TW202425945A - Use of thioethylamine composition for skin rejuvenation and improved synergistic effect when combined with an organic acid and/or azabenzene-4-carboxamide - Google Patents

Abstract

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.

Description

Use of thioethylamine composition in combination with organic acid and/or 4-nitrophenylcarboxamide for skin regeneration and improved synergistic effect

The present invention relates to the cosmetic use of a composition comprising thioethylamine and azobenzene-4-carboxamide and/or an organic acid for skin regeneration.

Over the past few decades, there has been a great deal of concern about personal aesthetics and attempts to delay or minimize the appearance of signs associated with aging.

The skin is the largest organ in the human body and is susceptible to both intrinsic and extrinsic aging. Skin aging is a complex biological process affected by a combination of endogenous and exogenous factors. Endogenous factors are typically genetics, cellular metabolism, hormones, and metabolic processes, while exogenous factors are typically long-term sunlight, pollution, ionizing radiation, chemicals, and toxins. The above endogenous and exogenous factors lead to changes in the skin and the appearance of defects therein, such as loss of firmness, wrinkling, roughness, and/or sagging. For example, human skin is often exposed to harsh external conditions, such as excessive sun exposure and general environmental exposure, which over time lead to tissue degeneration of the human skin. Symptoms of this degeneration are most evident on the face and around the eyes and often manifest as wrinkles, leathery skin texture, dryness, roughness, and precancerous bumps. Although the skin has the natural ability to repair such damage, the skin's ability to do so naturally decreases with age. Therefore, efforts have been made to treat human skin in order to slow down or counteract the aforementioned effects of aging on the skin and to renew or regenerate the dermis.

The three major structural components of the dermis are collagen, elastin, and glycosaminoglycans (GAGs), which have been the subject of most anti-aging research and skin-related anti-aging aesthetic strategies, ranging from "anti-wrinkle creams" to fillers. Much of the early research into skin renewal and regeneration focused on the use of vitamin A as a therapeutic agent. Many of these early treatments involved oral administration of vitamin A in the form of a vitamin A ester (vitamin A palmitate). This approach evolved over time to focus on topical administration of vitamin A in its acid form (retinoic acid), with early reports suggesting that vitamin A may slow the effects of aging on the skin. However, due to the side effects of using retinoic acid in its topical form (usually painful and uncomfortable peeling), the use of vitamin A in its many forms has limited applicability from a long-term management perspective. Therefore, attention to several other products with potential skin regenerative effects has been the focus of recent research for topical applications.

Vitamins have also been used alone or in combination to prevent or reverse skin damage and/or improve the skin quality of an individual, and particularly skin damage associated with inflammation resulting from UV radiation. For example, U.S. Patents 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 tocotrienols (vitamin E) to treat and prevent skin damage resulting from sun exposure.

Due to its viscoelastic properties and its ability to retain water, hyaluronic acid has also been used in the beauty industry to keep the skin hydrated, maintain elasticity and treat wrinkles by improving roughness, or even as a dermal filler. However, hyaluronic acid is currently obtained from several sources such as chicken combs or bacterial extracts, and these products may therefore contain impurities and need to be thoroughly characterized. In addition, the desired effect on skin roughness or anti-wrinkle effects may only be apparent after several weeks of treatment (Farwick et al., SÖFW Journal, 134(11), 17, 2008; Poetschke et al., MMW Fortschr. Med. 158 (Suppl. 4) (May 25, 2016) 1–6).

Despite this, skin products developed to date have not been effective enough to be fully embraced by those who suffer from skin damage or who wish to prevent premature skin aging or sagging (loss of skin firmness). While there are a number of treatments known to treat specific skin conditions, there remains a need for a simple, multi-purpose cosmetic treatment to increase skin firmness, thereby reducing the effects of aging and damage to the skin.

Despite the availability of numerous products, compounds and/or extracts in the art, there remains a need for alternative treatments for skin regeneration that are safer (unlike retinols, which can be irritants or photosensitizers) and/or more effective (unlike topical collagen or hyaluronic acid, which can have a long onset of action) and/or more readily available (unlike peptides, which are expensive to produce). An ideal skin regeneration composition would be effective, rapid and selective in action, have no short-term or long-term side effects, be well tolerated and be well accepted by the individuals being treated.

Aspects of the present invention provide a cosmetic method for skin regeneration, wherein the method comprises topically applying to an area of the skin of an individual in need thereof a composition comprising: ● 0.01% to 30% w/w thioethylamine, ● 0.01% to 30% w/w phenyl-4-carboxamide or a salt thereof, and/or ● 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof.

Another aspect of the present invention provides a cosmetic method for skin regeneration, which comprises the following steps: a) topically applying to an area of skin of an individual in need thereof a first composition comprising: 0.01% to 30% w/w thioethylamine, and 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, b) topically applying to the area of the skin a second composition comprising 0.01% to 30% w/w phenylamine or a salt thereof, c) repeating steps a) and b) to obtain a skin regeneration effect.

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

A further aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for individual topical application, wherein 1) the first composition comprises the following: ○ 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 a combination thereof, and 2) the second composition comprises the following: ○ 0.01% to 30% w/w of phenylamine-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 individual topical application, wherein 1) the first composition comprises the following: ○ 0.01% to 30% w/w of thioethylamine, and 2) the second composition comprises the following: ○ 0.01% to 30% w/w of phenylamine-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 a combination thereof.

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 should 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 event of a conflict, this specification (including definitions) will prevail. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as understood by one of ordinary skill in the art to which the present invention belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

The term "comprising" is generally used in an inclusive sense, that is, allowing the presence of one or more features or components. Also as used in this specification and claims, the term "comprising" may include similar embodiments described in terms of "consisting of" and/or "consisting essentially of".

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

As used in this specification and claims, the term "and/or" as used herein in phrases such as "A and/or B" 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 so described, or ingredients thereof, are suitable for use in contact with the skin of mammals, most preferably humans, without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

As used herein, the terms "cosmetics," "cosmetic techniques," or "cosmetic treatments" are non-therapeutic treatments of skin conditions that are not disease or pathological conditions.

As used herein, the term "topical", "topically" refers to applying the composition of the present invention to the surface or area of the skin and/or a part thereof (e.g., 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 area, skin on the scalp) so that it can exhibit local activity. Therefore, topical forms include cosmetic and/or dermatological formulations suitable for external use, resulting in direct contact with the skin and/or a part thereof.

As used herein, the term "subject" is well known in the art and is used herein to refer to mammals, and preferably humans. In some embodiments, the subject is a subject in need of skin regeneration or a subject showing signs of skin aging. The term does not denote a particular age or gender. Therefore, it is intended to cover adult subjects, whether male or female.

