JPS6056912A - External use preparation for skin - Google Patents

Abstract

PURPOSE:An external use preparation for skin that contains a hydroquinone glycoside, thus having remarkably improved skin color-lightening effect with high safety. CONSTITUTION:A hydroquinone glycoside of the formula (R is residue of pentoses, hexoses, aminosaccharides, or uronic acid or its methylated product) is added. This compound has very high safety and high stability and shows skin color- lightening effect at the same level as of hydroquinone. Especially, the combination of hydroquinone with beta-linked D-glucose, generic name: arbutin, is preferred. The agent containing the compound causes no irritation, scarce sensitization, permitting continuous use for a long period of time in high concentration to develop satisfactory skin color-lightening action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a skin preparation for external use. In addition, iiY'shi< is about a highly safe external skin preparation with significantly improved skin whitening effects.Although there are some unknowns about the mechanism of skin stains, in general, it is caused by hormonal abnormalities and El light. It is thought that melanin pigments are formed due to the stimulation of ultraviolet rays, which are deposited abnormally within the skin.Melanin pigments are thought to be deposited abnormally within the skin.Melanin pigments are thought to be deposited abnormally within the skin.Melanin pigments are thought to be deposited abnormally within the skin.Melanin pigments are thought to be deposited abnormally within the skin.
For example, methods include administering a large amount of vitamin C, injecting glutathione, etc., or applying L-ascorbic acid, cysteine, etc. locally in the form of ointment, cream, lotion, etc. Additionally, in Europe and America, hydroquino preparations are used as pharmaceuticals. However, L-ascorbic acids have stability problems and are unstable in systems containing water, causing discoloration and odor, while thiol compounds such as glucthione and cysteine have strong off-odors and are easily oxidized in cosmetics. 〇Furthermore, these compounds, with the exception of hydroquinone, have an extremely slow onset of their effects, so they do not have sufficient whitening effects. ・On the other hand, hydroquinone has been shown to be effective, but it does not cause skin irritation. Due to its chemical properties, its general use is restricted.In order to improve its safety, attempts have been made to make monoesters of higher fatty acids, but these esters are degraded by hydrolytic enzymes in the body. It cannot be said that it is necessarily safe because it is decomposed.◎ In view of these circumstances, we have conducted extensive research into the present invention, and have found that hydroquinone glycosides are extremely safe and stable. Furthermore, it was recognized that the skin whitening effect was almost as good as that of hydroquinone, leading to the completion of the present invention.

That is, the present invention is an external skin preparation characterized by containing a hydroquinone glycoside represented by the following general formula (υ).

(In formula (1), R represents a pentose residue, a hexose residue, an amino sugar residue, a uronic acid residue, or a methylated product thereof.) The skin external preparation of the present invention is non-irritating and sensitive. The composition of the present invention will be described in detail below.The composition of the present invention will be described in detail below.

In the present invention, a glycoside of hydroquinone represented by the general formula (1) is used. In formula (I), R is L-arabinose, D-arabinose, D-xylose, D-ribose, and xylulose. -Lixous, D! Residues of pentose sugars such as J broth % Six carbons such as D-glucose, D-galactose, L-galactose, D-mannose, D-grose, D-fructose, L-sorbose, D-tagatose, D-psicose, etc. Sugar residues, D-glucosamine, D-galactosamine, sialic acid, aminouronic acid, amino sugar residues such as cumramic acid, D-glucosamine, D
- Refers to uronic acid residues such as galacturonic acid, D-mannuronic acid, L-iduronic acid, and L-guluronic acid, or their methylated products, but has poor whitening effect, easy availability, stability, and safety. When R is a D-glutose residue, in particular hydroquinone β-bonded with D-glucose, that is, hydroquinone β-couglucose (generic name: arbutin 1 hereinafter referred to as arbutin) is most preferred.

The blending amount is 01 to 30% by weight, preferably 001 to 20% by weight of Q and OO in the total amount of the skin external preparation.

Next, various evaluation tests were conducted in comparison with the hydroquinone glycosides used in the present invention.

