CN1176602A - Ascorbyl-phosphoryl-cholesterol - Google Patents
Ascorbyl-phosphoryl-cholesterol Download PDFInfo
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- CN1176602A CN1176602A CN 96190509 CN96190509A CN1176602A CN 1176602 A CN1176602 A CN 1176602A CN 96190509 CN96190509 CN 96190509 CN 96190509 A CN96190509 A CN 96190509A CN 1176602 A CN1176602 A CN 1176602A
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- ascorbyl
- phosphoryl
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Abstract
The present invention relates to a L-ascorbyl new derivative, which is stable, and can be easily combined to excipient for cosmetic and can be divided into dissociate ascorbyl and harmless cholesterol component by biological reversible enzyme in the skin. The typical example is the 3'-(L-ascorbyl-2-phosphoryl)-cholesterol represented by Formula I.
Description
The present invention relates to the synthetic and purposes of L-ascorbic acid new derivative, this new derivative is stablized, is easy to be attached to the used for cosmetic excipient and can be its constituent by biological reversibility enzymolysis.Typical derivant comprises 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol and 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol and salt thereof.
Known L-ascorbic acid in food as the purposes of antioxidant.For example, the ascorbic acid of Steinhart in agricultural food product The Chemicals (1993, the 41st volume, 2257-2277 page or leaf) is at Fe
3+/ ascorbic acid/O
2To having described the purposes of L-ascorbic acid as antioxidant in the preceding antioxidation of L-tryptophan and the antioxidation, it is by removing free radical and self carrying out rapid oxidation and play a role in food in the system.
Similarly, the free L-ascorbic acid in the topical formulations shows weak stability and owing to partial oxidation and non-oxide degraded are easy to decompose.Ascorbic acid after the degraded loses activity and makes host's product lose aesthetic feeling owing to showing brown (can not be accepted by commercially available cosmetics) simultaneously.
Although think cholesterol right and wrong health, especially in the form of taking, with the skin barrier reparation be known with the benefit of the irrelevant cholesterol of L-ascorbic acid.For example, Menon was J.Invest.Dermatol. (1992, the 98th volume, 209-219 page or leaf) described among the Structural Basis for theBarrier Abnormality Following Inhibition of HMG CoA Reductase inMurine Epidermis in that the skin barrier repair mechanism shows deficiency when suppressing cholesterol by downward modulation HMG CoA reductase and synthesize.
According to present method that the product that L-ascorbic acid and cholesterol mechanical mixture get is also unstable, this is because unstability of L-ascorbic acid accounts for main effect.For example, United States Patent (USP) 4939128 the 3rd hurdle 21-22 line description with the bonded ascorbic acid of cholestane base.Obviously lack cholesterol and special indicate the cholestane base reflected open before this with L-ascorbic acid and cholesterol in conjunction with being unpractiaca or desired.
Attempted ascorbic acid and enoxolone group are combined, as describing in the European application 92104149.7; And point out in the United States Patent (USP) 3151127 ascorbic acid is combined with tocopherol.United States Patent (USP) 4564686 and 5306713 also discloses the tocopherol ascorbyl phosphate ester as antioxidant with following array structure.
Sakamoto is at IFSCC, Yokohama (1993, B206 volume, 823-864 page or leaf) described among the Measurement Method of Efficacy of Antidandruff Cosmetics andDevelopment of the New Active Commercial Product tocopherol has been coupled to purposes in the L-ascorbic acid.The tocopherol of coupling is a kind of antioxidant of preserving ascorbyl, but ascorbyl-tocopherol is used for skin treating but has a question because tocopherol not the Fel Elephatis sterin equally be the natural substrate of skin.
Prior art needs a kind of covalency and to be biological reversibility be attached to method on the L-ascorbic acid with cholesterol.The molecule of this coupling should be stablized, even like this owing to still can keep the repertoire activity after the acid phosphorus lipase of natural generation is uncoupled in the skin.The beneficial characteristics that this can provide the L-ascorbic acid comprises the generation that increases collagen and makes skin Lightening, and discharges cholesterol and the benefits such as skin elasticity, resistance, tone and insulation of the improvement that brings.
An object of the present invention is to provide a kind of covalency and biological reversibility is attached on the L-ascorbic acid cholesterol so that the stable method of gained molecule.
Another object of the present invention provides a kind of stable composition with various skin maintenance benefit.
Another object of the present invention provides a kind of L-ascorbic acid derivates, and this derivant is stable and be easy to be included in the cosmetic vehicle and can become free ascorbic acid and harmless cholesterol components by biological reversibility enzymolysis.
