USE OF THIOETHYLAMINE COMPOSITION FOR SKIN REJUVENATION AND IMPROVED SYNERGISTIC EFFECT WHEN COMBINED WITH AN ORGANIC

ACID AND/OR AZABENZENE-4-CARBOXAMIDE

FIELD OF THE INVENTION

The present invention relates to a cosmetic use of a composition comprising thioethylamine along with azabenzene-4-carboxamide and/or an organic acid for skin rejuvenation.

BACKGROUND OF THE INVENTION

In the last decades there is a significant concern in the population regarding personal aesthetics and wish to try to delay or minimize the appearance of signs related to aging.

The skin is the largest organ in humans and is subject to intrinsic aging and extrinsic aging. Skin aging is a complex biological process influenced by combination of endogenous and exogenous factors. The endogenous factors are typically genetics, cellular metabolism, hormone and metabolic processes, whereas the exogenous factors are typically chronic light exposure, pollution, ionizing radiation, chemicals, toxins. These endogenous and exogenous factors lead to changes in the skin and to the appearance of imperfections therein, such as loss of firmness, wrinkling, roughness and/or sagginess. For example, human skin is often subjected to harsh external conditions, such as excessive sun exposure and general environmental exposures, which over time lead to the anatomic degradation of human skin. The symptoms of such degradation are most pronounced on the face and around the eyes, and often manifest themselves as wrinkles, leathery skin texture, dryness, roughness, and premalignant growths. Though the skin has a natural ability to repair such damage, with aging, the ability of the skin to spontaneously repair itself decreases. Consequently, there have long been efforts to treat human skin in an effort to slow or counter these aging effects on the skin and renew or rejuvenate the dermal tissues.

Three primary structural components of the dermis are collagen, elastin and Glycosaminoglycans (GAGs), which have been the subjects of the majority of anti -aging research and efforts for aesthetic-anti-aging strategies pertaining to the skin, which range from “anti-wrinkle creams” to various filling agents. Much of the early work in skin renewal and rejuvenation focused on the use of vitamin A as a therapeutic agent. Many of these early treatment methodologies involved the oral administration of vitamin A in the form of the ester of vitamin A, vitamin A palmitate. This approach changed over time to focus on the topical application of vitamin A in its acid form (retinoic acid), which in early reports suggested that vitamin A could potentially retard the effects of aging on the skin. However, due to the side effects of the use of retinoic acid in its topical form (often a painful and unpleasant peeling of the skin), the use of vitamin A in its various forms has limited applicability from a long-term treatment standpoint. Therefore, interest in a number of other products with potential skin rejuvenating effects has been the focus of much recent research for topical application.

Vitamins have also been used, alone or in combinations, to prevent or reverse skin damage and/or improve the quality of skin in individuals, and in particular, skin damage associated with inflammation due to UV radiation. For example, U.S. Pat. Nos. 5,574,063, 5,545,398, 5,409,693, and 5,376,361 describe the use of fatty acid esters of ascorbic acid (e.g., vitamin C palmitate) or tocotrienol (vitamin E) for the treatment and prevention of skin damage from sun exposure.

Hyaluronic acid, due to its viscoelastic properties and its capacity to retain water, has also been used in the cosmetic industry to keep skin hydrated, maintain elasticity and treat wrinkles by improving the roughness or even used as a dermal filler. However, currently, hyaluronic acid, is obtained from several sources, such as rooster combs or bacterial extracts and, consequently, these products can contain impurities and need to be characterized thoroughly. Moreover, desired effects on skin roughness or anti-wrinkle effects appear only after several weeks of treatment (Farwick et al, SOFW Journal, 134(11), 17, 2008; Poetschke et al., MMW Fortschr. Med. 158 (Suppl. 4) (2016 May 25) 1-6).

Still, none of the skin products developed thus far have been effective enough to be entirely embraced by those suffering from damaged skin or wanting to deter premature aging or sagging (loss of skin firmness) of the skin. Although there are some treatments that are known to remedy specific skin conditions, there is a need for a simple all-in-one cosmetic treatment that increases skin firmness to thereby reduce aging effects and damage to the skin.

Despite the extensive variety of products, compounds and/or extracts in the field, there is still the need for alternative treatment methods for skin rejuvenation that are safer (unlike retinoids who can be irritant or photosensitizer) and/or more effective (unlike topical collagen or hyaluronic acid that may have long onset of action) and/or more accessible (unlike peptide that are expensive to produced). The ideal skin rejuvenation composition should have a potent, rapid and selective effect, carry no short- or long-term side-effects, be well tolerated and well accepted by the treated subjects.

SUMMARY OF THE INVENTION

An aspect of the present invention provides a cosmetic method of skin rejuvenation, wherein the method comprises topically applying to an area of the skin of a subject in need thereof a composition comprising

• 0.01% to 30% w/w of thioethylamine,

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, and/or

• 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof.

Another aspect of the present invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising

0.01% to 30% w/w of thioethylamine, and

0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, b) topically applying to said area of the skin a second composition comprising 0.01% to 30% w/w of an azabenzene-4-carboxamide or a salt thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects.

A further aspect of the present invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising 0.01% to 30% w/w of thioethylamine, b) topically applying to said area of the skin a second composition comprising 0.01% to 30% w/w of an azabenzene-4-carboxamide or a salt thereof, and 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects.

A further aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising o 0.01% to 30% w/w of thioethylamine, and o 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, and

2) the second composition comprising o 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof.

A further aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising o 0.01% to 30% w/w of thioethylamine, and

2) the second composition comprising o 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, and o 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. Also as used in the specification and claims, the language "comprising" can include analogous embodiments described in terms of "consisting of “ and/or "consisting essentially of’.

