Solubilization of Resveratrol Glycolate and Tartrate Derivatives

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation-in-part of U.S. non-provisional patent application No. 16 / 081,842 filed on August 31, 2018, which is a national phase application of international application PCT / US17 / 20923 filed on March 6, 2017, which claims priority to U.S. provisional application No. 62 / 304541 filed on March 7, 2016, all of which are incorporated herein by reference in their entirety. Technical Field

[0003] The invention belongs to the field of resveratrol derivative compounds and compositions and synthesis methods thereof. Background Art

[0004] Resveratrol, also known as 3,5,4'-trihydroxystilbene, is a polyhydroxy-substituted compound having the following general formula:

[0005]

[0006] It is present in red grapes, raspberries, blueberries and certain other plant berries or extracts. Resveratrol is known to be a potent antioxidant and has other anti-aging, anti-cancer and anti-viral effects. Resveratrol has been incorporated into various cosmetic formulations, such as skin creams, due to its fountain-of-youth properties. However, since resveratrol is somewhat unstable, it is prone to discoloration. In addition, it is most desirable to react resveratrol with other compounds to produce resveratrol derivatives, thereby maximizing the effectiveness of properties such as stability, activity and beneficial effects on the skin.

[0007] Alpha hydroxy acids, or AHAs, are known for their effectiveness in skin treatments. The carboxylic acid group on the compound aids in exfoliation to remove dead skin cells and debris from the surface of the skin. AHAs are also said to reduce the appearance of age-related skin changes such as fine lines, wrinkles, age spots, discoloration, yellowing, and sagging skin. However, AHAs can also cause skin irritation, redness, or dryness in individuals with overly sensitive skin.

[0008] Particularly effective AHAs are glycolic acid and tartaric acid. Glycolic acid has the following formula:

[0009]

[0010] Tartaric acid has the formula:

[0011]

[0012] Esterification of resveratrol with glycolic acid or tartaric acid provides resveratrol derivatives, which can be mono-, di- or tri-substituted esters on the hydroxyl groups to form resveratrol mono-, di- or triglycolic acid esters or mixtures thereof, or resveratrol mono-, di- or tritartaric acid esters 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 epidermis, whitening the skin, treating acne or other skin damage, and inhibiting matrix metalloproteinases that degrade collagen. Summary of the invention

[0013] Embodiments herein relate to compounds of the formula:

[0014]

[0015] Wherein each R is independently selected from:

[0016] (i) -OH, or

[0017] (ii)

[0018] or

[0019] (iii)

[0020]

[0021] The condition is that all three R cannot be -OH at the same time.

[0022] The present invention also relates to a method for synthesizing an ester of resveratrol and glycolic acid as follows:

[0023] a) deprotonating resveratrol by reaction with a base,

[0024] b) Prepare alpha hydroxy protected glycolic acid as follows:

[0025] (i) reacting the α-hydroxyl group of glycolic acid with a compound having a protective donor group to form protected α-hydroxyglycolic acid

[0026] (ii) reacting (i) with a halogen donor compound to form a reactive alpha hydroxy acyl halide,

[0027] c) reacting (a) and (b) to form alpha hydroxy protected resveratrol glycolate; and

[0028] d) deprotecting the protected α-hydroxyl group to form resveratrol glycolate.

[0029] The present invention also relates to a method for synthesizing resveratrol tartrate, which comprises the following steps:

[0030] (a) deprotonating resveratrol by reaction with a base,

[0031] (b) preparing α-hydroxy protected tartaric anhydride as follows:

[0032] (i) dehydrating tartaric acid to form reactive tartaric anhydride,

[0033] (ii) simultaneously reacting the α-hydroxyl group with a compound having a protective donor group to form protected tartaric anhydride,

[0034] (c) reacting (a) and (b) to form an alpha-hydroxy protected resveratrol tartrate; and

[0035] (d) deprotecting the protected α-hydroxyl group to form resveratrol tartrate.

[0036] The present invention also relates to a topical composition comprising a compound of the formula:

[0037] Embodiments herein also relate to compounds of the formula:

[0038]

[0039] Wherein each R is independently selected from:

[0040] (i) -OH, or

[0041] (ii)

[0042] or

[0043] (iii)

[0044]

[0045] The condition is that all three R cannot be -OH at the same time.

[0046] The present invention also relates to a method or process for solubilizing resveratrol glycolate as follows:

[0047] (a) heating the resveratrol glycolate compound and

[0048] (b) mixing a resveratrol glycolate compound with at least one diol solvent at room temperature for about 10 minutes to about 120 minutes. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 Shown is the HPLC chromatogram of resveratrol glycolate (1%) at 4°C.

[0050] Figure 2 Shown is the HPLC chromatogram of resveratrol monoglycolate (1%) at 4°C.

[0051] Figure 3 Shown is the HPLC chromatogram of resveratrol diglycolate (1%) at 4°C.

[0052] Figure 4 Shown is the HPLC chromatogram of resveratrol glycolate (1%) at 50°C.

[0053] Figure 5 Shown is the HPLC chromatogram of resveratrol monoglycolate (1%) at 50°C.

[0054] Figure 6 Shown is the HPLC chromatogram of resveratrol diglycolate (1%) at 50°C.

[0055] Figure 7 HPLC chromatograms showing resveratrol glycolate in pentylene glycol and butylene glycol at 4°C and 50°C, respectively.

[0056] Figure 8 HPLC chromatograms showing resveratrol monoglycolate in pentylene glycol and butylene glycol at 4°C and 50°C, respectively.