Another object of the present invention provides the stable cosmetic compositions that extends the shelf life.
These purposes will be with following open and bright and clear.
The present invention includes and a kind of L-ascorbic acid molecule is incorporated on the cholesterol molecule 2 or 3 of ascorbyl and 3 ' digit pair of cholesterol by biological reversibility phosphoric acid ester bond.Resulting composition also is a part of the present invention.Representational chemical compound comprises the sense or the structure homologue of 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol (general formula I), for example 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol (general formula I I).Two general formulas are as follows.
Formula I
Formula II
Cholesterol is dissolved in bonded 3 '-(L-ascorbyl-2-the phosphoryl)-cholesterol (general formula I) of preparation in the absolute ether (using the 4A molecular sieve drying) that contains 1.0 equivalent triethylamines (as alkali) in-10 ℃.Add phosphoryl chloride phosphorus oxychloride (1.0 equivalent) and get cholesterol phosphonic acids dichloride.The fusing point of cholesterol phosphonic acids dichloride is 121-122 ℃, and infrared (KBr ball) the analysis showed that P=O is absorbed in 1298 wavelength, and P-O-P is absorbed in 1019 wavelength, does not have hydroxyl to absorb.Then with cholesterol phosphonic acids dichloride at room temperature with 5,6-isopropylidene-L-ascorbic acid reacted 3 hours in the oxolane that contains 1.0 equivalent triethylamines.This reaction obtains 5,6-isopropylidene-2-phosphonic acids dichloride L-ascorbic acid and isomer 5 thereof, the mixture of 6-isopropylidene-3-phosphonic acids dichloride L-ascorbic acid.
With this isomer mixture in the THF aqueous solution hydrolysis and under room temperature with Amberlyst-15 (a kind of highly acid sulfonic acid ion exchange resin) stirred for several hour.Remove THF and water then, neutralize with ethyl acetate extraction end-product 3 ' (L-ascorbyl-2-phosphoryl)-cholesterol and with KOH.The lyophilizing of gained solution is got a potassium salt form.
But this new method covalency and biological reversibility have increased the bioavailability of ascorbic acid and cholesterol simultaneously with cholesterol and ascorbic acid coupling and ascorbic acid that must be stable.In ascorbyl-phosphoryl-cholesterol chemical compound of the present invention, the ascorbic acid of coupling can be resisted degraded.Cholesterol is as excipient and help nonpolar external protection (for example horny layer) transhipment of polarity ascorbic acid from skin, has increased the bioavailability of ascorbic acid topical application simultaneously.
Be present in native enzyme such as the phospholipase phospholipid key between cracking cholesterol and the ascorbic acid progressively in the skin, it can make free L-ascorbic acid and cholesterol continue to be discharged in the horny layer.The cholesterol that discharges is a kind of natural substrate of skin.The topical application cholesterol can improve elasticity, tone, and can resist drying.Topical formulations of the present invention comprises 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol or 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol.In addition, also ammonium salt, calcium salt, lithium salts, potassium salt or the sodium salt of these chemical compounds can be attached in the used for cosmetic excipient.According to the present invention, the salt of organic amine (for example ethanolamine) also can provide benefit.
Appropriate excipients comprises conventional washing liquid, facial cream or gel.Washing liquid can comprise 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol or 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol of about 0.1 to about 20.0%; about 0.5 to about 6.0% glycerol; about 2.0 to about 8.0% propylene glycol diocatanoate/two caprates; about 1.8 to about 4.0% Peg40 stearate; about 1.0 to about 2.5% Steareth-2; about 0.25 to about 0.7% xanthan gum; about 0.25 to about 0.7% hydroxyethyl-cellulose; about 0.15 to about 0.2% EDTA disodium and about 0.20 to about 0.25% methyl hydroxybenzoate, all scopes are all represented with percetage by weight.
Facial cream can comprise 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol or 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol of about 0.1 to about 20.0%; about 0.5 to about 4.0% glycerol; about 2.0 to about 6.0% propylene glycol diocatanoate/two caprates; about 1.8 to about 3.0% Steareth-20; about 0.8 to about 2.0% Steareth-2; about 0.25 to about 0.6 xanthan gum; about 0.25 to about 0.6% hydroxyethyl-cellulose, about 1.0 to about 2.5% spermol; about 0.9 to about 3.5% EDTA disodium and glyceryl monostearate and about 0.15 to about 0.2% EDTA disodium.
