CN1492755A - Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetic composition containing same - Google Patents

Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetic composition containing same Download PDF

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Publication number
CN1492755A
CN1492755A CNA018229956A CN01822995A CN1492755A CN 1492755 A CN1492755 A CN 1492755A CN A018229956 A CNA018229956 A CN A018229956A CN 01822995 A CN01822995 A CN 01822995A CN 1492755 A CN1492755 A CN 1492755A
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kojic acid
acid derivative
organic solvent
appa
kojyl
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李玉燮
金德嬉
张利燮
文圣浚
沈荣哲
金汉坤
姜鹤熙
白兴洙
黄在晟
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Amorepacific Corp
Pacific Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

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Abstract

There are provided a water-in stable kojic acid derivative represented by the following formula 1, a method for preparing the same and a skin-whitening cosmetic composition containing the same as an active ingredient.

Description

Stable kojic acid derivative and preparation method thereof in the water, and the whitening cosmetic compositions that contains it
Technical field
The present invention relates to a kind ofly, the invention still further relates to and contain its skin whitening compositions that applies some make up as active component by kojic acid derivative stable in the water shown in the following formula 1 (I) and preparation method thereof:
[formula 1]
Technical background
As a rule, kojic acid is a kind of gamma-pyrone chemical compound, its separate in aspergillus and can with the metal ion-chelant such as copper ion, the activity of coming restraint of tyrosinase, tryrosinase is a kind of enzyme relevant with the melanin biosynthesis.Therefore, kojic acid can be blocked the abnormal pigmentation of skin.Say in detail, tryrosinase is a kind of enzyme that catalysis DOPA quinone forms in following melanin biosynthesis continuous process: tyrosine → DOPA → DOPA quinone → dopachrome → melanin, and the copper ion of kojic acid by active site in the chelating tryrosinase activity of coming restraint of tyrosinase.
Based on this tyrosinase inhibitory activity, kojic acid has been widely used in preventing in the topical compositions of hyperpigmentation such as nevus and freckle.For example, JP 56-18569B, JP 53-3538A and JP 62-59084B disclose and have contained the whitening cosmetic compositions of kojic acid as active component.And, JP 54-92632A, JP 58-22152A and JP 60-9722A disclose the whitening cosmetic compositions that contains kojic acid derivative, wherein said kojic acid derivative such as kojic acid one or di fatty acid ester, it has superperformance, as stability, sensualness and dissolubility and improved tyrosinase inhibitory activity.In addition, JP 3-14508A, JP 4-145096A and JP 5-39298A have proposed various kojic acid derivative with strong tyrosinase inhibitory activity, as the kojic acid of kojic acid ether, glucosylation and the bent aminoacid of amino-protection.
Yet when being applied to cosmetics, kojic acid and derivant thereof are oxidized easily, and are difficult to long preservation thus.And it is renderd a service and activity can reduce in the process of preparation cosmetics, thereby can not obtain desired effect.
Therefore, for improving the stability of kojic acid, people have done a lot of effort.As a result, synthesize a lot of derivants, its active site (being 4-carbonyl and 5-hydroxyl) is protected and the 2-hydroxy position is substituted.These derivants are wished to have tyrosine and are suppressed active and have improved stability in water.But because the 5-hydroxyl is protected, still there is the problem of stable aspect in these derivants, as fade.
Under these situations, for the problem that solves above-mentioned kojic acid derivative and for exploitation new have a derivant of improving water stability, the present inventor has carried out deep research to kojic acid derivative.Result of study is found, its 5-hydroxy position is substituted with the kojic acid derivative (with the di-phosphate ester form) of 3-aminopropane phosphoric acid can realize said purpose, wherein 3-aminopropane phosphoric acid itself is a kind of active cosmetic material, its biosynthesis to fibroblastic hypertrophy and collagen has effect, and skin is had good safety, thereby be widely used in preventing in the cosmetics that skin aging uses.
Summary of the invention
Therefore, an object of the present invention is to provide a kind of by new kojic acid derivative or its salt shown in the following formula 1 (I):
[formula 1]
Figure A0182299500051
In addition, another object of the present invention provides a kind of preparation method of said kojic acid derivative.
A further object of the present invention provides a kind of skin whitening compositions that applies some make up, the biosynthesis that it can suppress melanic formation and can promote fibroblastic hypertrophy and collagen, and when being used in the base material of cosmetics, have good safety and good stable to skin.
To describe the present invention in detail below.
