HK1184158A - Paxillin stimulating compositions and cosmetic uses thereof - Google Patents

Description

Paxillin stimulating compositions and cosmetic uses thereof

Technical Field

The present invention relates generally to compositions for topical application to the skin comprising at least one paxillin stimulator, and the use of such compositions to provide benefits to the skin, in particular to provide anti-aging benefits to human skin.

Background

Consumers are constantly seeking to improve the appearance of their skin and in particular to reduce the visible signs of skin aging. Undesirable signs include lines and wrinkles, sagging or atrophy of the skin, and loss of suppleness, and there is also a need for products that address such signs of anti-aging, and more generally provide anti-aging and/or anti-wrinkle effects.

Recent studies have revealed that skin fibroblasts undergo morphological changes and cell body collapse in long-term and photoaged skin. See, e.g., Varani et al, 2004.j. invest.dermatol.122: 1471-9; and Varani et al, 2006, am.j.pathol.168: 1861-8. Such changes can result in a rough, matte and wrinkled appearance, which is characteristic of aging skin. Further studies suggest that collagen degradation along with altered integrins and focal adhesion molecules is a factor contributing to the loss of functional skin collagen matrix, with the consequence of cell body collapse due to loss of mechanical tension between fibroblasts and the matrix. See, e.g., Fisher et al, 2008.Arch dermaltol.144: 666-72.

Paxillin is an important adaptor protein mediating transmembrane integrin and growth factor signaling. It transduces information from the extracellular matrix, recruits other focal adhesion molecules to form complexes, and activates intracellular cytoskeletal assembly. Brown et al, 2004.Physiol rev.84: 1315-39. This process is important for cell adhesion and migration as well as muscle contraction. Paxillin-mediated signaling also affects long-term changes in gene expression, cell proliferation, and extracellular matrix organization, which are important for wound repair and tissue regeneration.

Paxillin exists as 3 isoforms in higher eukaryotes. Paxillin α is the major, ubiquitously expressed isoform, expressed in most adult tissues except brain; paxillin β and γ isoforms are expressed locally. The fourth isoform, paxillin δ, is found primarily in epithelial cells. Paxillin proteins consist of multiple protein binding motifs, corresponding to multiple protein-protein interactions and protein recognition sites, with many phosphorylation sites dispersed throughout the molecule. Paxillin binding partners range from structural actin-binding proteins such as neunin to signaling molecules such as Focal Adhesion Kinase (FAK) and integrin-linked kinase (ILK). Paxillin is phosphorylated at multiple tyrosine, serine and threonine sites in response to, for example, cell adhesion and/or various soluble growth factors and cytokines, and is thought to be at the cross-junctions of cell adhesion and growth factor regulation (crossroads) under normal conditions.

After exposure to oxidative stress, abnormalities in paxillin phosphorylation and cytoskeletal organization have been observed in cultured cells. Hao et al, 2006, Free radial Biol Med.41: 302-10; and Zhou et al, 1999J Cell Physiol.180: 182-9. In addition, altered levels and altered localization of various focal adhesion proteins have been observed in senescent cells in vitro. Nishio et al, 2005.Histochem cell diol.123: 263-73. However, there was no direct correlation involved between paxillin expression and visible signs of aging in human skin.

It is therefore an object of the present invention to provide a new method for combating the signs of skin aging by a paxillin-mediated pathway. It is a further object of the present invention to provide novel compositions and methods therefor. It is still a further object of the present invention to improve the overall appearance of skin, including treating, reversing and/or preventing signs of aging, using cosmetic compositions comprising an effective amount of one or more compounds that affect pilin production.

The foregoing discussion is presented merely to provide a better understanding of the nature of the problems faced in the art and should not be construed in any way as an admission as to prior art, nor should the citation of any reference herein be construed as an admission that such reference constitutes "prior art" to the present application.

Summary of The Invention

In accordance with the foregoing objects and others, it has surprisingly been found that disruption of normal paxillin production in human skin fibroblasts directly results in a change in cell shape, indicating a necessary role for paxillin in maintaining optimal cell morphology and optimal cell health. It has further surprisingly been found that paxillin levels in human skin cells can be stimulated by topical application of a composition comprising one or more paxillin stimulators, indicating a new way to combat the signs of skin aging.

In one aspect of the present invention, a cosmetic composition for improving the cosmetic appearance of skin is provided comprising an effective amount of at least one paxillin stimulator in a cosmetically acceptable vehicle. Paxillin stimulators may be selected from pyridone fused azabicyclic compounds having a structure of formula IV or V; a double-petal jasmine (Jasminum sambac) extract; red melon (coccaniagrandis) extract; an extract of snakehead gut (Eliptica prostrata Linn.); extract of Clitoria terna tea Linn; ozothamnus obcordiatus extract; erythrina indica (Erythrina indica) extract; loncho capasssa extract; sophora tomentosa (Sophora tomentosa) extract; extract of Trifoliumhybrid (Trifoliumhybridum); an extract of Aisha Michelle (Eremophila mitchelli); kunzea ambigua extract; tanshinone IIA; tetrandrine; carvacrol; cis-6-nonenol; retinol puniciate (retingl puniciate); retinol oleate; equol; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli (Zanthoxylum nitidum) extract; an extract of Ophiopogon Thunb.P.E.; radix Platycodi (Radix platycodonis) extract; terminalia catappa (Terminalia belerica) extract; an extract of Cocculus glaucescens; solid extract of Stephania japonica (Stephania); and rosemary extract. In certain embodiments, the cosmetic composition comprises one or more paxillin stimulators, and in other embodiments, the cosmetic composition comprises 2 or more paxillin stimulators.

In certain embodiments, the cosmetic composition comprises cis-6-nonenol as a paxillin stimulator in an amount effective to improve the cosmetic appearance of skin (e.g., to impart an anti-aging benefit to skin). In another embodiment, the cosmetic composition comprises cis-6-nonenol, as a first paxillin stimulator, and at least one other paxillin stimulator, cis-6-nonenol, and the other paxillin stimulators, present in the composition in an aggregate amount effective to impart an anti-aging benefit to the skin.

In certain embodiments, one or more substances of the group are excluded from the cosmetic composition. For example, in certain embodiments, the composition does not include a hybrid clover extract and/or does not include retinol oleate and/or does not include equol.

In certain embodiments, the cosmetic composition further comprises at least one other skin active selected from the group consisting of botanicals, keratolytic agents, desquamation agents (desquamation agents), keratinocyte proliferation enhancers, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, salicylic acid or salicylates, thiodipropionic acid or esters thereof, advanced glycation end-product (AGE) inhibitors, and alpha-hydroxy acids. In certain embodiments, the cosmetic composition further comprises a collagen stimulant, such as TDPA.

In another aspect, the present invention relates to a method comprising topically applying a cosmetic composition to skin, the cosmetic composition comprising one or more paxillin stimulators. The cosmetic composition will comprise an effective amount of at least one paxillin stimulator to provide an anti-aging benefit to human skin, for example to treat, reverse and/or prevent signs of skin aging. Anti-aging benefits include, but are not limited to, the following:

(a) treatment, reduction and/or prevention of fine lines or wrinkles,

(b) the reduction of the pore size of the skin pores,

(c) improvement in skin thickness, plumpness and/or tautness;

(d) improvement in skin softness and/or softness;

(e) improvement in skin tone, radiance and/or clarity;

(f) improvement in procollagen and/or collagen production;

(g) improvement in skin texture and/or promotion of re-texturing;

(h) improvement in skin barrier repair and/or function;

(i) treatment and/or prevention of skin sagging or atrophy; and/or

(j) Improvement in skin contour appearance;

(k) restoration of skin radiance and/or brightness;

(l) Supplementation of essential nutrients and/or constituents in the skin;

(m) improvement in skin appearance reduced by menopause;

(n) improvement in skin moisturization and/or hydration; and

(o) improvement in skin elasticity and/or resiliency.

Also provided are methods for imparting an anti-aging benefit to human skin comprising topically applying to skin in need thereof a composition comprising at least one paxillin stimulator in an amount effective to increase paxillin levels in skin fibroblasts, e.g., by upregulating paxillin expression. Skin in need thereof may be photoaged and/or damaged by UV radiation.

In another aspect of the present invention, there is provided a method of treating, reversing, ameliorating and/or preventing fine lines or wrinkles or sagging in human skin comprising topically applying to skin in need thereof, comprising directly applying to the wrinkles or fine lines a composition comprising at least one paxillin stimulator in an amount effective to increase paxillin levels in skin fibroblasts.

In another aspect, the invention relates to methods and compositions for determining whether a candidate material is a paxillin stimulator. The screening method may comprise contacting human skin cells with a candidate material and measuring up-regulation of paxillin mRNA. Assays for patulin mRNA upregulation may include branched DNA techniques using labeled probes specifically designed to identify patulin mRNA. In certain embodiments, the probe comprises nucleotide sequences that together cover the paxillin mRNA sequence. In certain embodiments, for example, the probe comprises a nucleic acid sequence according to SEQ ID NOS: 1. 2 and/or 3, and/or a variation thereof. Still other aspects of the invention relate to identifying candidate materials for paxillin stimulators, e.g., identified candidate materials that upregulate paxillin mRNA, using one or more probes, compositions, and/or methods described herein.

In another aspect, the present invention relates to a method for formulating a cosmetic composition for imparting an anti-aging benefit to human skin comprising determining whether a candidate material is a paxillin stimulator; and if so, incorporating the material into a cosmetically acceptable vehicle. In certain embodiments, the candidate material is a plant extract.

These and other aspects of the invention will be better understood by reference to the following detailed description.

Brief Description of Drawings

FIG. 1 illustrates the control vehicle in use (A); and (B) a human skin biopsy showing paxillin protein levels following topical treatment with a candidate paxillin stimulator.

Detailed description of the invention

It has surprisingly been found that a composition comprising one or more substances that stimulate paxillin can be topically applied to human skin to improve the cosmetic appearance of the skin, in particular to treat, reverse and/or prevent visible signs of aging. It has surprisingly been found that new substances, as well as many substances previously known in the cosmetic field, stimulate paxillin and will therefore be useful in topical cosmetic compositions with anti-aging benefits.

In view of these findings and others, topical compositions comprising one or more paxillin stimulators are contemplated to be useful in combating signs of skin aging, including reducing fine lines and wrinkles, preserving skin softness and softness, preventing skin sagging or atrophy, improving skin plumpness and/or tautness and counteracting other signs of skin aging and/or skin damage. In accordance with the present disclosure, it is further contemplated that other substances that stimulate paxillin production or otherwise promote increased intracellular paxillin levels in skin fibroblasts may be useful in anti-aging topical compositions. As used herein, "consisting essentially of means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods.

Paxillin stimulating compounds and compositions

One aspect of the present invention relates to compositions for topical application comprising one or more paxillin stimulators to impart anti-aging benefits to skin, such as treating, reversing, ameliorating, delaying and/or preventing signs of skin aging. Signs of anti-skin aging may include, but are not limited to, the following:

(a) treatment, reduction and/or prevention of fine lines or wrinkles,

(b) the reduction of the pore size of the skin pores,

(c) improvement in skin thickness, plumpness and/or tautness;

(d) improvement in skin softness and/or softness;

(e) improvement in skin tone, radiance and/or clarity;

(f) improvement in procollagen and/or collagen production;

(g) improvement in skin texture and/or promotion of re-texturing;

(h) improvement in skin barrier repair and/or function;

(i) treatment and/or prevention of skin sagging or atrophy; and/or

(j) Improvement in skin contour appearance;

(k) restoration of skin radiance and/or brightness;

(l) Supplementation of essential nutrients and/or constituents in the skin;

(m) improvement in skin appearance reduced by menopause;

(n) improvement in skin moisturization and/or hydration; and

(o) improvement in skin elasticity and/or resiliency.

In practice, the compositions of the present invention are applied to skin in need of treatment, i.e., skin that suffers from a defect or loss in or would otherwise benefit from any of the aforementioned skin attributes.

"paxillin stimulator" refers to any agent that can increase the paxillin level in human skin fibroblasts. An increase in paxillin levels may refer to an increase in paxillin mRNA transcribed in vitro or in vivo and/or an increase in paxillin protein expressed in fibroblasts, and may be measured by any method known in the art or as described herein. For example, paxillin stimulators may act as a positive regulator of paxillin expression within skin fibroblasts. See, e.g., example 1 below. In certain embodiments, the paxillin level is increased by at least about 10%, at least about 20%, at least about 60%, at least about 80%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% as compared to the paxillin level in the absence of the paxillin stimulus. "paxillin stimulators" may also include agents that cause an effective increase in paxillin levels by, for example, increasing the stability of paxillin RNA and/or protein, and/or increasing the localization of paxillin to the site of action.

Paxillin stimulators may be any organic or inorganic compound, small molecule, macromolecule, macromolecular complex, cell lysate, subcellular compartment, biologically derived extract, or combination thereof.