Gel can contain 0.1 to about 20.0% 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol or 3 '-(L-ascorbyl-3-the phosphoryl)-cholesterol of having an appointment; about 0.15 to about 0.2% EDTA disodium; about 2.0 to about 6.0% propylene glycol, about 0.4 to about 1.5% hydroxyethyl-cellulose and about 0.20 to about 0.25% methyl hydroxybenzoate.
Can the pH value of these preparations be adjusted to the acceptable level of physiology with ammonium hydroxide, calcium hydroxide, Lithium hydrate, potassium hydroxide, sodium hydroxide, ethanolamine, diethanolamine or the urea of capacity.
Chemical compound of the present invention can followingly synthesize: (i) with cholesterol and halophosphoric acid reagent reacting; (ii) with products therefrom and 5; the L-ascorbic acid coupling of 6-hydroxyl protection; (iii) the water hydrolyzate is (iv) sloughed protecting group and (v) product is used the method purification of lyophilization and recrystallization with acid numerical value.This derivant is stable in solution, has antioxidation and can stimulate the generation of collagen in the fibroblast.
The preparation of embodiment 1 di-phosphate ester acid and one potassium salt
Synthetic cholesterol di(2-ethylhexyl)phosphate chloride with the following method.250 milliliter of two neck 19/22ST round-bottomed flask selected in reaction.(Dropping funnel that contains the band side arm of 125 milliliters of 24/40ST) taken in its expansion that comprises a rubber stopper (have nitrogen and go into lancet), stirring rod and 19/22 to 24/40ST.With this device oven dry and under nitrogen current, cool off.With 4.64 gram (12 mM) Sigma 99+﹠amp; Cholesterol, 75 milliliters of ether (activated 4A molecular sieve drying) and 1.214 gram (12 mMs, 1.672 milliliters) anhydrous (using the KOH drying) triethylamines Dropping funnel of packing into.
28 milliliters of absolute ethers and 1.84 gram (12 mMs, 1.118 milliliters) phosphoryl chloride phosphorus oxychlorides are packed into cool off in the flask and in ice/methanol (10 ℃) is bathed.Be added dropwise to the ether that contains the cholesterol triethylamine through 20-30 minute.Solution is warming up to room temperature and stirred 2.5 hours.
With the solid that the buchner funnel filtering precipitates, wash with water 3 times under fully stirring.Importing air all ether in filtrate through buchner funnel all evaporates.Through another buchner funnel filtering solid sediment, cholesterol di(2-ethylhexyl)phosphate chloride is used the phosphorus pentoxide drying in vacuum desiccator.This experiment obtains the first batch of solid of 3.90 grams (65%), fusing point 121-122 ℃ and (29%) second batch of product of 1.74 grams, fusing point 117-118 ℃.IR analyzes (KBr bead) and shows that (C-H) is absorbed in 2947 wavelength, (=C-H) be absorbed in 2878 wavelength, (C=C) be absorbed in 1466 wavelength, (P=O) be absorbed in 1298 wavelength and (P-O-P) be absorbed in 1019 wavelength.
According to the synthetic ascorbic acid cholesterol di-phosphate ester chloride of following method.
This experimental selection is furnished with 50 milliliter of three neck 19/22ST round-bottomed flask that stirring rod, rubber stopper, nitrogen are gone into lancet and 50 milliliters of Dropping funnels.With this device oven dry and under nitrogen current, cool off.With 503 milligrams of (1 mM) cholesterol di(2-ethylhexyl)phosphate chlorides (122 ℃ of fusing points) and 15 milliliters of anhydrous THF Dropping funnel of packing into; In ice/methanol bath (10 ℃), mixture is cooled off.In cooled mixture, add 216 milligrams of (1 mM) Sigma 5,6-isopropylidene-L-ascorbic acid, 15 milliliters of anhydrous THF and 0.14 milliliter of (101 milligrams, 1 mM) anhydrous (KOH) triethylamine.After adding, mixture is warming up to room temperature and stirred 3 hours.
TLC (25% methanol/toluene) the analysis showed that and reacts completely.It shows that also product is 2-O and 3-O position mixture of isomers.The N,N-Diethylethanamine hydrochloride that precipitates with the filtering of groove paper.Remove THF by rotary evaporation and get the muriatic coarse crystal of 0.66 gram (97%) ascorbic acid cholesterol di-phosphate ester.
