JPS63246311A - External agent for skin - Google Patents

Abstract

PURPOSE:To obtain an external agent for skin, having high stability with time, excellent safety and excellent skin-beautifying effect, by using a specific hydroquinone derivative such as hydroxyalkyl ether of hydroquinone as an active component. CONSTITUTION:The objective external agent for skin contains 0.01-20wt.%, preferably 1-15wt.% (based on the whole external agent) of a hydroquinone derivative expressed by formula (R1 is 2-20C straight or branched-chain saturated or unsaturated aliphatic hydrocarbon group having >=1 OH group; R2 is H or 1-4C alkyl) [e.g. 2-(4-hydroxyphenoxy)-ethanol]. The compound of formula can be produced by reacting a halohydrin with hydroquinone or an alkylhydroquinone in the presence of an alkali.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a highly safe external skin preparation with significantly improved skin whitening effects. [Conventional technology] Although there are some points that are unclear about the mechanism by which skin spots occur, in general, melanin pigments are formed due to hormonal abnormalities or stimulation of ultraviolet rays from sunlight, and this is caused by the formation of melanin within the skin. It is thought that it is abnormally deposited. Treatments for such bruises include the administration of large amounts of substances that suppress melanin production, such as large doses of vitamin C, injections of glutathione, or the use of ointments, creams, and lotions containing L-ascorbic acid, cysteine, etc. Methods such as making it into a form and applying it locally are used. Additionally, hydroquinone preparations are used as pharmaceuticals in Europe and America. However, L-ascorbic acids have stability problems and are unstable in systems containing water, causing discoloration and odor, while thiol compounds such as glutathione and cysteine have strong off-odors and are easily oxidized in cosmetics. It is avoided to mix it with. Furthermore, these compounds, with the exception of hydroquinone, exhibit very slow effects and therefore do not have sufficient whitening effects. On the other hand, although hydroquinone has been shown to be effective, its use is generally restricted due to its sensitizing properties. In order to improve its safety, attempts have been made to create monoesters of higher fatty acids, but these esters are not necessarily safe because they are degraded by hydrolytic enzymes in the body. Therefore, the present inventors discovered that hydroquinone monoalkyl ethers are excellent compounds that can solve these problems, and filed a patent application (Japanese Patent Application Laid-Open No. 61-15
9943). And among these compounds, ethyl, n-
Ethers such as propyl and n-butyl are excellent in terms of stability, safety, and decolorizing effect, but those with too strong effects may cause unnatural effects (like vitiligo) if used for a long period of time. There is a risk of decolorization, and n-hexadecyl and n-octadecyl ether, which have slow effects, must be used at relatively high concentrations, and there may be restrictions such as the inability to use them depending on the dosage form. . [Problems to be Solved by the Invention] In view of the above circumstances, the present inventors aimed to obtain a skin preparation for external use that has good stability over time, is excellent in safety, and has an excellent whitening effect. As a result of extensive research, it was found that hydroxyalkyl ethers of hydroquinone are extremely safe and stable, and they also have a skin whitening effect that is greater than that of hydroquinone, leading to the completion of the present invention. . [Means for Solving the Problems] That is, the present invention is an external skin preparation characterized by containing a hydroquinone derivative represented by the following general formula (1). p [In formula (1), R1 is a carbon number 2 having one or more hydroxyl groups
~20 linear or branched saturated or unsaturated aliphatic hydrocarbons, and R2 represents H or an alkyl group having 1 to 4 carbon atoms. ] The skin external preparation of the present invention is non-irritating and has almost no sensitization,