In certain embodiments, the paxillin stimulator comprises an organic molecule. In certain embodiments, the paxillin stimulator comprises a pyridone fused azabicyclic compound, or a pharmaceutically or cosmetically acceptable salt and/or prodrug thereof. Pyridone fused azabicyclic compounds include, but are not limited to, paxillin stimulating compounds according to formula (I):

wherein R is₁、R₂R₃And R₄Independently selected from hydrogen; -R; halogen (-F, -C l, -Br, -I); -OH; -C ≡ C-R; -C ≡ N; -c (R) ═ N-R^N；-C＝N-N(R^N)₂；-C(＝NR_N)-N(R^N)₂；-CH₂OH；-CHO；-(C＝O)-R；-CO₂H；-CO₂ ^-；-CO₂R；-CS₂R；-(C＝O)-S-R；-S-(C＝O)-R；-(C＝O)-NH₂；-(C＝O)-NR^NR^N；-(C＝O)-NHNH₂；-O-(C＝O)-NHNH₂；-(C＝S)-NH₂；-(C＝S)-N(R^N)₂；-O-(C＝O)-H；-O-(C＝O)-R；-O-(C＝O)-NH₂；-O-(C＝O)-NR^NR^N；-OR；-SR；-NH₂；-NHR^N；-NR^N ₂；-N(R^N)₃ ⁺；-N(R^N)-OH；-N(→O)(R)₂；-O-N(R^N)₂；-N(R^N)-O-R；-N(R^N)-N(R^N)₂；-NR^N-(C＝O)-R；-NR^NC(＝O)O-R；-NR^N-CHO；-NR^N-(C＝O)-R；-NR^NC(＝O)NR^N；-N(R^N)-C(＝O)-N(R^N)₂；-N(R^N)-C(＝S)-N(R^N)₂；-N＝CR₂；-N＝N-R^N；-SCN；-NCS；-NSO；-SS-R；-SO-R；-SO₂-R；-O-S(＝O)₂-R；-S(＝O)₂-OR；-N(R^N)-SO₂-R；-SO₂-N(R)₂；-O-SO₃ ^-；-O-S(＝O)₂-OR；-O-S(＝O)-OR；-O-S(＝O)-R；-S(＝O)-OR；-S(＝O)-R；-NO；-NO₂；-NO₃；-O-NO；-O-NO₂；-N₃；-N₂；-N(C₂H₄)；-Si(R)₃；-CF₃；-O-CF₃；-(C＝O)-R；-PR₂；-O-P(＝O)(OR)₂(ii) a and-P (═ O) (OR)₂(ii) a And wherein any 2 adjacent radicals R₁、R₂And R₃May together form a 5 or 6 membered ring fused to the pyridone ring;

l is a bond (i.e., L is omitted), or is selected from the group consisting of- (C ═ O) -, -C (O) -, - (C ═ O) -NR^N-、-(CH₂)_a-、-(C＝O)-(CH₂)_a-C(O)-、-(C＝O)-(CH₂)_a-、-(CH₂)_a-part of C (O) -wherein "a" is an integer from 1 to 6; and wherein L is preferably- (C ═ O) -;

and R^NIndependently at each occurrence, selected from hydrogen or C₁-C₃₀Hydrocarbon radicals optionally including 1-20 heteroatoms, such as oxygen, sulfur and nitrogen atoms; wherein R and R^NPreferably selected from substituted or unsubstituted, branched, linear or cyclic, C₁-C₂₀An alkyl, alkenyl, alkynyl, aryl, benzyl, heteroaryl, alkylaryl, arylalkyl, alkyl-heteroaryl, heteroaryl-alkyl, heteroaryl-aryl, aryl-heteroaryl, bicycloalkyl, aryl, or heteroaryl radical, and combinations thereof; and wherein each of the foregoing radicals may be substituted with 1-6 heteroatoms and/or with any heteroatom-containing moiety, including, for example, acyl, acyloxy, amino, alkoxy, alkylamino, alkylthiol, alkylimino, alkylsulfonate, amide, azo, carboxyl, carboxamide, urea, cyano, dialkylamino, ester, halogen, hydroxyl, nitro, oxo, oxa, oxime, perfluoro, phosphate, phosphonyl, phosphinyl, sulfate, sulfoalkyl, thiol, thioether, thioester, thioalkoxy, thiocyanate, and combinations thereof.

In certain embodiments according to formula (I), R₁Is a group-R, wherein R is preferably selected from substituted or unsubstituted, branched, linear or cyclic, C₁-C₂₀An alkyl, alkenyl, alkynyl, aryl, benzyl, heteroaryl, alkylaryl, arylalkyl, alkyl-heteroaryl, heteroaryl-alkyl, heteroaryl-aryl, aryl-heteroaryl, bicycloalkyl, aryl, or heteroaryl radical, and combinations thereof; and wherein each of the foregoing radicals may be substituted with 1-6 heteroatoms and/or with any heteroatom-containing moiety, including, for example, acyl, acyloxy, amino, alkoxy, alkylamino, alkylthiol, alkylimino, alkylsulfonate, amide, azo, carboxyl, carboxamide, urea, cyano, dialkylamino, ester, halogen, hydroxyl, nitro, oxo, oxa, oxime, perfluoro, phosphate, phosphonyl, phosphinyl, sulfate, sulfoalkyl, thiol, thioether, thio, thia, thiathioalkoxy, thiocyanate, and combinations thereof.

R may comprise, for example, an aliphatic C₁-C₂₀A hydrocarbon radical; comprising an aliphatic group C₁-C₁₂Hydrocarbon radical, aliphatic C₁-C₈Hydrocarbon radicals, or aliphatic C₁-C₆Hydrocarbon radicals such as exemplified by substituted or unsubstituted branched, linear or cyclic, alkyl, alkenyl (e.g., vinyl, allyl, and the like), and alkynyl moieties; c₆-C₂₀Aromatic hydrocarbon radical, including C₆-C₁₂Aromatic hydrocarbon radical, C₆-C₁₀Aromatic hydrocarbon radical, or C₆An aromatic hydrocarbon group such as exemplified by a substituted or unsubstituted aryl group (e.g., phenyl), an alkaryl group (e.g., benzyl), an aralkyl group (e.g., toluoyl), and the like; or C₁-C₂₀A heteroaryl radical comprising one or more heteroatoms selected from O, N and S in the ring; comprising C₁-C₁₂Heteroaromatic atomic group, C₁-C₈A heteroaromatic atomic group, and C₁-C₆Examples of the heteroaromatic atomic group include heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl, and the like. In certain embodiments, R may be, for example, independently at each occurrence, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, benzyl, and the like, including halogen and perhalo derivatives thereof.

In certain embodiments, R₂And/or R₃Will be hydrogen. In certain embodiments, L is a group- (C ═ O) -. In other embodiments according to formula (I), R₁Is a group-R, wherein R is aryl or heteroaryl, any of which may be substituted by the group-R and/or by 1 to 6 heteroatoms and/or by any of the heteroatom containing moieties described above. Typically, when R is aryl or heteroaryl, the ring will contain 5 or 6 atoms in the ring system. In particular, paxillin stimulating compounds according to formula (II) are considered useful:

wherein R is₁As defined above, or is a group-Q (-R)_nWherein Q is a cyclic ring having 3,4. A ring of 5 or 6 atoms, including aromatic or heteroaromatic rings, and R represents a substitution on the ring and is as defined above for R, and is independently selected in each case. The substituents on ring Q, represented by R, may be attached to any available ring atom except for the attachment point to pyridones in the case of aromatic and heteroaromatic rings Q. The number of substituents is defined by "n", which is an integer from 0 (i.e., R x is absent) to 5, depending on the number of positions available for substitution on the ring; and wherein R₂、R₃And R₄As defined above. In certain embodiments according to formula (II), R₂And/or R₃Is hydrogen.

Non-limiting examples of 3-membered heterocyclic rings include, but are not limited to, aziridine, oxirane, thiirane, diaziridine, and oxaziridine. Non-limiting examples of 4-membered heterocyclic rings include, but are not limited to, azetidine, oxetane, thietane, diazetidine, oxazetidine, and 1, 2-oxathietane.

The 5-membered heterocyclic ring represents a presently preferred embodiment of the present invention for substituent Q. Non-limiting examples of 5-membered heterocyclic rings include, but are not limited to, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, thiazolidine, 1, 3-dioxane (dioiane), 1, 3-oxathiolane (oxzthiolane), 1, 3-dithiametallocene, imidazoline, pyrrolidine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1, 3, 4-oxadiazole, 1, 2, 4-oxadiazole, 1, 3, 4-thiadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-triazole, 1, 2, 3-triazole, and the like. Q may be selected from, for example, the following 5-membered heterocyclic rings, which are aromatic, fully saturated, or contain 1 or 2 double bonds:

these 5-membered rings may optionally be functionalized by one or more radicals R as defined above, with particular reference to C_1-4Alkyl (e.g., methyl, ethyl, isopropyl, etc.), C_1-4Alkoxy, halogen, hydroxy, oxo, thiol, amino, alkylamino, dialkylamino, -CH₂-N(CH₃)₂、-(CH₂)_1-6-N(R^N)₂、-(C＝O)-H、-(C＝O)-R、-(C＝O)-CH₃、-(C＝O)-CH₂CH₃、-O-(C＝O)-R、-O-(C＝O)-CH₃And- (C ═ O) -O-R. Further, any nitrogen atom may be optionally oxidized to an N-oxide, and any sulfur atom may be optionally oxidized to a sulfoxide.

Non-limiting examples of suitably selected 6-membered rings for Q include, but are not limited to, 2H-pyran, tetrahydropyran, piperidine, 1, 4-dioxane, morpholine, piperazine, 1, 4-dithiane, thiomorpholine, pyridine, pyrazine, pyridazine, pyrimidine, 1, 2, 3-triazine, 1, 2, 4-triazine, 1, 3, 5-triazine, 1, 2, 3, 4-tetrazine, and pentazine, to name a few. Q may be selected from, for example, the following 6 membered heterocyclic rings which are aromatic, fully saturated, or contain 1, 2 or 3 double bonds:

these 6-membered rings may optionally be functionalized by one or more radicals R as defined above, with particular reference to C_1-4Alkyl (e.g., methyl, ethyl, isopropyl, etc.), C_1-4Alkoxy, halogen, hydroxy, oxo, thiol, amino, alkylamino, dialkylamino, -CH₂-N(CH₃)₂、-(CH₂)_1-6-N(R^N)₂、-(C＝O)-H、-(C＝O)-R、-(C＝O)-CH₃、-(C＝O)-CH₂CH₃、-O-(C＝O)-R、-O-(C＝O)-CH₃And- (C ═ O) -O-R. Further, any nitrogen atom may be optionally oxidized to an N-oxide, and any sulfur atom may be optionally oxidized to a sulfoxide.

In one embodiment, Q is phenyl and "n" is 1, 2 or 3. In an advantageous embodiment, Q is phenyl, "n" is 1, and R is a group- (CH)₂)_1-6-N(R^N)₂And in particular-CH₂-N(CH₃)₂. In this embodiment, the attachment point of R to the pyridone ring may be para, meta or ortho, as exemplified in formula (III).

In this and all embodiments, R and/or R₄May be of low order (C)₁-C₆) Aliphatic radicalAnd include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, 1-methylbutyl, 1-dimethylpropyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, cyclohexyl and the like. These lower alkyl groups may also include 1-6 heteroatoms selected from O, S and N in or attached to the chain. With respect to R and/or R₄Representative groups of (A) include, but are not limited to- (CH)₂)_a-CH₃Wherein "a" is an integer of 1 to 5, including, for example, -CH₂-CH₃、-CH₂CH₂CH₃、-CH₂CH₂CH₂CH₃or-CH₂CH₂CH₂CH₂CH₃(ii) a General formula-O (CH)₂)_a-CH₃Wherein "a" is an integer from 1 to 5, including, for example, -OCH₂CH₃、-OCH₂CH₂CH₃or-OCH₂CH₂CH₂CH₃(ii) a form-O- (CH)₂)_a-O-(CH₂)_bCH₃Wherein "a" and "b" are each independently an integer from 1 to 4; - (CH)₂)_a-O-(CH₂)_bCH₃Or- (CH)₂)_aS(CH₂)_bCH₃Wherein "a" and "b" are each independently an integer from 1 to 4; or form- (CH)₂)_bNR^N ₂Wherein R is^NIndependently at each occurrence a radical- (CH)₂)_cCH₃Wherein "b" is an integer of 1 to 4, and "c" is an integer of 0 (zero) to 4. R and/or R₄Specific examples of (A) include, but are not limited to, -O-CH₃、-O-CH₂CH₃、-O-CH₂CH₂CH₃、-CH₂-O-CH₃、-CH₂-O-CH₂CH₃、-CH₂CH₂-O-CH₃、-N(CH₃)₂、-N(CH₂CH₃)₂、-N(CH₂CH₂CH₃)₂、-S-CH₃、-S-CH₂CH₃、-CH₂-S-CH₃、-CH₂-S-CH₂CH₃、-CH₂CH₂-S-CH₃、-S-CH₂CH₂CH₃、-CH₂CH₂-S-CH₃、-CH₂-S-CH₂CH₃、-CH₂-N(CH₃)₂、-CH₂-N(CH₂CH₃)₂、-N(CH₃)₂、-N(CH₂CH₃)₂、-CH₂-N(CH₂CH₂CH₃)₂、-CH₂CH₂-N(CH₃)₂and-CH₂-N(CH₂CH₃)₂To name a few.

