HK1146730A - Novel compounds, use thereof in cosmetic and cosmeceutic applications, and compositions comprising same - Google Patents

Description

Novel compounds, their use in cosmetic and pharmacosmetology applications and compositions comprising them

CROSS-REFERENCE TO RELATED APPLICATIONS

According to 35 u.s.c. § 119(e), the present application claims priority to U.S. provisional application serial No. 60/947,144 filed on 29/2007 and U.S. provisional application serial No. 60/984,136 filed on 31/2007. The contents of the above documents are incorporated herein by reference in their entirety.

Technical Field

The present invention relates generally to cosmetic, dermatological and pharmaceutical compositions and to food supplements. More particularly, the present invention relates to compounds, compositions and methods of treatment/prevention for skin conditions (skin conditions), for example, for preventing or treating signs of skin aging (e.g., wrinkles and fine lines) and loss of skin firmness and elasticity.

Background

The epidermis and dermis, separated by the basement membrane, constitute the skin covering layer on the subcutaneous tissue. The epidermis is the outermost layer of the skin and provides resistance and impermeability.

Although different types of cells coexist in the epidermis, keratinocytes constitute the majority of this layer and play a role in the resistance provided by the mucocutaneous barrier. The core activity of these cells is the synthesis of keratin, which accounts for nearly 90% of all proteins in the epidermis.

The dermis (the inner layer of the skin) is a connective tissue composed of cells (essentially fibroblasts) dispersed in a complex medium called the extracellular matrix (ECM). The matrix comprises collagen and elastin fibres, glycoproteins (fibronectin and laminin) and proteoglycans. The extracellular matrix provides the structure for cells, allowing tissues and organs to attach in multicellular organisms.

The interaction between epidermal cells and dermal fibers plays an important role in controlling cell behavior (e.g., healing), but also provides stability, for example, to the dermoepidermal junction (DEJ), which anchors the epidermis to the dermis and forms a protective barrier. DEJ works at different levels. First, it uses a collagen IV network to firmly anchor the epidermis to the dermis and thus acts as a mechanical support. It also exerts a biological effect by establishing a direct link with the basal cells of the epidermis. It also acts as an important depot for growth factors. Finally, it supports keratinocytes during the healing process.

The DEJ includes 2 layers: (A)substrateEpidermal cells adhere to the substrate. The substrate itself consists of 2 layers: a transparent plate and a dense plate. This is where type IV collagen, proteoglycans and glycoproteins are found, these components are organized in the anchoring fibrils that produce the plates. Laminins are glycoproteins that allow keratinocytes to adhere to the substrate. A large number of laminins are present in the substrate, the most common of which are laminin-5, laminin-6, and laminin-7 and laminin-1. Laminin-5 (also known as laminin 332) is a versatile matrix protein that is the most common laminin found in basement membranes of skin. It is the most common adhesion protein for cells in the epidermis. Laminin-5 plays a dual role: it is capable of inducing strong and strategic cell adhesion or, conversely, it is capable of producing weak, transient adhesion to cell migration. This property is well illustrated in the skin, since while laminin-5 immobilizes the epidermis, it also plays a role in the migration of keratinocytes during the healing process. In vivo skin healing studies have demonstrated higher expression of pre-laminin-5 in the ECM of keratinocytes located in the wound colonized zone, indicating that the lack of proteolytic maturation promotes fine cellsThe cells migrate. Laminin-5 also plays a key role in cellular remodeling and scarring.

(B)Screen plate: also known as the dense lower plate (sub-lamellar densa), which is attached to the dermis and comprises a dense matrix formed in part by fibrils of collagen VII, III and I and a basal material. Collagen VII (synthesized primarily by keratinocytes) is the major component of the dense lower plate, representing the essential anchoring fibers. In conjunction with laminin-5 or collagen IV of the dense plate, the sessile fibrillar protein collagen VII reaches down into the dermal matrix. The anchoring fibers form a solid structure, whose functional role is to connect the dense plates to the papillary dermis where they attach to dermal collagen fibers composed of types I, III and V collagen. At its N-terminus, each triple helix of collagen VII is flanked by globular NC1 domains. Two of these chains are joined at their C-termini to form a dimer. These dimers are short, striated fibrils that associate laterally to form anchoring fibrils. Collagen VII interacts with other components of the extracellular matrix through its NC1 domain, which is fixed to laminin-5 and the basement membrane to the dermis, where it is linked to other types of collagen (I and III). It can be seen that some inherited and rare diseases can be attributed to the lack of collagen VII. Any molecule found in either of the substrate and/or the mesh plate, such as collagen, proteoglycans, and glycoproteins (including laminin), is referred to herein as a DEJ molecule.

Skin aging results from 2 processes: (1) the internal process is equivalent to aging year by year; and (2) extrinsic processes mainly caused by the harmful effects of exposure to sunlight and environmental pollution.

When aged, it can be seen that the connective component of the dermis produces important changes: collagen loses its regular and fasciculate appearance, while matrix increases, elastic mass decreases and the fibroblast population becomes "dormant". Moreover, during skin aging, DEJ gradually loses its ability to exert its mechanical properties, which results in a weakening of the epidermal-dermal interface. The resulting dermal aging varies from person to person and is associated with a genetic background and exposure to multiple insults.

One of the goals of cosmetic research is to control or prevent skin aging. The traditional methods known today, based on supplying keratinocyte and fibroblast metabolism, are not sufficient, especially in light of the latest data on DEJ.

Therefore, there is a need to develop new methods of preventing and/or treating skin conditions such as skin aging.

Summary of The Invention

More specifically, according to the present invention, there is provided a compound of formula I (SEQ ID NO: 5):

R-A-Gly-His-B-R’(I)

wherein: a and B are each independently of the other an L-lysine residue, a D-lysine residue or NH in a side chain thereof₂The group comprises a modified L-or D-lysine residue, wherein the modification is (i) a substitution with hydrogen, (ii) acetylation, (iii) benzoylation or (iv) palmitoylation; gly is glycine residue; his is an L-or D-histidine residue; r is of the formula CH₃-(CH₂)_n-amino-terminal modification of CO-, wherein n ═ 2, 3, 4, 5, 6, 7, or 8; r' is a group of formula (II):

N(Z)(Z’) (II)

wherein: z and Z' are independently of each other hydrogen, methyl, ethyl, phenyl, hexyl, decyl or hexadecyl; or a racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a salt thereof.

In particular embodiments of the compounds of the present invention, n is 4, 5 or 6. In another particular embodiment, Z and Z' are hydrogen. In another particular embodiment, A and B are independently of each other an L-lysine residue or a D-lysine residue. In another specific embodiment, the lysine and histidine residues are in the L-configuration. In another specific embodiment, the compound is CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 1) or CH₃-(CH₂)₆-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 2). In another specific embodiment, the compound is CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 1). In SEQ ID NO: 1-4, -Lys-NH₂Amidation of the carboxyl group representing a lysine residue (i.e. -CONH)₂)。

According to another aspect of the invention, there is provided a composition comprising an effective amount of a compound of the invention together with a topical, cosmetic or pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides a composition for preventing, reducing, delaying or treating a skin condition in a subject, the composition comprising a compound of the present invention and a topically, cosmetically or pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides a composition for inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system, the composition comprising a compound of the present invention and a topically, cosmetically, or pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides a compound of the invention for use in preventing, reducing, delaying or treating a skin condition in a subject.

In another aspect, the present invention provides a compound of the invention for use in inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system.