The method for preparing kojic acid derivative of the present invention can may further comprise the steps:
(A) with 3-amino-1-propanol and phosphorus oxychloride with 1: the equivalent proportion of 1-1.3, in organic solvent, under the existence of organic base,, form 2-chlorine tetrahydrochysene-2H-1 0～5 ℃ of reaction 1-2 hour down, 3,2-phosphorus oxazole (oxazaphosphorin) P-oxide;
(B) with the 2-chlorine tetrahydrochysene-2H-1 of step (A), 3,2-phosphorus oxazole P-oxide and kojic acid are in organic solvent, in the existence reaction down of alkali;
(C) gains with step (B) filter, and concentrating under reduced pressure added acid solution then, at 5-100 ℃ of following hydrolysis 3-10 hour; And
(D) with the product polar organic solvent recrystallize of step (C), obtain kojic acid derivative.
And described method of the present invention can also comprise step (E): the kojic acid derivative of step (D) is neutralized with nertralizer.
Described method of the present invention can by under show that response path 1 illustrates:
[response path 1]
Figure A0182299500061
Figure A0182299500071
Shown in response path 1, below the preparation method of kojic acid derivative of the present invention will be described in more detail.
Step (A), with 3-Oxy-1-propanol and phosphorus oxychloride, in organic solvent, in organic base Exist down, reacted 1-2 hour down, form by the 2-chlorine tetrahydrochysene shown in the described formula (II) at 0-5 ℃ -2H-1,3,2-phosphorus oxazole (oxazaphosphorin) P-oxide:
In this step, preferred, the reaction between 3-amino-1-propanol and the phosphorus oxychloride can be 1: carry out under the equivalent proportion of 1-1.3.When described equivalent proportion is lower than 1: 1, can't obtain target product.And when described equivalent proportion is higher than 1: 1.3, can obtain too much by-product with target product.Therefore, preparing 2-chlorine tetrahydrochysene-2H-1 by described method, 3, during 2-phosphorus oxazole (oxazaphosphorin) P-oxide, generation 95% or more intermediate: 1: 1 coordination compound of 3-amino-1-propanol and phosphorus oxychloride, and produce 1-2% and by-product still less: 2: 1 coordination compounds of 3-amino-1-propanol and phosphorus oxychloride.Yet by-product can remove by chromatography or with the toluene recrystallize.Specifically, two in three chlorine atoms of phosphorus oxychloride are formed ring-type 2-chlorine tetrahydrochysene-2H-1 by the functionality hydroxyl of 3-amino-1-propanol and amino the displacement, and 3,2-phosphorus oxazole (oxazaphosphorin) P-oxide.And, the 3rd chlorine atom 5 ℃ or more under the low temperature be inactivation and do not replaced.Reason is 2-chlorine tetrahydrochysene-2H-1,3, and the chlorine atom of 2-phosphorus oxazole (oxazaphosphorin) P-oxide is stable in the inert water-free solvent, and is not easy to be replaced by 3-amino-1-propanol.Therefore, this method is by pressing 1 with 3-amino-1-propanol and phosphorus oxychloride: the equivalent proportion of 1-1.3, reacted 1-2 hour down at 0-5 ℃, and can prevent 2: 1 production of by-products of 3-amino-1-propanol and phosphorus oxychloride.Particularly, in the present invention, because the trichlorine atom of phosphorus oxychloride need not to be subjected to the protection of ester group or amide group, thereby technology is simple.
Used organic base can be pyridine, triethylamine etc. in the step (A), and triethylamine preferably.
And used organic solvent can be an atent solvent in the described step (A), as dichloromethane, oxolane, ethyl acetate, acetonitrile, chloroform and ether, and chloroform preferably.
In addition, reaction can be carried out under 0-5 ℃.If temperature is higher than 5 ℃, then have two equivalents or how normal 3-amino-1-propanol removes to replace phosphorus oxychloride, cause producing too much by-product.On the contrary, if temperature is lower than 0 ℃, dissolubility of reactants can reduce, and causes the reaction meeting to be carried out slow and difficultly.In this case, unreacted material can increase, thereby reduces productive rate.
Step (B), with the 2-chlorine tetrahydrochysene-2H-1 of step (A), 3,2-phosphorus oxazole (oxazaphosphorin) P-oxygen Change thing and kojic acid, in organic solvent, react down in the existence of alkali:
Used alkali can be organic base in this step (B), pyridine and triethylamine described in above-mentioned step (A); Or inorganic base, as sodium, sodium hydroxide, potassium hydroxide.It preferably can be potassium hydroxide.