Therefore, long-term continuous use and high concentration use are possible, and the skin whitening effect can be fully exhibited. Hereinafter, the configuration of the present invention will be explained in detail. The hydroquinone derivative (hydroxyalkyl ether) used in the present invention has the following general formula (1) [%' in formula (1)]
R1 represents a linear, saturated or unsaturated aliphatic hydrocarbon having 2 to 20 carbon atoms and having one or more hydroxyl groups; % R
2 represents H or an alkyl group having 1 to 4 carbon atoms. ] using a known synthesis method, for example, by reacting a given halohydrin with hydroquinone or alkylhydroquinone in the presence of an alkali such as sodium hydroxide, potassium hydroxide, pyridine, morpholine, or tetraethylammonium hydroxide. can be easily synthesized by To give specific examples of substance names, 2-(4-hydroxyphenoxy)-ethanol 3-(
4-hydroxyphenoxy)-1,2-propanediol 1-(4-hydroxyphenoxy)-2-methyl-2
-Propatool 1-(4-hydroxyphenoxy)-2
-Propatool 1-(4-hydroxyphenoxy)-2
-butanol 1-(4-hydroxyphenoxy)-2-
Pentanol 1-(4-hydroxyphenoxy)-2-
Hexanol 1-(4-hydroxyphenoxy)-2-
Hexanol 1-(4-hydroxyphenoxy)-2-
Cytanol 1-(4-hydroxyphenoxy)-2-
Nonanol 1-(4-hydroxyphenoxy)-2-decanol 1-(4-hydroxyphenoxy)-2-undecanol 1-(4-hydroxyphenoxy)-2-dodecanol 1-(4-hydroxyphenoxy)-2-tridecanol 1 -(4-hydroxyphenoxy)-2-
Tetradecanol 1-(4-hydroxyphenoxy)-
2-Pentadecanol 1-(4-hydroxyphenoxy)-2-hexadecanol 1-(4-hydroxyphenoxy)-2-heptadecanol 1-(4-hydroxyphenoxy)-2-octadecanol 1-( 4-hydroxyphenoxy)-2-no1decanol 1-(4-hydroxyphenoxy)-2-eicosanol 2-(4-hydroxy-2-methylphenoxy)-ethanol 2-(4
-human axy-3-methylphenoxy)-ethanol 3
-(4-hydroxy-2-methylphenoxy)-1,2
-Propanediol 3-(4-hydroxy-3-methylphenoxy)-1,2-propanediol 2-(4-hydroxy-2-t-butylphenoxy)-ethanol 2
-(4-HydroN-3-t-butylphenoxy)-ethanol 3-(4-hydroxy-2-t-butylphenoxy)-1,2-propanediol 3-(4-hydroxy-3-t-butylphenoxy) )-1,2-propanediol and the like. The blending amount is 0.01 to 20% by weight, preferably 1 to 15% by weight, based on the total amount of the skin external preparation. If it is less than 0.01% by weight, the whitening effect will be poor, and if it is more than 20% by weight, no increase in the effect can be expected. In addition to the above-mentioned essential constituents, the external skin preparation of the present invention contains other ingredients normally used in external skin preparations such as cosmetics and pharmaceuticals, such as oil, ultraviolet absorbers, antioxidants, surfactants, humectants, Perfumes, water, alcohol, thickeners, coloring materials, skin nutrients (tocopherol acetate, pantothenyl ethyl ether, glycyrrhizinate), etc. can be added as appropriate. Next, a synthesis example for synthesizing the derivatives used in the present invention will be described in detail. Synthesis example 1 2-(4-hydroxyphenoxy)
-Ethanol 11°Og of hydroquinone and 4.0g of sodium hydroxide were dissolved in 30J of water, and 8.0g of ethylene chlorohydrin was added dropwise over 20 minutes with stirring. The reaction temperature was maintained at about 70° C. and stirred for about 8 hours, then cooled to room temperature, hydrochloric acid was added to make the mixture weakly acidic, and the precipitated crystals were separated. Since the crystals contained unreacted hydroquinone and 1,4-bis-(2-hydroxyethoxy)-benzene in addition to this product, they were separated by silica gel chromatography (ethyl acetate:benzene). 6.3 g (yield 41%) of colorless crystals f! :Obtained. Melting point 89.6-91.3°C Mass spectrum m/z-154 C-13N MR spectrum (solvent: DMSO-d
s)'151.8 151.3 118.0 115.
Signal derived from benzene ring at 8 ppm or more. 70.4 Signal derived from hydroxyethyl groups at 60.0 ppm or more. In addition, if the condensate obtained by reacting in exactly the same manner using hydroquinone monobenzyl ether instead of hydroquinone in the above reaction is catalytically reduced using 10% Pd carbon in methanol, the yield can be improved to about 70%. can. l71J2 3-(4-hydroxyphenoxy)-
1,2-propanediol hydroquinone 1.1.0g
and 5.6 g of potassium hydroxide were dissolved in 40 mounds of water, and 11.05 g of α-monochlorohydrin was added dropwise over about 30 minutes while stirring and boiling. After finishing dropping, add 200 ml of ethyl acetate.