In a particular embodiment of the composition, the effective amount is about 10^-8M to about 10^-2And M. In another specific embodiment, the effective amount is about 10^-6M to about 10^-5And M. In another specific embodiment, the composition is a topical composition. In another specific embodiment, the composition is an aqueous solution, cream, oil-in-oilWater-in-water emulsions, oil-in-water emulsions, gels, sprays, ointments, lotions or pastes. In another particular embodiment, the composition further comprises at least one additional active agent.

According to another aspect of the present invention there is provided the use of a compound of the invention or a composition of the invention for the prevention, reduction, delay or treatment of a skin condition.

In a particular embodiment, the use of a compound or composition of the invention is for the preparation of a medicament for the prevention, reduction, delay or treatment of a skin condition.

In another specific embodiment, said skin condition is an aging-related skin condition. In another specific embodiment, said skin condition associated with aging is the appearance or presence of (a) wrinkles, (b) fine lines, or (c) both (a) and (b) on the skin. In another specific embodiment, said skin condition is a skin lesion. In another specific embodiment, the skin lesion is associated with a surgical treatment, dermabrasion, laser treatment, or peeling (peeling).

In another particular embodiment, the use of the compound or composition is for inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system.

In another specific embodiment, the at least one DEJ molecule is (a) laminin-5, (b) collagen VII, or (c) both (a) and (b). In another specific embodiment, the biological system is a cell, tissue or organ. In another specific embodiment, the cell is a skin cell. In another specific embodiment, the organ is skin.

According to another aspect of the present invention there is provided a method of preventing, reducing, delaying or treating a skin condition in a subject, the method comprising administering to the subject an effective amount of a compound of the invention or a composition of the invention. In the specific implementation of the methodIn the method, the skin condition is an aging-related skin condition. In another specific embodiment, said skin condition associated with aging is the appearance or presence of (a) wrinkles, (b) fine lines, or (c) both (a) and (b) on the skin. In another specific embodiment, said skin condition is a skin lesion. In another specific embodiment, the skin lesion is associated with a surgical treatment, dermabrasion, laser treatment, or peeling. In another specific embodiment, the administration is topical. In another specific embodiment, the effective amount is about 10^-8M to about 10^-2M of said compound. In another specific embodiment, the effective amount is about 10^-6M to about 10^-5M of said compound.

According to another aspect of the present invention, there is provided a method of inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system, the method comprising contacting the biological system with a compound of the present invention or a composition of the present invention. In particular embodiments of the method, the at least one DEJ molecule is (a) laminin-5, (b) collagen VII, or (c) both (a) and (b). In another specific embodiment, the biological system is a cell, tissue or organ. In another specific embodiment, the cell is a skin cell. In another specific embodiment, the organ is skin.

According to another aspect of the invention there is provided a kit or pack comprising a compound of the invention or a composition of the invention and instructions for preventing, reducing, delaying or treating a skin condition in a subject.

According to a further aspect of the invention there is provided a kit or pack comprising a compound of the invention or a composition of the invention and a container.

Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only and with reference to the accompanying drawings.

Brief Description of Drawings

In the drawings:

figure 1 is a photograph of canthus wrinkles in volunteer subjects on day 0 and day 28 after application of a composition comprising peptide I;

figure 2 is a graph showing the average progression of canthus wrinkle roughness after 28 days and 56 days of application of a composition comprising peptide I;

figure 3 is a graph showing the average progression of canthus wrinkle skin roughness after 28 days and 56 days of application of a composition comprising peptide I; and

figure 4 is high resolution ultrasound imaging (20MHz) of dermal texture at day 0 and day 168 after application of a composition comprising peptide I or placebo.

Description of illustrative embodiments

The applicant has found that: a family of compounds, more particularly the compounds of formula I below, are useful for treating skin conditions, for example, for preventing, retarding, reducing or treating the effects of aging on skin.

Accordingly, the present invention provides a compound of formula (I):

compounds of formula I (SEQ ID NO: 5)

R-A-Gly-His-B-R’ (I)

Wherein:

a and B are each independently of the other an L-lysine residue, a D-lysine residue or NH in a side chain thereof₂The group comprises a modified L-or D-lysine residue, wherein the modification is (i) deamination (e.g., replacement with hydrogen), (ii) acetylation, (iii) benzoylation, or (iv) palmitoylation;

gly is glycine residue;

his is an L-or D-histidine residue;

r is of the formula CH₃-(CH₂)_n-amino-terminal modification of CO-, wherein n ═ 2, 3, 4, 5, 6, 7, or 8;

r' is a group of formula (II):

N(Z)(Z’) (II)

wherein: z and Z' are independently of each other hydrogen, methyl, ethyl, phenyl, hexyl, decyl or hexadecyl;

or a racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a salt thereof.

In a particular embodiment, the above modification of the lysine residue is a protecting group for the amine functionality of the lysine side group/chain.

In particular embodiments, the amino-terminal modification R provides a useful hydrophilic/lipophilic balance that facilitates skin penetration.

The compounds of formula (I) may have one or more asymmetric carbon atoms in enantiomeric or diastereomeric form. Accordingly, the present invention provides enantiomers and diastereomers of the compounds of formula (I) and mixtures thereof, including racemic mixtures.

In one embodiment, the above compound is

CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 1) or CH₃-(CH₂)₆-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 2). In another embodiment, the above compound is CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO：1)。

The amino acids in the compounds of the invention may exist in their natural L-configuration, unnatural D-configuration or as a racemic mixture (DL).

In particular embodiments, the lysine and histidine residues of the compound are in the L-configuration.

The compounds of formula I of the present invention may be efficiently obtained by classical chemical synthesis or by enzymatic synthesis via procedures known to those skilled in the art.

According to the invention, the compounds of the general formula (I) can be prepared according to chemical synthesis methods in solution or on solid supports, for example on supports with resins. Among the resins used for this purpose are Rink resin (or 4- (2 ', 4' -dimethoxyphenyl-Fmoc-aminomethyl) -phenoxy resin) (h.rink, Tetrahedron let., 1987, 28, 3787) and MBHA resin (or 4-methyl-benzhydrylamine resin) (g.r. matsueda et al, Peptides, 1981, 2, 45).

The initial product obtained is usually a protected amino acid. The protecting groups may be acetyl (Ac) or 9-fluorenylmethoxycarbonyl (Fmoc) on the primary amino function, tert-butyloxycarbonyl (Boc), trityl (Trt) and 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl (Pmc) on the side chain function. Techniques and methods for washing, coupling and amino acid/peptide deprotection are well known in the art. The peptides thus obtained can be analyzed using techniques well known in the art, such as High Performance Liquid Chromatography (HPLC) and mass spectrometry.

The compounds of the invention may be modified using methods well known in the art, for example to increase their stability and/or to facilitate their uptake/absorption and/or to improve any other desired property or property of the compounds known to those skilled in the art. For example, the compound may be cyclized, the charge on the compound may be neutralized, and the compound may be attached to other chemical moieties.

The above compounds may take the form of salts prepared from any physiologically acceptable organic or inorganic acid. In one embodiment, the above salts are salts that stabilize the compound and are tolerated by the skin. In one embodiment, the salt is an acetate salt.

In another aspect, the invention provides compositions (e.g., cosmetic, dermatological and pharmaceutical compositions) or food supplements comprising a compound of formula (I) or a salt thereof.