And used organic solvent can be an atent solvent in the described step (B), as dichloromethane, oxolane, ethyl acetate, acetonitrile, chloroform and ether; Or polar solvent, as methanol, ethanol and propanol.Preferably can be methanol.
Step (C), with the gains filtration of step (B), concentrating under reduced pressure adds acid solution then, 5-100 ℃ of following hydrolysis 3～10 hours:
In this step, the gains of step (B) can be filtered, then filtrate decompression concentrated the acquisition residue, in the presence of such as strong cation-exchanging resin (amberlite 15), hydrochloric acid and vitriolic acidic catalyst, the form of hydrolysis is hydrolyzed routinely with this residue.After adding acid solution, when the chemical compound that above-mentioned steps (B) is obtained stirs, can make the hydrolysis of P-N key under 5-100 ℃.Therefore, after filtering and concentrating, hydrolysis is preferably by adding acid solution, at 5～100 ℃ and more preferably carried out about 5 hours under 40 ℃.The pH scope of acid solution can be 1-5, and 2-4 preferably.
Step (D), the product polar organic solvent recrystallize with step (C) obtains kojic acid derivative, Kojic acid 3-aminopropanol di-phosphate ester:
The used polar organic solvent of recrystallize can be (but being not limited thereto) in this step, methanol, ethanol, isopropyl alcohol, acetone, oxolane, acetonitrile or dioxanes.
Described method can also comprise step (E), and the kojic acid derivative neutralization with described step (D) obtains forms its salt.The form of the salt that is obtained by neutralizing can be an alkali metal salt, as sodium and potassium salt; Alkali salt is as calcium and magnesium salt; Or the salt of ammonia or amine such as triethanolamine.
Used nertralizer can be an alkali metal salt in this step (E), as sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide; Alkali salt is as calcium hydroxide; Metal-oxide is as calcium oxide and magnesium oxide; Basic amino acid is as lysine, arginine and histidine; Ammonia or amine are as triethanolamine; Cationic polymer is as polyquaternary amine-4 ,-6 ,-7 ,-10 ,-11 and-16; And cationic surfactant, as lauryl dimethyl benzyl ammonium chloride and stearyl dimethyl benzyl ammonium chloride.But be not limited thereto.
The kojic acid 3-aminopropanol di-phosphate ester that is obtained (below be called " Kojyl-APPA ") or its salt, in the compositions that can admixture to skin whitening applies some make up, addition content is counted 0.01-10wt% and preferred 0.02-4.0wt% with the gross weight of compositions.If this addition content is less than 0.01wt%, then may be difficult to obtain the effect of institute's phase.On the contrary, if this addition content surpasses 10wt%, then increase or the stability of formulation aspect to effect is no advantage.
The skin whitening of the present invention compositions that applies some make up can be mixed with (but being not limited thereto) skin softening agent, astringent, auxotype toilet perfume, nutrition breast, massage cream, essence, eye ointment, eye with essence, cleansing cream, cleansing cream, clean water, facial film, foundation cream, body and function dew, body and function cream, body and function essence or the like.And, according to preparation or its final purpose, can also other composition of admixture in the compositions.
The specific embodiment
The present invention will make more detailed description by the mode of following examples, and these embodiment not will be understood that it is limitation of the present invention.
＜preparation embodiment〉preparation 2-chlorine tetrahydrochysene-2H-1,3,2-phosphorus oxazole (oxazaphosphorin) P-oxidation Thing
34.1ml (0.36mol) phosphorus oxychloride is dissolved in the 400ml dichloromethane, in ice bath, is cooled to 0-5 ℃ then.In another reactor, 30ml (0.39mol) 3-amino-1-propanol and 102ml (0.73mol) triethylamine are diluted with the 200ml dichloromethane, slowly add in the above-mentioned solution with 2 hours time then.After having added,, remove triethyl ammonium chloride with the mixture filtration of gained.Filtrate is used the 100ml distilled water wash,, filter, then concentrating under reduced pressure through anhydrous sodium sulfate drying.To wherein adding toluene, obtain crystal.Then,, obtain the 53g 2-chlorine tetrahydrochysene-2H-1 of white powder with the product vacuum drying, 3,2-phosphorus oxazole (oxazaphosphorin) P-oxide.