[0057] Fig. 9 HPLC chromatograms showing resveratrol diglycolate in pentanediol and butylene glycol at 4°C and 50°C, respectively.

[0058] Fig.10 The stability of dissolved resveratrol glycolate (1%) in various formulations at 4°C and 50°C is shown.

[0059] Fig.11 The stability of dissolved resveratrol mono- and di-glycolates (10%) in various formulations at 4°C and 50°C is shown.

[0060] Fig.12 The stability of dissolved resveratrol mono- and di-glycolates (20%) in various formulations at 4°C and 50°C is shown.

[0061] Details

[0062] Resveratrol glycolate

[0063] Esters of resveratrol and glycolic acid can be prepared as follows:

[0064] a) deprotonating resveratrol by reaction with a base,

[0065] b) Prepare alpha hydroxy protected glycolic acid as follows:

[0066] (i) reacting the α-hydroxyl group of glycolic acid with a compound having a protective donor group to form protected α-hydroxyglycolic acid

[0067] (ii) reacting (i) with a halogen donor compound to form a reactive alpha hydroxy acyl halide,

[0068] c) reacting (a) and (b) to form alpha hydroxy protected resveratrol glycolate; and

[0069] d) deprotecting the protected α-hydroxyl group to form resveratrol glycolate.

[0070] Suitable bases for deprotonating resveratrol include alkali metal 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 at room temperature (25°C) in the presence of anhydrous argon and tetrahydrofuran. The reaction conditions can be 1 to 10 hours, most preferably 2 to 6 hours, and produce deprotonated resveratrol, wherein all three hydrogens are removed from the three hydroxyl groups of resveratrol.

[0071] Separately, glycolic acid is reacted with a compound having a protective donor group. Most preferred are pyran compounds, which are heterocyclic non-aromatic rings, particularly mono-, di-, tri- or tetrahydropyran (where mono-, di-, tri- and tetra- refer to the number of hydrogen atoms removed from the pyran ring), and short chain mono-, di- or trialkyl halides, wherein the alkyl is a short chain alkyl, such as methyl, ethyl, propyl, and the halogen is chlorine, fluorine, bromine, etc. Most preferred is dimethyl chloride. The reaction can be carried out in the presence of pyridine, p-toluenesulfonic acid, and preferably at room temperature for 3-12 hours. More preferably, the compound having a protective donor group is dihydropyran, and the alkyl halide is dimethyl halide, particularly dimethyl chloride. Approximately 1.5 moles of dihydropyran are reacted with 1 mole of glycolic acid to produce an alpha hydroxy glycolate protected by tetrahydropyran. Thereafter the reaction is continued in the presence of SOCl2, dimethylformamide and dimethyl chloride under reflux conditions for 4 to 6 hours to produce ethanolyl chloride, wherein the α-hydroxyl group is protected by tetrahydropyran. The final step is to deprotect the protected α-hydroxyl acyl group.

[0072] Alternatively, after glycolic acid is deprotonated, the hydroxyl group can be protected by reacting with trityl halogen, such as trityl chloride (triphenylmethyl chloride), wherein the α hydroxyl group is replaced by trityl. Thereafter, the protected compound and SOCl2, dimethylformamide and dimethyl chloride react under reflux conditions for about 4-6 hours to produce a compound with the α hydroxyl chloride group protected by trityl. Then, the trityl protected acyl halide form of the compound is reacted with deprotonated resveratrol to form resveratrol glycolate, wherein the α hydroxyl group on glycolic acid is still protected by trityl. The trityl protecting group is removed by reacting with one or more of trifluoroacetic acid, ethylene glycol, dimethyl sulfide and dimethyl chloride to form resveratrol glycolate.

[0073] Another alternative is to purchase commercially available 2-hydroxyacetyl chloride and react it with deprotonated resveratrol to form resveratrol glycolate. This reaction is carried out at room temperature for 12 to 72 hours in the presence of one or more of triethylamine and tetrahydrofuran. Resveratrol glycolate is finally obtained. Depending on the reaction conditions and reactant concentrations used, resveratrol glycolate can 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, different 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; 3,4'-diglycolate-5-hydroxystilbene; 4'5-diglycolate-3-hydroxystilbene; and 3,5,4'-triglycolate stilbene.

[0074] Resveratrol tartrate

[0075] The tartrate of resveratrol can be synthesized by first deprotonating resveratrol as described above in the synthesis of resveratrol glycolate and under the same reaction conditions. Separately, tartaric acid is reacted in the presence of acetic anhydride, acetic acid or pyridine at room temperature for 12-48 hours to produce the acetyl-protected tartaric anhydride, O,O'-diacetyl-L-tartaric anhydride. Alternatively, this compound can be purchased commercially.

[0076] Thereafter, 1 mol of deprotonated resveratrol is reacted with 3 mol of O,O'-diacetyl-L-tartaric anhydride to form acetyl-protected resveratrol tartrate. The protecting group is removed by reaction with potassium carbonate (10 mol) and methanol at room temperature for 1-6 hours to produce resveratrol tartrate. Depending on the reaction conditions and the amount of reactants used, resveratrol may be tartaric acid mono-, di- or tri-substituted, or may be a mixture of mono-, di- and tri-substituted tartaric acid-substituted resveratrol. In this case, the different compounds include 3-tartrate-5,4'-dihydroxystilbene; 5-tartrate-3,4'-dihydroxystilbene; 4'-tartrate-3,5-dihydroxystilbene; 3,5-ditartrate-4'-hydroxystilbene; 3,4'-ditartrate-5-hydroxystilbene; 3,4'-ditartrate-5-hydroxystilbene; 4'5-ditartrate-3-hydroxystilbene; and 3,5,4'-tricartrate stilbene.

