Solubilization of glycolate and tartrate derivatives of resveratrol.

Abstract

A method for solubilizing a resveratrol glycolate compound by heating the resveratrol glycolate and mixing the resveratrol glycolate with one or more glycols is disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a CIP of Non-Provisional Patent Application No. 16 / 081,842, filed August 31, 2018, which is a national stage application of International Application No. PCT / US17 / 20923, filed March 6, 2017, which claims the benefit of priority to U.S. Provisional Application No. 62 / 304541, filed March 7, 2016, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present invention is in the field of resveratrol derivative compounds and compositions, and methods for synthesizing the same. [Background technology]

[0003] Resveratrol, also known as 3,5,4'-trihydroxystilbene, has the general formula:

[0004] [ka] is a polyhydroxy-substituted compound having the formula:

[0005] It is present in the berries or extracts of red grapes, raspberries, blueberries, and certain other plants. Resveratrol is known to be a powerful antioxidant and to have other anti-aging, anti-cancer, and anti-viral effects. Resveratrol is incorporated into various cosmetic formulations, such as skin creams, due to its recognized rejuvenating properties. However, resveratrol is somewhat unstable, and therefore prone to discoloration. In addition, in order to maximize the effectiveness of resveratrol in terms of properties such as stability, activity, and beneficial effects on the skin, it is most desirable to react resveratrol with other compounds to produce resveratrol derivatives.

[0006] Alpha hydroxy acids or AHAs are known for their effectiveness in treating skin. The carboxylic acid group of the compound aids in exfoliation, removing dead skin cells and debris from the skin surface. AHAs are also said to reduce the appearance of age-related skin changes, such as lines, wrinkles, age spots, blemishes, yellowing, and sagging skin. However, AHAs can also cause skin irritation, redness, or dryness in people with sensitive skin.

[0007] Particularly effective AHAs are glycolic acid and tartaric acid. Glycolic acid has the following formula:

[0008] [ka]

[0009] Tartaric acid has the following formula:

[0010] [ka] has.

[0011] Esterification of resveratrol with glycolic or tartaric acid results in resveratrol derivatives that may be mono-, di- or trisubstituted esters at the hydroxyl groups to form resveratrol mono-, di- or triglycolates or mixtures thereof, or resveratrol mono-, di- or tritartrates or mixtures thereof, respectively. Such derivatives can be incorporated into cosmetic compositions to provide beneficial effects such as stimulating collagen or fibrillin synthesis, exfoliating the skin, whitening the skin, treating acne or other skin lesions, and inhibiting matrix metalloproteinases that degrade collagen. Summary of the Invention

[0012] The embodiments described herein include a compound having the formula:

[0013] [ka] (wherein each R is independently (i) -OH, or (ii)

[0014] [ka] or (iii)

[0015] [ka] provided that all three R cannot simultaneously be -OH. The compounds covered are:

[0016] The present invention also provides a method for synthesizing an ester of resveratrol and glycolic acid, comprising the steps of: a) deprotonating resveratrol by reacting it with a base; b) (i) reacting the alpha hydroxyl group of glycolic acid with a compound having a protecting donor group to form a protected alpha hydroxyglycolic acid; (ii) reacting (i) with a halogen donor compound to form a reactive alpha hydroxyl acyl halide. preparing alpha hydroxyl protected glycolic acid by c) reacting (a) and (b) to form an alpha hydroxyl protected resveratrol glycolate; and d) deprotecting the protected alpha hydroxyl group to form resveratrol glycolate. This applies to methods using the following:

[0017] The present invention also provides a method for synthesizing resveratrol tartrate, comprising the steps of: (a) deprotonating resveratrol by reacting it with a base; (b)(i) dehydrating tartaric acid to form reactive tartaric anhydride; (ii) simultaneously reacting the alpha hydroxyl group with a compound having a protected donor group to form a protected tartaric anhydride. preparing an alpha hydroxyl protected tartaric anhydride by (c) reacting (a) and (b) to form an alpha hydroxyl protected resveratrol tartrate; and (d) deprotecting the protected alpha hydroxyl group to form resveratrol tartrate. The present invention relates to a method comprising:

[0018] The present invention is also directed to topical compositions comprising a compound of the formula:

[0019] The embodiments described herein also include compounds of the formula:

[0020] [ka] (wherein each R is independently (i) -OH, or (ii)

[0021] [ka] or (iii)

[0022] [ka] provided that all three R cannot simultaneously be -OH. The compounds covered are:

[0023] The present invention also provides a method or process for solubilizing resveratrol glycolate, comprising: (a) heating a resveratrol glycolate compound; and (b) mixing the resveratrol glycolate compound with at least one glycol solvent at room temperature for about 10 minutes to about 120 minutes; This applies to methods using the following: [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 shows an HPLC chromatogram of resveratrol glycolate (1%) at 4° C. [Diagram 2] FIG. 1 shows an HPLC chromatogram of resveratrol monoglycolate (1%) at 4° C. [Diagram 3] FIG. 1 shows an HPLC chromatogram of resveratrol diglycolate (1%) at 4° C. [Figure 4] FIG. 2 shows an HPLC chromatogram of resveratrol glycolate (1%) at 50° C. [Diagram 5] FIG. 2 shows an HPLC chromatogram of resveratrol monoglycolate (1%) at 50° C. [Figure 6] FIG. 2 shows an HPLC chromatogram of resveratrol diglycolate (1%) at 50° C. [Figure 7] FIG. 1 shows HPLC chromatograms of resveratrol glycolate in pentylene glycol and butylene glycol at 4° C. and 50° C., respectively. [Figure 8] FIG. 1 shows HPLC chromatograms of resveratrol monoglycolate in pentylene glycol and butylene glycol at 4° C. and 50° C., respectively. [Figure 9] FIG. 1 shows HPLC chromatograms of resveratrol diglycolate in pentylene glycol and butylene glycol at 4° C. and 50° C., respectively. [Figure 10] FIG. 1 shows the stability of resveratrol glycolate (1%) dissolved in each formulation at 4° C. and 50° C. [Figure 11] FIG. 1 shows the stability of resveratrol mono- and diglycolate (10%) dissolved in the respective formulations at 4° C. and 50° C. [Figure 12] FIG. 1 shows the stability of resveratrol mono- and diglycolate (20%) dissolved in the respective formulations at 4° C. and 50° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Resveratrol glycolate (resveratrol glycolate) Esters of resveratrol and glycolic acid can be made as follows: a) deprotonating resveratrol by reacting it with a base; b) (i) reacting the alpha hydroxyl group of glycolic acid with a compound having a protecting donor group to form a protected alpha hydroxyglycolic acid; (ii) reacting (i) with a halogen donor compound to form a reactive alpha hydroxyl acyl halide; 2. Prepare alpha hydroxyl protected glycolic acid by c) reacting (a) and (b) to form an alpha-hydroxyl protected resveratrol glycolate; and d) deprotecting the protected alpha hydroxyl group to form resveratrol glycolate.