As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

As used in the specification and claims, the term "and/or" used in a phrase such as "A and/or B" herein is intended to include "A and B", "A or B", "A", and "B".

As used herein, the term “at least one” means “one or more” and also encompasses the terms “at least two”, “at least three”, “at least four”, etc.

As used herein the term "cosmetically acceptable" means that the compositions or components thereof so described are suitable for use in contact with skin of a mammal, preferably of human, without undue toxicity, incompatibility, instability, irritability, allergic response, and the like.

As used herein, the term "cosmetic", "cosmetic management" or "cosmetic treatment" is non- therapeutic treatment of skin conditions that are not diseases or pathological states.

As used herein the term "topical" or "topically" refers to the application of the composition of the present invention onto the surface or an area of the skin and/or a portion thereof, such as facial skin, skin on the neck, skin on the arms, skin on the elbows, skin on the hands, skin on the legs, skin on the knees, skin on the male or female genital areas, and skin on the scalp, so that it can display local activity. Accordingly, the topical forms embrace cosmetical, and/or dermatological dosage forms which are suitable for external use, so that a direct contact with the skin and/or a portion thereof results.

As used herein the terms "subject" are well -recognized in the art, and, are used herein to refer to a mammal, and most preferably a human. In some embodiments, the subject is a subject in need of skin rejuvenation or a subject presenting signs of skin aging. The term does not denote a particular age or sex. Thus, adult subjects, whether male or female, are intended to be covered.

As used herein, "skin rejuvenation" and "skin rejuvenation effects" include one or more of the following: reducing the appearance of fine lines and wrinkles; reducing deep wrinkles; enhancing skin elasticity; reducing skin roughness; and producing a younger looking skin. Specifically, "skin rejuvenation" includes one or more of the following: anti -wrinkle effects (such as reduction of wrinkle depth, of wrinkle area, of wrinkle volume, of wrinkle number, reduction or prevention of fine lines, improvement in skin roughness), firming effects (such as plumping, anti-sagging, improvement in skin thickness, skin elasticity/suppleness), improving the skin barrier (such as improvement of the skin texture, of the skin moisturization level, reduction of the transepi dermal water loss) as well as decrease in age perception of the subject (either by herself/himself or by another person).

The terms "smoothing" and "softening" as used herein mean altering the surface of the skin and/or keratinous tissue such that its tactile feel is improved (softening) or reducing the skin relief and eliminate the skin roughness (smoothing). "Signs of skin aging" include, but are not limited to, all outwardly visible or tactilely perceptible manifestations as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by intrinsic factors or extrinsic factors, e.g., chronological aging and/or environmental damage. These signs may result from processes that include, but are not limited to, the development of textural discontinuities such as wrinkles and coarse deep wrinkles, skin lines, crevices, bumps, large pores (e.g., associated with adnexal structures such as sweat gland ducts, sebaceous glands, or hair follicles), or unevenness or roughness, loss of skin elasticity (loss and/or inactivation of functional skin elastin), sagging (including puffiness in the eye area and jowls), loss of skin firmness, loss of skin tightness, loss of skin recoil from deformation, hyperkeratinization, elastosis, collagen breakdown, and other histological changes in the stratum comeum, dermis, epidermis, the skin vascular system (e.g., telangiectasia or spider vessels), and underlying tissues, especially those proximate to the skin. The inventors surprisingly found that thioethylamine in combination with azabenzene-4- carboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, gluconolactone and/or combination thereof, is capable of having anti-wrinkle effects (such as reduction of wrinkle depth, of wrinkle area, of wrinkle volume of wrinkle number, reduction or prevention of fine lines, improvement in skin roughness), firming effects (such as plumping, anti-sagging, improvement in skin thickness, skin elasticity/suppleness), as well as improving the skin barrier (such as improvement of the skin texture, of the skin moisturization level, reduction of the transepidermal water loss) leading in a global skin rejuvenation and thereby decrease in age perception.

Thus an aspect of the present invention provides a cosmetic method of skin rejuvenation, wherein the method comprises topically applying to an area of the skin of a subject in need thereof a composition comprising

• 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% w/w of thioethylamine,

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1 to 20% w/w of azabenzene-4-carboxamide or a salt thereof, and/or

• 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof,

In preferred embodiments, the skin or an area of the skin is at least one of facial skin, skin on the neck, skin on the arms, skin on the hands, skin on the legs and skin on the scalp.

In preferred embodiments, the skin rejuvenation consists in reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, enhancing skin elasticity, and/or reducing skin roughness.

Fine lines are the start of wrinkles and look like small creases on the skin. Fine lines are closer to the surface of the skin, whereas wrinkles are deeper into the skin.

Reducing the appearance of fine lines and wrinkles can be measured by any one of the following methods known in the art: • Visual assessment or clinical a grading done on a scale, by a dermatologist.

• Quantification of the skin microstructure via 2D or 3D image capture.

• Quantification of wrinkle/fine line depth, wrinkle/fine line volume, wrinkle/fine line surface, wrinkle/fine lines number measurements through 2D or 3D skin image analysis or replica images.

• Quantification of the mean depth, the spread angle the volume of 1 or several main wrinkles/fine line through 2D or 3D skin image analysis replica images.

• Quantification of skin roughness by digital or analogical dematoscopy method or by 2D or 3D skin image analysis or by replica images.

Reducing deep wrinkles can be assessed by methods known in the art, such as by measuring the depth, the volume, the number, the surface, the spread angles of one or several main wrinkles.

Skin elasticity can be measured by methods known in the art, such as by cutometer, by a pinching test, by measuring the displacement of skin pore, skin deformation using unidirectional force, by measuring stress under suction application, or by measuring the velocity of ultrasonic waves through skin tissue.

