Dermatological composition including EGCG and ascorbic acid

Description

1 Dermatological composition comprising EGCG and ascorbic acid The present invention relates to a dermatological composition in an essentially liquid form, particularly in the form of a serum, comprising epigallocatechin gallate (EGCG), ascorbic acid and an additional antioxidant from the polyphenol family. The appearance of the skin and skin treatments are constantly being improved in order to prevent skin aging. Skin aging has, on the one hand, an intrinsic cause linked to the degradation of physiological functions over time, and on the other hand, an extrinsic cause linked to external aggressions. These aggressions come from environmental factors such as exposure to UV (in particular UVA, UVB and UVC), infrared (IR) and other elements of the solar spectrum, air pollution, or malnutrition.To prevent skin imperfections, particularly facial imperfections, solutions are developed to protect the epidermis from external aggressions, to stimulate skin regeneration, and to reduce skin inflammation. In the field of skin treatments, many cosmetic formulations rely on the use of active substances that protect and regenerate the epidermis. Among these active substances, catechins, particularly epigallocatechin gallate (EGCG), and ascorbic acid (or vitamin C) are preferred components used in dermatological formulations. Catechins (including EGCG) and ascorbic acid are known for their effects in maintaining and improving the appearance of the epidermis. Their participation in the modulation of 30 cellular signaling pathways involved in inflammation and cell survival, such as MAPK and NF-κB, contributes to cell regeneration and tissue repair.Furthermore, due to their powerful antioxidant actions, EGCG and ascorbic acid neutralize free radicals and reduce oxidative stress, which contributes to cellular aging. Their anti-UV properties also provide optimal protection of the skin against external aggressions. In addition, EGCG and ascorbic acid stimulate collagen production, which contributes to improved skin elasticity. An improvement in these various parameters helps to protect the skin against imperfections. Dermatological compositions containing EGCG and ascorbic acid are known and are available in cream form since these two active substances are inherently unstable in the aqueous phase. Indeed, once dissolved in water, EGCG and ascorbic acid are susceptible to oxidation and degrade. ce quinerendpaspossiblelaformulationdesolutionsaqueusestables compagneses deuxsubstancesactifs.However, in cosmetics, and particularly in dermatology, the use of liquid or predominantly liquid formulations, such as serums, is widely preferred, notably to increase the penetration coefficient of active ingredients into the epidermis and thus improve their efficacy. Unfortunately, as mentioned above, current dermatological formulations containing EGCG and ascorbic acid as active ingredients are presented in cream form, which considerably limits the penetration of active ingredients into the epidermis. Consequently, the effects of the active ingredients (for example, the protective and regenerating effects) contained in creams are reduced at the level of the epidermal cells. There is therefore a real need to procure a composition comprising EGCG and ascorbic acid which is stable30 2024 / 5950 BE2024 / 5950 3 over time and which guarantees optimal penetration of the active ingredients into / through the epidermis.To at least partially solve these problems, the invention provides a dermatological composition in an essentially liquid form, particularly in the form of a serum, comprising: - epigallocatechin gallate (EGCG), - ascorbic acid, and - an additional antioxidant from the polyphenol family. Within the scope of the present invention, it has been shown that such a dermatological composition according to the invention is stable over time, even if the dermatological composition is in an essentially liquid form, particularly in the form of a serum, with the EGCG and ascorbic acid not degrading or degrading only insignificantly over time.More specifically, it has been shown that the presence of an additional antioxidant from the polyphenol family15 in a dermatological composition comprising EGCG and ascorbic acid makes it possible to formulate an essentially liquid composition, for example, a serum, in which these two active substances are stable over time or at least exhibit increased stability over time, particularly compared to compositions20 in the form of creams comprising these same two active substances. In other words, such a dermatological composition according to the present invention makes it possible to obtain a composition in an essentially liquid form having increased stability over time, particularly with regard to EGCG and ascorbic acid, whose stability25 is increased over time.In this sense, a dermatological composition according to the present invention makes it possible to ensure the preservation of the dermatological properties of EGCG and ascorbic acid over a long period, even though these two active substances are present in a dermatological composition in an essentially liquid form. By the term "stabilize," it is understood that the therapeutic effect provided by the active ingredients of the dermatological composition is maintained throughout the storage period of said composition, this being reflected in the maintenance over time of the concentration of each of the active ingredients in the dermatological composition. With such a dermatological composition according to the invention, the