[0077] Cosmetic composition

[0078] Resveratrol esters can be incorporated into topical cosmetic compositions which can be in the form of creams, lotions, serums, solutions, dispersions, and the like. The composition can be an emulsion formulation - water-in-oil or oil-in-water. Suitable emulsions contain about 1 to 90% water and 10-90% other ingredients, including oil. Such additional ingredients include, but are not limited to, the following.

[0079] Oil

[0080] Suitable oils include silicones, esters, vegetable oils, synthetic oils, including but not limited to those set forth herein. The oil can be volatile or non-volatile, and is preferably in the form of a pourable liquid at room temperature. If present, the oil can be approximately 0.5 to 85 wt %, preferably approximately 1-75 wt %, more preferably approximately 5-65 wt % of the total composition.

[0081] Cyclic and linear volatile silicones are available from a variety of commercial sources, including Dow Corning Corporation and General Electric. Dow Corning linear volatile silicones are sold under the trade names Dow Corning 244, 245, 344 and 200 fluids. These fluids include hexamethyldisiloxane (viscosity 0.65 centistokes (abbreviated as cst)), octamethyltrisiloxane (1.0 cst), decamethyltetrasiloxane (1.5 cst), dodecamethylpentasiloxane (2 cst) and mixtures thereof, all viscosity measurements being made at 25°C.

[0082] Suitable branched volatile silicones include alkyl trimethicones, such as methyl trimethicone, a branched volatile silicone having the general formula:

[0083]

[0084] Methyl trimethicone is available, for example, from Shin-Etsu Silicones under the trade name TMF-1.5 and has a viscosity of 1.5 centistokes at 25°C.

[0085] Various straight or branched chain alkanes 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, are also suitable. Suitable hydrocarbons include pentane, hexane, heptane, decane, dodecane, tetradecane, tridecane and C 8-20 Isoparaffin. Suitable C 12 Isoparaffins are manufactured by Permethyl Corporation under the trade name Permethyl 99A. Various commercially available C16 isoparaffins, such as isohexadecane (having the trade name Permethyl R), are also suitable.

[0086] Esters formed by the reaction of carboxylic acids and alcohols are also suitable. Alcohols and carboxylic acids may both have a fatty (C6-30) chain. Examples include hexyl laurate, butyl isostearate, cetyl isostearate, cetyl palmitate, isostearyl neopentanoate, stearyl enanthate, isostearyl isononanoate, stearyl lactate, stearyl caprylate, stearyl stearate, isononyl isononanoate, etc.

[0087] The ester may also be in the form of a dimer or trimer. Examples of such esters include diisostearyl malate, neopentyl glycol dioctanoate, dibutyl sebacate, dicetyl stearyl dimer dilinoleate, dicetyl adipate, diisocetyl adipate, diisononyl adipate, diisostearyl dimer dilinoleate, diisostearyl fumarate, diisostearyl malate, dioctyl malate, and the like.

[0088] Examples of other types of esters include esters of arachidonic acid, citric acid or behenic acid, such as triarachidin, tributyl citrate, triisostearyl citrate, tri-C citrate, and tri-C 12-13 Alkyl esters, tricaprylin, trioctyl citrate, tridecyl behenate, trioctyldodecyl citrate, tridecyl behenate; or tridecyl coconut oil, tridecyl isononanoate, etc.

[0089] Synthetic or naturally occurring fatty acid glycerides, or triglycerides, are also suitable for use in the composition. Both vegetable and animal sources may be used. Examples of such oils include castor oil, lanolin oil, C 10-18 Triglycerides, caprylic / capric / triglycerides, sweet almond oil, almond oil, sesame oil, camelina oil, tamanu seed oil, coconut oil, corn oil, cottonseed oil, linseed oil, ink oil, olive oil, palm oil, ice grass fat, rapeseed oil, soybean oil, grapeseed oil, sunflower seed oil, walnut oil, etc.

[0090] Synthetic or semi-synthetic glycerides, such as fatty acid mono-, di- and triglycerides, are also suitable, which are modified natural fats or oils, for example mono-, di- or triesters of polyols such as glycerol. 12-22 ) carboxylic acid reacts with one or more repeating glyceryl groups. Glyceryl stearate, diisostearate, polyglyceryl-3 isostearate, polyglyceryl-4 isostearate, polyglyceryl-6 ricinoleate, dioleyl glyceryl, diisostearate, tetraisostearate, tricaprylyl, distearate, linoleyl glyceryl, myristic glyceryl, isostearyl glyceryl, PEG castor oil, PEG glyceryl oleate, PEG glyceryl stearate, PEG glyceryl tallowate, and the like.

[0091] Water-soluble and water-insoluble non-volatile silicone oils are also suitable for use in the composition. Such silicones preferably have a viscosity of about greater 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.

[0092] Surfactants

[0093] The composition may contain one or more surfactants, especially if in emulsion form. However, if the composition is anhydrous, such surfactants may be used and help disperse polar ingredients, such as pigments. Such surfactants may be silicone-based or organic-based. Surfactants help form stable emulsions in either water-in-oil or oil-in-water form. If present, the surfactant may be present in an amount of about 0.001 to 30% by weight of the total composition, preferably about 0.005 to 25% by weight, and more preferably about 0.1 to 20% by weight.