Skin roughness can be measured by method known in the art, such as by digital or analogical dematoscopy method or by 2D or 3D skin image analysis or by replica images.

The Applicant has surprisingly found that a combination of thioethylamine, azabenzene-4- carboxamide or a salt thereof and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof provides a synergistic effect on skin rejuvenation, while being very well tolerated by human skin.

In the present disclosure, the % w/w of thioethylamine or a salt thereof refers to % w/w of thioethylamine (thioethylamine free base). Thus reference to any particular mass of "thioethylamine or a salt thereof' refers to the mass equivalent of the free base (thioethylamine free base) and reference to any particular mass of a specific salt of thioethylamine, such as thioethylamine hydrochloride, refers to the mass of the specific salt. The above-mentioned definition can be also applied to % w/w of azabenzene-4-carboxamide or a salt thereof, for example reference to any particular mass of "azabenzene-4-carboxamide or a salt thereof' refers to the mass equivalent of the free base (azabenzene-4-carboxamide).

The term “thioethylamine” is intended here to cover any acceptable salt, ester, solvate, hydrate, prodrug, or any other compound which, upon administration to the patient is capable of providing (directly or indirectly) thioethylamine. The salts of thioethylamine are pharmaceutical acceptable salts, cosmetical acceptable salts, and dermatological acceptable salts. Preferred salts of thioethylamine are hydrochloride, bitartrate, phosphate. Any compound that is a prodrug of thioethylamine is within the scope and spirit of the invention. The term “prodrug” is used in its broadest sense and encompasses those derivatives that are converted in vivo to thioethylamine. The prodrug can hydrolyze, oxidize, or otherwise react under biological conditions to provide thioethylamine. Examples of prodrugs include, but are not limited to, derivatives and metabolites of thioethylamine that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Prodrugs can typically be prepared using well-known methods, such as those described by Burger in “Medicinal Chemistry and Drug Discovery” 6th ed. (Donald J. Abraham ed., 2001, Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985, Harwood Academic Publishers). In addition, thioethylamine referred to herein may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known within the art.

The salts of the azabenzene-4-carboxamide of the invention are pharmaceutical acceptable salts, cosmetical acceptable salts, and dermatological acceptable salts.

The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the desired biological activity of thioethylamine and azabenzene-4-carboxamide and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of thioethylamine and azabenzene-4- carboxamide may be prepared from an inorganic acid or from an organic acid or can be prepared in situ during the final isolation and purification of thioethylamine and azabenzene-4- carboxamide. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of azabenzene- 4-carboxamide include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention.

The compositions of the present invention can be prepared by any method known in the art for cosmetic and/or dermatological compositions. Generally, the method comprises the simple mixing or blending of the components; though, especially where insoluble or immiscible components are employed higher agitation or homogenization may be necessary to prepare an appropriate composition, e.g., an emulsion or suspension, etc. Additionally, during the preparation, it may be desirable to add known pH adjusters, in order to maintain a proper pH of the composition for topical application, especially if basic ingredients are to be employed. Generally, the pH should range from about be 3.5 to about 8.

In some embodiments, the compositions of the invention are cosmetic compositions further comprising cosmetically acceptable excipients for topical administrations.

In some embodiments, the compositions of the inventions are dermatological compositions further comprising dermatologically acceptable excipients for dermatological administrations.

The cosmetic compositions and dermatological compositions according to the invention further comprise one or more cosmetically or dermatologically acceptable excipients, as are used conventionally in such compositions, for example preservatives, antioxidants, bactericides, perfumes, substances for preventing foaming, dyestuffs, pigments which have a colouring effect, thickeners, chelating agents, propellants, surfactant substances, emulsifiers, softening, moisturizing and/or moisture-retaining substances, distilled water, fats, oils, waxes or other conventional constituents of cosmetic or dermatological compositions, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. The cosmetic compositions, dermatological compositions and cosmetic combination products according to the invention do not contain polystyrenes, such as water-soluble polystyrenes or appropriate salts thereof. The necessary amounts of the cosmetically or dermatologically acceptable excipients can, based on the desired product, easily be chosen by a person skilled in the art.

A moisturizing substance may be incorporated into compositions of the invention to maintain hydration or rehydrate the skin. Moisturizers that prevent water from evaporating from the skin by providing a protective coating are called emollients. Additionally, an emollient provides a softening or soothing effect on the skin surface and is generally considered safe for topical use. Preferred emollients include mineral oils, lanolin, petrolatum, capric/caprylic tri glyceraldehydes, cholesterol, silicones such as dimeticone, cyclometicone, almond oil, jojoba oil, avocado oil, castor oil, sesame oil, sunflower oil, coconut oil and grape seed oil, cocoa butter, olive oil, aloe extracts, fatty acids such as oleic and stearic, fatty alcohols such as cetyl and hexadecyl (ENJAY), diisopropyl adipate, hydroxybenzoate esters, benzoic acid esters of Cg-is-alcohols, isonononyl isononanoate, ethers such as polyoxypropylene butyl ethers and polyoxypropylene cetyl ethers, and C12-15- alkyl benzoates, and mixtures thereof. Moisturizing substances that bind water, thereby retaining it on the skin surface are called humectants. Suitable humectants can be incorporated into the compositions of the present invention such as glycerin, polypropylene glycol, polyethylene glycol, lactic acid, pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin, ceramides, lecithin sorbitol, PEG-4, and mixtures thereof.