Be prepared as follows the acid of ascorbic acid cholesterol di-phosphate ester.60 milliliters of THF solution of thick ascorbic acid cholesterol di-phosphate ester chloride (6.76 grams, 9.9 mMs) are merged with 30 ml waters and the 20 moistening Amberlyst-15 of gram (rinsing is crossed three times in water).Under the room temperature with gained mixture vigorous stirring 55 hours.With groove paper filtering Amberlyst-15, with 20 milliliter 1: 1THF/ water with its rinsing once.Remove most of THF and get 53 milliliters dense muddy water suspensions with nitrogen current.
53 milliliters of THF are added in this suspension and the acid of 106 milliliters of nearly clarifying raw phosphoric acid diester 1: the 1THF/ aqueous solution.With this 1: the 1THF/ aqueous solution is added on C-18 reverse phase silica gel (472 gram) post and the acid of purifying phosphoric acid diester, with 1: the 1THF/ water elution.Get the water slurry of the di-phosphate ester acid of 215 milliliters of purification with nitrogen current clarification THF.The plan gross production rate is 1.74 grams (28%); The actual separation productive rate is 1.84 grams (30%).Reversed-phase HPLC the analysis showed that to be 90% purity.
Ascorbic acid cholesterol di-phosphate ester diacid one potassium salt be by at first with monovalent standardization potassium hydroxide solution handle 1% two aqueous acids then the lyophilization preparation get.This di-phosphate ester diacid (579 milligrams, 0.927 mM) is dissolved in 57.9 ml waters, handles with 9.44 milliliters of 0.0986N potassium hydroxide solutions (0.1931 mM).Solution lyophilization after will neutralizing then and primary water obtain the fluffy white solid of 603 milligram (98%) one potassium salt.Embodiment 2 is by anti-phase C-18 chromatography purification
Chromatography (1980, the 13rd volume, 5-10 page or leaf) 1 kilogram of anti-phase C-18 silica gel of preparation according to Evans.With 1: 1THF/ water (90: 1 packing ratios) is purified to 90% level with di-phosphate ester acid, removes THF with nitrogen current then and removes by lyophilization and anhydrate.Studying other solvent system with inverse thin layer chromatography can (i) improve purity level, (ii) discerns a kind of effective separating medium that can remove by rotary evaporation and (iii) can use low packing ratio.Because anti-phase C-18 silica gel is recycling, so this method can make purification reach 1000 grams.
The appropriate solvent system comprises THF/ methanol, THF/ ethanol, THF/ isopropyl alcohol, dioxanes/methanol, dioxanes/ethanol, dioxanes/isopropyl alcohol, ether/methanol, ether, ether/isopropyl alcohol, ethyl acetate/methanol, ethyl acetate/ethanol, ethyl acetate/isopropyl alcohol, dichloromethane/ethanol, methylene chloride, dichloromethane/isopropyl alcohol, DME/ methanol, DME/ ethanol and DME/ isopropyl alcohol.
Combine with cholesterol and can make the polarity ascorbic acid be converted into nonpolar close ester ascorbyl, it is easy to absorb by horny layer.In case by horny layer, the chemical compound that is absorbed can influence following fibroblast.Explained the ascorbic acid after biology is reversible and the benefit front of cholesterol.But, unexpectedly, in conjunction with after chemical compound itself can stimulate the synthetic of collagen, it can strengthen the integrity and the elasticity of skin.Other details is as described in the embodiment 3.The research of embodiment 3 fibroblasts
Present embodiment has been summed up a research, has wherein illustrated the ability that 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol irritate human skin fibroblast produces.With 3 ' of various dose-(L-ascorbyl-2-phosphoryl)-cholesterol carry out this area approval [
3H]-proline is in conjunction with test.Juva. analysis of biochemical (1966, the 15 volumes, 77-83 page or leaf); The biochemical biophysics collected works of Booth (1981, the 675 volumes, 117-122 page or leaf).
With fibroblast and 0 μ g/ml, 11.3 μ g/ml, 22.5 μ g/ml, 45 μ g/ml, 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol cultivated totally 48 hours.First are after 24 hours, will [
3H]-proline is added in the culture medium.Second after 24 hours, collecting cell also prepares to be used for the test of collagen biosynthesis.
Add protease and prevent collagen and other proteinic degraded.Cellular layer is scraped in the solution that contains 0.4MNaCl and 0.01M Tris (pH7.5).The supersound process extract is with broken cell membrane.Each solution (each 1 milliliter) dialysis in deionized water (changing for several times) that contains cell is spent the night.Dialysis is removed and is oozed abundant thing and spend the night in 120 ℃ of hydrolysis in 6N hydrochloric acid.This test is carried out oxidation with the 2M chloramine-T.Sample is carried out the radiocounting analysis, its representative newly synthetic [
3H]-hydroxyproline-synthetic index of Xin collagen.
