CN1352546A - Skin whitener - Google Patents

Abstract

The present invention relates to skin whitener which can be used as pharmaceuticals and cosmetic materials having skin whitening effect, particularly as a skin whitener, which is safe and has an excellent skin whitening effect, and is comprised of an effective constitutent of selina-4(14),7(11)-dien-8-one.

Description

skin brightener

Cross References to Related Applications

This application is based on Application No. 98-17641 filed with the Korean Industrial Property Office on May 22, 1998, the contents of which are incorporated herein by reference.

Background of the Invention

(a) Field of Invention

The present invention relates to a skin whitening agent which can be used together with a drug and a cosmetic substance having a skin whitening effect, especially containing sesquiterpene which has an excellent melanin formation suppressing effect for fading freckles or spots and whitening the skin Brightener of ene-type selina-4(14), 7(11)-dien-8-one.

(b) Description of related technology

Human skin color is usually determined genetically by the concentration and distribution of melanin in the skin. However, it is also affected by ambient or physiological conditions such as the sun's ultraviolet rays, fatigue and stress. The above-mentioned melanin is formed after the enzyme tyrosinase acts on the amino acid tyrosine to convert it into dopa and dopaquinone through a non-enzymatic oxidation reaction.

It follows that the process of melanin formation is known, but the mechanism of inducing melanin synthesis or the steps preceding the action of tyrosinase has not been disclosed in detail.

Therefore, commonly used substances having tyrosinase inhibitory activity such as hydroquinone, ascorbic acid, kojic acid and glutathione have been used for skin whitening and fading freckles and spots after being mixed with ointments or cosmetics.

However, these products suffer from limited applicability due to poor product safety, skin irritation, and limited effectiveness.

Summary of Invention

Therefore, the present invention is to solve the above-mentioned problems. The object of the present invention is to provide a skin whitening agent which has a strong effect of inhibiting melanin formation and causes fewer problems in use.

The skin whitening agent of the present invention for achieving the above object is characterized in that it comprises cnidone-4(14),7(11)-dien-8-one represented by the following general formula 1.

[Formula 1]

Although studies have reported that the above-mentioned cnidone-4(14), 7(11)-dien-8-one has anti-inflammatory effect [Chem.Pharm.Bull., 27(12), 2954, 1979], anti-dementia effect [ Japanese published patent JP09094452] etc., but these effects are completely different from the present invention.

Cnidium-4(14), 7(11)-dien-8-one is an organic compound of 15 carbon atoms, which is a generally known substance mentioned in various literatures and can be obtained from microorganisms, plants and animals obtained from.

It can be said that the skin whitening agent of the present invention can be contained in red atractylodes rhizome, white atractylodes rhizome, atractylodes rhizome, hepatica, bladhia japanica, It can be obtained from cnidium-4(14), 7(11)-dien-8-one in asiasarum and bladhia japanica.

Brief description of attached drawings

A more complete appreciation of the invention and its many attendant advantages will become readily apparent when the invention is better understood and referred to the following detailed description when considered in connection with the accompanying drawings, in which:

Fig. 1 is the NMR spectrogram of isolated cnidone-4(14), 7(11)-dien-8-one; and

Figure 2 is the mass spectrum of isolated cnidone-4(14),7(11)-dien-8-one.

Detailed description of the preferred implementation plan

In the following detailed description, preferred embodiments of the invention are described simply by way of illustration of the best mode contemplated by the inventors for carrying out the invention. As will be realized, the invention is capable of modifications in various obvious respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not restrictive.

As mentioned above, it is an object of the present invention to provide a skin lightening agent characterized in that it comprises cnidone-4(14),7(11)-dien-8-one, a sesquiterpene which is capable of Natural organic compounds obtained from nature.

The above-mentioned cnidone-4(14),7(11)-dien-8-one is preferably extracted from plants which are especially sold as raw materials. Sources of Cnidium-4(14), 7(11)-dien-8-one include plants such as Rhizoma Atractylodes Rhizome, Atractylodes Rhizoma Atractylodes Rhizome, Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Atractylodes Rhizoma Rhizoma Atractylodes Rhizoma Rhizoma Atractylodes Rhizome, Zijinniu, Hydrangea, Hydrangea and other plants.

Techniques for isolating cnidone-4(14),7(11)-dien-8-one from these plants include various commonly known methods, for example, drying the The extract was then suspended in water, and the same volume of hexane was added to the suspension. The hexane fraction obtained by liquid-liquid partition was dried, from which pure cnidone-4(14),7(11)-dien-8-one was obtained by column chromatography and high performance liquid chromatography.