The compositions of the invention can also contain the usual alcohols, especially lower alcohols, preferably ethanol and/ or isopropanol, low diols or polyols and their ethers, preferably propyleneglycol, glycerin, ethyleneglycol, ethyleneglycol monoethyl- or monobutylether, propyleneglycol monomethyl- or monoethyl- or -monobutylether, diethyleneglycol monomethyl- or monoethylether and analogue products, polymers, foam stabilizers; electrolytes and especially one or more thickeners. Thickeners that may be used in the compositions of the invention to assist in making the consistency of a product suitable include carbomer, silicium dioxide, magnesium and/ or aluminium silicates, beeswax, stearic acid, stearyl alcohol polysaccharides and their derivatives such as xanthan gum, hydroxypropyl cellulose, polyacrylamides, acrylate crosspolymers preferably a carbomer, such as Carbopol® of type 980, 981, 1382, 2984, 5984 alone or mixtures thereof.

Suitable stabilizing agents which may be included in the compositions of the invention to stabilize components such as e.g. an emulsifier or a foam builder/ stabilizer include but are not limited to alkali hydroxides such as a sodium and potassium hydroxide; organic bases such as diethanolamine (DEA), triethanolamine (TEA), aminomethyl propanol, and mixtures thereof; amino acids such as arginine and lysine and any combination of any foregoing.

The compositions of the present invention may also contain filter substances that absorb UV radiation, or sunscreens, wherein the total quantity of filter substances is, for example 0.001 to 30 %, preferably 0.5 to 10 %, based on the total weight of the preparation. The compositions may also serve as sunscreen agents for the skin. Such UV filter substances include, for example, the following: avenobenzene, cinoxate, dioxybenzone, homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, phenylbenzimidazole sulfonic acid, sulisobenzone, titanium dioxide, trolamine salicylate, and zinc oxide.

The compositions of the invention may also include one or more skin penetrants. These are additives that, when applied to the skin, have a direct effect on the permeability of the skin barrier: increasing the speed with which and/or the amount by which certain other compounds are able to penetrate into the skin layers. Exemplary organic penetration enhancers include dimethyl sulfoxide; isopropyl myristate; decyl, undecyl or dodecyl alcohol; propylene glycol; polyethylene glycol; C9-11 or C12-15 fatty alcohols; azone; alkyl pyrrolidones; diethoxy glycol (Transcutol); lecithin; etc. Surfactants can also be used as penetration enhancers.

According to an embodiment, the compositions of the invention may further comprise at least one anti -wrinkles benefit agent selected from the group comprising coenzyme Q10, sodium hyaluronate, hyaluronic acid, hyaluronic acid fragments, gold particles, peptides (selected from Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide, Acetyl Hexapeptide-8, Palmitoyl Tripeptide-5, Palmitoyl pentapeptide-4, Cu-GHK peptide, and dipalmitoyl hydroxyproline), tocopherol, ceramids, retinoids (selected from retinol, retinoic acid, retinyl palmitate, retinal, sodium retinoyl hyaluronate and adapalene), bakuchiol, collagen, resveraterol, heparan sulfate and their analogs, dermatan sulfate and their analogs, chondroitin sulfate and their analogs, panthenol, algae extract, perfluorohexane, carnosine, geranylgeranylpropanol, pullulan, copper, alpha lipoic acid, biotin, curcuminoids, natural moisturizing factors, sugars such as Xylitylglucoside, Anhydroxylitol, Xylitol, plant extracts such as Moringa Oleifera Seed Oil, Date Palm Kernel extract, Rosa Damascena Flower Water, Camellia Japonica Flower Extract, Centella Asiatica Extract, Lepidium sativum (garden cress) sprout extract, green tea extracts, Tazman Pepper extract and mixtures thereof. According to another embodiment, the compositions of the invention may further comprise at least one anti-wrinkles benefit agent selected from the group comprising coenzyme Q10, sodium hyaluronate, hyaluronic acid, gold particles, peptides (selected from Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide, Acetyl Hexapeptide-8, Palmitoyl Tripeptide-5, Palmitoyl pentapeptide-4, Cu-GHK peptide, and dipalmitoyl hydroxyproline), tocopherol, ceramids, retinoids (selected from retinol, retinoic acid, retinyl palmitate, retinal, sodium retinoyl hyaluronate and adapalene), bakuchiol, collagen, resveraterol, heparan sulfate, dermatan sulfate, chondroitin sulfate, panthenol, algae extract, perfluorohexane, carnosine, geranylgeranylpropanol, pullulan, copper, alpha lipoic acid, biotin, curcuminoids, natural moisturizing factors (selected from Xylitylglucoside, Anhydroxylitol, and Xylitol), plant extracts such as Moringa Oleifera Seed Oil, Date Palm Kernel extract, Rosa Damascena Flower Water, Camellia Japonica Flower Extract, Centella Asiatica Extract, Lepidium sativum (garden cress) sprout extract, green tea extracts, Tazman Pepper extract) and mixtures thereof.

According to another embodiment, the compositions of the invention may also further include liposomes (unilamellar and/or multilamellar liposomes of any size), niosome, or any encapsulation system (such as microencapsulation, nanoencapsulation, cubosome) in order to facilitate the delivery of any component(s) of the composition to its site of action. The optimal type and size of the liposome(s), the niosome(s) and/or the encapsulation system(s), and the nature of the medium in which they are dispersed, can be easily chosen by a person skilled in the art.

In some embodiments of the cosmetic method of skin rejuvenation, the composition consists of • 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% w/w of thioethylamine, o 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1 to 20% w/w of azabenzene-4-carboxamide or a salt thereof, and/or o 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof,

• 0.01% to 1% retinol, and

• at least one cosmetically acceptable excipient for topical administration (qsp 100%).

In some embodiments of the cosmetic method of skin rejuvenation, the composition consists of

• 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% w/w of thioethylamine, o 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably

0.1 to 20% w/w of azabenzene-4-carboxamide or a salt thereof, and/or o 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof,

• at least one cosmetically acceptable excipient for topical administration (qsp 100%).