[0094] Silicone surfactants may be generally referred to as dimethicone copolyols or alkyl dimethicone copolyols. In some cases, the number of repeating ethylene oxide or propylene oxide units in the polymer is also specified, such as dimethicone copolyol, also referred to as PEG-15 / PPG-10 dimethicone, which refers to a dimethicone having a substituent containing 15 ethylene glycol units and 10 propylene glycol units on the siloxane backbone. One or more methyl groups in the above general structure may also be substituted with longer chain alkyl groups (e.g., ethyl, propyl, butyl, etc.) or ethers, such as methyl ether, ethyl ether, propyl ether, butyl ether, etc.

[0095] Examples of silicone surfactants are those sold under the trade name Dow Corning 3225C Formulation Aid with the CTFA name Cyclotetrasiloxane (and) Cyclopentasiloxane (and) PEG / PPG-18 Dimethicone; or 5225C Formulation Aid with the CTFA name Cyclopentasiloxane (and) PEG / PPG-18 / 18 Dimethicone; or Dow Corning 190 Surfactant with the CTFA name PEG / PPG-18 / 18 Dimethicone; or Dow Corning 193 Fluid, Dow Corning 5200 with the CTFA name Lauryl PEG / PPG-18 / 18 Methicone; or Abil EM sold by Goldschmidt with the CTFA name Cetyl PEG / PPG-14 / 14 Dimethicone. 90; or Abil EM 97 sold by Goldschmidt with the CTFA name Bis-Cetyl PEG / PPG-14 / 14 Dimethicone; or Abil WE 09 sold by Shin-Etsu Silicones with the CTFA name Cetyl PEG / PPG-10 / 1 Dimethicone in the form of a mixture also containing Polyglyceryl-4 Isostearate and Hexyl Laurate; or KF-6011 sold by Shin-Etsu Silicones with the CTFA name PEG-11 Methyl Ether Dimethicone; or KF-6012 sold by Shin-Etsu Silicones with the CTFA name PEG / PPG-20 / 22 Butyl Ether Dimethicone; or KF-6013 sold by Shin-Etsu Silicones with the CTFA name PEG-9 Dimethicone; or KF-6015 sold by Shin-Etsu Silicones with the CTFA name PEG-3 Dimethicone; or or KF-6038 sold by Shin-Etsu Silicones under the CTFA name Lauryl PEG-9 Polydimethylsiloxyethyl Dimethicone.

[0096] Also suitable are the various types of cross-linked silicone surfactants, commonly referred to as emulsifying elastomers, which contain at least one hydrophilic portion, such as a polyoxyalkylenated group. Polyoxyalkylene silicone elastomers useful 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 a dimethicone / PEG-10 / 15 crosspolymer dispersed in dimethicone); KSG-310 (which is a PEG-15 lauryl dimethicone crosspolymer); KSG-320 (which is a PEG-15 lauryl dimethicone crosspolymer dispersed in isododecane); KSG-330 (the former dispersed in triethylhexanoin), KSG-340 (which is a mixture of PEG-10 lauryl dimethicone crosspolymer and PEG-15 lauryl dimethicone crosspolymer).

[0097] Polyglycerolated silicone elastomers, such as those disclosed in PCT / WO2004 / 024798, which is incorporated herein by reference in its entirety, are also suitable. Such elastomers include Shin-Etsu's KSG series, such as KSG-710, which is a dimethicone / polyglyceryl-3 crosspolymer dispersed in dimethicone; or lauryl dimethicone / polyglyceryl-3 crosspolymer dispersed in various solvents, such as isododecane, dimethicone, triethylhexanoin, sold under the Shin-Etsu trade names KSG-810, KSG-820, KSG-830, or KSG-840. Silicones sold by Dow Corning under the trade names 9010 and DC9011 are also suitable.

[0098] 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, typically ethylene oxide or propylene oxide. The alcohol is preferably a fatty alcohol having 6 to 30 carbon atoms. Examples of such ingredients include stearyl polyoxyethylene (2-100) ether formed by the reaction of stearyl alcohol and ethylene oxide and having 2 to 100 ethylene oxide units; behenyl polyoxyethylene (5-30) ether formed by the reaction of behenyl alcohol and ethylene oxide, wherein the number of repeating ethylene oxide units is 5 to 30; cetearyl polyoxyethylene (2-100) ether formed by the reaction of a mixture of cetyl alcohol and stearyl alcohol with ethylene oxide, wherein the number of repeating ethylene oxide units in the molecule is 2 to 100; cetyl polyoxyethylene (1-45) ether formed by the reaction of cetyl alcohol and ethylene oxide and having 1 to 45 repeating ethylene oxide units, and the like. All recitations of units include all integers between the ranges.

[0099] Other alkoxylated alcohols are formed by the reaction of fatty acids and mono-, di- or polyols with alkylene oxides. 6-30 The reaction products of fatty carboxylic acids and polyols (which are monosaccharides such as glucose, galactose, methyl glucose, etc.) with alkoxylated alcohols. Examples include polymerized alkylene glycols reacted with fatty acid glycerides, such as PEG oleic acid glycerides, PEG stearic acid glycerides; or PEG polyhydroxyalkanoates, such as PEG dipolyhydroxystearate, wherein the number of repeating ethylene glycol units is 3 to 1000.