As used herein, "skin regeneration" and "skin regeneration effect" 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 younger-looking skin. Specifically, "skin regeneration" includes one or more of the following: anti-wrinkle effects (e.g., reduction in wrinkle depth, reduction in wrinkle area, reduction in wrinkle volume, reduction in wrinkle volume, reduction and prevention of fine lines, improvement in skin roughness), firming effects (e.g., plumping, anti-sagging, skin thickness, improvement in skin elasticity/suppleness), improvement of the skin barrier (e.g., improvement in skin texture, increase in skin moisture retention, reduction in transepidermal water loss), and cognitive decline in age in an individual (by herself/himself or by others).

As used herein, the terms "smoothing" and "softening" refer to changes in the surface of the skin and/or keratinous tissue such that the touch is improved (softening) or the skin relief is reduced and the skin roughness is eliminated (smoothing). "Signs of skin aging" include but are not limited to all externally visible or tactile manifestations and any other macroscopic or microscopic effects resulting from skin aging. Such signs may be caused or contributed to by intrinsic or extrinsic factors, such as chronological aging and/or environmental damage. Such signs may result from processes including, but not limited to, the development of textural discontinuities such as wrinkles or enlarged deep lines, skin lines, folds, bumps, enlarged pores (e.g., associated with structures such as sweat ducts, sebaceous glands, or hair follicles), or from deformation, hyperkeratinization, elastic tissue degeneration, collagen breakdown, and stratum corneum, dermis, epidermis, and dermis. Heterogeneity or roughness of the skin, cutaneous vasculature (e.g., telangiectasia or spider vessels), and other histological changes in the subcutaneous tissue (especially that adjacent to the skin), loss of skin elasticity (loss of functional elastin and/or inactivation), laxity (including swelling in the eye area and jawline), loss of skin firmness, and loss of skin tautness.

The inventors unexpectedly discovered that the combination of thioethylamine and 4-nitrophenylcarboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, gluconolactone and/or a combination thereof can have an anti-wrinkle effect (e.g., reduction in wrinkle depth, reduction in wrinkle area, reduction in wrinkle volume, reduction in wrinkle amount, reduction in fine lines and prevention, improvement of skin roughness), firming effects (e.g. plumping, anti-sagging, skin thickness, improvement of skin elasticity/suppleness), and improvement of the skin barrier (e.g. improvement of skin texture, increase in skin moisture retention, reduction in transepidermal water loss), leading to overall skin regeneration and thus cognitive decline with age.

Therefore, the present invention provides a cosmetic method for skin regeneration, wherein the method comprises topically applying to an area of the skin of an individual in need thereof a composition comprising: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% w/w thioethylamine, ● 0.01% to 30% w/w phenylamine-4-carboxamide or a salt thereof, preferably 0.1 to 20% w/w phenylamine-4-carboxamide or a salt thereof, and/or ● 0.1% to 50% w/w organic acid, preferably 1% to 30% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof.

In a preferred embodiment, the skin or area of 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, skin regeneration involves reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, enhancing skin elasticity, and/or reducing skin roughness.

Fine lines are the beginning of wrinkles and look like small folds in the skin. Fine lines are closer to the surface of the skin, while wrinkles are deeper into the skin.

Reduction in the appearance of lines and wrinkles can be measured by any of the following methods known in the art: ● Visual assessment or clinical grading on a scale by a dermatologist. ● Quantification of skin microstructure via 2D or 3D image capture. ● Quantification of wrinkle/wrinkle depth, wrinkle/wrinkle volume, wrinkle/wrinkle surface, wrinkle/wrinkle number measurement via 2D or 3D image analysis or duplicate images. ● Quantification of average depth, volume, and angle of spread of one or several major wrinkles/wrinkles via 2D or 3D skin image analysis or duplicate images. ● Quantification of skin roughness by digital or analog dermatoscopy or by 2D or 3D skin image analysis or by replicating the image.

Reduction of deep wrinkles can be assessed by methods known in the art, for example by measuring the depth, volume, number, surface, or spread angle of one or more major wrinkles.

Skin elasticity can be measured by methods known in the art, such as by a meter, by a pinch test, by measuring the displacement of skin pores using a unidirectional force, skin deformation, by measuring the stress applied by suction, or by measuring the velocity of ultrasound waves passing through skin tissue.

Skin roughness can be measured by methods known in the art, such as digital or analog dermoscopy or by 2D or 3D skin image analysis or by reconstructing the image.

The applicant unexpectedly discovered that the combination of thioethylamine, 4-nitrophenylcarboxamide or its salts and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combinations thereof provides a synergistic effect on skin regeneration while having excellent tolerability to human skin.

In the present disclosure, % w/w of thioethylamine or its salt refers to % w/w of thioethylamine (thioethylamine free base). Therefore, any specific mass referred to as "thioethylamine or its salt" refers to the mass equivalent of the free base (thioethylamine free base), and any specific mass referred to as a specific salt of thioethylamine (e.g., thioethylamine hydrochloride) refers to the mass of the specific salt. The above definition can also be applied to % w/w of phenylthiophene-4-carboxamide or its salt, for example, any specific mass referred to as "phenylthiophene-4-carboxamide or its salt" refers to the mass equivalent of the free base (phenylthiophene-4-carboxamide).

The term "thioethylamine" is intended to encompass any acceptable salt, ester, solvate, hydrate, prodrug, or any other compound capable of providing (directly or indirectly) thioethylamine immediately after administration to a patient. Salts of thioethylamine are pharmaceutically acceptable salts, cosmetically acceptable salts, and dermatologically acceptable salts. Preferred salts of thioethylamine are hydrochlorides, hydrotartrates, and phosphates. Any compound that is a prodrug of thioethylamine falls within the scope and spirit of the present invention. The term "prodrug" is used in its broadest sense and includes those derivatives that are converted to thioethylamine in vivo. Prodrugs 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, including, for example, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acyl ureas, and biohydrolyzable phosphate analogs of biohydrolyzable moieties. Prodrugs can generally be prepared using well-known methods, such as those described by Burger in "Medicinal Chemistry and Drug Discovery", 6th edition (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers). In addition, the thioethylamine referred to herein may be in crystalline or non-crystalline form, as a free compound or a solvate (e.g., a hydrate) and all forms are intended to fall within the scope of the present invention. The solvation method is generally known in the art.

The salt of 4-nitrophenylcarboxamide of the present invention is a pharmaceutically acceptable salt, a cosmetically acceptable salt, and a dermatologically acceptable salt.

As used herein, "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of thioethylamine and azobenzene-4-carboxamide and include pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of thioethylamine and azobenzene-4-carboxamide can be prepared from inorganic or organic acids, or can be prepared in situ during the final isolation and purification of thioethylamine and azobenzene-4-carboxamide. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, arylsulfonic acid. Suitable pharmaceutically acceptable base addition salts of phenylamine-4-carboxamide include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc, and organic salts made from organic bases such as choline, diethanolamine, and morpholine. Other examples of organic acids are ammonium salts, quaternary salts such as tetramethylammonium salts, amino acid addition salts such as salts of 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 where the agent is a solid, it should be understood by those skilled in the art that the compounds, agents and salts of the present invention may exist in different crystalline or non-crystalline forms, which are intended to fall within the scope of the present invention.