(1) Whitening effect As an indicator of whitening effect, each of the oxidative enzymes that inhibit melanin production, tyrosinase, is
Aqueous solutions with concentrations of 50, aoo and 600 mM were prepared.

Substrate solution Nidopa 5I119 was dissolved in M) ml of water.

Enzyme solution: 10 m9 of tyrosinase (200 units/■, Shikuma Corporation) was dissolved in water and IO-bound.

Measurement: Add substrate solution α5- and phosphate buffer solution α9- to sample α05-, and incubate at 5°C for 5 minutes. An enzyme solution α05- previously incubated at 5° C. was added to this and reacted for IJ minutes, and the zero inhibition rate was calculated by measuring the absorbance at 475 nm using the following formula.

T: Absorbance when inhibitor is added T': Absorbance when inhibitor is added and no substrate is added 0: Absorbance when no inhibitor is added C': Absorbance result when neither inhibitor nor substrate is added is attached to Table-1. As is clear from Table 1, arbutin showed stronger inhibition of tyrosinase than hydroquinone.

(2) Cumulative skin irritation After clipping and shaving the backs of white guinea pigs (5 animals in each group), 1%, 5%, and 10% of hydroquinone, arbutin, and hydroquinone monocaprylate were tested. Water (1:l) dissolved rycHte (solution or suspension) was applied once a day for 40 days, and the presence or absence of irritation was visually determined every day. The results are shown in Table-2. table~
2 The denominator indicates the number of guinea pigs subjected to the test, and the numerator indicates the number of guinea pigs that showed a positive reaction. Generally, hydroquinone is not very irritating, but arbutin is particularly mild. In contrast, hydroquinone monocaprylate was found to be a strong stimulus.

(Leaving space below) Table 2 4 (3) Contact sensitization bond test method Using healthy guinea pigs with a body weight of 370-420 (i), Sato et al.'s method (5ato Y, , Ka
lsumuraY, , lohikawa 1N,,
Kobayashi T, et al A moa
ifietechnique of guinea
pig testing to 1dentit7de
layered hypersensitivity al
lergens, Oontact Dermatiti
ag 225-237. (1981); Erythema and derma formation samples: Tests were conducted on three types: hydroquinone, arbutin, and hydroquinone monocapnylate.

The results are shown in Table-3. As is clear from Table 3, the strength of contact sensitization is in the order of hydroquinone monocaprylate, hydroquinone, and arbutin, and it is clear that the sensitization of arbutin is extremely low. (Left below) (4) Stability over time 0. Hydroquinone, arbutin and hydride were added to an aqueous sodium hydroxide solution to a concentration of 1+++M. The results are shown in Figure 1. In Figure 1, the song fl;! (1)
It is. As is clear from FIG. 1, while hydroquinone quickly colors, hydroquinone monocaprylate is quite stable. However, it can be seen that arbutin is more stable and does not stain at all.

Next, in order to confirm the stability in the formulation system, a stability test was conducted using the neutral cream of Example 3 described below.

That is, the samples were those of Example 3 described below, and those of Example 3 in which arbutin was replaced with hydroquinone, and those of Example 3 in which arbutin was replaced with hydroquinone monocabrilate. The above three samples were heated at 37℃ for 1, 2, 3
Table 4 shows the degree of coloration after storage. As is clear from Table 4, the stability over time of arbutin according to the present invention is extremely good.

O: Slight coloring.

62 Color.

× Two terrible coloring.

In addition to the above-mentioned essential components, the external skin preparation of the present invention contains various components commonly used in cosmetics, pharmaceuticals, etc., including aqueous components, powder components, surfactants, humectants, thickeners, preservatives, and ultraviolet rays. Absorbers, coloring agents, drugs, fragrances, etc. can be added. Of course, these must be used within a quantitative and qualitative range that does not impair the effects of the present invention.

The whitening cosmetic composition of the present invention may be in any desired dosage form, and may be, for example, a solubilized type such as a lotion, an emulsified type such as a milky lotion or a cream, or a dosage form such as an ointment or a dispersion.