The benefits of the composition comprising thioethylamine in combination with azabenzene-4- carboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, are for example:

• anti-wrinkle effects (such as reduction of wrinkle depth, of wrinkle number, reduction or prevention of fine lines, improvement in skin roughness),

• firming effects (plumping, anti-sagging, improvement in skin thickness, skin elasticity/suppleness),

• skin barrier improvement (skin texture, skin moisturization level), leading to skin rejuvenation and decrease in age perception.

The benefits of the composition comprising thioethylamine in combination with azabenzene-4- carboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, on the skin structure are for example:

• Epidermal hyperplasia (ie increase skin thickness through increase of epidermal skin layers),

• Increase of intrinsic collagen and elastin production (and reduction of their degradation) leading to increase skin thickness as well, • Anti-glycation effect, preventing cells damage (from intrinsic and extrinsic factors such as: ROS, stress, oxidation, UV, AGEs. . . .), leading to an increase of elasticity.

In addition, the inventors observed that thioethylamine in combination with azabenzene-4- carboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, has better, synergistic effects when compared to thioethylamine used alone.

The compositions of the invention may be cosmetic or dermatologic compositions, and may exist in a wide variety of forms, such as emulsions, suspensions, solutions and the like. In certain embodiments, the compositions of the invention are in the form of lotions, creams, gels, solutions, sprays, cleansers, powders, ointments, waxes, lipsticks, soaps, shampoos, hydroalcoholic solutions, suspensions, scrubs, saturated pads, skin conditioning agents, and other types of cosmetic compositions. In further embodiments, the compositions of the invention may be, for example anhydrous preparations, oil-free preparations, emulsions or microemulsions of the type water-in-oil (W/O) or of the type oil-in-water (O/W), multiple emulsions, for example of the type water-in-oil-in-water (W/O/W), solid sticks, or even aerosols. The preferred forms of the compositions of the invention are gels, lotions, emulsions, powder forms.

While not wishing to be limited by or bound to a specific theory, it is believed that the compositions described herein provide their cosmetic effect in combating skin wrinkles, in skin rejuvenation, and in minor wound repair, at least in part due to their effects on collagen and elastin.

In some embodiments the compositions of the invention are used for cosmetic skin rejuvenation of human natural healthy skin, i.e. non-therapeutic use, that is not related to treatment of diseases or pathological states of the skin. In some embodiments, cosmetic skin rejuvenation relates to anti-wrinkle effects (such as reduction of wrinkle depth of wrinkle area, of wrinkle volume, of wrinkle number, reduction or prevention of fine lines, improvement in skin roughness) firming effects (such as plumping, anti-sagging, improvement in skin thickness, skin elasticity/ suppleness), improving the skin barrier (such as skin texture, skin moisturization level) leading in a global skin rejuvenation (and decrease in age perception). Specifically, in some embodiments, cosmetic skin rejuvenation consists in in reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, enhancing skin elasticity, reducing skin roughness. For example, the method of skin rejuvenation can be used if a subject desires to improve appearance of skin of at least a region of skin for cosmetic reasons.

Another aspect of the present invention provides use of the compositions of the invention for cosmetic skin rejuvenation. In preferred embodiments, the skin or an area of the skin is at least one of facial skin, skin on the neck, skin on the arms, skin on the elbows, skin on the hands, skin on the legs, skin on the knees, skin on the male or female genital areas, and skin on the scalp.

In an embodiment, the method of skin rejuvenation of the invention is repeated for number of times sufficient to obtain skin rejuvenation effects and decrease in age perception. In a further embodiment of the method of skin rejuvenation of the invention, when desired results or effects have been achieved, the method of skin rejuvenation of the invention can be continued to be applied not every day, not every consecutive day or one to several times a week to maintain the skin rejuvenation results or effects.

In the methods according to the invention for skin rejuvenation, the compositions are applied to the skin or an area of the skin, preferably human skin. The amount of the composition that is to be applied to the skin depends upon the form of the composition and its mode of application. For example, a spray formulation may be applied so as to provide a light, even coat on the skin. Similarly, lotions, creams, gels, shampoos and the like are typically applied in an amount to provide a light coating to the treatment area, consistent with the application of topical cosmetic ointments, creams, lotions, and the like. Generally, the rate of application, especially where all or substantially all of the skin surface, including hairy or non-hairy skin, is to be treated, is about 20 to 60 ml for the entire body, i.e., for the exposed skin of an "average individual" wearing a swimsuit and standing 1.65 m tall, weighing 68 kg, and having a 0.81 m waist. This translates to an application rate of about 2 mg/cm ² of skin surface, including hairy or non-hairy skin surface. On the face, a typical application rate is 0.5 to 1.0 ml. At such levels of application, the amount of composition applied lies in the range of from about 0.1 to about 10 mg/cm ² , preferably from about 1 to about 3 mg/cm ² , of skin.

The compositions of the invention may be applied once or more times per day depending on the activities the particular subject is engaged in. For example, a subject engaging in normal workday activities may wish to apply the compositions twice a day, once in the morning, and once in the evening, in conjunction with normal grooming. On the other hand, if the subject plans outdoor activities such as sunbathing and athletics, the compositions may be applied prior to, and during, such activities, much like a sunscreen composition is applied periodically during the day. The compositions of the present invention may also be applied to the entire body, particularly areas which are not covered by clothing, such as the arms, neck, and lower legs.

