KR20140033815A

KR20140033815A - Derivatives of quinic acid and the use thereof

Info

Publication number: KR20140033815A
Application number: KR1020120100159A
Authority: KR
Inventors: 김청택
Original assignee: 주식회사 알엔에스
Priority date: 2012-09-10
Filing date: 2012-09-10
Publication date: 2014-03-19

Abstract

The present invention relates to derivatives of quinic acid having enhanced whitening activities and to a composition for skin whitening which includes one selected from a group including a mixture of the derivatives of quinic acid. The derivatives of quinic acid have excellent skin whitening effects and outstanding safety by not generating side effects.

Description

Derivatives of quinic acid and the use thereof

The present invention relates to a cosmetic composition for skin whitening containing a quinic acid derivative as an active ingredient, and more particularly, to a composition for skin whitening that can be safely used without side effects on the skin and has an excellent effect of inhibiting melanin production.

Skin is the largest tissue in the human body and plays an important role in protecting the interior of the skin from external stimuli as a primary barrier. These skins appear differently in color with age or with age, depending on the concentration and distribution of melanin inside the skin. Skin melanogenesis is a defense mechanism against stimuli such as ultraviolet light in melanocyte-producing cells (melanocyte), and a large amount of melanin produced by the melanin is transferred to keratinocyte and accumulated on the skin surface layer Results. Although melanin protects the skin, hyperpigmentation of the skin causes skin irritation, freckles, darkening of the skin after inflammation of the skin and aging pigmentation spots. This causes the discomfort of the person not only the cosmetic discomfort but also the psychological negative affect on the social activities. . Melanin is produced by tyrosine tyrosine, an enzyme called tyrosinase, converted into DOPA or dopaquinone, and then enzymatically oxidized to form an abnormal deposit in the skin And it is known that it produces spots and black spots.

Various compositions have conventionally been used to inhibit melanin production of the skin as described above. For example, various extracts extracted from L-ascorbic acid and its derivatives, hydroquinone, arbutin and licorice, and lettuce skin are used as skin whitening agents. However, L-ascorbic acid is easily oxidized to cause irritation to the skin, and the cosmetics containing it cause discoloration and discoloration problems. The substances derived from plant extracts have a great difference in efficacy depending on the plant's origin, thus maintaining homogeneity of the product. It is difficult to do, and arbutin has the disadvantage of low effect.

As to solve the above problems, the present invention provides a cosmetic composition comprising a quinic acid derivative and / or a mixture thereof as an active ingredient having no side effect on the skin and excellent melanin production inhibitory effect.

The present invention provides a cosmetic composition comprising any one or more selected from the group consisting of compounds represented by the following formula (1) excellent in melanin production inhibitory effect as an active ingredient.

[Formula 1]

R ₁ , R ₂ , R ₃ , and R ₄ of Formula 1 are each independently a substituent selected from hydrogen, caffeoyl, galloyl, or feruloyl, and R ₁ , R ₂ , Hydrogen out of R <_3> , R <_4> is 1-3.

The present invention provides a composition for skin whitening containing any one or more selected from the group consisting of the compound represented by Formula 1 as an active ingredient.

The cosmetic composition of the present invention has an excellent whitening effect, almost no skin irritation to the human body, so the safety of the product is excellent, it can be usefully used as a cosmetic composition for skin whitening.

Hereinafter, the present invention will be described in more detail.

Illustrative substance names of Chemical Formula 1 according to the present invention are as follows.

For example, 1-caffeoylquinic acid, 3-caffeoylquinic acid, 4-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid ( 5-caffeoylquinic acid), 1,3-dicaffeoylquinic acid, 1,4-dicaffeoylquinic acid, 1,5-dicaffeoylquinic acid 1,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 4,5- Dicafeoylquinic acid (1,3,5-triaffeoylquinic acid), 3,4,5-tricaoylquinic acid (3,5,3-triaffeoylquinic acid) 4,5-tricaffeoylquinic acid), 1,3,4,5-tetracafeoylquinic acid (1,3,4,5-tetracaffeoylquinic acid), 3-galloylquinic acid, 4-galloylqui 4-galloylquinic acid, 5-galloylquinic acid, 3,5-digalloylquinic acid, 3-feruloylquinic acid, 4-ferullo Ilquinic acid (4-feruloylquinic acid), 5-feruloylquinic acid (5-feruloylquinic acid) and the like, but is not limited thereto.