[0026] Suitable bases for deprotonating resveratrol include alkali or alkaline earth metal hydrides, such as sodium, potassium, magnesium, lithium, etc. Preferably, about 0.5 to 2 moles, most preferably 1 mole of resveratrol is reacted with about 2 to 10 moles of metal hydride, preferably sodium hydride. In addition, the reaction conditions are room temperature (25°C) in the presence of anhydrous argon gas and tetrahydrofuran. The reaction conditions can range from 1 to 10 hours, most preferably 2 to 6 hours, which results in deprotonated resveratrol with all three hydrogens removed from the three hydroxyl groups of resveratrol.

[0027] Separately, glycolic acid is reacted with a compound having a protected donor group. Most preferred are pyran compounds that are heterocyclic non-aromatic rings, especially mono-, di-, tri-, or tetrahydropyran (mono-, di-, tri-, and tetra- refer to the number of hydrogen atoms removed from the pyran ring) and short chain mono-, di-, or trialkyl halogens, where the alkyl is a short chain alkyl, e.g., methyl, ethyl, propyl, and the halogen is chlorine, fluorine, bromine, etc. Dimethyl chloride is most preferred. The reaction may be carried out in the presence of pyridine, p-toluenesulfonic acid, preferably at room temperature for a period ranging from 3 to 12 hours. More preferred is when the compound having a protected donor group is dihydropyran and the alkyl halide is dimethyl halogen, especially dimethyl chloride. About 1.5 moles of dihydropyran are reacted with 1 mole of glycolic acid to obtain tetrahydropyran protected alpha hydroxyl glycolate. Then, the reaction is continued for 4 to 6 hours under reflux conditions in the presence of SOCl2, dimethylformamide, and dimethyl chloride to obtain glycolic acid acyl chloride whose alpha hydroxyl group is protected with tetrahydropyran. The final step is to deprotect the protected alpha hydroxyl acyl.

[0028] Alternatively, after deprotonating glycolic acid, the hydroxyl group can be protected by reaction with a trityl halogen, such as trityl chloride (triphenylmethyl chloride), in which case the alpha hydroxyl group is replaced with a triphenylmethyl group. The protected compound is then reacted with SOCl2, dimethylformamide, and dimethyl chloride under reflux conditions for about 4-6 hours to give a compound with a trityl-protected alpha hydroxyl chloride group. The trityl-protected acyl halide form of the compound is then reacted with deprotonated resveratrol to form resveratrol glycolate, in which the alpha hydroxyl group of glycolic acid remains protected with a trityl group. The trityl-protecting group is removed by reaction with one or more of trifluoroacetic acid, ethanediol, dimethyl sulfide, and dimethyl chloride to form resveratrol glycolate.

[0029] Another alternative is to purchase commercially available 2-hydroxyacetyl chloride and react it with deprotonated resveratrol to form resveratrol glycolate. The reaction is carried out at room temperature for 12 to 72 hours in the presence of one or more of triethylamine and tetrahydrofuran. The final product is resveratrol glycolate. Depending on the reaction conditions and reactant concentrations used, the resveratrol glycolate may be mono-, di- or tri-substituted with glycolic acid or in the form of a mixture of mono-, di- or tri-substituted esters. In this case, the various compounds include 3-glycolate-5-4'-dihydroxystilbene, 5-glycolate-3,4'dihydroxystilbene, 4'-glycolate-3,5-dihydroxystilbene, 3,5-diglycolate-4'-hydroxystilbene, 3,4'-diglycolate-5-hydroxystilbene, 3,4'-diglycolate-5-hydroxystilbene, 4'5-diglycolate-3-hydroxystilbene, and 3,5,4'-triglycolate stilbene.

[0030] Resveratrol tartrate (resveratrol tartrate) The tartrate ester of resveratrol can be synthesized by first deprotonating resveratrol under the same reaction conditions as described above for the synthesis of resveratrol glycolate. Separately, tartaric acid is reacted in the presence of acetic anhydride, acetic acid, or pyridine at room temperature for 12-48 hours to give the acetyl-protected tartaric anhydride, O,O'-diacetyl-L-tartaric anhydride. Alternatively, this compound can be purchased commercially.

[0031] One mole of deprotonated resveratrol is then reacted with 3 moles of O,O'-diacetyl-L-tartaric anhydride to form acetyl-protected resveratrol tartrate. The protecting groups are removed by reaction with potassium carbonate (10 moles) and methanol at room temperature for 1-6 hours to give resveratrol tartrate. Depending on the reaction conditions and amounts of reactants used, the resveratrol may be mono-, di- or tri-substituted with tartaric acid or may be in the form of a mixture of mono-, di- and tri-substituted resveratrol tartrates. In this case, the various compounds include 3-tartrate-5-4'-dihydroxystilbene, 5-tartrate-3,4'dihydroxystilbene, 4'-tartrate-3,5-dihydroxystilbene, 3,5-dihydroxystilbene, 3,4'-ditartarate-4'-hydroxystilbene, 3,4'-ditartarate-5-hydroxystilbene, 3,4'-ditartarate-5-hydroxystilbene, 4'5-ditartarate-3-hydroxystilbene, and 3,5,4'-tritartarate stilbene.