After extraction with rJ and filtering off the salt, the solvent was removed, and the resulting solid was separated by silica gel column chromatography (ethyl acetate:benzene). colorless crystal 11
．． 5 g (yield 62.4%) was obtained. Melting point 124.0-125.0°C Mass spectrum m/z=184 C-13N MR spectrum (solvent: DMS
0-da)”151.8 151.2 N5.8 1
A signal originating from a benzene ring at 15.7 ppm or more. 70.5 70.2 Signal derived from 63.0 ppm or more of chrycerol groups. In the above reaction, hydroquinone monobenzyl ether and glycidol were heated at about 120°C in dimethylformamide.
The reaction mixture is heated and stirred for 4 hours to obtain glycerol ether, which is catalytically reduced in methanol using 10% Pd-carbon to obtain the desired hydroquinone monoglycerol ether. Synthesis example 3 1-(4-hydroxyphenoxy)-2
-Propertool Hydroquinone Monobenzyl Ether 2
．． Dissolve 0gt-diglyme in 20kg of lysine, add 14g of lysine, and add 11g of propylene oxide while stirring at about 150°C.
, 2 g was dissolved in 20 g of diglyme and added dropwise over about 2 hours. Thereafter, the reaction was continued for about 2 hours. Next, after cooling to room temperature, the solvent was distilled off under reduced pressure at about 70°C, and the residual liquid was purified by silica gel column chromatography (ethyl acetate:benzene) to form pale yellow crystals with a melting point of 101.2-101.9°C. 1.7 g of substance (yield 66.0%) was obtained. Next, this product was catalytically reduced in methanol using 10% Pd-carbon, the catalyst was filtered off, and the methanol was distilled off to obtain the desired product as a colorless wax sample solid. Melting point 87.8-88.6°C Mass spectrum m/z=168 C-13N MR spectrum (solvent: DMSO-d
a): 151.7 151.2 115.8 115.
Signal derived from benzene ring at 7 ppm or more. 74.2 64.8 20. A signal derived from propyl groups of lppm or more. Synthesis example 4 1-(4-hydroxyphenoxy)-
2-Methyl-2-propertool hydroquinone 1t,o
8@Diglyme 50 dissolved in sodium hydroxide 5.
Add 28 and add 1,2 while stirring at about 150°C.
- 7.28 g of epoxy isobutane was dissolved in 30 d of diglyme and added dropwise over about 2 hours. Thereafter, the reaction was continued for about 2 hours. Next, after cooling to room temperature, the solvent was distilled off under reduced pressure at about 70°C, extracted with tetrahydrofuran, filtered to remove insoluble matter, and concentrated to obtain a solid.
Purified by silica gel column chromatography (ethyl acetate:benzene), 6.2 g of colorless crystals (yield: 3
4.1%). Melting point 107.0-109.3°C Mass spectrum m/Z: 182 C-13N MR spectrum (solvent: DMSO-d
a) '152.2 151.3 Signal originating from the benzene ring at 115.8 ppm or more. 77.4 68.9 Signal derived from isobutyl group at 26.6 ppm or more. Synthesis example 5 1-(4-hydroxyphenoxy)
- 11.0 g of 2-tetradecanol hydroquinone was dissolved in 50 ml of diglyme, 5.2 g of sodium hydroxide was added, and while heating and stirring at about 150°C, 21.2 g of 1,2-epoxytetradecane was dissolved in 50 ml of diglyme. and added dropwise over about 2 hours. Thereafter, the reaction was continued for about 2 hours. Next, after cooling to room temperature, the solvent was distilled off under reduced pressure at about 70°C, dissolved in ethyl acetate, insoluble matter was filtered off, and the resulting solid was concentrated using silica gel column chromatography (ethyl acetate:benzene). ) to obtain 6.2 g (yield 34.1%) of a colorless waxy substance. Melting point: 119.8-120.3°C (recrystallized with methanol) Mass spectrum: m/z = 322 C-13 NMR spectrum (solvent: DMSO-da)
152.0 151.4 115.9115.8ppm
The above signals originate from the benzene ring. 73.5 68,9 33,9 31,4 29,3
29,2 28.825.1 22,2 13.8pp
A signal derived from m or more tetradecyl groups. Synthesis Example 6 3-(4-hydroxy-2-methylphenoxy)-1,2-propanediol and 3-
(4-hydroxy-3-methylphenoxy)-1,2-
It was dissolved in 14.4 g of propanediol methylhydroquinone and 5.6 gr*4 o of potassium hydroxide, and 11.05 g of α-monochlorohydrin was added dropwise over about 30 minutes while stirring at boiling. The product was purified in the same manner as in Synthesis Example 2. The yield was 13.9 g (70% yield) of a brown viscous liquid. Mass spectrum m/z=198 C-13N MR spectrum (solvent: DMSO-da
)'151.7 150.9 150.0149.2
127.3 124.8117.6 11? , 3 11
5.3113.5 112.7 Signal derived from the benzene ring at 112.6 ppm or more. 71.5 70.8 70.4 70.3 63.0
62.9 62.746.9 16.0 15.9 or more Signal due to chrycerol group and methyl group. Example 7 3-(4-hydroxy-2-t-
butylphenoxy)-1,2-propanediol and 3-(4-hydroxy-3-t-butylphenoxy)
-1,2-propanediol Dissolve 16.62 g of t-butylhydroquinone, 5.6 g of potassium hydroxide, and 40 g of water, and add 11 g of α-monochlorohydrin while boiling and stirring.