The compositions of the present invention may be prepared by any method known in the art for use in cosmetic and/or dermatological compositions. Generally, the method involves simply combining or mixing the ingredients; however, particularly where insoluble or immiscible ingredients are used, a higher degree of agitation or homogenization may be required to prepare a suitable composition, such as an emulsion or suspension, etc. In addition, during preparation, it may be necessary to add known pH adjusters to maintain the appropriate pH of the composition for topical application, particularly where alkaline ingredients are employed. Generally, the pH should be in the range of from about 3.5 to about 8.

In some embodiments, the compositions of the present invention are cosmetic compositions, which further comprise a cosmetically acceptable formulation for topical administration.

In some embodiments, the composition of the present invention is a dermatological composition, which further comprises a dermatologically acceptable formulation for dermal administration.

The cosmetic and dermatological compositions according to the invention may further comprise one or more cosmetically or dermatologically acceptable excipients as are conventionally used in such compositions, such as preservatives, antioxidants, bactericides, perfumes, substances for preventing foaming, dyes, pigments with a coloring effect, thickeners, chelating agents, propellants, surfactant substances, emulsifiers, softening, moisturizing and/or water-retaining substances, distilled water, fats, oils, waxes or other conventional ingredients of cosmetic and dermatological compositions such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. The cosmetic compositions, dermatological compositions and cosmetic composition products according to the present invention do not contain polystyrene, such as water-soluble polystyrene or suitable salts thereof. The necessary amount of cosmetically or dermatologically acceptable excipients can be easily selected by a person skilled in the art to which the present invention pertains based on the desired product.

Moisturizing substances can be incorporated into the compositions of the present invention to maintain hydration or replenish moisture to the skin. Moisturizing creams that prevent water from evaporating from the skin by providing a protective coating are called emollients. In addition, emollients provide a softening or soothing effect on the skin surface and are generally considered safe for topical use. Preferred emollients include mineral oils, lanolin, wax, capric/caprylic triglyceraldehydes, cholesterol, silicones such as dimethicone, cyclomethicone, almond oil, jojoba oil, avocado oil, castor oil, sesame oil, sunflower oil, coconut oil and grape seed oil, cocoa butter, olive oil, aloe vera extract, fatty acids such as oleic acid and stearic acid, fatty alcohols such as cetyl and hexadecyl (ENJAY), diisopropyl adipate, hydroxybenzoate, benzoate of C _9-15 alcohols, isononanoate, ethers such as polyoxypropylene butyl ether and polyoxypropylene cetyl ether, and C _12-15 alkyl benzoate, and mixtures thereof. Moisturizing substances that bind water and thereby retain it on the surface of the skin are called humectants. Suitable humectants can be incorporated into the composition of the present invention, for example, glycerin, polypropylene glycol, polyethylene glycol, lactic acid, pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin, ceramide, lecithin, sorbitol, PEG-4, and mixtures thereof.

The composition of the present invention may also contain commonly used alcohols, especially lower alcohols, preferably ethanol and/or isopropanol; lower diols or polyols and their ethers, preferably propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether or monobutyl ether, propylene glycol monomethyl ether or monoethyl ether or monobutyl ether, diethylene glycol monomethyl ether or monoethyl ether and similar products, polymers, foam stabilizers; electrolytes, and especially one or more thickeners. Thickeners that can be used in the composition of the present invention to help make the product have a suitable viscosity include carbomer, silica, magnesium silicate and/or aluminum silicate, beeswax, stearic acid, such as xanthan gum, hydroxypropyl cellulose, polyacrylamide, stearyl polysaccharide and its derivatives of acrylate crosslinked polymers, preferably carbomer, such as Carbopol® 980, 981, 1382, 2984, 5984 alone or in mixtures thereof.

Suitable stabilizers such as emulsifiers or foam generators/stabilizers that can be included in the composition of the present invention to stabilize the ingredients include, but are not limited to, alkali metal hydroxides such as sodium hydroxide 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 the foregoing.

The composition of the present invention may also contain a filter or sunscreen that absorbs UV radiation, wherein the total amount of the filter is 0.001 to 30%, preferably 0.5 to 10%, based on the total amount of the preparation. The composition can also be used as a sunscreen for the skin. Such UV filters include, for example, the following: phenoxybenzone, cinoxate, benzophenone-8, methyl salicylate, menthyl phthalate, octocrylene, octyl methoxycinnamate, octyl salicylate, benzophenone-3, padimate O, phenylbenzimidazole sulfonic acid, benzophenone-4, titanium dioxide, triethanolamine salicylate, and zinc oxide.

The compositions of the present invention may also include one or more skin penetrants. These are additives that have a direct effect on the permeability of the skin barrier when applied to the skin: increasing the rate at which certain other compounds can penetrate into the skin layer and/or increasing the amount of certain other compounds that can penetrate into the skin layer. Exemplary organic penetration enhancers include dimethyl sulfoxide; isopropyl myristate; decanol, undecanol or dodecanol; propylene glycol; polyethylene glycol; C _9-11 or C _12-15 fatty alcohols; azone; alkyl pyrrolidone; diethoxy glycol (Transcutol); lecithin, etc. Surfactants can also be used as penetration enhancers.

According to one embodiment, the composition of the present invention may further include at least one anti-wrinkle benefit agent selected from the group consisting of: coenzyme Q10, sodium hyaluronate, hyaluronic acid, hyaluronic acid fragments, gold particles, peptides (selected from palmitoyl tetrapeptide-7, palmitoyl oligopeptide, acetyl hexapeptide-8, palmitoyl tetrapeptide-5, palmitoyl pentapeptide-4, Cu-GHK peptide, and dipalmitoyl hydroxyproline), tocopherol, ceramide, retinoid (selected from retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene), sucrose, collagen Protein, resveratrol, acetyl heparan sulfate and its analogs, dermatin sulfate and its analogs, chondroitin sulfate and its analogs, panthenol, algae extract, perfluorohexane, carnosine, geranylgeranyl propanol, pullulan, copper, alpha-lipoic acid, biotin, curcuminoids, natural moisturizing factors, such as xylitol glucoside, dehydrated xylitol, sugars of xylitol, plant extracts such as moringa seed oil, coconut extract, damask rose water, camellia extract, centella asiatica extract, water celery sprout extract, green tea extract, Tasman pepper extract, and mixtures thereof. In another embodiment, the composition of the present invention may further include at least one anti-wrinkle benefit agent selected from the group consisting of: coenzyme Q10, sodium hyaluronate, hyaluronic acid, gold particles, peptides (selected from palmitoyl tetrapeptide-7, palmitoyl oligopeptide, acetyl hexapeptide-8, palmitoyl tetrapeptide-5, palmitoyl pentapeptide-4, Cu-GHK peptide, and dipalmitoyl hydroxyproline), tocopherol, ceramide, retinoid (selected from retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene), fusinolide, Collagen, resveratrol, acetyl heparin sulfate, dermatin sulfate, chondroitin sulfate, algae extract, perfluorohexane, carnosine, geranylgeranyl propanol, pullulan, copper, alpha-lipoic acid, biotin, curcuminoids, natural moisturizing factors (selected from xylitol glucoside, dehydrated xylitol, xylitol), plant extracts such as moringa seed oil, coconut extract, damask rose water, camellia extract, centella asiatica extract, water celery sprout extract, green tea extract, Tasman pepper extract, and mixtures thereof.