[0032] Cosmetic Composition Resveratrol esters can be incorporated into topical cosmetic compositions that can be in the form of creams, lotions, serums, solutions, dispersions, etc. The compositions can be in the form of either water-in-oil or oil-in-water emulsion formulations. Suitable emulsions contain about 1 to 90% water and 10-90% other ingredients, such as oils. Such additional ingredients include, but are not limited to:

[0033] oil Suitable oils include silicone, ester, vegetable oils, synthetic oils, including but not limited to those described herein. The oil may be volatile or non-volatile, and is preferably in the form of a pourable liquid at room temperature. When present, the oil may range from about 0.5 to 85% by weight of the total composition, preferably about 1-75% by weight, more preferably about 5-65% by weight.

[0034] Cyclic and linear volatile silicones are available from a variety of commercial suppliers, including Dow Corning Corporation and General Electric. Dow Corning's linear volatile silicones are sold under the trade names Dow Corning 244, 245, 344, and 200 fluid. These fluids include hexamethyldisiloxane (viscosity 0.65 centistokes (abbreviated cst)), octamethyltrisiloxane (1.0 cst), decamethyltetrasiloxane (1.5 cst), dodecamethylpentasiloxane (2 cst), and mixtures thereof, with all viscosity measurements at 25°C.

[0035] Suitable branched volatile silicones include alkyl trimethicones, such as methyl trimethicone, having the general formula:

[0036] [ka] Methyl trimethicone is, for example, available from Shin-Etsu Silicones under the trade name TMF-1.5, which has a viscosity of 1.5 centistokes at 25°C.

[0037] Also suitable are various straight or branched chain paraffinic hydrocarbons having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, more preferably 8 to 16 carbon atoms. Suitable hydrocarbons include pentane, hexane, heptane, decane, dodecane, tetradecane, tridecane, and C 8~20Contains isoparaffins. 12 Isoparaffins are manufactured by Permethyl Corporation under the trade name Permethyl 99A. 16 Isoparaffins such as isohexadecane (trade name Permethyl®) are also suitable.

[0038] Esters formed by the reaction of carboxylic acids and alcohols are also suitable. Both the alcohol and carboxylic acid may have a fatty (C6-30) chain. Examples include hexyl laurate, butyl isostearate, hexadecyl isostearate, cetyl palmitate, isostearyl neopentanoate, stearyl heptanoate, isostearyl isononanoate, stearyl lactate, stearyl octanoate, stearyl stearate, isononyl isononanoate, and the like.

[0039] The esters may also be in the form of dimers or trimers. Examples of such esters include diisotearyl malate, neopentyl glycol dioctanoate, dibutyl sebacate, dicetyl dimer dilinoleate, dicetyl adipate, diisocetyl adipate, diisononyl adipate, diisostearyl dimer dilinoleate, diisostearyl fumarate, diisostearyl malate, dioctyl malate, etc.

[0040] Examples of other types of esters include those derived from arachidonic acid, citric acid, or behenic acid, such as triarachidin, tributyl citrate, triisostearyl citrate, trialkyl citrate (C 12 ~ 13 ), tricaprylin, tricaprylyl citrate, tridecyl behenate, trioctyldodecyl citrate, tridecyl behenate, or tridecyl coconut oil fatty acid, tridecyl isononanoate, etc.

[0041] Synthetic or naturally occurring glyceryl esters of fatty acids, or triglycerides, are also suitable for use in the compositions. Both vegetable and animal sources may be used. Examples of such oils include castor oil, lanolin oil, C 10~18 These include triglycerides, caprylic / capric / triglycerides, almond oil, apricot kernel oil, sesame oil, camelina sativa oil, calendula seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, ink oil, olive oil, palm oil, illipe oil, rapeseed oil, soybean oil, grapeseed oil, sunflower seed oil, and walnut oil.

[0042] Also suitable are synthetic or semi-synthetic glyceryl esters, such as fatty acid mono-, di- and triglycerides that are modified natural fats and oils, such as mono-, di- or triesters of polyols, such as glycerin. 12~22 ) carboxylic acids are reacted with one or more repeating glyceryl groups, such as glyceryl stearate, diglyceryl diiosostearate, polyglyceryl-3 isostearate, polyglyceryl-4 isostearate, polyglyceryl-6 ricinoleate, glyceryl dioleate, glyceryl diisotearate, glyceryl tetraisostearate, glyceryl trioctanoate, diglyceryl distearate, glyceryl linoleate, glyceryl myristate, glyceryl isostearate, PEG castor oil, PEG glyceryl oleate, PEG glyceryl stearate, PEG glyceryl tallowate, and the like.

[0043] Nonvolatile silicone oils, both water-soluble and water-insoluble, are also suitable for use in the composition.Such silicones preferably have a viscosity ranging from about more than 5 to 800,000 cst, preferably 20 to 200,000 cst at 25°C.Suitable water-insoluble silicones include amine-functional silicones such as amodimethicone.Examples include dimethicone, phenyl dimethicone, diphenyl dimethicone, phenyl trimethicone, or trimethylsiloxyphenyl dimethicone.Other examples include alkyl dimethicones, such as cetyl dimethicone, stearyl dimethicone, behenyl dimethicone, and the like.

[0044] Surfactants The composition may contain one or more surfactants, especially when it is in emulsion form. However, such surfactants can also be used when the composition is anhydrous, and are useful for dispersing polar components, such as pigments. Such surfactants may be silicone-based or organic-based. Surfactants aid in the formation of stable emulsions, either water-in-oil or oil-in-water. When present, surfactants may range from about 0.001 to 30% by weight, preferably about 0.005 to 25% by weight, more preferably about 0.1 to 20% by weight of the total composition.

[0045] Silicone surfactants can be collectively referred to as dimethicone copolyol or alkyl dimethicone copolyol.In some cases, the number of repeating ethylene oxide or propylene oxide units in the polymer is also specified, for example, dimethicone copolyol also referred to as PEG-15 / PPG-10 dimethicone, which refers to dimethicone with a substituent containing 15 ethylene glycol units and 10 propylene glycol units on the siloxane backbone.It is also possible to replace one or more of the methyl groups in the above general structure with longer alkyl chains (e.g., ethyl, propyl, butyl, etc.) or ethers, such as methyl ether, ethyl ether, propyl ether, butyl ether, etc.