．． 05g was added dropwise over about 30 minutes. The product was purified in the same manner as in Synthesis Example 6. It is initially obtained as a pale brown viscous liquid, but it gradually crystallizes. Revenue Q18. Og (yield 75%). Mass spectrum m/z"240 C-13N MR spectrum (solvent: DMSO-da
):151.5 149.7 136.7116.5
114.0 Signal originating from the benzene ring at 111.7 ppm or more. 7L5 70.3 70.2 63.0 62.9 4
6,9 34,329.9 29.4 ppm or more Signal due to glycerol group and t-butyl group. The melting point was measured using FP80 manufactured by Mettler AG, West Germany. [Effects of the Invention] Next, in order to clarify the whitening effect of hydroxyethyl and chrycerol ether derivatives, which are typical among the hydroquinone derivatives used in the present invention, various types of derivatives were compared with hydroquinone and hydroquinone monocabrilate. Evaluation ([Test I was conducted. (1) Whitening effect a) A method of expressing the inhibition rate (inhibition rate) of tyrosinase, an oxidative enzyme for melanin production, which is generally used as an indicator of whitening effect, was used. Sample solutions: 150.300 and 600mM aqueous solutions for hydroquinone, 3.6.12mM aqueous solutions for 2-(4-hydroxyphenoxy)ethanol and 3-(4-hydroxyphenoxy)-1,2-propanediol, respectively. adjusted. Substrate solution: 5 mg of Dopa was dissolved in 10 μl of distilled water. Enzyme solution: 10 mg of tyrosinase (2000 units/ms, Sigma) was dissolved in distilled water to prepare 10 enzymes. Measurement: Add 0.9114L of phosphate buffer solution between substrate solutions o, s-1 and 1715 to 0.05T*L of sample,
Enzyme solutions o and osJ, which had been incubated at °C for 5 minutes, were added and reacted for 1.5 minutes, and the absorbance at 475 nm was measured. The inhibition rate was calculated using the following formula. T-T' Inhibition rate = (, 1--) Absorbance C' when no inhibitor is added: Absorption 11 intensity when neither inhibitor nor substrate is added Plot the inhibition rate at each concentration on semi-log graph paper and find the concentration representing 50% inhibition rate from the graph. Ta. The results are shown in Table 1. (The following is a blank space) From the above results, it can be seen that the ethers of the present invention exhibit a marked inhibitory effect compared to hydroquinone. Mouth) Next, we tested the therapeutic effect of the emulsion of Example 6 on patients suffering from melasma! I did 9. (Test method) A panel of 40 subjects suffering from melasma was used, half of the 20 subjects received the emulsion from Example 6, and the remaining 20 subjects received the emulsion from Examples 6 to 2.