Fusing point: 79-82 ℃
IR(CHCl 3，cm -1)：3254，1477，1274，1092，1036，996
1H-NMR(CDCl 3)：δ(ppm)：1.7(m，1H)，1.1(m，1H)，3.3(m，2H)，4.4(m，2H)，4.9(br，1H)
＜embodiment 1〉preparation kojic acid 3-aminopropanol di-phosphate ester (Kojyl-APPA)
The 10g kojic acid is dissolved in the 80ml methanol.The 4.3g potassium hydroxide is dissolved in the 20ml methanol, slowly is added in the above-mentioned solution then.After at room temperature stirring 30 minutes, to wherein slowly adding 11.2g (1.1 equivalent) 2-chlorine tetrahydrochysene-2H-1,3,2-phosphorus oxazole P-oxide.After having added, mixture in stirred overnight at room temperature, is filtered then.Filtrate decompression is concentrated, then 0-5 ℃ of following store overnight.With formed solid filtering and vacuum drying, obtain [2-(methylol)-4-oxo-4H-pyrans-5-base oxygen base]-1,3 of white powder, 2-phosphorus oxazole P-oxide.
The solid that is obtained is dissolved in the aqueous solution of 30ml pH4, under 40 ℃ of calorstats, stirred 5 hours then.After the stirring, in reactant mixture, add the 150ml isopropyl alcohol, filter then and remove crystal.With the crystal vacuum drying, obtain the kojic acid 3-aminopropanol di-phosphate ester (Kojyl-APPA) of 16g pale yellow powder shape.
Fusing point: 118-128 ℃ (decomposition)
IR(KBr，cm -1)：3446，3322，2904，1658，1616，1250，1090，863
1H-NMR(D 2O)：δ(ppm)：2.05(m，2H)，3.15(t，2H)，4.12(m，2H)，4.54(m，2H)，6.64(s，1H)，8.27(s，1H)
＜embodiment 2〉sodium salt of preparation kojic acid 3-aminopropanol di-phosphate ester
The 1g Kojyl-APPA that embodiment 1 is obtained is dissolved in the 30ml distilled water, and to wherein adding 5% sodium carbonate, is adjusted to pH7.With the solution lyophilization that is obtained, obtain the sodium salt of the kojic acid 3-aminopropanol di-phosphate ester of white powder.
＜embodiment 3〉potassium salt of preparation kojic acid 3-aminopropanol di-phosphate ester
The 1g Kojyl-APPA that embodiment 1 is obtained is dissolved in the 30ml distilled water, and to wherein adding 5% potassium carbonate, is adjusted to pH7.With the solution lyophilization that is obtained, obtain the potassium salt of the kojic acid 3-aminopropanol di-phosphate ester of white powder.
＜embodiment 4〉calcium salt of preparation kojic acid 3-aminopropanol di-phosphate ester
The 1g Kojyl-APPA that embodiment 1 is obtained is dissolved in the 30ml distilled water, and to wherein adding calcium hydroxide, is adjusted to pH7.With the solution lyophilization that is obtained, obtain the calcium salt of the kojic acid 3-aminopropanol di-phosphate ester of white powder.
＜embodiment 5〉preparation The magnesium salt of kojic acid 3-aminopropanol di-phosphate ester
The 1g Kojyl-APPA that embodiment 1 is obtained is dissolved in the 30ml distilled water, and to wherein adding magnesium oxide, is adjusted to pH7.With the solution lyophilization that is obtained, obtain the magnesium salt of the kojic acid 3-aminopropanol di-phosphate ester of white powder.
＜embodiment 6〉triethanolamine salt of preparation kojic acid 3-aminopropanol di-phosphate ester
The 1g Kojyl-APPA that embodiment 1 is obtained is dissolved in the 30ml distilled water, and to wherein adding 5% triethanolamine, is adjusted to pH7.With the solution lyophilization that is obtained, obtain the triethanolamine salt of the kojic acid 3-aminopropanol di-phosphate ester of white powder.
＜EXPERIMENTAL EXAMPLE 1〉stabilizing member in the Kojyl-APPA water
The water stability that compares Kojyl-APPA and kojic acid.
Kojyl-APPA and kojic acid that the embodiment 1 of the 2g that respectively does for oneself is obtained are dissolved in the serial aqueous solution that 100ml is adjusted to pH2-pH8, then 3 weeks of preservation in 50 ℃ of calorstats.Between preservation term, observation is the unstability of passage in time, as fades, and estimates according to following scoring system:
-: colourless and faint yellow+: fade a little ++: to a certain degree fade +++: seriously fade
The results are shown in table 1.