In one embodiment, the invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising

0.01% to 99% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, and

0.1% to 99% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, b) topically applying to said area of the skin a second composition comprising 0.01% to 99% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects (endpoint), wherein the azabenzene-carboxamide isomer is selected from the group comprising azabenzene- 4-carboxamide, azabenzene-3-carboxamideand azabenzene-2-carboxamide, alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid, beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid, poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid. In a preferred embodiment, the invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising

0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% of thioethylamine, and 0.1% to 50% w/w of an organic acid, preferably 1% to 30% of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, b) topically applying to said area of the skin a second composition comprising 0.01% to 30% w/w of an azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% of an azabenzene-4-carboxamide or a salt thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects (endpoint).

In an embodiment of the cosmetic method of skin rejuvenation of the invention, the method further comprises removing the first composition by any suitable method before topically applying the second composition. In some embodiments, the suitable method is selected from rinsing with water with or without a suitable detergent, removing with any suitable solvent or cleanser, removing with a dry or wet pad, and/or combination thereof

In some embodiments, the skin rejuvenation consists in reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, enhancing skin elasticity, and/or reducing skin roughness.

In an embodiment of the cosmetic methods of skin rejuvenation of the invention, a suitable detergent is typically a skin cleansing product, such as personal care cleanser, used for example in person washing, selected from bars, liquids, gels, pastes, etc., such as liquid or solid soaps or shampoos.

In an embodiment of the cosmetic method of skin rejuvenation of the invention, a time period between topical application of the first composition and the topical application of the second composition is few seconds (application of the second composition right after the first one), up to several hours later, such as 1 hour, 2 hours, 3 hours, 4 hours. Preferably, the second composition is applied right after the application of the first composition or up to 2 hours later.

The cosmetic method of skin rejuvenation of the invention is repeated for a time period or number of times sufficient to obtain the desired skin rejuvenation effects (endpoint), such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, 2 months, three months, one year, two years, three years, or more; or such as one to four weeks, one to eight weeks, one week to one year, one week to two years, one week to five years. In another embodiments, after achievement of desired skin rejuvenation effects, the cosmetic method skin rejuvenation of the invention is repeated not every day, not every consecutive day or to maintain the skin rejuvenation results or effects, the cosmetic method skin rejuvenation of the invention is repeated one to four times a week.

In an embodiment of the cosmetic method of skin rejuvenation of the invention, the first composition comprises 0.1% to 20% w/w of thioethylamine or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine or a salt thereof and 0.1% to 40% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, and wherein o alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid. o beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid. o poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment of the cosmetic method of skin rejuvenation of the invention, the first composition comprises 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine and 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof.

In an embodiment of the cosmetic method of skin rejuvenation of the invention, the second composition comprises 0.01% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, wherein the azabenzene-carboxamide isomer is selected from the group comprising azabenzene-4-carboxamide, azabenzene-3-carboxamideand azabenzene-2- carb oxami de.

In a preferred embodiment of the cosmetic method of skin rejuvenation of the invention, the second composition comprises 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide or a salt thereof.

In another embodiment, the invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising 0.01% to 99% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, b) topically applying to said area of the skin a second composition comprising 0.01% to 99% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, and

0.1% to 99% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects (endpoint), wherein the azabenzene-carboxamide isomer is selected from the group comprising azabenzene- 4-carboxamide, azabenzene-3-carboxamideand azabenzene-2-carboxamide, alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid, beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid, poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment, the invention provides a cosmetic method of skin rejuvenation comprising the steps of a) topically applying to an area of the skin of a subject in need thereof a first composition comprising 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% w/w of thioethylamine, b) topically applying to said area of the skin a second composition comprising 0.01% to 30% w/w of an azabenzene-4-carboxamide or a salt thereof, preferably

0.1% to 20% w/w of an azabenzene-4-carboxamide or a salt thereof, and

0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, c) repeating the steps a) and b) to obtain skin rejuvenation effects (endpoint).

In an embodiment of the cosmetic method of skin rejuvenation of the invention, the method further comprises removing the first composition by any suitable method before topically applying the second composition. In some embodiments, the suitable method is selected from rinsing with water with or without a suitable detergent, removing with any suitable solvent or cleanser, removing with a dry or wet pad, and/or combination thereof

In some embodiments, the skin rejuvenation consists in reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, enhancing skin elasticity, and/or reducing skin roughness. In an embodiment of the cosmetic methods of skin rejuvenation of the invention, a suitable detergent is typically a skin cleansing product, such as personal care cleanser, used for example in person washing, selected from bars, liquids, gels, pastes, etc., such as liquid or solid soaps or shampoos.

In an embodiment of the cosmetic method of skin rejuvenation of the invention, a time period between topical application of the first composition and the topical application of the second composition is few seconds (application of the second composition right after the first one), up to several hours later, such as 1 hour, 2 hours, 3 hours, 4 hours. Preferably, the second composition is applied right after the application of the first composition or up to 2 hours later.

In a preferred embodiment of the cosmetic method of skin rejuvenation of the invention, the first composition comprises 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine.

In an embodiment of the cosmetic method of skin rejuvenation of the invention, the second composition comprises 0.1% to 20% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, and 0.1% to 40% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, and wherein

• the azabenzene-carboxamide isomer is selected from the group comprising azabenzene- 4-carboxamide, azabenzene-3-carboxamideand azabenzene-2-carboxamide, and

• alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid.

• beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid.

• poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment of the cosmetic method of skin rejuvenation of the invention, the second composition comprises 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, and 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof.

In further embodiments of the cosmetic methods of skin rejuvenation of the invention, the first composition and the second composition further comprise at least one cosmetically acceptable excipient.

In another embodiment, the cosmetic methods of skin rejuvenation of the invention is repeated for the time period sufficient to obtain skin rejuvenation effects, the time period can be few days (1 to 7 days), few weeks (1 to 4 weeks or 1 to 8 weeks or 2 to 8 weeks or 4 to 8 weeks), few months (1 to 3 months or 1 to 6 months or 1 to 12 months), few years (1 to 5 years) or a life cosmetic treatment, depending on desired skin rejuvenation effects or results.

