HK1158966B - Compositions comprising an nfkb-inhibitor and a tropoelastin promoter - Google Patents

Description

Comprising NFKComposition of B inhibitor and tropoelastin promoter

Technical Field

The present invention provides compositions comprising NF_KA combination of an inhibitor B and a tropoelastin promoter. The compositions are useful, for example, for topical application to the skin.

Background

Aging of the skin can be understood as being influenced by intrinsic and extrinsic factors. Intrinsic factors include natural changes in the skin, which are regulated by genetic makeup. Extrinsic factors include exogenous influences such as ultraviolet damage, environmental factors, and the like.

Aging of the skin adversely affects the elasticity and strength of the skin through changes in two fibrous proteins, collagen and elastin, which are the main components of the dermal extracellular matrix. For example, elastin is a large fibrous protein formed from the cross-linking of elastin precursor protein molecules (e.g., tropoelastin) into helical fibrils. Collagen, which is more ubiquitous than elastin, is another fibrous protein that can form a network of skin structures.

Certain substances are known for their beneficial effect of inhibiting the degradation of crosslinked elastin. For example, Matrix Metalloproteinases (MMPs), a group of enzymes capable of breaking down macromolecules in the extracellular matrix, are known to play an important role in elastin degradation. Many plant extracts have been described as inhibitors of various MMPs. Lamason describes, for example, the inhibition of elastase (porcine pancreatic elastase) by extracts of plants selected from the rosaceous family, and attributes this inhibition to tannins contained in these extracts. Pharmaceutiques Francaises 1990, 48, 335-. Herrmann et al disclose that the hydroalcoholic extract of blackberry leaves, SymMatrix, has been shown to have MMP-1, MMP-2, and MMP-9 inhibitory activity. SOFW Journal (2006), 132(4), 42-46.

In addition, certain natural or synthetic compounds are known to have the beneficial effect of promoting the production of elastin precursors and/or promoting the formation of collagen. For example, retinoids can upregulate elastin production in fibroblasts. Liu et al, Am J physiol.1993 Nov; 265(5Pt 1): l430-437. Retinoids are also known to promote collagen formation.

In addition, it has been shown that certain substances can positively influence the crosslinking of tropoelastin. For example, lysyl oxidase can act as a crosslinking enzyme and can act as a component of a scaffold to ensure that elastin is deposited in a defined space. Liu et al, Nature Genetics (2004), 36(2), 178-182. Valerie et al disclose dill extracts that induce the expression of genes of Lysyl Oxidase (LOXL), which is responsible for elastin crosslinking in humans. Experimental Dermatology (2006), 15(8), 574-81. In addition, blackcurrant, cardamom, black radish, flower bamboo cypress (box holy), asaea foetida (asaa foetida) glue, ethyl hexenoate, methyl butyrate and ethyl decadienoate are disclosed as promoters of LOXL gene expression. GB2,438,999.

Thus, various pathways and agents have been proposed to positively affect elastin and collagen and their associated skin properties. However, the present inventors have recognized a need for novel agents and combinations of agents that can further positively affect elastin or collagen or both.

The present inventors have now unexpectedly discovered the beneficial effects of a particular class of anti-inflammatory compounds, agents, which inhibit the nuclear transcription factor k-B (NF)_KB) In that respect The inventors have found that despite NF_KB inhibitors may not enhance tropoelastin activity per se, but when NF is present_KWhen B inhibitors are combined with tropoelastin promoters, the resulting combination may exhibit an unexpectedly large, surprising synergistic enhancement in tropoelastin promoting efficacy.More unexpectedly, the inventors have determined that it is previously known to be on NF_KCertain compounds having inhibitory activity (e.g., resorcinol derivatives) are particularly suitable for significantly enhancing the tropoelastin activity of tropoelastin promoters.

Disclosure of Invention

In one aspect, the present invention provides a composition comprising NF_KA combination of an inhibitor B and a tropoelastin promoter.

According to another aspect, the invention provides a method of treating signs of skin aging, the method comprising topically applying to skin in need of such treatment a composition comprising NF_KA combination of an inhibitor B and a tropoelastin promoter.

Other features and advantages of the invention will be apparent from the description of the invention and from the claims.

Detailed Description

It is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following specific examples 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 this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. Unless otherwise indicated, percentages or concentrations refer to weight percentages or weight concentrations (i.e., (W/W)). Unless otherwise indicated, all ranges include endpoints, e.g., "4 to 9" includes endpoints 4 and 9.

The products described herein may optionally be in finished packaging 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 additionally have packaging such as a plastic or cardboard box for storing the container. In one embodiment, the product comprises a composition of the present invention and has instructions directing the user to apply the composition to the skin to treat the signs of skin aging as discussed below. Such instructions may be printed on the container, label insert, or any other packaging.

As used herein, "topical application" means directly applying or spreading on the external skin, scalp or hair, for example, using the hand or an applicator such as a wipe, roller, or sprayer.

As used herein, "cosmetically acceptable" means that the ingredients described by the term are suitable for use in contact with tissue (e.g., skin or hair) without undue toxicity, incompatibility, instability, irritation, allergic response, or the like.