In one embodiment, R is a group- (CH)₂)_1-6-N(R^N)₂And in particular-CH₂-N(CH₃)₂. In another embodiment, R₄Is a group-CH₂-S-CH₃. Excellent results have been obtained with compounds according to formulae (IV-a) and (IV-B) shown below, wherein R comprises a tertiary amine group ortho or para to the point of attachment of the pyridone ring, and R₄Comprising a linear thioether moiety:

in the formulae (I) to (III), R₄It may also be, for example, a group-Q (-R)_nWherein Q is independently selected from R₁Any cyclic group as defined above. In certain embodiments, R₁And R₄Independently is a group-Q (-R)_nWherein Q is the same or different in 2 cases. In one embodiment, R₁Is an optionally substituted 5-or 6-membered aromatic group, e.g. a 5-membered furyl group, and R₄Is an optionally substituted 5 or 6 membered aromatic group, for example phenyl. Compounds according to formula (V) have been found to be useful:

in addition to paxillin stimulating compounds according to formulas (I) - (V), other pyridone fused azabicyclic compounds capable of stimulating paxillin are also contemplated, including but not limited to international patent application publication WO 98/18798; EP 0581457; those described in U.S. patent No. 6,630,467, U.S. patent No. 6,235,734, the disclosures of which are incorporated herein by reference in their entirety.

In other embodiments, paxillin stimulators comprise another class of organic molecules, such as tanshinone iia; tetrandrine; carvacrol; and/or cis-6-nonenol, and/or salts thereof. Tanshinone IIA or 1, 6, 6-trimethyl-8, 9-dihydro-7H-naphtho [1, 2-g ] [1] benzofuran-10, 11-dione is a diterpene naphthoquinone and is an active ingredient of certain traditional Chinese medicines based on Salvia militarinzhia. It is believed to have anti-inflammatory activity and induce apoptosis in a variety of cell lines. H.j.sung et al exp.mol.med.1999, volume 31: 174. it has been suggested for use in the treatment of sepsis, septicaemia and endotoxic shock. See, for example, International patent application publication WO2007/084419, which is incorporated herein by reference in its entirety. Tanshinone IIA is commercially available, for example it may be obtained from Biomol Research Laboratories, PA.

Tetrandrine or 6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyl-berbaman is a bishenne alkaloid that has been used in traditional chinese medicine for centuries, for example, for the treatment of cardiovascular diseases. It is believed to be a calcium channel blocker and Ca²⁺Activated potassium channel blockers. Dworkzky et al J.Neurosci.1996. volume 16: 4543; and Gadwood et al annu. rep. med. chem.1989, volume 24: 187. It is also commercially available, for example from BiomolResearch Laboratories, PA.

Carvacrol or carvacrol C₆H₃CH₃(OH)(C₃H₇) It is a monoterpenoid phenol, with a characteristic pungent, warm odor similar to that of origanum, and is also known for its pizza-like taste. Ultra a. et al (2000) j.food prot.63 (5): 620-4. Carvacrol is present in the oils of oregano (Origanum vulgare), thyme, pepper (pepper) and wild bergamot. It is known to inhibit the growth of many bacterial strains and has therefore been used as a food additive to prevent bacterial contamination. Ultra a. et al (2001) int.j.food microbiol.64 (3): 373-8.

Cis-6-nonenol is an unsaturated fatty alcohol. cis-6-Nonenol has the structure of formula (VI) shown below and has been further described in U.S. patent application No. 12/342,197, which is incorporated herein by reference in its entirety, and which was filed in 2008, 12 and 23, under the designation "Topical Compositions contacting cis-6-Nonenol and itsDerivatives and Methods for Treating Skin".

In certain embodiments, the paxillin stimulator comprises a larger organic molecule, such as retinol puniciate (retinyl puniciate); retinol oleate; and/or equol. Retinol Punicate and retinol oleate are esters of retinol (vitamin A) with the fatty acids Punicate and oleic acid, respectively. The ester may be obtained as known in the art, for example, by esterification. Retinol oleate has been suggested for use in enhancing skin and for treating dermatological conditions, including acne, oily skin and rosacea. See, for example, EP 0807429, incorporated herein by reference in its entirety. Equol or 4', 7-isoflavandiol have been suggested for use in the treatment of androgen-mediated skin and trichopathies by blocking the hormonal effects of 5-dihydrotestosterone. See, for example, international patent application publication WO 2005/107770, which is incorporated herein by reference in its entirety. It is an isoflavandiol and a non-steroidal estrogen produced by the bacterial flora in the intestine of certain individuals. Wang, X.L. et al Applied and Environmental Microbiology (2005) 71: 214-219; frankenfeld, C.L. et al The British journal of Nutrition (2005) 94: 873-876.

In certain embodiments, the paxillin stimulator comprises a biological extract, such as a plant extract. Plant extracts useful as paxillin stimulators in the present invention include, but are not limited to, jasminum bivalvular extracts; red melon extract; an eclipta prostrata extract; a sphenoidea extract; extract of ozathamunsobcordatus; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; extract of Trifolium pratense; (ii) marshall aisha extract; kunzea ambigua extract; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; terminalia catappa extract; an extract of Cocculus glaucescens; solid extract of Stephania japonica; and/or rosemary extract, preferably rosemary PE 50%.

Double-petal jasmine is a species of jasmine that grows in earth in southwestern and south asia, philippines, india, burma and srilanka, produces strongly fragrant flowers, is used as an ornamental plant, makes aromatic rosettes, and is used as a main ingredient in jasmine tea. Red melon is also known as ivy gourd, a tropical vine plant that grows in certain parts of the world due to its small edible fruit. The fruit is commonly eaten, for example, in the indian diet, while the vine is considered an invasive plant in the united states and hawaii. Red melons have been suggested as being useful in skin whitening applications, see for example JP 2000095663, which is incorporated herein by reference in its entirety. Snakeheads, also known as False Daisy (False Daisy) or bhringraj, grow as weeds in moist areas including india, china, brazil and thailand, and are used in many traditional medicine in those areas. For example, in brazil it is used to treat snake bites and in india it is used to improve hair growth. Chopra et al 1955.gloss of Indian Plastic plants.C.S.I.R., New Delhi. Traditional chinese medical applications for this plant include the treatment of athlete's foot, eczema and dermatitis. Sphenopalata, also known as butterfly bean, is grown in tropical and temperate regions, including southeast asia earthy growths. The flower can be used as a food color and the root extract is considered to have medicinal properties in certain countries, for example for the treatment of pertussis. Ozothamnus obcordia tus, also known as Grey Everlasting, is a shrub grown in soil in some parts of australia and is considered to have commercial cut flower potential.

Erythrina, also known as Coral erythrina (Coral Bean), is a shrub having red flowers in attractive clusters and soybean pods with highly toxic red beans. It has been proposed for use in extraction to obtain useful chemicals from plants. See, e.g., U.S. patent application publication No. 2002/0132021, which is incorporated by reference herein in its entirety. Lonchocarpus capasssa, also known as apple leaves or rain trees, is found in south africa. It is famous for its smooth, bare trunk with a highly branched sparse crown. The tree is usually infected with aphids that secrete droppings to form a wet patch (wet patch) under the tree, giving it the name "rain tree". Maacklacepod, also known as "necklacepod", is a shrub with yellow flowers and silver, hairy leaves. The plant is native to the coastal region of florida and caribbean. Hybrid clover, also known as "hybrid clover", is a plant in the legume family, with high stem, pinkish flowers, sometimes growing as feed. Plant extracts have been used in dermatological applications, superficially as inhibitors of extracellular proteases. See, e.g., U.S. patent application publication No. 2007/0122492, which is incorporated by reference herein in its entirety. Michelle Amazoa, also known as "fake sandalwood," is a shrub or treelet of Australian native soil growth with white or pale pink flowers. Kunzea ambigua, also known as "power bush," is a shrub found to grow in sandstone soil in australia, eastern. It is used in horticulture and sand dune stabilization. It has also been suggested for use in the treatment of psoriasis. See, for example, international patent application publication WO 2009/086595, which is incorporated herein by reference in its entirety.

Radix zanthoxyli is a shrub known for its root and sometimes bark use in traditional Chinese medicine. Several alkaloids believed to contribute to their medicinal properties have been isolated from extracts of this plant. Mingjin l. et al (2006) j.of pharm.and biomed.anal.42 (2): 178-183. Ophiopogon is a grass-like shrub widely cultivated in china due to its tuberous roots, which are used as a medicine. Extracts are commercially available, for example, from Wuchang Yuancheng Technology development co., ltd. Platycodon grandiflorum is another plant used in traditional Chinese medicine. For example, its roots may be dried to form a brown powder, which is commercially available from Qi Lu Chemical, china. Terminalia catappa, also known as bibhitaka, is a tall tree growing throughout India with brown grey bark and unpleasant-smelling flowers. In sanskrit, babhitaka means something that avoids disease, and parts of the tree are widely used in traditional medicine. Extracts have also been suggested for use as depigmenting agents. See, for example, international patent application publication WO 96/24327, which is incorporated herein by reference in its entirety. Cocculus glaucescens is a large woody vine used in traditional Chinese medicine. Stephania is a flowering plant grown in soil in east asia and south asia and australia that grows as perennial vines. Certain species provide herbal medicines for use in traditional Chinese medicine, and plant parts such as solid extracts of roots are commercially available, for example from Natural Nutritionals, GA and Naturex, Inc, NJ, which provide a stephaniae japonica solid extract suitable for use in accordance with the present invention. Rosemary, rosemary (Rosmarinus officinalis), is a woody perennial herb with aromatic evergreen needle-like leaves, native to the mediterranean region and widely used in traditional mediterranean-type diets. Rosemary extracts suitable for use in the present invention are commercially available, for example, from Naturex, inc.

In certain embodiments, the paxillin stimulator comprises other biological materials, such as myco fusion Coriolus black corn biomass and/or myco fusion Maitake waxy naked barley biomass. Myco fusions Coriolus black corn biomass and Myco fusions Maiteake waxy naked barley biomass are commercially available, for example, from Nutagenesis, LLC, VT.

Cosmetic compositions for topical application to the skin will comprise at least one paxillin stimulator in a cosmetically acceptable vehicle. The paxillin stimulator may be at least one substance selected from the group consisting of: a pyridone-fused azabicyclic compound having a structure of formula IV or V; a double-petal jasmine extract; red melon extract; an eclipta prostrata extract; a sphenoidea extract; extract of ozathamunsobcorda tus; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; extract of Trifolium pratense; (ii) marshall aisha extract; kunzea ambigua extract; tanshinone IIA; tetrandrine; carvacrol; cis-6-nonenol; retinol punicic acid ester; retinol oleate; equol; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; terminalia catappa extract; an extract of Cocculus glaucescens; solid extract of Stephania japonica; and rosemary PE 50%. In certain embodiments, the cosmetic composition comprises one or more paxillin stimulators, and in other embodiments, the cosmetic composition comprises 2 or more paxillin stimulators. In a preferred embodiment, the combination of 2 or more paxillin stimulators produces a synergistic effect, e.g., a synergistic anti-aging benefit.

In certain embodiments, a cosmetic composition for topical application to the skin comprises cis-6-nonenol and at least one other paxillin irritant in a cosmetically acceptable vehicle in an amount effective to impart an anti-aging benefit to human skin. The paxillin stimulator may be at least one compound selected from the group consisting of: a pyridone-fused azabicyclic compound having a structure of formula IV or V; a double-petal jasmine extract; red melon extract; an eclipta prostrata extract; a sphenoidea extract; extract of ozathamunsobcorda tus; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; extract of Trifolium pratense; (ii) marshall aisha extract; kunzea ambigua extract; tanshinone IIA; tetrandrine; carvacrol; retinol punicic acid ester; retinol oleate; equol; mycofusion Coriolus black corn biomass; mycofusamaitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; terminalia catappa extract; an extract of Cocculus glaucescens; solid extract of Stephania japonica; and rosemary PE 50%. In certain embodiments, the composition comprising cis-6-nonenol further comprises at least 2, at least 5, at least 8, at least 10, at least 15, at least 20, at least 25, or all 28 materials selected from those recited above. In a preferred embodiment, the combination of 2 or more paxillin stimulators produces a synergistic effect, e.g., a synergistic anti-aging benefit.

In certain preferred embodiments, the cosmetic composition comprises at least one paxillin stimulator selected from the group consisting of: a pyridone-fused azabicyclic compound having a structure of formula IV or V; a double-petal jasmine extract; an eclipta prostrata extract; a sphenoidea extract; ozothamnus obcordiatus extract; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; tetrandrine; carvacrol; retinol punicic acid ester; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; and an extract of Cocculus glaucescens. In certain preferred embodiments, the paxillin stimulator comprises one or more of an extract of hybrid clover, an extract of Kunzea ambigua, tanshinone IIA, equol, an extract of terminalia, or an extract of rosemary. In certain embodiments, one or more of Trifolium pratense extract, Kunzea ambigua extract, tanshinone IIA, equol, Terminalia catappa extract, and rosemary extract are used in combination with cis-6-nonenol to impart an anti-aging benefit to the skin.