Each of these compounds has an excellent whitening effect by inhibiting melanin production. Therefore, the compounds are useful as a cosmetic composition for skin whitening. In addition, the cosmetic composition of the present invention is safe on human skin because it does not show a distinctive pattern in the skin accumulation stimulation test.

The compounds may be obtained through synthetic processes by conventional methods or may be obtained by extraction and purification from natural products.

The natural products from which the compounds can be obtained include poisonous A (angelica pubescens), poisonous B (aralia cordata), larvae (artemisia sp), roots (boahmaria nivea), chrysanthemum morifolium, capsicum annuum, cnidium officinale, lake (coriandrum sativum), hawthorn (Crataegus sp.), cucumis sativus, cuscusa chinensis, fennel (foeniculum vulgare), soybean (glycine max), helianthus annuus, houttuynia cordata, imperata cylindrica, inula britannica, kaempferia galanga, kalopanax pictus, lamium album, lonicera sp., phytolacca sp. platycodon grandiflorum, prunus persica, pterocarpus santalinus, pyrrosia sp., sambucus javanica, solannum melongena, solanum nigrum, sournum nigrum, sorghum bicolor, and tombs spinacia oleracea, stellaria media, taraxacum sinicum, tussilago farfara, vitis vin ifera, geranium thunbergii, gleditsia japonica, corn (zea mays), wild cattle (ipomoea batatas), thistle (cisium japonicum), artichoke (cynara scolymus), and the like.

The content of the compounds and / or mixtures thereof contained in the preparation of external skin ointments or cosmetics is 0.00001 to 10.0% by weight, preferably 0.001 to 1.0% by weight, based on the total weight of the composition. If the content of the compound and / or mixtures thereof is less than 0.00001% by weight in dry weight based on the total amount of the composition can not be expected to have a noticeable effect such as skin whitening, when the content of more than 10.0% by weight increases the apparent effect increases with the content Did not appear.

The components included in the cosmetic composition of the present invention include components conventionally used in cosmetic compositions in addition to the compounds and / or mixtures thereof as active ingredients, and include, for example, antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings. Such conventional adjuvants, and carriers.

The cosmetic composition of the present invention may be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it can be manufactured in the form of a flexible lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

Experimental Example 1

Inhibitory effect of melanin production at the cellular level

1-cafeoylquinic acid, 3-cafeoyl quinic acid, 4-cafeoyl quinic acid, 5-cafeoyl quinic acid, 1,3-dicao yl quinic acid, 1,4-dicao yl quinic acid, 1, 5-dicafeoylquinic acid, 3,4-dicafeoylquinic acid, 3,5-dicafeoylquinic acid, 4,5-dicafeoylquinic acid, 1,3,5-tricafeoylquinic acid, 3,4,5-tricafeoylquinic acid, 1,3,4,5-tetracafeoylquinic acid, 3-galloylquinic acid, 4-galloylquinic acid, 5-galloylquinic acid, 3,5-digallo Ilquinic acid, 3-feruloyl quinic acid, 4-feruloyl quinic acid, and 5-feruloyl quinic acid were added to the culture medium of B-16 mouse melanoma cells, respectively, to achieve a whitening effect at the cellular level. The experiment was as follows (Lotan R., Lotan D. Cancer Res. 40: 3345-3350, 1980).

Each compound was added to the culture medium at the final concentration of 1 ㎍ / ml, 10 ㎍ / ml to cultivate B-16 melanoma cells, incubated for 3 days and treated with trypsin, the culture vessel The melanin was extracted after removing from the centrifugation. Sodium hydroxide solution to the extraction of melanin (1N concentration) 1 ml and the reaction mixture was dissolved melanin boiled for about 10 minutes, the amount of the produced melanin by measuring the absorbance at 400 nanometers (nm) with a spectrophotometer unit cell allowance (10 ⁶ The experiment was carried out by a method showing the absorbance of the cell). The experiment was repeated three times and the average value was used to calculate the relative melanin production relative to the control group as inhibition rate (%), and the results are shown in Table 1 below.

