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    • 专利摘要:
    The present invention relates to a cosmetic or dermatological composition comprising dihydromyricetin and a zinc salt, particularly suitable for the treatment of acne and acne-prone oily skin.
    公开号:FR3042710A1
    申请号:FR1560091
    申请日:2015-10-22
    公开日:2017-04-28
    发明作者:Jean-Noel Thorel
    申请人:Jean-Noel Thorel；
    IPC主号:
    专利说明:

    COMPOSITION BASED ON DIHYDROMYRICETIN AND ZINC SALT FOR THE TREATMENT OF ACNE AND FAT SKINS
    Field of the invention
    The present invention relates to a cosmetic and / or dermatological composition comprising dihydromyricetin, whose interest in the prevention and treatment of acne is reported in the present application. Advantageously, dihydromyricetin is combined with a zinc salt such as zinc gluconate. The combination of these two assets is very promising for the treatment of acne or more generally oily skin.
    STATE OF THE ART Acne is an inflammatory pathology affecting the pilosebaceous follicle, affecting the face, the thorax and the back. It is an extremely common disease that affects more than 80% of adolescents. In about 50% of individuals affected by juvenile acne, acne persists in adulthood. In most cases, acne is not an acute pathology but a chronic condition, which therefore requires prolonged treatment. In this perspective, it is imperative that the treatments administered have minimal toxicity. From a clinical point of view, acne is, by definition, a polymorphic condition that associates retinal lesions (microcysts, comedones) and / or inflammatory lesions (papules, pustules or nodules). These two types of lesions can coexist or succeed one another during relapses. The etiopathogenesis of acne is multifactorial and remains partly to elucidate. It has been established, however, that the quantity and quality of sebum play a key role.
    Sebum is a lipid secretion product, rich in fatty acids and especially squalene, an aliphatic carbide with 30 carbon atoms, a precursor of cholesterol. Sebum is produced by dedicated cells called sebocytes. Under physiological conditions, it plays a positive role, particularly in the protection of the skin and in the formation of the hydrolipidic film. However, quantitative or qualitative changes in sebum can promote acne. Thus, the hyperproduction of sebum and / or the alteration of the lipid composition of sebum, in particular their oxidation, contribute to the appearance and severity of acne.
    Excessive sebum production by the sebaceous glands, also known as hyperseborrhea, occurs in the scalp and face, especially in the mid-air region, but also in the upper back and chest. These are also the areas most affected by acne. Hyperseborrhoeic skin has a shiny appearance, a condition generally called "oily skin". Hyperseborrhoea is particularly pronounced during puberty, when the increase in the level of circulating hormones (especially testosterone) causes hyperactivation of the glands, directly correlated with the onset of acne characteristic of adolescence. The hormone IGF-1 in particular seems to be directly responsible for the onset of cutaneous symptoms of acne: Thus, a correlation between severity of acne and serum level of IGF-1 has been established (Cappel et al. 2005). In addition, IGF-1 and its receptor are overexpressed in acne lesions (Isard et al., 2011). It has also been shown that IGF-1 stimulates lipid synthesis in the sebaceous glands (Deplewski et al., 2000) and induces the activity of 5a reductase (Horton et al., 1993), an enzyme involved in sebum production. . In addition, consistent with the involvement of this hormone in the onset of acne, a peak in IGF-1 synthesis is observed during adolescence (Deplewski et al., 1999).
    The excessive production of sebum creates a favorable environment for bacterial proliferation, in particular of the gram-positive anaerobic bacterium Propionibacterium acnes, which aggravates the pathology by accentuating the inflammatory skin state. An effective treatment limiting this proliferation is benzoyl peroxide, a broad spectrum antimicrobial agent. However, benzoyl peroxide has many undesirable effects, including an irritant effect, the generation of free radicals, a photosensitizing effect, and the discoloration of clothing. Zinc salts are also of interest in the treatment of acne because of their antimicrobial, anti-inflammatory and inhibitory activity of 5α-reductase (Stamatiadis et al., 1988). However, the effectiveness of zinc salts as an active ingredient for use alone in the treatment of acne remains limited.
    A promising treatment against acne is therefore aimed at reducing hyperseborrhea. In this context, oral intake of isotretinoin (a derivative of vitamin A) has shown good results. The systemic mechanism of action of isotretinoin appears to be mainly based on a modification of the sebaceous glands and a suppression of their activity (Orfanos et al., 1998). Thus, treatments based on isotretinoin allow significant attenuation or even the sometimes permanent disappearance of cutaneous symptoms of acne. However, taking large doses of oral isotretinoin is associated with many adverse side effects, including teratogenic. For these reasons, isotretinoin is now reserved for the dermatological treatment of severe nodular recalcitrant acne, which is strictly contraindicated during pregnancy.
    There is therefore a clear need for new actives that can reduce hyperseborrhea without causing side effects.
    As already stated, in addition to the deleterious effects of excess sebum, studies have shown that the composition of sebum plays an active role in acne. In particular, it has been observed that in acne patients, the amount of squalene is increased in sebum, where it is further found in oxidized form. Thus, the sebum of acne patients is particularly rich in oxidized squalene. However, oxidized squalene is responsible for the thickening of sebum that causes the obstruction of the pores, but also for hyperkeratinization in the pilosebaceous follicles, the hyperproliferation of P. acnes bacteria and the induction of a local inflammatory reaction responsible for the development of acne lesions (Saint Léger et al., 1986, Chiba et al., 1999, Chiba et al., 2000 and Ottaviani et al., 2006).