[0046] Examples of silicone surfactants are those sold under the trade name Dow Corning 3225C Formulation Aid by Dow Corning, which has the CTFA name Cyclopentasiloxane (and) Cyclopentasiloxane (and) PEG / PPG-18 Dimethicone; or 5225C Formulation Aid, which has the CTFA name Cyclopentasiloxane (and) PEG / PPG-18 / 18 Dimethicone; or Dow Corning 190 Surfactant, which has the CTFA name PEG / PPG-18 / 18 Dimethicone; or Dow Corning 193 Fluid, Dow Corning 5200, which has the CTFA name Lauryl PEG / PPG-18 / 18 Methicone; or Abil EM, sold by Goldschmidt, which has the CTFA name Cetyl PEG / PPG-14 / 14 Dimethicone. 90; or Abil EM 97 sold by Goldschmidt, which has the CTFA name Bis-Cetyl PEG / PPG-14 / 14 Dimethicone; or Abil WE 09, in the form of a mixture also containing Polyglyceryl-4 Isostearate and Hexyl Laurate, which has the CTFA name Cetyl PEG / PPG-10 / 1 Dimethicone; or KF-6011 sold by Shin-Etsu Silicones, which has the CTFA name PEG-11 Methyl Ether Dimethicone; KF-6012 sold by Shin-Etsu Silicones, which has the CTFA name PEG / PPG-20 / 22 Butyl Ether Dimethicone; or KF-6013 sold by Shin-Etsu Silicones, which has the CTFA name PEG-9 Dimethicone; or Shin-Etsu Silicones, which has the CTFA name PEG-3 Dimethicone. or KF-6016 sold by Shin-Etsu Silicones, which has the CTFA name PEG-9 Methyl Ether Dimethicone; or KF-6017 sold by Shin-Etsu Silicones, which has the CTFA name PEG-10 Dimethicone; or KF-6038 sold by Shin-Etsu Silicones, which has the CTFA name Lauryl PEG-9 Polydimethylsiloxyethyl Dimethicone.

[0047] Also suitable are various kinds of crosslinked silicone surfactants, often referred to as emulsifying elastomers, which contain at least one hydrophilic part, such as polyoxyalkylenated group.Polyoxyalkylenated silicone elastomers that can be used in at least one embodiment of the present invention include those sold by Shin-Etsu Silicones under the names KSG-21, KSG-20, KSG-30, KSG-31, KSG-32, KSG-33; KSG-210, which is dimethicone / PEG-10 / 15 crosspolymer dispersed in dimethicone; KSG-310, which is PEG-15 lauryl dimethicone crosspolymer; KSG-320, which is PEG-15 lauryl dimethicone crosspolymer dispersed in isododecane; KSG-330 (the above dispersed in triethylhexanoin), KSG-340, which is a mixture of PEG-10 lauryl dimethicone crosspolymer and PEG-15 lauryl dimethicone crosspolymer.

[0048] Polyglycerolized silicone elastomers are also suitable, such as those disclosed in PCT / WO 2004 / 024798, which is incorporated herein by reference in its entirety.Such elastomers include Shin-Etsu's KSG series, such as KSG-710, which is a dimethicone / polyglycerin-3 crosspolymer dispersed in dimethicone; or lauryl dimethicone / polyglycerin-3 crosspolymer dispersed in various solvents, such as isododecane, dimethicone, triethylhexanoin, sold under the trade names KSG-810, KSG-820, KSG-830, or KSG-840 by Shin-Etsu.Silicon sold under the trade names 9010 and DC9011 by Dow Corning are also suitable.

[0049] The composition may include one or more nonionic organic surfactants. Suitable nonionic surfactants include alkoxylated alcohols or ethers formed by the reaction of an alcohol with an alkylene oxide, usually ethylene or propylene oxide. Preferably, the alcohol is any of the fatty alcohols having 6 to 30 carbon atoms. Examples of such ingredients include Steareth 2-100, formed by the reaction of stearyl alcohol and ethylene oxide, with the number of ethylene oxide units ranging from 2 to 100; Beheneth 5-30, formed by the reaction of behenyl alcohol and ethylene oxide, with the number of repeating ethylene oxide units ranging from 5 to 30; Ceteareth 2-100, formed by the reaction of a mixture of cetyl and stearyl alcohol with ethylene oxide, with the number of repeating ethylene oxide units in the molecule ranging from 2 to 100; Ceteth 1-45, formed by the reaction of cetyl alcohol and ethylene oxide, with the number of repeating ethylene oxide units ranging from 1 to 45, and the like. All references to units include all integers between the ranges.

[0050] Other alkoxylated alcohols are formed by the reaction of fatty acids and mono-, di- or polyhydric alcohols with alkylene oxides. 6~30 They are the reaction products of fatty carboxylic acids and polyhydric alcohols (monosaccharides such as glucose, galactose, methyl glucose, etc.) with alkoxylated alcohols. Examples include polymeric alkylene glycols reacted with glyceryl fatty acid esters, such as PEG glyceryl oleate, PEG glyceryl stearate; or polyhydroxyalkanoates, such as PEG dipolyhydroxystearate, in which the number of repeating ethylene glycol units ranges from 3 to 1000.

[0051] Other suitable nonionic surfactants include alkoxylated sorbitan and alkoxylated sorbitan derivatives. For example, alkoxylation, especially ethoxylation, of sorbitan results in polyalkoxylated sorbitan derivatives. Esterification of polyalkoxylated sorbitan results in sorbitan esters such as polysorbates. For example, polyalkoxylated sorbitan can be esterified with C6-30, preferably C12-22 fatty acids. Examples of such components include polysorbates 20-85, sorbitan oleate, sorbitan sesquioleate, sorbitan palmitate, sorbitan sesquiisostearate, sorbitan stearate, etc.