In certain preferred embodiments, one or more substances are excluded from the cosmetic composition. For example, in certain embodiments, the composition does not include a hybrid clover extract and/or does not include retinol oleate and/or does not include equol.

The cosmetic compositions of the present invention generally comprise an amount of paxillin irritant that is effective to provide a benefit to human skin, for example an amount of cis-6-nonenol. In a preferred embodiment, the composition comprises an amount of paxillin stimulator effective to increase paxillin transcription and/or expression in human skin fibroblasts. The cosmetic compositions described herein are useful as anti-aging agents, for example, as detailed below.

Cosmetic use of paxillin stimulating compositions

Another aspect of the invention relates to the cosmetic use of a composition comprising a paxillin stimulator, such as cis-6-nonenol. The cosmetic composition surprisingly acts to increase the paxillin level in human skin fibroblasts and is accordingly useful in anti-aging products.

In certain embodiments, a method for providing at least one benefit to human skin is provided, wherein the method comprises topically applying to skin in need thereof at least one paxillin stimulator in a cosmetically acceptable vehicle. The composition will contain an effective amount of the substance. An "effective amount" or "effective amount" to provide a particular benefit to the skin refers to an amount of paxillin stimulator activity that, when applied for a sufficient time, is sufficient to provide a clinically measurable improvement in a particular manifestation of the skin. An "effective amount" or "effective amount" to provide a particular benefit to the skin refers to the amount of activity of each of the 2 or more paxillin stimulators used in combination that, when applied for a sufficient time, provides a clinically measurable improvement in a particular performance of the skin. The effective amount of each substance when used in combination with another may be the same as, greater than, or less than the effective amount of the substance used alone. When used in combination with other paxillin stimulators, the use of lower amounts of the individual substances is contemplated, for example due to synergistic effects in producing clinically measurable improvements in specific manifestations of the skin. Such benefits include, but are not limited to, the following:

(a) treatment, reduction and/or prevention of fine lines or wrinkles,

(b) the reduction of the pore size of the skin pores,

(c) improvement in skin thickness, plumpness and/or tautness;

(d) improvement in skin softness and/or softness;

(e) improvement in skin tone, radiance and/or clarity;

(f) improvement in procollagen and/or collagen production;

(g) improvement in skin texture and/or promotion of re-texturing;

(h) improvement in skin barrier repair and/or function;

(i) treatment and/or prevention of skin sagging or atrophy; and/or

(j) Improvement in skin contour appearance;

(k) restoration of skin radiance and/or brightness;

(l) Supplementation of essential nutrients and/or constituents in the skin;

(m) improvement in skin appearance reduced by menopause;

(n) improvement in skin moisturization and/or hydration; and

(o) improvement in skin elasticity and/or resiliency.

The compositions of the present invention may be applied to skin in need of treatment, e.g., skin suffering from a defect or loss in any of the aforementioned attributes or conditions or that would otherwise benefit from the anti-aging effects of the compositions, e.g., as described herein. For example, one or more paxillin stimulators may be provided in a cosmetically acceptable vehicle, topically applied to a desired area of skin, and allowed to remain on the area in an amount effective to treat and/or prevent an undesirable skin feature or condition, and/or to improve the cosmetic appearance of skin.

"condition of the skin" or "skin condition" is used herein interchangeably with "skin disorder". As used herein, "treating" and related terms refer to eradicating, reducing, ameliorating, or reversing one or more undesirable characteristics associated with the skin condition to be treated, thereby causing the consumer to perceive an improvement or other therapeutic benefit in terms of the condition. As used herein, "preventing" and related terms refer to providing a benefit to skin that has not been affected by a condition that acts to avoid, delay, prevent or minimize one or more undesirable characteristics associated with the skin condition to be prevented. Such prophylactic benefits include, for example, delaying the progression of the condition, or if it eventually progresses, reducing the duration, severity, or intensity of one or more undesirable characteristics associated with the condition.

Anti-aging benefits

In certain preferred embodiments, the cosmetic compositions described herein can be used to treat and/or prevent signs of skin aging or other skin damage (e.g., from UV). Signs of skin aging include any dermatological signs of aging, including signs caused by intrinsic (chronologic) aging, or signs caused by extrinsic (e.g., photoaging). The composition may be applied to skin that has shown visible signs of aging, or that may show such signs, for example due to age or sun exposure.

Early signs of skin aging involve the gradual development of facial wrinkles, whether fine surface lines or deeper folds and folds. While wrinkling and other signs of aging are intrinsic to the skin, the process can be accelerated by external factors such as overexposure to the sun and other damaging elements, overactive facial expression muscles, frequent use of tobacco products, malnutrition, or specific skin conditions. Fine lines on the surface that progress to deeper folds, deepening facial wrinkles due to repeated skin folds, and deep folds that develop with maturity are visible changes associated with aging.

Treating signs of skin aging refers to eradicating, reducing, ameliorating, or reversing one or more undesirable characteristics associated with skin aging, such as by reducing lines and/or wrinkles to a noticeable degree. For example, the compositions and methods of the present invention can be used to reverse or treat signs of post-manifestation skin aging, such as is common in individuals over the age of 25. Preventing signs of skin aging refers to providing a benefit to the skin that acts to avoid, delay, prevent, or minimize one or more undesirable characteristics associated with aging, such as by slowing the appearance of lines and/or wrinkles as the skin eventually ages. That is, the compositions and methods of the present invention can be employed prophylactically, e.g., to prevent signs of skin aging in individuals who have not yet exhibited signs of skin aging, most commonly in individuals under the age of 25.

The improvement in the undesirable characteristics and/or overall cosmetic appearance may include one or more of the following: reducing dermatological signs of juvenile aging, photoaging, hormonal aging, and/or actinic aging; preventing and/or reducing the appearance of lines and/or wrinkles; reducing facial lines and wrinkles, facial wrinkles on the cheeks, forehead, vertical wrinkles between the eyes, horizontal wrinkles on the eyes and around the mouth, marionette lines and in particular the significance of deep wrinkles or folds (nooticality); preventing, reducing and/or diminishing the appearance and/or depth of lines and/or wrinkles; improving the appearance of infraorbital and/or periocular lines; reducing the appearance of crow's feet; rejuvenating and/or rejuvenating skin, particularly aged skin; reducing skin fragility; preventing skin atrophy; improving skin tone, radiance and/or clarity; preventing, reducing and/or ameliorating skin sagging; improving skin firmness, plumpness, tautness, softness and/or softness; improving skin texture and/or promoting re-texturing; improving skin barrier repair and/or function; improving the appearance of skin contours; restoring skin radiance and/or brightness; minimizing dermatological signs of fatigue and/or stress; resistance to environmental stress; supplementing ingredients in the skin that are reduced by aging and/or menopause, such as essential nutrients or other skin constituents; ameliorating the effects of estrogen imbalance; improving communication in skin cells; increasing cell proliferation and/or reproduction; increasing skin cell metabolism decreased by aging and/or menopause; delaying cell aging; improving skin moisturization and/or hydration; improving production and/or reducing loss of collagen and/or procollagen; enhancing skin thickness; increase skin elasticity and/or resiliency; and any combination thereof. Without wishing to be bound by theory, it is believed that the compositions of the present invention enhance and improve the cosmetic appearance of skin by enhancing pilin expression and increasing pilin levels in skin fibroblasts.

In certain preferred embodiments, the compositions and methods of the present invention relate to the treatment and/or prevention of fine lines or wrinkles in the skin. In the context of treatment, the composition is applied to skin in need of such treatment, by which is meant skin having wrinkles and/or fine lines. The fine lines and/or wrinkles may appear on any surface of the skin, including but not limited to the skin of the hands, arms, legs, neck, chest, and face, including the forehead. Preferably, the composition is applied directly to the fine lines and/or wrinkles. For example, a method for treating fine lines and wrinkles may comprise topically applying a composition described herein to the skin of an individual in need thereof, e.g., directly topically applying to the fine lines and/or wrinkles in an amount and for a time sufficient to reduce the severity of the fine lines and/or wrinkles; or to inhibit the formation of new lines and/or wrinkles. The effect of the composition on the appearance of fine lines and wrinkles can be assessed qualitatively, e.g., by visual inspection, or quantitatively, e.g., by microscopic or computer-assisted wrinkle morphology measurements (e.g., number, depth, length, area, volume, and/or width/unit area of skin of wrinkles).

The term "creping" or "creping" refers to fine and/or coarse creping. Fine wrinkles or fine lines refer to superficial lines and wrinkles on the skin surface. Coarse wrinkles refer to deep furrows on the face and around the eyes, particularly deep lines/wrinkles, including expression lines such as frown lines and wrinkles, frontal lines and wrinkles, fishtail lines and wrinkles, nasolabial folds, and marionette lines and wrinkles. Frontal lines and wrinkles refer to superficial lines and/or deep furrows in the skin of the forehead. The fishtail lines and wrinkles refer to superficial and/or deep lines on the skin around the eye region. The marionette lines and wrinkles refer to superficial lines and/or deep furrows on the skin around the mouth.

It is also contemplated that the compositions of the present invention are useful for treating thin skin by topically applying the compositions to the thin skin of an individual in need thereof. "thin skin" is intended to include skin that is thinned due to age-related aging, menopause, or photodamage. In certain embodiments, the treatment is for thin skin in men, while other embodiments treat thin skin in pre-or post-menopausal women, as the skin is believed to thin differently with age in men and women, and particularly in women of different life stages.

Without wishing to be bound by theory, it is believed that the compounds described herein may act to increase the paxillin level in skin fibroblasts, thereby maintaining cell shape and health, and delaying one or more undesirable characteristics associated with skin aging. It has surprisingly been found that in human skin fibroblasts, paxillin protein levels decrease with aging. For example, skin fibroblasts from older donors show 20.6% lower paxillin levels compared to younger donors (n ═ 3). Furthermore, interference with the normal production of paxillin mRNA and protein leads to changes in the cell shape of human skin fibroblasts. Collapsed fibroblasts have a lower proliferation rate and a reduced ability to produce a collagen matrix. Accordingly, increasing paxillin levels can maintain youthful skin cell morphology and thus cell function, including slowing cell aging and stimulating collagen synthesis. Younger paxillin levels may improve and/or restore skin cell shape, increase cell proliferation and production of extracellular matrix proteins, thus resulting in overall healthier skin with fewer lines and wrinkles.

In certain preferred embodiments, the compositions and methods of the present invention are directed to improving skin firmness, plumpness and/or tautness. Loss of firmness, wrinkling and/or other signs of aging result in part from loss of collagen from the skin over time. As used herein, "collagen" is used interchangeably with "collagen I" or "collagen type I" as the type present in skin as a component of the skin matrix. Collagen I consists of 3 protein chains intertwined together in a tight triple helix, which provides a tensile strength greater than that of steel and is produced by fibroblasts. Collagen gives skin its firmness, strength, durability, and a youthful, smooth, plump appearance. Without wishing to be bound by theory, it is believed that increasing the pilin level may result in increased collagen production and thus increased collagen skin levels, thereby delaying one or more undesirable characteristics associated with skin aging, for example, by instead maintaining skin firmness and plumpness.

In a particular embodiment, the composition of the invention comprises a paxillin stimulator, such as cis-6-nonenol, in an amount sufficient to increase the paxillin level in a given skin area when topically applied thereto. As used herein, "increasing paxillin levels" and related expressions refer to stimulating, inducing, or up-regulating paxillin mRNA (and protein) production to increase paxillin content in an area of skin, preferably to improve skin appearance to an appreciable extent. For example, in certain embodiments, the paxillin level is increased by at least about 10%, at least about 20%, at least about 60%, at least about 80%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% as compared to the paxillin level in the absence of the composition. Paxillin levels in skin can be determined by suitable assays, such as in vitro assays described herein or known in the art. For example, example 1 below provides experimental details of an assay for measuring paxillin levels in human skin fibroblasts.

In certain embodiments, the cosmetic composition for treating and/or preventing signs of skin aging may further comprise an additional anti-aging agent. For example, a cosmetic composition comprising one or more paxillin stimulators in an amount effective to treat and/or prevent signs of skin aging may further comprise at least one other anti-aging agent. In certain embodiments, it is contemplated that synergistic improvements may be obtained with such combinations.

Exemplary anti-aging agents include, but are not limited to, botanicals (e.g., butea frondosa) extract); thiodipropionic acid (TDPA) and its esters; retinoids (e.g., all-trans retinoic acid, 9-cis retinoic acid, phytanic acid, and others); hydroxy acids (including alpha-hydroxy acids and beta-hydroxy acids), salicylic acid, and salicylates; antioxidants, exfoliating agents (e.g., glycolic acid, 3, 6, 9-trioxaundecanedioic acid, and the like), estrogen synthase stimulating compounds (e.g., caffeine and derivatives); compounds capable of inhibiting 5 α -reductase activity (e.g., linolenic acid, linoleic acid, finasteride, and mixtures thereof); barrier function enhancing agents (e.g., ceramides, glycerides, cholesterol and esters thereof, alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, and the like); a collagenase inhibitor; an elastase inhibitor; anti-aging botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, and skin plumping agents (plumpers) that act as additional collagen enhancers for the skin, to name a few. An example of a suitable skin plumper is palmitoyl oligopeptide. Other skin plumping agents include other collagen and/or other glycosaminoglycan (GAG) enhancing agents. Exemplary maintenance classes include, but are not limited to, retinoic acid (e.g., all-trans or 13-cis) and derivatives thereof, retinol (vitamin a) and esters thereof, such as retinol palmitate, retinol acetate, and retinol propionate and salts thereof. In certain embodiments, the present invention relates to the synergistic effect of one or more of the compositions described herein with TDPA, for example, to provide enhanced anti-aging benefits to the skin.