The invention includes methods of administering a compound in an amount effective to provide the desired result. For example, when the compounds of the present invention are applied topically, the compound of formula (I) is present in the compositions of the present invention at about 10^-8M to about 10^-2The concentration of M is present. In another embodiment, the compound of formula (I) may be present in the compositions of the present invention at about 10^-6M to about 10^-5The concentration of M is present. In another embodiment, the compound of formula (I) is present in the compositions of the invention at about 0.5mg/kg to about 50mg/kg (i.e., 0.5 to 50PPM or 0.88X 10)^-6M to 0.88X 10^-4M) is present.

The compounds of formula (I) of the present invention may be formulated in topically applicable cosmetic compositions (e.g., topical formulations). Non-limiting examples of such topically applicable compositions include skin creams, cleansing creams, ointments, skin care emulsions, skin care gels, skin care foams, sun care (sun care) compositions, dump creams, dump emulsions, foundation creams, emulsion foundations, bath and shower preparations, deodorant compositions, antiperspirant compositions, shaving product compositions, post-shave gels or emulsions, cosmetic auxiliary compositions, depilatory creams, soap compositions, hand sanitizer compositions, skin cleansing bar (cleansing bar), baby care products, hair care products, shampoos, styling lotions, treatment emulsions (treatment), hair creams, hair gels, coloring compositions, restructuring compositions (restructuring compositions), permanent compositions (managementcompositions), anti-sloughing compositions, or any other composition suitable for use in a topical cosmetic regimen.

Creams, as are well known in the pharmaceutical and cosmeceutical arts, are viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Cream bases are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase (also referred to as the "internal phase") typically consists of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase is typically, although not necessarily, in volume excess of the oil phase and typically contains a humectant. The emulsifier in a cream formulation is typically a nonionic, anionic, cationic or amphoteric surfactant.

Emulsions (lotions) are formulations that are applied to the skin surface without friction, usually liquid or semi-liquid formulations, in which solid particles (including active agents) are present in a water or alcohol matrix. Emulsions are generally solid suspensions, preferably comprising oil-in-water liquid oily emulsions for the purposes of the present invention. Emulsions are preferred formulations for handling large body areas because of the ease with which more fluid compositions can be applied. It is often necessary to subdivide the insoluble material in the emulsion. Emulsions will generally contain a suspending agent to give better dispersion and a compound useful for localizing and maintaining the active agent to the skin, such as methylcellulose, sodium carboxymethylcellulose, and the like.

A solution is a homogeneous mixture made by dissolving one or more chemical substances (solutes) in a liquid so that the molecules of the dissolved substance are dispersed in the solvent molecules. The solution may contain other pharmaco-cosmetically acceptable chemicals to buffer or stabilize or preserve the solutes. Common examples of solvents used to prepare the solution are ethanol, water, propylene glycol or any other pharmaceutically cosmetically acceptable carrier.

Gels are semi-solid suspension-type systems. Single phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also preferably contains an alcohol and optionally an oil. The "organic macromolecule", i.e.the gelling agent, is a crosslinked acrylic acid polymer, for example of the "carbomer" family, such as, for example, Carbopol^TMCommercially available carboxypolyalkenes (carboxypolyalkylenes). Other examples are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose phthalate and methyl cellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. For preparing a homogeneous gel, one may addDispersing agents such as alcohols or glycerol, or the gelling agent may be dispersed by grinding, mechanical mixing or stirring or a combination thereof.

Ointments are semisolid preparations which are usually based on petrolatum or other petroleum derivatives. As will be appreciated by those skilled in the art, the particular ointment base used is one that will provide a number of desirable characteristics, such as emolliency, etc. The ointment base, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing. Ointment bases can be divided into four categories as explained in Remington: The Science and Practice of Pharmacy, 19 th edition (Iston, Pa.: Mack publishing company, 1995) at pages 1399-1404: a greasy base; an emulsifiable base; an emulsion-type matrix; and a water-soluble base. Oleaginous ointment bases include, for example, vegetable oils, fats derived from animals, and semi-solid hydrocarbons derived from petroleum. Emulsifiable ointment bases (also known as absorbent ointment bases) contain no or almost no water, and include, for example, hydroxystearyl sulfate, anhydrous lanolin, and hydrophilic petrolatum. The emulsion-type ointment base is a water-in-oil (W/O) type emulsion or an oil-in-water (O/W) type emulsion, which includes, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights; for further information, see again Lee's pharmaceutical sciences and practices.

Pastes are semisolid dosage forms in which the active agent is suspended in a suitable matrix. Pastes are classified as fatty pastes or pastes prepared from single-phase aqueous gels, depending on the nature of the matrix. The base in the fatty paste is usually vaseline, hydrophilic vaseline or the like. Pastes prepared from single-phase aqueous gels typically incorporate carboxymethyl cellulose or the like as a base.

Liposomes, micelles and microspheres may also be used to prepare the formulations. Liposomes are tiny vesicles having a lipid wall comprising a lipid bilayer, herein encapsulating one or more components of an anti-aging formulation. Liposomal formulations herein include cationic (positively charged), anionic (negatively charged) formulationsLotus) and neutral preparations. Cationic liposomes are readily available. For example, N1-2, 3-dioleyloxy]Propyl radical]Liposomes of-N, N, N-triethylammonium (DOTMA) can be sold under the trade name Lipofectin^TM(GIBCOBRL, Grand Island, N.Y.). Similarly, anionic and neutral liposome sheets are readily available, such as from Avanti Polar Lipids (burmingham, Ala.), or can be readily prepared using readily available materials. Such materials include phosphatidylcholine, cholesterol, phosphatidylethanolamine, Dioleoylphosphatidylcholine (DOPC), Dioleoylphosphatidylglycerol (DOPG), and Dioleoylphosphatidylethanolamine (DOPE). These materials may also be mixed with DOTMA in appropriate proportions. Methods for preparing liposomes using these materials are known in the art.

Micelles are known in the art to comprise surfactant molecules arranged such that their polar head groups form an outer spherical shell, while the hydrophobic hydrocarbon chains form a core towards the centre of the sphere. Micelles are formed in an aqueous solution containing a surfactant at a concentration sufficiently high to naturally form micelles. Surfactants that may be used to form micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecyl sulfonate, sodium lauryl sulfate, sodium docusate, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyethylene-8-dodecyl ether, polyoxyethylene-12-dodecyl ether, nonylphenol polyether 10, and nonylphenol polyether 30.

Similarly, microspheres may be added to the present formulation. Like liposomes and micelles, microspheres substantially encapsulate one or more components of the formulation. Although not necessarily so, they are typically formed from lipids, preferably charged lipids such as phospholipids. The preparation of lipid microspheres is well known in the art and is described in the relevant text and literature.

In one embodiment, the composition of the invention further comprises at least one additional active ingredient/agent. In another embodiment, the at least one additional active ingredient described above modulates at least one of cell differentiation, cell metabolic activity, cell structure, cell proliferation, extracellular processes, and pigmentation.

The composition of the invention may also comprise at least one of the following: substances regulating cell differentiation or proliferation, anesthetics, anti-acne agents, anti-aging agents, antibacterial agents, anti-cellulite agents, antifungal agents, anti-inflammatory agents, anti-irritants, antioxidants, antiparasitic agents, anti-staining agents, antipruritic agents, anti-rosacea agents, anti-seborrheic agents, anti-stress agents (anti-stress agents), anti-microvascular dilating agents, antiviral agents, anti-wrinkle agents, infant care agents, bath and body agents, soothing agents (bathing agents), cleansing agents, collagen synthesis agents, elastase inhibitors, exfoliants, facial exfoliants, firming agents, foot care agents, free radical scavengers, immune function regulators, keratolytic agents, lifting agents (lifting agents), makeup removers, melanogenesis stimulators, hair care agents, matrix metalloproteinase inhibitors, Moisturizers (moisturizing agents), oil absorbing agents, penetration modifiers, anti-photoaging agents, protectants, rejuvenating agents, sensitive skin materials, shaving product materials, skin defense enhancers, cleansing product materials, skin rejuvenating agents, slimming agents, soothing agents (smoothening agents), emollients (soothing agents), sunscreens, sunless tanning agents, tightening agents (tightening agents) and whitening agents, or any other material suitable for use in a cosmetic regimen including topical application of the cosmetic composition and to supplement or complement the effects of the compounds of the present invention.