    To limit the potentially harmful effects of oxidized squalene in sebum, the body adopts a strategy of self-defense by releasing vitamin E on the surface of the skin. However, for reasons still unknown, the cutaneous level of vitamin E is reduced in acne patients, thus unable to play its protective role (Thiele et al., 1999, Picardo et al., 2009, Ottaviani et al., 2010).
    According to this aspect, it is therefore desirable to limit the oxidation of squalene present in sebum. Cosmetic or dermatological compositions for topical use having such activity are for example described in document EP 2 583 662.
    In addition to the unsightly appearance of acne breakouts, acne lesions often lead to scarring, which is the first fear of acne patients.
    In practice, there are three types of acne scars. Macular erythematous or pigmented scars appear as red or dark spots. They are not permanent and tend to disappear quickly. Hypertrophic or keloid scars are characterized by post-lesional hyperproliferation of the tissues and are thus in relief. The majority of acne scars (between 80% and 90%) belong to the third group, atrophic scars by loss of substance. These scars, characterized by more or less pronounced depressions, can be flexible, fibrous or semi-rigid. A particular type of atrophic scarring is "ice-pick" scars, which are punctate and can be very deep.
    The pathogenesis of atrophic acne scars is not fully understood. A correlation exists between the duration or magnitude of the inflammatory response, and the formation of atrophic scars.
    Matrix metalloproteins (or MMPs for Matrix Metallo-Proteinase) play a key role in post-lesion remodeling of the extracellular matrix. In the case of a normal average wound, they allow the complete disappearance of the scar in a few days or weeks. These enzymes are secreted by fibroblasts and keratinocytes in response to stimulation by several cytokines (IGF1, EGF, TNFα, TGFpetPDGF).
    It is now considered that the typical inflammatory response of acne lesions causes hyperactivation of MMPs, such as collagenases, gelatinases and elastases. Indeed, in the context of acne, the inflammatory response is exacerbated and prolonged, and causes a chronic increase in the level of inflammatory cytokines. This increase induces an imbalance between the expression of MMPs and tissue inhibitors of MMPs, TIMPs (for "Tissue Inhibitor of Metalloproteinase"). In the case of atrophic scars, the hyperactivity of lytic MMPs, following acne, would cause a decrease in the deposition of collagen fibers during the process of regeneration and remodeling of the extracellular matrix, leading to the formation of visible depressions with the naked eye (Chivot et al., 2006).
    To date, there is no effective preventive treatment for the formation of atrophic scars. At best, these are treated after their training by surgical techniques (punch, subcutaneous incision or subcision) or techniques of resurfacing (dermabrasion, laser-abrasion, peeling, fractional photothermolysis ...) (Chivot et al. 2006).
    As is apparent from the foregoing, acne is a multifactorial pathology for which there is a continuing need to identify new assets or combinations of assets that may act on one or more of the mechanisms mentioned above. above.
    Description of the invention
    Surprisingly, the Applicant has shown that compositions comprising dihydromyricetin, advantageously in combination with other active agents, make it possible to meet this need, in particular by virtue of the properties of this molecule to reduce sebocyte hyperproduction of sebum, to protect squalene from sebum against oxidation and to inhibit the activity of MMP enzymes. It is also reported the advantage of associating this molecule with a zinc salt, such as zinc gluconate. Such cosmetic or dermatological compositions are therefore of obvious interest in the prevention and treatment of acne and its symptoms, and more generally for the care of oily or acne-prone skin.
    Dihydromyricetin (DHM), also known as ampelopsin or ampelopine, is a flavanolol belonging to the group of flavonoids found in several plant extracts used in traditional Chinese, Japanese and Korean medicine for the treatment of fevers, liver diseases, and as a laxative. EMS is particularly used in preparations for the management of venalgia or "hangover" (Shen et al., 2012). Studies on the purified molecule have indeed shown a hepatoprotective effect for DHM and oral drug preparations containing it, as described in CN1483 801. Recent studies have also shown that DHM has anti-cancer properties (Wu et al. 2013). In cosmetics, DHM is used in "anticellulite" preparations for its effects on the metabolism and differentiation of adipocytes. It is also found in preparations able to delay the regrowth of hair.
    However, and to the knowledge of the Applicant, the properties of the DHM reported in this application, and the applications that result, have never been described.
    According to a first aspect, the present invention relates to a cosmetic or dermatological composition comprising dihydromyricetin or DHM.
    Dihydromyricetin, also known as ampelopsin or ampelopine (2R, 3R) -3,5,7-trihydroxy-2- (3,4,5-trihydroxyphenyl) -2,3-dihydrochromen-4-one), is a flavonol having the following structure:
    Dihydromyricetin is one of the main anthocyanidins found in nature, especially in plants (Gerats et al., 1982). Dihydromyricetin is usually obtained from plants or plant extracts. It can also be obtained from fungi or bacteria, or be synthesized. Examples of plants or plant extracts used as a source of dihydromyricetin are Myrica cerifera, Ampelopsis spp., Cercidiphyllum japonicum, Hovenia dulcis, Rhododendron cinnabarinum, Pinus spp., Cedrus spp. and Salix spp.
