WO2000071092A1

WO2000071092A1 - Skin whitener

Info

Publication number: WO2000071092A1
Application number: PCT/KR1999/000255
Authority: WO
Inventors: Cheong-Taek Kim; Ho-Jeong Kim; Min-Hwan Jung; Mu-Hyun Jin
Original assignee: Lg Household & Health Care Ltd.
Priority date: 1999-05-21
Filing date: 1999-05-21
Publication date: 2000-11-30
Also published as: JP2003500346A; AU4063299A; CN1352546A; JP4772190B2; CN1189156C

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 constituent of selina-4(14),7(11)-dien-8-one.

Description

SKIN WHITENER

CROSS REFERENCE TO RELATED APPLICATION

This application is based on application No 98-17641 filed in the

Korean Industrial Property Office on May 22, 1998, the content of which is

incorporated hereinto by reference.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The present invention relates to skin whitener which can be used with

pharmaceuticals and cosmetic materials having a skin whitening effect,

particularly with skin whiteners comprising a type of sesquiterpene of selina-

4(14),7(11)-dien-8-one having an excellent melanin formation restraining

effect for fading freckles or flecks and skin whitening.

(b) Description of the Related Art

Generally human skin color is determined hereditarily according to the

concentration and distribution of melanin inside the skin. However, it is

influenced also by environmental or physiological conditions such as solar

ultraviolet rays, fatigue, and stress. The above described melanin is made

through a non-enzymatic oxidation reaction after the enzyme tyrosinase acts

on the amino acid tyrosin changing it into dopa and dopaquinone.

In this way the process in which melanin is formed is known, but the mechanism which induces the melanin synthesis, or the step before

tyrosinase acts, is not yet disclosed in detail.

Therefore, conventional materials having tyrosinase restraining

activity (such as hydroquinone, ascorbic acid, kojic acid, and glutathione)

have been used after being mixed with ointments or cosmetics for skin

whitening and freckle and fleck fading.

However, these products have disadvantages of restricted

applications due to poor product safety, skin irritation, and limited

effectiveness.

SUMMARY OF THE INVENTION

Therefore, this invention is for solving the above described problems.

The object of the present invention is to provide skin whitener which has

strong melanin formation restraining effects and less problems in use.

Skin whitener of the present invention for accomplishing the above

described objects is characterized in that it comprises selina-4(14),7(11)-dien-

8-one, indicated in the below General Formula 1.

[General Formula 1]

Although research has reported that the above described selina-

4(14)N(11)-dien-8-one has an anti-inflammation effect [Chem. Pharm. Bull.,

27(12), 2954, 1979], an anti-dementia effect [Japanese reported patent

JPO9094452], etc., these effects are totally distinct from the present invention.

Selina-4(14),7(11)-dien-8-one is a 15 carbon atom organic compound

which is a commonly known material mentioned in various literature, and can

be obtained from microorganisms, plants, and animals.

As one might say, the skin whitener of the present invention can be obtained

by extracting selina-4(14),7(11)-dien-8-one contained in red atractylodes

rhizome, white atractylodes rhizome, atractylodes rhizome, hepatica, bladhia

japanica, asiasarum root, eupatorium Chinese, etc.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention, and many of the

attendant advantages thereof, will be readily apparent as the same becomes

better understood by reference to the following detailed description when

considered in conjunction with the accompanying drawings, wherein:

FIG. 1 is the plot NMR spectrum of the separated selina-4(14),7(11)-

dien-8-one; and

FIG. 2 is the mass spectrum of the separated selina-4(14),7(11)-dien-

8-one.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following detailed description, only the preferred embodiment of the invention has been shown and described, simply by way of illustration of

the best mode contemplated by the inventors of carrying out the invention.

As will be realized, the invention is capable of modification 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 described above, the object of the present invention is to provide

skin whitener characterized in that it comprises selina-4(14),7(11)-dien-8-one,

as a kind of sesquiterpene, which is a natural organic compound which can be

obtained from nature.