The compositions of the present invention are suitable for treating signs of skin aging. As used herein, "signs of skin aging" include the presence of fine lines and wrinkles, loss of elasticity, uneven skin tone, scarring. In a particularly preferred embodiment, the signs of aging are the presence of fine lines and wrinkles and/or loss of elasticity.

As used herein, "treating signs of skin aging" refers to reducing, preventing, ameliorating, or eliminating the presence or signs of skin aging described above.

As used herein, "wrinkles" include 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, eyebrow lines, and smile lines around the mouth.

As used herein, "loss of elasticity" includes loss of elasticity or structural integrity of skin or tissue, including but not limited to sagging, loose and loose tissue. Loss of elasticity or structural integrity of a tissue can be caused by a variety of factors including, but not limited to, disease, aging, hormonal changes, mechanical trauma, environmental damage, or as a result of the application of a product such as cosmetics or pharmaceuticals to the tissue.

As used herein, "uneven skin tone" refers to a skin condition associated with diffuse or mottled pigmentation that can be classified as hyperpigmentation, such as post-inflammatory hyperpigmentation.

As used herein, "scarring" means a skin condition associated with redness or erythema.

As used herein, "cosmetic" refers to a cosmetic substance or article that maintains, restores, imparts, stimulates or enhances the appearance of a body beauty or that appears to enhance the appearance or youthfulness, particularly as it relates to the appearance of tissue or skin.

As used herein, "cosmetically effective amount" means an amount of a physiologically active compound or composition that is sufficient to treat one or more signs of skin aging, but low enough to avoid serious side effects. The cosmetically effective amount of the compound or composition will vary depending on the following factors: the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated/prevented, the duration of the treatment, the nature of the other treatments, the particular compound or product/composition employed, the particular cosmetically acceptable carrier utilized, and the like.

NF _K B inhibitors

The compositions of the present invention comprise NF_KAnd B, inhibitor. As used herein, "NF_KB inhibitor "means that it can inhibit the cell transcription nuclear factor k-B (NF)_KB) The compound of (1). In one embodiment, NF_KB inhibitors in accordance with the definition of "NF" below_KB inhibition test "has at least about 35%, preferably at least about 55%, more preferably at least about 70%, and most preferably at least about 90% NF when tested at a concentration of preferably 1 microgram per ml to about 100 micrograms per ml_KB percent inhibition. Also hasThat is, the compounds exhibit the listed NF at least one concentration in the range of 1 microgram per ml to 100 milligrams per ml_KB percent inhibition. The compound need not provide the listed NF at all concentrations from 1 mg per ml to 100 mg per ml_KB percent inhibition, but at least one concentration within this range provides the listed NF_KB percent inhibition.

In a preferred embodiment, NF is present when tested at a concentration of 10 milligrams per milliliter_KThe B inhibitor has an NF of at least about 35%, preferably at least about 55%, more preferably at least about 70%, most preferably at least about 90%_KB percent inhibition.

“NF_KThe B inhibition test "was performed in the following manner. FB293 cells, a stably transfected human epithelial cell line containing a reporter gene for NF-kB, were used. They are available, for example, from Panomics (Fremont, CA). FB293 at 5X 10⁴The cells/mL are seeded at a density in a suitable medium, for example Dartbox Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (Invitrogen, San Diego, CA). The FB293 cells were stimulated with 100ng/mL tumor necrosis factor-alpha (TNF α, available from Sigma-Aldrich, St Louis, Mo.) in the presence of the test samples. In addition, a control sample was tested in which no test sample was applied. At 37 deg.C, 5% CO₂After 24 hours of incubation, the cells were lysed with 40. mu.L of reporter lysis buffer (Promega, Madison, Wis.). Aliquots of 20 μ L of the lysate were assayed using the luciferase assay kit (Promega) and counted in an Lmax luminometer (Molecular Devices, Sunnyvale, Calif.) for 10 seconds, with data expressed in relative light units/second. NF of test sample_KPercent B inhibition was calculated as follows:

NF_Kb inhibition ═ 1- (L)_{Sample (I)}/L_Control)]*100

Wherein L is_{Sample (I)}Luminescence of the sample, L_ControlLuminescence for the control.

NF_KThe B inhibitor may be present in the compositions of the present invention in any suitable amount, for example, from about 0.01% to about 100% by weight, preferably from about 0.1% to about 20%, more preferably from about 0.1% to about 5%, even more preferably from about 0.2% to about 2%.

In one embodiment, NF_KThe B inhibitor is selected from the following compounds: substituted resorcinols, (E) -3- (4-methylbenzenesulfonyl) -2-propenenitrile (e.g., "Bay 11-7082," commercially available from Sigma-Aldrich (st. louis, Missouri)), tetrahydrocurcumin (e.g., tetrahydrocurcumin CG, available from sabina Corporation, Piscataway, NJ), and combinations thereof.