    In practice, dihydromyricetin may be used in the composition of the invention in the form of purified or isolated dihydromyricetin, preferably of purity of at least 60%, 70%, 80%, 90% or even at least 95%. Alternatively, it may be in the form of a plant extract comprising dihydromyricetin, advantageously representing from 1% to 70% by weight relative to the total weight of the extract.
    For the purposes of the present application, the percentages of purity of the compounds indicated correspond to the percentages by weight relative to the total weight of the compound added.
    According to a particular embodiment, the dihydromyricetin is derived from an extract of the plant Myrica cerifera, including leaves, flowers or barks. According to a preferred embodiment, the dihydromyricetin is isolated and purified from the Myrica cerifera plant, for example the product titrated with dihydromyricetin, marketed by PROVITAL under the name TELOCAPIL SPE ™ or MYRICELINE ™.
    Preferably, the dihydromyricetin is typically from 0.0001% to 10% by weight of the composition, preferably from 0.001% to 2% by weight of the composition, still more preferably 0.01% by weight of the composition.
    Advantageously, the composition of the invention further comprises at least one other ingredient preferably chosen from: zinc salts, advantageously zinc gluconate; biochanin A, advantageously derived from an extract of red clover; an extract of Ginkgo biloba, advantageously an extract of Ginkgo biloba comprising flavonoids; a meroterpene, advantageously bakuchiol; a polyol, advantageously chosen from xylitol, sorbitol and mannitol; a lipophilic antioxidant, advantageously chosen from propyl gallate, octyl gallate and dodecyl gallate; a keratolytic agent, advantageously chosen from salicylic acid, glycolic acid, citric acid, malic acid and lactic acid; glycyrrhetinic acid or one of its derivatives or salts.
    Zinc salts are known antibacterial agents and may help to limit the proliferation of Propionibacterium acnes. Surprisingly, the Applicant has established that zinc salts stimulate the effects of dihydromyricetin. The Applicant has in particular determined that the combination of DHM and at least one zinc salt is particularly beneficial in the treatment of acne. Indeed and as supported by the experimental part, this combination of ingredients has a synergistic inhibitory effect on several phenomena causing acne and scars that result. This synergistic effect is particularly observed on hyperseborrhea, in particular induced by IGF-1, and on the activity of MMPs, the enzymes responsible for the formation of atrophic scars.
    Thus and according to a particular embodiment, the composition according to the invention comprises dihydromyricetin and a zinc salt.
    Advantageously according to the invention, the zinc is provided in the form of a zinc salt which makes it possible to release zinc in its Zn2 + ionic form. Several zinc salts, alone or in combination, are suitable for use in compositions according to the invention. Preferably, the zinc salt is selected from zinc gluconate, zinc sulfate and zinc oxide. In a preferred embodiment, the zinc salt is zinc gluconate. According to a particular embodiment, the zinc salt is not a zinc oxide, moreover known for their use as sunscreens.
    Preferably, the zinc salt is from 0.1% to 10% by weight of the composition, preferably from 1% to 5%, still more preferably 1%, 2% or 3% by weight of the composition.
    According to another embodiment, the composition according to the invention comprises biochanin A.
    Biochanin A (5,7-dihydroxy-3- (4-methoxyphenyl) -chromen-4-one) is a flavonoid having the following structure:
    Biochanin A has proven antioxidant properties and is used in cosmetics to protect skin cells from the harmful effects of UV radiation. Biochanin A also has an inhibitory activity of the 17PHSD enzymes (Le Lain et al., 2001) and 3PHSD (Ohno et al., 2004), two enzymes involved in the synthesis of androgens and especially testosterone. As already stated, testosterone stimulates the production of sebum and the appearance of cutaneous symptoms of acne.
    Biochanin A is generally obtained from plants or plant extracts comprising this active ingredient. Plants or plant extracts serving as a source of biochanin A are for example Glycine max (soybean), Cicer arietinum (chickpea) Medicago sativa (alfalfa) or Trifolium pratense (red clover).
    In practice, the biochanin A may be provided by the addition of purified biochanin A, preferably having a degree of purity of at least 60%, or even at least 70%, 80%, 90% or even at least 95%, or by adding a plant extract comprising biochanin A.
    According to a particular embodiment, the composition comprises a plant extract comprising biochanin A, preferably at a level of from 0.1 g / l to 10 g / l. According to one embodiment, the plant extract comprising biochanin A is an extract of the plant Trifolium pratense (red clover). According to another embodiment, the plant extract comprising biochanin A is an extract of leaves. In a particular embodiment, the extract comprising biochanin A is a titrated extract corresponding to the INCI Trifolium pratense (clover) leaf extract. By way of example, the hydrolytic extract of red clover leaves marketed by Greentech can be used within the scope of the invention.
    Preferably, the solids content comprising biochanin A represents from 0.001% to 1% by weight of the composition, advantageously from 0.01% to 0.1% by weight of the composition.
    Advantageously, the composition according to the invention comprises an extract of Ginkgo biloba.