The above selina-4(14),7(11)-dien-8-one is preferably extracted from

plants specifically to be sold as crude drug. Sources of selina-4(14),7(11)-

dien-8-one comprise plants such as red atractylodes rhizome, white

atractylodes rhizome, atractylodes rhizome, hepatica, bladhia japanica,

asiasarum root, eupatorium Chinese, etc.

Techniques for isolating selina-4(14),7(11)-dien-8-one from these

plants include various commonly known methods, for example, the extract

from finely crushed plant fragments by using organic solvent is dried, and then

is suspended in water, and the same volume of hexane is added in the

suspension. The hexane fraction obtained by liquid-liquid partition is dried,

from which pure selina-4(14),7(11)-dien-8-one is obtained by column

chromatography and high performance liquid chromatography.

When mouse B-16 melanoma cells were treated with this purely

isolated selina-4(14),7(11)-dien-8-one, a very strong melanin synthesis restraining effect was shown. Additionally, when this compound was put in

various cosmetic materials such as external skin ointment or lotion and

applied to human skin, the skin whitening effect was excellent. Furthermore

other side effects were not shown, so it was seen to be an improved safe and

very effective agent for freckle or fleck fading and skin whitening.

The preferred dry content of selina-4(14),7(11)-dien-8-one in

cosmetics or external-use skin ointments is 0.000001 to 10 weight %.

However, the range of 0.001 to 1 weight % is more preferable as the skin

whitening effect was not as good below 0.001 weight % and conspicuous

improvements in effect were not observed when the content increased over 1

weight %.

Although the present invention is explained below in detail in

accordance with following tests, comparative examples, and manufacturing

examples, the present invention is not limited to these examples.

EXAMPLE 1

After white atractylodes rhizome was purchased and crushed, 100 g

of the crushed fragments of white atractylodes rhizome was put into 500 ιιι£

of 100 % n-hexane solvent, boiled in a reflux extractor with a cooling

condenser for 3 hours, after which it was extracted and then filtered with 300

mesh filter cloth. The remaining material was again processed once more

with the same method as above. The extracted liquids were combined,

filtered with Whatman No. 2 filter paper, and insoluble materials were

removed. The liquid was then concentrated at 60 ^°C in reduced pressure with distillation equipment, and the concentrate was suspended in 300 ml of

purified water. 300 ml of hexane were added, the mixture was shaken well,

and hexane soluble material was obtained. 450 mg of the fraction containing

effective constituents were obtained by chromatographing this soluble

material with a silicagel column. This fraction was again refined by high

performance liquid chromatography, and 210 mg of selina-4(14),7(11)-dien-8-

one was separated.

The proton NMR spectrum of the separated selina-4(14),7(11)-dien-8-

one is represented in Fig. 1 , and the mass spectrum is represented in Fig. 2.

EXAMPLE 2

After white atractylodes rhizome was purchased and crushed, 100 g

of crushed fragments of white atractylodes rhizome was put into 500 ml of

100 % ethanol solvent, and 155 mg of selina-4(14),7(11)-dien-8-one was

obtained by following the same procedure as in the above described

EXAMPLE 1.

EXAMPLE 3

After white atractylodes rhizome was purchased and crushed, 100 g

of crushed fragments of white atractylodes rhizome was put into 500 ml of

100 % chloroform solvent, and 175 mg of selina-4(14),7(11)-dien-8-one was

obtained by following the same procedure as in the above described

EXAMPLE ! EXAMPLE 4

After white atractylodes rhizome was purchased and crushed, 100 g

of the crushed fragments of white atractylodes rhizome was put into 500 ml

of 100% capric/caprillic triester, boiled in a reflux extractor with a cooling

5 condenser for 3 hours, after which it was extracted, and then filtered with 300

mesh filter cloth. It was also filtered with Whatman No. 2 filter paper at the

room temperature, and the insoluble materials removed. As a result of

quantifying selina-4(14),7(11)-dien-8-one using high performance liquid

chromatography, 280 mg of selina-4(14),7(11)-dien-8-one were obtained from

10 100 g of crushed fragments.