Without limitation, substances that regulate cell differentiation or proliferation include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts (animalderitive extracts), and synthetic compounds. More specifically, such substances include retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoyl glucuronides (retinoyl glucoronoides), tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl esters), vitamin D and its derivatives (cholecalciferol, ergocalciferol, 25-hydroxycholecalciferol), growth factors, and estradiol derivatives.

The anesthetic includes, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include lidocaine hydrochloride and its derivatives.

Without limitation, anti-acne agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include benzoyl peroxide, retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, retinoyl glucuronide, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl ester), salicylic acid, sulfur-containing lime, alcohols, and acetone.

The anti-aging/anti-wrinkle agent includes, but is not limited to, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include hyaluronic acid, sodium 2-pyrrolidone formate, glycosaminoglycans, kinetin, retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoylglucuronide, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl esters), epidermal growth factor, ceramide, manganese ethyl bisiminomethyl guaiacol chloride, glycation inhibitors, Chrysanthemum indicum (Chrysanthemum indicum) extract, and Aphanidinum aquaticum (Aphanomenon flos aquae) extract.

The antimicrobial agent includes, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include eucalyptus extract, clindamycin phosphate, cavacrol (carvacrol), erythromycin, and tetracycline antibiotics.

Antifungal agents include, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such agents include econazole, ketoconazole, miconazole, amphotericin B, terbinafine, and pyridone ethanolamine salt (octopirox).

The anti-inflammatory agent includes, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include allantoin, vitamin E and its derivatives (alpha-tocopherol, delta-tocopherol, gamma-tocopherol), chamomile oil, ginkgo biloba (gingko biloba) oil, and camellia sinensis (camellia sinensis) extract.

Non-limiting examples of anti-irritants/emollients/soothing agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include allantoin, camellia sinensis extract, lavender oil, aloe vera (aloe vera), linden extract, willowherb (Epilobium angustifolium) extract, chrysanthemum indicum (Chrysanthemum indicum) extract, Cola nitida (cola nitida) extract, and alteromonas (alteromonas) ferment extract.

Antioxidants include, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include furfuryl adenine, panthenol, lipoic acid, ubiquinone, niacinamide, melatonin, catalase, glutathione, superoxide dismutase, polyphenols, cysteine, allantoin, kinetin, vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate), vitamin E and its derivatives (alpha-tocopherol, delta-tocopherol, gamma-tocopherol), grape seed extract and camellia sinensis extract.

Without limitation, antipruritic agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include cinalidine (thenaldine), alimemazine, cyproheptadine.

Without limitation, anti-rosacea/anti-microvascular dilators include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and their derivatives, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include metronidazole, vasoconstrictors, benzoyl peroxide, azelaic acid, sulphur, soy protein and glycosaminoglycans.

Without limitation, anti-seborrhea agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include progesterone derivatives, isoluterol and hinokitiol.

The sensitive skin substance includes, but is not limited to, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such materials include rose oil and jasmine oil.

Without limitation, detergents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include ammonium lauryl sulfate, ammonium polyoxyethylene lauryl ether sulfate, cocamide MEA, triethanolamine lauryl sulfate, sodium stearate, and nettle leaf extract.

Without limitation, collagen synthesizing agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoylglucuronide, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl ester), vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate), growth factors and their derivatives.

Without limitation, exfoliants include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include alpha/beta hydroxy acids, salicylic acid, glycolic acid, lactic acid, citric acid (citrus acid) and walnut shell powder.

Without limitation, facial exfoliants include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such materials include glycolic acid, lactic acid, trichloroacetic acid and phenol.

Without limitation, skin firming/firming agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More particularly, such materials include dimethylaminoethanol, neuro-cosmetic actives (e.g., Botox)^TM) Chitosan, arnica extract, fennel-sweet oil (fennel-sweet oil) and papaya extract.

Without limitation, free radical scavengers/anti-fouling agents/anti-stress agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include grape seed extract, alpha-tocopherol and its esters, superoxide dismutase, some metal chelators, vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate).

Hair conditioners include, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such materials include poly-D-glucosamine, poly-N-acetyl-D-glucosamine, stearyl dimethylbenzyl ammonium chloride, and triethanolamine lauryl sulfate.

Without limitation, matrix metalloproteinase inhibitors include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include Camellia sinensis extract, polyphenols, caulis Spatholobi (spatholobi caulis) extract, Euonymus alatus (euonymus alatus) extract, Notopterygii rhizoma (rhizopus notopterygii) extract, quercetin, glycosaminoglycans, polymethoxyflavonoids, N-acetyl-cysteine, 2-furobinodioxime, isoflavones, vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate), retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, retinoylglucuronide, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl ester), and hydroxamic acid derivatives.

Without limitation, humectants include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include cucumber extract, sodium 2-pyrrolidone formate, sodium PCA, sodium hyaluronate, chitin and its derivatives, alpha hydroxy acids, hyaluronic acid and hydrolyzed wheat protein.

Without limitation, osmolytes include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such materials include mannitol, dulcitol and betaine.

The protectant includes, without limitation, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include poly-N-acetyl-D-glucosamine, poly-D-glucosamine, alkyl (alcohol) amides (alkyloamides), chitosan, chrysanthemum indicum (Chrysanthemum indicum) extract, Camellia sinensis extract, and alteromonas (alteromonas) ferment extract.

Non-limiting examples of pro-pubertal agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More specifically, such substances include rosemary extract, rosewood (rosewood) extract, geranium extract and vitamin E and its derivatives (alpha-tocopherol, delta-tocopherol, gamma-tocopherol).

Without limitation, skin rejuvenating agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts, and synthetic compounds. More particularly, such materials include retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoyl glucuronide, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, adapalene, beta-carotene, retinyl esters), allantoin, eucalyptus extract, lavender oil, rose oil, and activators of collagen synthesis and of extracellular matrix components of the skin.

The weight-reducing/anti-cellulite agent includes, but is not limited to, plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include wild chrysanthemum (Chrysanthemum indicum) extract, dihydromyricetin, theobromine, theophylline, aminophylline, caffeine, isopropyl norepinephrine hydrochloride, epinephrine, alpha-MSH agonists, adenylate cyclase activators, and phosphodiesterase inhibitors.

Without limitation, sunscreens/photoaging agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such materials include PABA (p-aminobenzoic acid) and derivatives, gluconolactone, salicylates, cinnamates, benzophenone, dibenzoylmethane, oxybenzone, vitamin E and its derivatives (α -tocopherol, δ -tocopherol, γ -tocopherol), ethylbisiminomethylguaiacol manganese chloride, glycosaminoglycans, retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoylglucuronide, retinoic acid, isotretinoin, etretinate, acitretin, abamectin, tazarotene, adapalene, β -carotene, retinyl ester), titanium dioxide, methoxyoctyl, benzophenone, octyl salicylate, willow extract, rumex occidentalis extract, benzoic acid (rumex ocidinals) extract, Wild chrysanthemum (Chrysanthemum indicum) extract, big leaf tea extract and alteromonas (alteromonas) fermentation extract.