[0052] Moisturizer It may also be desirable to include one or more humectants in the composition. When present, such humectants may range from about 0.001 to 25%, preferably from about 0.005 to 20%, more preferably from about 0.1 to 15% by weight of the total composition. Examples of suitable humectants include glycols, sugars, and the like. Suitable glycols are in the form of monomers or polymers, including polyethylene and polypropylene glycols, e.g., PEG 4-200, which is a polyethylene glycol having 4 to 200 repeating ethylene oxide units; and C 1~6 Alkylene glycols include propylene glycol, butylene glycol, pentylene glycol, etc. Suitable sugars, some of which are also polyhydric alcohols, are also suitable humectants. Examples of such sugars include glucose, fructose, honey, hydrogenated honey, inositol, maltose, mannitol, maltitol, sorbitol, sucrose, xylitol, xylose, etc. Urea is also suitable. Preferably, the humectant used in the composition of the present invention is C 1~6 , preferably C 2~4 Alkylene glycol, most particularly butylene glycol.

[0053] plant extract It may be desirable to include one or more plant extracts in the composition. In that case, suggested ranges are about 0.0001 to 10% by weight of the total composition, preferably about 0.0005 to 8% by weight, more preferably about 0.001 to 5% by weight. Suitable plant extracts include extracts from plants (herbs, roots, flowers, fruits, seeds), such as flowers, fruits, vegetables, etc., such as yeast fermentation extract, Padina Pavonica extract, Thermus thermophilis fermentation extract, Camelina seed oil, Boswellia serrata extract, Olive extract, Arabidopsis Thaliana extract, Acacia Dealbata extract, Silver maple extract, and the like. Saccharinum (sugar maple), acidophilus, acorus, aesculus, agaricus, agave, agrimonium, algae, aloe, citrus, brassica, cinnamon, orange, apple, blueberry, cranberry, peach, pear, lemon, lime, pea, seaweed, caffeine, green tea, chamomile, willow bark, mulberry, poppy, and those listed in the CTFA Cosmetic Ingredient Handbook, 8th Edition, Volume 2, pages 1646 to 1660.Further examples include Glycyrrhiza glabra, Salix nigra, Macrocycstis pyrifera, Pyrus malus, Saxifraga sarmentosa, Vitis vinifera, Morus nigra, Scutellaria baicalensis, Anthemis nobilis, Salvia sclarea, Rosmarinus officianalis, Citrus medica limonum, Panax ginseng, Siegesbeckia orientalis, Fructus mume, Ascophyllum nodosum, nodosum, Bifida fermentation lysate, soybean (Glycine soja) extract, beet (Beta vulgaris), Haberlea rhodopensis, Japanese knotweed (Polygonum cuspidatum), orange (Citrus aurantium dulcis), grape, selaginella tamariscina, hops (Humulus lupulus), mandarin orange (Citrus reticulata) peel, pomegranate (Punica granatum), asparagopsis armata, turmeric (Curcuma longa), menyanthes trifoliata, sunflower (Helianthus annuus), barley (Hordeum vulgare), cucumber (Cucumis sativus, Evernia prunastri, Evernia furfuracea, and mixtures thereof.

[0054] Particulate material The compositions of the present invention may contain particulate materials in the form of pigments, inert particulates, or mixtures thereof. If present, suggested ranges are about 0.01-75% by weight of the total composition, preferably about 0.5-70% by weight, more preferably about 0.1-65% by weight. If the composition may contain a mixture of pigments and powders, suitable ranges include about 0.01-75% pigments and 0.1-75% powders, by weight based on the weight of the total composition.

[0055] The particulate material may be a coloured or uncoloured powder. Suitable non-pigmented powders include bismuth oxychloride, titanium dioxide, fumed silica, spherical silica, polymethylmethacrylate, micronized teflon, boron nitride, acrylate copolymers, aluminum silicate, aluminum starch octenylsuccinate, bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceous earth, fuller's earth, glyceryl starch, hectorite, hydrous silica, kaolin, magnesium aluminum silicate, magnesium trisilicate, maltodextrin, montmorillonite, microcrystalline cellulose, rice starch, silica, talc, mica, titanium dioxide, zinc laurate, zinc myristate, zinc rosinate, alumina, attapulgite, calcium carbonate, calcium silicate, dextran, kaolin, nylon, silica silylate, silk powder, sericite, soy flour, tin oxide, titanium hydroxide, trimagnesium phosphate, walnut shell powder, or mixtures thereof. The powders described above can be surface treated with lecithin, amino acids, mineral oil, silicones, or a variety of other agents, either alone or in combination, which coat the powder surface and render the particles more lipophilic in nature.

[0056] Suitable pigments are organic or inorganic. Organic pigments are of the various aromatic types including azo, indigoid, triphenylmethane, anthroquinone, and xanthine dyes commonly referred to as D&C and FD&C blues, browns, greens, oranges, reds, yellows, etc. Organic pigments generally consist of insoluble metal salts of approved color additives called lakes. Inorganic pigments include iron oxide, ultramarine, chromium, chromium hydroxide colorants, and mixtures thereof. Red, blue, yellow, brown, black iron oxides, and mixtures thereof are suitable.

[0057] Vitamins and Antioxidants The composition of the present invention may contain vitamins and / or coenzymes, as well as antioxidants. In that case, 0.001-10% by weight, preferably 0.01-8% by weight, more preferably 0.05-5% by weight of the total composition is suggested. Suitable vitamins include ascorbic acid and its derivatives, such as ascorbyl palmitate, tetrahexydecyl ascorbate, etc.; vitamin B, such as thiamine, riboflavin, pyridoxine, etc., and coenzymes, such as thiamine pyrophoshate, flavin adenine dinucleotide, folic acid, pyridoxal phosphate, tetrahydrofolic acid, etc. Vitamin A and its derivatives are also suitable. Examples are vitamin A in the form of retinyl palmitate, retinol, retinoic acid, and beta-carotene. Vitamin E and its derivatives, such as vitamin E acetate, nicotinate, or other esters, are also suitable. In addition, vitamins D and K are suitable.