Based on the teachings provided herein, one of skill in the art will recognize other cosmetic and/or pharmaceutical applications for the compositions described herein, and such applications are also considered to be within the scope of the present invention. For example, the compositions described herein may also be useful in personal care products, such as skin care products, where it is desirable to produce the skin benefits described herein after application of the product. Personal care products for the skin include, for example, skin lotions, body tonics, and the like. It is contemplated that compositions such as described herein may be useful in lotions, tonics, and/or wash formulations that reduce the appearance of lines and wrinkles on various surfaces of the body.

Paxillin stimulators are topically applied to individuals in need thereof, by which is meant individuals who adhere to benefit from reducing visible signs of skin damage or aging. The present invention provides methods for providing a skin benefit by topically applying a composition comprising at least one paxillin stimulator on an area of skin for a period of time sufficient to produce one or more benefits described herein. The compositions will generally be applied to the skin 1, 2 or 3 times per day as needed to achieve the desired result, such as the anti-aging benefits described herein. Such treatment regimens may comprise daily application or every other day application for at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, or more. Long-term treatment regimens are also contemplated, for example in terms of prophylactic treatment aimed at preventing one or more signs of skin aging or other damage. The treatment and/or prevention regimen may also depend on the particular paxillin stimulator or stimulators to be used, for example because a particular paxillin stimulator may produce anti-aging skin benefits more rapidly than others.

Additional candidate paxillin stimulators for use as anti-aging agents may be screened for use in treating skin in need thereof, e.g., as described in more detail below.

Method for screening candidate paxillin stimulators

Another aspect of the invention relates to screening candidate paxillin stimulators, for example to find substances suitable for formulating an anti-aging cosmetic composition by incorporation into a cosmetically acceptable vehicle. A wide variety of substances can be screened, and it is understood that a candidate paxillin stimulator may be used alone or in combination with another paxillin stimulator, although not necessarily explicitly stated.

In certain embodiments, the candidate agent comprises a natural, synthetic, or semi-synthetic organic compound based on multiple core structures. The reagent may comprise one or more of a wide variety of chemical classes, preferably comprising functional groups necessary for structural interaction with the protein, particularly hydrogen bonding, for example generally comprising at least an amine, carbonyl, hydroxyl or carboxyl group, and usually at least 2 of the functional chemical groups. Candidate agents are also found in biomolecules, including but not limited to peptides, sugars, fatty acids, steroids, purines, pyrimidines, benzodiazepines, derivatives, structural analogs, polynucleotides, macromolecular complexes, or combinations thereof.

Candidate agents may be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. In certain embodiments, the candidate paxillin stimulators may be any organic or inorganic compound, and a number of natural and/or synthetic compound libraries may be used to provide candidate agents. See, e.g., NCI Open Synthetic Compound Collection library, Bethesda, Md.; pirrung et al, 2008, "Synthetic library of Fungal Natural products" ChemInformim 39: 2; shang et al, 2005, "Advancing chemistry and biology through direction division-oriented synthesis of natural products-like libraries" curr. Opin. chem. biol. 9: 248-58; WebbTR, 2005, "Current directions in the evolution of compounds" Current. opin. drug discov. device.8: 303-8; fodor et al, 1991, Science 251: 767-73; medynski, 1994, BioTechnology 12: 709- > 710; ohlmeyer et al, 1993, proc.natl.acad.sci.usa90: 10922-26; erb et al, 1994, proc.natl.acad.sci.usa91: 11422-26; jayawickreme et al, 1994, proc.natl.acad.sci.usa 91: 1614-18; and Salmon et al, 1993, proc.natl.acad.sci.usa90: 11708-712).

Further, numerous methods are available for the random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. In addition, natural or synthetically produced libraries and compounds are readily modified by conventional chemical, physical and biochemical methods and can be used to generate combinatorial libraries. Directed or random chemical modifications, such as acylation, alkylation, esterification, amidation, and the like, can be performed on known pharmacological agents to produce structural analogs. Candidate agents may also include cell lysates or subcellular compartments, extracts of plant or animal origin, or any combination thereof.

A candidate agent can be assayed by any method known in the art and/or described herein to determine whether it can stimulate paxillin. For example, example 1 below describes an assay for screening candidate paxillin stimulators by testing for an increase in paxillin mRNA. In certain embodiments, the methods involve contacting a human skin cell with a candidate agent or candidate material and measuring up-regulation of paxillin mRNA. The concentration of the candidate agent in the test sample will vary depending on the nature of the agent. For example, a candidate agent can be tested at one or more concentrations, e.g., at about 5%, at about 2%, about 1%, 0.1%, about 0.05%, about 0.01%, about 0.001%, about 0.0001%, about 0.00001%, about 0.000001%, etc.

In certain preferred embodiments, up-regulation of paxillin mRNA is determined using multiplex assays employing branched DNA techniques. This technique is a target-specific RNA quantification method based on hybridization, which uses a labeled DNA probe to amplify one or more signals instead of the target RNA. Probes for paxillin have been designed and synthesized. The probes preferably cover the target sequence to be identified. That is, the probes may be designed such that the nucleotide sequence corresponding to the paxillin mRNA is covered or substantially covered by the complementary sequences of the plurality of probes. The probes generally include a Capture Extender (CE), a Label Extender (LE), and a blocking agent (BL). Capture extenders are short sequences that bind RNA to the beads used, such as beads commercially available from Luminex. The labeled extenders are short sequences that allow RNA to bind to DNA oligomers (bDNA amplification oligonucleotides, which may also be referred to as preamplifiers, amplicons, or labeled probes) used in amplification. A blocker is a short sequence that binds to RNA on a region within the target sequence not covered by CE or LE. This arrangement provides a target sequence that is double-stranded in that the target sequence is covered (or substantially covered) by a combination of multiple probes directed to different regions of the target. Without wishing to be bound by theory, it is believed that providing a double stranded target sequence improves the specificity and/or sensitivity of the assay, for example by improving the hybridization efficiency.

In one embodiment, the CE, LE and BL sequences used to identify paxillin correspond to SEQ ID NOS: 1. 2 and 3, as follows:

gggaagacgtggcacccctcccggaacttcttcgagccccgcgctgctactactgcaacggccccatcctggaagccttctttggtcccgaaaacggcagcttcttcgagc(SEQ IDNO：1)；

gagcacttcgtctgcacccactgccaggaggagatcggataaagtggtgacagcccttgaccggacgtggcaccctgagggttccacgagaaggacggcaaggcctactgtcgcaagtgctttgtgtgccgggaatgcttcacgccattcgtgacgacgggcagccctactgtgaggtgcactaccacgagc (SEQ ID NO: 2); and

acacttcttctgtgcacagtgtggggactacttcgacatgttcgcacccaagtgtggcggctgcgcccgggccatcctggagaactatatctcagccctcaacacgctgtggcatcctga(SEQ ID NO：3)。

in other embodiments, the probes used may comprise one or more variations from the above sequences. For example, in certain embodiments, the CE, LE and/or BL probes have nucleotide sequences that are identical to SEQ ID NOS: 1. 2 and 3 is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical. In certain embodiments, the CE, LE and/or BL probes have nucleotide sequences that, under stringent conditions, hybridize to SEQ ID NOS: 1. 2 and 3. Stringent conditions may include conditions of low stringency, moderate stringency, or high stringency.

"high stringency conditions" can include, but are not limited to, the following: (1) low ionic strength and high temperature are used for washing, for example 0.015M sodium chloride/0.0015M sodium citrate/0.1% sodium lauryl sulfate at 50 ℃; (2) during hybridization at 42 ℃ with a denaturing agent such as formamide, e.g., 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750mM sodium chloride, 75mM sodium citrate; or (3) at 42 deg.C with 50% formamide, 5XSSC (0.75M NaCl, 0.075M sodium citrate), 50mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 XDenhardt's solution, sonicated salmon sperm DNA (50. mu.g/mL), 0.1% SDS and 10% dextran sulfate, with a wash at 42 ℃ in 0.2XSSC (sodium chloride/sodium citrate) and at 55 ℃ in 50% formamide, followed by a high stringency wash consisting of 0.1XSSC with EDTA at 55 ℃. For example and without limitation, procedures using high stringency conditions are as follows. Pre-hybridization of DNA-containing filters was performed at 65 ℃ for 8 hours to overnight in a buffer consisting of 6 XSSC, 50mM Tris-HCl (pH 7.5), 1mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA and 500. mu.g/ml denatured salmon sperm DNA. Filters containing 100. mu.g/ml denatured salmon sperm DNA and 5-20X 10 at 65 ℃⁶cpm³²The P-labeled probe was hybridized in the prehybridization mixture for 48 hours. Washing of the filters was done in a solution containing 2XSSC, 0.01% PVP, 0.01% Ficoll and 0.01% BSA at 37 ℃ for 1 hour. This was followed by 45 min washes in 0.1X SSC prior to autoradiography at 50 ℃. Other conditions of high stringency that can be used are well known in the art. Selection of suitable conditions for such stringency is well known in the art (see, e.g., Sambrook et al, 1989, Molecular Cloning, A Laboratory Manual, 2 nd edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; see also, Ausubel et al, eds., in the Current Protocols in Molecular Biology series of Laboratory techniques1987-1997，Current1994-1997John Wiley and Sons, Inc.; see also, Dyson, 1991, "Immobilizat ion of nucleic acids and dhybridization analysis," In: essential Molecular Biology: APractical Aproach, volume 2, T.A.Brown, eds, page 111-156, IRLPress at Oxford University Press, Oxford, UK) (each of which is incorporated herein by reference in its entirety).

"moderately stringent conditions" are determined by Sambrook et al, Molecular Cloning: alamoutory manual.2.sup.nd ed., New York: those in Cold Spring harborPress, 1989, but are not limited thereto, and include the use of less stringent wash solutions and hybridization conditions (e.g., temperature, ionic strength, and% SDS) than those described above. An example of moderately stringent conditions is overnight incubation at 37 ℃ in a solution comprising: 20% formamide, 5XSSC (150mM NaCl, 15mM trisodium citrate), 50mM sodium phosphate (pH 7.6), 5 XDenhardt's solution, 10% dextran sulfate, and 20mg/mL denatured sheared salmon sperm DNA, followed by washing of the filters at about 37-50 ℃ at 1 XSSC.

"Low stringency conditions" can include, but are not limited to, the following. The filters containing the DNA were pretreated at 40 ℃ for 6 hours in a solution containing 35% formamide, 5XSSC, 50mM Tris-HCl (pH 7.5), 5mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA and 500. mu.g/ml denatured salmon sperm DNA. Hybridization was performed in the same solution with the following modifications: 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100. mu.g/ml salmon sperm DNA, 10% (weight/volume) dextran sulfate, and 5-20X 10⁶ cpm³²P-labeled probes. The filters were incubated in the hybridization mixture at 40 ℃ for 18-20 hours and then washed at 55 ℃ for 1.5 hours in a solution containing 2XSSC, 25mM Tris-HCl (pH 7.4), 5mM EDTA and 0.1% SDS. The wash was replaced with fresh solution and incubated at 60 ℃ for another 1.5 hours. The filters were blotted dry and exposed for autoradiography. If necessary, wash a third time at 65-68 ℃ and re-expose to film. Other conditions of low stringency that can be used are well known in the art (e.g., as used for hybridization of crossed species). (see also Shilo and Weinberg, 1981, Proc. Natl. Acad. Sci. U.S.A.78, 6789-S.6792).

The assay methods using labeled probes involve capturing the target sequence using one or more signal amplification steps and identifying the captured sequence. In certain embodiments, appropriately diluted cell lysates are hybridized to paxillin and a reference probe. Once the paxillin and reference mRNAs are captured, unbound material can be filtered and washed. Signal amplification can be performed in one or more steps, typically in 2 steps using a "pre-amplicon" probe followed by an "amplicon" probe, where unbound pre-amplicon is filtered and washed before amplification with amplicon. The sample may then be hybridized to the labeled probe, filtered and washed as before, and finally the label read or measured.

The increase in paxillin levels can be measured as a percentage increase relative to a control. Preferred paxillin stimulators increase paxillin levels by at least about 60%, at least about 80%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, or at least about 300% as compared to paxillin levels in the absence of the composition or in the presence of a control. Candidate materials may thus be identified as paxillin stimulators, e.g., candidate materials may be identified as upregulating paxillin mRNA, using one or more probes, compositions, and/or methods described herein, and such identified candidate materials are included within the scope of the present invention.