In a preferred embodiment, NF_KThe B inhibitor is a substituted resorcinol. Resorcinol is a dihydric phenol compound (i.e., 1, 3 dihydroxybenzene) having the structure:

as used herein, "substituted resorcinol" means resorcinol having at least one substituent in the 2,4, 5 or 6 position. Thus, a substituted resorcinol may have as few as one and as many as four substituents. The positions 1 and 3 of the substituted resorcinols have an-OH hydroxyl group, as shown above.

It is highly preferred that all substituents of the substituted resorcinols are phenyl-free (-C)₆H₅Aromatic) moiety. In certain embodiments, all substituents are free of aromatic moieties (with or without heteroatoms).

In another embodiment, it is preferred that all substituents of the substituted resorcinol be free of ketone functionality (carbonyl groups bonded to two other carbon atoms).

In certain preferred embodiments, all substituents of the substituted resorcinol have neither a phenyl nor a ketone functionality.

In certain preferred embodiments, the substituted resorcinol comprises at least one substituent having from 5 to 11 carbon atoms, preferably from 5 to 10 carbon atoms, more preferably from 5 to 9 carbon atoms, and most preferably from 5 to 8 carbon atoms. In certain other embodiments, at least one substituent comprises an alkyl group, such as an alkyl group having the above-described number of carbon atoms. The alkyl group is preferably unsaturated.

In certain embodiments, the 4 position of resorcinol is substituted, and in certain embodiments, only the 4 position is substituted. In another embodiment, the 4-position is substituted with an alkyl group. In certain preferred embodiments, the substituted resorcinol comprises a single substituent at the 4-position, which substituent comprises an alkyl group. In certain other preferred embodiments, the substituted resorcinol contains a single 4-position substituent consisting of an alkyl group bonded directly to the phenyl ring.

Particularly suitable substituted resorcinols include 4-hexylresorcinol and 4-octylresorcinol, especially 4-hexylresorcinol. 4-hexylresorcinol and 4-octylresorcinol are shown below:

4-hexylresorcinol is commercially available as "SYNOVEA HR" from Sytheon (Lincoln Park, NJ). 4-Octylresorcinol is commercially available from City Chemical LLC (West Haven, Connecticut).

In certain embodiments, the substituted resorcinol has at least two substituents at the 2,4, 5, or 6 positions. Such substituents may optionally be linked to form a ring, for example a cyclic aliphatic hydrocarbon optionally containing heteroatoms such as sulphur or oxygen. For example, the attached substituent may contain 5 to 10 carbon atoms, such as 8 to 10 carbon atoms, and optionally include 1 to 3 heteroatoms. Examples of suitable substituted resorcinols having a cyclic aliphatic substituent linking the 2 and 3 positions include zearalenone and β -zearalanol:

zearalenone and β -zearalanol are commercially available from Sigma Chemicals (st. louis, Missouri).

In certain other embodiments, the substituted resorcinol has halogen-containing and/or nitroso-containing substituents. Suitable examples contain-Cl or-N ═ O bonded directly to the phenyl ring. These substituents may be present, for example, in the 2 and 4 positions, 2 and 6 positions or 4 and 6 positions. An example of a dihalo-substituted resorcinol is 2, 6-dichlororesorcinol. An example of a dinitroso-substituted resorcinol is a2, 4-dinitroso resorcinol:

2, 6-dichlororesorcinol and 2, 4-dinitrosorcinol are available from City Chemical LLC (West Haven, Connecticut).

Substituted resorcinols can be prepared by methods known in the art, for example, using the techniques described in U.S. patent No.4,337,370, the contents of which are incorporated herein by reference.

The substituted resorcinol can have any suitable molecular weight. In certain embodiments, the molecular weight of the substituted resorcinol ranges between about 175 to about 300.

The substituted resorcinol is present in the composition in a safe and effective amount, for example, in an amount of 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.

Tropoelastin promoter

As used herein, "tropoelastin promoter" refers to a class of compounds that have biological activity that enhances the production of tropoelastin. According to the present invention, tropoelastin promoters include all natural or synthetic compounds capable of enhancing the production of tropoelastin in the human body.

Suitable tropoelastin promoters may be determined, for example, using the "tropoelastin promoter assay" below. The "tropoelastin promoter assay" is performed as follows: rat cardiac myoblast H9C2 (which is commercially available, for example, from ATCC (Manassas, VA)) was used. Cultures were maintained in dartbox modified eagle medium (DMEM, Invitrogen Life Technologies, Carlsbad, Calif) supplemented with 10% fetal bovine serum, 2mM glutamine, 100 units/mL penicillin, and 50ug/mL streptomycin (Invitrogen Life Technologies, Carlsbad, CA). Cell cultures were transiently transfected with an elastin promoter-luciferase reporter construct (elp2.2, a 2.2kb elastin promoter fragment from nt-2267 to nt +2, driving the firefly luciferase gene, available from Promega (Madison Wis)). DNA was prepared by Qiagen Maxi columns (Qiagen Valencia, CA). In all transfections, a construct (pRL-TK, Promega, Madison Wis.) with a thymidine kinase promoter and a Renilla luciferase reporter gene was included as an internal control. Typically, cells cultured in 48-well plates were transfected with 0.45ug total DNA/well using Lipofectamine 2000(Invitrogen Life Technologies, Carlsbad, CA). One day after transfection, cells were treated with reagents at the indicated concentrations for approximately 24 hours and then lysed for luciferase assays using a dual luciferase reporter system purchased from Promega (Madison, Wis.) according to the manufacturer's protocol. Firefly luciferase activity (representing elastin promoter activity) was first measured and then renilla luciferase activity (internal control) was measured using luminometer LMAX purchased from Molecular Devices (Sunnyvale, CA). The ratio of these two luciferase activities (RLU) was used to evaluate "tropoelastin promoter activity".