In a further embodiment of the cosmetic methods of skin rejuvenation of the invention, when desired skin rejuvenation effects or results have been achieved, the methods of the invention can be continued to be applied not every day, not every consecutive day or one to six times a week to maintain the skin rejuvenation results or effects.

The cosmetic methods of skin rejuvenation of the invention are repeated (step c) for a number of times sufficient to obtain skin rejuvenation effects or results (endpoint) and/or, after achievement of desired skin rejuvenation results or effects (endpoint), the method of the invention is repeated not every day, not every consecutive day or one to six times a week to maintain the skin rejuvenation results or effects.

In the cosmetic methods of skin rejuvenation of the invention, one of ordinary skill in the art will appreciate that the endpoint chosen in a particular case will vary according to the skin desired appearance, the outcome desired by the subject and other factors. For example, endpoints can be defined subjectively such as, for example when the subject is simply "satisfied" with the results of the cosmetic treatment.

The advantages of the cosmetic methods of skin rejuvenation comprising separate administrations of the first composition comprising thioethylamine and an organic acid, selected from an alpha-hydroxy acid (AHA), a beta-hydroxy acid (BHA) and a poly-hydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, (step a) and the second composition comprising an azabenzene-carboxamide isomer or a salt thereof, preferably comprising azabenzen-4-carboxamide or a salt thereof, (step b) are as follows:

- When the above-mentioned compositions are applied in 2 steps according to the present invention, the skin rejuvenation effect is surprisingly improved comparing to a composition comprising all threes compounds, namely thioethylamine, an organic acid selected from an alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, and an azabenzene-carboxamide isomer or a salt thereof, preferably azabenzene-4- carboxamide or a salt thereof.

The advantages of the cosmetic methods of skin rejuvenation comprising separate administrations of the first composition comprising thioethylamine (step a) and the second composition comprising an azabenzene-carboxamide isomer or a salt thereof, preferably comprising azabenze-4-carboxamide or a salt thereof, and an organic acid, selected from an alpha-hydroxy acid (AHA), a beta-hydroxy acid (BHA) and a poly-hydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, (step b) are as follows:

- When the above-mentioned compositions are applied in 2 steps according to the present invention, the skin rejuvenation effect is surprisingly improved comparing to a composition comprising all threes compounds, namely thioethylamine, an organic acid selected from an alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, and an azabenzene-carboxamide isomer or a salt thereof, preferably azabenzene-4- carboxamide or a salt thereof. Another aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising

0.01% to 99% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, and

0.1% to 99% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, and wherein o alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid. o beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid. o poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid. and

2) the second composition comprising

0.01% to 99% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, wherein the azabenzene-carboxamide isomer is selected from the group comprising azabenzene-4-carboxamide, azabenzene-3-carboxamideand azabenzene-2-carboxamide.

In a preferred embodiment, the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising

• 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, and • 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof, and

2) the second composition comprising

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide or a salt thereof.

In further embodiments of the cosmetic combination product, the first composition and the second composition further comprise at least one cosmetically acceptable excipient.

In another preferred embodiment, the present invention provides a cosmetic combination product consisting of a first composition and a second composition for separate topical application, wherein

1) the first composition consists of

• 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, and

• 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof,

• 0.01% to 1% retinol, and

• at least one cosmetically acceptable excipient (qsp 100%), and

2) the second composition consists of

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide or a salt thereof.

• 0.1 to 15% w/w of skin anti -wrinkle agents selected from the group comprising Xylitylglucoside, Anhydroxylitol, Xylitol, Panthenol, Tazman pepper natural extract and retinoids, preferably retinoids are selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, sodium retinoyl hyaluronate and adapalene,

• at least one cosmetically acceptable excipients (qsp 100%). In the context of the present invention, Tazman pepper is a natural Australian active ingredient extracted from the Tasmanian pepper berry.

Another aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising

0.01% to 99% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine. and

2) the second composition comprising

0.01% to 99% w/w of an azabenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of an azabenzene-carboxamide isomer or a salt thereof, wherein the azabenzene-carboxamide isomer is selected from the group comprising azabenzene-4-carboxamide, azabenzene-3-carboxamideand azabenzene-2-carboxamide, and

0.1% to 99% w/w of an organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of an organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), poly-hydroxy acid (PHA) and/or combination thereof, and wherein o alpha-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or combination thereof. In a preferred embodiment, the alpha-hydroxy acid is selected from the group comprising glycolic acid and lactic acid. o beta-hydroxy acid (BHA) is selected from the group comprising salicylic acid, beta 5 hydroxybutanoic acid, tropic acid, trethocanic acid and/or combination thereof. In a preferred embodiment, the beta-hydroxy acid is salicylic acid. o poly-hydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or combination thereof. In a preferred embodiment, the poly-hydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment, the present invention provides a cosmetic combination product comprising a first composition and a second composition for separate topical application, wherein

1) the first composition comprising • 0.01% to 30% w/w of thioethyl amine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine, and

2) the second composition comprising

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide isomer or a salt thereof, and

• 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof.

In further embodiments of the cosmetic combination product, the first composition and the second composition further comprise at least one cosmetically acceptable excipient.