The identified paxillin stimulators may be used to formulate cosmetic compositions, as known in the art. The cosmetic composition is useful in anti-aging products, preferably formulated for topical application to the skin, for example, in a cosmetically acceptable vehicle. Formulations for anti-aging cosmetic products comprising paxillin stimulators are described in more detail below.

Cosmetic formulations of paxillin stimulating compounds

Compositions according to the present invention may be formulated for topical application in a variety of forms and will comprise from about 0.000001% to about 5% by weight of paxillin stimulator, from 0.00001% to about 2% by weight of paxillin stimulator, and preferably will comprise from about 0.0001% to about 1% by weight, more preferably from about 0.001% to about 0.1% by weight, and even more preferably from 0.01% to about 0.05% by weight, based on the total weight of the composition. The above amounts refer to the "active amount" of the paxillin stimulator, e.g., the amount of cis-6-nonenol. The term "active amount" refers to the amount of paxillin stimulant in the absence of diluents, solvents, carriers, fillers, and the like. The composition will comprise one or more effective amounts of one or more paxillin stimulators, by which is generally meant one or more amounts sufficient to increase the paxillin mRNA and/or protein levels in a given area of skin when topically applied thereto for a sufficient period of time.

In certain embodiments, the cosmetic composition comprises cis-6-nonenol and optionally at least one other paxillin stimulator. In certain such embodiments, the composition is substantially free of trans-6-nonenol isomers or substantially free of nonenol isomers having a double bond in a position other than the 6-position. By "substantially free" it is meant that such other nonenol constituting ingredients will comprise less than 5% by weight, preferably less than 2.5% by weight, and more preferably less than 1% by weight of the total amount of nonenol. In other embodiments, the composition will be free of nonenol other than cis-6-nonenol.

The compositions will be formulated in a variety of product forms, such as lotions, creams, sera, sprays, aerosols, cakes (cakes), ointments, serums, gels, pastes, patches, pens, towelettes, masks, sticks, foams, elixirs, concentrates, and the like, particularly for topical administration. Preferably, the composition is formulated as a lotion, cream, ointment or gel.

The compositions may include a cosmetically acceptable vehicle, including any pharmaceutically, physiologically, or dermatologically acceptable vehicle, diluent, or carrier. Such vehicles may take any form known in the art suitable for application to the skin, and may include water (e.g., deionized water); a vegetable oil; mineral oil; esters such as octyl palmitate, isopropyl myristate and isopropyl palmitate; ethers such as dioctyl ether and dimethyl isosorbide ester; alcohols such as ethanol and isopropanol; fatty alcohols such as cetyl alcohol, cetearyl alcohol, stearyl alcohol and biphenyl alcohol; isoparaffins such as isooctane, isododecane, and isohexadecane (isohexacan); silicone oils such as cyclomethicone, dimethicone crosspolymer, polysiloxane and derivatives thereof, preferably organically modified derivatives; hydrocarbon oils such as mineral oil, petrolatum, isoeicosane and polyisobutylene; polyhydric alcohols such as propylene glycol, glycerin, butylene glycol, pentylene glycol, and hexylene glycol; waxes such as beeswax and vegetable waxes; or any combination or mixture of the foregoing.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol phase, a silicone phase, or mixtures thereof. The cosmetically acceptable vehicle may also comprise an emulsion. Non-limiting examples of suitable emulsions include water-in-oil emulsions, oil-in-water emulsions, silicone-in-water emulsions, water-in-silicone emulsions, wax-in-water emulsions, water-oil-water triple emulsions, and the like, having the appearance of a cream, gel, or microemulsion. The emulsion may include an emulsifier, such as a nonionic, anionic or zwitterionic surfactant.

The oil phase of the emulsion preferably has one or more organic compounds, including emollients; humectants (e.g., butylene glycol, propylene glycol, methyl glucitol polyether-20, and glycerin); other water-dispersible or water-soluble components include thickeners such as Veegum or hydroxyalkyl celluloses; gelling agents such as high MW polyacrylic acid, CARBOPOL 934; and mixtures thereof. The emulsion may have one or more emulsifiers capable of emulsifying the various components present in the composition.

Compounds suitable for use in the oil phase include, but are not limited to, vegetable oils; esters such as octyl palmitate, isopropyl myristate and isopropyl palmitate; ethers such as dioctyl ether; fatty alcohols such as cetyl alcohol, stearyl alcohol and behenyl alcohol; isoparaffins such as isooctane, isododecane, and isohexadecane; silicone oils such as dimethicones, cyclic silicones, and polysiloxanes; hydrocarbon oils such as mineral oil, petrolatum, isoeicosane and polyisobutylene; natural or synthetic waxes, and the like. Suitable hydrophobic hydrocarbon oils may be saturated or unsaturated, aliphatic in character and straight or branched chain, or contain aliphatic or aromatic rings. The oleaginous phase may consist of a single oil or a mixture of different oils.

Hydrocarbon oils include those having from 6 to 20 carbon atoms, more preferably from 10 to 16 carbon atoms. Representative hydrocarbons include decane, dodecane, tetradecane, tridecane and C_8-20An isoparaffin. Paraffinic hydrocarbons may be prepared under the ISOPARS trademarkExxon, and from Permethyl Corporation. Furthermore, C_8-20Paraffinic hydrocarbons, for example, having the trade name Permethyl 99A^TMC manufactured by Permethyl corporation₁₂Isoparaffins (isododecane) are also considered suitable. Various commercially available C' s₁₆Isoparaffins such as isohexadecane (having the trade name:)) Are also suitable. Examples of preferred volatile hydrocarbons include polydecanes such as isododecane and isodecane, including, for example, Permethyl-99A (Presperse Inc.) and C₇-C₈Up to C₁₂-C₁₅Isoparaffins such as Isopar Series available from Exxon Chemicals. A representative hydrocarbon solvent is isododecane.

The oil phase may comprise one or more waxes including, for example, rice bran wax, carnauba wax, ouricury wax (ouricurry wax), candelilla wax, montan wax, sugar cane wax, ozokerite wax, polyethylene waxes, Fischer-Tropsch waxes, beeswax, microcrystalline waxes, silicone waxes, fluorinated waxes, and any combination thereof.

Non-limiting emulsifiers include emulsifying waxes, emulsifying polyols, polyether polyols, polyethers, mono-or diesters of polyols, ethylene glycol monostearate, glycerol distearate, silicone containing emulsifiers, soy steroids, fatty alcohols such as cetyl alcohol, acrylates, fatty acids such as stearic acid, fatty acid salts and mixtures thereof. Preferred emulsifiers include soy steroids, cetyl alcohol, stearic acid, emulsifying waxes, acrylates, silicone-containing emulsifiers, and mixtures thereof. Other specific emulsifiers that may be used in the compositions of the present invention include, but are not limited to, one or more of the following: sorbitan esters; polyglyceryl-3-diisostearate; c_10-30An alkyl acrylate crosspolymer; dimethicone PEG-7 isostearate, acrylamide copolymer; mineral oil; sorbitan monostearate, sorbitan tristearate, sorbitan sesquioleate, sorbitan monooleate; glycerides such as glycerol monostearateEsters and glycerol monooleate; polyoxyethylene phenols such as polyoxyethylene octylphenol and polyoxyethylene nonylphenol; polyoxyethylene ethers such as polyoxyethylene cetyl ether and polyoxyethylene stearyl ether; polyethylene glycol esters; polyoxyethylene sorbitan esters; dimethicone copolyol; polyglyceryl esters such as polyglyceryl-3-diisostearate; glyceryl laurate; steareth-2, Steareth-10 and Steareth-20, to name a few. Additional emulsifiers are provided in INCI Ingredient Dictionary and Handbook, 11 th edition 2006, the disclosure of which is incorporated herein by reference.

These emulsifiers are generally present in the compositions in an amount of about 0.001% to about 10% by weight, particularly about 0.01% to about 5% by weight, and more preferably about 0.1% to about 3% by weight.

The oil phase may comprise one or more volatile and/or non-volatile silicone oils. Volatile silicones include cyclic and linear volatile dimethylpolysiloxane silicones. In one embodiment, the volatile silicone may include a cyclomethicone, including tetramer (D4), pentamer (D5), and hexamer (D6) cyclomethicones, or mixtures thereof. Volatile cyclomethicone-hexamethylcyclotrisiloxane, octamethyl-cyclotetrasiloxane and decamethyl-cyclopentasiloxane may be mentioned in particular. Suitable dimeticones may be known under the name Dow CorningObtained from Dow Corning at Fluid, and has a viscosity ranging from 0.65 to 600,000 centistokes or higher. Suitable non-polar, volatile liquid silicone oils are disclosed in U.S. Pat. No. 4,781,917, incorporated herein by reference in its entirety. Additional Volatile Silicone materials are described in Todd et al, "Volatile Silicone Fluids for Cosmetics", Cosmetics and oils, 91: 27-32 (1976). Linear volatile silicones generally have a viscosity of less than about 5 centistokes at 25℃, while cyclic silicones have a viscosity of less than about 10 centistokes at 25℃. Examples of volatile silicones of varying viscosity include Dow Corning 200, Dow Corning 244, Dow Corning 245, Dow Corning344 and Dow Corning 345, (Dow Corning corp.); SF-1204 and SF-1202 Silicone Fluids (G.E. silicones), GE 7207 and 7158(General Electric Co.); and SWS-03314(SWS Silicones Corp.). Linear, volatile silicones include low molecular weight dimethylpolysiloxane compounds such as hexamethyldisiloxane, octamethyltrisiloxane, decamethyltetrasiloxane, and dodecamethylpentasiloxane, to name a few.

The non-volatile silicone oil typically comprises a polyalkylsiloxane, a polyarylsiloxane, a polyalkylarylsiloxane, or mixtures thereof. Polydimethylsiloxane is the preferred non-volatile silicone oil. The non-volatile silicone oil generally has a viscosity of from about 10 to about 60,000 centistokes at 25 ℃, preferably between about 10 to about 10,000 centistokes, and more preferably between about 10 to about 500 centistokes; and a boiling point greater than 250 ℃ at atmospheric pressure. Non-limiting examples include dimethylpolysiloxane (dimethicones), phenyltrimethicones, and diphenyldimethicones. The volatile and nonvolatile silicone oils may be optionally substituted with a variety of functional groups such as alkyl, aryl, amine, vinyl, hydroxyl, haloalkyl, alkaryl, and acrylate groups, to name a few.

The water-in-silicone emulsion may be emulsified with a non-ionic surfactant (emulsifier), such as a polydiorganosiloxane-polyoxyalkylene block copolymer, including those described in U.S. Pat. No. 4,122,029, the disclosure of which is incorporated herein by reference. These emulsifiers generally comprise a polydiorganosiloxane backbone, generally polydimethylsiloxane, having an average of- (EO)_m-and/or- (PO)_nSide chains of the radical, where EO is ethyleneoxy and PO is 1, 2-propyleneoxy, the side chains generally being hydrogen or lower alkyl (e.g. C)_1-6Generally is C_1-3) Capped or terminated. Other suitable water-in-silicone emulsifiers are disclosed in U.S. Pat. No. 6,685,952, the disclosure of which is incorporated herein by reference. Commercially available water-in-silicone emulsifiers include those available from Dow Corning under the trade names 3225C and 5225C FORMULATION AID; SILICONE SF-1528 available from general electric; available from Goldschmidt chemical CoABIL EM 90 and EM 97 obtained by rporation (Hopewell, Va.); and the SILWET emulsifier series sold by OSISPECIATIONIES (Danbury, CT).

Examples of water-in-silicone emulsifiers include, but are not limited to, dimethicone PEG 10/15 crosspolymer, dimethicone copolyol, cetyl dimethicone copolyol, PEG-15 lauryl dimethicone crosspolymer, cyclomethicone and dimethicone copolyol, dimethicone copolyol (and) caprylic/capric triglyceride, polyglyceryl-4 isostearate (and) cetyl dimethicone copolyol (and) hexyl laurate, and dimethicone copolyol (and) cyclopentasiloxane. Preferred examples of water-in-silicone emulsifiers include, but are not limited to, PEG/PPG-18/18 dimethicone (trade name 5225C, Dow Corning), PEG/PPG-19/19 dimethicone (trade name BY25-337, Dow Corning), cetyl PEG/PPG-10/1 dimethicone (trade name Abil EM-90, Goldschmidt Chemical Corporation), PEG-12 dimethicone (trade name SF 1288, General Electric), lauryl PEG/PPG-18/18 methylpolysiloxane (trade name 5200FORMULATION AID, Dow Corning), PEG-12 dimethicone crosspolymer (trade name 9010 and 9011 silicone elastomer blends, Dow Corning), PEG-10 dimethicone crosspolymer (trade name KSG-20, Shin-Etsu), dimethicone PEG-10/15 crosspolymer (trade name KSG-210, Shin-Etsu) and dimethicone PEG-7 isostearate.

Water-in-silicone emulsifiers are generally present in the compositions in an amount of from about 0.001% to about 10% by weight, particularly from about 0.01% to about 5% by weight, and more preferably less than 1% by weight.