The tropoelastin promoter preferably has a tropoelastin promoter activity of at least 1.1, preferably at least 1.25, more preferably at least 1.3 and most preferably at least 1.5 at least one concentration in the range of 0.5 microgram/ml to 2.5 mg/ml (calculated as active substance) and preferably at least one concentration in the range of 1.0 microgram/ml to 2.5 mg/ml (calculated as active substance).

Although it is envisaged that NF_KThe B inhibitor and the tropoelastin promoter may be one and the same compound, molecule or functional group, but in preferred embodiments, the NF is_KThe B inhibitor and the tropoelastin promoter are two separate unique compounds.

Suitable tropoelastin promoters include, but are not limited to, blackberry extracts, cotinus coggygria extracts, feverfew extracts, extracts of Phyllanthus niruri and bimetallic complexes having a copper and/or zinc component. The bimetallic complex having a copper and/or zinc component can be, for example, copper-zinc citrate, copper-zinc oxalate, copper-zinc tartrate, copper-zinc malate, copper-zinc succinate, copper-zinc malonate, copper-zinc maleate, copper-zinc aspartate, copper-zinc glutamate, copper-zinc glutarate, copper-zinc fumarate, copper-zinc glucarate, copper-zinc polyacrylate, copper-zinc adipate, copper-zinc pimelate, copper-zinc suberate, copper-zinc azelate, copper-zinc sebacate, copper-zinc dodecanoate, or a combination thereof. In a preferred embodiment, the tropoelastin promoter is selected from the group consisting of blackberry extract, cotinus coggygria extract, feverfew extract and combinations thereof. In a particularly preferred embodiment, the tropoelastin promoter is selected from the group consisting of blackberry extracts, feverfew extracts, and combinations thereof.

By "Cotinus coggygria extract" it is meant an extract of the leaves of Cotinus coggygria, e.g. an aqueous extract thereof, obtainable from bilkoop (Sofia, Bulgaria).

By "FEVERFEW extract" it is meant an extract of the plant "FEVERFEW (TANACETUM)" which may be prepared, FOR example, according to the details set forth in U.S. patent application publication No.2007/0196523 entitled "PARTHENOLIDE FREE bio-active ingredient FROM FEVERFEW (TANACETUM PARTHENIUM) AND process FOR the PRODUCTION of THEIR process" (a method FOR preparing the same). A particularly suitable feverfew extract is commercially available as about 20% active feverfew from Integrated cosmetic Technologies (Ossinging, NY).

By "blackberry extract" it is meant a blend of compounds isolated from a plant of the genus Rubus (Rubus), preferably blackberry (Rubus fructicosus). In one embodiment, the compound is isolated from a flower of the plant. In another embodiment, the extract is isolated from dried flowers of the plant. Such compounds may be isolated from one or more parts of a plant (e.g., the whole plant, flower, seed, root, rhizome, stem, fruit, and/or leaf of the plant). In a preferred embodiment, the blackberry extract is a blackberry leaf extract.

The extraction process may include physically removing a piece of such plant and, for example, grinding it. Further extraction of suitable compounds may also be accomplished by extraction methods well known in the art (e.g., using organic solvents such as lower C)₁-C₈Alcohol, C₁-C₈Alkyl polyol, C₁-C₈Alkyl ketones, C₁-C₈Alkyl ethers, acetic acid C₁-C₈Alkyl esters and chloroform, and/or inorganic solvents such as water, inorganic acids such as hydrochloric acid, and inorganic bases such as sodium hydroxide).

For example, the blackberry leaf extract can be prepared by extraction with water, an alcohol such as ethanol, or a combination thereof. However, it is preferred to prepare the extract with a solvent comprising both ethanol and water.

The blackberry leaves are preferably dried prior to extraction. It is also preferred that only the leaves of the blackberry plant are used for extraction, and that other plant parts of the blackberry, such as the fruit (berry) or its branches and roots, are not also used.

In one embodiment, the extraction process for preparing the blackberry leaf extract comprises the steps of: a) adding a solvent comprising a solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol to the blackberry leaves, b) extracting the blackberry leaves with the solvent for up to 72 hours.

A detailed process for preparing blackberry leaf extracts is disclosed in U.S. patent application publication No.2008/0095719, the disclosure of which is incorporated herein in its entirety.

One particularly suitable blackberry extract is prepared by extracting blackberry leaves with a mixture of water and ethanol, compounding with a maltodextrin matrix at an activity of about 5% to about 10%, commercially available from Symrise Inc (terboro, NJ) and sold under the name "SymMatrix".