    Advantageously, the Ginkgo biloba extract is a Ginkgo biloba extract comprising flavonoids, advantageously titrated with flavonoids. The Ginkgo biloba extract is advantageously an extract of leaves. In a particular embodiment, the Ginkgo biloba extract corresponds to the INCI Ginkgo biloba leaf extract. By way of example, the glycolic extract of Ginkgo biloba leaves with a 5% dry matter marketed by Greentech can be used within the framework of the invention.
    Preferably, the Ginkgo biloba extract represents from 0.0001% to 1% by weight of the composition, preferably from 0.001% to 0.1% by weight of the composition.
    Advantageously, the composition according to the invention comprises a meroterpene.
    Meroterpenes have an antimicrobial action but are also useful for reducing sebum oxidation and suppressing the activity of elastases and collagenases, enzymes involved in the formation of atrophic acne scars.
    Meroterpenes are usually obtained from plants or plant extracts. They can also be obtained from mushrooms or be synthesized. Herbs used as a source for meroterpenes are, for example, Psoralea coryfolia, Psoralea spp. and Otholobium pubescens (Fabaceae).
    In practice, meroterpene can be provided by the addition of isolated and purified meroterpene, preferably having a degree of purity of at least 60%, or even at least 70%, 80%, 90% or even at least equal to 95%, or by adding a plant extract including meroterpene.
    According to a preferred embodiment, the composition comprises a plant extract comprising meroterpene, preferably from 1% to 70% by weight of meroterpene relative to the total weight of the extract. The plant extract comprising meroterpene is advantageously a plant extract selected from Psoralea coryfolia, Psoralea spp. and Otholobium pubescens (Fabaceae). By way of example, the meroterpenes described in document WO2008 / 143761 and WO2008 / 140673 may be used in the context of the present invention.
    According to a preferred embodiment, the meroterpene used in the context of the invention is bakuchiol (4 - [(1E, 3S) -3-ethenyl-3,7-dimethylocta-1,6-dienyl] phenol) , having the following structure:
    Advantageously, the bakuchiol is provided by the addition of a plant extract comprising it, preferably a seed extract of Psoralea coryfolia. According to another embodiment, the bakuchiol is isolated and purified from the P. coryfolia plant, advantageously from its seeds, such as, for example, the product titrated with bakuchiol, sold by SYTHEON LTD under the name Sytenol®. In this product, bakuchiol has a purity higher than 95%.
    Preferably, the meroterpene is from 0.01% to 5% by weight of the composition, preferably from 0.1% to 2% by weight of the composition, still more preferably 0.25% by weight of the composition.
    The composition according to the invention may comprise a polyol, advantageously chosen from xylitol, sorbitol and mannitol. Preferably, the polyol is xylitol.
    The xylitol may be powdered xylitol, for example of vegetable origin, in particular obtained from wood by hydrogenation of xyloses, preferably having a purity greater than 95%. The mannitol may for example be mannitol powder, of plant origin (corn, potato, wheat), preferably having a purity higher than 98%. By way of example, the company IMCD markets the product Pearlitol® that can be used in the context of the invention.
    Suitably, the polyol is from 0.0001% to 10% by weight of the composition, preferably from 0.001% to 2% by weight of the composition, more preferably 0.1% by weight of the composition.
    Advantageously, the composition according to the invention comprises a lipophilic antioxidant. By way of example, the lipophilic antioxidants described in document FR 2 857 266 may be used in the context of the invention. The lipophilic antioxidant is preferably selected from propyl gallate, octyl gallate and dodecyl gallate. In a preferred embodiment, the lipophilic antioxidant is propyl gallate.
    According to one embodiment, the lipophilic antioxidant represents from 0.001% to 1% by weight of the composition, advantageously from 0.01% to 0.5% by weight of the composition.
    According to a preferred embodiment, the composition according to the invention comprises a keratolytic agent, preferably chosen from salicylic acid, glycolic acid, citric acid, malic acid and lactic acid, advantageously the glycolic acid. Preferably, the keratolytic agent is from 1% to 10% by weight of the composition, preferably from 2% to 8% by weight of the composition, more preferably 5% by weight of the composition.
    According to another embodiment, the composition according to the invention comprises glycyrrhetinic acid or one of its derivatives or salts. Glycyrrhetinic acid is a known soothing agent useful for the treatment of inflammatory lesions in acne.
    In practice, glycyrrhetinic acid can be provided by adding the purified compound, preferably at least 90% pure, or by adding a plant extract comprising or titrated therein. Preferably, the plant extract comprising glycyrrhetinic acid is a licorice extract (Glycyrrhiza spp.). In a preferred embodiment, the composition of the invention comprises an extract of Glycyrrhiza, preferably selected from Glycyrrhiza uralensis, Glycyrrhiza inflata and Glycyrrhiza glabra. According to a particular embodiment, it is a root extract. By way of example, purified glycyrrhetinic acid, with a purity of at least 90% by weight, marketed by INDENA or MARUZEN under the name INCI GLYCYRREEETINIC ACID may be used in the context of the invention.
    Advantageously, glycyrrhetinic acid, or one of its derivatives or salts, represents from 0.01% to 1% by weight of the composition, advantageously from 0.1% to 0.5% by weight of the composition, still more preferably 0.3% by weight of the composition.