In another preferred embodiment, the present invention provides a cosmetic combination product consisting of a first composition and a second composition for separate topical application, wherein

1) the first composition consists of

• 0.01% to 30% w/w of thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine,

• 0.1 to 15% w/w of skin anti -wrinkle agents selected from the group comprising peptides, Panthenol, sodium hyaluronate, hyaluronic acid, retinoids, natural moisturizing factors, and sugars selected from Xylitylglucoside, Anhydroxylitol and Xylitol, and

• at least one cosmetically acceptable excipients (qsp 100%), and

2) the second composition consist of

• 0.01% to 30% w/w of azabenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azabenzene-4-carboxamide isomer or a salt thereof, and

• 0.1% to 50% w/w of an organic acid, preferably 1% to 30% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combination thereof. • 0.1 to 15% w/w skin anti -wrinkle agents selected from the group peptides, Panthenol, sodium hyaluronate, hyaluronic acid, Tazman pepper extract, retinoids, natural moisturizing factors, and sugars selected from Xylitylglucoside, Anhydroxylitol and Xylitol, and

• at least one cosmetically acceptable excipients (qsp 100%).

In some embodiments of the cosmetic combination product of the invention, retinoids are selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, sodium retinoyl hyaluronate and adapalene.

In some embodiments of the cosmetic combination product of the invention, peptides are selected from the group consisting of Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide, Acetyl Hexapeptide-8, Palmitoyl Tripeptide-5, Palmitoyl pentapeptide-4, Cu-GHK peptide, and dipalmitoyl hydroxyproline.

In some embodiments of the cosmetic combination product of the invention, the natural moisturizing factors are selected from the group consisting of PCA salts, Arginine, Glycine, Alanine, Glutamic Acid, urea and ceramides.

In another embodiment of the cosmetic combination products of the invention, the first composition and the second composition are separately topically applied. Typically, a time period between topical application of the first composition and the topical application of the second composition is few seconds (application of the second composition right after the first one), up to several hours later, such as 1 hour, 2 hours, 3 hours, 4 hours. Preferably, the second composition is applied right after the application of the first composition or up to 2 hours later.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practising the present invention and are not intended to limit the application and the scope of the invention.

EXAMPLES

Examples of the compositions of the invention:

Composition A (emulsion O/W)

2% Butylene Glycol

2.5% Glyceryl Stearate Citrate

2% Cetearyl alcohol

0.3% Xanthan Gum

1% Shea Butter

2% Caprylic/Capric Triglyceride

3% Dicaprylyl Carbonate

1% Sunflower oil

0.25% Tocopheryl acetate

0.8% Phenoxyethanol

10% Thioethylamine Hydrochloride

15% Azabenzene-4-Carboxamide

- QSP Water

Composition B (aqueous gel)

30% Glycerin

20% Sorbitol

5% Polysorbate 60

1% Carbomer

0.5% Benzyl Alcohol

10% Lactic Acid

1% Thioethylamine

QSP water Composition C (aqueous gel)

30% Glycerin

20% Sorbitol

5% Polysorbate 60

1% Carbomer

0.5% Benzyl Alcohol

2% Glycolic Acid

1% Thioethylamine

QSP water

Composition D (emulsion O/W)

5% Glycerin

0.05% disodium EDTA

1% Acrylates/C 10-30 Alkyl Acrylate Crosspolymer

1% Mineral oil

5% Octyldodecanol

3% Glyceryl Stearate

- 2% PEG- 100 Stearate

1% Cetyl Alcohol

0.3% Tocopherol

0.8% Phenoxyethanol

5% Thioethylamine Hydrochloride

15% Gluconolactone

QSP for pH 4 by Sodium Hydroxide

QSP water

Composition E (emulsion O/W)

2% Sucrose Stearate

3% Cetyl Phosphate

2% Behenyl Alcohol

5% Myristyl Myristate

2% Olive Oil

3% Propylene Glycol 0.5% Sodium Benzoate

0.3% Potassium sorbate

7% Thioethylamine Hydrochloride

7% Azabenzene-4-Carboxamide

10% Glycolic Acid

Example of the composition when application is done in 2 steps

Composition F applied for 30min before being rinsed off

30% Glycerin

5% Polysorbate 60

1% Carbomer

0.5% Benzyl Alcohol

7% Thioethylamine

10% Glycolic acid

QSP water

Composition G applied after composition G as a leave-on

2% Propylene Glycol

2% Butylene Glycol

2.5% Glyceryl Stearate Citrate

2% Cetearyl Alcohol

0.3% Xanthan Gum

1% Shea Butter

2% Caprylic/Capric Triglyceride

3% Dicaprylyl Carbonate

1% Sunflower oil

0.25% Tocopheryl Acetate

0.8% Phenoxyethanol

5% Azabenzene-4-carboxamide

- QSP Water

Composition H applied for 15min before being rinsed off

20% Sorbitol

5% Polysorbate 60 1% Carbomer

0.8% Phenoxyethanol

7% Thioethylamine Hydrochloride

QSP water

Composition applied after composition as a leave-on

2% Propylene Glycol

2.5% Glyceryl Stearate Citrate

2% Cetearyl Alcohol

0.3% Xanthan Gum

1% Shea Butter

2% Caprylic/Capric Triglyceride

3% Dicaprylyl Carbonate

1% Sunflower oil

0.25% Tocopheryl Acetate

0.8% Phenoxyethanol

5% Azabenzene-4-carboxamide

3.5% Glycolic acid

- QSP Water

Example 1

Example of efficacy through mRNA-RT-PCR assay on human dermal fibroblasts

* significative versus vehicle

** synergistic effect of the combination Example 2: Proven efficacy and synergistic effect shown in a clinical study on 8 volunteers per group, with daily application for 7 days and 4 weeks.

* significative versus vehicle

** synergistic effect of the combination Example 3

In vitro efficacy through colorimetry assay after treatment of normal human dermal fibroblasts (comparison versus non treated) and in vivo efficacy on 8 volunteers per group, with daily application for 4 weeks.

* significative versus vehicle

** synergistic effect of the combination