[0100] Other suitable nonionic surfactants include alkoxylated sorbitan and alkoxylated sorbitan derivatives. For example, alkoxylation of sorbitan, particularly ethoxylation, provides polyalkoxylated sorbitan derivatives. Esterification of polyalkoxylated sorbitan provides sorbitan esters, such as polysorbates. For example, polyalkoxylated sorbitan can be esterified with C6-30, preferably C12-22 fatty acids. Examples of such ingredients include polysorbate 20-85, sorbitan oleate, sorbitan sesquioleate, sorbitan palmitate, sorbitan sesquiisostearate, sorbitan stearate, and the like.

[0101] Moisturizer

[0102] It may also be desirable to include one or more humectants in the composition. If present, such humectants may be from about 0.001 to 25% by weight of the total composition, preferably from about 0.005 to 20% by weight, and more preferably from about 0.1 to 15% by weight. Examples of suitable humectants include glycols, sugars, and the like. Suitable glycols are in monomeric or polymeric form and include polyethylene glycol and polypropylene glycol, such as PEG 4-200, which is a polyethylene glycol having 4 to 200 repeating ethylene oxide units; and C 1-6 Alkylene glycols, such as propylene glycol, butylene glycol, pentylene glycol, etc. Suitable sugars (some of which are also polyols) 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. The humectant used in the composition of the present invention is preferably C 1-6 , preferably C 2-4 Alkylene glycols, most especially butanediol.

[0103] Plant Extracts

[0104] It may be desirable to include one or more plant extracts in the composition. If so, a suggested range is about 0.0001 to 10 wt %, preferably about 0.0005 to 8 wt %, more preferably about 0.001 to 5 wt % of the total composition. Suitable plant extracts include extracts from plants (herbs, roots, flowers, fruits, seeds), such as flowers, fruits, vegetables, etc., including yeast fermentation extract, Fanula extract, Thermus thermophilis fermentation extract, Camelina seed oil, Frankincense extract, Olive extract, Aribodopsis Thaliana extract, Silver Wax extract, Acer Saccharinum (Sugar Maple), Acidopholus, Calamus, Horse Chestnut, Agaricus, Agave, Agrimonia, 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 on pages 1646 to 1660 of CTFA Cosmetic Ingredient Handbook, Eighth Edition, Vol. 2.Further specific examples include, but are not limited to, Glycyrrhiza Glabra, Salix Nigra, Macrocycstis Pyrifera, Pyrus Malus, Saxifraga Sarmentosa, Vitis Viinifera, Morus Nigra, Scutellaria Baicalensis, Anthemis Nobilis, Salvia Sclarea, Rosmarinus Officianaalis, Citrus Medica Limonum, Panax Ginseng, Siegesbeckia Orientalis, Fructus Mume, Ascophyllum Nodosum, Bifida Ferment Lysate, Glycine Soja Extract, Beta Vulgaris, Balkan giant moss (Haberlea Rhodopensis), Japanese knotweed (Polygonum Cuspidatum), sweet orange (Citrus Aurantium Dulcis), grape (Vitis Vinifera), Selaginella (Selaginella Tamariscina), hops (Humulus Lupulus), citrus peel (Citrus Reticulata Peel), pomegranate (Punica Granatum), spiny seaweed (Asparagopsis armata), turmeric (Curcuma Longa), sleeping lettuce (Menyanthes Trifoliata), sunflower (Helianthus Annuus), barley (Hordeum Vulgare), cucumber (Cucumis Sativus), oak moss (Evernia Prunastri), tree moss (Evernia Furfuracea), and mixtures thereof.

[0105] Granular materials

[0106] The compositions of the present invention may contain particulate material in the form of pigments, inert particles or mixtures thereof. If present, a suggested range is 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. Where the composition may contain a mixture of pigments and powders, suitable ranges include about 0.01-75% pigment and 0.1-75% powder, the weights being based on the weight of the total composition.

[0107] The particulate material may be a colored or uncolored powder. Suitable non-pigmented powders include bismuth oxychloride, titanium mica, fumed silica, spherical silica, polymethyl methacrylate, micronized Teflon, boron nitride, acrylate copolymers, aluminum silicate, aluminum starch octenyl succinate, bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceous earth, fuller's earth, glycerol starch, hectorite, hydrated silica, kaolin, magnesium aluminum silicate, magnesium trisilicate, maltodextrin, montmorillonite, microcrystalline cellulose, rice starch, silicon dioxide, 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 mentioned above may be surface treated with lecithin, amino acids, mineral oil, silicone or various other agents, alone or in combination, which coat the powder surface and render the particles more lipophilic in nature.

[0108] Suitable pigments are organic or inorganic. Organic pigments are generally various aromatic types, including azo, indigo, triphenylmethane, anthraquinone and xanthine dyes, which are designated as D&C and FD&C blue, brown, green, orange, red, yellow, etc. Organic pigments are generally composed of insoluble metal salts of certified color additives known as lakes. Inorganic pigments include iron oxides, ultramarine, chromium, chromium hydroxide pigments and mixtures thereof. Red, blue, yellow, brown, black iron oxides and mixtures thereof are suitable.