EXAMPLE 5

100 g of crushed fragments of atractylodes rhizome were put into 500

ml of n-hexane solvent, and 170 mg of selina-4(14),7(11)-dien-8-one were

obtained by following the same procedure as in the above described

15 EXAMPLE 1.

EXAMPLE 6

100 g of crushed fragments of red atractylodes rhizome were put into

500 ml of n-hexane solvent, and 150 mg of selina-4(14),7(11)-dien-8-one

were obtained by following the same procedure as in the above described

20 EXAMPLE !

EXAMPLE 7

100 g of crushed fragments of hepatica were put into 500 ml of n- hexane solvent, and 170 mg of selina-4(14),7(11)-dien-8-one were obtained

by following the same procedure as in the above described EXAMPLE 1.

EXAMPLE 8

100 g of crushed fragments of bladhia japanica were put into 500 ml

of n-hexane solvent, and 140 rag of selina-4(14),7(11)-dien-8-one were

obtained by following the same procedure as in the above described

EXAMPLE !

EXAMPLE 9

100 g of crushed fragments of asiasarum root were put into 500 ml of

n-hexane solvent, and 150 mg of selina-4(14),7(11)-dien-8-one were obtained

by following the same procedure as in the above described EXAMPLE 1.

EXAMPLE 10

100 g of crushed fragments of eupatorium Chinese were put into 500

ml of n-hexane solvent, and 165 mg of selina-4(14),7(11)-dien-8-one were

obtained by following the same procedure as in the above described

EXAMPLE !

TEST EXAMPLE 1

Whitening effect was tested at the cellular level by treating selina-

4(14), 7(11)-dien-8-one obtained according to the above described EXAMPLE

1 on mouse B16 melanoma cells (Lotan R., Lotan D. Cancer Res. 40:3345-

3350, 1980).

Mouse B16 melanoma cells were cultured in Eagle's MEM medium

containing 5% FCS for one day, and then transferred to ςε> 60mm dishes. Then, media containing 1 μg/ml, 5 μg/ml and 20 μg/ml of seiιna-4(14),7(11)-

dien-8-one and 1 μg/ml of hydroquinone as the positive control were added

to the dishes respectively, and culture was carried out for three more days.

The cells were harvested in tubes by centrifugation. 1 ml of sodium hydroxide

solution (1 N concentration) was added to these tubes, and the tubes were

incubated in a boiling water bath for 10 minutes to dissolve the melanins.

Melanin contents were measured by reading the absorbances at 400 nm,

expressed as A₄₀₀/10⁶cells, and the relative melanin formation amount to the

control was calculated as a inhibition ratio (%). The results are shown in

Table 1. In this table, selina-4(14),7(11)-dien-8-one is represented as "AT-

1", which was the result of tests repeated 3 times.

[Table 1]

As shown in the results of the above Table 1 , it can be seen that the

selιna-4(14),7(11)-dien-8-one obtained according to the examples has an

equal melanin formation inhibitability on cultured mouse melanoma cells when

compared with a currently known whitening material hydroquinone

Furthermore, hydroquinone has strong melanin formation inhibitability at low

concentration, but it can not be tested above 1 μg/ml of concentration due to

its high cell toxicity Selιna-4(14),7(11)-dιen-8-one, on the other hand, does not show cell toxicity even at the concentration of 20 μg/ml and has a higher

melanin formation inhibiting effect than hydroquinone.

Formulation examples of cosmetic materials containing selina-

4(14),7(11)-dien-8-one were also represented by the following manufacturing

examples:

MANUFACTURING EXAMPLE 1 AND COMPARATIVE EXAMPLE 1

Formulation example of skin ointment for external use containing

selιna-4(14),7(11)-dιen-8-one is as the following Table 2.

[Table 2]

MANUFACTURING EXAMPLE 2 AND COMPARATIVE EXAMPLE 2

Formulation example of cosmetic creams containing selina-

4(14), 7(11)-dien-8-one is as the following Table 3.