(The following is a blank space) Next, the present invention will be explained in more detail with reference to Examples.◇The present invention is not limited thereto. The blending amount is % by weight.

[Example 1] Vanishing cream Stearic acid 5.0 Stearyl alcohol 40 Butyl alcohol stearate &0 Esterin glyceryl-monostearic acid palisade ester 2.0 Propylene glycol 10α0 Arbutin L〇Caustic potash α2 Preservative/antioxidant Appropriate amount Fragrance Appropriate amount Ion-exchanged water remainder (manufacturing method) Add arbutin, propylene glycol and caustic potassium to ion-exchanged water, dissolve, heat and keep at 70°C (aqueous phase). Mix other ingredients, heat and melt and keep at 70'C (oil phase)
. Gradually add the oil phase to the water phase - 44r: JJ - After all addition is complete, keep at that temperature for a while to allow reaction to occur.

Then, emulsify the mixture uniformly using a homomixer, and cool to 50°C while stirring well.

[Example 2] Vanishing cream Stearic acid 6.0 sorbitan monostearate Esthetics A/2.0 Polyoxyethylene (20 moles) Sorbitan monostearic acid 1.5 ester Propylene glycol 1o.

Hydroquinone-β-D-arabinose 5.0 Preservative/Antioxidant Appropriate amount Fragrance Appropriate Jit 6＼゛Ion-exchanged water Mulberry (Production method) Hydroquinone-β-D-arabinose and propylene glycol are added to ion-exchanged water and heated. and keep it at 70'C (
Water phase) 0 Mix other ingredients, heat and melt and maintain at 70'C (oil phase). Pre-emulsify by adding the oil phase to the water phase. Uniformly emulsify with a homomixer. After emulsification, stir while cooling.

[Example 3] Neutral cream Stearyl alcohol 7.0 Stearic acid 2+0 Hydrogenated lanolin zO Squalane 5.0 2-,t-ctyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) Cetyl alcohol ether 3.0 Glycerin monomer Stearic acid ester 2-0 Propylene Glyfur 50 Arbutin 10.0 Fragrance Appropriate amount Preservative/Antioxidant Appropriate amount Tokyu Ion Exchange Water M Rei (Production method) Add arbutin and propylene glycol to ion exchange water and heat to 70'C. (Aqueous phase) - Mix other ingredients, heat and melt and keep at 70°C (Oil phase).

Add the oil phase to the water phase and pre-emulsify it. Uniformly emulsify with a homomixer, and after emulsification, mix while cooling.

(Left below) 8 [Example 4] Cold cream solid paraffin 5.0 Beeswax 1α0 Vaseline 15.0 Liquid paraffin 4LO Nglycerin monostearate 2-0 Polyoxyethylene (2:1 mol) Sorbitan monolaurate 20 Soap powder
01 Borax α2 Arbutin 0.0001 Ion-exchanged water Residual fragrance Appropriate amount Preservative, antioxidant Appropriate amount (Production method) Add arbutin, soap powder, and borax to ion-exchanged water, heat and dissolve, and keep at 70°C (water phase ).

Mix other ingredients, heat and dissolve and keep at 70°C (oil phase) 0 Gradually add the oil phase to the aqueous phase while stirring to perform a reaction. After the reaction is complete, homogeneously emulsify using a homomixer, and after emulsification, cool to 30' while stirring well.

[Example 5] Emulsion stearic acid z5 Cetyl alcohol L5 Vaseline 5.0 Liquid paraffin 1α0 Polyoxyethylene (10 mol) Monooleic acid ester &0 Polyethylene glycol 1500 3.0 Triethanolamine LO Arbutin 2α0 Ion exchange water Residual fragrance Appropriate amount Preservative/Antioxidant Appropriate amount (manufacturing method) Add arbutin, polyethylene glycol, and triethanolamine to ion-exchanged water, heat and dissolve, and keep at 70°C (water phase). Mix the other ingredients, heat and dissolve and keep at 70"C (oil phase). Add the oil phase to the water phase and pre-emulsify, homogeneously emulsify with a homomixer, and after emulsification cool to 70 °C without stirring. do.