The aqueous phase of the emulsion may include one or more additional solvents including lower alcohols such as ethanol, isopropanol, and the like. The volatile solvent may also be a cosmetically acceptable ester, such as butyl acetate or ethyl acetate; ketones such as acetone or ethyl methyl ketone, and the like.

The oil-containing phase generally comprises from about 10% to about 99%, preferably from about 20% to about 85%, and more preferably from about 30% to about 70% by weight based on the total weight of the emulsion, and the aqueous phase generally comprises from about 1% to about 90%, preferably from about 5% to about 70%, and more preferably from about 20% to about 60% by weight of the total emulsion. The aqueous phase typically comprises from about 25% to about 100%, more typically from about 50% to about 95%, by weight, of water.

In particular embodiments, the compositions may include up to about 70% by weight of one or more volatile solvents, including volatile organic solvents. In particular, the composition may comprise up to about 60%, preferably up to about 50%, more preferably up to about 40%, and even more preferably up to about 30% by weight of one or more volatile solvents. In other embodiments, the composition may be free of volatile solvents, including volatile organic solvents.

The composition may include liposomes. The liposomes may include other additives or substances and/or may be modified to more specifically reach or remain on the site after administration.

The composition may optionally include other cosmetic actives and excipients that will be apparent to those skilled in the art including, but not limited to, fillers, emulsifying agents, antioxidants, surfactants, film formers, chelating agents, gelling agents, thickeners, emollients, humectants, moisturizers, vitamins, minerals, viscosity and/or rheology modifiers, opacifiers, keratolytic agents, depigmenting agents, retinoids, hormonal compounds, alpha-hydroxy acids, alpha-keto acids, antimycobacterial agents, antifungal agents, antimicrobial agents, antiviral agents, analgesics, lipid compounds, antiallergic agents, H1 or H2 antihistamines, anti-inflammatory agents, anti-irritants, antineoplastic agents, immune system boosters, immune system inhibitors, anti-acne agents, anesthetics, bactericides, insect repellents, skin cooling compounds, skin protectants, and the like, Skin penetration enhancers, exfollients, lubricants, fragrances, colorants, depigmenting agents, whitening and depigmenting agents, preservatives (e.g., DMDM hydantoin/iodopropynyl butyl carbonate), stabilizers, pharmaceutical agents, photostabilizers, neutralizers (e.g., triethanolamine), and mixtures thereof. In addition to the foregoing, the cosmetic compositions of the present invention may contain any other compound useful for treating skin conditions.

Colorants may include, for example, organic and inorganic pigments and nacre agents (pearlescentings). Suitable inorganic pigments include, but are not limited to, titanium oxide, zirconium oxide, and cerium oxide, as well as zinc oxide, iron oxide, chromium oxide, and ferric blue (ferric blue). Suitable organic pigments include barium, strontium, calcium and aluminum lakes and carbon black. Suitable nacre agents include mica coated with titanium oxide, iron oxide or natural pigments.

Various fillers and additional components may be added. Fillers are generally present in an amount of about 0 wt% to about 20 wt%, preferably about 0.1 wt% to about 10 wt%, based on the total weight of the composition. Suitable fillers include, but are not limited to, silica, treated silica, talc, zinc stearate, mica, kaolin, nylon powders such as Orgasol^TMPolyethylene powder, Teflon^TMStarch, boron nitride, copolymer microspheres such as Expancel^TM(Nobel Industries)、Polytrap^TM(Dow Corning) and Silicone resin Microbeads (Tospearl from Toshiba)^TM) And the like.

In one embodiment of the present invention, the compositions of the present invention may comprise a fragrance. Fragrances are substances that can impart an aesthetically pleasing aroma to a composition. Typical fragrances include aromatic materials extracted from plant sources (i.e., rose petals, gardenias, jasmine flowers, etc.), which may be used alone or in any combination to produce essential oils. Alternatively, an alcoholic extract may be prepared for incorporation of a fragrance. However, due to the relatively high cost of obtaining fragrances from natural substances, the modern trend is to use synthetically prepared fragrances, particularly in high volume products. One or more fragrances may optionally be included in the composition in an amount ranging from about 0.001 to about 5 weight percent, preferably from about 0.01 to about 0.5% by weight. Fragrances may also be imparted to the composition by the paxillin stimulant, for example when the paxillin stimulant comprises a plant extract having a pleasant or desirable aroma. In other embodiments, the compositions of the present invention will be fragrance-free by which is meant that the compositions do not contain fragrances, particularly components added to provide the primary benefit of fragrance.

The compositions of the present invention may also contain one or more insect repellent actives. Such actives include, but are not limited to, N diethyl m-toluamide (DEET), ethyl butylacetylaminopropionate (IR 3535 by Merck co., inc.), hydroxyethylisobutylpiperidine carboxylate (1-piperidinecarboxylic acid) (Bayer KBR 3023), p-menthane-3, 8-diol, citronella oil, soybean oil, lemongrass oil, geranium/geraniol oil, neem oil and other natural essential oils, p-menthane-3, 8-diol, or any mixture thereof. The insect repellent active may be present in an amount of about 0.05 wt% to about 90 wt%, preferably about 0.1 wt% to about 50 wt%, and most preferably about 0.1 wt% to about 30 wt%, based on the total weight of the composition. In other embodiments, the compositions of the present invention are free of insect repellent actives by which is meant that the compositions do not contain insect repellents, such as components typically added as a result of the primary benefit of repelling insects.

In one embodiment of the present invention, the composition may include additional skin actives such as, but not limited to, botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, collagenase inhibitors, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, salicylic acid or salicylates, thiodipropionic acid or esters thereof, advanced glycation end product (AGE) inhibitors, and alpha-hydroxy acids.

In a particular embodiment, the composition may comprise at least one additional botanical, such as a plant extract, an essential oil, or the plant itself. Suitable botanicals include, but are not limited to, extracts from: fir (Abies pindrow), catechu (Acacia catechu), ulmus latifolia (Angoeissus latifolia), Osmunda japonica (Asmunda japonica, suspected of Osmunda japonica), neem tree (Azadirachta indica), Butea frondosa, Oryza sativa (Butea monosperma), Himalayan cedar (Cedrus deodara), Emblica officinalis (Emblica officinalis), Banyana banyana (Ficus benghassima), Glycyrrhiza glabra (Glycyrrhiza glabra), Ilex purpurea (Ilex purpira Hassk), saussurea racemosa (Inula racemosa), Ligusticum wallichii (Ligusticum wallichii argyroensis) and Angelica acutiloba (Ligusticum wallichii), Angelica gigas (Ligusticum acutiloba), Ligusticum acutillus longifolia (Ligusticum acutillus), Lycopersis officinalis (Morinarum nigrum officinale), Morus officinalis (Morinarum nigra), Morus alba (Morinarum nigra), Morinarum (Morinarum nigra indica), Morinarum (Morinaceae), Morinaceae (Morinaceae) and Morinaceae (Morinaceae).

The composition may contain additional active ingredients with anti-aging benefits as it is contemplated that synergistic improvements may be obtained with such combinations. Exemplary anti-aging components include, but are not limited to, botanicals (e.g., butea monosperma extract); thiodipropionic acid (TDPA) and its esters; retinoids (e.g., all-trans retinoic acid, 9-cis retinoic acid, phytanic acid, and others); hydroxy acids (including alpha-hydroxy acids and beta-hydroxy acids), salicylic acid, and salicylates; exfoliating agents (e.g., glycolic acid, 3, 6, 9-trioxaundecanedioic acid, and the like), estrogen synthase stimulating compounds (e.g., caffeine and derivatives); compounds capable of inhibiting 5 α -reductase activity (e.g., linolenic acid, linoleic acid, finasteride, and mixtures thereof); barrier function enhancing agents (e.g., ceramides, glycerides, cholesterol and esters thereof, alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, and the like); a collagenase inhibitor; and elastase inhibitors, to name a few.

Exemplary retinoids include, but are not limited to, retinoic acid (e.g., all-trans or 13-cis) and its derivatives, retinol (vitamin a) and its esters, such as retinol palmitate, retinol acetate and retinol propionate and their salts.

In another embodiment, the topical composition of the present invention may further comprise one or more of the following: skin penetration enhancers, emollients, skin plumpers, optical dispersants, sunscreens, exfoliants, and antioxidants.

Emollient provides enhanced skin lighteningSlippery and reduces the functional benefits of the appearance of fine lines and coarse wrinkles. Examples include isopropyl myristate, petrolatum, isopropyl lanolate, silicones (e.g., methyl polysiloxane, dimethyl polysiloxane), oils, mineral oil, fatty acid esters, cetyl ethylhexanoate, C_12-15Alkyl benzoate, isopropyl isostearate, diisopropyl dimer dilinoeate or any mixture thereof. It may be preferred that the emollient be present in an amount of about 0.1% to about 50% by weight of the total weight of the composition.

Skin plumping agents act as additional collagen enhancers to the skin. An example of a suitable and preferred skin plumper is palmitoyl oligopeptide. Other skin plumping agents are collagen and/or other glycosaminoglycan (GAG) enhancing agents. When present, the skin plumper may comprise about 0.1 wt% to about 20 wt% of the total weight of the composition.

Optical dispersants are particles that alter the surface optometrics of the skin, resulting in visual blurring and softening of, for example, lines and wrinkles. Examples of optical dispersants that may be used in the present invention include, but are not limited to, boron nitride, mica, nylon, Polymethylmethacrylate (PMMA), polyurethane powder, sericite, silica, silicone powder, talc, teflon, titanium dioxide, zinc oxide, or any mixture thereof. When present, the optical dispersant may be present in an amount of about 0.01 wt% to about 20 wt% of the total weight of the composition.

Sunscreens for protecting the skin from damaging ultraviolet radiation may also be included. Preferred sunscreens are those with a broad range of UVB and UVA protection, such as octocrylene, avobenzone (Parsol 1789), octyl methoxycinnamate, octyl salicylate, oxybenzone, homosylate, benzophenone, camphor derivatives, zinc oxide and titanium dioxide. When present, the sunscreen may comprise from about 0.01% to about 70% by weight of the composition.

Suitable exfoliating agents include, for example, alpha-hydroxy acids, beta-hydroxy acids, oxyacids (oxa acids), oxaziids, and derivatives thereof such as esters, anhydrides, and salts thereof. Suitable hydroxy acids include, for example, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic acids, mandelic acid, salicylic acid and derivatives thereof. A preferred exfoliating agent is glycolic acid. When present, the exfoliating agent can comprise from about 0.1% to about 80% by weight of the composition.

Antioxidants act in particular to scavenge free radicals from the skin, in order to protect the skin from environmental aggressors. Examples of antioxidants that may be used in the presented compositions include compounds having phenolic hydroxyl functionality, such as ascorbic acid and its derivatives/esters; an alpha-hydroxy acid; beta-carotene; a catechin; curcumin; ferulic acid derivatives (e.g. ethyl ferulate, sodium ferulate); gallic acid derivatives (e.g., propyl gallate); lycopene; reducing the acid; rosmarinic acid; tannic acid; tetrahydrocurcumin; tocopherols and their derivatives (e.g., tocopheryl acetate); uric acid; or any mixture thereof. Other suitable antioxidants are those having one or more thiol functions (-SH) in reduced or non-reduced form, such as glutathione, lipoic acid, thioglycolic acid and other sulfhydryl compounds. The antioxidants can be inorganic, such as bisulfites, metabisulfites, sulfites, or other sulfur-containing inorganic salts and acids. The compositions of the present invention may comprise antioxidants in the range of preferably from about 0.001% to about 10% by weight, and more preferably from about 0.01% to about 5% by weight of the total weight of the composition.

Other conventional additives include: vitamins such as tocopherol and ascorbic acid; vitamin derivatives such as ascorbyl monopalmitate; thickeners such as hydroxyalkyl cellulose; a gelling agent; structuring agents (structuring agents) such as bentonite, montmorillonite, magnesium aluminum silicate and lithium magnesium silicate; metal chelators such as EDTA; pigments such as zinc oxide and titanium dioxide; a colorant; an emollient; and a wetting agent.

Preferably, the composition is substantially free of components having a strong oxidizing potential, including, for example, organic or inorganic peroxides. By "substantially free of" these components is meant that they are present in an amount insufficient to have a measurable effect on the beneficial activity of one or more paxillin stimulators. In certain embodiments, this will be less than 1% on a molar basis relative to the amount of paxillin stimulator(s).

In one embodiment, the compositions of the present invention comprising at least one paxillin stimulator may have a pH between about 1 and about 8. In particular embodiments, the pH of the composition will be acidic, i.e., less than 7.0, and preferably between about 2 and about 7, more preferably between about 3.5 and about 5.5.

All terms used herein are intended to have their ordinary meaning unless otherwise provided.

As used herein, "weight percent" or "% by weight" refers to the weight percentage of the components relative to the total weight of the composition (i.e., including any carriers, vehicles, solvents, emollients, fillers, or other components added prior to application to the skin), unless otherwise specified.

