KR20100040107A - Composition for improving skin wrinkle - Google Patents

Abstract

The present invention relates to a wrinkle improving composition comprising the compound of formula (I) as an active ingredient. The compound of formula (I) of the present invention not only promotes collagen synthesis but also inhibits collagenase activity, has excellent solubility and stability, and is therefore well suited for use as an active ingredient of a wrinkle improving composition. Therefore, the composition of the present invention comprising the compound provides an excellent wrinkle improvement effect.

[Formula I]

Description

Composition for improving skin wrinkles

The present invention relates to a composition for improving wrinkles, which exhibits excellent collagen synthesis promoting activity and collagenase inhibitory activity.

Collagen is a major substrate protein produced in skin fibroblasts and is present in extracellular epilepsy. Collagen is known to provide mechanical firmness of skin, resistance of connective tissue and binding of tissue, and to perform functions such as sustaining cell adhesion, inducing cell division and differentiation (when organic growth or wound healing) (van der Rest et al., 1990). This collagen is reduced by photoaging by age and UV irradiation, which is known to be closely related to wrinkle formation of the skin (Arthur K. Balin et al., "Aging and the skin", 1989). In recent years, extensive research on aging of the skin has been developed to reveal the important function of collagen in the skin.

Based on the skin moisturizing effect of collagen, products that incorporate collagen in cosmetics have been released. However, these cosmetics can be said to apply collagen to the surface of the skin, which can not be expected to moisturize by the transdermal absorption of the collagen polymer, which provides an essential skin function improvement.

On the other hand, it is known that the active ingredients that promote the collagen synthesis to exhibit the wrinkle improvement effect. For example, retinoic acid, transforming growth factor (TGF) (Cardinale G. et al, Adv. Enzymol., 41, p. 425, 1974), protein from animal placenta (JP8-231370), betul Belinic acid (JP8-208424), chlorella extract (JP9-40523, JP10-36283) and the like are known as collagen synthesis promoting substances. However, the active ingredients are limited in the amount of use due to safety problems such as irritation and redness when applying the skin, or there is a problem that can not be expected to effectively improve the skin function by substantially promoting the collagen synthesis of the skin. Therefore, there is an urgent need for the development of components that are safe for the living body, the active ingredients are stable, and above all, the anti-wrinkle activity that is superior to the conventional collagen synthesis promoting substance.

Collagen is a major substrate protein produced in skin fibroblasts and is present in extracellular epilepsy. Collagen is known to provide mechanical firmness of skin, resistance of connective tissue and binding of tissue, and to perform functions such as sustaining cell adhesion, inducing cell division and differentiation (when organic growth or wound healing) (van der Rest et al., 1990). This collagen is reduced by photoaging by age and UV irradiation, which is known to be closely related to wrinkle formation of the skin (Arthur K. Balin et al., "Aging and the skin", 1989). In recent years, extensive research on aging of the skin has been developed to reveal the important function of collagen in the skin.

Based on the skin moisturizing effect of collagen, products that incorporate collagen in cosmetics have been released. However, these cosmetics can be said to apply collagen to the surface of the skin, which can not be expected to moisturize by the transdermal absorption of the collagen polymer, which provides an essential skin function improvement.

On the other hand, it is known that the active ingredients that promote the collagen synthesis to exhibit the wrinkle improvement effect. For example, retinoic acid, transforming growth factor (TGF) (Cardinale G. et al, Adv. Enzymol., 41, p. 425, 1974), protein from animal placenta (JP8-231370), betul Belinic acid (JP8-208424), chlorella extract (JP9-40523, JP10-36283) and the like are known as collagen synthesis promoting substances. However, the active ingredients are limited in the amount of use due to safety problems such as irritation and redness when applying the skin, or there is a problem that can not be expected to effectively improve the skin function by substantially promoting the collagen synthesis of the skin. Therefore, there is an urgent need for the development of components that are safe for the living body, the active ingredients are stable, and above all, the anti-wrinkle activity that is superior to the conventional collagen synthesis promoting substance.