[Example 6] Milk Stearic acid L5 Cetyl alcohol o5 Beeswax aO Polyoxyethylene (10 mol) Monooleate LO Glycery-monostearate LO Quince seed extract (5% aqueous solution) 2α0 Propylene glycol 5.0 Ethyl Alcohol 10.0 Arbutin αo1 Ion-exchanged water Residual fragrance Appropriate amount Preservative/ultraviolet F;I absorber Appropriate amount (Production method) Add arbutin and propylene glycol to ion-exchanged water, heat and dissolve, and keep at 70°C (water phase). Add fragrance and UV absorber to ethyl alcohol and dissolve (alcohol phase). Mix other ingredients except quince seed extract, heat and dissolve and keep at 70'C (oil phase).

Pre-emulsify by adding the oil phase to the water phase and homogeneously emulsify with a homomixer. While stirring, add the alcohol phase and quince seed extract. Then cool to 3D'C without stirring.

(Space below) 2 [Example 7] Emulsion microcrystalline wax LO Beeswax zO Silanone 20.0 Liquid paraffin 10.0 Squalane sorbitan heptaschioleate 4° Polyoxyethylene (2) °mol) Sorbitan monooleate LO Propylene glycol 7.0 Arbutin. 6. Ion-exchanged water Remaining Preservatives, UV absorbers Appropriate amount (manufacturing method) Add arbutin and propylene glycol to ion-exchanged water, heat and keep at 70°C (water phase).

Mix other ingredients and heat to dissolve and maintain at 70'C (oil phase).

While stirring the oil phase, gradually add the water phase to it and uniformly emulsify with a homomixer. After emulsification, stir while stirring for 30 minutes.
"Cool to C.

[Example 8] Lotion (alcohol phase) 95% ethanol 25.0 Polyoxyethylene (ω mol) hydrogenated castor oil ether
2.0 Antioxidants/Preservatives Suitable j1 Fragrance Suitable amount qζ1,600 t (Aqueous phase) Arbutin α5 Glycerin 5.0 Sodium hexametaphosphate Suitable amount Ultraviolet absorber Suitable Ji Amount Ion-exchanged water Residual (manufacturing method) Solubilize after adjusting the aqueous phase and alcohol phase [Example 9] Jelly 95% ethanol 1α0 Dipropylene glycol 15.0 Polyoxyethylene (15 mol) Oleyl alcohol ether z.

Carboxyvinyl polymer (product name: Kerr Hanboru 941) 10 Caustic potash α
15 L-Arginine α1 0 Arbutin Divide UV absorber Appropriate amount Fragrance Appropriate amount Preservative Appropriate amount Ion-exchanged water Remainder (manufacturing method) Ion-exchanged water with Arbutin and half a ball 9
41 was uniformly dissolved, and on the other hand, dipropylene glyfur, boriooxyethylene (15 mol), oleyl alcohol ether, and other components were dissolved in 95% ethanol and added to the aqueous phase. Then, it is neutralized and thickened with caustic potassium and L-arginine.

[Example] Peel-off type bag (alcohol phase) 95% ethanol 10.0 Polyoxyethylene (15 mol) Oleyl alcohol ether z0 Preservative appropriate amount Fragrance appropriate amount (aqueous phase) Arbutin 3.0 Polyvinyl alcohol 12C Glycerin 3.0 Polyethylene glycol 1500 LO amount Ion-exchanged water Remainder (manufacturing method) The aqueous phase is adjusted at 8oC and cooled to 50''C.Then, the alcohol phase adjusted at room temperature is added and evenly mixed and allowed to cool.

(Margins below) [Example n] Powder pack (alcohol phase) 95% ethanol 20 Preservatives Appropriate amount Fragrance Appropriate Landscape agent Appropriate amount (Aqueous phase) Arbutin 7.0 Propylene glycol 7.0 Zinc white 250 (Production method) The aqueous phase is adjusted uniformly at room temperature.Then, the alcohol phase adjusted at room temperature is added and mixed uniformly.

