CA2877471A1 - Topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene - Google Patents

Abstract

The present invention relates to compositions 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof, and methods of treating human skin using said compositions.

Description

TOPICAL APPLICATION OF
1-HYDROXYL 3,5-BIS(4'HYDROXYL STYRYL)BENZENE
FIELD OF THE INVENTION
The invention relates to compositions and methods for the topical application of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene.
BACKGROUND OF THE INVENTION
It is known to provide active agents to the skin for purposes of treating the signs of skin aging, providing anti-inflammatory benefits to the skin, or lightening the skin.
A particular class of anti-inflammatory agents is those that inhibit the cell transcription factor nuclear kappa-B (NFKB). For example, it is known that certain substituted resorcinols such as 4-hexyl resorcinol and tetrahydrocurcuminoids are NFKB
inhibitors. Such compounds provide anti-aging benefits when applied to the skin.
However, only a relatively small group of compounds have been identified as both effective and cosmetically acceptable.
It is known to apply anti-inflammatory compounds to the skin to provide anti-pigmentation benefits. A particular class of anti-inflammatory agents used for this purpose is agents that reduce the amount of melanin in melanocytes by means of inhibiting inflammatory mediator molecules. However, only a relatively small group of compounds have been identified as suitable for topical use to regulate melanin formation in skin.
SUMMARY OF THE INVENTION
The inventors have now surprisingly found that 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene is a potent NFKB inhibitor and is suitable for topical application to skin, and that 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and cosmetically acceptable salts thereof may be used to treat signs of skin aging, are inhibitors of melanin formation in melanocytes, and may be applied to skin in need of skin lightening treatment.
In one aspect, the invention provides a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof; and a cosmetically acceptable topical carrier comprising an ingredient selected from the group consisting of wetting agents, emulsifiers, emollients, humectants, and fragrances.

The invention further provides a method of treating human skin, comprising topically applying to said human skin a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof The invention also provides a method of treating a sign of skin aging, comprising topically applying to skin in need of such treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof The invention provides a method of lightening skin, comprising the step of topically applying to skin in need of skin lightening treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof The invention further provides a method of inhibiting the growth of a microorganism, comprising applying to said microorganism 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. Unless otherwise indicated, a percentage or concentration refers to a percentage or concentration by weight (i.e., %
(W/W). Unless stated otherwise, all ranges are inclusive of the endpoints, e.g., "from 4 to 9" includes the endpoints 4 and 9.
Products described herein may optionally be in finished packaged form. In one embodiment, the package is a container such as a plastic, metal or glass tube or jar containing the composition. The product may further contain additional packaging such as a plastic or cardboard box for storing such container. In one embodiment, the product comprises a composition of the invention and contains instructions directing the user to apply the composition to the skin to treat the signs of skin aging as discussed infra. Such instructions may be printed on the container, label insert, or on any additional packaging.
As used herein, "topically applying" means directly laying on or spreading on outer skin, the scalp, or hair, e.g., by use of the hands or an applicator such as a wipe, roller, or spray.
As used herein, "cosmetically acceptable" means that the ingredients the term describes are suitable for use in contact with tissues (e.g., the skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic response, or the like.
As used herein, "cosmetic" refers to a beautifying substance or preparation which preserves, restores, bestows, simulates, or enhances the appearance of bodily beauty or appears to enhance the beauty or youthfulness, specifically as it relates to the appearance of tissue or skin.
As used herein, "skin in need of treatment for the signs of aging" means a skin that is, but not limited to, sagging, loose, lax, rough, wrinkly, thinned, or uneven. Improving the signs of aging means improving the firmness of the skin, improving the texture of the skin, improving the appearance of wrinkles in skin, improving the skin tone, or the treating external aggressions in skin.
As used herein, "improving the firmness of skin" means the enhancing of the firmness or elasticity of the skin, preventing the loss of firmness or elasticity of skin, or preventing or treating sagging, lax and loose skin. The firmness or elasticity of the skin can be measured by use of a cutometer. See Handbook of Non-Invasive Methods and the Skin, eds. J. Serup, G. Jemec & G. Grove, Chapter 66.1 (2006). The loss of skin elasticity or firmness may be a result of a number of factors, including but not limited to aging, environmental damage, or the result of an application of a cosmetic to the skin.
As used herein, "improving the texture of skin" means the smoothing of the surface of the skin to remove either bumps or crevasses on the skin surface.
As used herein, "improving the appearance of wrinkles in skin" means preventing, retarding, arresting, or reversing the process of wrinkle formation in skin.
As used herein, "wrinkle" includes fine lines, fine wrinkles, or coarse wrinkles.
Examples of wrinkles include, but are not limited to, fine lines around the eyes (e.g., "crow's feet"), forehead and cheek wrinkles, frown-lines, and laugh-lines around the mouth.