problems mentioned above are at least partially solved. In this sense, the problem of the stability of the active ingredients, such as EGCG and ascorbic acid, in a composition in an essentially liquid form, is solved by an increase and maintenance of the stability of the active ingredients over time.Consequently, such a dermatological composition in an essentially liquid form according to the invention makes it possible to preserve the beneficial effects conferred by the 15 active substances throughout the shelf life of the dermatological composition according to the invention. Furthermore, a formulation in an essentially liquid form, for example in the form of a serum, conferring an increase in the skin penetration coefficient of the active substances, the beneficial effects of the active substances at the level of the epidermis are increased with a dermatological composition according to the invention, this making it possible to ensure better protection and better regeneration of the epidermis and to fight more effectively against skin aging. According to the invention, the dermatological composition comprises 25% epigallocatechin gallate (EGCG) and ascorbic acid. These two active compounds / active substances are powerful antioxidants playing a protective role against the external environment by reducing oxidative stress induced by free radicals.These two active compounds also induce protection against pollution, UV, and DNA denaturation. In particular, the dermatological composition according to the invention is an anti-aging composition. The term "dermatological composition" is understood in the context of this invention to mean a composition intended for use by topical administration, preferably on the skin, hair, nails, or mucous membranes. Such a composition, comprising a dermatologically active amount of EGCG and ascorbic acid, allows for an enhanced effect of EGCG and ascorbic acid locally at the area of ​​administration. In the context of this invention, said dermatological composition contributes to reducing the effects of aging, more particularly, by slowing down the skin aging process, including cellular aging partly due to oxidative stress and external aggressions such as exposure to UV radiation (particularly UVA, UVB, and UVC), infrared radiation (IR), and other elements of the solar spectrum.15. The term "dermatological composition in essentially liquid form" is used in the context of this invention to mean a composition having low density and low viscosity, in particular an essentially aqueous composition in which the components of the dermatological composition have solubilized / dissolved. 20. A dermatological composition in essentially liquid form, compared with a dermatological composition in the form of a cream or ointment, advantageously offers a significantly increased coefficient of skin penetration (transcutaneous penetration) of the active substances at the administration sites. 25. A better coefficient of skin penetration increases the skin absorption of the active ingredients and consequently increases the efficacy of the treatment, for example, against skin aging. Typically, dermatological compositions in an essentially liquid form are packaged in the form of bottles 30 equipped with a dropper, a roll-on, or a pump.2024 / 5950 BE2024 / 5950 6 The term "additional antioxidant" means, for the purposes of this invention, an antioxidant other than the essential compounds already included in the dermatological composition according to the invention, such as EGCG and ascorbic acid. The additional antioxidant according to the invention, being an additional antioxidant of the polyphenol family, is any antioxidant of the polyphenol family other than EGCG. Polyphenols are organic molecules characterized by the presence of at least one phenol group. According to the invention, the additional antioxidant of the polyphenol family may be any polyphenol other than EGCG, such as, for example, a flavonoid, a phenolic acid, a lignan, or even a stilbene. With a dermatological composition according to the invention, EGCG and ascorbic acid exhibit an increased coefficient of skin penetration at the level of the epidermis when administered topically15 compared with a composition in the form of a cream or ointment comprising these same two active ingredients.Consequently, the essentially liquid form of the dermatological composition according to the invention allows for an enhanced effect, particularly for skin repair, for protection against skin aging, and for protection against external aggressions such as exposure to UV radiation (in particular UVA, UVB, and UVC), infrared radiation (IR), and other elements of the solar spectrum. Furthermore, unlike creams or ointments which generally leave a greasy film on the skin, a dermatological composition in an essentially liquid form according to the invention allows for a more pleasant application without the formation of a greasy film on the surface of the epidermis.Advantageously, according to the invention, epigallocatechin gallate (EGCG) is present at a level of at least 1% by weight, preferably at least 3% by weight, preferably at least 4% by weight, more preferably at least 5% by weight, more preferably still at least 6% by weight, relative to the total weight of the dermatological composition. Advantageously, according to the invention, epigallocatechin gallate (EGCG) is present at a level of 3 to 4% by weight relative to the total weight of the dermatological composition. Preferably, according to the invention, ascorbic acid is present at a concentration of at least 1% by