sample Concentration (/ / ml) Inhibition rate (%) Control group (no addition) - 0 1-Cape Oil Quinic Acid One 26 10 75 3-cafeoylquinic acid One 28 10 74 4-cafeoylquinic acid One 31 10 75 5-cafeoylquinic acid One 25 10 69 1,3-dicafeoylquinic acid One 47 10 85 1,4-dicafeoylquinic acid One 39 10 78 1,5-dicafeoylquinic acid One 41 10 79 3,4-dicafeoylquinic acid One 42 10 81 3,5-dicafeoylquinic acid One 45 10 79 4,5-dicafeoylquinic acid One 51 10 87 1,3,5-tricafeoylquinic acid One 32 10 75 3,4,5-tricafeoylquinic acid One 32 10 65 1,3,4,5-tetracafeoylquinic acid One 31 10 59 3-galloylquinic acid One 32 10 58 4-galloylquinic acid One 25 10 53 5-galloylquinic acid One 27 10 58 3,5-digalloylquinic acid One 42 10 76 3-feruloylquinic acid One 23 10 51 4-feruloylquinic acid One 32 10 57 5-feruloylquinic acid One 32 10 61 Hydroquinone One 42 10 Cell death

Iterations = 3

As shown in Table 1, it can be seen that the quinic acid derivatives have comparable melanin production inhibitory ability against cultured mouse melanoma cells compared to hydroquinone, which is a known whitening substance. In addition, hydroquinone has a strong melanin production inhibitory ability at low concentrations, but the cytotoxicity is severe and can not be tested at 10 ㎍ / ml or more, but quinic acid derivatives have a higher melanin production inhibitory effect than hydroquinone without showing cytotoxicity This indicates that the present invention can be very useful for improving blemishes and freckles and skin whitening.

Preparation Examples 1 to 4 and Comparative Example 1

Each of the ingredients shown in Table 2 below was mixed as shown in the following Table 2 to prepare an ointment for external use on the skin.

Composition weight% Production Example 1 Production Example 2 Production Example 3 Production Example 4 Comparative Example 1 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
Diethyl sebacate
Prepayment
Polyoxyethylene oleyl ether phosphate
Sodium benzoate
vaseline 0.01
-
-
-
8
5
6
Suitable amount
Remaining amount * -
0.01
-
-
8
5
6
Suitable amount
Remaining amount * -
-
0.01
-
8
5
6
Suitable amount
Remaining amount * -
-
-
0.01
8
5
6
Suitable amount
Remaining amount * -
-
-
-
8
5
6
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Preparation Examples 5 to 8 and Comparative Example 2

Nutrient creams were prepared by mixing the respective ingredients shown in Table 3 below in the proportions shown in Table 3 below.

Composition weight% Production Example 5 Production Example 6 Production Example 7 Production Example 8 Comparative Example 2 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
Stearic acid
Cetanol
Fiji-20 sorbitan monostearate
Sorbitan monostearate
Mineral oil
Trioctanoate
Triethanolamine
Carbomer
glycerin
Propylene glycol
antiseptic
incense
Purified water 0.01
-
-
-
1.0
2.0
1.0
1.0
10.0
5.0
0.5
0.2
5.0
3.0
Suitable amount
Suitable amount
Remaining amount * -
0.01
-
-
1.0
2.0
1.0
1.0
10.0
5.0
0.5
0.2
5.0
3.0
Suitable amount
Suitable amount
Remaining amount * -
-
0.01
-
1.0
2.0
1.0
1.0
10.0
5.0
0.5
0.2
5.0
3.0
Suitable amount
Suitable amount
Remaining amount * -
-
-
0.01
1.0
2.0
1.0
1.0
10.0
5.0
0.5
0.2
5.0
3.0
Suitable amount
Suitable amount
Remaining amount * -
-
-
-
1.0
2.0
1.0
1.0
10.0
5.0
0.5
0.2
5.0
3.0
Suitable amount
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Preparation Examples 9 to 12 and Comparative Example 3

The respective ingredients shown in the following Table 4 were mixed in the ratios shown in the following Table 4 to prepare a flexible lotion.