Examples

Example 1: stimulation of paxillin mRNA in vitro

Normal human skin fibroblasts (Cascade Biologics) were cultured in 96-well tissue culture treatment plates, with 200. mu.l DMEM/well in 10% serum, and at 37 ℃ and 10% CO₂The mixture was incubated for 24 hours. In some cases, normal human epidermal keratinocytes (Cascade Biologics) were cultured in 200. mu.l EpiLife medium (Cascade Biologics)/well and at 37 ℃ and 5% CO₂The mixture was incubated overnight.

Stock solutions of candidate paxillin stimulators (test materials) were prepared in suitable solvents (e.g. DMSO, water, ethanol, 50: 50 ethanol: water mixtures) to give the wt% as shown in table 1 below. Cells were tested with test material diluted in growth medium or respective vehicle control in the presence of 10% CO₂Is treated in a humidified 37 ℃ incubator for 24 hours. After incubation, growth medium from each plate was removed and 100 μ Ι lysis buffer was added to the wells and placed with 5% CO₂At 37 ℃ for 30 minutes in an incubator. At the end of the incubation, the cells were collected in a fridge plate and placed in a-80 ℃ fridge until the time of analysis.

Using techniques using branched DNAMultiplex assay (Panomics inc. ca) analyzed changes in mRNA for paxillin in cell lysates after treatment. This technique is a target-specific RNA quantification method based on hybridization, which uses a labeled DNA probe to amplify one or more signals instead of the target RNA. The probe for the paxillin gene (ID: NM-005953) has been designed and synthesized. The paxillin probe, the reference probes PPIB and GAPDH, along with a set of other probes, were used in this multiplex assay.

Probes used include Capture Extenders (CE), Label Extenders (LE) and blocking agents (BL). As described above, this arrangement provides a target sequence that is double stranded, thereby improving hybridization efficiency. The CE, LE and BL sequences used to identify the paxillin mRNA correspond to SEQ ID NOS: 1. 2 and 3.

The appropriately diluted cell lysates were hybridized with paxillin and reference probe in hybridization plates in a vortex shaker incubator at 54 ℃. + -. 1 ℃ and 600rpm for 18-22 hours. After the paxillin and reference mRNAs were captured, the unbound material was filtered using a filter plate and washed 3 times with wash buffer. Signal amplification was performed using 2 steps: 2.0 preamplifiers (Panomics Inc.) were added first and incubated for 1 hour at 54 ℃. + -. 1 ℃ and 600rpm in a vortex incubator. Unbound pre-amplicons were filtered using filter plates and washed 2 times. The samples were next exposed to 2.0 amplicons (Panomics Inc.) and incubated, filtered and washed as with the preamplifiers. Next, the sample was hybridized with the biotinylated labeled probe and incubated at 54 ℃. + -. 1 ℃ and 600rpm for 1 hour. The sample was then filtered and washed as above. Finally, streptavidin-conjugated phycoerythrin (SAPE) working reagent was added and the mixture was shaken for 30 minutes at room temperature covered with aluminum foil. Unbound SAPE was filtered and washed 2 times. SAPE wash buffer was added to each well with shaking for 2-5 minutes, and then readings were immediately taken using a Luminex machine.

Values for the amount of paxillin mRNA were determined along with those for the reference genes PPIB and GAPDH. Values were normalized to GAPDH to determine changes in paxillin mRNA after treatment. The percentage increase in mRNA for paxillin was calculated in each case by comparing the values after treatment with candidate paxillin stimuli with the values after treatment with vehicle controls.

The results for an exemplary paxillin stimulus are presented in table 1 below.

TABLE 1

Fibroblasts treated with the indicated wt% of the various respective paxillin stimulators showed significant% stimulation in mRNA levels, as shown in table 1.

Example 2: stimulation of paxillin protein in human skin biopsies

Compositions comprising paxillin stimulators were each tested in 21 subject volunteers. For each paxillin stimulus, the composition was applied topically via patches attached to the back of the forearm of 21 volunteers each randomly selected, and vehicle controls were similarly applied to the back of the volunteers' forearms. After 3 weeks, human skin biopsies were obtained from the treated skin of multiple volunteers and immunohistochemical preparations were performed. Paxillin protein levels were confirmed by specific antibody staining followed by microscopy. Elevated protein levels were determined for each treated subject by comparison to vehicle controls. Results are expressed as the percentage of subjects showing improvement.

Results for an exemplary paxillin stimulus are presented in table 2.

TABLE 2

¹Results were not read for 1 subject treated with a topical composition comprising Lonchocarpus capasssa extract.

As illustrated in table 2, cis-6-nonenol showed increased paxillin levels in 71.4% of the subjects tested; whereas the loncho capasssa extract showed a positive result in 30.0%.

Further, an increase in paxillin protein was visibly observed in human skin biopsies. Representative photographs were obtained from the above biopsies. FIGS. 1A and B demonstrate the results in which the darker staining represents paxillin protein. As illustrated in FIG. 1, treatment with cis-6-nonenol (B) increases paxillin protein in human skin compared to treatment with control (A).

Example 3: exemplary compositions

Cosmetic compositions for topical application to the skin comprising the paxillin stimulator cis-6-nonenol are provided in table 3 below.

TABLE 3

All references cited herein, including patent applications and publications in their entirety and incorporated by reference herein for all purposes, are to the extent that each individual publication or patent application is specifically and individually indicated to be incorporated by reference in its entirety for all purposes. As will be apparent to those skilled in the art, many modifications and variations of the present invention can be made without departing from its spirit and scope. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims (34)

1. A topical composition for imparting an anti-aging benefit to skin comprising:

a paxillin irritant in an amount effective to impart an anti-aging benefit to skin, the paxillin irritant comprising at least one substance selected from the group consisting of: a pyridone fused azabicyclic compound of formula IV; a pyridone fused azabicyclic compound of formula V; a double-petal jasmine extract; a sphenoidea extract; ozothamnus obcordiatus extract; an erythrina variegate extract; loncho carpuscapassa extract; sophora Mollissima extract; tetrandrine; carvacrol; retinol punicic acid ester; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; and Cocculuglaucescens extract; and

a cosmetically acceptable vehicle.

2. A topical composition for imparting an anti-aging benefit to skin comprising:

a paxillin irritant in an amount effective to impart an anti-aging benefit to the skin, the paxillin irritant comprising at least 2 substances selected from the group consisting of: a pyridone fused azabicyclic compound of formula IV; a pyridone fused azabicyclic compound of formula V; a double-petal jasmine extract; red melon extract; an eclipta prostrata extract; a sphenoidea extract; ozothamnus obcordiatus extract; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; extract of Trifolium pratense; (ii) marshall aisha extract; kunzea ambigua extract; tanshinone IIA; tetrandrine; carvacrol; cis-6-nonenol; retinol punicic acid ester; retinol oleate; equol; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; terminalia catappa extract; an extract of Cocculus glaucescens; solid extract of Stephania japonica; and rosemary extract; and

a cosmetically acceptable vehicle.

3. The topical composition according to claim 2, wherein at least one of the paxillin stimulators comprises a pyridone fused azabicyclic compound of formula IV; a pyridone fused azabicyclic compound of formula V; a double-petal jasmine extract; an eclipta prostrata extract; a sphenoidea extract; ozothamnus obcordiatus extract; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; cis-6-nonenol; tetrandrine; carvacrol; retinol punicic acid ester; mycofusion Coriolus black corn biomass; mycofusion Maitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; or an extract of Cocculus glaucescens.

4. The topical composition according to claim 2, wherein the other paxillin stimulator comprises a hybrid clover extract, a Kunzea ambigua extract, tanshinone IIA, equol, a terminalia extract, or a rosemary extract.

5. The topical composition according to claim 2, wherein at least one of the paxillin stimulators is cis-6-nonenol.

6. The topical composition according to claim 5, wherein the other paxillin stimulator comprises a double-petal jasmine extract; an eclipta prostrata extract; a sphenoidea extract; ozothamnus obcordiatus extract; an erythrina variegate extract; loncho capasssa extract; sophora Mollissima extract; tetrandrine; carvacrol; mycofusion Coriolus black corn biomass; mycofusamaitake waxy naked barley biomass; radix Zanthoxyli extract; an extract of Ophiopogon japonicus; a platycodon grandiflorum extract; or an extract of Cocculus glaucescens.

7. The topical composition according to claim 1, wherein the composition does not comprise a hybrid clover extract and/or does not comprise retinol oleate and/or does not comprise equol.

8. The topical composition according to claim 2, wherein the composition does not comprise a hybrid clover extract and/or does not comprise retinol oleate and/or does not comprise equol.

9. The topical composition according to claim 5, wherein the composition does not comprise Trifolium hybridum extract and/or does not comprise retinol oleate and/or does not comprise equol.

10. The topical composition according to claim 5, wherein the paxillin stimulator is present in an amount sufficient to increase expression of paxillin.

11. The topical composition according to claim 1, wherein the composition further comprises a collagen stimulator.

12. The topical composition according to claim 2, wherein the composition further comprises a collagen stimulator.

13. The topical composition according to claim 5, wherein the composition further comprises a collagen stimulator.

14. A topical composition according to claim 13, wherein the collagen stimulator is TDPA.

15. The topical composition according to claim 1, further comprising at least one other skin active selected from the group consisting of botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, salicylic acid or salicylates, thiodipropionic acid or esters thereof, advanced glycation end product (AGE) inhibitors, and alpha-hydroxy acids.

16. The topical composition according to claim 2, further comprising at least one other skin active selected from the group consisting of botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, salicylic acid or salicylates, thiodipropionic acid or esters thereof, advanced glycation end product (AGE) inhibitors, and alpha-hydroxy acids.

17. The topical composition according to claim 5, further comprising at least one other skin active selected from the group consisting of botanicals, keratolytic agents, desquamating agents, keratinocyte proliferation enhancers, elastase inhibitors, depigmenting agents, anti-inflammatory agents, steroids, anti-acne agents, antioxidants, salicylic acid or salicylates, thiodipropionic acid or esters thereof, advanced glycation end product (AGE) inhibitors, and alpha-hydroxy acids.

18. A topical composition for imparting an anti-aging benefit to skin comprising:

cis-6-nonenol and a paxillin irritant other than cis-6-nonenol, said cis-6-nonenol and said paxillin irritant being present in said composition in an aggregate amount effective to impart an anti-aging benefit to said skin; and

a cosmetically acceptable vehicle.

19. A method for imparting an anti-aging benefit to human skin comprising topically applying the topical composition according to claim 1 to the skin of an individual in need thereof.

20. A method for imparting an anti-aging benefit to human skin comprising topically applying the topical composition according to claim 2 to the skin of an individual in need thereof.

21. A method for imparting an anti-aging benefit to human skin comprising topically applying the topical composition according to claim 5 to the skin of an individual in need thereof.

22. The method according to claim 21, wherein said anti-aging benefit is selected from the group consisting of:

(a) treatment, reduction and/or prevention of fine lines or wrinkles,

(b) the reduction of the pore size of the skin pores,

(c) improvement in skin thickness, plumpness and/or tautness;

(d) improvement in skin softness and/or softness;

(e) improvement in skin tone, radiance and/or clarity;

(f) improvement in procollagen and/or collagen production;

(g) improvement in skin texture and/or promotion of re-texturing;

(h) improvement in skin barrier repair and/or function;

(i) treatment and/or prevention of skin sagging or atrophy; and/or

(j) Improvement in skin contour appearance;

(k) restoration of skin radiance and/or brightness;

(l) Supplementation of essential nutrients and/or constituents in the skin;

(m) improvement in skin appearance reduced by menopause;

(n) improvement in skin moisturization and/or hydration; and

(o) improvement in skin elasticity and/or resiliency.

23. The method according to claim 22, wherein said anti-aging benefit is the treatment, reduction and/or prevention of fine lines or wrinkles.

24. The method according to claim 22, wherein the anti-aging benefit is the treatment and/or prevention of skin sagging or atrophy.

25. The method according to claim 22, wherein the anti-aging benefit is an improvement in skin thickness, plumpness, and/or tautness.

26. The method of claim 22, wherein the paxillin stimulator does not include horehound extract, retinol oleate, and equol.

27. A method for formulating a cosmetic composition for imparting an anti-aging benefit to human skin comprising:

assaying to determine whether the candidate material is a paxillin stimulator; and

incorporating the candidate material into a cosmetically acceptable vehicle.

28. The method according to claim 27, wherein the candidate material is a plant extract.

29. The method according to claim 27, wherein said candidate material is cis-6-nonenol.

30. The method of claim 27, wherein said assaying to determine whether the candidate material is a paxillin stimulator comprises contacting a human skin cell with said candidate material and assaying for upregulation of paxillin mRNA.

31. The method of claim 29, wherein said assaying to determine whether the candidate material is a paxillin stimulator comprises contacting a human skin cell with said candidate material and assaying for upregulation of paxillin mRNA.

32. A method for treating wrinkles and/or fine lines, comprising:

topically applying to the skin of an individual in need thereof an effective amount of paxillin stimulator in a cosmetically acceptable vehicle for a time sufficient to reduce the severity of the wrinkles and/or fine lines,

wherein the paxillin stimulator is identified by contacting human skin cells with a candidate material and measuring upregulation of paxillin mRNA.

33. The method according to claim 32, wherein the candidate material is a plant extract.

34. The method according to claim 32, wherein said candidate material is cis-6-nonenol.