weight, preferably at least 3% by weight, preferably at least 4% by weight, more preferably at least 5% by weight, more preferably still at least 10% by weight, relative to the total weight of the dermatological composition. Preferably, according to the invention, ascorbic acid is present at a concentration of 3 to 4% by weight relative to the total weight of the dermatological composition.15 Preferably, according to the invention, the additional antioxidant from the polyphenol family is present at a concentration of at least 1% by weight, preferably at least 2% by weight, more preferably at least 3% by weight, more preferably at least 4% by weight, and more preferably still at least 5% by weight, relative to the total weight of the dermatological composition. Advantageously, according to an embodiment of the invention, epigallocatechin gallate (EGCG) is present in a plant extract. According to the embodiment, the epigallocatechin gallate (EGCG) is therefore natural (of natural origin). 25 Preferably, according to the invention, the plant extract in which the epigallocatechin gallate (EGCG) is present is green tea.Preferably, according to the invention, said plant extract in which epigallocatechin gallate (EGCG) is present contains at least 25% by weight of epigallocatechin gallate (EGCG), preferably at least 30% by weight of epigallocatechin gallate (EGCG), preferably at least 40% by weight of epigallocatechin gallate (EGCG), more preferably at least 50% by weight of epigallocatechin gallate (EGCG), relative to the total weight of said plant extract. According to another embodiment of the invention, epigallocatechin gallate (EGCG) is synthetic. Preferably, according to the invention, the additional antioxidant from the polyphenol family is chosen from campherol, aquercetin, rutin, catechin, or polyphenols from the phlorotin family, and mixtures thereof. Advantageously, according to an embodiment of the invention, the additional antioxidant from the polyphenol family is present in a plant extract.According to this embodiment, the additional antioxidant from the polyphenol family is therefore natural (of natural origin). Preferably, according to the invention, the plant extract in which the additional antioxidant from the polyphenol family is present is a Ginkgobiloba extract. Polyphenols are essentially present in plants such as fruits, vegetables, legumes, aromatic herbs, spices, and tea. According to the invention, the additional antioxidant from the polyphenol family can be derived from a Ginkgobiloba leaf extract, in which case several polyphenols can be present simultaneously and constitute the additional antioxidant from the polyphenol family as provided for in the present invention. According to another embodiment of the invention, the additional antioxidant from the polyphenol family is synthetic. The term "of natural origin" is understood in the context of this invention to mean compounds extracted from elements derived from nature / originating from nature.30 2024 / 5950 BE2024 / 5950 9 For the purposes of this invention, the term "antioxidant" is defined as an agent that slows down or prevents oxidation. An antioxidant agent reduces oxidation, in particular, by capturing free radicals that are responsible for oxidative stress and consequently for cellular aging. 5 According to the present invention, EGCG can be extracted from tea, L-ascorbic acid can be extracted from a citrus fruit, and the additional antioxidant from the polyphenol family can be extracted from a plant containing polyphenols, such as, for example, a Ginkgo biloba leaf extract. 10 In its natural state, EGCG is mainly present in green tea, oolong tea, white tea, or black tea, as well as in fruits or nuts, such as cranberries, strawberries, blackberries, squid, cherries, ewes, peaches, apples and avocados, or even pecans, pistachios and hazelnuts.Ascorbic acid can be obtained from a natural source as it is present in plants in general, and more particularly in certain citrus fruits such as lemon, orange, and grapefruit.20 According to an embodiment of the invention, ascorbic acid is L-ascorbic acid, which represents the natural form of vitamin C. Preferably, the dermatological composition according to the invention also includes phytic acid as an additional antioxidant.25 Since phytic acid has antioxidant properties, its potential presence in the dermatological composition according to the invention further increases its durability over time. Preferably, according to the invention, phytic acid is present at a rate of at least 0.5% by weight, preferably at a rate of at least 1% by weight, even more preferably at a rate of at least 1.5% by weight, preferably at a rate of at least 2% by weight, relative to the total weight of the dermatological composition.Preferably, the dermatological composition according to the invention comprises, in addition, at least one solvent selected from water, 1,2-propanediol, 1,3-propanediol, isopentyldiol, and mixtures thereof. According to a preferred embodiment of the invention, said at least one solvent is 1,3-propanediol. The use of such a solvent in a dermatological composition according to the invention is advantageous in that it is a solvent of natural origin ("green solvent") and not a synthetic solvent such as 1,2-propanediol. Furthermore, the presence of 1,3-propanediol, rather than the presence of 1,2-propanediol, in the dermatological composition according to the invention allows for obtaining an equally stable dermatological composition. For the purposes of this invention, the solvent is an aqueous compound which allows the active