Non-limiting examples of sunless tanning agents/melanogenesis stimulators include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such agents include dihydroxyacetone, alpha-MSH agonists, adenylate cyclase activators, and phosphodiesterase inhibitors.

Without limitation, soothing emollients (soothing agents) include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include nettle extract, neroli extract, rosewood extract and witch hazel extract.

Without limitation, whitening/pigmentation agents include plant extracts, algae extracts, fruit extracts, vegetable extracts, legume extracts, fermentates, protein hydrolysates, peptides, yeast extracts and derivatives thereof, microbial extracts, animal derived extracts and synthetic compounds. More specifically, such substances include arbutin, azelaic acid (azeleic acid), vitamin C and its derivatives (ascorbyl palmitate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate), hydroquinone, N-acetyl-4-S-cysteine phenol (N-acetyl-4-S-cysteinylphenol), kojic acid, melanostatin, retinoic acid and its derivatives (retinol, retinal, retinyl palmitate, trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid, retinoylglucuronide, retinoic acid, isotretinoin, etretinate, acitretin, abamectin A, tazarotene, adapalene, beta-carotene, retinyl ester), rumex acetogenin (extract), licorice, morus, bearberry (castanostylosin-sius), tyrosinase inhibitors, Melanosome transfer inhibitors and melanin scavengers.

In one embodiment, the composition of the invention further comprises a pharmaceutically acceptable topical carrier, vehicle or excipient or additive (i.e., a topically/cosmetically acceptable carrier, vehicle, excipient or additive). Such carriers, vehicles, excipients or additives are well known in the art and can be used to improve the final formulation, for example in terms of organoleptic properties, skin penetration and accessibility of the active ingredient. Examples of carriers, vehicles or excipients include: buffering agents, carrier agents, chelating agents, conditioning agents, coloring agents, detackifying agents, emollients, emulsifiers, film forming agents, foaming agents, humectants, lactylating agents, lipophilic agents, lubricants, neutralizers, oils, opacifiers, preservatives, solubilizers, solvents, stabilizers, surfactants, thickeners, viscosity agents, water absorbents, wetting agents, fragrances, and hot water (hot water).

The compositions of the present invention may be formulated to provide a delivery system that is specifically controlled. Non-limiting examples of such delivery systems include slow delivery systems, fast delivery systems, immediate delivery systems, delayed delivery systems, zero order delivery systems, and dual or multi-rate delivery systems. Such controlled delivery systems can be achieved with specific formulations including chemical delivery systems, multilayer emulsions, microemulsions, nanoemulsions, encapsulates such as liposomes, microspheres, nanospheres, microsponges, beads and cyclodextrins, polymeric matrices, polymeric cosmetic complexes, oil bodies/oleosins, oil-soluble molecular membranes, skin patches, unit doses.

Without limitation, a buffer is a salt of a base/acid that is compatible with the nature of the skin or with its pH. Sodium acetate is an example of a commonly used buffer.

Without limitation, a carrier agent is an ingredient that can aid in the application of the active ingredient. Isohexadecane is an example of a commonly used carrier.

Without limitation, chelating agents are ingredients capable of binding monovalent and divalent cations, such as tetrasodium EDTA and disodium EDTA.

Without limitation, conditioning agents are ingredients having a lubricating effect and a hydrating effect, such as cetrimide, dicetyldimethylammonium chloride, trideceth-12, quaternium-Z7, quaternium-18, polyquaternium-10, behenyltrimethylammonium methylsulfate, cetearyl alcohol, stearamidopropyl dimethylamine, trimethylsilyl aminodimethicone, isolaureth-6, octylphenol polyether-4, dimethicone, dimethiconol alcohol, cyclopentadimethicone (cyclopentasiloxane), polyether-7 (pareth-7), alkyl alcohol polyether-9, linoleic acid, and glycerin.

Without limitation, detackifiers are ingredients capable of adsorbing to and reducing the tendency of tacky materials to stick, such as cyclopentadimethylsiloxane, polydimethylsiloxane and vinylpolydimethylsiloxane, phenylpolytrimethylsiloxane, isopropyl ester, isostearate, dimethyl sebacate, and dipropyl sebacate.

Without limitation, emollients are ingredients having a lubricating effect and a hydrating effect, such as isopropyl palmitate, sunflower seed oil, mineral oil, stearyl stearate, isopropyl myristate, lanolin, caprylic/capric triglyceride, cyclopentadimethylsiloxane, polydimethylsiloxane, vinyl polydimethylsiloxane, bis-phenylpropyl polydimethylsiloxane, alkyl polydimethylsiloxane, sorbitan stearate, sucrose distearate, myristyl alcohol, myristyl lactate, cetyl acetate, dioctyl ether, floraester-20, maleated soybean oil, cyclomethicone, shea butter, hydrogenated coconut oil, isopropyl palmitate, diisostearoyl trimethylolpropane siloxysilicate, and alkyl benzoate.

Without limitation, emulsifiers are ingredients that prevent separation of immiscible materials in an emulsion, aid in uniform dispersion of one material in another, improve texture, homogeneity, consistency and stability, such as cetearyl alcohol, glyceryl stearate, alkanol acrylate crosspolymers, stearic acid, emulsifying wax, sorbitan oleate, sorbitan stearate, polysorbates, polyethylene glycerol polysorbates, triethanolamine, cyclopentadimethylsiloxane, polydimethylsiloxane copolymers (dimethylhicone copolyol), PEG-30 dipolyhydroxystearate, sucrose distearate, PEG-100 stearate, dioctyl sodium sulfosuccinate, polyacrylamide, isoparaffins, laureth-7, cetyl phosphate, DEA cetyl phosphate, ethylene glycol stearate, stearyl alcohol, Cetyl alcohol, behenyltrimethylammonium methylsulfate, and ceteareth-2.

Without limitation, film formers are ingredients capable of forming dimensionally stable and continuous films to minimize formulation stickiness, such as wheat protein, eicosene copolymer, perfluoromethyl isopropyl ether, diisostearoyl trimethylolpropane siloxysilicate, trimethylsiloxysilicate, polydimethylsiloxane, vinyl polydimethylsiloxane, and cyclopentadimethylsiloxane.

Without limitation, foaming agents are ingredients capable of regulating the amount of air in the product, such as lauramide DEA and cocamide MEA, disodium laureth sulfosuccinate, disodium N-octadecyl sulfosuccinamate, ammonium lauryl sulfate, triethanolamine lauryl sulfate, sodium lauryl sulfate, and sodium 2-ethylhexyl sulfate.

Without limitation, humectants are ingredients that are capable of maintaining constant humidity and maintaining wetness, such as glycerin, PEG-8, butylene glycol, and propylene glycol.

Without limitation, lubricants are ingredients that increase lubricity and reduce friction to improve application, such as polydimethylsiloxanes and polydimethyl siloxane copolymers.

Without limitation, neutralizing agents are ingredients capable of altering the acid-base equilibrium, such as triethanolamine and sodium hydroxide.

Without limitation, opacifiers are ingredients capable of changing the appearance of a clear or translucent product to a creamy or pearl-like product, such as glyceryl stearate and PEG-100 stearate.

Preservatives are, without limitation, ingredients capable of retarding or preventing microbial or chemical spoilage and avoiding discoloration, such as DMDM hydantoin, methyl paraben, propyl paraben, phenoxyethanol, ethyl paraben, butyl paraben, imidazolidinyl urea, bis (hydroxymethyl) imidazolidinyl urea (diazolidinyl urea), quaternary ammonium salt-8, quaternary ammonium salt-14, quaternary ammonium salt-15, propylene glycol, dehydroacetic acid, methylchloroisothiazolinone, methylisothiazolinone, and megermaben.