According to another embodiment, the composition of the present invention may also further comprise liposomes (unilamellar and/or multilamellar liposomes of any size), lipidoids, or any encapsulation system (e.g., microencapsulation, nanoencapsulation, cubic) to facilitate delivery of any component of the composition to its site of action. The best type and size of liposomes, lipidoids and/or encapsulation systems, as well as the nature of the medium in which they are dispersed, can be easily selected by those of ordinary skill in the art to which the present invention belongs.

In some embodiments of the cosmetic method for skin regeneration, the composition is composed of: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% w/w thioethylamine, ○ 0.01% to 30% w/w phenylamine or a salt thereof, preferably 0.1 to 20% w/w phenylamine or a salt thereof, and/or ○ 0.1% to 50% w/w organic acid, preferably 1% to 30% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a 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 for skin regeneration, the composition is composed of: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% w/w thioethylamine, ○ 0.01% to 30% w/w azobenzene-4-carboxamide or a salt thereof, preferably 0.1 to 20% w/w azobenzene-4-carboxamide or a salt thereof, and/or ○ 0.1% to 50% w/w organic acid, preferably 1% to 30% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof; ● At least one cosmetically acceptable excipient for topical administration (qsp 100%).

The benefits of the composition comprising thioethylamine and 4-nitrophenylcarboxamide and/or an organic acid combination selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof are, for example: ● Anti-wrinkle effect (e.g., reduction in wrinkle depth, reduction in wrinkle volume, reduction or prevention of fine lines, improvement in skin roughness); ● Firming effect (plumping, anti-sagging, skin thickness, improvement in skin elasticity/suppleness); ● Improvement of skin barrier (skin texture, skin moisturizing), leading to skin regeneration and age-related cognitive decline.

The benefits of the composition comprising thioethylamine and 4-nitrophenylcarboxamide and/or an organic acid combination selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof on the skin structure are, for example: ● Skin hyperplasia (i.e., increasing skin thickness by increasing the epidermal layer); ● Increased production of endogenous collagen and elastin (and reduced degradation), which leads to increased skin thickness; ● Anti-glycation effect, preventing cell damage (from endogenous and extrinsic factors such as ROS, stress, oxidation, UV, AGE, etc.), leading to increased elasticity.

Furthermore, the inventors have observed that the combination of thioethylamine with 4-nitrophenylcarboxamide and/or an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or combinations thereof has a superior, synergistic effect when compared to thioethylamine used alone.

The compositions of the present invention may be cosmetic or dermatological compositions and may be in a variety of forms, such as emulsions, suspensions, solutions, etc. In some embodiments, the compositions of the present invention are in the form of paints, creams, gels, solutions, sprays, cleansers, powders, ointments, waxes, lipsticks, soaps, shampoos, hydroalcoholic solutions, suspensions, scrubs, impregnated pads, skin conditioners, and other types of cosmetic compositions. In further embodiments, the composition of the present invention may be, for example, an anhydrous preparation, an oil-free preparation, an emulsion or microemulsion of the water-in-oil (W/O) type or the oil-in-water (O/W) type, a multiple emulsion of the water-in-oil-in-water (W/O/W) type, a solid stick, or even an aerosol. The preferred form of the composition of the present invention is a gel, a paint, an emulsion, or a powder.

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

In some embodiments, the compositions of the present invention are used for cosmetic skin regeneration of natural healthy human skin, i.e., non-therapeutic use not related to the treatment of skin diseases or pathological conditions. In some embodiments, cosmetic skin regeneration involves anti-wrinkle effects (e.g., reduction in wrinkle depth, reduction in wrinkle area, reduction in wrinkle volume, reduction in wrinkle volume, reduction or prevention of fine lines, improvement in skin roughness), firming effects (e.g., plumping, anti-sagging, skin thickness, improvement in skin elasticity/suppleness), improving skin barrier (e.g., skin texture, skin moisturizing), leading to overall skin regeneration (and age-recognized reduction). Specifically, in some embodiments, cosmetic skin regeneration is reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, increasing skin elasticity, and reducing skin roughness. For example, if an individual desires to improve the appearance of at least one skin area for cosmetic reasons, a method of skin regeneration may be used.

Another aspect of the invention provides the use of the composition of the invention for cosmetic skin regeneration. In preferred embodiments, the skin or skin area is 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 area, and skin on the scalp.

In one embodiment, the method of skin regeneration of the present invention is repeated a number of times sufficient to obtain the skin regeneration effect and age-related cognitive decline. In a further embodiment of the method of skin regeneration of the present invention, when the desired result or effect has been achieved, the method of skin regeneration of the present invention can be continued as non-daily application, non-continuous daily application, or one to several applications per week to maintain the skin regeneration result or effect.

In the method for skin regeneration according to the present invention, the composition is applied to the skin or skin area, preferably human skin. The amount of the composition to be applied to the skin depends on the form of the composition and its mode of application. For example, a spray formulation can be applied to provide a light, uniform coating on the skin. Similarly, paints, creams, gels, shampoos, etc. are usually applied to the treatment area in an amount to provide a light coating, which is consistent with the application of topical cosmetic ointments, creams, paints, etc. Generally speaking, especially where all or substantially all skin surfaces (including hairy or hairless skin) are to be treated, the application rate for the whole body (i.e., for the exposed skin of an "average individual" wearing a swimsuit and 1.65 m tall, weighing 68 kg, and having a 0.81 m waist circumference) is about 20 to 60 ml. This translates into an application rate of about 2 mg/cm ² of skin surface (including hairy or hairless skin surface). On the face, the application rate is usually 0.5 to 1.0 ml. At such application levels, the amount of composition applied is in the range of from about 0.1 to about 10 mg/cm ² of skin, preferably from about 1 to about 3 mg/cm ² .

The compositions of the present invention may be applied one or more times per day, depending on the activities in which a particular individual is engaged. For example, an individual engaged in normal daytime activities may wish to apply the composition twice per day (once in the morning and once in the evening) in conjunction with general grooming. On the other hand, if an individual plans outdoor activities such as sunbathing and exercise, the composition may be applied before and during such activities, just as a sunscreen composition is applied regularly during the day. The compositions of the present invention may also be applied to the whole body, especially to areas not covered by clothing, such as the arms, neck, and calves.