[table 1]
Fade
1 week 2 weeks 3 weeks
??Kojyl-APPA Kojic acid ??Kojyl-APPA Kojic acid ??Kojyl-APPA Kojic acid
??pH2 ??- ????+ ??- ????+ ??+ ????++
??pH3 ??- ????+ ??- ????+ ??+ ????++
??pH4 ??- ????- ??- ????+ ??- ????++
??pH5 ??- ????- ??- ????+ ??- ????++
??pH6 ??- ????+ ??- ????+ ??- ????++
??pH7 ??- ????+ ??+ ????++ ??+ ????+++
??pH8 ??- ????+ ??+ ????++ ??+ ????+++
As shown in table 1, do not observe and fade or precipitate, illustrate that chemical compound of the present invention is highly stable and have a high-purity in water.
＜EXPERIMENTAL EXAMPLE 2〉stability of Kojyl-APPA
Relatively be present in the Kojyl-APPA in the dilute solution and the stability of kojic acid.
In the hydrion buffer solution that Kojyl-APPA that embodiment 1 is obtained and kojic acid are dissolved in pH7 separately, be adjusted to 50 μ M concentration, then preservation in 50 ℃ of calorstats.Between preservation term, measure the UV trap under the 254nm, with residual rate (%) evaluation test stability of sample.The results are shown in table 2.
[table 2]
0.5 hour 1 hour 3 hours 6 hours 24 hours 6 days 15 days 21 days
????Kojyl- ????APPA ???100 ????100 ????100 ???100 ??99.1 ????95.5 ????92.5 ????91.5
Kojic acid ???17.2 ????1.0 ????0 ???0 ??0 ????0 ????0 ????0
As a rule, the stability of chemical compound in dilute solution can very fast decline, as kojic acid, just it decomposed in 1 hour in aqueous solution.But as shown in table 2, the chemical compound of embodiment 1 is highly stable in neutral aqueous solution.
＜embodiment 7 and comparative example 1-5〉the nutrition breast
Material Embodiment 7 The comparative example
????1 ????2 ????3 ????4 ????5
1. cetearyl alcohol ???1.0 ????1.0 ????1.0 ????1.0 ????1.0 ????1.0
2. lipophile glycerol monostearate ???1.0 ????1.0 ????1.0 ????1.0 ????1.0 ????1.0
3. monostearate polyethenoxy sorbitan (E.O.20) ???1.5 ????1.5 ????1.5 ????1.5 ????1.5 ????1.5
4. self-emulsifying type glycerol monostearate ???1.0 ????1.0 ????1.0 ????1.0 ????1.0 ????1.0
5. myristic acid octadecane ester ???6.0 ????6.0 ????6.0 ????6.0 ????6.0 ????6.0
6. isopropyl myristate ???7.0 ????7.0 ????7.0 ????7.0 ????7.0 ????7.0
7. squalane ???3.0 ????3.0 ????3.0 ????3.0 ????3.0 ????3.0
8. tocopherol acetas ???1.0 ????1.0 ????1.0 ????1.0 ????1.0 ????1.0
9. allantoin (alantoin) ???0.3 ????0.3 ????0.3 ????0.3 ????0.3 ????0.3
10. glycerol ???7.0 ????7.0 ????7.0 ????7.0 ????7.0 ????7.0
11. butanediol ???7.0 ????7.0 ????7.0 ????7.0 ????7.0 ????7.0
12. cellulose gum ???0.5 ????0.5 ????0.5 ????0.5 ????0.5 ????0.5
13. antiseptic In right amount In right amount In right amount In right amount In right amount In right amount
14. spice In right amount In right amount In right amount In right amount In right amount In right amount
15. kojic acid ???- ????- ????0.5 ????- ????- ????0.25
16. aminopropane phosphoric acid (APPA) ???- ????- ????- ????0.5 ????- ????0.25
(17.Kojyl-APPA the chemical compound of embodiment 1) ???0.5 ????- ????- ????- ????- ????-
18. two Palmic acid kojic acid esters ???- ????- ????- ????- ????0.5 ????-
19. distilled water To 100 To 100 To 100 To 100 To 100 To 100
(preparation method)
Respectively water (material 15-19) and oil phase (material 1-14) are heated to dissolving.With these two kinds of mixture blending under stirring condition, be cooled to room temperature then, obtain cosmetics.