As used herein, "uneven skin" means a condition of the skin associated with diffuse or mottled pigmentation, which may be classified as hypemigmentation, such as post-inflammatory hypemigmentation.
As used herein, "blotchiness" means a condition of the skin associated with redness or erythema.
As used herein, "treatment of external aggressions in skin" means the reduction or prevention of the damage from external aggressions in skin. Examples of external aggressions include, but are not limited to, damage to the skin from the use of cleansers (e.g., topical cleansers containing surfactants), make-up, shaving as well as environmental damage such as from UV light (e.g., sundamage from sunlight or damage from non-natural sources such as UV lamps and solar simulators), ozone, exhaust, pollution, chlorine and chlorine containing compounds, and cigarette smoke. Effects of external aggressions on the skin include, but are not limited to, oxidative and/or nitrosative damage to and modifications on lipids, carbohydrates, peptides, proteins, nucleic acids, and vitamins. Effects of external aggressions on the skin also include, but are not limited to, loss of cell viability, loss or alteration of cell functions, and changes in gene and/or protein expression.
As used herein, "improving the skin tone" means the lightening of the appearance of the skin (e.g., lightening pigmented marks or lesions, reducing skin sallowness, and/or evening the color of the skin).
As used herein, "skin in need of reducing skin inflammation" means a skin exhibiting redness or erythema, edema, or being reactive or sensitive to external elements.
External elements include, but are not limited to, sun rays (UV, visible, IR), microorganisms, atmospheric pollutants such as ozone, exhaust pollutants, chlorine and chlorine generating compounds, cigarette smoke, cold temperature, heat.
Inflammatory disorders and related conditions which may be treated or prevented by use of the compositions of this invention include, but are not limited to the following:
arthritis, bronchitis, contact dermatitis, atophic dermatitis, psoriasis, seborrheic dermatitis, eczema, allergic dermatitis, polymorphous light eruptions, inflammatory dermatoses, folliculitis, alopecia, poison ivy, insect bites, acne inflammation, irritation induced by extrinsic factors including, but not limited to, chemicals, trauma, pollutants (such as cigarette smoke) and sun exposure, secondary conditions resulting from inflammation including but not limited to xerosis, hyperkeratosis, pruritus, postinflammatory hyperpigmentation, scarring and the like. Preferably, the inflammatory disorders and related conditions which may be treated or prevented using the methods of the invention are arthritis, inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphous light eruptions, irritation, including erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, folliculitus, alopecia, and secondary conditions and the like.
As used herein, the term "lightening the skin" refers generally to lightening, brightening, whitening, and/or evening of the skin tone, skin color, and/or shade of skin, and/or to the reduction in sallowness, and/or to the lightening and/or fading of hyperpigmented marks and/or lesions including, but not limited to, pigmented spots, melanin spots, age spots, sun spots, senile lentigos, freckles, lentigos simplex, pigmented solar keratosis, seborrhoeic keratosis, melasma, acne marks, post-inflammatory hyperpigmentation, lentigines, ephelides, combinations of two or more thereof and the like. In certain embodiments, "lightening the skin" also refers to increased skin radiance, glow, translucency and/or luminescence and/or obtaining a more radiant, glowing, translucent or luminous skin tone appearance or a less yellow or sallow skin tone. In certain preferred embodiments, "lightening the skin" refers to lightening and evening the skin tone, increasing skin radiance and/or lightening age spots.
As used herein, the term "skin in need of skin lightening treatment" refers generally to skin that exhibits one or more property selected from the group consisting of:
skin having a measured Individual Typology Angle (ITA) value below 41 as determined per the COLIPA GUIDELINE: GUIDELINE FOR THE COLORIMETRIC
DETERMINATION OF SKIN COLOUR TYPING AND PREDICTION OF THE
MINIMAL ERYTHEMAL DOSE (MED) WITHOUT UV EXPOSURE published in 2007, which is incorporated herein by reference and further described below, darkened and/or sallow skin, including skin darkened by UV, skin with uneven skin tone, or skin with one or more hyperpigmented marks and/or lesions including, but not limited to, pigmented spots, melanin spots, age spots, sun spots, senile lentigos, freckles, lentigos simplex, pigmented solar keratosis, seborrhoeic keratosis, melasma, acne marks, post-inflammatory hyperpigmentation, lentigines, ephelides, combinations of two or more thereof and the like. In the COLIPA guidelines, skin color is defined function of the ITA
value as: very light skin >55; Light skin 41-55, Intermediate 28-41, and Tan skin <28. In certain preferred embodiments, "skin in need of skin lightening" refers to individuals with a skin having an ITA value of less than 41, such as about 40 or less, about 35 or less, about 30 or less, or more preferably about 28 or less. In certain other preferred embodiments, the present invention is directed to compositions and methods for use on skin in need of skin lightening treatment selected from sallow and/or darkened skin. In certain other preferred embodiments, the present invention is directed to compositions and methods for use on skin in need of skin lightening treatment selected from the group consisting of age spots, freckles, marks left after acne, and combinations of two or more thereof.
As used herein, unless otherwise specified, all percentages of ingredients in compositions are weight percent of active/solids ingredient based on the total weight of composition.
As used herein, "substantially free" of an ingredient means containing less than about 1% by weight, such as less than about 0.5% by weight, such as less than about 0.25% by weight, such as less than about 0.1% by weight of such ingredient. In one embodiment, "substantially free" means completely free of such ingredient.
Compositions of the present invention are suitable for treating human skin, e.g., skin on the face or body, for signs of skin aging, or for inflammation. In a particularly preferred embodiment, a composition according to the invention is used to treat the presence of lines and wrinkles and/or loss of elasticity. Compositions of the present invention are suitable for treating human skin, e.g., skin on the face or body, to lighten the skin.
1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene Compositions of the present invention comprise 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene is a curcumin analog having the structure below:

OH

*
HO OH
As described in US Patent No. 7,745,670, 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene can be made by reacting 1-(bromomethyl)-4-methoxybenzene with triethyl phosphate using an Arbuzov reaction to produce diethyl [(4-methoxyphenyl)methyl]phosphonate. This is coupled with 5-methoxybenzene-1,3-dicarbaldehyde-using sodium hydride as base in THF, followed by reaction with boron trichloride and dichloromethane to replace methoxy groups with hydroxyls.
Salts of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene can be made by, for example, reacting the 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene with a base such as piperazine, or another base, to produce at least some phenoxide salt of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene.
Topical Compositions Generally, the 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or salt thereof is present in the composition in a cosmetically effective amount, such as from about 0.01%
to about 10%, preferably from about 0.1% to about 5%, more preferably from about 0.2%
to about 2%, even more preferably from about 0.5% to about 1.5%, by weight of the composition.
The compositions of the present invention are applied topically to human skin and/or hair.
The compositions may be spreadable. They may be topically applied by spreading, for example spreading over the skin or hair, in particular over skin of the face or hands.
In one embodiment, a composition of the invention is topically applied without a voltage.
In addition to 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene, the composition may further include a cosmetically acceptable topical carrier that may be from about 50% to about 99.99%, by weight, of the composition (e.g., from about 80% to about 99%, by weight, of the composition). In a preferred embodiment of the invention, the cosmetically acceptable topical carrier includes water.
The cosmetically acceptable topical carrier may be unsuitable for ingestion.
The cosmetically acceptable topical carrier may include an ingredient selected from one or more of the following five classes: wetting agents, emulsifiers, emollients, humectants, and fragrances. In certain embodiments, the cosmetically acceptable topical carrier includes ingredients from two or more of the above-mentioned classes, such as ingredients from at least three or more of such classes.
In one embodiment, the cosmetically acceptable topical carrier includes water, an emulsifier, and an emollient.
The compositions may be made into a wide variety of product types that include but are not limited to lotions, creams, gels, sticks, sprays, ointments, cleansing liquid washes and solid bars, shampoos and hair conditioners, hair fixers, pastes, foams, powders, mousses, shaving creams, wipes, patches, hydrogels, film-forming products, facial masks and skin masks, films and make-up such as foundations, and mascaras.
These product types may contain several types of cosmetically acceptable topical carriers including, but not limited to solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, solids and liposomes.
The compositions useful in the present invention can be formulated as solutions.
Solutions typically include an aqueous or organic solvent (e.g., from about 50% to about 99.99% or from about 90% to about 99% of a cosmetically acceptable aqueous or organic solvent). Examples of suitable organic solvents include humectants (e.g., water-retaining or hygroscopic materials) such as propylene glycol, pentylene glycol, polyethylene glycol, polypropylene glycol, glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol;
as well as ethanol, and mixtures thereof Solutions can optionally include a wetting agent, such as to provide foam, e.g, an anionic, non-ionic, or cationic wetting agent.
Compositions useful in the subject invention may be formulated as a solution comprising an emollient. Such compositions preferably contain from about 2% to about 50% of an emollient(s). As used herein, "emollients" refer to materials used for the prevention or relief of dryness, such as by preventing the transepidermal loss of water from the skin. Examples of emollients include hydrophobic compounds such as vegetable oils, mineral oils (e.g., petrolatum), fatty esters (e.g., isopropyl palmitate, c12-c15 alkyl benzoate) including those fatty esters of glycerol, silicone oils (e.g., dimethicone) and the like.
A lotion can be made from such a solution. Lotions typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of an emollient(s) and from about 50% to about 90% (e.g., from about 60% to about 80%) of water.
Another type of product that may be formulated from a solution is a cream. A
cream typically contains from about 5% to about 50% (e.g., from about 10% to about 20%) of an emollient(s) and from about 45% to about 85% (e.g., from about 50%
to about 75%) of water.
Although it is preferred that the composition of the present invention includes water, the composition may alternatively be anhydrous or an ointment that includes no water but organic and/or silicone solvents, oils, lipids and waxes. An ointment may contain a simple base of animal or vegetable oils or semi-solid hydrocarbons.
An ointment may contain from about 2% to about 10% of an emollient(s) plus from about 0.1% to about 2% of a thickening (gelling) agent(s).
The composition may be formulated as an emulsion. If the topical carrier is an emulsion, from about 1% to about 10% (e.g., from about 2% to about 5%) of the topical carrier contains an emulsifier(s). Emulsifiers may be nonionic, anionic or cationic.
Examples of suitable emulsifiers include those typically identified as such in the art of personal care and cosmetic formulations, e.g., cationic emulsifiers such as disteryldimonium chloride, non-ionic emulsifiers such as stereth-2, stereth-21; anionic emulsifiers such as potassium cetyl phosphate; polymeric emulsifiers such as acryloyldimethyltaurateNP copolymers, and the like.
Lotions and creams can be formulated as emulsions. Typically such lotions contain from 0.5% to about 5% of an emulsifier(s). Such creams typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of an emollient(s);
from about 20% to about 80% (e.g., from 30% to about 70%) of water; and from about 1% to about 10% (e.g., from about 2% to about 5%) of an emulsifier(s).
Single emulsion skin care preparations, such as lotions and creams, of the oil-in-water type and water-in-oil type are well-known in the cosmetic art and are useful in the subject invention. Multiphase emulsion compositions, such as the water-in-oil-in-water type or the oil-in-water-in-oil type, are also useful in the subject invention. In general, such single or multiphase emulsions contain water, emollients, and emulsifiers as essential ingredients.
The compositions of this invention can also be formulated as a gel (e.g., an aqueous, alcohol, alcohol/water, or oil gel using a suitable gelling agent(s)). Suitable gelling agents for aqueous and/or alcoholic gels include, but are not limited to, natural gums, (cross-linked) acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose).
Suitable gelling agents for oils (such as mineral oil) include, but are not limited to, hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/styrene copolymer. Such gels typically contains between about 0.1% and 5%, by weight, of such gelling agents.
The compositions of the present invention can also be formulated into a solid formulation (e.g., a wax-based stick, soap bar composition, powder, or a wipe containing powder).
The compositions useful in the subject invention may contain, in addition to the aforementioned components, a wide variety of additional oil-soluble materials and/or water-soluble materials conventionally used in compositions for use on skin and hair, at their art-established levels.
Additional Cosmetically Active Agents In one embodiment, the composition includes an additional NFKB-inhibitor such as a substituted resorcinol, (E)-3-(4-methylphenylsulfony1)-2-propenenitrile (such as "Bay 11-7082," commercially available from Sigma-Aldrich of St. Louis, Missouri), a tetrahydrocurcuminoid (such as Tetrahydrocurcuminoid CG, available from Sabinsa Corporation of Piscataway, NJ), paulownin, extracts of Paulownia wood (for example the wood of Paulownia tomentosa, P aulownia fortunei, Paulownia elongate, Paulownia taiwaniana, andl orP aulownia kawakamii,), and combinations thereof In one embodiment, the composition further contains another cosmetically active agent. As used herein, a "cosmetically active agent" is a compound (e.g., a synthetic compound or a compound isolated from a natural source or a natural extract) that has a cosmetic or therapeutic effect on the skin including, but not limiting to anti-aging actives, anti-inflammatory agents, tropoelastin promoters, anti-acne agents, anti-microbial agents, anti-inflammatory agents, anti-mycotic agents, external analgesics, sunscreens, antioxidants, keratolytic agents, vitamins, skin lightening agents and skin firming agents.
In one embodiment, the composition includes a skin-lightening agent such as a tyrosinase inhibitor, melanin-degradation agent, melanosome transfer inhibiting agent including PAR-2 antagonists, retinoids, antioxidants, tranexamic acid, tranexamic acid cetyl ester hydrochloride, skin bleaching agent, linoleic acid, adenosine monophosphate disodium salt, Chamomilla extract, allantoin, opacifier, talc or silica, zinc salt, or the like, or other agent as described in Solano et al. Pigment Cell Res. 19 (550-571) and Ando et al.
Int J Mol Sci 11(2566-2575).
Examples of suitable tyrosinase inhibitors include but, are not limited to, vitamin C and its derivatives, vitamin E and its derivatives, kojic acid, arbutin, resorcinols, hydroquinone, flavones e.g., licorice flavanoids, licorice root extract, mulberry root extract, dioscorea coposita root extract, saxifraga extract and the like, ellagic acid, salicylates and derivatives, glucosamine and derivatives, fullerene, hinokitiol, dioic acid, acetyl glucosamine, 5,5'-dipropyl-bipheny1-2,2'-diol (magnolignan), 4-(4-hydroxypheny1)-2-butanol (4-HPB), combinations of two or more thereof, and the like.
Examples of vitamin C derivatives include, but are not limited to, ascorbic acid and salts, ascorbic acid-2-glucoside, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and natural extract enriched in vitamin C.
Examples of vitamin E derivatives include, but are not limited to, alpha-tocopherol, beta, tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, delta-tocotrienol and mixtures thereof, tocopherol acetate, tocopherol phosphate and natural extracts enriched in vitamin E derivatives.
Examples of resorcinol derivatives include, but are not limited to, resorcinol, 4-substituted resorcinols like 4-alkylresorcinols such as 4-butyresorcinol (rucinol), 4-hexylresorcinol (SYNOVEA HR, SYNTHEON), phenylethyl resorcinol (SYMWHITE, SYMRISE), 1-(2,4-dihydroxypheny1)-3-(2,4-dimethoxy-3-methylpheny1)-propane (nivitol, UNIGEN) and the like and natural extracts enriched in resorcinols.
Examples of salicylates include, but are not limited to, 4-methoxy potassium salicylate, salicylic acid, acetylsalicylic acid, 4-methoxysalicylic acid and their salts.
In certain preferred embodiments, the tyrosinase inhibitors include a 4-substituted resorcinol, a vitamin C derivative, or a vitamin E derivative. In more preferred embodiments, the tyrosinase inhibitor comprises phenylethyl resorcinol, 4-hexyl resorcinol, or ascorbyl-2-glucoside.
Examples of suitable melanin-degradation agents include, but are not limited to, peroxides and enzymes such as peroxidases and ligninases. In certain preferred embodiments, the melanin-inhibiting agents include a peroxide or a ligninase.
Examples of suitable melanosome transfer inhibiting agents include PAR-2 antagonists such as soy trypsin inhibitor or Bowman-Birk Inhibitor, vitamin B3 and derivatives such as niacinamide, essential soy, whole soy, soy extract. In certain preferred embodiments, the melanosome transfer inhibiting agents includes a soy extract or niacinamide.
Examples of retinoids include, but are not limited to, retinol (vitamin A
alcohol), retinal (vitamin A aldehyde), retinyl acetate, retinyl propionate, retinyl linoleate, retinoic acid, retinyl palmitate, isotretinoin, tazarotene, bexarotene, adapalene, combinations of two or more thereof and the like. In certain preferred embodiments, the retinoid is selected from the group consisting of retinol, retinal, retinyl acetate, retinyl propionate, retinyl linoleate, and combinations of two or more thereof In certain more preferred embodiments, the retinoid is retinol.
Other skin lightening agents include vitamin B5, vitamin B12, glycolic acid and extracts of Paulownia wood (for example the wood of Paulownia tomentosa, Paulownia fortunei, Paulownia elongate, Paulownia taiwaniana, andl orPaulownia kawakamii).
Examples of antioxidants include, but are not limited to, water-soluble antioxidants such as sulfhydryl compounds and their derivatives (e.g., sodium metabisulfite and N-acetyl-cysteine, glutathione), lipoic acid and dihydrolipoic acid, stilbenoids such as resveratrol and derivatives, lactoferfin, iron and copper chelators and ascorbic acid and ascorbic acid derivatives (e.g., ascoby1-2-glucoside, ascorbyl palmitate and ascorbyl polypeptide). Oil-soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to, butylated hydroxytoluene, retinoids (e.g., retinol and retinyl palmitate), tocopherols (e.g., tocopherol acetate), tocotrienols, and ubiquinones. Natural extracts containing antioxidants suitable for use in the compositions of this invention, include, but not limited to, extracts containing flavonoids and isoflavonoids and their derivatives (e.g., genistein and diadzein), extracts containing resveratrol and the like. Examples of such natural extracts include grape seed, green tea, black tea, white tea, pine bark, feverfew, parthenolide-free feverfew, oat extracts, blackberry extract, cotinus extract, soy extract, pomelo extract, wheat germ extract, hesperedin, grape extract, portulaca extract, licochalcone, chalcone, 2,2'-dihydroxy chalcone, primula extract, propolis, and the like.
Other Materials Various other materials may also be present in the composition, as known in the art. These include humectants, pH adjusters, chelating agents (e.g., EDTA), fragrances, dyes and preservatives (e.g., BHT, benzyl alcohol).
In one embodiment, the composition is substantially free, preferably completely free, of preservatives. This is because, advantageously, 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and salts thereof are active for inhibiting and/or killing microorganisms.
Accordingly, compositions according to the invention can be formulated with little or no conventional preservatives. Conventional preservatives for example are selected from the group consisting of parabens, benzoic acid and salts thereof, phenoxyethanol, isothaizolones, imidazolidinyl urea, iodo propynyl butyl carbamate, DMDM
hydantoin, caprylyl glycol, dehydroacetic acid, sorbic acids and salts thereof, chlorophensin, glyceryl caprylate, phenylpropanol, sodium levulinate, anisic acid, ethylhexylglycerin, benzyl alcohol and combinations thereof The composition and formulations and products containing such compositions of the present invention may be prepared using methodology that is well known by an artisan of ordinary skill.
Methods of Use Compositions of the present invention may be topically applied to human skin, e.g., skin that is in need of treatment for one or more signs of skin aging as described above. In one embodiment, the compositions are applied to skin in need of treatment for lines and wrinkles and/or loss of elasticity. The compositions may be applied to the skin in need of such treatment according to a suitable treatment regimen, e.g., every month, every week, every other day, every day, twice a day, or the like.
1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene, cosmetically acceptable salts thereof and compositions containing the same may be used to provide antimicrobial effects (e.g., antibacterial, antifungal, antiviral, or anti-parasitic effects).