The present inventors have a strong collagen synthesis promoting activity and collagenase inhibitory activity, the compound of formula (I) in the process of screening an active ingredient that is safe for the skin, easy to formulate formulations, and stable in the manufacture and storage of cosmetics It was found to have the same properties. Therefore, the present invention provides a composition for improving wrinkles comprising the compound of formula (I) as an active ingredient.

The compound of the formula (I) of the present invention is not only excellent in collagen synthesis promoting activity and collagenase inhibitory activity, but also excellent in solubility and stability, which is very suitable for use as an active ingredient of the composition for improving wrinkles. Therefore, the composition of the present invention comprising the compound provides an excellent wrinkle improvement effect.

The present invention provides a composition for improving wrinkles comprising the compound of formula (I) as an active ingredient.

[Formula I]

In order to achieve an excellent wrinkle improvement effect when applied to the skin, the wrinkle improving ingredient exhibits high activity at the low concentration, has an excellent ability to absorb and penetrates the skin, and can stay for a sufficient time for the wrinkle improvement effect. It is desirable to have low volatility, to keep the active ingredient stable on the composition or the skin, to be easily formulated into medicine or cosmetics, and to be safe for the skin. However, among the known wrinkle improvement components, wrinkle improvement components that satisfy all of the above characteristics are rare. For example, some wrinkle improving ingredients have excellent wrinkle improving activity even at low concentrations in vitro, but are difficult to apply to actual skin due to their poor ability to absorb and penetrate the skin. Other anti-wrinkle ingredients are less hydrophilic and difficult to formulate in medicine or cosmetics. In addition, some wrinkle improving ingredients may decompose or be transformed into other compounds when exposed to heat, light, or oxygen, and the wrinkle improving effects may already disappear before being applied to the skin.

As can be seen in the following examples, the compound of formula (I) exhibits an excellent inhibitory activity of collagenase activity at low concentrations compared to retinoic acid, which is a known wrinkle improvement component, and shows an excellent effect of promoting collagen synthesis. In addition, the high solubility in the hydrophilic solvent showed a low volatility, excellent skin permeability, and easy formulation when applying the product. In addition, the stability with the passage of light, heat or time was found to be excellent. In addition, even at low concentrations, it has been shown to be very safe for the skin because it is sufficiently effective for improving wrinkles.

Therefore, the compound of formula (I) may be used as an active ingredient exhibiting wrinkle improvement in pharmaceuticals or cosmetics. The present invention therefore also provides the use of a compound of formula (I) for the preparation of a pharmaceutical composition for improving wrinkles or a cosmetic composition for improving wrinkles and a method for improving wrinkles comprising applying an effective amount of the compound of formula (I) to the skin.

The compound of the formula (I) 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 wrinkles generated on the skin or alleviating wrinkles already generated.

The wrinkle improvement composition of the present invention may provide a desirable wrinkle improvement effect when an effective amount of the compound of formula (I) is included. In the present invention, the term 'effective amount' means an amount of a compound capable of inhibiting or inhibiting generation of wrinkles on the skin or alleviating wrinkles already produced. The effective amount of the compound included in the composition for improving wrinkles 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 to stay in the skin. For example, when the composition for improving wrinkles is commercialized as a medicament for dermatological treatment according to the generation of wrinkles on the skin, the compound of formula (I) may be included at a higher concentration than when it is commercialized to cosmetics that are applied to the skin on a daily basis. There will be. Even in the case of cosmetics, the wash-off type of cosmetics such as makeup remover, detergent, etc., in which the active ingredient stays on the skin within a short time, may include a relatively high concentration of the compound of formula (I). On the other hand, in the case of a leave-on type cosmetic such as a lotion, an emulsion, a cream, or an essence in which the active ingredient stays on the skin for a long time, the compound of the formula (I) has a lower concentration than the wash-off type cosmetic. It will be alright. Although not limited thereto, in one embodiment of the present invention, the composition for improving wrinkles may include 0.0001% by weight to 10% by weight of the compound of formula (I). When the wrinkle improving composition of the present invention contains less than 0.0001% by weight of the compound of the formula (I), a sufficient wrinkle improvement effect cannot be expected, and when it contains more than 10% by weight, unwanted reaction such as allergy or skin safety occurs. There may be a problem, so it is to prevent this.