Without limitation, solubilizers are ingredients that can allow incompatible ingredients to become part of a homogeneous solution, such as polysorbates, ceteareth, steareth, and PEG.

Without limitation, stabilizers are ingredients capable of maintaining physical and chemical properties during and after processing, and preventing or limiting the change in physical properties of a substance during the life of the product, such as polyethylene, sodium chloride, stearyl alcohol, xanthan gum, tetrasodium EDTA, and dimethicone copolymers.

Without limitation, surfactants are ingredients that can reduce surface tension when dissolved in water or aqueous solutions, can reduce interfacial tension between two liquids or between a liquid and a solid, such as dioctyl sodium sulfosuccinate, octyl phenol polyether-40, isolaureth-6, ammonium lauryl sulfate, lauryl alcohol, lauramide DEA, and cocamidopropyl betaine (cocoamidopropyl betaine).

Without limitation, thickeners are ingredients capable of absorbing water to impart body, improve consistency or texture, and stabilize emulsions, such as stearic acid, magnesium aluminum silicate, carbomers, alkanol acrylate crosspolymers, polyacrylamides, isoparaffins, laureth-7, cetyl alcohol, xanthan gum, alkyl dimethicones, hydroxyethyl cellulose, glyceryl stearate, pentaerythritol tetrastearate, stearyl alcohol, and polyquaternium-10.

Without limitation, viscosity agents are ingredients that can control the degree of fluidity exhibited by a fluid and the internal resistance to flow, such as magnesium aluminum silicate, caprylyl glycol, and myristyl alcohol.

Without limitation, water absorbents are ingredients capable of absorbing water of the product to maintain wetness, such as carboxyvinyl polymers, acrylic acid copolymers, polyacrylamides, polysaccharides, natural gums, clays, modified clays, metal salts, and fatty acids.

Without limitation, wetting agents are ingredients that can reduce the surface tension of water to give better penetration or ductility across surfaces, such as caprylate, caprylic glycol, capric acid glyceride, polyglyceryl-2 caprate, polyglyceryl-6, polyglyceryl-3 laurate and TEA-laureth sulfate.

The compounds or compositions of the present invention may be packaged in any suitable manner, including but not limited to, cans, bottles, tubes, sticks, roll-on applicators, aerosol spray devices, and the like, in a conventional manner. The compounds or compositions of the present invention may be packaged in a kit of two or more compartments comprising a compartment containing the active ingredient and a second compartment containing a topically/dermally acceptable medium which may be mixed together at some fixed point in time prior to use. For example, the active ingredient in cream, powder, tablet, capsule or liquid form may be contained in a single-use sealed cartridge that can be opened and mixed with a topically acceptable medium, or stored in a pre-measured form in a single-use sealed cartridge. Alternatively, the active ingredient and the topically acceptable medium may be provided in larger amounts from which the desired amount can be removed using various measuring devices (e.g., using a measuring spoon or cup for solids, or a graduated bottle or dropper for liquids). The compounds or compositions of the present invention may be applied to a substrate and then packaged. Suitable substrates include dressings (dressings), including film dressings and bandages. In one embodiment, the kit or pack may contain instructions for use/application, e.g., instructions for preventing, reducing, delaying or treating a skin condition.

In another aspect, the invention provides the use (e.g. cosmetic or therapeutic use) of a compound of formula (I) for preventing, reducing, delaying or treating a skin condition in a subject.

In another aspect, the invention relates to the use of a compound of formula (I) for improving the harmonicity (consistency) and thickness of the dermis by improving the homogeneity of the dermis.

In another aspect, the invention relates to the use (e.g. cosmetic use) of a compound of formula (I) for inducing and/or increasing the production of DEJ molecules in a biological system. In another embodiment, the DEJ molecule is laminin-5 and/or collagen VII.

In another aspect, the present invention relates to the use of a compound of formula (I) to enhance the dermoepidermal junction (DEJ).

In another aspect, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention, reduction or treatment of a skin condition.

In another aspect, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for improving dermal tone (consistency) and thickness by improving dermal homogeneity.

In another aspect, the present invention relates to the use of a compound of formula (I) for the preparation of a medicament for inducing and/or increasing the production of at least one DEJ molecule in a biological system. In one embodiment, the at least one DEJ molecule is laminin-5 and/or collagen VII.

In another aspect, the present invention relates to the use of a compound of formula (I) in the manufacture of a medicament for enhancing the dermoepidermal junction (DEJ).

In one embodiment, the skin condition described above is an aging-related skin condition of the skin (e.g., intrinsic aging). For example, skin conditions associated with aging may include wrinkles, fine lines, age spots, sun damage (particularly oxidative stress caused by UV radiation), blemishes, hyperpigmented skin, age spots, increased skin thickness, loss of skin elasticity and collagen content, dry skin, pigmented spots and/or melasma, and any combination thereof. In one embodiment, the skin condition associated with aging described above is the appearance or presence of (a) wrinkles, (b) fine lines, or (c) both (a) and (b) on the skin.

In another embodiment, the skin condition described above is skin damage caused by cosmetic or therapeutic treatment or caused by injury (e.g., surgery involving the skin, laser treatment of the skin, dermabrasion, or peeling (e.g., to promote a healing process)).

In one embodiment, the biological system described above is one or more cells, tissues, organs or individuals. In another embodiment, the one or more cells described above are skin cells, such as fibroblasts or a combination of cells comprising fibroblasts. In another embodiment, the organ is skin.

The method of delivery of the compounds or compositions of the present invention may vary widely, but generally involves application to an area of skin susceptible to or affected by an aging-related skin condition, such as a skin condition or disorder associated with, caused by, or affected by intrinsic aging and/or extrinsic aging. Skin conditions associated with aging may include, for example, wrinkles, fine lines, age spots, sun damage (e.g., oxidative stress caused by UV radiation), blemishes, hyperpigmented skin, increased skin thickness, loss of skin elasticity and collagen content, dry skin, pigmented spots, and/or melasma.

Creams, lotions, gels, ointments, pastes, etc. may be applied to the affected surface and gently rubbed. The solution may be used in the same manner, but is more commonly applied and carefully applied to the affected area using a dropper, swab, or the like.

The application regimen will depend on a number of factors that can be readily determined, such as the severity of the condition and responsiveness to initial treatment, but typically involves application one or more times per day on an extended basis. One of ordinary skill in the art can readily determine the optimal amount of formulation to be administered, the method of administration, and the rate of repetition. It is generally considered that the formulations of the present invention are used in the range of once or twice weekly to once or twice daily.

In one embodiment, the subject is a mammal. In another embodiment, the mammal is a human.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(peptide I, SEQ ID NO: 1) Synthesis

Peptide I was synthesized on a solid support using Rink amide resin, which has a functionality between 0.3 and 0.6mmole/g of resin. First, Rink amide resin was prepared by washing with Dimethylformamide (DMF) (washing 2 times), followed by the following deprotection step. For each coupled amino acid, the following steps are repeated: coupling amino acids, washing the resin, deprotecting the amino functions of the backbone, and then washing the resin. The resulting peptide contains 4 amino acid residues in the L configuration.