A milky lotion formulated without -(4-hydroxyphenoxy)-I'mnol (comparative example) was applied to the face every day for 3 months, and the lightening effect after use was judged based on the criteria below. did. (Judgment criteria) Excellent effect: Pigmentation became less noticeable. Effective dipigmentation has faded considerably. Slightly effective dipigmentation became slightly lighter. There was no change in null bipigmentation. (Judgment) ◎: When the proportion of subjects showing excellent response and efficacy is 80% or more O: The proportion of subjects showing excellent response and efficacy is 50 to 8
0% ×: When the percentage of subjects showing significant response and efficacy is 50% or less (results) (2) Cumulative skin irritation After the backs of white guinea pigs (5 animals in each group) were shaved and , hydroquinone, hydroquinone monocabrilate, 2-(4-hydroxyphenoxy)-ethanol, 3-(4-hydroxyphenoxy)-1,2-
Propanediol, 1-(4-hydroxyphenoxy)
-2-propatol, 1%, 5%, 10 of 1-(4-hydroxyphenoxy)-2-methyl-2-propatol
% ethanol-water (1:1) solution (solution or suspension) was applied once every day for four days, and the presence or absence of irritation was visually determined every day. The results are shown in Table 2. The numbers in Table 2 represent the number of guinea pigs in which stimulation appeared. As is clear from Table 2, hydroquinone monocabrilate is highly irritating, whereas the ethers of the present invention are particularly less irritating. (Margin below) Table 2 (3) Stability over time 0, IN Sodium hydroxide aqueous solution was mixed with hydroquinone, hydroquinone monocabrilate, 2-(4-hydroxyphenoxy)-ethanol, 3-(4) to a concentration of 1 mM. -hydroxyphenoxy)-1,2-propanediol, 1-(4-hydroxyphenoxy)-
2-tetradecanol was dissolved and the change in degree of coloring over time was measured at 37° C. by absorbance at 420 nm. The results are shown in Figure 1. In FIG. 1, curve (1) is the change in absorbance over time of hydroquinone, curve (2) is hydroquinone monocabrilate, and curve (3) is the absorbance of each of the ethers of the present invention. As is clear from FIG. 1, hydroquinone quickly becomes colored, whereas hydroquinone monofobrilate is quite stable. However, it can be seen that the ether group of the present invention is more stable and hardly colored. Next, in order to confirm the stability in the formulation system, a stability test was conducted using the cream of Example 2 described below. That is, the samples were prepared in Example 2 and 3-( of Example 2, which will be described later).
4-Hydroxyphenoxy)-1,2-benzile replaced with hydroquinone, hydroquinone monocaprylate replaced with 2-(4-hydroxyphenoxy)-Itanol, 1-(' Substituted for 4-hydroxyphenoxy)-2-methyl-2-durobanol, 1-(4-hydroxyphenoxy)-2
- Instead of propatool, the above 6 samples were heated at 37°C.
Table 3 shows the degree of coloration after storage for 1 month, 2 months, and 8 months. As is clear from Table 3, the oral stability of the ether derivative of hydroquinone according to the present invention is extremely good. (Leaving space below) Table 3 0: Hardly colored ○: Mildly colored △: Colored ×: Severely colored (4) Contact sensitization test method: Using healthy guinea pigs weighing 370 to 420, et al.'s method (5ato Y, Katsumur
a Y,, Ichikawa) (,, Kobayas
hi T,, et al,, A modification
dtechnique of guinea ptgt
estLng to Identify delayed
hypersensitivity allerge
ns; Contact Dermatftis, 7
, 225-237.1981). Judgment criteria: Formation of erythematous plaques and epidermis ((lower margin of Di5) Edema formation test v4: Hydroquinone, hydroquinone monopropyl ether, 3-(4-hydroxyalkoxy)-1,2-
Tests were conducted on three types of propanediol. The results are shown in Table 4. As is clear from Table 4, the strength of contact sensitization is hydroquinone) hydroquinone monopropyl ether > 3-(4-hydroxyphenoxy)-1
, 2-propanediol, and it is clear that hydroquinone monohydroxyalkyl derivatives are even less sensitizing than simple alkyl ethers. Table 4 [Example] Next, the present invention will be explained in more detail with reference to Examples. The present invention is not limited thereby. The blending amount is in weight%. Example 1 Cream stearic acid 5.0 Stearyl alcohol 4.0 Stearic acid butyl alcohol ester 8.0 Glycerin monostearate 2.0 Propylene glycol 10.02-(4
-Hydroxyphenoxy)-Itanol
1.0 caustic potash
0.2 Sodium bisulfite
0.01 fragrance
Appropriate amount of ion exchange water
Residue (manufacturing method) Add propylene glycol and caustic potash to ion-exchanged water, dissolve, heat, and keep at 70°C (water phase). Mix other ingredients, heat and melt and keep at 70°C (oil phase). Gradually add the oil phase to the water phase, and after all addition is complete, maintain the temperature for a while to allow the reaction to occur. Then, emulsify the mixture uniformly using a homomixer, and cool to 30°C while stirring well. Example 2 Cream stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monostearate 1.5 Propylene glycol 10.03-(4
-hydroxyphenoxy)-1,2-propanediol 5.0 Sodium bisulfite
0.01 ethylparaben
0.3 fragrance
Appropriate amount of ion exchange water
Residue (manufacturing method) Add propylene glycol to ion-exchanged water and heat.