In one embodiment, the present invention provides a method for skin regeneration comprising the steps of: a) topically applying to an area of skin of an individual in need thereof a first composition comprising: 0.01% to 99% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, and 0.1% to 99% w/w organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group comprising alpha-hydroxy acid (AHA), beta-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, b) Topically applying to the area of the skin a second composition comprising 0.01% to 99% w/w of azobenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azobenzene-carboxamide isomer or a salt thereof, c) repeating steps a) and b) to obtain a skin regeneration effect (end point), wherein the azobenzene-carboxamide isomer is selected from the group comprising azobenzene-4-carboxamide, azobenzene-3-carboxamide, azobenzene-2-carboxamide; the α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, the α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutanoic acid (beta 5 hydroxybutanoic acid), tropic acid, trethocanic acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; Polyhydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment, the present invention provides a cosmetic method for skin regeneration comprising the steps of: a) topically applying to an area of skin of an individual in need thereof a first composition comprising: 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% thioethylamine, and 0.1% to 50% w/w organic acid, preferably 1% to 30% organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, b) topically applying to the area of the skin a first composition comprising 0.01% to 30% w/w of phenylamino-4-carboxamide or its salt, preferably a second composition of phenylamino-4-carboxamide or its salt at 0.1% to 20%, c) repeating steps a) and b) to obtain a skin regeneration effect (end point).

In one embodiment of the cosmetic method for skin regeneration of the present invention, the method further comprises removing the first composition by any suitable method prior to topical application of the second composition. In some embodiments, the suitable method is selected from the following: Rinse with water with or without a suitable detergent; Removal with any suitable solvent or cleanser; Removal with a dry or wet pad; and/or A combination thereof.

In some embodiments, skin regeneration involves reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, increasing skin elasticity, and/or reducing skin roughness.

In one embodiment of the cosmetic method of skin regeneration of the present invention, suitable cleansing agents are typically skin cleansing products, such as personal care cleansers for surface cleansing, for example selected from bars, liquids, gels, pastes, etc., such as liquid or solid soaps or shampoos.

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

The cosmetic method for skin regeneration of the present invention is repeated for a time period and number of times sufficient to obtain the desired skin regeneration effect (end point), such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, two months, three months, one year, two years, three years, or longer; or for example, 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 embodiment, after the desired skin regeneration effect, the cosmetic method for skin regeneration of the present invention is repeated in a non-daily, non-consecutive daily manner, or in order to maintain the skin regeneration result or effect, the cosmetic method for skin regeneration of the present invention is repeated one to four times a week.

In one embodiment of the skin regeneration cosmetic method of the present invention, the first composition comprises 0.1% to 20% w/w of thioethylamine or its salt, preferably 0.1% to 20% or 0.1% to 30% w/w of thioethylamine or its salt; and 0.1% to 40% w/w of organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w of organic acid, wherein the organic acid is selected from the group comprising α-hydroxy acid (AHA), β-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, and wherein ○ α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, the α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; ○ β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutyric acid, tropic acid, trocasol acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; ○ Polyhydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment of the skin regeneration cosmetic method of the present 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 a combination thereof.

In one embodiment of the skin regeneration cosmetic method of the present invention, the second composition comprises 0.01% to 30% w/w of azobenzene-carboxamide isomers or salts thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azobenzene-carboxamide isomers or salts thereof, wherein the azobenzene-carboxamide isomers are selected from the group consisting of azobenzene-4-carboxamide, azobenzene-3-carboxamide, and azobenzene-2-carboxamide.

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

In another embodiment, the present invention provides a cosmetic method for skin regeneration comprising the steps of: a) topically applying to an area of skin of an individual in need thereof a first composition comprising 0.01% to 99% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, b) topically applying to the area of skin a second composition comprising: 0.01% to 99% w/w azobenzene-carboxamide isomer or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w azobenzene-carboxamide isomer or a salt thereof, and 0.1% to 99% w/w 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 α-hydroxy acid (AHA), β-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, c) repeating steps a) and b) to obtain a skin regeneration effect (end point), wherein the phenyl-carboxamide isomer is selected from the group comprising phenyl-4-carboxamide, phenyl-3-carboxamide, phenyl-2-carboxamide; the α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, the α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutyric acid, tropic acid, trocasol acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; Polyhydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment, the present invention provides a cosmetic method for skin regeneration comprising the steps of: a) topically applying to an area of skin of an individual in need thereof a first composition comprising 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% thioethylamine, b) topically applying to the area of skin a second composition comprising: 0.01% to 30% w/w phenylthiazolamide or a salt thereof, preferably 0.1% to 20% w/w phenylthiazolamide 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. w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, c) repeating steps a) and b) to obtain a skin regeneration effect (end point).

In one embodiment of the cosmetic method for skin regeneration of the present invention, the method further comprises removing the first composition by any suitable method prior to topical application of the second composition. In some embodiments, the suitable method is selected from the following: Rinse with water with or without a suitable detergent; Removal with any suitable solvent or cleanser; Removal with a dry or wet pad; and/or A combination thereof.

In some embodiments, skin regeneration involves reducing the appearance of fine lines and wrinkles, reducing deep wrinkles, increasing skin elasticity, and/or reducing skin roughness.

In one embodiment of the cosmetic method of skin regeneration of the present invention, suitable cleansing agents are typically skin cleansing products, such as personal care cleansers for surface cleansing, for example selected from bars, liquids, gels, pastes, etc., such as liquid or solid soaps or shampoos.

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

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

In one embodiment of the skin regeneration cosmetic method of the present invention, the second composition comprises 0.1% to 20% w/w of azobenzene-carboxamide isomers or salts thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azobenzene-carboxamide isomers or salts 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 α-hydroxy acid (AHA), β-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, and wherein ● The isomer of phenylamine carboxamide is selected from the group comprising phenylamine-4-carboxamide, phenylamine-3-carboxamide, phenylamine-2-carboxamide, and ● α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; ● β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutyric acid, tropic acid, trocasol acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; ● The polyhydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group comprising gluconolactone and lactobionic acid.

In a preferred embodiment of the cosmetic method for skin regeneration of the present invention, the second composition comprises 0.01% to 30% w/w of 4-nitrophenylamine or its salt, preferably 0.1% to 20% or 0.1% to 30% w/w of 4-nitrophenylamine or its salt; 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 a combination thereof.

In a further embodiment of the cosmetic method for skin regeneration of the present invention, the first composition and the second composition further comprise at least one cosmetically acceptable excipient.

In another embodiment, the cosmetic method of skin regeneration of the present invention is repeated for a period of time sufficient to obtain the skin regeneration effect, which period of time can be several days (1 to 7 days), several weeks (1 to 4 weeks or 1 to 8 weeks or 2 to 8 weeks or 4 to 8 weeks), several months (1 to 3 months or 1 to 6 months or 1 to 12 months), several years (1 to 5 years) or lifelong cosmetic treatment, depending on the desired skin regeneration effect or result.