When the pure isolated cnidone-4(14),7(11)-dien-8-one was used to treat mouse B-16 melanoma cells, it showed a very strong inhibitory effect on melanin synthesis. In addition, when this compound is put into various cosmetic substances such as skin external ointment or lotion and applied to human skin, the skin whitening effect is excellent. In addition, no other side effects were shown, so it can be seen that it is a highly safe and very effective agent for fading freckles or spots and whitening the skin.

The preferred solids content of cnidone-4(14),7(11)-dien-8-one in cosmetic or external skin ointments is 0.000001 to 10% by weight. However, since the skin whitening effect is not so good when the content is less than 0.001% by weight and no significant improvement in effect is observed when the content is increased above 1% by weight, the range of 0.001 to 1% by weight is more preferable of.

Although the present invention will hereinafter be described in detail based on the following experiments, comparative examples, and production examples, the present invention is not limited to these examples.

Example 1

After purchasing and crushing Atractylodes Rhizome, put 100 g of crushed Atractylodes Rhizome into 500 ml of 100% n-hexane solvent, boil for 3 hours in a reflux extractor with a cooling condenser, then extract it and filter it with 300 mesh Cloth filter. The remaining material was treated again in the same manner as above. Combine the extracts and filter with Whatman No. 2 filter paper to remove insoluble substances. The liquid was then concentrated at 60°C under reduced pressure using a distillation apparatus, and the concentrate was then suspended in 300 ml of purified water. 300 ml of hexane was added and the mixture was shaken uniformly to obtain a hexane-soluble material. The soluble matter was separated by silica gel column chromatography to obtain 450 mg of a fraction containing the active ingredient. This fraction was purified again by high performance liquid chromatography, and 210 mg of cnidone-4(14),7(11)-dien-8-one were isolated.

Figure 1 shows the proton NMR spectrum of isolated cnidone-4(14),7(11)-dien-8-one, and Figure 2 shows the mass spectrum.

Example 2

After purchasing and pulverizing Atractylodes Rhizome, put 100 grams of pulverized Atractylodes Rhizome fragments into 500 milliliters of 100% ethanol solvent, and obtain 155 mg of Cnidium-4(14), 7(11)- Dien-8-one.

Example 3

After purchasing and pulverizing Atractylodes Rhizome, put 100 grams of pulverized Atractylodes Rhizome fragments into 500 ml of 100% chloroform solvent, and obtain 175 mg of Cnidium-4(14), 7(11)- Dien-8-one.

Example 4

After purchasing and crushing Atractylodes Rhizome, put 100 g of crushed Atractylodes Rhizoma Atractylodes into 500 ml of 100% capric/caprillic triester and boil for 3 hours in a reflux extractor with a cooling condenser, which Then extract it and filter it with a 300-mesh filter cloth. Filter with Whatman No. 2 filter paper at room temperature to remove insoluble substances. Quantification of cnidone-4(14),7(11)-dien-8-one using high performance liquid chromatography resulted in 280 mg of cnidone-4(14),7(11) from 100 g of pulverized fragments -dien-8-one.

Example 5

100 g of pulverized Atractylodes atractylodes fragments were put into 500 ml of n-hexane solvent, and 170 mg of cnidone-4(14),7(11)-dien-8-one was obtained in the same manner as in Example 1 above.

Example 6

100 g of pulverized rhododendron fragments were put into 500 ml of n-hexane solvent, and 150 mg of cnidone-4(14),7(11)-dien-8-one was obtained in the same manner as in Example 1 above.

Example 7

Put 100 grams of pulverized Swertia Herba fragments into 500 milliliters of n-hexane solvent, obtain 170 milligrams of Cnidium-4(14), 7(11)-diene-8- ketone.

Example 8

100 g of pulverized Zijinniu fragments were put into 500 ml of n-hexane solvent, and 140 mg of cnidone-4(14),7(11)-dien-8-one was obtained in the same manner as in Example 1 above.

Example 9

The hydrangea root fragments of 100 grams of pulverization are put into 500 milliliters of n-hexane solvents, obtain 150 milligrams of cnidone-4(14), 7(11)-dien-8-ones according to the same method as in the above-mentioned Example 1 .

Example 10

The Huazelan fragments of 100 grams of pulverization were put into 500 milliliters of n-hexane solvents, and 165 milligrams of cnidone-4(14), 7(11)-dien-8-ones were obtained in the same manner as in the above-mentioned Example 1 .