Wrinkle improvement composition of the present invention may further include a known wrinkle improvement component in addition to the compound of formula (I). Including an additional wrinkle improving component may further enhance the wrinkle improving effect of the composition of the present invention. Those skilled in the art will be able to select additional ingredients from known wrinkle improvement ingredients in consideration of skin safety, ease of formulation, and stability of the active ingredients according to combined use. In one embodiment of the present invention, the composition for improving wrinkles is a wrinkle improving component known in the art, for example, from the group consisting of retinoic acid, TGF, protein from animal placenta, betulinic acid and chlorella extract It may further comprise one or more wrinkle improving ingredients selected. Additional anti-wrinkle ingredients may be included from 0.0001% to 10% by weight relative to the total weight of the composition, wherein the weight percentages promote collagen synthesis or collagenase inhibitory activity, skin safety, formulation with a compound of formula (I). It may be adjusted according to requirements such as ease of use.

In the present invention, the wrinkle improving composition may be a pharmaceutical composition or a cosmetic composition. When the composition for improving wrinkles is formulated into a medicament or cosmetics, it may contain a known dermatologically acceptable excipient which serves as a carrier for the active ingredient. When formulated as a medicament, reference may be made to what is disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and when formulated as a cosmetic, International cosmetic ingredient dictionary, 6th ed., The cosmetic, Toiletry and Fragrance Association , Inc., Washington, 1995. Such documents are incorporated as part of this specification.

When the composition for improving wrinkles of the present invention is a cosmetic composition, the composition is not limited thereto, such as a lotion such as a flexible lotion or a nourishing lotion, an emulsion such as a facial lotion or a body lotion, a nutrient cream, a moisture cream, an eye cream, or the like. Foundations, such as creams, essences, ointments, sprays, gels, packs, sunscreens, makeup bases, liquids, solids or sprays, makeup removers such as powders, cleansing creams, cleansing lotions, cleansing oils, cleansing foams, soaps And detergents such as body washes and the like. In this case, the cosmetic composition may include a surfactant, an emulsifier, a soap acid, a solvent, a colorant, a preservative, an antioxidant, an antifoaming agent, an antibacterial agent, an antideposition agent, an enzyme, a plant or mineral oil, a fat, a fluorescent substance, a fungicide, a hydrophobic agent, Excipients, including moisturizers, fragrances, fragrance carriers, preservatives, proteins, silicones, solubilizers, sugar derivatives, sunscreens, vitamins, plant extracts, waxes and the like.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various forms. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Example

Example 1 Confirmation of the Inhibitory Effect of the Compound of Formula I

The inhibitory effect of collagenase activity of the compound of formula (I) was confirmed as follows.

In order to observe the inhibitory effect of collagen degrading enzyme activity, collagenase decomposes Gly-Leu binding of Dabcyl-r-Abu-Pro-GLu-Gly-Leu-Glu (EDANS) -Ala-Lys-NH2. The N terminus of the group and the C terminus of the EDNAS are experiments using the mechanism of action as a quencher. Into a 96-well plate incubator (96-well plate) by the concentration of the compound of formula I ((+)-Cedrol, more than 99%, C15H26O; Fluka 22135, USA) and the reaction buffer and commercially available substrate for 1 hour at 37 ℃ After the reaction, 5ul of EDTA was added to terminate the reaction. The color development was measured by measuring the absorbance at 340nm / 520nm using a flurometer (Bob Beekman et al., FEBS, 390, 221-225, 1996). As a negative control group, a group without addition of the compound of formula I was used, and a group containing 1% retinoic acid was used as a positive control group. Collagenase activity inhibition rate was calculated by the following equation 1, the results are shown in Table 1.