(Leaving space below) Wood [same as the example] Drool-absorbing ointment petrolatum 400 Stearyl alcohol 1&0 Japanese wax 20.0 Polyoxyethylene (grained mole) Monooleic acid ester O,XS Glycerin monostearate 0.25 Arbutin 1α0 Ion exchange water Remain Other (manufacturing method) Add arbutin to ion-exchanged water and heat at 70°C.
(aqueous phase). Mix and dissolve other ingredients at 70°C (oil phase).

Add the oil phase to the water phase, homogeneously emulsify with a homomixer, and then cool.

All of the external skin preparations of Examples 1 to 12 had excellent whitening effects, little skin irritation and sensitization, and excellent stability over time.

(Margin below)

[Brief explanation of drawings]

FIG. 1 shows the stability over time (absorbance at 490 nm) of arbutin, which is a glycoside of no-hydroquinone, and other compounds according to the present invention. (1) Arbutin (2) Hydroquinone (3) Hydroquinone monocab 1 root patent applicant
Shiseido Co., Ltd. Procedural amendment (spontaneous) 1. Indication of the case Patent Application No. 164815 of 1982 2. Name of the invention Skin external preparation 3. Amendment 1. 4. Subject of the amendment Column 5 for detailed explanation of the invention in Book III. Contents of amendment (1) The phrase "long-term continuous use" in the third line from the bottom of page 3 of the specification is amended to read "long-term continuous use". First. (2) On page 4 of the specification, line 2 from the bottom, the word "glucose" should be corrected to "glucopyranoside." (3) On page 8 of the specification, line 5 from the bottom, 1-eL al A
First, I corrected the word “J” with “reL al,, ^”. (4) 3rd line from the bottom of page 8 of the specification r allerge
ns, contact J and rallerge
n; Correct with Contact J. (5) 2nd line from the bottom of page 8 of the specification r DermatiL
is Yu225", rDermatiLis, 7
．． Correct it to 225J. (6) In the second line of page 9 of the specification, the phrase "erythema and dermatitis" has been amended to "erythema and dermatitis." (7) "Erythema" in the fourth line of page 9 of the specification will be corrected to "erythema." (8) The phrase "erythema" on page 9, line 5 of the specification has been corrected to "erythema." (9) "Erythema" in line 6 of page 9 of the specification will be corrected to "erythema." (10) Page 9, line 7 of the specification “Red 1m, J and Aru 4
, 1 night, 1 spot" is corrected. (11) In page 9, line 8 of the specification, the phrase "erythema with slight peeling" has been corrected to "erythema with slight peeling." (12) In the 8th line of page 11 of the specification, the words ``Kabuture-1.'' will be corrected to ``Cabrirate.'' (13) Insert 1゛Table-4'' next to ``ru.'' on page 12, line 4 of the specification. (14) In the 7th line from the bottom of page 15 of the specification, "Hyde II quinone-β-D-arabinose" is replaced with "Hyde"1.
Quinone β-L-arabinocyte” and correction stripe 4゛. (I5) Page 15 of the specification, lines 2 to 1 from the bottom [)1
ido IJ quinone-β-D~arabinose” (
't＼・(llJ quinone β-L-arabinocyto)''.Procedure Nailj Masajakuji (spontaneous) December 1981 111 1. Indication of the case 1988 Patent Application No. 164815 2. Invention (4) Name of external skin preparation 3, Person making the amendment 4, Detailed explanation of the invention in the specification subject to amendment 5, Contents of the amendment (1) "Whitening cosmetics" on page 13, line 5 of the specification Correct the word ``externally applied to the skin'' to ``external skin preparation.''

Claims (1)

[Claims] (Phantom) A skin external preparation characterized by containing a glycoside of a hyde-convex quinone represented by the following general formula. 0) indicates a sugar residue, an amino sugar residue, a uronic acid residue, or a methylated product thereof