Coupling of: 2 equivalents of benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP) (or 2- (1H-benzotriazol-1-yl) 1, 1, 3, 3-tetramethyluronium hexafluorophosphate, HBTU), 2 equivalents of Diisopropylethylamine (DIEA) (or N-methylmorpholine, NMM) and 2 equivalents of 9-fluorenylmethyloxycarbonyl (Fmoc) -AA-OH were brought in DMF for 2 hours.

Washing machine: washing with DMF 2 times, methanol 1 time, dichloromethane 2 times and DMF 1 time.

Deprotection of the amino acid: 80/20 DMF/piperidine mixture containing 2% ethylene glycol (to capture the groups) was used once for 3 minutes and then for 7 minutes.

Washing machine: (same as above).

After the amino acid had been coupled, the acid was coupled to the N-terminal functional group in the same manner as the amino acid, and the peptide was separated from the resin by subjecting to 50/50 trifluoroacetic acid (TFA)/dichloromethane mixture containing 2% ethylene glycol for 90 minutes.

Dichloromethane and TFA were evaporated under a nitrogen stream, then precipitated with diethyl ether and purified by preparative liquid chromatography using a reverse phase C18 column.

Synthesis of CH with protected amino acids and coupling to the N-terminal function with hexanoic acid₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(peptide I): Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH and Fmoc-Gly-OH.

Example 2

CH₃-(CH₂)₆-CO-Lys-Gly-His-Lys-NH₂(peptide II; SEQ ID NO: 2) Synthesis

Peptide II was synthesized using the same method as described in example 1, except that caprylic acid was used instead of caproic acid for coupling to the N-terminal functional group of the first lysine residue. The resulting peptide contains 4 amino acid residues in the L configuration.

Example 3

CH₃-(CH₂)₂-CO-Lys-Gly-His-Lys-NH₂(peptide III; SEQ ID NO: 3)

Peptide III was synthesized using the same method as described in example 1, except that butyric acid was used instead of caproic acid for coupling to the N-terminal functional group of the first lysine residue. The resulting peptide contains 4 amino acid residues in the L configuration.

Example 4

CH₃-(CH₂)₈-CO-Lys-Gly-His-Lys-NH₂(peptide IV; SEQ ID NO: 4) Synthesis

Peptide IV was synthesized using the same method as described in example 1, except that capric acid was used instead of caproic acid for coupling to the N-terminal functional group of the first lysine residue. The resulting peptide contains 4 amino acid residues in the L configuration.

Example 5

Effect of peptide I on the novel Synthesis of laminin in the Normal human fibroblast model

In the presence or absence of 50ng/ml Transforming Growth Factor (TGF) -beta or 2 concentrations (i.e., 10)^-6M and 10^-7M), normal human dermal fibroblasts were incubated for 48 hours. At the end of the incubation period, laminin was quantified using an e.i.a. enzyme immunoassay kit. The proteins contained in the cell lysates were also quantified by spectrocolorimetry according to the Bradford method. TGF-. beta.and peptide I were tested in dose response to fibroblasts.

The data shown in table I below represent: laminin synthesis in single cell monolayers was relatively increased in human dermal fibroblast cell culture medium in the presence of peptide I or TGF- β compared to untreated cells (controls).

TABLE I

These results indicate that peptide I increases laminin synthesis in human dermal fibroblasts.

Example 6

Effect of peptide I on collagen VII Synthesis in human skin model

At 0.05% w/v cutaneous corticosteroid and 10^-7Fragments of normal human skin were treated or not treated in the presence of peptide I at a concentration of M. Cutaneous corticosteroids are known to alter cellular metabolism. Then theSkin samples were frozen on day 3 for immunohistochemical analysis of collagen VII. Immunodetection was performed by 3-layer indirect immunoperoxidase method (ABC peroxidase kit, Vector laboratories) using primary antibodies specific for collagen VII.

The amount of collagen VII markers was determined using the semi-quantitative scores shown in table II:

TABLE II

Collagen VII no-labeled 0 point

Collagen VII light marker score 1

Collagen VII moderate marker (Normal skin) 2 points

Collagen VII Normal marker (Normal skin) 3 points

Collagen VII overexpression score 4

The results shown in table III indicate that peptide I increases collagen VII synthesis in a human skin model.

TABLE III

Treatment of	Scoring	Relative change
			Control skin (untreated)	1.9±0.8	---
Skin + corticosteroid	1.6±0.5	-16％
			Skin + corticosteroid + peptide I10-7M	2.25±0.2	+34％

Example 7

Effect of peptide I on laminin-5 Synthesis in human skin model

At 0.05% w/v cutaneous corticosteroid or 10^-7Fragments of normal human skin were treated or not treated in the presence of peptide I at a concentration of M. Skin samples were then frozen on day 3 for immunohistochemical analysis of laminin-5. Immunodetection was performed by 3-layer indirect immunoperoxidase method (ABC peroxidase kit, Vector laboratories) using a primary antibody specific for laminin-5.

The amount of laminin-5 label was determined using the semi-quantitative score shown in table IV:

TABLE IV

Laminin-5 no label 0 point

Laminin-5 mild labeling score 1

Laminin-5 moderate marker (normal skin) 2 points

Laminin-5 Normal marker (Normal skin) 3 points

Laminin-5 overexpression score 4

The results shown in Table V indicate that peptide I increases laminin-5 synthesis in the human skin model.

TABLE V

Treatment of	Scoring	Relative change
			Control skin (untreated)	2.1±1.3	---
Skin + corticosteroid	1.17±0.8	-45％

Treatment of	Scoring	Phase (C)For change
			Skin + corticosteroid + peptide I10-7M	2.2±0.8	+49％

Example 8

In vivo anti-wrinkle Activity of peptide I

Among 30 subjects (+ 10%) selected according to inclusion/non-inclusion criteria, peptide I was tested against its placebo in the formulations described in table VI below.

TABLE VI

Anti-wrinkle aqueous gel comprising peptide I

Composition of	Measurement of
		Water (W)	69.66(w/w)
Caprylic/capric triglyceride	10％(w/w)
		Myristyl myristate	4.5％(w/w)
Glycerol	3％(w/w)
		Butanediol	3％(w/w)
Stearic acid glyceride	3％(w/w)
		Polysorbate 60	3％(w/w)
Butyrospermum parkii (shea butter) fruit	1.5％(w/w)
		Phenoxyethanol, methyl paraben, ethyl paraben, butyl paraben, propyl paraben and isobutyl paraben	0.8％(w/w)
Sorbitan stearate	0.75％(w/w)
		Polydimethylsiloxane	0.60％(w/w)
Tea-carbomer	0.16％(w/w)
		Peptide I	5ppm

At 5ppm (0.88X 10)^-5M) peptide I was detected.

The study lasted 56 days after the first application. Volunteers applied the product twice daily to randomly determined temporal canthus wrinkles.

The study was a simple blind trial comparing the results obtained in one treated area after application of the composition of the invention with the results obtained in another area treated with placebo.

The efficacy evaluation of the formulations comprising peptide I was performed using (a) an explanatory digital photograph of the canthus wrinkles and (b) a silicone rubber replica of the canthus wrinkles (analysis of wrinkles and skin network by fringe projection).

Figure 1 shows photographs of canthus wrinkles in one of the volunteers on day 0 and day 28 after application of a formulation comprising peptide I.

In vitro fringe projection-topography-wrinkles the relief (relief) of the skin was reproduced by a silicone rubber replica (in vitro). All silicone rubber replicas were analyzed by fringe projection to observe the relief of the skin. The following parameters were measured: (a) and (4) SPa: average roughness; (b) SPq: an even spread of the undulation variation; (c) SPt: maximum amplitude of undulations and (d) SDev: a surface of deployment. The results of these experiments are shown in figure 2.