[0109] Vitamins and Antioxidants

[0110] The composition of the present invention may contain vitamins and / or coenzymes, and antioxidants. If so, it is recommended to be 0.001-10% by weight of the total composition, preferably 0.01-8% by weight, and more preferably 0.05-5% by weight. Suitable vitamins include ascorbic acid and its derivatives, such as ascorbyl palmitate, tetrahexyldecyl ascorbate, etc.; B vitamins, such as thiamine, riboflavin, pyridoxine, etc., and coenzymes, such as thiamine pyrophosphate, flavin adenine dinucleotide, folic acid, pyridoxal phosphate, tetrahydrofolate, etc. Vitamin A and its derivatives are also suitable. Examples are vitamin A in the form of retinol palmitate, retinol, retinoic acid, and beta-carotene. Vitamin E and its derivatives are also suitable, such as vitamin E acetate, nicotinate, or other esters thereof. In addition, vitamin D and K are suitable.

[0111] The present invention further comprises treating the skin to stimulate collagen synthesis by topical application of a composition of a tripeptide or tetrapeptide, at least one pentapeptide or hexapeptide, at least one Laminaria extract and whey protein. The composition can be applied as part of a skin care regimen in the form mentioned herein. For example, the composition can be applied to the skin as a night cream or a cream applied to the skin during periods of rest for the body, such as before a nap or sleep. The composition can be applied twice a day, in the morning and in the evening, after cleansing the skin. The composition can be applied to the skin in the form of a foundation or other makeup product over a skin care product.

[0112] Solubility

[0113] Typically, resveratrol glycolate as a raw material is a solid substance and difficult to formulate. In its original and raw material form, resveratrol glycolate is a hard, rock-like solid substance and difficult to break apart for use in formulations. In addition, resveratrol glycolate can form lumps in solution. Therefore, resveratrol is difficult to dissolve or formulate, and it is also difficult to handle the raw material.

[0114] In the past, experiments have been conducted to solubilize resveratrol glycolate in oil, alcohol or using emulsifiers. However, such solvents are not suitable for cosmetic applications due to their irritation to human skin, so it is found that it is inappropriate to use such solvents for cosmetic applications. The formulations used for topical application on human skin must be skin-friendly. Such formulations should also be easy to mix without lumps or forming turbid mixtures. In addition, in the case of topical application, products containing active ingredients in dissolved form generally show improved skin utilization compared to those products with dispersed active ingredients. The improved solubility of resveratrol glycolate improves the ease of preparing the material. In addition, when resveratrol glycolate is provided in dissolved form rather than in its original solid form, pre-dissolved resveratrol glycolate can be directly added to the formula without further processing.

[0115] Given the difficulty in handling resveratrol in solid form and the need for non-irritating and skin-friendly solvents, it is imperative to identify solvents that can solubilize resveratrol in a manner that is useful and adaptable 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.

[0116] 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% of the total percentage of the solution. The method for solubilizing resveratrol glycolate according to the present invention comprises the steps of heating resveratrol glycolate at a temperature not higher than 45°C and mixing resveratrol glycolate with a glycol co-solvent in a propeller mixer at room temperature for about ten (10) to about one hundred and twenty (120) minutes. In a preferred embodiment, the method for solubilizing resveratrol glycolate according to the present invention comprises the steps of heating resveratrol glycolate at a temperature not higher than 45°C and mixing resveratrol glycolate with a glycol co-solvent in a propeller mixer at room temperature for about ten (10) to about one hundred and twenty (120) minutes. In a preferred embodiment, the starting raw materials are heated to about 40°C before mixing. The time required for solubilization (i.e., the time required for resveratrol glycolate to dissolve and the solution to become clear) and the appearance of the solution is about 1 minute to about 120 minutes.

[0117] Surprisingly, the applicant has convincingly demonstrated that a glycol solvent, in particular a combination of at least two glycol cosolvents, increases the solubility of resveratrol glycolate in an aqueous phase. Among glycol solvents, examples are butylene glycol, pentylene glycol, isopentylene glycol, propylene glycol, butanediol, phenoxyethanol, ethoxydiglycol, butoxydiglycol, propylene glycol caprylate, polyethylene glycol (PEG) and mixtures or combinations thereof. In a preferred embodiment, the glycol cosolvent used is butylene glycol. In another preferred embodiment, the cosolvents used in combination are pentylene glycol and butanediol. The cosolvent ratio according to the invention is from about 1:1 to about 1:100. In a preferred embodiment, pentylene glycol and butanediol are used in a ratio of from about 1:5 to about 1:50. It must also be noted that resveratrol glycolate has limited solubility in glycerol.

[0118] The resulting resveratrol glycolate solution with solubilized resveratrol glycolate can be added directly to a formulation / composition at an appropriate temperature, or it can be used as a sub-phase for incorporation of other ingredients (e.g., botanicals, particles, and active materials listed above). Exemplary compositions include topical cosmetic compositions, which can be in the form of creams, lotions, serums, solutions, dispersions, etc. The composition can be in the form of an emulsion, such as a water-in-oil or an oil-in-water emulsion.

[0119] Furthermore, when provided as a solution or when formulated into a suitable form, the effectiveness of resveratrol glycolate remains the same and is not negatively affected.

[0120] Resveratrol glycolate solutions are stable for about 1 to 2 years at 4° C. and for up to 1 month at 50° C. In cosmetic applications, stability at 50° C. is considered the most severe condition, so good stability at 50° C. generally means to those skilled in the art that the product has a shelf life of about 2 or 3 years.

[0121] The invention is further described in conjunction with the following examples, which are given by way of illustration only.

[0122] Example 1

[0123] The glycolate of resveratrol was prepared by reacting resveratrol (1 molar concentration) with NaH (6 molar) in an argon stream in the presence of tetrahydrofuran (an aprotic solvent) at room temperature (25° C.) for 2-6 hours to form deprotonated resveratrol.