    As already stated, the combination of dihydromyricetin and a zinc salt is preferred according to the invention. However, it is possible to add to these two active ingredients other ingredients having an activity of interest in the context of the management of skins or scalps fat or acne, especially chosen from those listed here -above. Thus, according to this aspect, the composition of the invention comprises dihydromyricetin, a zinc salt, advantageously zinc gluconate, and at least one ingredient chosen from: biochanin A, advantageously derived from a red clover extract ; an extract of Ginkgo biloba, advantageously an extract of Ginkgo biloba comprising flavonoids; a meroterpene, advantageously bakuchiol; a polyol, advantageously chosen from xylitol, sorbitol and mannitol; a lipophilic antioxidant, advantageously chosen from propyl gallate, octyl gallate and dodecyl gallate; a keratolytic agent, advantageously chosen from salicylic acid, glycolic acid, citric acid, malic acid and lactic acid; glycyrrhetinic acid or one of its derivatives or salts.
    Advantageously, these different ingredients are added, alone or in combination, in the concentration ranges mentioned above with respect to each of them.
    According to a particular embodiment, the composition of the invention comprises dihydromyricetin, a zinc salt, advantageously zinc gluconate, and biochanin A.
    Of course, any other cosmetic or pharmaceutical grade active agent having an activity of interest in the context of the applications contemplated by the present application may be incorporated into a composition according to the invention, such as vitamin derivative, hydrophilic antioxidant, anti -inflammatory...
    According to the invention, the composition is a cosmetic or dermatological composition, in other words is intended for cosmetic or dermatological use. Therefore, and advantageously, all the ingredients present in such a composition must be acceptable in these fields of application.
    In view of the intended applications, a composition according to the invention is preferably intended to be applied topically, advantageously at the level of the skin or the scalp.
    Thus, and in a preferred manner, the composition according to the invention is in a form suitable for topical administration of the skin: cream, emulsion, advantageously oil in water (O / W), water in oil (W / O) or water in silicone (I / O), solution, suspension, gel, milk or lotion, micellar water, preferably in the form of cream, gel or lotion.
    Therefore, the present composition may contain any additive or excipient suitable for its formulation and its application, such as for example suspending agents, emulsifiers, anionic, cationic or nonionic polymers, amphoteric, proteins, vitamins, surfactants, mineral or vegetable oils, antioxidants, waxes, gums, resins, thickening, acidifying or alkalizing agents, pH stabilizers, anti-UV agents, filters and sunscreens, preservatives, perfumes, dyes, conventional adjuvants for cosmetics and dermatology.
    As already stated, the composition according to the invention is particularly suitable for the treatment of cutaneous pathologies associated with the presence of P. acnes. More generally, it is of interest in the management of subjects with at least one of the symptoms of acne, regardless of its stage of development, or who are likely to develop it, particularly in people with oily skin and / or with an acne tendency.
    According to another aspect, the invention therefore relates to a composition as described above for its use in the prevention and / or treatment of acne.
    The composition of the invention can also be used in non-therapeutic applications, such as cosmetic applications, in particular those targeting oily skin or acne-prone scalps. Thus and according to another aspect, the invention relates to a cosmetic treatment method for oily or acne-prone skin and / or acne-prone scalp comprising applying to the skin and / or the scalp a composition according to the invention. invention.
    In the context of the present application and as will be illustrated below, interesting and unprecedented properties of dihydromyricetin, advantageously combined with a zinc salt such as zinc gluconate, have been demonstrated. According to another aspect, the use of a composition according to the invention is also described, such as: sebo-regulating agent, in particular via its inhibitory action on the hyperproduction of sebum by the sebocytes; and / or fluidifying agent of sebum, in particular via its protective activity of sebum squalene against oxidation; and / or agent capable of preventing the formation of atrophic scars of acne, in particular via its inhibitory action on the activity of MMP-type enzymes.
    Examples of realization
    The way in which the invention can be realized and the advantages which result therefrom will emerge more clearly from the following exemplary embodiments, given by way of non-limiting indication, in support of the appended figures.
    Figure 1 shows the effect of dihydromyricetin (DHM) at 3 concentrations (0.0005%, 0.001% and 0.003% by weight) on IGF-1 induced lipid synthesis (20 ng / ml) in sebocytes after 14 days of culture.
    Figure 2 shows the effect of 0.001% by weight DHM and / or 0.001% by weight zinc gluconate on IGF-1 induced lipid synthesis in sebocytes after 14 days of culture.
    Figure 3 shows the effect of DHM (0.002% and 0.005% by weight), zinc gluconate (0.1%) and their combination (0.002% and 0.1% by weight, respectively) on the collagenase activity of an MMP ("Marix Metallo-Proteinase") derived from Clostridium histolyticum. I / Examples of formulation:
    The amounts indicated are given in percentage by weight. Example 1: Water-in-Silicone Emulsion (I / O)
    Example 2: Emulsion Oil in Water (O / W)
    II / Protection of the oxidation of squalene by the dihromyramine.etin ΓΡΗΜ)
    II. 1 INTRODUCTION The objective of this test is to evaluate the inhibition by dihydromyricetin (DHM) of the oxidation of squalene, induced by hydrogen peroxide (H2O2). Trolox (6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a water-soluble equivalent of vitamin E, is a known antioxidant and is used in these tests as a positive control.