All replicas were analyzed by fringe projection to observe the skin network analysis. The following parameters were measured: (a) SRa: roughness average (mm); and (b) SRq: average (mm) in terms of quadratic average. The results of these experiments are shown in figure 3.

These data show the effectiveness of peptide I in reducing wrinkles and reducing canthus wrinkle skin network roughness after 28 days and 56 days of application.

Example 9

Long-term in vivo anti-aging Activity of peptide I

Among the 27 subjects selected according to inclusion/non-inclusion criteria, peptide I was tested in the formulation described in table VI above relative to its placebo.

At 5ppm (0.88X 10)^-5M) peptide I was detected. The study was a simple blind trial comparing the results obtained after application of the composition of the invention comprising peptide I in one area with the results obtained after application of the composition comprising placebo in another area.

Peptide I or placebo was applied to the canthus wrinkles for a period of 168 days (6 months), and the dermal texture was analyzed by high resolution ultrasound (20MHz) on days 0 and 168. The texture analysis uses a second order statistical technique: a co-occurrence matrix method. 2 symbiotic parameters were calculated: entropy and homogeneity of co-occurrence matrices. Entropy corresponds to human perception of coarseness. Uniformity corresponds to texture uniformity.

Table VII summarizes the mean percentage change in the study parameters (T168 days-T0)/T0 calculated from the mean values.

TABLE VII

Dermis texture of temple

Statistical analysis of the results obtained with peptide I treatment showed a significant increase in 2 study parameters: symbiotic entropy: + 1.3% (p ═ 3.00 × 10^-3Wilcoxon test, two-tailed, for paired groups, 5%). Symbiotic homogeneity: + 2.1% (p ═ 3.60 × 10)^-2Wilcoxon test, two-tailed, for paired groups, 5%).

Figure 4 shows a dermis analysis based on ultrasound imaging.

Example 9

Anti-wrinkle oil/water emulsion containing peptide I

Although the present invention has been described above by way of specific embodiments thereof, changes may be made thereto without departing from the spirit and nature of the subject invention as defined in the appended claims.

Claims (43)

1. A compound of formula I (SEQ ID NO: 5):

R-A-Gly-His-B-R’ (I)

wherein:

a and B are each independently of the other an L-lysine residue, a D-lysine residue or NH in a side chain thereof₂The group comprises a modified L-or D-lysine residue, wherein the modification is (i) a substitution with hydrogen, (ii) acetylation, (iii) benzoylation or (iv) palmitoylation;

gly is glycine residue;

his is an L-or D-histidine residue;

r is of the formula CH₃-(CH₂)_n-amino-terminal modification of CO-, wherein n ═ 2, 3, 4, 5, 6, 7, or 8;

r' is a group of formula (II):

N(Z)(Z’) (II)

wherein: z and Z' are independently of each other hydrogen, methyl, ethyl, phenyl, hexyl, decyl or hexadecyl;

or a racemate, enantiomer or diastereomer thereof, or a mixture thereof, or a salt thereof.

2. The compound of claim 1, wherein n-4, 5 or 6.

3. The compound of claim 1 or 2, wherein Z and Z' are hydrogen.

4. A compound according to any one of claims 1 to 3, wherein a and B are independently of each other an L-lysine residue or a D-lysine residue.

5. The compound of any one of claims 1-4, wherein the lysine and histidine residues are in the L-configuration.

6. The compound of claim 1, wherein said compound is

CH₃-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO: 1) or

CH₃-(CH₂)₆-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO：2)。

7. The compound of claim 1, wherein said compound is

CH3_-(CH₂)₄-CO-Lys-Gly-His-Lys-NH₂(SEQ ID NO：1)。

8. A composition comprising an effective amount of a compound according to any one of claims 1 to 7 and a topically, cosmetically or pharmaceutically acceptable excipient or carrier.

9. The composition of claim 8, wherein said effective amount is about 10^-8M to about 10^-2M。

10. The composition of claim 9, wherein said effective amount is about 10^-6M to about 10^-5M。

11. The composition of any one of claims 8-10, wherein the composition is a topical composition.

12. The composition of any one of claims 8-11, wherein the composition is an aqueous solution, a cream, a water-in-oil emulsion, an oil-in-water emulsion, a gel, a spray, an ointment, an emulsion, or a paste.

13. The composition of any one of claims 8-12, further comprising at least one additional active agent.

14. Use of a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 13 for the prevention, reduction, delay or treatment of a skin condition.

15. Use of a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 13 in the manufacture of a medicament for the prevention, reduction, delay or treatment of a skin condition.

16. The use of claim 14 or 15, wherein said skin condition is an aging-related skin condition.

17. The use of claim 16, wherein said skin condition associated with aging is the appearance or presence on the skin of (a) wrinkles, (b) fine lines, or (c) both (a) and (b).

18. The use of claim 14 or 15, wherein the skin condition is skin damage.

19. The use of claim 18, wherein the skin injury is associated with surgical treatment, dermabrasion, laser treatment, or peeling.

20. Use of a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 13 for inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system.

21. The use of claim 20, wherein the at least one DEJ molecule is (a) laminin-5, (b) collagen VII, or (c) both (a) and (b).

22. The use of claim 20 or 21, wherein said biological system is a cell, tissue or organ.

23. The use of claim 22, wherein said cell is a skin cell.

24. The use of claim 22, wherein said organ is skin.

25. A method of preventing, reducing, delaying or treating a skin condition in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-7 or a composition of any one of claims 8-13.

26. The method of claim 25, wherein said skin condition is an aging-related skin condition.

27. The method of claim 26, wherein said skin condition associated with aging is the appearance or presence of (a) wrinkles, (b) fine lines, or (c) both (a) and (b) on the skin.

28. The method of claim 25, wherein said skin condition is a skin lesion.

29. The method of claim 28, wherein the skin lesion is associated with a surgical procedure, dermabrasion, laser treatment, or peeling.

30. The method of any one of claims 25-29, wherein the administration is topical.

31. The method of claim 25, wherein said effective amount is about 10^-8M to about 10^-2M of said compound.

32. The method of claim 31, wherein said effective amount is about 10^-6M to about 10^-5M of said compound.

33. A method for inducing or increasing production of at least one dermoepidermal junction (DEJ) molecule in a biological system, the method comprising contacting the biological system with a compound of any of claims 1-7 or a composition of any of claims 8-13.

34. The method of claim 33, wherein the at least one DEJ molecule is (a) laminin-5, (b) collagen VII, or (c) both (a) and (b).

35. The method of claim 33, wherein the biological system is a cell, tissue or organ.

36. The method of claim 35, wherein said cell is a skin cell.

37. The method of claim 35, wherein said organ is skin.

38. A kit or pack comprising a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 13 together with instructions for preventing, reducing, delaying or treating a skin condition in a subject.

39. A kit or pack comprising a compound according to any one of claims 1 to 7 or a composition according to any one of claims 8 to 13 and a container.

40. A composition for preventing, reducing, delaying or treating a skin condition in a subject, the composition comprising a compound of any one of claims 1-7 and a topically, cosmetically or pharmaceutically acceptable excipient or carrier.

41. A composition for inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system, the composition comprising a compound according to any one of claims 1 to 7 and a topically, cosmetically, or pharmaceutically acceptable excipient or carrier.

42. A compound according to any one of claims 1 to 7 for use in the prevention, reduction, delay or treatment of a skin condition in a subject.

43. A compound according to any one of claims 1 to 7 for use in inducing or increasing the production of at least one dermoepidermal junction (DEJ) molecule in a biological system.