Keep at 0°C (aqueous phase). Mix other ingredients and heat and melt 7.
Keep at 0°C (oil phase). The oil phase is pre-emulsified by adding the oil phase to the water phase, uniformly emulsified using a homomixer, and then cooled to 30°C while stirring well. Example 3 Cream Stearyl Alcohol 7.0 Stearic Acid 2.0 Hydrogenated Lanolin
2.0 squalane
5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) Cetyl alcohol ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0l-(4-hydroxyphenoxy)-2-methyl-2- Property Tools 10.
0 fragrance n Appropriate amount Sodium bisulfite 0.03 Ethyl paraben 0.3 After cooling to 30"C while stirring well. Example 4 Cream solid paraffin 5.0 Beeswax 10.0 Vaseline
15.0 Liquid paraffin
41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2.0 Soap powder
0.1 borax
0.2l-(4-hydroxyphenoxy)-2-tetradecanol
0.01 Ion exchange water Residual fragrance Appropriate amount Sodium bisulfite 0.03 Ethyl paraben
0.3 (manufacturing method) Add soap powder and borax to ion-exchanged water, heat and dissolve.70
Keep at °C (aqueous phase). Mix the other ingredients and heat and melt for 70 minutes.
Keep at °C (oil phase). The oil phase is gradually added to the water phase while stirring to carry out the reaction. After the reaction is completed, the mixture is uniformly emulsified using a homomixer, and after emulsification, the mixture is cooled to 30°C while stirring well. Example 5 Emulsion Stearic acid 2.5 Cetyl alcohol 1.5 Vaseline
5.0 liquid paraffin
10.0 polyoxyethylene (10
Mol) Monooleic acid ester 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 l-(4-hydroxyphenoxy)-2-propanol
20.0 Ion-exchanged water Residual fragrance F+ Appropriate amount Sodium bisulfite 0.01 Ethylparaben 0.3 (Production method) Add polyethylene glycol 1500 and triethanolamine to ion-exchanged water, heat and dissolve, and keep at 70°C (water phase) . Mix other ingredients, heat and melt and keep at 70°C (oil phase). The oil phase is pre-emulsified by adding the oil phase to the water phase, and the mixture is uniformly emulsified using a homomixer. After emulsification, the mixture is cooled to 30°C while stirring well. Example 6 Emulsion (oil phase) Stearic acid 1.0 piece wax 1.0 Vaseline
2.5 Deodorized lanolin
1. May primrose oil
2.0 Isopropyl myristate
5.0 Polyoxyethylene (601 Nyl) Hydrogenated castor oil 2.0 Acetate tocoffecting roll ・o, os Ethylparaben 0.2 Butylparaben 0.1 Fragrance
Appropriate amount (aqueous phase) 2-(4-hydroxyphenoxy)-I tanol
8.0 Sodium Bisulfite
0.01 glycerin
5.0 Sodium hyaluronate 0
．． 01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water
Residue (manufacturing method) Oil phase f! Dissolve at near 09C. Water phase part 70'
(Dissolve in step 1, mix the oil phase with the water phase, emulsify with an emulsifier, and cool to 30°C with a heat exchanger. Example 7 Emulsion Microcrystalline Wax 1.0 Beeswax 2.0 Lanolin
20.0 Liquid paraffin 10.0 Squalane
5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) Sorbitan monooleate 1.0 Propylene glycol 7.03-(4-
Hydroxy-2or3-methylphenoxy)-1,2-
Propanediol 3.0 ion exchange water
residual fragrance
Appropriate amount of ethylparaben
0.3 Sodium bisulfite
0.01 (manufacturing method) Add propylene glycol to ion-exchanged water and heat it.7
Keep at 0°C (aqueous phase). Mix other ingredients and heat to dissolve 7.