[0058] The present invention further includes treating the skin to stimulate collagen synthesis by topically applying a composition comprising a tri- or tetrapeptide, at least one penta- or hexapeptide, at least one extract from the Laminaria genus, and whey protein. The composition may be applied in the form described herein as part of a skin care regimen. For example, the composition may be applied to the skin as a night cream or cream applied to the skin before a period of physical rest, such as a nap or sleep. The composition may be applied twice a day, in the morning and in the evening, after washing the skin. The composition may be applied to the skin over a skin care product in the form of a foundation or other colored cosmetic product.

[0059] solubility Typically, resveratrol glycolate as raw material is a solid material and is very difficult to formulate.In its original raw form, resveratrol glycolate is a rock-like solid material with a hard texture and can be difficult to grind for use in formulations.In addition, resveratrol glycolate can form agglomerates in solution.Therefore, resveratrol is difficult to solubilize or formulate, and the raw material is also very difficult to handle.

[0060] In the past, experiments have been carried out to solubilize resveratrol glycolate in oil, alcohol, or using emulsifiers. However, such solvents are not suitable for cosmetic applications because they are highly irritating to human skin, and therefore, their use in cosmetic applications has been found to be inappropriate. Formulations intended for topical application to human skin must be skin-friendly. Such formulations should also be easy to mix without clumping or forming a cloudy mixture. Furthermore, for topical application, products containing a solubilized form of the active ingredient often show increased availability on the skin than products containing dispersed active ingredients. Improved solubility of resveratrol glycolate improves the ease of formulation of the material. Furthermore, if resveratrol glycolate is provided in a solubilized form rather than in its original solid form, the pre-solubilized resveratrol glycolate can be added directly to the formulation without further processing.

[0061] Considering the difficulty in handling resveratrol in solid form and the need for a solvent that is not harsh and is gentle on the skin, it is necessary to determine a solvent that can solubilize resveratrol in a manner that is useful and compatible for topical cosmetic applications. Various experiments were performed to determine the solubility of resveratrol glycolate, examples of which are shown in Tables 1-4 below.

[0062] The present invention provides a method or process for solubilizing resveratrol glycolate in an aqueous phase at a concentration of about 0.01% to about 30% based on the total solution percentage. The method for solubilizing resveratrol glycolate according to the present invention comprises heating the resveratrol glycolate at a temperature of 45° C. or less, and mixing the resveratrol glycolate with a glycol solvent in a propeller mixer at room temperature for about 10 to about 120 minutes. In a preferred embodiment, the method for solubilizing resveratrol glycolate according to the present invention comprises heating the resveratrol glycolate at a temperature of 45° C. or less, and mixing the resveratrol glycolate with a glycol co-solvent in a propeller mixer at room temperature for about 10 to about 120 minutes. In a preferred embodiment, the starting materials are warmed to about 40° C. prior to mixing. The length of time for solubilization (i.e., the time for the resveratrol glycolate to dissolve and the solution to become clear) and the appearance of the solution range from about 1 minute to about 120 minutes.

[0063] Surprisingly, the applicants have effectively demonstrated that glycol solvents, particularly a combination of at least two glycol co-solvents, increase the solubility of resveratrol glycolate in the aqueous phase. Among the glycol solvents, illustrative are butylene glycol, pentylene glycol, isoprene glycol, propanediol, butylene glycol, phenoxyethanol, ethoxydiglycol, butoxydiglycol, propylene glycol caprylate, polyethylene glycol (PEG), and mixtures or combinations thereof. In a preferred embodiment, the glycol co-solvent used is butylene glycol. In another preferred embodiment, the co-solvents used in combination are pentylene glycol and butylene glycol. The ratio of the co-solvents according to the present invention is from about 1:1 to about 1:100. In a preferred embodiment, pentylene glycol and butylene glycol are utilized in a ratio of from about 1:5 to about 1:50. It should also be noted that resveratrol glycolate has limited solubility in glycerin.

[0064] The resveratrol glycolate solution obtained by solubilizing the resveratrol glycolate can be added directly to the formulation / composition at the appropriate temperature or can be used as a sub-phase to incorporate other ingredients (e.g., botanicals, particulates, and active materials listed above). Exemplary compositions include topical cosmetic compositions that can be in the form of creams, lotions, serums, solutions, dispersions, and the like. The composition can be in the form of an emulsion, such as a water-in-oil or oil-in-water emulsion.

[0065] Furthermore, the effectiveness of the resveratrol glycolate remains the same and is not adversely affected when provided as a solution or formulated into an appropriate form.

[0066] Resveratrol glycolate solutions are stable for about 1-2 years at 4° C. and up to 1 month at 50° C. In cosmetic applications, stability at 50° C. is considered the most severe condition, and therefore, the preferred stability at 50° C. generally translates to a shelf life of about 2 or 3 years for the product, according to those skilled in the art.

[0067] The invention will now be further described with reference to the following examples, which are given for illustrative purposes only. EXAMPLES

[0068] [Example 1] The glycolate ester of resveratrol is prepared by reacting resveratrol (1 molar) with NaH (6 molar) in the presence of tetrahydrofuran, an aprotic solvent, in a stream of argon gas for 2-6 hours at room temperature (25 °C) to form deprotonated resveratrol.

[0069] [ka]

[0070] The glycolic acid is then reacted with a mixture of dihydropyran (1.5 molar), p-toluenesulfonic acid, pyridine, and dimethyl chloride at OC-RT for 3-12 hours to form glycolic acid in which the terminal hydroxyl group is protected with tetrahydropyran. The protected glycolic acid is then reacted with a mixture of SOCl2 (5 molar), dimethylformamide (catalyst), and dimethyl chloride under reflux conditions for 4-6 hours to form tetrahydropyran-protected glycolic acid acyl chloride.

[0071] [ka]

[0072] The deprotonated resveratrol formed in step (A) is then reacted with protected glycolic acid acyl chloride (B) to form an intermediate alpha hydroxyl protected resveratrol glycolate, which is then deprotected by reaction with a mild acid (what acid?) to form resveratrol glycolate in the form of a mixture of mono-, di- and triester forms.