[Equation 1]

% Collagenase activity inhibition =

{1- (Responsiveness of Sample and Substrate / Responsiveness of Control)} X100

[Table 1] Collagenase activity inhibitory effect according to the concentration

sample Inhibition rate of collagen degrading enzyme activity (%) 1% compound of formula (I) 76 0.5% compound of formula (I) 42 0.1% compound of formula (I) 21 0.05% compound of formula (I) 10 0.001% compound of formula (I) 4 Voice control group (no processing) 0 Positive control group (retinoic acid 1%) 56

As can be seen from Table 1, the compound of formula (I) was found to exhibit an excellent inhibitory effect of collagenase activity at low concentrations compared to retinoic acid.

Example 2: Confirmation of the collagen synthesis promoting effect of the compound of formula (I)

The compound of formula (I) was added to the culture of human-derived fibroblasts to test the collagen synthesis promoting effect at the cellular level. Biosynthetic collagen was measured using a PICP EIA kit (Procollagen Type I C-Peptide Enzyme ImmunoAssay KIT,) (TAKARA, Japan).

Compounds of formula (I) were added to the culture medium of human fibroblasts at a final concentration of 0.5 µg / ml, 1 µg / ml, 2 µg / ml, 5 µg / ml and 10 µg / ml, respectively, and cultured for 1 day. As a negative control group, a group not treated with the compound of formula I was used, and as a positive control group, Vit. The group treated with C was used. After incubation, the culture medium was taken, and the degree of collagen biosynthesis at each concentration was measured at 450 nm using a spectrophotometer with PICP EIA Kit. Collagen biosynthesis was calculated relative to the negative control group without the addition of any collagen synthesis promoter. The results are shown in Table 2.

TABLE 2 Collagen Biosynthesis Effect at the Cell Level According to Concentration

sample Collagen production amount (average) % Increase Voice control group (no addition) 1.522 - Compound of Formula I (final concentration 0.5 mg / ml) 1.714 112.60% Compound of Formula (I) (final concentration 1 mg / ml) 1.828 120.10% Compound of Formula I (final concentration 2 mg / ml) 1.951 128.20% Compound of Formula (I) (final concentration 5 mg / ml) 2.074 136.30% Compound of Formula I (final concentration 10 mg / ml) 2.078 136.50% Compound of Formula I (final concentration 20 mg / ml) 2.128 139.80% Positive control (Vit. C, final concentration 52.8 mg / ml) 1.874 123.10%

                                                            * Repeat count = 5

As can be seen from the results of Table 2, the compound of formula (I) has a good collagen biosynthesis on fibroblasts derived from humans. In particular, Vit. It can be seen that it shows excellent collagen biosynthesis even at a lower concentration than C.

Example 3: Evaluation of the Wrinkle Improvement Effect of the Compound of Formula (I) in vivo

The wrinkle-improving effect of the compound of formula (I) was tested for wrinkles induced by light using a 6 week old hairless mouse. The compound of formula (I) was dissolved in 0.3% of 1,3-butylene glycol and used as a sample. The test method is as follows.

The hairless mouse was irradiated with 2MED for 3 days and 10 weeks a week using a solar simulator to form wrinkles. The degree of improvement was qualitatively determined in the group treated with 0.5 ml / cm ² (1.5 mg / cm ² as the compound of Formula I) for 6 weeks, twice a day.

Wrinkle improvement was judged by visual inspection and photographing of the sample processing area, and the criterion was judged by three stages of no improvement, slight improvement, and significant improvement compared to the sample treatment group and the control group. Table 3 shows.