In one embodiment, the invention provides a method of inhibiting the growth of a microorganism, comprising applying to said microorganism 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene, a cosmetically acceptable salt thereof, or a composition containing the same.
Microorganisms that may be inhibited or killed by such application include gram positive bacteria, gram negative bacteria and fungi including Staphylococcus aureus, Staphylococcus epidermic/is, Propionibacterium acnes, Escherichia colt, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.
It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The following non-limiting examples further illustrate the invention.
Example 1: NFKB-Inhibition NFKB-INHIBITION TESTS were performed on various concentrations of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and a vehicle control (DMSO). The 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene was prepared as described in US
Patent No.
7,745,670.
The NF-M3 INHIBITION TEST was conducted as follows. Rat cardiac myoblasts H9c2 cells were purchased from ATCC (Manassas, VA.). Cultures were maintained in Dulbecco's modified Eagle's medium (DMEM, Invitrogen Life Technologies, Carlsbad, CA.) supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 50 ug/ml streptomycin (Invitrogen life technologies, Carlsbad, CA.). 1x104 cells grown in 96-well plates were transiently transfected with 0.45ug total DNA per well using Lipofectamine 2000 (Invitrogen life technologies, Carlsbad, Calif). In all transfections, a construct with the thymidine kinase promoter and the Renilla luciferase reporter gene (pRL-TK, Promega, Madison Wis.) was included as an internal control in addition to the NF-kB
luciferase promoter. One day after transfection, cells were treated with the indicated samples (in DMSO as vehicle) at indicated concentrations and stimulated with 100 ng/mL
of Tumor Necrosis Factor-a (TNFa , Sigma-Aldrich, St Louis, MO) for approximately 24 hours before they were lysed for luciferase assays, using Dual-Luciferase Reporter System from Promega (Madison, Wis.), following manufacturer's protocol. Briefly, the firefly luciferase activity was measured first (representing NF-kB promoter activity), followed by the renilla luciferase (internal control), using luminometer LMAX, from Molecular Devices (Sunnyvale, Calif.). The ratio of these two luciferase activities (RLU) was used to evaluate the activity of each promoter:
NF-KB Inhibition = [1¨( RLUsample /RLUcontrol)] * 100 where RLUsample and RLUcontrol are the normalized luciferase activity ratios of the sample and control, respectively.
The results are shown in Table 1, in which NF-kB Gene Reporter Activation (Luminescence, L) is reported. Percent NF-kB Inhibition is also reported.