In a further embodiment of the cosmetic method for skin regeneration of the present invention, when the desired skin regeneration effect or result has been achieved, the method of the present invention can be continued as non-daily application, non-consecutive daily application or one to six applications per week to maintain the skin regeneration result or effect.

The cosmetic method of skin regeneration of the present invention is repeated (step c) a number of times sufficient to obtain the skin regeneration effect or result (end point), and/or after the desired skin regeneration result or effect is achieved (end point), the method of the present invention is repeated non-daily, non-consecutive days, or one to six times a week to maintain the skin regeneration result or effect.

In the cosmetic method of skin regeneration of the present invention, one of ordinary skill in the art to which the present invention pertains will appreciate that the endpoint selected in a particular situation will vary depending on the desired appearance of the skin, the individual's desired results, and other factors. For example, an endpoint may be defined subjectively, such as when the individual is completely "satisfied" with the results of the cosmetic treatment.

The advantages of the skin regeneration cosmetic method comprising separately administering a first composition comprising thioethylamine and an organic acid selected from the group consisting of α-hydroxy acid (AHA), β-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof (step a); and a second composition comprising azobenzene-carboxamide isomers or salts thereof, preferably azobenzene-4-carboxamide or a salt thereof (step b) are as follows: - When the above composition is applied in two steps according to the present invention, the skin regeneration effect is unexpectedly improved compared to a composition comprising all three compounds, namely thioethylamine, an organic acid selected from the group consisting of α-hydroxy acid (AHA), β-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, and preferably a phenylamine-carboxamide isomer or a salt thereof of phenylamine-4-carboxamide or a salt thereof.

The advantages of the skin regeneration cosmetic method comprising the individual administration of a first composition comprising thioethylamine (step a); and a second composition comprising an isomer of 4-aminophenylcarboxamide or a salt thereof, preferably 4-aminophenylcarboxamide or a salt thereof, and an organic acid selected from the group consisting of α-hydroxy acid (AHA), β-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof (step b) are as follows: - When the above composition is applied in two steps according to the present invention, the skin regeneration effect is unexpectedly improved compared to a composition comprising all three compounds, namely thioethylamine, an organic acid selected from the group consisting of α-hydroxy acid (AHA), β-hydroxy acid (BHA) and polyhydroxy acid (PHA), preferably an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, and preferably a phenylamine-carboxamide isomer or a salt thereof of phenylamine-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 individual topical application, wherein 1) the first composition comprises the following: 0.01% to 99% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, and 0.1% to 99% w/w organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group comprising α-hydroxy acid (AHA), β-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, and wherein ○ α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, the α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; ○ The β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutyric acid, tropic acid, trocasol acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; ○ The polyhydroxy acid (PHA) is selected from the group comprising gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group comprising gluconolactone and lactobionic acid; and 2) the second composition comprises 0.01% to 99% w/w of azobenzene-carboxamide isomers or salts thereof, preferably 0.1% to 20% or 0.1% to 30% w/w of azobenzene-carboxamide isomers or salts thereof, wherein the azobenzene-carboxamide isomers are selected from the group comprising azobenzene-4-carboxamide, azobenzene-3-carboxamide, and azobenzene-2-carboxamide.

In a preferred embodiment, the present invention provides a cosmetic combination product comprising a first composition and a second composition for individual topical application, wherein 1) the first composition comprises the following: ● 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 a combination thereof, and 2) the second composition comprises the following: ● 0.01% to 30% of 4-nitrophenylamine or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w phenyl-4-carboxylic acid amide or its salt.

In a further embodiment 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 comprising a first composition and a second composition for individual topical application, wherein 1) the first composition is composed of: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, and ● 0.1% to 50% w/w 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 a combination thereof, ● 0.01% to 1% retinol, and ● at least one cosmetically acceptable excipient (qsp 100%), and 2) the second composition is composed of: ● 0.01% to 30% w/w of phenylamino-4-carboxamide or its salt, preferably 0.1 to 20% or 0.1% to 30% w/w of phenylamino-4-carboxamide or its salt, ● 0.1 to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of xylitol glucoside, dehydrated xylitol, xylitol, panthenol, Tasman pepper extract and retinoids, preferably the retinol is selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene, ● At least one cosmetically acceptable excipient (qsp 100%).

In the context of the present invention, Tasman Pepper is an Australian natural active ingredient extracted from Tasmanian pepper berries.

Another aspect of the present invention provides a cosmetic combination product comprising a first composition and a second composition for individual topical application, wherein 1) the first composition comprises the following: 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 comprises the following: 0.01% to 99% w/w of azobenzene-carboxamide isomer or a salt thereof, preferably 0.1 to 20% or 0.1% to 30% w/w of azobenzene-carboxamide isomer or a salt thereof, wherein the azobenzene-carboxamide isomer is selected from the group consisting of azobenzene-4-carboxamide, azobenzene-3-carboxamide, azobenzene-2-carboxamide, and 0.1% to 99% w/w organic acid, preferably 0.1% to 40% or 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group comprising α-hydroxy acid (AHA), β-hydroxy acid (BHA), polyhydroxy acid (PHA) and/or a combination thereof, and wherein ○ α-hydroxy acid (AHA) is selected from the group comprising glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and/or a combination thereof. In a preferred embodiment, α-hydroxy acid is selected from the group comprising glycolic acid and lactic acid; ○ β-hydroxy acid (BHA) is selected from the group comprising salicylic acid, β-5-hydroxybutyric acid, tropic acid, trocasol acid and/or a combination thereof. In a preferred embodiment, the β-hydroxy acid is salicylic acid; ○ The polyhydroxy acid (PHA) is selected from the group consisting of gluconolactone, galactose, ellagic acid, lactobionic acid and/or a combination thereof. In a preferred embodiment, the polyhydroxy acid is selected from the group consisting of 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 individual topical application, wherein 1) the first composition comprises the following: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, and 2) the second composition comprises the following: ● 0.01% to 30% azobenzene-4-carboxamide or a salt thereof, preferably 0.1% to 20% or 0.1% to 30% w/w azobenzene-4-carboxamide or a salt thereof, and ● 0.1% to 50% w/w organic acid, preferably 1% to 30% w/w w/w organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof.

In a further embodiment 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 comprising a first composition and a second composition for individual topical application, wherein 1) the first composition is composed of: ● 0.01% to 30% w/w thioethylamine, preferably 0.1% to 20% or 0.1% to 30% w/w thioethylamine, ● 0.1% to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of peptides, panthenol, sodium hyaluronate, hyaluronic acid, retinoids, natural moisturizing factors, and sugars selected from xylitol glucoside, dehydrated xylitol and xylitol, and ● at least one cosmetically acceptable excipient (qsp 100%), and 2) the second composition is composed of: ● 0.01% to 30% w/w of 4-nitrophenylamine or its salt, preferably 0.1 to 20% or 0.1 to 30% w/w of 4-nitrophenylamine isomer or its salt, ● 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 a combination thereof, ● 0.1 to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of peptides, panthenol, sodium hyaluronate, hyaluronic acid, Tasman pepper extract, retinoids, natural moisturizing factors, and xylitol glucoside, dehydrated xylitol and xylitol sugars, and ● At least one cosmetically acceptable excipient (qsp 100%).

