 1 is 0.0001-10% by weight of the total composition. The composition for improving skin wrinkles according to claim 1, wherein the composition is a cosmetic composition. The composition for improving skin wrinkles according to claim 1, wherein the composition is a pharmaceutical composition. The composition according to claim 1, wherein the composition further comprises at least one wrinkle improving component selected from the group consisting of retinoic acid, TGF, animal placenta-derived protein, betulinic acid and chlorella extract. Composition. The composition for improving skin wrinkles according to claim 7, wherein the additional wrinkle improving agent is contained in an amount of 0.0001 wt% to 10 wt% based on the total weight of the composition.