NF-1(13 Gene Reporter Percent NF-1(13 Activation Inhibition (Luminescence, L) Untreated 131.5 TNFa (10Ong/m1) Stimulated, "Lcontrol" 452.4 TNFa + Vehicle (0.1% DMSO) 588.3 0%
TNFa + 1-hydroxyl 3,5-bis(4'hydroxyl 585.5 0.5%
styryl)benzene (0.2 ug/ml) TNFa + 1-hydroxyl 3,5-bis(4'hydroxyl 458.6 22.1%
styryl)benzene (0.5 ug/ml) TNFa + 1-hydroxyl 3,5-bis(4'hydroxyl 283.8 51.7%
styryl)benzene (1 ug/ml) TNFa + 1-hydroxyl 3,5-bis(4'hydroxyl 170.5 71.0%
styryl)benzene (2 ug/ml) TNFa + 1-hydroxyl 3,5-bis(4'hydroxyl 22.6 96.1%
styryl)benzene (4 ug/ml) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene showed a strong reduction in NF-kB mediated inflammatory response in human skin cells.
Example 2: Anti-Inflammatory Activity The topical anti-inflammatory activities of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt were evaluated as follows.

Epidermal equivalents (EPI 200 HCF), multilayer and differentiated epidermis consisting of normal human epidermal keratinocytes, were purchased from MatTek (Ashland, MA). Upon receipt, epidermal equivalents were incubated for 24 hours at 37 C
in maintenance medium without hydrocortisone. Equivalents were topically treated (2mg/cm2) with 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene thereof in a 70:30 Ethanol-Propylene glycol vehicle two hours before exposure to solar ultraviolet light (1000W-Oriel solar simulator equipped with a 1-mm Schott WG 320 filter; UV dose applied: 70 kJ/m2 as measured at 360nm). The equivalents were incubated for 24 hours at 37 C with maintenance medium then supernatants were analyzed for IL-8 cytokine release using commercially available kits (Millipore Corp., Billerica, MA).
The results are shown in Table 2.

Sample Change over vehicle % inhibition over UV
alone (Normalized to treatment 100) Vehicle (70/30: Ethanol + 100 28 Propylene Glycol) Vehicle + UV 134 42 UV + 1-hydroxyl 3,5- 82 21 39%
bis(4'hydroxyl styryl)benzene - Free Phenol (0.5%) UV + 1-hydroxyl 3,5- 80 26 40%
bis(4'hydroxyl styryl)benzene - Free Phenol (1%) UV + 1-hydroxyl 3,5- 85 14 37%
bis(4'hydroxyl styryl)benzene - Piperazine salt (0.5%) UV + 1-hydroxyl 3,5- 81 31 40%
bis(4'hydroxyl styryl)benzene - Piperazine salt (1%) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt showed strong reduction in UV-induced inflammation in human skin cells.
Example 3: Induction of Elastin and CollagenlA gene expression Primary human dermal fibroblasts (Lifeline Cell Technologies, Frederick, MD) were grown until confluence in DMEM media (Invitrogen/Life Technologies, Carlsbad, CA) with 10% FBS and 1% Penicillin-Streptomycin on 24 well tissue culture plates, followed by treatment with 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene (0.1ug/mL) with and without TNF-a for 48 hr. Post-treatment, cells were lysed using RLT
buffer and total RNA was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA).
Quantitative PCR was performed using the Gene Amp PCR System 9700 and 7500 Real Time PCR
System cycler (Applied Biosystems)/Life Technologies, Carlsbad, CA). Elastin (Qiagen) and Collagenlal primers (custom sequence -sense: 5'-TCC-CCA-GCT-GTC-TTA-TGG-CT-3' and anti-sense: 5'-CAG-GCA-CGG-AAA-TTC-CTC-C-3') were used. The housekeeping gene GAPDH was used for normalization (custom primer sequence: F
5'-ATC-TCT-GCC-CCC-TCT-GCT-G-3' and R 5'-ATG-GTT-CAC-ACC-CAT-GAC-GA-3'; Invitrogen/Life Technologies, Carlsbad, CA). Fold-changes in PCR
(normalized to GAPDH) were calculated from untreated.
The results are shown in Tables 3A and 3B.

Collagen lA Elastin Normalized Fold-change in Normalized Fold-change in PCR PCR
(Mean) (Mean) Untreated 1.0 1.0 1-hydroxyl 3,5- 2.96 6.23 bis(4'hydroxyl styryl)benzene (0.1ug/mL) Collagen lA Elastin Normalized Fold-change in Normalized Fold-change in PCR PCR
(Mean) (Mean) Untreated 1.0 1.0 TNF-a (lOng/mL) 0.52 0.41 TNF-a (lOng/mL) + 1- 1.36 1.12 hydroxyl 3,5-bis(4'hydroxyl styryl)benzene (0.1ug/mL) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene increased the expression of genes associated with collagen and elastin production.
Example 4: Inhibition of TNF-a - Induced MMP-9 levels The ability of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene to inhibit TNF-a induced MMP-9 levels was tested at different concentrations as follows. The formation of TNF-a induced MMP-9 is involved in the undesirable breakdown of extracellular matrix in human skin.
Epidermal equivalents (EPI 200 HCF) were purchased from MatTek (Ashland, MA). Upon receipt, the epidermal equivalents were incubated for 24 hours at 37 C in maintenance medium without hydrocortisone. The equivalents were topically treated (2mg/cm2 ) with 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene extracts in a 70%

ethanol/30% propylene glycol vehicle 2 hours before treatment with TNF-a (10Ong/mL).
the equivalents were incubated for 48 hours at 37 C with maintenance medium then supernatants were analyzed for MMP -9 using commercially available kits (R&D
Systems, Minneapolis, MN).
The results are shown in Table 4.

Treatment (Dose, as % w/v) Mean of MMP-9 Percent Inhibition of Release (ng/ml) MMP-9 Production (over TNF-a alone) Untreated 1422 611 TNF-a alone 3557 1181 TNF-a + 1-hydroxyl 3,5- 1392 627 60.9 bis(4'hydroxyl styryl)benzene (0.25%) TNF-a + 1-hydroxyl 3,5- 1012 249 71.6 bis(4'hydroxyl styryl)benzene (0.5%) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene inhibited the formation of TNF-a induced MMP-9.
Example 5: Melanogensis Inhibition Test Ultraviolet (UV) radiation from the sun is the most important external stimulus for melanin formation leading to skin darkening. Reducing melanin formation in the skin may be achieved by inhibiting multiple steps of the melanin biogenesis process.
Tyrosinase is the key regulatory enzyme of melanogenesis. Agents that inhibit tyrosinase will reduce melanin synthesis.
1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene (0.0001, 0.001, and 0.01% w/v) was tested for tyrosinase inhibition as follows.
Mushroom tyrosinase samples (Sigma, T7755, 10 U/reaction) were treated with the samples of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and control samples.
Reaction was initiated by addition of 10 mM L-dopa (Research Organics, #2111D) at 37 C. Tyrosinase activity was measured by recording light absorption (optical density) at 492 nm after 30 min for both control samples (no exposure to test compound) and test samples that were exposed to the test compound.
Percent Inhibition of Tyrosinase was related to the reduction in absorption at nm (relative to the control) by the following formula:
Percent Inhibition of Tyrosinase = [ Teoniroi - Tsample Teontrol)] *100 where Tcontroi is the tyrosinase activity of the control and Tsampie is the tyrosinase activity in the presence of test compound. Samples were tested in duplicate and Percent Inhibition of Tyrosinase was averaged and standard deviation was reported. The control had an average optical density of 0.622.
The results are provided in Table 5.