In some embodiments of the cosmetic composition of the present invention, the retinoid is selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene.

In some embodiments of the cosmetic composition of the present invention, the peptide is selected from the group consisting of palmitoyl tetrapeptide-7, palmitoyl oligopeptide, acetyl hexapeptide-8, palmitoyl tetrapeptide-5, palmitoyl pentapeptide-4, Cu-GHK peptide, and disalmitoyl hydroxyproline.

In some embodiments of the cosmetic composition of the present invention, the natural moisturizing factor is selected from the group consisting of PCA salt, arginine, glycine, alanine, glutamine, urea and ceramide.

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

Those of ordinary skill in the art to which the present invention belongs will appreciate that the present invention described herein is susceptible to variations and modifications other than those specifically described. It is understood that the present invention includes all such variations and modifications without departing from its spirit or essential characteristics. The present invention also includes the owners of the steps, features, components and compounds mentioned or implied in this specification, either individually or collectively, and any and all combinations or any two or more of the steps or features. The present disclosure is therefore deemed to be included in the described and non-limiting aspects, the scope of the present invention is indicated by the attached claims, and all variations that fall within the meaning and range of equivalents are intended to be included therein.

The above description will be more fully understood with reference to the following examples. However, such examples are illustrative methods for practicing the present invention and are not intended to limit the application and scope of the present invention.

Examples of the composition of the present 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% phenylamine-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/C10-30 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 with pH 4 using 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% Azobenzene-4-Carboxamide- 10% Glycolic Acid

Example of a composition to be applied in two steps: < Composition F applied for 30 minutes 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% 4-aminobenzoic acid amide - QSP water < Composition H applied for 15 minutes before being rinsed off > - 20% Sorbitol - 5% Polysorbate 60 - 1% Carbomer - 0.8% Phenoxyethanol - 7% Thioethylamine hydrochloride - QSP water < Composition I applied after composition I as a rinse-free product > - 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% Azobenzene-4-carboxamide - 3.5% Glycolic acid - QSP water Example 1

Example of efficacy measured by mRNA-RT-PCR on human dermal fibroblasts. Stimulates collagen I gene expression Stimulates elastin gene expression Base 2% 1% 5% Thioethylamine hydrochloride twenty three%* 32%* 10% Thioethylamine hydrochloride 28%* 38%* 5% 4-nitrophenylamine 2% 5% 5% Glycolic Acid 8%* 11%* 10% Glycolic Acid 10%* 12%* 10% Lactic Acid 7%* 10%* 20% Lactic Acid 10%* 11%* 15% Gluconolactone 8%* 10%* 8% Lactobionic acid 10%* 9%* 10% Thioethylamine hydrochloride + 5% 4-nitrophenylamine 49%** 70%** 10% Thioethylamine Hydrochloride + 10% Glycolic Acid 51%** 68%** 10% Thioethylamine Hydrochloride + 20% Lactic Acid 49%** 66%** 5% Thioethylamine Hydrochloride + 15% Gluconolactone 48%** 67%** 5% Thioethylamine hydrochloride + 8% lactobionic acid 50%** 68%** 10% Thioethylamine hydrochloride + 5% glycolic acid + 5% 4-nitrophenylamine 51%* 70%* 5% Thioethylamine hydrochloride + 8% lactobionic acid + 5% 4-nitrophenylamine 52%* 69%* *Significantly relative to base**Synergistic effect of the combination

Example 2 : Proven efficacy and synergistic effects shown in a clinical study of 8 volunteers per group with daily administration for 7 days and 4 weeks. Reduction in wrinkle depth relative to baseline after 7 days/4 weeks Changes in cognitive age relative to baseline after 7 days/4 weeks Reduction in TEWL from baseline after 7 days/4 weeks Base -1% / -3% +0.1 / -0.1 -3% / -5% 10% Thioethylamine hydrochloride -8%* / -12%* -0.8* / -1.3* -15%* / -21%* 5% 4-nitrophenylamine -twenty three% -0.1 / -0.3 -3% / -5% 5% Glycolic Acid -5%* / -7%* -0.5* / -0.6* -9%* / -10%* 10% Gluconolactone -5%* / -6%* -0.4* / -0.6* -8% / -10% 10% Thioethylamine hydrochloride + 5% 4-nitrophenylamine -21%** / -34%** -1.8** / -3.9** -35%** / -47%** 10% Thioethylamine Hydrochloride + 5% Glycolic Acid -20%** / -31%** -1.6**/-3.5** -36%** / -47%** 10% Thioethylamine Hydrochloride + 10% Gluconolactone -19%** / -28%** -1.5**/-3.2** -34%** / -45%** 10% Thioethylamine hydrochloride + 5% glycolic acid + 5% 4-nitrophenylamine -20%** / -31%* -1.6**/-3.4* -35%** / -46%* 10% thioethylamine hydrochloride + 5% glycolic acid (step a, apply 15 minutes before rinsing off) + 5% 4-nitrophenylamine (step b, apply after rinsing off) -33%*** / -45%*** -2.5***/- 4.6*** -51%*** / -63%*** 10% Thioethylamine Hydrochloride + 10% Gluconolactone + 5% Nitrophenyl-4-carboxamide -19%** / -30%* -1.6**/- 3.6%* -35%** / -47%* 10% thioethylamine hydrochloride + 5% glycolic acid (step a, apply 15 minutes before rinsing off) + 5% 4-nitrophenylamine (step b, apply after rinsing off) -32%*** / -42%*** -2.4***/ -4.5*** -48%*** / -61%*** 10% thioethylamine hydrochloride (step a, apply 15 minutes before rinsing off) + 5% glycolic acid + 5% 4-nitrophenylamine (step b, apply after rinsing off) -27%*** / -38%*** -2.0***/- 4.2*** -43%*** / -55%*** *Significantly relative to base**Synergistic effect of this combination Example 3

Eight volunteers in each group were administered daily for 4 weeks, and the in vitro efficacy (compared with untreated cells) and in vivo efficacy were measured by colorimetry after treatment of normal human dermal fibroblasts. Collagen synthesis Synthesis of elastin Reduction of wrinkles and fine lines Base +5% +2% -1% 10% Thioethylamine hydrochloride +83%* +42%* -15%* 5% phenylamine-3-carboxamide +12% +5% -2% 5% 4-nitrophenylamine +15% +7% -3% 5% Glycolic Acid +23%* +18%* -6%* 5% tartaric acid +15% +10% -4% 5% Mandelic acid +18%* +13%* -5%* 10% Thioethylamine hydrochloride + 5% Nitrophenyl-3-carboxamide +87%* +46%* -15%* 10% Thioethylamine hydrochloride + 5% 4-nitrophenylamine +144%** +75%** -26%** 10% Thioethylamine hydrochloride + 5% 3-nitrophenylamine carboxylic acid + 5% glycolic acid +92%* +50%* -18%* 10% Thioethylamine hydrochloride + 5% 4-nitrophenylamine carboxylic acid + 5% glycolic acid +150%** +75%** -28%** 10% Thioethylamine hydrochloride + 5% tartaric acid +89%* +47%* -16%* 10% Thioethylamine Hydrochloride + 5% Mandelic Acid +90%* +49%* -17%* *Significantly relative to base**Synergistic effect of the combination