＜embodiment 8 and comparative example 6-10〉the skin softening agent
Material Embodiment 8 The comparative example
??1 ??2 ??3 ??4 ??5
1. distilled water To 100 To 100 To 100 To 100 To 100 To 100
2. octyl group dodeses-25 ??0.5 ??0.5 ??0.5 ??0.5 ??0.5 ??0.5
3. anhydro sorbitol polyoxyethylene (20) ether laurate ??0.5 ??0.5 ??0.5 ??0.5 ??0.5 ??0.5
4. glycerol ??10.0 ??10.0 ??10.0 ??10.0 ??10.0 ??10.0
5. propylene glycol ??3.0 ??3.0 ??3.0 ??3.0 ??3.0 ??3.0
6. betanin (Betain) ??3.0 ??3.0 ??3.0 ??3.0 ??3.0 ??3.0
7. allantoin (Alantoin) ??0.3 ??0.3 ??0.3 ??0.3 ??0.3 ??0.3
8. HANSHENGJIAO ??0.2 ??0.2 ??0.2 ??0.2 ??0.2 ??0.2
9. kojic acid ??- ??- ??0.5 ??- ??- ??0.25
10. aminopropane phosphoric acid (APPA) ??- ??- ??- ??0.5 ??- ??0.25
(11.Kojyl-APPA the chemical compound of embodiment 1) ??0.5 ??- ??- ??- ??- ??-
12. two Palmic acid kojic acid esters ??- ??- ??- ??- ??0.5 ??-
13. ethanol ??8.0. ??8.0. ??8.0. ??8.0. ??8.0. ??8.0.
14. spice In right amount In right amount In right amount In right amount In right amount In right amount
15. antiseptic In right amount In right amount In right amount In right amount In right amount In right amount
(preparation method)
Be added in the material 8 material 1 and heating.To wherein adding other water-containing materials 2-12 and mixing, obtain cosmetics with ethanol part (material 13-15).
＜embodiment 9〉the O/W emulsion
Material Embodiment 9
1. ceresine ????3.0
2. lauric acid hexyl ester ????6.0
3. cetyl dimethicone copolyol ????3.0
4. silica gel ????20.0
5. trimethylsiloxy silicate ????3.0
6. acryl-silicone copolymer ????4.0
7. annular dimethyl polysiloxane ????15.0
8. pigment composition ????15.0
9. distilled water To 100
10. glycerol ????5.0
(11.Kojyl-APPA the chemical compound of embodiment 1) ????0.5
12. antiseptic In right amount
13. spice In right amount
(preparation method)
Oil phase (material 1-6) is heated to dissolving and adds material 7 and 8, and in homogeneous mixer, disperse.In these cosmetics, the pigment composition of material 8 is by making 70.0wt% titanium dioxide, 20.0wt% ferrum oxide and the mixing of 10.0wt% Talcum and efflorescence for twice.Then, will contain water (material 9-11) and be heated to dissolving, add to then in the described oil phase.After the stirring, to wherein adding materials 12 and 13, emulsifying then.With the emulsion cooling, obtain cosmetics.
＜EXPERIMENTAL EXAMPLE 3〉fibroblastic hypertrophy
The skin that will obtain from newborn epidermal tissue is handled with 1 Collagen Type VI enzyme, so that remove epidermis.The fibroblast that is obtained is cultivated in DulbeccoShi modification EagleShi culture medium (DMEM).Measure fibroblastic amount by means of mtt assay.The Kojyl-APPA that the result shows embodiment 1 demonstrates effective fibroblast-hypertrophy effect being low to moderate under the concentration of 30mM.
＜EXPERIMENTAL EXAMPLE 4〉Kojyl-APPA is to the safety of live body
For evaluation contains the safety of the cosmetic composition of Kojyl-APPA to live body, by toxicity and the zest of following measuring Kojyl-APPA to live body.The result shows that the Kojyl-APPA of embodiment 1 is safe material as cosmetic composition, nontoxic and nonirritant.
(4-1) elementary skin irritation test
Ten two (12) New Zealand's white adult male rabbit are tested, using specimen preceding 24 hours, with its back depilation.And, the Kojyl-APPA of 1.0ml embodiment 1 is diluted with normal saline, obtain 50% specimen.Specimen (the every position of 0.5ml) is applied to two positions at right back, and (2.5cm * 2.5cm), one of them position is that undamaged skin and another are to gall skin.In contrast, with two positions at left back (2.5cm * 2.5cm) handle with the 1.0ml normal saline.Each test position is covered with gauze, gauze is fixed with the non-irritating adhesive tape.After 24 hours, with normal saline washing test position.
After 24 hours or after 72 hours, observation erythema and edema." food and medicine toxicity test standard instruct (Standard guide for toxicitytest of foods and drugs) " according to 96-8 number of korean foods drug administration announcement tests.As a result, do not observe skin abnormality (common symptom or weight change).And, in being coated with the worn-off skin of specimen, observe seldom unusual, as erythema and edema,, show that specimen is non-stimulated safe material so calculate 0.396 Draize ' s PII (primary stimulus index).