Percent Inhibition of Tyrosinase activity (mean standard deviation) 1-hydroxyl 3,5-bis(4'hydroxyl 3.3 1.95 styryl)benzene - Free Phenol (0.0001%) 1-hydroxyl 3,5-bis(4'hydroxyl 8.21 1.27 styryl)benzene - Free Phenol (0.001%) 1-hydroxyl 3,5-bis(4'hydroxyl 11.84 3.22 styryl)benzene - Free Phenol (0.01%) 1-hydroxyl 3,5-bis(4'hydroxyl 2.03 3.94 styryl)benzene - Piperazine salt (0.0001%) 1-hydroxyl 3,5-bis(4'hydroxyl 11.52 3.16 styryl)benzene - Piperazine salt (0.001%) 1-hydroxyl 3,5-bis(4'hydroxyl 16.64 2.76 styryl)benzene - Piperazine salt (0.01%) 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene showed a substantial and dose dependent inhibition of tyrosinase enzyme activity.
Example 6: Inhibition of UV-induced Melanogenesis One or more samples of B16(F10) cells were prepared and each pre-treated with a test sample followed by UVB exposure as described below. Upon treatment, UVB
stimulated melanogenesis in the cells and test compounds were evaluated based on their ability to inhibit or slow down the rate of melanogenesis. The cells were lysed for protein measurement at 595nm and melanin content at 470nm. The potency of the test compounds were determined by comparing the % inhibition achieved by the test compounds against the treated control.
On a first day, murine melanoma B16(F10) cells were seeded in 60mm plates with a density of ¨1 million cells per plate and incubated for 48hrs at 37 C, 5%
CO2. On day 2, the cells with a confluency rate of 90-100% were treated with test compound at a predetermined concentration (e.g. 25 [tg/mL) for two hours (for test compound samples only) followed by exposure to UVB 200mJ/cm2 (for test samples and treated control). The cells were harvested on day 3 (24 h post UVB irradiation for test samples and treated control) and lysed in protein lysis buffer (50mM Tris, pH 8, 2mM EDTA, 150mM
NaC1, and 1%TRITON X 100 - a nonionic surfactant purchased from BioRad Cat.#: 161-0407), and centrifuged.
The resulting supernatant was mixed well with a protein dye assay (Bio-rad protein assay reagent) and a spectrophotometer (Molecular Devices VERSAmax) was used to determine the optical density (OD) of the sample at 595nm, which was recorded as the "protein assay OD." The cell pellet remaining after removal of the supernatant was dissolved in alkaline DMSO buffer, and the resulting solution was similarly tested using a spectrophotometer for melanin absorbance assay at 470 nm. The absorbance was recorded as the "melanin assay OD."
Control samples of B16(F10) murine melanoma cells were prepared and harvested as indicated above, but without addition of any test sample and without exposure to UVB
(untreated control). Other samples were prepared and harvested as indicated above, but without addition of test sample and exposed to UVB as described below (treated control).
Three samples each of the untreated control, treated control, and each test sample were made and the Melanin OD and Protein OD measured for each. The normalized melanin for each untreated control (3 samples), treated control (3 samples) and test sample (3 samples for each test compound) was calculated via the following equation:
Normalized Melanin = melanin assay OD/protein assay OD.
The averages of the Normalized Melanin of the untreated controls and treated controls were calculated (sum of the three calculated values/3).
The Induction value of the Control (which can be thought of as the UV-induced increase in melanin, without the benefit of any test sample to reduce melanogensis) was determined by subtracting the average Normalized Melanin of untreated control from the average Normalized Melanin of treated control. Similarly, the Induction value of each test sample (which can be thought of as the amount of additional melanin over and above the baseline of the sample not treated with UV) wass then calculated by subtracting average Normalized Melanin of untreated control from the Normalized Melanin of the test sample.
The Percent Inhibition for each test sample was then calculated via the equation:

Percent Inhibition = 100 x [(Induction value of Control ¨ Induction value with Test Sample)/Induction value of Control].
The average Percent Inhibition was calculated as the sum of the three resulting Inhibition % values for each test sample divided by three.
The calculation sequence for Percent Inhibition are demonstrated using the example of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene - Free Phenol (0.0001%), in Table 6A, below.
Table 6A: Example Calculations of Percent Inhibition of UV-induced Melanogenesis Average Normalized Melanin Untreated 0.122 control Average Normalized Melanin UVB 0.234 treated control Induction value of control 0.234-0.122=0.112 Normalized Melanin value 0.19 (Si) (duplicate test sample Si & S2) 0.187(S2) Induction value with Test sample 0.19-0.122 = 0.068 0.187 ¨0.122 = 0.065 Percent Inhibition for Test sample [(0.112 ¨ 0.068)/0.112] x 100 = 39.05%
(Si) [(0.112 ¨ 0.065)/0.112] x 100 = 41.93%
(S2) Ave = (39.05 + 41.93)/2 = 40.49%
1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt were evaluated according to the Inhibition of UV-induced Melanogenesis Test described above.
The results are reported in Table 6B.