[0073] [ka]

[0074] [Example 2] Resveratrol glycolate is prepared by deprotonating resveratrol as in step (A) above. Separately, glycolic acid is reacted with trityl chloride (1.5 molar) in N,N-diisopropylethylamine (DIEA) to form trityl chloride-protected glycolic acid. The trityl chloride-protected glycolic acid is then further reacted with SOCl2 (5 molar), dimethylformamide (DMF), and dimethyl chloride (DMC) at reflux for 4-6 hours to form trityl chloride-protected glycolic acid acyl chloride.

[0075] [ka]

[0076] One mole of (A) is then mixed with 3 moles of (C) and reacted with triethylamine, tetrahydrofuran at room temperature (25° C.) for 12-72 hours to form trityl chloride protected resveratrol glycolate, which is then treated with trifluoroacetic acid, 1,2-ethanediol, dimethyl sulfide, and dimethyl chloride to remove the protecting groups and obtain resveratrol glycolate.

[0077] [ka]

[0078] [Example 3] Resveratrol glycolate is prepared by reacting the deprotonated resveratrol obtained in step 1(A) of Example 1 with commercially available glycolic acid acyl chloride in the presence of triethylamine and tetrahydrofuran at room temperature for 12-72 hours to form resveratrol glycolate.

[0079] [ka]

[0080] [Example 4] The tartrate ester of resveratrol is prepared by deprotonating resveratrol as described in Example 1, step 1(A). L-tartaric acid is then reacted with a mixture of acetic acid, acetic anhydride, and pyridine at room temperature for 12-48 hours to form +-O-O'-diacetyl-L-tartaric anhydride.

[0081] [ka]

[0082] One mole of A is then reacted with 3 moles of B in the presence of trimethylamine and tetrahydrofuran at room temperature for 12-72 hours to form the acyl-protected tartaric acid, which is then reacted with K2CO3 (10 molar), methanol at OC-RT for 1 hour to form resveratrol tartrate.

[0083] The term "OT-RT" means 0 degrees Celsius to room temperature.

[0084] [ka]

[0085] [Example 5] An emulsion composition containing resveratrol glycolate and resveratrol tartrate is made as follows:

[0086] [Table 1]

[0087] The composition is prepared by combining the ingredients, mixing thoroughly and emulsifying into a lotion.

[0088] [Example 6] An anhydrous composition is prepared as follows:

[0089] [Table 2]

[0090] The composition is prepared by combining the ingredients and mixing thoroughly to form a serum.

[0091] [Example 7] Solubility of Resveratrol Glycolate: The following experiment was performed to determine the solubility of resveratrol glycolate in glycol solvents. As described in this invention, glycol or glycol co-solvents improve the solubility of resveratrol glycolate. In addition, heating the resveratrol glycolate raw material or mixture can also improve the solubility of resveratrol glycolate. The heating step may be performed at a temperature of 45°C or less. Each of the formulations in Table 1 was prepared by heating a resveratrol glycolate sample to about 40°C and then mixing the heated resveratrol glycolate with the respective glycol solvent at room temperature using a propeller mixer for 10-120 minutes. The length of time to solubilize (i.e., the resveratrol glycolate dissolves and the solution becomes clear) and the appearance of the solution were recorded.

[0092] Resveratrol glycolate has relatively low solubility in glycerin as shown in Table 1, Formulation 2. Table 2 shows an example of solubilization of various amounts of resveratrol glycolate in propanediol.

[0093] [Table 3]

[0094] Table 2 shows examples of solubilization of various amounts of resveratrol glycolate in propanediol. The formulations in Table 2 were also prepared as described above by heating and mixing the respective amounts of resveratrol glycolate and propanediol at room temperature for 10-120 minutes using a propeller mixer. The length of time to solubilize (i.e., the resveratrol glycolate dissolves and the solution becomes clear) and the appearance of the solution were recorded.

[0095] [Table 4]

[0096] As shown above in Tables 1 and 2, propanediol can solubilize up to 25% of resveratrol glycolate with propeller mixing at room temperature. Combining glycols and / or heating can also increase the solubility of resveratrol glycolate, thereby improving the ease of formulation of resveratrol glycolate.

[0097] Tables 3-5 show the results of solubilizing resveratrol glycolate using combinations of glycol co-solvents. Samples were stored at 4° C. for 3 months and at 50° C. for 1 month, after which the samples were removed and stored at ambient conditions until experimental analysis described below. Table 3 below shows representative formulations and associated descriptions along with storage temperatures.

[0098] [Table 5]

[0099] [Table 6]

[0100] Table 4 shows the solubilization of resveratrol glycolate in the formulations corresponding to Table 3. In further experiments, 1% of formulations 1-4, 6, 8 and 9 were introduced into water to determine whether precipitation of resveratrol glycolate occurred in the aqueous phase. The stability of each of the formulations was also tested at 4°C and 50°C to determine whether crystallization, precipitation or discoloration occurred at low and high temperatures (4°C and 50°C). As can be seen in Table 4, no visible solid particles were observed immediately after analysis. After 4 weeks at 4°C, no precipitation was observed and a clear solution was obtained. The stability experiments are described in Example 8 below.

[0101] [Example 8] Stability of Resveratrol Glycolate in Glycol Co-solvents: In addition to determining the solubility of resveratrol glycolate in glycolic solvents, the stability and amount of resveratrol glycolate (mono- and diglycolate) in the samples was also determined. The experiments were performed using HPLC and the results were analyzed by LC-MS. The stability data obtained by HPLC chromatograms are shown in Figures 1-9. The HPLC chromatogram results for resveratrol mono- and diglycolate are shown in Figures 10-12.

[0102] Figure 1 shows an HPLC chromatogram of resveratrol glycolate (1%) at 4° C. Figure 2 shows an HPLC chromatogram of resveratrol monoglycolate (1%) at 4° C. Figure 3 shows an HPLC chromatogram of resveratrol diglycolate (1%) at 4° C.