    II.2 MATERIALS AND METHODS
    Squalene (Sigma Aldrich) is first solubilized in a reaction chamber. The oxidation of squalene is induced by the addition of a solution of hydrogen peroxide (H2O2 at a final concentration of 6%).
    Assets to be evaluated are added to the reaction mixture. Thus, Trolox 0.8% by weight is used as a positive control of the protection against the oxidation of squalene.
    A positive control, corresponding to squalene incubated in the presence of H202, and a negative control, corresponding to squalene not exposed to ΓΗ2Ο2, are also performed.
    The resulting mixture is stirred for one hour at room temperature and protected from light.
    Squalene is then extracted from the reaction medium using a liquid / liquid extraction. After evaporation of the organic solution, the residue is solubilized in a solution of chloroform and squalene is analyzed by GC / MS chromatography method.
    Measurement of the squalene concentration makes it possible to estimate the amount of squalene having been oxidized during the reaction. Indeed and according to the measurement technique used, only the non-oxidized form is detected.
    II.3 RESULTS AND CONCLUSIONS
    The results obtained are shown in Table 1 below:
    Table 1: Effect of trolox (0.8%) and DHM (0.005%, 0.01% and 0.05%) on the protection against oxidation of squalene induced by hydrogen peroxide. CV: coefficient of variation
    It is found that dihydromyricetin has a protective activity against the oxidation of squalene induced by hydrogen peroxide, which is otherwise dose-dependent. At a concentration of 0.05%, the DHM has a protective activity against the oxidation of squalene comparable to that of Trolox, when it is used at a concentration 16 times higher (0.8%).
    These experiments demonstrate a protective effect of dihydromyricetin (DHM) against the oxidation of squalene, comparable to that observed in the presence of known antioxidants. III / Effect of dihydromyricetin and / or zinc gluconate on lipid production in a human seboc- vit model
    III. 1 INTRODUCTION
    This test is based on the use of the sebocyte line SEB0662 described by Barrault et al.
    The present study aims to investigate the effect of dihydromyricetin (DHM) and / or zinc gluconate (Zn) on the inhibition of lipid synthesis, induced by the addition of IGF-1, in sebocytes. This effect is followed by labeling, using a lipid fluorescent probe coupled to the Bodipy®, sebocytes SEB0662 cultured monolayer for 14 days in differentiation medium (supplemented with IGF-1 at 20 ng / ml).
    III.2. MATERIALS AND METHODS III.2.1. Biological models
    In this study, the human sebocyte line SEB0662 is used.
    The cells are cultured in the standard culture medium of the sebocytes, at 37 ° C. and in the presence of 5% of CO2. The cells are used at the 7th pass.
    For the evaluation of the active ingredients, a so-called differentiation medium (conventional culture medium supplemented with dihydrotestosterone, serum bovine albumin, linoleic acid, glucose, fetal calf serum, hydrocortisone and PPAR agonists ("Peroxysome Proliferator Activated Receptor")), supplemented with IGF-1 at 20 ng / ml, is used. The addition of IGF-1 stimulates the production of lipids by the sebocytes. III.2.2 Crops and treatments
    Sebocytes SEB0662 are seeded at a very high density (50000 cells / well) in 96-well plate and cultured in conventional culture medium for 24 hours. After incubation, the medium is replaced by the differentiation medium described above, which may or may not contain the compounds to be tested. The following controls are carried out: conventional culture medium and differentiation medium devoid of IGF-1.
    The selection of the active doses is carried out thanks to a cell viability test at MTT. We retain the doses that maintain a viability greater than 90%.
    After 7 days of culture, the media containing IGF-1 are again supplemented with IGF-1 (20 ng / ml) and test compound (s). After a total of 14 days of culture, the labeling of the lipid droplets is carried out as described below.
    All experimental conditions are repeated three times. III. 2.3. In situ labeling of lipid droplets
    The differentiation medium is removed and the cells are rinsed, fixed and permeabilized. The lipid droplets contained in the cells are then labeled using a fluorescent lipid probe coupled to Bodipy®. In parallel, the nuclei of the cells are stained with Hoechst 33258 (bis-benzimide). Image acquisition is performed with a high resolution imaging system, INCell Analyzer ™ 1000 (GE Healthcare). For each well, 10 entries of scanned images are made for each marking.
    The labels are quantified by measuring the fluorescence intensity of the probe relative to the number of nuclei identified by the Hoechst (digital data integration by the Developer Toolbox 1 .5 software, GE Healthcare). III.2.4 Data processing
    The raw data is transferred and processed under Microsoft Excel® software.
    Intergroup comparisons are performed using the unpaired bilateral Student T test. Statistical analyzes are provided for information only.
    Formulas used for the analysis of the results: The standard error of the mean (esm) represents the difference of the mean of the sample with the average of the population. The esm is calculated by dividing the standard deviation (Sd) by the square root of the sample size (sqrt (n)).