The extract of "Phyllanthus niruri" can be collected and used as a whole plant, or optionally one or more parts of the plant (such as flowers, seeds, roots, rhizomes, stems, fruits and/or leaves of the plant). The phyllanthus niruri plant or parts thereof can be finely divided (e.g., by grinding or milling) into a powder. Suitable milled forms of phyllanthus niruri are commercially available from Raintree Nutrition, Inc (Carson City, Nevada). Preferably, a low molecular weight fraction of Phyllanthus niruri is used, for example a fraction of Phyllanthus niruri which is substantially free of molecular species having a molecular weight greater than about 100,000 daltons. Preferably, such low molecular weight fraction is extractable from the phyllanthus niruri plant.

The compositions of the present invention may comprise a cosmetically effective amount of one or more tropoelastin promoters, such as the tropoelastin promoters described above. The composition preferably comprises from about 0.1% to about 10% of the tropoelastin promoter, more preferably from about 0.5% to about 5% of the tropoelastin promoter, and most preferably from about 0.5% to about 2% of the tropoelastin promoter, on an active basis.

NF in the composition_KB inhibitor concentration and elastinThe ratio of the concentration of the pro-promoter may vary depending on the desired efficacy of the composition in enhancing tropoelastin formation and for other reasons (e.g., composition stability, aesthetics, etc.). For example, NF_KThe B inhibitor and the tropoelastin promoter may be in a weight concentration ratio (weight concentration percent by weight with NF) of about 0.001 to about 100, preferably about 0.01 to about 10, more preferably about 0.02 to about 2_KThe weight concentration of B inhibitor divided by the weight concentration of tropoelastin promoter).

Topical compositions

The compositions of the present invention may be topically applied to human skin and/or hair. Except NF_KB inhibitor and tropoelastin promoter, the composition may further comprise a cosmetically acceptable topical carrier, which 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 present invention, the cosmetically acceptable topical carrier comprises water. The cosmetically acceptable topical carrier may include one or more materials selected from the group consisting of humectants, emollients, oils, humectants, and the like. In one embodiment, the cosmetically acceptable topical carrier comprises a substrate such as a nonwoven fabric or film material.

The compositions may be prepared in a variety of product types including, but not limited to, lotions, creams, gels, sticks, sprays, ointments, cleansing liquid lotions and solid soaps, shampoos and hair conditioners, hair fixatives, pastes, foams, powders, mousses, shaving creams, wipes, patches, hydrogels, film-forming products, facial masks and skin films, and cosmetics 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 (e.g., microemulsions and nanoemulsions), gels, solids, and liposomes.

The compositions useful in the present invention may be formulated as solutions. Solutions typically comprise 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 propylene glycol, polyethylene glycol, polypropylene glycol, glycerol, 1, 2, 4-butanetriol, sorbitol esters, 1, 2, 6-hexanetriol, ethanol, and mixtures thereof.

The compositions useful in the subject invention may be formulated as a solution comprising an emollient. Such compositions preferably comprise from about 2% to about 50% of one or more emollients. As used herein, "emollient" refers to a substance used to prevent or reduce dryness, for example, by preventing the loss of skin moisture through the skin. Examples of emollients include, but are not limited to, vegetable oils, mineral oils, aliphatic esters, and the like.

Lotions may be prepared from such solutions. Lotions typically contain from about 1% to about 20% (e.g., from about 5% to about 10%) of one or more emollients and from about 50% to about 90% (e.g., from about 60% to about 80%) moisture.

Another type of product that can 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 one or more emollients and from about 45% to about 85% (e.g., from about 50% to about 75%) moisture.

Although it is preferred that the compositions of the present invention comprise water, the compositions may alternatively be anhydrous or an ointment which does not comprise water but is an organic and/or silicone solvent, grease, lipid and wax. Salves may contain a simple base of animal or vegetable oils or semi-solid hydrocarbons. The salve may contain from about 2% to about 10% of one or more emollients and from about 0.1% to about 2% of one or more thickeners.

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 one or more emulsifiers. The emulsifier may be nonionic, anionic or cationic. Examples of suitable emulsifiers include those generally identified as suitable emulsifiers in the personal care and cosmetic formulation arts.

Lotions and creams may be formulated as emulsions. Typically such lotions contain from 0.5% to about 5% of one or more emulsifiers. Such creams typically contain from about 1% to about 20% (such as from about 5% to about 10%) of one or more emollients; from about 20% to about 80% (e.g., from 30% to about 70%) water; and from about 1% to about 10% (such as from about 2% to about 5%) of one or more emulsifiers.

Oil-in-water and water-in-oil single emulsion skin care formulations, such as lotions and creams, are well known in the cosmetic arts and may be used in the subject invention. Multiple emulsion compositions (e.g., water-in-oil-in-water and oil-in-water-in-oil) can also be used in the subject invention. Typically, such single or multiple phase emulsions contain water, emollients, and emulsifiers as their essential ingredients.