Composition weight% Production Example 9 Production Example 10 Production Example 11 Production Example 12 Comparative Example 3 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
ethanol
Polyoxyethylene hardened castor oil
Paraoxybenzoic Acid Methyl
glycerin
1,3-butylene glycol
incense
Pigment
Purified water 0.01
-
-
-
10.0
1.0
2
5.0
6.0
Suitable amount
Suitable amount
Remaining amount * -
0.01
-
-
10.0
1.0
2
5.0
6.0
Suitable amount
Suitable amount
Remaining amount * -
-
0.01
-
10.0
1.0
2
5.0
6.0
Suitable amount
Suitable amount
Remaining amount * -
-
-
0.01
10.0
1.0
2
5.0
6.0
Suitable amount
Suitable amount
Remaining amount * -
-
-
-
10.0
1.0
2
5.0
6.0
Suitable amount
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Preparation Examples 13 to 16 and Comparative Example 4

Essence was prepared by mixing each component shown in Table 5 in the same ratio as shown in Table 5 below.

Composition weight% Production Example 13 Production Example 14 Production Example 15 Production Example 16 Comparative Example 4 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
Propylene glycol
glycerin
Sodium hyaluronate aqueous solution (1%)
ethanol
Polyoxyethylene hardened castor oil
Paraoxybenzoic Acid Methyl
Carbomer
Triethanolamine
incense
Purified water 0.01
-
-
-
10.0
10.0
5.0
5.0
1.0
0.1
0.3
0.4
Suitable amount
Remaining amount * -
0.01
-
-
10.0
10.0
5.0
5.0
1.0
0.1
0.3
0.4
Suitable amount
Remaining amount * -
-
0.01
-
10.0
10.0
5.0
5.0
1.0
0.1
0.3
0.4
Suitable amount
Remaining amount * -
-
-
0.01
10.0
10.0
5.0
5.0
1.0
0.1
0.3
0.4
Suitable amount
Remaining amount * -
-
-
-
10.0
10.0
15.0
5.0
1.0
0.1
0.3
0.4
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Preparation Examples 17 to 20 and Comparative Example 5

A pack was prepared by mixing the respective components shown in Table 6 below in the proportions shown in Table 6 below.

Composition weight% Production Example 17 Production Example 18 Production Example 19 Production example 20 Comparative Example 5 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
glycerin
Propylene glycol
Polyvinyl alcohol
ethanol
Polyoxyethylene hardened castor oil
Polyoxyethylene Oleethyl
Paraoxybenzoic Acid Methyl
incense
Pigment
Purified water 0.01
-
-
-
5.0
4.0
15.0
8.0
1.0
1.0
0.2
Suitable amount
Suitable amount
Remaining amount * -
0.01
-
-
5.0
4.0
15.0
8.0
1.0
1.0
0.2
Suitable amount
Suitable amount
Remaining amount * -
-
0.01
-
5.0
4.0
15.0
8.0
1.0
1.0
0.2
Suitable amount
Suitable amount
Remaining amount * -
-
-
0.01
5.0
4.0
15.0
8.0
1.0
1.0
0.2
Suitable amount
Suitable amount
Remaining amount * -
-
-
-
5.0
4.0
15.0
8.0
1.0
1.0
0.2
Suitable amount
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Preparation Examples 21 to 24 and Comparative Example 6

Nutritional lotion was prepared by mixing the respective ingredients shown in the following Table 7 as shown in Table 7 below.

Composition weight% Production Example 11 Production Example 11 Production Example 12 Production Example 11 Comparative Example 6 3-cafeoylquinic acid
1,3-dicafeoylquinic acid
3,4,5-tricafeoylquinic acid
1,3,4,5-tetracafeoylquinic acid
Polyoxyethylene hardened castor oil
Paraoxybenzoic Acid Methyl
glycerin
1,3-butylene glycol
Carbomer
Triethanolamine
Propylene glycol
ethanol
Carboxyvinyl polymer
Pigment
incense
Purified water 0.01
-
-
-
1.0
Suitable amount
6.0
5.0
0.2
0.3
5.0
2
One
Suitable amount
Suitable amount
Remaining amount * -
0.01
-
-
1.0
Suitable amount
6.0
5.0
0.2
0.3
5.0
2
One
Suitable amount
Suitable amount
Remaining amount * -
-
0.01
-
1.0
Suitable amount
6.0
5.0
0.2
0.3
5.0
2
One
Suitable amount
Suitable amount
Remaining amount * -
-
-
0.01
1.0
Suitable amount
6.0
5.0
0.2
0.3
5.0
2
One
Suitable amount
Suitable amount
Remaining amount * -
-
-
-
1.0
Suitable amount
6.0
5.0
0.2
0.3
5.0
3.2
0.1
Suitable amount
Suitable amount
Remaining amount *