Test Example 1

By treating the cnidium-4(14), 7(11)-di En-8-ones test the whitening effect at the cellular level.

Mouse B16 melanoma cells were cultured in Eagle's MEM medium containing 5% FCS for one day, and then transferred to Φ60mm dishes.

Then, add 1 μg/ml, 5 μg/ml and 20 μg/ml cnidone-4(14), 7(11)-dien-8-one and 1 μg/ml of hydroquinone as a positive control to the plate respectively. medium and cultured for another three days. Cells are collected in test tubes by centrifugation. 1 ml of sodium hydroxide solution (1N concentration) was added to these test tubes, and the test tubes were incubated in a boiling water bath for 10 minutes to dissolve the melanin. The melanin content was measured by reading the absorbance at 400 nm, expressed as A400/10 ⁶ cells, and the amount of melanin formation relative to the control group was calculated as the inhibition ratio (%). The results are shown in Table 1. In the table, cnidone-4(14),7(11)-dien-8-one is indicated as "AT-1", which is the result of repeating the test 3 times.

[Table 1] sample melanin formation Inhibition ratio (%) control 0.044±0.004 - AT-1 (concentration 1μg/ml) 0.032±0.001 28 AT-1 (concentration 5μg/ml) 0.019±0.003 57 AT-1 (concentration 20μg/ml) 0.007±0.001 85 Hydroquinone (concentration 1μg/ml) 0.025±0.002 43

As shown in Table 1 above, it can be seen that the cnidone-4(14),7(11)-dien-8-one obtained according to the examples, when compared with the currently known whitening substance hydroquinone Has equal melanin formation inhibitory effect on cultured mouse melanoma cells. In addition, hydroquinone has strong melanin formation inhibitory properties at low concentrations, but it cannot be tested at concentrations above 1 μg/ml due to its high cytotoxicity. In contrast, cnidone-4(14), 7(11)-dien-8-one, showed no cytotoxicity even at a concentration of 20 μg/ml and had a higher melanin formation inhibitory effect than hydroquinone.

Formulation examples of cosmetic substances containing cnidone-4(14),7(11)-dien-8-one are also represented by the following formulation examples:

Formulation Example 1 and Comparative Example 1

Formulation examples of topical skin ointments containing cnidone-4(14),7(11)-dien-8-one are shown in Table 2 below.

[Table 2] Element weight% Formulation Example 1 Comparative Example 1 Cnidone-4(14), 7(11)-dien-8-one 0.01 - Diethyl sebacate 8 8 spermaceti 5 5 Polyoxyethylene oleyl ether phosphate 6 6 sodium benzoate Appropriate amount Appropriate amount Petrolatum to 100 to 100

Formulation Example 2 and Comparative Example 2

The preparation example of the cosmetic ointment containing cnidone-4(14), 7(11)-dien-8-one is represented by the following table 3:

[table 3] Element Formulation Example 1 (% by weight) Comparative Example 1 (% by weight) Cnidone-4(14), 7(11)-dien-8-one 0.01 - stearic acid 15.0 15.0 Cetearyl alcohol 1.0 1.0 Potassium hydroxide 0.7 0.7 glycerin 5.0 5.0 Propylene Glycol 3.0 3.0 anticeptive Appropriate amount Appropriate amount Fragrance Appropriate amount Appropriate amount purified water to 100 to 100

Formulation Example 3 and Comparative Example 3

Formulation examples of mild toilet water (lotion) cosmetics containing cnidium-4(14), 7(11)-dien-8-one are shown in Table 4 below.

[Table 4] Element weight% Formulation Example 1 Comparative Example 1 Cnidone-4(14), 7(11)-dien-8-one 0.01 - ethanol 10.0 10.0 Polysorbate 20 1.0 1.0 Methylparaben 0.2 0.2 glycerin 5.0 5.0 1,3-Butanediol 6.0 6.0 Fragrance Appropriate amount Appropriate amount Colorant Appropriate amount Appropriate amount purified water to 100 to 100

Formulation Example 4 and Comparative Example 4

The formulation examples of cosmetic fragrances containing cnidone-4(14), 7(11)-dien-8-one are shown in Table 5 below.

[table 5] Element weight% Formulation Example 1 Comparative Example 1 Cnidone-4(14), 7(11)-dien-8-one 0.01 - Propylene Glycol 10.0 10.0 glycerin 10.0 10.0 Sodium Hyaluronate (1%) 5.0 5.0 ethanol 5.0 5.0 Hydrogenated castor oil (POE40) 1.0 1.0 Methylparaben 0.1 0.1 Fragrance Appropriate amount Appropriate amount purified water to 100 to 100

Formulation Example 5 and Comparative Example 5

Formulation examples of cosmetic face creams containing cnidone-4(14),7(11)-dien-8-one are shown in Table 6 below.