substances to be transported optimally in a suitable form so that their active properties are at least preserved and at best increased but never diminished.Preferably, the dermatological composition according to the invention further comprises one or more skin penetration factors and / or one or more humectant agents and / or one or more surfactants. For example, transcutol can be used as a skin penetration factor or as a transcutaneous vector. Such a skin penetration factor allows the active ingredients of a dermatological composition to cross the skin barrier or epidermis all the more easily to reach a target, for example, a therapeutic target. For example, EG-1 Liponic® can be used as a humectant. Such a humectant allows the dermatological composition to be formulated under optimal conditions for preserving the active ingredients. It also ensures improved hydration of the skin / epidermis. For example, dimethicone, such as PEG-8 dimethicone, can be used as a surfactant.The presence of one or more surfactants in the dermatological composition according to the invention 5 improves its elasticity and homogeneity. The surfactant can also contribute to the production of a dermatological composition that improves the penetration of the active ingredients and the feeling of comfort upon cutaneous application. Advantageously, the dermatological composition according 10 of the invention has a pH less than 7, preferably a pH less than 6, more preferably a pH less than 5, even more preferably a pH less than 4, and even more preferably a pH of 3.5. Preferably, the pH of a dermatological composition according to the invention is 3.5, which allows for improved transcutaneous penetration of ascorbic acid. Preferably, the dermatological composition according to the invention is in the form of a solution, a serum, a lotion, an aerosol, a spray, a dispersion or an essentially liquid gel.20 According to a preferred embodiment of the invention, the dermatological composition is in the form of a serum. Serums are defined as essentially liquid formulations in which the active ingredients are present at higher concentrations than those observed in other types of formulations. Thus, 25 when the dermatological composition according to the invention is in the form of a serum, the effect of the active ingredients is increased at the application area compared with other types of dermatological compositions. The serum is advantageous for obtaining maximum efficacy of the active substances in the dermatological composition. 30 2024 / 5950 BE2024 / 5950 12 According to another embodiment of the invention, the dermatological composition according to the invention is in the form of a lotion. A dermatological composition in the form of a lotion is less concentrated in active substances than a dermatological composition in the form of a serum.5. According to yet another embodiment of the invention, the dermatological composition according to the invention is in the form of an essentially liquid gel. A dermatological composition in the form of an essentially liquid gel is less concentrated in active substances than a dermatological composition in the form of a serum. Preferably, the density of a dermatological composition according to the invention is between 1 and 1.1, preferably equal to 1.05. Preferably, the dermatological composition according to the invention is intended for topical administration, preferably on the skin and / or hair. The present invention also relates to the use of a composition according to the invention as a medicinal product.Preferably, a dermatological composition according to the invention is used as a medicinal product in the treatment or prevention of damage caused by ultraviolet rays, in particular by UVA, UVB and UVC, by infrared rays and / or by other elements of the solar spectrum, of a disorder causing skin lesions, of a disorder causing premature skin aging, of a disorder causing skin inflammation, and / or of a disorder causing alteration / denaturation of DNA, collagen and / or the extracellular matrix (ECM).The use of a dermatological composition according to the invention as a medicinal product ensures, in particular, the treatment or prevention of skin disorders such as skin lesions, skin inflammation, and skin aging, but also the treatment or prevention of the mutagenic effects of UV rays, IR rays, and other elements of the solar spectrum by protecting epidermal cells against lesions and modifications induced by ultraviolet rays, particularly UVA, UVB, and UVC, on deoxyribonucleic acid (DNA). Disorders causing skin lesions or skin inflammation within the meaning of the present invention include, for example, acne, psoriasis, atopic dermatitis, and urolar eczema. Disorders causing premature skin aging include, for example, the disease... de Gottron, Werner syndrome, or Hutchinson-Gilford syndrome.10 Damage caused by ultraviolet rays includes skin distension and cellular aging.The present invention relates further to a non-therapeutic cosmetic use of the dermatological composition according to the invention, to promote the densification and / or homogenization of the epidermis, to reduce wrinkles, to plump and / or firm the skin, to protect the skin from damage caused by ultraviolet rays, in particular by UVA, UVB and UVC, by infrared rays and / or by other elements of the solar spectrum, to protect the skin from a disorder causing skin lesions, from a disorder causing premature skin aging and / or from a disorder causing skin inflammation and / or to protect DNA, collagen and / or the extracellular matrix (ECM). Preferably, according to