Claims (15)

A cosmetic method for skin regeneration, wherein the method comprises topically applying to an area of the skin of an individual in need thereof a composition comprising: ● 0.01% to 30% w/w thioethylamine, ● 0.01% to 30% w/w phenyl-4-carboxamide or a salt thereof and/or ● 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof. The cosmetic method for skin regeneration of claim 1, wherein the composition further comprises at least one cosmetically acceptable formulation for topical administration. A cosmetic method for skin regeneration as claimed in claim 1 or 2, wherein the composition is composed of the following: ● 0.01% to 30% w/w thioethylamine, ● 0.01% to 30% w/w phenyl-4-carboxamide or its salt and/or 0.1% to 50% w/w organic acid, ● At least one cosmetically acceptable formulation for topical administration, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof. The cosmetic method for skin regeneration of any one of claims 1 to 2, wherein the composition further comprises at least one anti-wrinkle benefit agent selected from the group consisting of: coenzyme Q10, sodium hyaluronate, hyaluronic acid, hyaluronic acid fragments, gold particles, peptides, tocopherol, ceramides, retinoids, scutellariae, collagen, resveratrol, heparan sulfate and its analogs, dermatan sulfate and its analogs , chondroitin sulfate and its analogs, algae extract, perfluorohexane, carnosine, geranylgeranyl propanol, pullulan, copper, alpha-lipoic acid, biotin, curcuminoids, natural moisturizing factors, plant extracts such as moringa seed oil, coconut extract, damask rose water, camellia extract, centella asiatica extract, water celery sprout extract, green tea extract, and mixtures thereof. A cosmetic method for skin regeneration as claimed in claim 1 or 2, wherein the composition is composed of: ● 0.01% to 30% w/w thioethylamine, ● 0.01% to 30% w/w phenyl-4-carboxamide or its salt and/or 0.1% to 50% w/w organic acid, ● 0.01% to 1% retinol, and ● At least one cosmetically acceptable formulation for topical administration, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof. A cosmetic method for skin regeneration according to any one of claims 1 to 5, wherein the skin regeneration is to reduce the appearance of fine lines and wrinkles, reduce deep wrinkles, enhance skin elasticity, and/or reduce skin roughness. A cosmetic method for skin regeneration, comprising the steps of: a) topically applying to an area of skin of an individual in need thereof a first composition comprising: 0.01% to 30% w/w thioethylamine, and 0.1% to 50% w/w organic acid, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, b) topically applying to the area of the skin a second composition comprising 0.01% to 30% w/w phenylamine or a salt thereof, c) repeating the steps a) and b) to obtain a skin regeneration effect. A cosmetic method for skin regeneration, comprising the steps of: a) topically applying a first composition comprising 0.01% to 30% w/w thioethylamine to an area of skin of an individual in need thereof, b) topically applying a second composition comprising: 0.01% to 30% w/w phenylamine or a salt thereof, and 0.1% to 50% w/w organic acid to the area of the skin, wherein the organic acid is selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, c) repeating the steps a) and b) to obtain a skin regeneration effect. A cosmetic method for skin regeneration as claimed in claim 7 or claim 8, wherein the method further comprises removing the first composition by any suitable method before topically applying the second composition. A cosmetic method for skin regeneration as claimed in any one of claims 7 to 9, wherein the skin regeneration is to reduce the appearance of fine lines and wrinkles, reduce deep wrinkles, enhance skin elasticity, and/or reduce skin roughness. A cosmetic combination product comprising a first composition and a second composition for individual topical application, wherein 1) the first composition comprises the following: ○ 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 a combination thereof, and 2) the second composition comprises the following: ○ 0.01% to 30% w/w of phenylamine-4-carboxamide or a salt thereof. A cosmetic combination product as claimed in claim 11, which consists of a first composition and a second composition for individual topical application, wherein 1) the first composition consists of: ● 0.01% to 30% w/w thioethylamine, and ● 0.1% to 50% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, ● 0.01% to 1% retinol, and ● at least one cosmetically acceptable excipient, and 2) the second composition consists of: ● 0.01% to 30% w/w phenylamine or a salt thereof, ● 0.1 to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of xylitol glucoside, dehydrated xylitol, xylitol, panthenol, Tasman pepper extract and retinoids, preferably the retinol is selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene, ● At least one cosmetically acceptable formulator. A cosmetic combination product comprising a first composition and a second composition for individual topical application, wherein 1) the first composition comprises the following: ○ 0.01% to 30% w/w of thioethylamine, and 2) the second composition comprises the following: ○ 0.01% to 30% w/w of phenylamine-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 a combination thereof. A cosmetic combination product as claimed in claim 13, which consists of a first composition and a second composition for individual topical application, wherein 1) the first composition consists of the following: ● 0.01% to 30% w/w of thioethylamine, ● 0.1 to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of peptides, panthenol, sodium hyaluronate, hyaluronic acid, retinoids, natural moisturizing factors, and sugars selected from xylitol glucoside, dehydrated xylitol and xylitol, and ● at least one cosmetically acceptable excipient, and 2) the second composition consists of the following: ● 0.01% to 30% w/w of phenylamine or its salt, and ● 0.1% to 50% w/w of an organic acid selected from the group consisting of glycolic acid, lactic acid, lactobionic acid, gluconolactone and/or a combination thereof, ● 0.1 to 15% w/w of a skin anti-wrinkle agent selected from the group consisting of peptides, panthenol, sodium hyaluronate, hyaluronic acid, Tasman pepper extract, retinoids, natural moisturizing factors, and xylitol glucoside, dehydrated xylitol and xylitol sugar, and ● At least one cosmetically acceptable form. The cosmetic combination product of claim 14, wherein the retinol is selected from the group consisting of retinol, retinoic acid, retinyl palmitate, retinal, retinol sodium hyaluronate and adapalene; the peptide is selected from the group consisting of palmitoyl tetrapeptide-7, palmitoyl oligopeptide, acetyl hexapeptide-8, palmitoyl tetrapeptide-5, palmitoyl pentapeptide-4, Cu-GHK peptide, and disalmitoyl hydroxyproline; the natural moisturizing factor is selected from the group consisting of PCA salt, arginine, glycine, alanine, glutamine, urea and ceramide.