The compositions of the present invention may also be formulated as gels (e.g., aqueous, alcoholic/aqueous, or oily gels using suitable gelling agents). Suitable gelling agents for aqueous and/or alcoholic gels include, but are not limited to, natural gums, acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose). Suitable gelling agents for oils (e.g., mineral oils) include, but are not limited to, hydrogenated butylene/ethylene/styrene copolymers and hydrogenated ethylene/propylene/styrene copolymers. Such gels typically contain between about 0.1% and 5% by weight of such gelling agents.

The compositions of the present invention may also be formulated as solid formulations (e.g., wax-based sticks, bar compositions, powders, or wipes containing powders).

In addition to the above components, the compositions useful in the subject invention may contain a variety of other oil-soluble and/or water-soluble materials conventionally used in compositions for use on skin and hair at levels determined in the art.

Additional cosmetic active agents

In one embodiment, the composition further comprises an additional cosmetically active agent. As used herein, a "cosmetically active agent" is a compound (such as a synthetic compound or a compound isolated from a natural source or natural extract) that has a cosmetic or therapeutic effect on the skin or hair, including, but not limited to, anti-acne agents, oil control agents, antimicrobial agents, anti-inflammatory agents, antifungal agents, anti-parasitic agents, external analgesics, sunscreen agents, photoprotective agents, antioxidants, keratolytic agents, surfactants, warming agents, nutritional agents, vitamins, energy enhancers, antiperspirant agents, astringents, deodorants, firming agents, anti-keratolytic agents, and agents for conditioning the hair and/or skin.

In one embodiment, the agent is selected from, but not limited to, hydroxy acids, benzoyl peroxide, D-panthenol, octyl methoxycinnamate, titanium dioxide, octyl salicylate, homosalate, avobenzone, carotenoids, radical scavengers, spin traps, amines (such as neutrol), retinoids such as retinol and retinyl palmitate, ceramides, polyunsaturated fatty acids, essential fatty acids, enzymes, enzyme inhibitors, minerals, hormones such as estrogens, steroids such as hydrocortisone, 2-dimethylaminoethanol, copper salts such as copper chloride, copper salts such as Cu: copper-containing peptides such as Gly-His-Lys, coenzyme Q10, peptides, amino acids such as proline, vitamins, lactobionic acid, acetyl-coenzyme A, niacin, riboflavin, thiamine, ribose, electron transport substances such as NADH and FADH2, and other plant extracts such as aloe, feverfew, oatmeal, and derivatives and mixtures thereof. The cosmetically active agent will generally be present in the composition in an amount of from about 0.001% to about 20%, for example from about 0.005% to about 10%, such as from about 0.01% to about 5%, by weight of the composition of the present invention.

Examples of vitamins include, but are not limited to, vitamin a, vitamin B (e.g., vitamin B3, vitamin B5, and vitamin B12), vitamin C, different forms of vitamin K and vitamin E (e.g., alpha, beta, gamma, or delta tocopherols), or mixtures and derivatives thereof.

Examples of hydroxy acids include, but are not limited to, glycolic acid, lactic acid, malic acid, salicylic acid, citric acid, and tartaric acid.

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), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin, and ascorbic acid derivatives (e.g., ascorbyl palmitate and ascorbyl polypeptide). Oil-soluble antioxidants suitable for use in the compositions of the present invention include, but are not limited to, butylated hydroxytoluene, retinoids (e.g., retinol and retinyl palmitate), tocopherols (e.g., tocopheryl ethyl ester), tocotrienols, and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of the present invention include, but are not limited to: extracts containing flavonoids and isoflavones and their derivatives (e.g., genistein and bigeminy zein), extracts containing resveratrol, etc. Examples of such natural extracts include grape seed, green tea, pine bark and propolis.

Other materials

Various other materials may also be present in the present compositions, as is known in the art. These include humectants, pH adjusters, chelating agents (e.g., EDTA), fragrances, and preservatives (e.g., parabens). Examples of such agents are listed on pages 2922-23, 2926-28 and 2892 of the ICI handbook.

Water or alcohol soluble dyes may also be suitable for use in the compositions of the present invention. Examples of dyes suitable for use in the compositions of the present invention include caramel, carmine, fluorescein derivatives, methoxypsoralen, trimethacelactone, azo dyes, anthraquinone dyes, blue azulene, guaiazulene, 1, 4-dimethyl azulene (chamazulene), erythrosine, rose bengal, phloxine, cyanosine, dapphin, eosin G, cosin 10B, acid red 51, red dye 4, red dye 40, blue dye 1 and yellow dye 5, or mixtures thereof.

When used, the amount of dye in the composition can vary from about 0.0001 to about 0.1, preferably from about 0.0025 to about 0.025, weight percent, based on the total weight of the composition.

Compositions and formulations and products containing such compositions of the invention may be prepared by methods well known to those skilled in the art.

Application method

The compositions of the present invention may be topically applied to mammalian skin in need of treatment for one or more signs of skin aging as described above. In one embodiment, the composition may be applied to skin in need of treatment for fine lines and wrinkles and/or loss of elasticity. The composition may be applied to skin in need of such treatment according to a suitable treatment regimen, such as monthly, weekly, every other day, daily, twice daily, and the like.