[0124]

[0125] Then, glycolic acid is reacted with a mixture of dihydropyran (1.5 mol), p-toluenesulfonic acid, pyridine, dimethyl chloride OC-RT for 3 to 12 hours to form glycolic acid in which the terminal hydroxyl group has been protected by tetrahydropyran. The protected glycolic acid is then reacted with a mixture of SOCl2 (5 mol), dimethylformamide (cat.) and dimethyl chloride under reflux conditions for 4-6 hours to form tetrahydropyran protected glycolyl chloride.

[0126] Step 2.

[0127]

[0128] The deprotonated resveratrol formed in step (A) is then reacted with a protected glycolyl chloride (B) to form an intermediate α-hydroxy protected resveratrol glycolate, which is subsequently deprotected by reaction with a weak acid to form resveratrol glycolate as a mixture of mono-, di- and triester forms.

[0129]

[0130] Example 2

[0131] Resveratrol glycolate is prepared by deprotonating resveratrol in the same manner as in step 1(A) above. Separately, glycolic acid is reacted with trityl chloride (1.5 mol) in N,N-diisopropylethylamine (DIEA) to form glycolic acid in which the hydroxyl group is protected by trityl chloride. The trityl chloride-protected glycolic acid is then further reacted with SOCl2 (5 mol), dimethylformamide (DMF), dimethyl chloride (DMC) under reflux conditions for 4-6 hours to form trityl chloride-protected glycolyl chloride.

[0132] Step 2.

[0133]

[0134] Then 1 mol of (A) is mixed with 3 mol of (C) and reacted with triethylamine and 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-ethylene glycol, dimethyl sulfide and dimethyl chloride to remove the protecting group, thereby producing resveratrol glycolate.

[0135]

[0136] Example 3

[0137] Resveratrol glycolate was prepared by reacting the deprotonated resveratrol obtained in step 1(A) of Example 1 with commercially available glycolyl chloride in the presence of triethylamine and tetrahydrofuran at room temperature for 12-72 hours to form resveratrol glycolate.

[0138]

[0139] Example 4

[0140] The tartrate of resveratrol was prepared by deprotonating resveratrol in the same manner as described in Example 1, Step 1(A). L-tartaric acid was 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.

[0141]

[0142] Then 1 mol of A is reacted with 3 mol of B in the presence of trimethylamine and tetrahydrofuran at room temperature for 12-72 hours to form acyl protected tartaric acid, which is subsequently reacted with K2CO3 (10 mol), methanol OC-RT for 1 hour to form resveratrol tartrate.

[0143] The term "OC-RT" refers to 0 degrees Celsius - room temperature.

[0144]

[0145] Example 5

[0146] An emulsion composition containing resveratrol glycolate and tartrate was prepared as follows:

[0147]

[0148]

[0149] The composition is prepared by combining the ingredients and mixing thoroughly to emulsify into an emulsion.

[0150] Example 6

[0151] The anhydrous composition was prepared as follows:

[0152]

[0153] The composition is prepared by combining the ingredients and mixing thoroughly to form a serum.

[0154] Example 7: Solubility of Resveratrol Glycolate:

[0155] The following experiment was conducted to determine the solubility of resveratrol glycolate in a glycol solvent. As described in the present invention, a glycol or glycol cosolvent improves 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 can be performed at a temperature not higher than 45°C. Each formulation in Table 1 was prepared by heating a resveratrol glycolate sample to approximately 40°C and then mixing the heated resveratrol glycolate with the respective glycol solvent at room temperature for ten (10) to one hundred and twenty (120) minutes using a propeller mixer. The time required for solubilization (i.e., the resveratrol glycolate dissolves and the solution becomes clear) and the appearance of the solution were recorded.

[0156] As shown in Table 1, Formulation 2, the solubility of resveratrol glycolate in glycerol is relatively low. Table 2 shows examples of solubilizing various amounts of resveratrol glycolate in propylene glycol.

[0157] Table 1. Solubility of resveratrol glycolate in glycol solvents :

[0158]

[0159] Table 2 shows examples of solubilizing various amounts of resveratrol glycolate in propylene glycol. The formulations in Table 2 were also prepared as described above by heating the respective amounts of resveratrol glycolate and mixing with propylene glycol using a propeller mixer at room temperature for ten (10) to one hundred and twenty (120) minutes. The length of time required for solubilization (i.e., the resveratrol glycolate dissolved and the solution became clear) and the appearance of the solution were recorded.

[0160] Table 2. Solubility of resveratrol glycolate in propylene glycol

[0161]

[0162] As shown above in Tables 1 and 2, propylene glycol can dissolve up to 25% of resveratrol glycolate at room temperature with propeller mixing. Combinations of glycols and / or heating can also increase the solubility of resveratrol glycolate, thereby improving the ease of formulating resveratrol glycolate.

[0163] Tables 3-4 show the results of solubilizing resveratrol glycolate using a combination of glycol cosolvents. The samples were stored at 4°C for 3 months and at 50°C for 1 month, after which they were removed and stored in ambient conditions until the experimental analysis described below. Table 3 below indicates representative formulations and associated descriptions as well as storage temperatures.