Keep at 0°C (oil phase). While stirring the oil phase, gradually add the water phase to it and uniformly emulsify with a homomixer. After emulsification, cool to 30°C while stirring well. Example 8 Lotion (alcohol phase) 95% ethyl alcohol 25.0 Polyoxyethylene (25 mol) Hardened castor oil ether 2.0 Antioxidant Appropriate amount preservative
Appropriate amount of incense'pr
Appropriate amount of 3-(4-human ax-2or3-t
ert-butylphenoxy) = 1,2-propanediol 1.0 (aqueous phase) Glycerin 5.0 Sodium hexametaphosphate 3Sffi ultraviolet absorber
Appropriate amount of ion exchange water
Residue (manufacturing method) Solubilize after adjusting the aqueous phase and alcohol phase. Example 9 Jelly 95% ethyl alcohol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (15 mol) Oleyl alcohol ether 2.0 Carboxy vinyl polymer (manufactured by Gutdrich, USA: Product name: Carbopol 941) 1.0 Caustic soda 0.15L-arginine 0,13-(4-hydroxyphenoxy)-1,2-furopanediol
7.0 UV absorber Appropriate amount Fragrance 3a amount Methylparaben 0.2 Ethylparaben 0.3 Ion exchange water
Residue (manufacturing method) Carboxyvinyl polymer was uniformly dissolved in ion-exchanged water, while dipropylene glycol and dipropylene glycol were dissolved in 95% ethanol.
Polyoxyethylene (15 moles), oleyl alcohol ether, and other ingredients are dissolved and added to the aqueous phase. Then, it is neutralized and thickened with caustic soda and L-arginine. Example 10 Beauty essence (A) Ethanol (95%) 10.
0 Polyoxyethylene (207) Oleylether 1.0 Methylparaben 0.15 Pantothenyl ethyl ether 0.1 (B) Potassium hydroxide 0.1 (C) Glycerin 5.0 Dipropylene glycol 10.0 Hydrogen sulfite Sodium 0.031-(4-hydroxyphenoxy)-2-propatol
7.0 carboxyvinyl polymer
0.2 Purified water Dissolve the remaining A and C uniformly, and add A to C to solubilize. Then, after adding B, filling is performed. Example 11 Back 2-(4-hydroxyphenoxy)-ethanol
3.0 Sodium bisulfite 0.03 Polyvinyl alcohol (degree of saponification 90, degree of polymerization 2.000) 13
．． 0 Ethanol 7.0 Glycerin 10.0 Olive oil 3.0 Tocopherol acetate 0.2 Ethylparaben
0.2 fragrance
0.2 Purified water
Remainder (manufacturing method) Filling is performed after heating and mixing each component at 80°C. Example 12 Powder bag (alcohol phase) 95% ethanol 2.0 Ethylparaben 0.3 Fragrance
Appropriate amount of coloring material
Appropriate amount of 3-(4-hydroxy-2-
methylphenoxy)-1,2-propanediol and
3-(4-hydroxy-3-methylphenoxy)-1
,2-propanediol
7.0 (aqueous phase) Propylene glycol 7.0 Zinc white
25.0 kaolin
20.0 ion exchange water
Residue (manufacturing method) Adjust the aqueous phase uniformly at room temperature. Then, the alcohol phase prepared at room temperature is added and mixed uniformly. [Brief explanation of drawings]

[Brief explanation of drawings]

FIG. 1 shows the stability over time (absorbance at 420 nm) of the hydroquinone derivative according to the present invention. (1) Hydroquinone (2) Hydroquinone monocabrilate (3) a
2-(4-hydroxyphenoxy)-ethanol b
3-(4-hydroxyphenoxy)-1,2-propanediol c 1-(4-hydroxyphenoxy)-2-tetradecanol Patent applicant Co., Ltd.
Engraving of Shiseido's drawings (no change in content J No. 1-rXl Time 1Iiff (minutes) Procedural amendment (method) July 1, 1985

Claims (1)

[Claims] (1) An external skin preparation characterized by containing a hydroquinone derivative represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is a carbon number of 2 to 2 with one or more hydroxyl groups.
0 represents a linear or branched saturated or unsaturated aliphatic hydrocarbon, and R_2 represents H or an alkyl group having 1 to 4 carbon atoms. ]