[Table 3]

MANUFACTURING EXAMPLE 3 AND COMPARATIVE EXAMPLE 3

Formulation example of soft toilet water (lotion) cosmetics containing

selιna-4(14),7(11)-dιen-8-one is as the following Table 4.

[Table 4]

MANUFACTURING EXAMPLE 4 AND COMPARATIVE EXAMPLE 4

Formulation example of a cosmetic essence containing sehna-

4(14),7(11)-dιen-8-one is as the following Table 5.

[Table 5]

MANUFACTURING EXAMPLE 5 AND COMPARATIVE EXAMPLE 5

Formulation example of cosmetic facial packs containing selina-

4(14)7(11)-dien-8-one is as the following Table 6.

[Table 6]

MANUFACTURING EXAMPLE 6 AND COMPARATIVE EXAMPLE 6

Formulation example of nutritive toilet water (lotion) cosmetics

containing selina-4(14)7(11)-dιen-8-one is as the following Table 7.

[Table 7]

TEST EXAMPLE 2

A group of 20 people comprised of young men and women were

selected for irradiation with a 1 ,000 watt ORIEL solar simulator. Prior to

irradiation, aluminum foil masks, with 7 milimeter (mm) diameter holes

arranged in two rows of 6 holes each, covered the lower parts of both arms.

The target areas were also well cleaned with a 70 % ethanol aqueous solution.

The arms were irradiated from a distance of 10 centimeters (cm) at an

intensity of 60 milliJoules per square centimeter. Material from

MANUFACTURING EXAMPLES 1 through 6 and COMPARATIVE

EXAMPLES 1 through 6 were coated on the skin of the people in the tests at

the sites of their designated respective holes. This coating was applied two

time per day, starting from three days before commencing the irradiation, and

continued for three weeks after the irradiation. (Note that the facial pack

formulations of MANUFACTURING EXAMPLE 5 and COMPARATIVE

EXAMPLE 5 were detached 15 minutes after application.)

The degree of pigment deposition for the MANUFACTURING

EXAMPLES and the COMPARATIVE EXAMPLES hole sites were determined

by visual observation with the naked eye. The degree of pigment deposition

inhibition was graded as either effective or no difference, with the results

presented in the following Table 8.

[Table 8]

As shown in the results of the above Table 10, ointment and cosmetic

materials containing selina-4(14),7(11)-dien-8-one manufactured according to

MANUFACTURING EXAMPLES 1 to 6 showed whitening effects for at least

10 persons out of the 20 persons of test. Especially in MANUFACTURING

EXAMPLE 1 , in which a large amount of selina-4(14),7(11)-dien-8-one was

applied, 70% showed pigment deposition inhibiting effects, and no negative

side effects were detected. Therefore it can be seen that selina-4(14),7(11)-

dien-8-one is safe and a very effective and improved agent for fading freckles

and flecks or skin whitening.

As described above in detail, skin whitener comprising effective

constituent of selina-4(14)7(11 )-dien-8-one according to the present invention

is not only safe and without negative effects on skin, but also has excellent

freckle and fleck fading as well as skin whitening effects.

While the present invention has been described in detail with

reference to the preferred embodiments, those skilled in the art will appreciate

that various modifications and substitutions can be made thereto without

departing from the spirit and scope of the present invention as set forth in the

appended claims.

Claims

WHAT IS CLAIMED IS:

1. Skin whitener comprising an effective constituent of selina-

4(14)7(11)-dien-8-one.

2. Skin whitener in accordance with claim 1 which is characterized in

that the selina-4(14),7( 1)-dien-8-one is extracted from one or more plants

selected from a group comprised of white atractylodes rhizome, red

atractylodes rhizome, atractylodes rhizome, hepatica, bladhia japanica,

asiasarum root, and eupatorium Chinese.

3. Skin whitener in accordance with claim 1 which is characterized in

that it contains 0.000001 to 10 weight % of selina-4(14)7(11)-dien-8-one.