[Table 6] Element weight% Formulation Example 1 Comparative Example 1 Cnidone-4(14), 7(11)-dien-8-one 0.01 - Propylene Glycol 4.0 4.0 glycerin 5.0 5.0 polyvinyl alcohol 15.0 15.0 ethanol 8.0 8.0 Polyoxyethylene (10) oil ether 1.0 1.0 Methylparaben 0.2 0.2 Fragrance Appropriate amount Appropriate amount Colorant Appropriate amount Appropriate amount purified water to 100 to 100 Formulation Example 6 and Comparative Example 6

The formulation examples of nutritious toilet water (lotion) cosmetics containing Cnidium-4(14), 7(11)-dien-8-one are shown in Table 7 below.

[Table 7] Element weight% Formulation Example 1 Comparative Example 1 Cnidone-4(14), 7(11)-dien-8-one 0.01 - Petrolatum 2.0 2.0 Sorbitan Sesquioleate 0.8 0.8 Polyoxyethylene (10) oil ether 1.2 1.2 Methylparaben Appropriate amount Appropriate amount Propylene Glycol 5.0 5.0 ethanol 3.2 3.2 carboxyvinyl polymer 18.0 18.0 Calcium hydroxide 0.1 0.1 Colorant Appropriate amount Appropriate amount Fragrance Appropriate amount Appropriate amount purified water to 100 to 100

Test Example 2

A selected group of 20 young men and women were irradiated with a 1,000-watt ORIEL solar simulator. An aluminum foil mask, arranged in two rows of 6 wells each with a diameter of 7 millimeters (mm), covered the lower part of both arms before irradiation. The target area was also scrubbed clean with 70% ethanol in water. The arm was irradiated with an intensity of 60 millijoules per square centimeter from a distance of 10 centimeters (cm). The substances from Production Examples 1 to 6 and Comparative Examples 1 to 6 were applied to the respectively designated hole positions of the test human skin. The coating was applied twice a day, starting three days before starting the irradiation and continuing for three weeks after the irradiation. (Note that the face cream formulations of Manufacturing Example 5 and Comparative Example 5 were removed 15 minutes after application.)

The degree of pigment deposition in the pores of the formulation examples and comparative examples was determined by visual observation with the naked eye. The degree of inhibition of pigmentation was graded as effective or no difference and the results are shown in Table 8 below.

[Table 8] test substance effective (person) no difference (person) Formulation Example 1 14 6 Formulation Example 2 12 8 Formulation Example 3 10 10 Formulation Example 4 11 9 Formulation Example 5 11 9 Formulation Example 6 12 8

As shown in the results in Table 8 above, the ointment and cosmetic substances containing cnidium-4(14),7(11)-dien-8-one prepared according to Production Examples 1 to 6 were significantly more effective among the 20 people tested. At least 10 people showed a whitening effect. Especially in Production Example 1, where a large amount of cnidone-4(14),7(11)-dien-8-one was used, 70% showed the effect of inhibiting pigment deposition, and no negative side effects were detected. It can thus be seen that cnidone-4(14),7(11)-dien-8-one is a safe and very effective improver for freckles and spots fading or skin whitening.

As described in detail above, the skin whitening agent comprising the active ingredient cnidium-4(14),7(11)-dien-8-one of the present invention is not only safe, has no negative effect on the skin, but also has extremely Good for fading freckles and spots and brightening the skin.

Although the present invention has been described in detail according to its preferred embodiments, those skilled in the art will appreciate that various modifications and substitutions can be made therein without departing from the spirit and scope of the invention as set forth in the appended claims.

Claims (3)

CLAIMS 1. A skin whitening agent comprising the active ingredient Cnidium-4(14), 7(11)-dien-8-one. 2. The skin whitening agent according to claim 1, characterized in that Cnidium-4(14), 7(11)-dien-8-ketone is selected from the group consisting of Atractylodes Rhizoma Atractylodes Rhizome, Rhizoma Atractylodes Rhizome, Atractylodes Rhizome, Swertia Asarum, Zijin Extracted from one or more plants of bovine, hydrangea and roselands. 3. Skin lightening agent according to claim 1, characterized in that it contains 0.000001 to 10% by weight of cnidone-4(14),7(11)-dien-8-one.