Table 6B: Percent inhibition of UV-induced Melanogenesis Percent inhibition of UV-induced melanogenesis (mean SD) 1-hydroxyl 3,5-bis(4'hydroxyl 18.93 5.92 styryl)benzene - Free Phenol (0.00001%) 1-hydroxyl 3,5-bis(4'hydroxyl 33.27 4.39 styryl)benzene - Free Phenol (0.00005%) 1-hydroxyl 3,5-bis(4'hydroxyl 40.49 2.04 styryl)benzene - Free Phenol (0.0001%) 1-hydroxyl 3,5-bis(4'hydroxyl 13.93 11.33 styryl)benzene - Piperazine salt (0.00001%) 1-hydroxyl 3,5-bis(4'hydroxyl 33.52 1.54 styryl)benzene - Piperazine salt (0.00005%) 1-hydroxyl 3,5-bis(4'hydroxyl 55.70 4.44 styryl)benzene - Piperazine salt (0.0001%) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt showed a strong inhibition in melanogenesis that was UV-induced.
Example 7: Inhibition of Pigmentation Skin epidermal equivalent tissues obtained from MatTek's MelanoDermTM System were used as follows. MatTek's MelanoDermTM System consists of normal, human-derived epidermal keratinocytes (NHEK) and melanocytes (NHM) which have been cultured to form a multilayered, highly differentiated model of the human epidermis.
Specifically, MEL-300-B tissues, each 9mm in diameter were used in the following tests.
1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt were prepared in an appropriate vehicle and applied topically to the skin model daily. The experiment lasted for eight days. Measurement was taken on day 9.
The Degree of Lightness for each skin model tissue (L- Value) was measured using a spectrophotometer (Konica Minolta CM-2600d). The AL (degree of lightness as compared to vehicle-treated control) for each test sample was calculated using following formula:
AL = L-value of treated sample ¨ L-value of control sample The results are shown in Table 7.
Table 7 Degree of Lightness (AL) 1-hydroxyl 3,5-bis(4'hydroxyl 1.46 0.71 styryl)benzene - Piperazine salt (0.1%) 1-hydroxyl 3,5-bis(4'hydroxyl 2.83 0.41 styryl)benzene - Piperazine salt (0.25%) 1-hydroxyl 3,5-bis(4'hydroxyl 4.60 0.61 styryl)benzene - Piperazine salt (0.5%) 1-hydroxyl 3,5-bis(4'hydroxyl 4.23 0.64 styryl)benzene - Free Phenol (0.5%) 1-Hydroxyl 3,5-bis(4'hydroxyl styryl)benzene and its piperazine salt showed inhibition in melanogenesis in epidermal equivalent tissues.
Example 8 The activity of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene was evaluated against representative gram positive bacteria, gram negative and fungal species as follows.
A 4% (40mg/mL) stock solution was prepared by weighing 200mg of 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene powder (test article) in an amber-vial and dissolving it in 5mL DMSO by vortexing at room temperature.
Antimicrobial susceptibility testing to determine the Minimum Inhibitory Concentration (MIC) of the test article was performed by broth assay based on the standard National Committee for Clinical Laboratory Standards (NCCLS) protocol (NCCLS, 2000). The MIC in this assay was defined as the lowest concentration of the test article that inhibited the visible growth of the microorganism under study.
Seven different microorganisms were tested: three (3) gram positive bacteria (Staphylococcus aureus (MO-012-015), Staphylococcus epidermic/is (MO-012-045), and Propionibacterium acnes (ATCC# 6919)), two (2) gram negative bacteria (Escherichia coli (ATCC# 8739) and Pseudomonas aeruginosa (ATCC# 9027)), and two (2) fungal species (Candida albicans (ATCC# 10231) and Aspergillus niger (ATCC# 16404)).
All species, minus the Staphylococcus spp., were obtained from the American Type Culture Collection (ATCC). The two (2) Staphylococcus spp. were obtained as clinical isolates.

The MIC for each of the seven strains was determined for the test article using dilutions made from the original 4% w/v stock of the test article to yield preparations of a 1.00% w/v starting concentration and a 0.25% w/v starting concentration for the assay.
The antimicrobial susceptibility test was performed in a 96-well microtitre plate.
In this assay, two-fold dilutions of the test article starting concentrations were performed sequentially along the first 10 rows of the microtiter plate (rows 11 and 12 served as positive and negative controls for test organism).
A suspension of inoculum was created for each test organism and adjusted to the turbidity of an optical density at 600 nm (0D600). This inoculum was diluted 1:100 and 100u1 was added to each well of the microtiter plate, to yield a final inoculum of ¨1x106 CFU/well.
Plates were covered and incubated at 35 C for bacteria (Propionibacterium acnes incubated under anaerobic conditions), and 25 C for fungi. Microplates were examined 48 hours later and determined for MIC (Propionibacterium acnes plates were incubated for ¨72 hours, and fungal spp. plates were incubated for ¨120 hours). The MIC
was the lowest concentration of antimicrobial agent that yielded no growth by visual reading after incubation.
The Minimal Biocide Concentration (MBC) assay is designed to determine the lowest concentration at which the test article will demonstrate bactericidal or fungicidal properties against a particular microorganism. After the MIC plates were analyzed, a 96 Solid Pin Multi-Blot Replicator was flame sterilized, cooled, and aligned so each pin was dipped into one well of the MIC microtiter plate. The replicator was then used to stamp a fresh agar plate, so that a small aliquot of the volume from the well of the MIC microtiter plate was impregnated in the agar matrix of the MBC plate. Microplates were examined 48 hours later and determined for MBC (Propionibacterium acnes plates were incubated for ¨72 hours, and fungal spp. plates were incubated for ¨120 hours). The minimum biocide concentration (MBC) was defined as the minimum concentration of biocide in which there is no bacterial or fungal growth.
MIC and MBC values were calculated for the test article against each test organism. The results are shown in Table 8.

Table 8 Test S. aureus S. P. acnes E. coil P. C. A.
epidermidis aeruginosa albicans niger MIC 0.0004% 0.0008% 0.0008% 0.031% 0.25% <0.002% 0.50%
MBC 0.0008% 0.0008% 0.0008% >1.0% >1.0% <0.002% >1.0%
Data are presented as MIC or MBC (minimum inhibitory concentration or minimum biocide concentration) in values of (%, w/v), and demonstrates 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene was found to inhibit the growth of gram positive bacteria, gram negative bacteria, and fungal species. The compound also demonstrated biocidal activity against gram positive bacteria and yeast species. These data further suggest that 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene has enhanced activity against gram positive bacteria and yeast compared to gram negative bacteria and mold.
Example 9 A composition according to the invention is prepared by blending the ingredients in Table 9.

Trade Name INCI Name %wt Deionized Water Water 70.64 Sodium Chloride Sodium Chloride 0.01 1-hydroxyl 3,5-bis(4'-hydroxyl 1.00 styryl)benzene Snow White Petrolatum Petrolatum 4.00 ISOFOL 28 Dodecylhexadecanol 2.50 9120 (20 CS) Dimethicone 1.25 KESSCO IPP Isopropyl PaImitate .00 VARISOFT TA-100 Distearyldimonium Chloride 5.00 Glycerin Glycerin 12.00 Benzyl Alcohol Benzyl Alcohol 0.60 Water is added to a process vessel. Mixing is begun and salt is added and mixed until dissolved. Heat is applied and mixing continued until to 85 C is reached. 1-hydroxyl 3,5-bis(4'-hydroxyl styryl)benzene is solublized in glycerin, then added while mixing is continued and the temperature is maintained at 85 C.
Distearyldimonium chloride is added, along with petrolatum and dodecylhexadecanol, dimethicone, and isopropyl palmitate. The composition is mixed at 85 C for another 10-15 minutes. The composition is then removed from heat, mixed and cooled. At 40 C, benzyl alcohol is added, q.s. with water, mixed and cooled to 30-35 C. The composition is then filled into packaging.

A composition according to the invention is prepared by blending the ingredients in Table 10.