[0103] Figure 4 shows an HPLC chromatogram of resveratrol glycolate (1%) at 50° C. Figure 5 shows an HPLC chromatogram of resveratrol monoglycolate (1%) at 50° C. Figure 6 shows an HPLC chromatogram of resveratrol diglycolate (1%) at 50° C.

[0104] Figure 7 shows HPLC chromatograms of resveratrol glycolate in pentylene glycol and butylene glycol (1%, Formulation No. 1 and 10%, Formulation No. 3, respectively) at 4°C and 50°C, respectively. Figure 8 shows HPLC chromatograms of resveratrol monoglycolate in pentylene glycol and butylene glycol (1, Formulation No. 1 and 10%, Formulation No. 3, respectively) at 4°C and 50°C, respectively. Figure 9 shows HPLC chromatograms of resveratrol diglycolate in pentylene glycol and butylene glycol (1%, Formulation No. 1 and 10%, Formulation No. 3, respectively) at 4°C and 50°C, respectively.

[0105] Figure 10 shows the stability of resveratrol glycolate (1%) dissolved in each formulation at 4° C. and 50° C. Figure 11 shows the stability of resveratrol mono- and diglycolate (10%) dissolved in each formulation at 4° C. and 50° C. Figure 12 shows the stability of resveratrol mono- and diglycolate (20%) dissolved in each formulation at 4° C. and 50° C.

[0106] The experimental results show that the pentylene glycol / butylene glycol co-solvent combination is more stable compared to the propanediol / butylene glycol or isopropene glycol co-solvents. Additionally, it was also observed that the 10% resveratrol glycolate and 20% resveratrol glycolate solutions (shown in Figures 11-12) exhibited a higher degree of degradation compared to the 1% resveratrol glycolate solution at elevated temperature storage conditions.

[0107] As shown in Figure 10, at 4°C, Formulation 1 is about 21% more stable when compared to Formulation 2, and Formulation 1 is about 23% more stable than Formulation 6. Similarly, at 50°C, Formulation 1 is about 24% more stable when compared to Formulation 6, and Formulation 1 is about 30% more stable than Formulation 6.

[0108] As shown in FIG. 11, Formulation 3 at 4° C. is about 55% more stable than at 50° C., and Formulation 7 at 4° C. is about 21% more stable than at 50° C.

[0109] As shown in FIG. 12, Formulation 4 is about 48% more stable at 4° C. than at 50° C.

[0110] [Example 9] Compositions containing resveratrol glycolate as an anhydrous formulation, by weight:

[0111] [Table 7]

[0112] The compositions are prepared by combining the ingredients and thoroughly mixing to form an anhydrous formulation. The ratios of resveratrol glycolate, butylene glycol and pentylene glycol are shown in the respective columns and are first combined in solution and then introduced into the formulation phase.

[0113] [Example 10] Compositions containing Resveratrol Glycolate as a Serum / Gel Formulation, by Weight:

[0114] [Table 8]

[0115] The compositions are prepared by combining the ingredients and mixing thoroughly to form the serum / gel formulation. The ratios of resveratrol glycolate, butylene glycol and pentylene glycol are shown in the respective columns and are first combined in solution and then introduced into the formulation phase.

[0116] [Example 11] Compositions containing Resveratrol Glycolate as a Cream / Lotion Formulation, by Weight:

[0117] [Table 9]

[0118] The compositions are prepared by combining the ingredients and mixing thoroughly to form a cream / lotion formulation. The ratios of resveratrol glycolate, butylene glycol and pentylene glycol are shown in the respective columns and are first combined in solution and then introduced into the formulation phase.

[0119] While the present invention has been described in connection with preferred embodiments, it is not intended to limit the scope of the invention to the particular forms described, but on the contrary, it is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the invention as defined by the appended claims. Some embodiments are given below. Item 1 1. A method for solubilizing a resveratrol glycolate compound, comprising: (a) heating the resveratrol glycolate compound; and (b) mixing the resveratrol glycolate compound with at least one glycol solvent at room temperature for about 10 minutes to about 120 minutes; The method includes: Section 2 Item 2. The method according to item 1, wherein the resveratrol glycolate is present in an amount of about 0.1% by weight to about 30% by weight of the solution. Section 3 3. The method of claim 2, wherein the at least one glycol solvent is selected from the group consisting of propanediol, phenoxyethanol, butylene glycol, pentylene glycol, isopropene glycol, propylene glycol caprylate, ethoxydiglycol, butoxydiglycol, glycerin, and combinations or mixtures thereof. Section 4 Item 11. The method of item 1, wherein the heating step is carried out at a temperature of 45°C or less. Section 5 4. The method of claim 3, wherein the at least one glycol solvent is butylene glycol. Section 6 4. The method of claim 3, wherein the at least one glycol solvent is a combination of pentylene glycol and butylene glycol. Section 7 Item 7. The method according to item 6, wherein the ratio of pentylene glycol to butylene glycol is within the range of about 1:1 to about 1:50. Section 8 Resveratrol glycolate has the formula: [ka] (wherein each R is (i) -OH or (ii) [ka] or (iii) [ka] are independently selected from where all three R groups cannot be -OH simultaneously. The method according to item 1, comprising: Section 9 Item 1. A product obtained by the method described in item 1.

Claims

1. 1. A method for solubilizing a resveratrol glycolate compound, comprising: (a) heating the resveratrol glycolate compound; and (b) mixing the resveratrol glycolate compound with at least one glycol solvent at room temperature for 10 minutes to 120 minutes, wherein the at least one glycol solvent comprises pentylene glycol and butylene glycol in a ratio of 1:1 to 1:50; The method includes:

2. 2. The method of claim 1, wherein the resveratrol glycolate is present at 0.1% to 30% by weight of the solution.

3. 10. The method of claim 1, wherein the heating step is carried out at a temperature of 45°C or less.

4. Resveratrol glycolate has the formula: 【Chemistry 1】 (wherein each R is (i) -OH or (ii) 【Chemistry 2】 or (iii) 【Chemistry 3】 are independently selected from where all three R groups cannot be -OH simultaneously.

2. The method of claim 1, comprising:

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