*: Amount to be 100% by weight in total

Experimental Example 3

Whitening effect test in clinical

Twenty healthy men and women were selected and covered with aluminum foil in two rows of four holes with a diameter of 7 mm in the lower forearm of both arms, and 60 mJ with a ORIEL Solar Simulator 1000W at a distance of 10 cm from the arm. The amount of light of / cm 2 was investigated. Samples containing the quinic acid derivatives prepared according to Preparation Examples 13-16 and Comparative Example 4 and bases not contained were applied to the same lines twice a day from 3 days before irradiation to 3 weeks after irradiation. The degree of pigmentation of the preparation examples and the comparative examples was visually determined for each of the above. The results are shown in Table 8 below.

Experimental material Distinct effect (n.) Effective (persons) No difference (persons) Production Example 13 One 10 9 Production Example 14 3 11 6 Production Example 15 2 10 8 Production Example 16 One 9 10

As shown in Table 8, the essences prepared according to 13-16 in the preparation showed a whitening effect on at least 10 or more of 20 subjects, and also showed no side effects in the skin, thus making it safe and freckled. It can be seen that the skin whitening agent has an excellent effect on improvement.

Claims

A composition for skin whitening comprising a quinic acid derivative of Formula 1 and / or a mixture thereof as an active ingredient.
[Chemical Formula 1]

In Formula 1, R ₁ , R ₂ , R ₃ , R ₄ are each independently a substituent selected from hydrogen, caffeoyl, galloyl or feruloyl, R ₁ , R ₂ , R ₃ , R ₄ is 0 to 3 hydrogen.

The method of claim 1, wherein the derivative is 1-caffeoylquinic acid, 3-caffeoylquinic acid, 4-caffeoylquinic acid, 4-caffeoylquinic acid, 5- 5-caffeoylquinic acid, 1,3-dicaffeoylquinic acid, 1,4-dicaffeoylquinic acid, 1,5 1,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid , 4,5- dicaffeoylquinic acid, 1,3,5-triaffeoylquinic acid, 3,4,5-tricaooil Quinic acid (3,4,5-tricaffeoylquinic acid), 1,3,4,5-tetracafeoylquinic acid (1,3,4,5-tetracaffeoylquinic acid), 3-galloylquinic acid , 4-galloylquinic acid, 5-galloylquinic acid, 3,5-digalloylquinic acid, 3-feruloylquinic acid (3 -feru Loylquinic acid), 4-feruloylquinic acid (4-feruloylquinic acid), 5-feruloylquinic acid (5-feruloylquinic acid) derivatives or their pharmacologically acceptable salts as a composition for skin whitening.

3. The method according to claim 1 or 2,
Single A (angelica pubescens), single B (aralia cordata), lobice (artemisia sp), root (boahmaria nivea), chrysanthemum morifolium, capsicum annuum, cnidium officinale, lake (coriandrum sativum), Crataegus sp., Cucumis sativus, Cuscuta chinensis, Feniculum vulgare, Glycine max, Helicopterus (helianthus annuus), Huttuynia cordata, Hair root (imperata cylindrica) Inula britannica, kaempferia galanga, kalopanax pictus, lamium album, lonicera sp., Phytolacca sp., Playcodon grandiflorum, prunus persica , Pterocarpus santalinus, pyrrosia sp., Sabucus javanica, solanum melongena, solannum nigrum, soorghum bicolor, spinacia oleracea, panlu (stellaria media), Pogongyoung (taraxacum sinicum), Kanto (tussilago farfara), grape root (vitis vinifera), herbaceous (geranium thunbergii), sculpture (gleditsia japoni) ca), corn (zea mays), cacalia firma, ipomoea batatas, thistle (cisium japonicum), artichoke (cynara scolymus) composition for skin whitening comprising as an active ingredient .

A skin external pharmaceutical composition for the prevention, treatment and whitening of hyperpigmentation, blemishes, freckles and blotch, comprising the compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.

A composition for skin whitening comprising 0.00001 to 10.0 wt% of the compound according to any one of claims 1 to 3 and / or a mixture thereof, based on the total amount of the composition.

The composition according to any one of claims 1 to 3, wherein the composition is formed of any one formulation selected from the group consisting of skin, lotion, cream, foundation, essence, gel, pack, product cleansing and ointment. Composition.