Trade Name INCI Name % Wt Deionized Water Water 70.55 Snow White Petrolatum Petrolatum 4.00 ISOFOL 28 Dodecylhexadecanol 2.50 Dow Corning Q7-9120 Dimethicone 1.25 (20 CS) BHT BHT 0.10 Kessco IPP Isopropyl Palmitate 3.00 Varisoft TA-100 Distearyldimonium Chloride 5.00 1-hydroxyl 3,5-bis(4'hydroxyl 1.0 styryl)benzene Glycerin Glycerin 12.00 Retinol 10S Gylcine Sofa (Soybean) Oil and Retinol 1.00 Benzyl Alcohol Benzyl Alcohol 0.60 Water is added to a process vessel and the temperature is set to 85 C. Mixing is begun and glycerin is added and mixed until dissolved. VARISOFT TA-100 is added, along with petrolatum and ISOFOL 28, DOW CORNING Q7-9120 20 CS, and isopropyl palmitate. The composition is mixed at 85 C for another 10-15 minutes. The composition is then removed from heat, mixed and cooled.
A composition according to the invention is prepared by blending the ingredients in Table 11.

Trade Name INCI Name % Wt Deionized Water Water 73 HYDROLITE 5 Pentylene glycol 5 1-hydroxyl 3,5-bis(4'-hydroxyl 5 styryl)benzene NATRULON OSF Carthamus Tinctorius Oleosome 10 FINSOLV TN C12-15 Alkyl Benzoate 4 ARISTOFLEX AVC Ammonium 2 AcryloyldimethyltaurateNP
Copolymer Tanacetum parthenium Chrysanthemum Parthenium 1 (Feverfew) Leaf/Flower/Stem extract Juice 1-hydroxyl 3,5-bis(4'-hydroxyl styryl)benzene is weighed and dissolved in HYDROLITE 5 and deionized water is added to form Phase A. Oleosomes and FINSOLV TN are mixed to form Phase B. Phase B is added to Phase A very slowly under continuous mixing. Mixing is continued for 15 minutes until a uniform emulsion is formed. ARISTOFLEX AVC is added to the emulsion under continuous mixing at high speed to obtain a thick, smooth and homogenous formulation.
A composition according to the invention is prepared by blending the ingredients in Table 12.

Trade Name INCI Name % Wt Deionized Water Water 67.70 Carbomer Cross-linked polyacrylic acid 0.60 VERSENE NA Disodium EDTA 0.20 Brij 72 Steareth-2 0.75 Brij 721 Steareth-21 1.50 FINSOLV TN C12-15 Alkyl Benzoate 2.00 Dimethicone NF Dow corning Q7-9120 Silicone Fluid 5.00 (20 cst) PHENONIP XB Phenoxyethanol, Methylparaben, 1.00 Ethylparaben, Propylparaben LYS'LASTINE Peucedanum graveolens (10% active) 10.00 SYMMATRIX Maltodextrin, Rubus Fruticosus 10.00 (Blackberry) Leaf Extract (10%
active) 1-hydroxyl 3,5-bis(4'- 0.25 hydroxyl styryl)benzene Glycerin Glycerin 1.0 An oil phase is prepared by adding FINSOLV TN to a clean glass beaker.
Agitation is begun and the vessel is heated to 55-60 C. When the oil phase reaches 55 C
or higher, Brij 72 and Brij 721 are added. When the oil phase reaches 55-60 C, it is held at that temperature and mixed for 15 min (or until uniform). The temperature is then held at 55-60 C with mixing until addition to water phase.
A water phase is prepared by adding water to a clean glass beaker. Agitation is begun and the vessel is heated to 55-60 C. Disodium EDTA is added. At 55-60 C, the ingredients are mixed for 15 min or until homogeneous. The temperature is then held at 55-60 C with mixing for phasing.
The oil phase is added to the water phase with increased agitation and then mixed at high speed for 10-20 min. At 50 C or lower, dimethicone is added. At 40 C
or lower, PHENONIP XB is added. The phases are then mixed for 10 min or until uniform.
Sodium hydroxide is added (target pH is 5.4). The composition is then mixed for 10 min or until uniform. LYS'LASTINE and SYMMATRIX are then added. 1-hydroxyl 3,5-bis(4'-hydroxyl styryl)benzene is weighed and dissolved in glycerin and added to the mixture, which is mixed until uniform. Water is then added to QS and the composition is mixed for 10 additional minutes.
It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.

Claims (16)

1. A composition comprising:
1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof; and a cosmetically acceptable topical carrier comprising an ingredient selected from the group consisting of wetting agents, emulsifiers, emollients, humectants, and fragrances.

2. The composition of claim 1, wherein the cosmetically acceptable topical carrier comprises ingredients selected from at least two of the following classes:
wetting agents, emulsifiers, emollients, humectants, and fragrances.

3. The composition of claim 1, wherein the cosmetically acceptable topical carrier comprises an emollient and an emulsifier.

4. The composition of claim 1, wherein the cosmetically acceptable topical carrier comprises ingredients selected from at least three of the following classes:
wetting agents, emulsifiers, emollients, humectants, and fragrances.

5. The composition of claim 1, further comprising an additional NF.KAPPA.B-inhibitor.

6. The composition of claim 1, wherein the composition comprises about 0.01% to about 10% of said 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or salt thereof.

7. The composition of claim 1, further comprising a skin lightening agent.

8. The composition of claim 1 substantially free of preservatives.

9. The composition of claim 8, wherein said preservatives are selected from the group consisting of parabens, benzoic acid and salts thereof, phenoxyethanol, isothaizolones, imidazolidinyl urea, iodo propynyl butyl carbamate, DMDM hydantoin, caprylyl glycol, dehydroacetic acid, sorbic acids and salts thereof, chlorophensin, glyceryl caprylate, phenylpropanol, sodium levulinate, anisic acid, ethylhexylglycerin, benzyl alcohol and combinations thereof.

10. A method for the cosmetic treatment of human skin, comprising topically applying to said human skin a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.

11. A method of the cosmetic treatment of a sign of skin aging, comprising topically applying to skin in need of such treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.

12. The method of claim 11, wherein said sign of skin aging is selected from the group consisting of lines and wrinkles, loss of elasticity, uneven skin, and blotchiness.

13. A method for the cosmetic lightening of skin, comprising the step of topically applying to skin in need of skin lightening treatment a composition comprising 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.

14. The method of claim 10, wherein the composition is applied using an applicator selected from the group consisting of masks and wipes.

15. A method of inhibiting the growth of a microorganism, comprising applying to said microorganism 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or a cosmetically acceptable salt thereof.

16. The method of claim 15, wherein said 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or cosmetically acceptable salt thereof is contained in a composition comprising 0.02%% to 1% by weight 1-hydroxyl 3,5-bis(4'hydroxyl styryl)benzene or cosmetically acceptable salt thereof.