the invention, the non-therapeutic cosmetic use of the dermatological composition according to the invention is topical, preferably on the skin and / or hair.25 Other features, details and advantages of the invention will become apparent from the examples given below, by way of non-limiting example.30 2024 / 5950 BE2024 / 5950 14 Examples Example 1: Preparation of a dermatological composition according to the invention 5 A dermatological composition according to the invention, in the form of a serum whose pH is equal to 3.67, was prepared by mixing the following different compounds (percentage by weight relative to the total weight of the composition): EGCG (1 to 5%), ascorbic acid (5 to 10%), phytic acid (0.5 to 2%), Ginkgobiloba extract (25 to 35%), water (1 to 10 73.5%), 1,3-propanediol (15 to 20%), aminomethylpropanol (AMP) (0.5 to 2%), dimethicone (0.5 to 2%), Liponic EG-1® (0.4%), transcutol (1 to 3%), isopentyldiol (20 to 25%). Example 2: Evaluation of the elasticity of the active substances of a dermatological composition according to the invention. The elasticity of the dermatological composition prepared according to Example 1 was evaluated over a period of 2 months, for EGCG and L-ascorbic acid. For EGCG, a calibration curve was produced by dissolving an initial solution comprising a concentration of 20 mg / mL of EGCG in a 70:30 (v / v) water:methanol solution to obtain concentrations of 0, 1, 0, 2, 1, 0 and 2, 0 mg / mL of EGCG.For L-ascorbic acid, a calibration curve was carried out by dissolving an initial solution comprising a concentration of 20mg / mL of L-ascorbic acid in a 50:50 (v / v) water:acetonitrile solution to obtain concentrations of 0, 1, 0, 2, 1, 0 and 2, 0mg / mL of L-ascorbic acid. Each of the calibration curves for the analysis of EGCG and for the analysis of L-ascorbic acid was carried out from 2024 / 5950 BE2024 / 5950 15 four points relating the areas under the peaks measured by HPLC at 275 nm as a function of the mass of EGCG or at 254 nm as a function of the mass of L-ascorbic acid injected onto the HPLC column and the concentrations of the standards respectively. Each standard solution was analyzed three times by HPLC to perform an average on the integrations of the area under the signal corresponding to EGCG or L-ascorbic acid, respectively. For the analysis of EGCG, a sample of the dermatological composition of 163.1 mg was weighed in a 10 mL flask and then diluted in 5 mL of a 70:30 (v / v) water:methanol solution. The aqueous solution was centrifuged for 10 minutes at 4,500 rpm.Finally, 1 mL of the centrifuged solution is collected for HPLC analysis. For the analysis of L-ascorbic acid, a 57.9 mg dermatologically composed sample was weighed in a 10 mL flask and then diluted in 5 mL of a 50:50 (v / v) water:15 acetonitrile solution. The solution was centrifuged for 10 minutes at 4,500 rpm. Finally, 1 mL of the centrifuged solution was collected for HPLC analysis. The analytical conditions were as follows: - Apparatus: Agilent 1100 series HPLC connected to a 20 UV-Vis detector. -Column:AgilentEclipsePlusC18(3.5µm)–4.6x100mm -Flow: ofor EGCG analysis:1.2mL / min, ofor ascorbic acid:1.0mL / min25 -Injection volume:2µL -Eluant: oFor EGCG analysis:the mobile phase is one solution composed of 70:30 (v / v) water: methanol. oFor the analysis of ascorbic acid: the mobile phase is a solution composed of 50:50 (v / v) aqueous solution 2024 / 5950 BE2024 / 5950 16 (4mM) of NaHpSO containing 0.1% by weight of HCOOH: acetonitrile.-Column temperature: 40°C -Selected wavelengths: oFor EGCG analysis: 275nm5 oFor L-ascorbic acid analysis: 254nm The EGCG content and L-ascorbic acid content in the dermatological composition were evaluated over a period of 2 months. For this purpose, the quantity of EGCG on the one hand and the quantity of L-ascorbic acid10 on the other were measured at regular intervals. Stability was evaluated under normal storage conditions (20-25°C, RH=60%, in the dark). The results of these experiments are presented in Table 1 below.15 Table 1 Shelf life (months) EGCG dosage (% by weight relative to the total weight of the dermatological composition) L-ascorbic acid dosage (% by weight relative to the total weight of the dermatological composition) 03,868,62 23,828,50 The results obtained demonstrate that the dermatological composition according to the invention presents a quantity of EGCG and L-ascorbic acid 20 compliant (>90%) over the entire duration of the stability study, i.e. 2 months under commercial conditions.Furthermore, over the entire duration of the test, no alteration of the color or odor of the dermatological composition could be observed. These observations are surprising given that EGCG and ascorbic acid are generally oxidized within a few hours in cosmetic formulations of this type, i.e., in essentially liquid cosmetic formulations. The present invention has been described in relation to specific embodiments, which are purely illustrative and should not be considered limiting. In general, it will be evident to those skilled in the art that the present invention is not limited to the examples illustrated and / or described above. The use of the verbs "comprendre" (to understand), "inclure" (to include), "comporter" (to include), or any other variant, as well as their conjugations, cannot in any way exclude the presence of elements other than those mentioned. The use of the indefinite article "un" (a / an), or the definite article "le" (the), "la" (a / an), or "l'" (an / an) to introduce an element does not exclude the presence of a plurality of these elements.2024 / 5950 BE2024 / 5950.