[Table 3] Wrinkle improvement effect on the mouse

sample No improvement Minor improvements A significant improvement Control 9 0 One Compound Treatment Group of Formula I One 6 3

                                                    Population in each group = 10

Example 4 Evaluation of Stability of Compounds of Formula (I)

The compound of formula (I) was dissolved in 70% ethanol at 0.5% and then exposed to the following conditions to evaluate the stability: light (natural light, 2 weeks), heat (80 ° C., 8 hours), over time (shading, 25 ° C., 3) month)

Table 4 shows the results of analyzing the stability of the compound of formula (I).

Table 4 Stability Analysis of Compounds of Formula (I)

sample Natural light (2 weeks) Heat (80 ?, 8 hours) Neglected (shaded, 25 ?, 3 months) 1% compound of formula I (50% ethanol) 100% 100% 100%

As can be seen from Table 4, the compounds of formula I have been shown to be stable to flow at light, heat and time.

Preparation Example 1 and Comparative Example 1

A skin external ointment comprising the compound of formula (I) as described in the table below was prepared according to conventional methods. In addition, the external skin ointment prepared with the remaining components except for the compound of formula (I) was prepared in Comparative Example 1.

TABLE 5

Composition Preparation Example 1 (% by weight) Comparative Example 1 -Compound of formula (I)-Diethyl sebacate-Lead-Polyoxyethylene oleyl ether phosphate-Sodium benzoate-Vaseline 2 8 5 6 Suitable to 100 -8 5 6 Suitable to 100

Preparation Example 2 and Comparative Example 2

A cream comprising the compound of formula (I) as described in the table below was prepared according to conventional methods. In addition, a cream prepared with the remaining ingredients except for the compound of formula I was prepared in Comparative Example 2.

TABLE 6

Composition Preparation Example 2 (% by weight) Comparative Example 2 -Compounds of formula I-Stearic acid-Cetanol-Potassium hydroxide-Glycerine-Propylene glycol-Preservative-Fragrance-Purified water 0.5 15.0 1.0 0.7 5.0 3.0 Proper quantity to 100 -15.0 1.0 0.7 5.0 3.0 Proper quantity to 100

Preparation Example 3 and Comparative Example 3

A flexible lotion containing a compound of formula (I) as described in the table below was prepared according to conventional methods. In addition, a flexible lotion prepared with the remaining components except for the compound of formula (I) was prepared in Comparative Example 3.

TABLE 7

Composition Preparation Example 3 (wt%) Comparative Example 3 -Compounds of formula (I)-Ethanol-Polylauric acid polyoxyethylene sorbitan-Paraoxybenzoic acid methyl-Glycerine-1, 3- butylene glycol-Flavor-Pigment-Purified water 0.2 10.0 1.0 0.2 5.0 6.0 Proper quantity to 100 -10.0 1.0 0.2 5.0 6.0 Proper quantity to 100

Preparation Example 4 and Comparative Example 4

A nutritional lotion comprising a compound of formula (I) as described in the table below was prepared according to conventional methods. In addition, the nutritional lotion prepared with the remaining ingredients except for the compound of formula (I) was prepared in Comparative Example 4.

TABLE 8

Composition Preparation Example 4 (wt%) Comparative Example 4 -Compound of formula I-Waselin-Sesquioleate sorbitan-Polyoxyethylene oleyl ethyl-Paraoxy benzoic acid methyl-Propylene glycol-Ethanol-Carboxy vinyl polymer-Potassium hydroxide-Pigment-Flavor-Purified water 0.1 2.0 0.8 1.2 appropriate 5.0 3.2 18.0 0.1 appropriate volume to 100 -2.0 0.8 1.2 appropriate 5.0 3.2 18.0 0.1 proper quantity to 100

Preparation Example 5 and Comparative Example 5

Packs containing the compounds of formula (I) as described in the table below were prepared according to conventional methods. In addition, a pack prepared with the remaining ingredients except for the compound of formula I was prepared in Comparative Example 5.