    Standard error of mean (esm) = standard deviation (Sd) / sqrt (n)
    Percent Viability: Viability (%) = (Compound OD / Endo) x 100 Percentage of Stimulation: Stimulation (%) = [(Value / Mean of Control) x 100] -100
    Percent inhibition: Inhibition (%) = 100- [(Value / average of the control) x 100] III.3 RESULTS AND CONCLUSIONS III. 3.1 Cytotoxicity test
    Under the culture conditions used, the DHM alone, tested up to a dose of 0.003%, showed no cytotoxic effect. Doses of 0.0005%, 0.001% and 0.003% are selected for performing the tests.
    Zinc gluconate does not exhibit cytotoxicity at a dose of 0.001%. The dose of 0.001% is selected for performing the tests.
    In combination, the presence of 0.001% zinc gluconate and 0.001% DHM makes it possible to maintain a cell viability of always greater than 90%. III.3.2 Effects on lipogenesis
    The differentiation medium supplemented with IGF-1 induces, under the conditions of the test, an increase in the number of lipid vesicles (168% of the control). This expected result validates the experimental conditions.
    All the conditions tested for dihydromyricetin (3 concentrations) induce a significant decrease in the intensity of Bodipy® labeling and a decrease in the formation of lipid droplets. Thus, and as illustrated in FIG. 1, the DHM inhibits IGF-1-induced lipid synthesis by: 19% at the 0.0005% dose; 12% at a dose of 0.001%; and 17% at the 0.003% dose.
    Moreover, and as shown in FIG. 2, 0.001% zinc gluconate also inhibits lipid synthesis by about 15%. Remarkably, the addition of 0.001% DMM further enhances the inhibition of IGF-1 induced lipid synthesis. IV / Effect of dihydromyricetin and / or zinc gluconate on the collagenase activity of MMP-1 by an in tubo test
    IV. 1 INTRODUCTION
    The tests carried out make it possible to evaluate the effect of dihydromyricetin, zinc gluconate, and their association on the collagenase activity of an MMP.
    IV.2. MATERIALS AND METHODS IV.2.1 Principle of the test The anti-collagenase activity is measured using the MMP-1 kit (Molecular Probes, Ref E12055). The principle is based on the ability of an enzyme from the zinc-dependent MMP ("Marix Metallo-Proteinase") family, in this case collagenase from Clostridium histolyticum, to hydrolyze its substrate (collagen-I) to give measurable fluorescent compounds.
    In the presence of an inhibitor, the action of the enzyme is impaired preventing the hydrolysis of its substrate. 1,10 Phenanthroline is used as the positive control for inhibition of the enzyme. The fluorescence emitted at 535 nm is measured after excitation at 485 nm. IV.2.2 Dilution of assets and controls
    1,10-Phenanthroline monohydrate (10mM), a known MMP inhibitor provided in the kit, is used as a positive control
    The following negative controls were carried out: H20 control: This control was used to solubilize 1-10-phenantroline monohydrate; it arbitrarily represents 100% activity of the enzyme compared to the results obtained with this control. - solvent control (DMSO 1%): amount of solvent included in all the assets and associations to be tested; it arbitrarily represents 100% activity of the enzyme compared to the results obtained with the active agents and associations tested.
    Zinc gluconate was tested at a concentration of 0.1% (by weight).
    The EMI was tested at the following concentrations: 0.002% and 0.05% (by weight). The combination of 0.1% zinc gluconate + 0.002% DHM was also tested. IV.2.3. Statistical analyzes
    Quantitative analyzes are expressed as mean ± standard deviation. Statistical significance is determined by a Student test. Differences are considered statistically significant between the tested active and its solvent control from p <0.05. (NS: p <0.05; *: p <0.01; **: p <0.001 ***).
    IV.3. RESULTS AND CONCLUSIONS
    The anti-collagenase activities of the controls, the actives and their association are evaluated by a test of the MMP-1 activity. The results are presented in Figure 3. The analysis of the results reveals the following effects:
    As expected, the positive collagenase inhibition control (10mM 1-10-phenanthroline monohydrate) significantly inhibited collagenase activity (observed inhibition: 79.6%).
    Zinc gluconate tested at 0.1% significantly inhibited the collagenase activity of MMP-1 (observed inhibition: 80.2%).
    EMC, tested at 0.002% and 0.05%, significantly and dose-dependently inhibited the collagenase activity of MMP (observed inhibition: 3.5% and 30.1%, respectively). The combination of 0.1% zinc gluconate + 0.002% DHM very significantly inhibited the collagenase activity of MMP (observed inhibition of 90.7%), revealing a synergy between the two compounds under these conditions.
    REFERENCES BARRAULT C, DICHAMP I, GARNIER J, PEDRETTI N, JUCHAUX F, DEGUERCY A, AGIUS G, BERNARD FX. Immortalized sebocytes can spontaneously differentiate into a sebaceous-like phenotype when cultured as a 3D epithelium. Exp Dermatol.