(4-2) people's paster is tested
According to CTFA guide (cosmetics, toilet articles and fragrance association, Washington D.C., 20023,1991), average 25.4 years old 26 (26) healthy womens and four (4) healthy males are tested.The back of object with 70% washing with alcohol and drying, is coated with then and pastes finn chamber (chamber), and this finn chamber (chamber) is the Kojyl-APPA that contains 20 μ l 10% in the patch base material.This finn chamber is fixed to the test position with the micropore adhesive tape.After 24 hours, remove adhesive tape and chamber, and testing the position marking with marking pen.After 24 hours or 48 hours, the skin response at observation test position and according to the zest of the standard evaluation skin of ICDRG (International Contact Dermatitis Research Group).As a result, be difficult to observe the primary stimulus response.Just as shown in table 3, the average response degree is 0.00.
[table 3]
Sample Responsiveness (%), N=30
24 hours 48 hours The average response degree *
The Kojyl-APPA of embodiment 1 (in the patch base material 10%) ????0 ????0 ???0.00
The patch base material ????0 ????0 ???0.00
? *The grade of average response degree=sample/{ 4 (greatest level) * 30 (total sample) * 100 * 1/2
＜EXPERIMENTAL EXAMPLE 5〉to skin safety
For evaluation contains the safety of whitening cosmetic compositions on skin of Kojyl-APPA, the compositions of embodiment 7-8 and comparative example 1-10 is carried out conventional paster test, and according to following scoring system assessment skin irritation:
+++: extremely seriously stimulates, and estimates to be not suitable as cosmetics
++: the serious stimulation, estimate as cosmetics not so good
+: stimulate a little, it is careful to get when estimating as cosmetics
±: almost non-stimulated
-: do not stimulate, estimate to be suitable for sensitive skin
=: coating does not all have to stimulate repeatedly
[table 4]
Embodiment The comparative example
??7 ??8 ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9 ??10
Estimate ??＝ ??- ??＝ ??+ ??＝ ??- ??± ??＝ ??+ ??- ??± ??±
As shown in table 4, the compositions that contains Kojyl-APPA does not stimulate skin.
＜EXPERIMENTAL EXAMPLE 6〉the skin whitening effect
The skin whitening effect that contains the cosmetic composition of Kojyl-APPA for evaluation is carried out following experiment to the compositions of embodiment 7-8 and comparative example 1-10.
Apply patch for the bottom of two arms of ten (10) healthy volunteers with four (4) 1.5cm diametric hole, then in distance apart from its 10cm, use TL20W/12UV lamp (Philips) and TL20W/09UV lamp (Philips) to carry out the UV roentgenization, press 1.5MED once a day, totally 2 days.Then, object is divided into two groups, A group and B group.Use each unguentum of embodiment 7 and comparative example 1-5 preparation and use each skin softening agent of embodiment 8 and embodiment 6-10 preparation to the B group to A group, twice of every day be totally 6 weeks.Bore hole is observed the skin whitening effect and is evaluated as: invalid, effectively and effect remarkable.The results are shown in table 5.
[table 5]
Sample composition Effect is remarkable Effectively Invalid
Embodiment 7 ????2 ????2 ????6
Embodiment 8 ????1 ????3 ????6
The comparative example 1 ????- ????- ????10
The comparative example 2 ????3 ????2 ????5
The comparative example 3 ????- ????2 ????8
The comparative example 4 ????1 ????3 ????6
The comparative example 5 ????1 ????2 ????7
The comparative example 6 ????- ????- ????10
The comparative example 7 ????2 ????3 ????5
The comparative example 8 ????- ????1 ????9
The comparative example 9 ????1 ????2 ????7
The comparative example 10 ????- ????2 ????8
As shown in table 5, the whitening effect that contains the compositions (embodiment 7 and 8) of Kojyl-APPA brightens with the routine that contains the compositions (comparative example 4 and 9) of two Palmic acid kojic acid esters uses the material weak effect few, but some is not as containing the compositions (comparative example 2 and 7) of kojic acid.
＜EXPERIMENTAL EXAMPLE 7〉stability of Kojyl-APPA in base material of cosmetics
Be to estimate the stability of Kojyl-APPA in base material of cosmetics, the stability of passage in time of the compositions that contains Kojyl-APPA of observation embodiment 8 and comparative example 9 the compositions that contains two Palmic acid kojic acid esters (its known have good stable).Each compositions is deposited in the calorstat of 5 ℃, 25 ℃ and 45 ℃, observation fading and the precipitation situation of passage in time then, be evaluated as: 0-does not have, 1-does not almost have, 2-seldom, 3-some and 4-are serious.The results are shown in table 6.