In certain embodiments, the compositions of the present invention may also be used to treat other needs associated with the skin. For example, the compositions of the present invention may be used to treat post-inflammatory hyperpigmentation, to reduce pore size, to reduce sebum production, and to mitigate scarring. In certain other embodiments, the compositions of the present invention may be administered simultaneously with or within hours of a mechanical or physical exfoliation treatment (e.g., microdermabrasion treatment), or with a chemical exfoliant or keratolytic agent such as salicylic acid. In certain other embodiments, the compositions of the present invention can be administered to a mucosal membrane or other tissue, such as vaginal tissue, oral tissue, or ocular tissue. In certain other embodiments, the compositions of the present invention may be applied to mild wounds or post-operative sites to promote healing, to insect bites, to poison ivy skin disorders or similar skin conditions, or generally to reduce itching.

NF according to the invention_KThe combination of B inhibitor and tropoelastin promoter being compared to NF alone_KB inhibitors or tropoelastin promoters alone may provide tropoelastin promotersWith increased, preferably synergistic, promotion. For example, the combination may provide an increase in tropoelastin promotion of at least about 30-40%, preferably at least about 40-50%, more preferably greater than about 50% as compared to the tropoelastin promotion provided by the tropoelastin promoters alone, as measured by the "tropoelastin promoter assay".

It is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following specific examples 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

The following test samples were subjected to the above-mentioned "NF_KB inhibition test ": bay 11-7082 test samples (Sigma-Aldrich, St. Louis, MO), tetrahydrocurcumin CG (Sabinsa Corporation, Piscataway, NJ), and various concentrations of 4-hexylresorcinol. The results are shown in table 1, where NF-kB reporter activation (luminescence, L) was recorded for the test and control samples. Percent NF-kB inhibition was also recorded.

TABLE 1

Bay 11-7082 and tetrahydrocurcumin CG showed strong NF-kB inhibition. Unexpectedly, 4-hexylresorcinol also resulted in a significant reduction in NF-kB activation. More unexpectedly, 4-hexylresorcinol showed significant NF-kB inhibition even at low concentrations.

Example 2

The above "NF" was performed on a series of substituted resorcinols each at a concentration of 10ug/mL_KB inhibition test ". As a result, areShown in table 2.

TABLE 2

As can be seen from the data in Table 2, substituted resorcinols containing only no phenyl functionality, substituted resorcinols containing only no ketone functionality, and substituted resorcinols containing substituents having from 5 to 11 carbon atoms provided better NF_KB, inhibiting.

Example 3

The following compounds were subjected to the "tropoelastin promoter assay": feverfew (a parthenolide-free feverfew extract from Integrated cosmetic Technologies (ossingn, NY)), blackberry (SymMatrix, from Symrise), various preparations of phyllanthus urinaria (raintre, inc., Carson City, Nevada) (subsequently extracted with water and fractionated to include only substances with a molecular weight of less than 100,000 daltons) and 4-hexyl resorcinol (Synovea HR, sythenontd).

These compounds were diluted in cell culture medium (DMEM medium of Invitrogen (San Diego, CA)) to the "active" concentrations indicated in table 3 below. These compounds were added to transfected H9C2 cells and incubated for 24 hours. The test samples were compared to DMSO vehicle.

The results are shown in table 3.

TABLE 3

P < 0.05 compared to compounds/extracts alone using paired t-test

From the results shown in Table 3, it can be seen that 4-hexylresorcinol and feverfew exhibit a percentage change in the tropoelastin promoting effect of-12% and 13.3%, respectively, compared to the vehicle control. In contrast, the combination of both 4-hexylresorcinol and feverfew showed an 84% increase in tropoelastin promotion compared to vehicle control. This performed much better than the effect of only one additive.

Similar synergistic enhancement was observed when the concentration of feverfew was increased from 1ug/mL to 5 ug/mL. The higher concentration of feverfew showed a change in the percentage of tropoelastin promotion to 59.3% compared to vehicle control, whereas the combination of 4-hexylresorcinol and feverfew achieved a change in the percentage of tropoelastin promotion to 115.8% compared to vehicle control.

Similarly, 4-hexylresorcinol and Phyllanthus niruri showed a percentage change in the tropoelastin promoting effect of-12% and 18.9%, respectively, compared to vehicle control. The synergistic enhancement percentage of the tropoelastin promotion achieved by the combination of 4-hexylresorcinol and feverfew changed to 67.8% compared to vehicle control.

Compared to the vehicle control, 4-hexylresorcinol and blackberry showed a percentage change in the tropoelastin promotion of-12% and 30.4%, respectively, while the combination of 4-hexylresorcinol and blackberry achieved a percentage change in the tropoelastin promotion of 77.3%. This is much higher than would be expected from the effect of only one additive.

An additional "tropoelastin promoter assay" demonstrated the synergistic effect of another NF-kB inhibitor tetrahydrocurcumin CG in combination with feverfew. The results are shown in table 4 below.