[0164] Table 3

[0165]

[0166] Table 4: Solubility of resveratrol glycolate in glycol cosolvents :

[0167]

[0168] Table 4 shows the solubilization of resveratrol glycolate in the corresponding formulations of Table 3. In further experiments, 1% of formulations 1-4, 6, 8 and 9 were introduced into water to determine whether any precipitation of resveratrol glycolate would occur in the aqueous phase. The stability of each formulation was also tested at 4°C and 50°C to determine whether any crystallization, precipitation or discoloration occurred at low and high temperatures (4°C and 50°C). As observed 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 experiment is described in Example 8 below.

[0169] Example 8: Stability of resveratrol glycolate in glycol cosolvent:

[0170] In addition to determining the solubility of resveratrol glycolate in glycol solvents, the stability and amount of resveratrol glycolate (monoglycolate and diglycolate) in the samples were determined. The experiments were performed using HPLC and the results were analyzed by LC-MS. Figure 1-9 The stability data were obtained from the HPLC chromatograms shown in . The results of the HPLC chromatograms of resveratrol monoglycolate and diglycolate are shown in Figure 10-12 middle.

[0171] Figure 1 Shown is the HPLC chromatogram of resveratrol glycolate (1%) at 4°C. Figure 2 Shown is the HPLC chromatogram of resveratrol monoglycolate (1%) at 4°C. Figure 3 Shown is the HPLC chromatogram of resveratrol diglycolate (1%) at 4°C.

[0172] Figure 4 Shown is the HPLC chromatogram of resveratrol glycolate (1%) at 50°C. Figure 5 Shown is the HPLC chromatogram of resveratrol monoglycolate (1%) at 50°C. Figure 6 Shown is the HPLC chromatogram of resveratrol diglycolate (1%) at 50°C.

[0173] Figure 7 HPLC chromatograms are shown for resveratrol glycolate in pentylene glycol and butylene glycol (Formulation #1, 1% and Formulation #3, 10%, respectively) at 4°C and 50°C, respectively. Figure 8 Shown are HPLC chromatograms of resveratrol monoglycolate in pentylene glycol and butylene glycol (Formulation #1, 1% and Formulation #3, 10%, respectively) at 4°C and 50°C, respectively. Fig. 9HPLC chromatograms are shown for resveratrol diglycolate in pentylene glycol and butylene glycol (Formulation #1, 1% and Formulation #3, 10%, respectively) at 4°C and 50°C, respectively.

[0174] Fig.10 The stability of dissolved resveratrol glycolate (1%) in various formulations at 4°C and 50°C is shown. Fig.11 The stability of dissolved resveratrol mono- and di-glycolates (10%) in various formulations at 4°C and 50°C is shown. Fig.12 The stability of dissolved resveratrol mono- and di-glycolates (20%) in various formulations at 4°C and 50°C is shown.

[0175] The experimental results show that the combination of pentylene glycol / butylene glycol cosolvent is more stable than propylene glycol / butylene glycol or isoprene glycol cosolvent. In addition, it was observed that 10% resveratrol glycolate and 20% resveratrol glycolate solutions (shown in Figure 11-12 Middle) shows higher degradation at elevated storage conditions compared to 1% resveratrol glycolate solution.

[0176] like Fig.10 As shown in , at 4°C, Formulation 1 is approximately 21% more stable than Formulation 2, and Formulation 1 is approximately 23% more stable than Formulation 6. Similarly, at 50°C, Formulation 1 is approximately 24% more stable than Formulation 2, and Formulation 1 is approximately 30% more stable than Formulation 6.

[0177] like Fig.11 As shown in , Formulation 3 is approximately 55% more stable at 4°C than at 50°C, and Formulation 7 is approximately 21% more stable at 4°C than at 50°C.

[0178] like Fig.12 As shown in , Formulation 4 is approximately 48% more stable at 4°C than at 50°C.

[0179] Example 9

[0180] Compositions containing resveratrol glycolate by weight in an anhydrous formulation:

[0181]

[0182] The composition was prepared by combining the ingredients and mixing thoroughly to form an anhydrous formulation. The ratios of resveratrol glycolate, butylene glycol, and pentylene glycol are shown in the respective columns, which were initially combined in solution and then introduced into the phases of the formulation.

[0183] Example 10

[0184] Compositions containing resveratrol glycolate in serum / gel formulations by weight:

[0185]

[0186] The composition was prepared by combining the ingredients and mixing thoroughly to form a serum / gel formulation. The ratios of resveratrol glycolate, butylene glycol, and pentylene glycol are shown in the respective columns, which were initially combined in solution and then introduced into the phases of the formulation.

[0187] Embodiment 11

[0188] Composition by weight containing resveratrol glycolate in a cream / lotion formulation:

[0189]

[0190]

[0191] The composition was 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, which were initially combined in solution and then introduced into the phases of the formulation.

[0192] Although the present invention has been described in connection with the preferred embodiments, it is not intended to limit the scope of the invention to the specific forms presented, but on the contrary, it is intended to cover such alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Claims

1. A method for solubilizing a resveratrol glycolate compound, comprising the following steps: (a) heating the resveratrol glycolate compound and (b) mixing a resveratrol glycolate compound with a combination of pentylene glycol and butylene glycol at room temperature for 10 to 120 minutes; wherein the ratio of pentanediol to butanediol is 1:1 to 1:50; Wherein the resveratrol glycolate has the following formula: Wherein each R is independently selected from: (i) -OH, or (ii) or (iii) and All three R groups cannot be –OH at the same time.

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

3. The method according to claim 1, wherein the heating step is performed at a temperature not higher than 45°C.

4. Product obtained by the process according to claim 1.

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