[table 6]
Compositions Temperature (℃) 5 days 10 days 15 days 30 days
????D * ????P * ????D * ????P * ????D * ????P * ????D * ????P *
Embodiment 8 ????5 ????0 ????0 ????0 ????0 ????0 ????0 ????0 ????0
????25 ????0 ????0 ????0 ????0 ????0 ????0 ????0 ????0
????45 ????0 ????0 ????1 ????0 ????1 ????0 ????2 ????1
The comparative example 9 ????5 ????0 ????1 ????0 ????1 ????0 ????2 ????0 ????3
????25 ????0 ????0 ????0 ????1 ????1 ????2 ????1 ????3
????45 ????1 ????0 ????1 ????1 ????2 ????2 ????2 ????3
(notes) D *: fade P *: precipitation
As shown in table 6, the compositions that contains Kojyl-APPA of embodiment 8 does not cause precipitation under 5 ℃ and 25 ℃, and sees 45 ℃ of following bore holes and only to cause flaxen fading.This shows with two Palmic acid kojic acid esters compares, and chemical compound of the present invention has improved stability.
As mentioned above, kojic acid derivative of the present invention, kojic acid 3-aminopropanol di-phosphate ester or its salt, highly stable and have a high-purity in the water base material of desire with aqueous cosmetics.And it can resolve into to have and suppress kojic acid that melanin forms and fibroblast-hypertrophy and collagen-biosynthesis are had effect and skin had the 3-aminopropanol phosphoric acid of good safety.Therefore, in the water of the present invention stable kojic acid derivative can skin whitening with and prevent that skin aging is used widely in applying some make up.
Although top the preferred embodiments of the invention of having described in detail of this paper, but should be understood that, in basic inventive concept teaching herein, can make a lot of change apparent to those skilled in the art, these changes belong to the spirit and scope of the invention equally, and scope of the present invention will define in appending claims.

Claims (8)

1. by the kojic acid derivative shown in the following formula 1 (I):
[formula 1]
Figure A0182299500021
2. the preparation method of the described kojic acid derivative of claim 1, this method may further comprise the steps:
(A) with 3-amino-1-propanol and phosphorus oxychloride with 1: the equivalent proportion of 1-1.3, in organic solvent, under the existence of organic base,, form 2-chlorine tetrahydrochysene-2H-1 0～5 ℃ of reaction 1-2 hour down, 3,2-phosphorus oxazole P-oxide;
(B) with the 2-chlorine tetrahydrochysene-2H-1 of step (A), 3,2-phosphorus oxazole P-oxide and kojic acid are in organic solvent, in the existence reaction down of alkali;
(C) gains with step (B) filter, and concentrating under reduced pressure added acid solution then, at 5-100 ℃ of following hydrolysis 3-10 hour; And
(D) with the product polar organic solvent recrystallize of step (C), obtain kojic acid derivative;
And by under show that response path 1 illustrates:
[response path 1]
Figure A0182299500022
3. method according to claim 2, also comprise step (E): the kojic acid derivative of step (D) is neutralized with nertralizer, and wherein said nertralizer is selected from the group of being made up of alkali metal salt, alkali salt, metal-oxide, alkalescence amino, ammonia, amine, cationic polymer and cationic surfactant.
4. according to claim 2 or 3 described methods, wherein said step (A) or (B) in the described organic solvent that uses be selected from the group of forming by dichloromethane, oxolane, ethyl acetate, acetonitrile, chloroform, ether, methanol, ethanol and propanol.
5. according to each described method among the claim 2-4, wherein said step (A) or (B) in the described alkali that uses be selected from the group of forming by pyridine, triethylamine, sodium, sodium hydroxide and potassium hydroxide.
6. according to each described method among the claim 2-5, the described polar organic solvent that uses in the wherein said step (D) is selected from the group of being made up of methanol, ethanol, isopropyl alcohol, acetone, oxolane, acetonitrile He diox.
7. the skin whitening compositions that applies some make up contains the kojic acid derivative that claim 1 method said or by claim 2 obtains.
8. the skin whitening according to claim 7 compositions that applies some make up, it contains with the kojic acid derivative of composition weight meter 0.01-10wt% or its salt.
CNA018229956A 2001-03-09 2001-05-02 Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetic composition containing same Pending CN1492755A (en)

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KR0141616B1 (en) * 1995-02-17 1998-06-01 한동근 Cosmetic composition containing aminopropane phosphoric acid or its salt
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