TABLE 9

Composition Preparation Example 5 (% by weight) Comparative Example 5 -Compound of formula I-Glycerine-Propylene glycol-Polyvinyl alcohol-Ethanol-Polyoxyethylene oleyl ethyl-Paraoxybenzoic acid methyl-Pigment-Flavor-Purified water 0.2 5.0 4.0 15.0 8.0 1.0 0.2 Proper quantity to 100 -5.0 4.0 15.0 8.0 1.0 0.2 Proper volume to 100

Preparation Example 6 and Comparative Example 6

Essences comprising a compound of formula (I) as described in the table below were prepared according to conventional methods. In addition, an essence prepared with the remaining components except for the compound of formula (I) was prepared in Comparative Example 6.

TABLE 10

Composition Preparation Example 6 (wt%) Comparative Example 6 -Compound of formula (I)-Propylene glycol-Glycerin-Sodium hyaluronate aqueous solution (1%)-Ethanol-Polyoxyethylene hardened castor oil-Paraoxybenzoic acid methyl-Fragrance-Purified water 0.5 10.0 10.0 5.0 5.0 1.0 0.1 dose to 100 -10.0 10.0 5.0 5.0 1.0 0.1 dose to 100

Experimental Example: Confirmation of the wrinkle improvement effect of the compound of formula (I)

For the essences of Preparation Example 6 and Comparative Example 6 Wrinkle improvement effect was carried out in healthy 35 to 50 year old women as follows.

Twenty women aged 35 to 50 years old were divided into two groups, and group 1 group 10 contained the essence of Preparation Example 6 containing the compound of formula I in the right eye area and the essence of Comparative Example 6 once a day on the left side. For two months, ten people in Group 2 were coated with the essence of Preparation Example 6 containing the compound of Formula I at the left eye and the essence of Comparative Example 6 on the right side once a day for two months.

After 2 months, the improvement of wrinkles on the left and right sides was evaluated through a questionnaire and image analysis of the wrinkles. The subject's questionnaire was judged in three stages of improvement, slight improvement, and significant improvement compared to before use regarding wrinkle improvement and elasticity improvement. The results are shown in Table 11.

Table 11 Wrinkle improvement effect of the production example according to the present invention (name)

sample No improvement Minor improvements A significant improvement Comparative Example 6 14 5 One Preparation Example 6 3 9 8

As can be seen in Table 11, it can be seen that when the essence of Preparation Example 6 according to the present invention is used, the wrinkle improvement effect is excellent.

Image analysis of wrinkles was performed by taking replicas under the eyes (Xantopren, Bayer) before the experiment began, and immediately after the experiment was finished, replicas were taken from the same area under the eyes. Dimensional analysis determined the density of wrinkles. The results of the measurement of wrinkle density by image analysis are shown in Table 12 by averaging the reduction ratio for wrinkle density before use.

[Table 12] Wrinkle improvement effect of the preparation example (image analysis)

sample Wrinkle Density Reduction (%) Comparative example 8% Production Example 27%

As can be seen from Table 12, when the essence of Preparation Example 6 according to the present invention is applied, it can be seen that the density of wrinkles is greatly reduced than before use. In addition, it can be seen that it is a safe substance without any skin side effects during the test period.

Claims (5)

Wrinkle improvement composition comprising a compound of formula (I) as an active ingredient. [Formula I]

The composition for improving wrinkles according to claim 1, wherein the compound of Formula I is contained in an amount of 0.0001% to 10% based on the total weight of the composition. The composition for improving wrinkles according to claim 1, further comprising at least one wrinkle improving component selected from the group consisting of retinoic acid, TGF, protein from animal placenta, betulinic acid and chlorella extract. The wrinkle improvement composition of claim 3, wherein the additional wrinkle improvement component is contained in an amount of 0.0001% to 10% based on the total weight of the composition. According to claim 1, wherein the wrinkle improvement composition is selected from the group consisting of lotion, milky lotion, cream, essence, cosmetic ointment, spray, gel, pack, sunscreen, makeup base, foundation, powder, makeup remover and cleaning agent Wrinkle improvement composition having a formulation.