TABLE 4

P < 0.05 compared to compounds/extracts alone using paired t-test

The percentages of the elastin promotion effect achieved by the combination of tetrahydrocurcumin CG and feverfew were changed to-28% and 11.4%, respectively, compared to the vehicle control, whereas the percentage of the elastin promotion effect achieved by the combination of tetrahydrocurcumin CG and feverfew was changed to 41.4%, compared to the vehicle control.

These data demonstrate that the combination of an NF-kB inhibitor and a tropoelastin promoter can produce an incredible synergistic increase in tropoelastin promoting activity.

Example 4

Compositions according to the invention using the ingredients shown in table 5 below were prepared.

TABLE 5

INCI name	Trade name	Percentage of
			Deionized water	Purified water	77％
Pentanediol	HYDROLITE 5	5％
			Hexyl resorcinol	SYNOVEA HR	1％
Oleosome	NATRULON OSF oleosomes	10％
			Benzoic acid C12-15 alkyl ester	Finsolv TN	4％
Acryloyldimethyl ammonium taurate/VP copolymer	ARISTOFLEX AVC	2％
			Leaf/flower/stem juice of feverfew	Feverfew extract	1％

FINSOLV TN is available from Finetex, Inc. (Elmwood Park, NJ)

HYDROLITE 5 is available from Symrise (Teterboro, NJ)

SYNOVEA HR is available from Sytheon (Lincoln Park, NJ)

ARISTOFLEX AVC available from Clariant (Frankfurt, Germany)

NATRULON OSF oleosomes from Lonza (Allcndale, NJ)

The composition was prepared by the following method. Synove HR was weighed and dissolved in HYDROLITE 5, and deionized water was added to form phase A. Oleosomes were mixed with Finsolv TN to form phase B. Phase B was added very slowly to phase a with continued mixing. Mixing was continued for 15 minutes until a homogeneous emulsion was formed. ARISTOFLEX was added rapidly to the above emulsion with constant mixing to obtain a thick, smooth and homogeneous formulation.

It should be understood that while the invention has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the following claims. Other aspects, advantages, and modifications are within the scope of the claims.

Claims (18)

1. A composition, comprising:

NF_Kb inhibitors, said NF_KThe B inhibitor is selected from substituted resorcinols, (E) -3- (4-methylbenzenesulfonyl) -2-acrylonitriles, tetrahydrocurcumin, and combinations thereof; and

a tropoelastin promoter selected from the group consisting of blackberry extract, cotinus coggygria extract, feverfew extract, extracts of Phyllanthus niruri (Phyllanthus niruri) and combinations thereof.

2. The composition of claim 1, wherein the substituted resorcinol comprises only substituents without phenyl functionality.

3. The composition of claim 1, wherein the substituted resorcinol comprises only substituents free of ketone functional groups.

4. The composition of claim 1, wherein the substituted resorcinol comprises at least one substituent having from 5 to 11 carbon atoms.

5. The composition of claim 1, wherein the substituted resorcinol comprises a single substituent having from 5 to 11 carbon atoms.

6. The composition of claim 1, wherein the substituted resorcinol is selected from the group consisting of 4-hexyl resorcinol and 4-octyl resorcinol.

7. The composition of claim 1, wherein the substituted resorcinol is 4-hexyl resorcinol.

8. The composition of claim 1, wherein the NF is_KThe B inhibitor and the tropoelastin promoter are present in a concentration ratio of 0.001 to 100 by weight.

9. The composition of claim 1, further comprising a cosmetically acceptable topical carrier.

10. A method of treating signs of skin aging, said method comprising topically applying to skin in need of such treatment a composition comprising NF_KA combination of a B inhibitor and a tropoelastin promoter, wherein the NF_KB inhibitor is selected fromSubstituted resorcinol, (E) -3- (4-methylbenzenesulfonyl) -2-acrylonitrile, tetrahydrocurcumin, and combinations thereof, wherein said tropoelastin promoter is selected from the group consisting of blackberry extracts, cotinus coggygria extracts, feverfew extracts, extracts of phyllanthus niruri, and combinations thereof, and said method is for non-therapeutic purposes.

11. The method of claim 10, wherein the substituted resorcinol comprises only substituents without phenyl functionality.

12. The method of claim 10, wherein the substituted resorcinol comprises only substituents without ketone functional groups.

13. The method of claim 10, wherein the substituted resorcinol comprises at least one substituent having from 5 to 11 carbon atoms.

14. The method of claim 10, wherein the substituted resorcinol comprises a single substituent having from 5 to 11 carbon atoms.

15. The method of claim 10, wherein the substituted resorcinol is selected from the group consisting of 4-hexyl resorcinol and 4-octyl resorcinol.

16. The method of claim 10, wherein the substituted resorcinol is 4-hexyl resorcinol.

17. The method of claim 10, wherein the NF_KThe B inhibitor and the tropoelastin promoter are present in a concentration ratio of 0.001 to 100 by weight.

18. The method of claim 10, wherein the composition further comprises a cosmetically acceptable topical carrier.