Find that 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol can increase the generation of new collagen in dose-dependent mode by human skin fibroblast, as shown in the table.
[
+H]-combination of proline
The concentration (μ g/ml) of 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol
Can carry out various modifications and change to the present invention according to disclosure text.These changes and interpolation should be within the scope of the invention, and the following claims of essence of the present invention are described.
Claims (9)
1. a topical formulations contains suitable topical vehicle and a kind of chemical compound that is selected from 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol, 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol and salt thereof.
2. the topical formulations of claim 1, wherein said salt is selected from ammonium salt, calcium salt, lithium salts, potassium salt, sodium salt and organic amine salt.
3. the topical formulations of claim 1, wherein said excipient is selected from washing liquid, facial cream and gel.
4. topical formulations, it comprises:
(a) about 0.1 to about 20.0% chemical compound that is selected from 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol and 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol;
(b) about 0.5 to about 6.0% glycerol;
(c) about 2.0 to about 8.0% propylene glycol diocatanoate/two caprates;
(d) about 1.8 to about 4.0% Peg40 stearic acid;
(e) about 1.0 to about 2.5% Steareth-2;
(f) about 0.25 to about 0.7% xanthan gum;
(g) about 0.25 to about 0.7% hydroxyethyl-cellulose;
(h) about 0.15 to about 0.2% EDTA disodium; And
(i) about 0.20 to about 0.25% methyl hydroxybenzoate.
5. the topical formulations of claim 4, the pH value of wherein said preparation can be adjusted to the acceptable level of physiology be selected from ammonium hydroxide, calcium hydroxide, Lithium hydrate, potassium hydroxide, sodium hydroxide, ethanolamine, diethanolamine or the urea of capacity.
6. topical formulations, it comprises:
(a) about 0.1 to about 20.0% chemical compound that is selected from 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol and 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol;
(b) about 0.5 to about 4.0% glycerol;
(c) about 2.0 to about 6.0% propylene glycol diocatanoate/two caprates;
(d) about 1.8 to about 3.0% Steareth-20;
(e) about 0.8 to about 2.0% Steareth-2;
(f) about 0.25 to about 0.6% xanthan gum;
(g) about 0.25 to about 0.6% hydroxyethyl-cellulose;
(h) about 1.0 to about 2.5% spermol;
(I) about 0.9 to about 3.5% glyceryl monostearate; And
(j) about 0.15 to about 0.2% EDTA disodium.
7. the topical formulations of claim 6, the pH value of wherein said preparation can be adjusted to the acceptable level of physiology be selected from ammonium hydroxide, calcium hydroxide, Lithium hydrate, potassium hydroxide, sodium hydroxide, ethanolamine, diethanolamine or the urea of capacity.
8. topical formulations, it comprises:
(a) about 0.1 to about 20.0% chemical compound that is selected from 3 '-(L-ascorbyl-2-phosphoryl)-cholesterol and 3 '-(L-ascorbyl-3-phosphoryl)-cholesterol;
(b) about 0.15 to about 0.2% EDTA disodium;
(c) about 2.0 to about 6.0% propylene glycol;
(d) about 0.4 to about 1.5% hydroxyethyl-cellulose;
(h); And
(e) about 0.20 to about 0.25% methyl hydroxybenzoate.
9. the topical formulations of claim 8, the pH value of wherein said preparation can be adjusted to the acceptable level of physiology be selected from ammonium hydroxide, calcium hydroxide, Lithium hydrate, potassium hydroxide, sodium hydroxide and the ethanolamine of capacity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96190509 CN1176602A (en) | 1996-05-14 | 1996-05-14 | Ascorbyl-phosphoryl-cholesterol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96190509 CN1176602A (en) | 1996-05-14 | 1996-05-14 | Ascorbyl-phosphoryl-cholesterol |
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| Publication Number | Publication Date |
|---|---|
| CN1176602A true CN1176602A (en) | 1998-03-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96190509 Pending CN1176602A (en) | 1996-05-14 | 1996-05-14 | Ascorbyl-phosphoryl-cholesterol |
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|---|---|
| CN (1) | CN1176602A (en) |
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1996
- 1996-05-14 CN CN 96190509 patent/CN1176602A/en active Pending
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