    2012 Apr; 21 (4): 314-6. CAPPEL M, MAUGER D, THIBOUTOT D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women. Arch Dermatol. March 2005; 141 (3): 333-8. CHIBA K; SONE T; KAWAKAMI K; M. Skin roughness and wrinkle formation by repeated application of squalene monohydroperoxide to the hairless mouse. Exp Dermatol., December 1999, vol. 8 (6), 471-9. CHIBA K, YOSHIZAWA K, MAKINO I, KAWAKAMI K, ONUEE M. Comedogenicity of squalene monohydroperoxide in the skin after topical application. J Toxicol Sci 2000; 25: 77-83. CHIVOT M., PAWIN H., BEYLOT C., CHOSIDOW O., DRENO B., FAURE M., POLI F., REVUZ J., acne scars: epidemiology, physiopathology, clinical, treatment. Acne scars: epidemiology, physiopathology, clinical features and treatment Ann Dermatol Venereol Oct. 2006: Vol 133, 813-824. DEPLEWSKI D, ROSENFIELD RL. Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation. Endocrinology.
    1999 Sep; 140 (9): 4089-94. DEPLEWSKI D, ROSENFIELD RL. Role of hormones in pilosebaceous unit development. Endocr Rev.
    2000 Aug; 21 (4): 363-92. Review. GERATS AG OF VLAMING P, DOODEMAN M, AL B, SCHRAM AW. Genetic control of the conversion of dihydroflavonols into flavonols and anthocyanins in flowers of Petunia hybrida. Planta.
    1982 Aug; 155 (4): 364-8. doi: 10.1007 / BF00429466. HORTON R, PASUPULETTI V, ANTONIPILLAI I. Androgen induction of steroid 5 alpha-reductase can be mediated via insulin-like growth factor-I. Endocrinology.
    1993 Aug; 133 (2): 447-51. ISARD O, KNOL AC, MF ARIES, NGUYEN JM, KHAMMARI A, CASTEX-RIZZI N, DRENO B. Propionibacterium acnes activates IGF-1 / IGF-1R system in the epidermis and induces keratinocyte proliferation. J Invest Dermatol.
    Jan 2011; 131 (1): 59-66. doi: 10.1038 / jid.2010.281. Epub 2010 Oct 7. R LA, NICHOLLS PJ, SMITH HJ, MAHARLOUIE FH. Inhibitors of human and rat microsomal 17beta-hydroxysteroid dehydrogenase (17beta-HSD) assays as potential agents for prostatic cancer. J Enzyme Inhib.
    2001 Jan; 16 (1): 35-45. OHNO S., MATSUMOTO N, WATANABE M, NAKAJIN S. Flavonoid inhibition of overexpressed human 3beta-hydroxysteroid dehydrogenase type II. J Steroid Biochem Mol Biol.
    2004 Feb; 88 (2): 175-82. ORFANOS CE, ZOUBOULIS CC. Oral retinoids in the treatment of seborrhoea and acne. Dermatology. 1998; 196 (1): 140-7. OTTAVIANI M .; CAMERA E; PICARDO M. Lipidmediators in acne. Mediators lnflamm, 25 August 2010 OTTAVIANI M; ALESTAS T; FLORI E; MAS-TROFRANCESCO A, ZOUBOULIS CC; PICARDO M. Peroxidated squalene induces the production of inflammatory mediators in HaCaT keratinocytes: possible role in acne vulgaris. J Invest Dermatol., June 15, 2006, vol. 126 (11), 2430-7 PICARDO M; OTTAVIANI M; CAMERA E; MASTROFRANCESCO A. Sebaceous glans lipids. Dermatoendocrinol, March 2009, vol. 1 (2), 68-71. SAINT-LÉGER D et al. A possible role for squalene in the pathogenesis of acne. In vivo study of squalene oxides in skin surface and intra-comedonal lipids of acne patients. Br J Dermatol, 1986, vol. 114, 543-552 SHEN Y, LINDEMEYER AK, GONZALEZ C, S H AO XM, SPIGELMAN I, OLSEN RW, LIANG J. Dihydromyricetin as a novel anti-alcohol intoxication medication. J Neurosci.
    2012 Jan 4; 32 (1): 390-401 STAMATIADIS D, BULTEAU-PORTOIS MC, MOWSZOWICZ I.
    1988 Inhibition of 5- α-reductase activity in human skin by Zinc and azelaic acid. British Journal of Dermatology 119 (5): 627-632. THIRD JJ; WEBER SU; PACKER L. Sebaceous glans secretion is a major physiology route of vitamins E delivery to skin. J lnvest Dermatol., Dec. 1999, vol. 113 (6), 1006-10 WU S, LIU B, ZHANG Q, LIU J, ZHOU W, WANG C, LI Μ, BAO S, ZHU R Dihydromyricetin reduced Bcl-2 expression via p53 in human hepatoma HepG2 cells. PLoS One.
    2013 Nov 4; 8 (1 l): e76886.
    权利要求:
    Claims (5)
    [1" id="c-fr-0001]
    1 / Cosmetic or dermatological composition comprising dihydromyricetin and a zinc salt.
    [0002]
    2 / A composition according to claim 1, characterized in that the dihydromyricétine represents from 0.0001% to 10% by weight of the composition, advantageously from 0.001% to 2%.
    [0003]
    3 / Composition according to one of the preceding claims, characterized in that the zinc salt is zinc gluconate.
    [0004]
    4 / Composition according to one of the preceding claims, characterized in that the zinc salt is from 0.1 to 10% by weight of the composition, preferably 1 to 5%.
    [0005]
    5 / composition according to one of the preceding claims, characterized in that it further comprises at least one ingredient selected from: - biochanin A, preferably from a red clover extract; an extract of Ginkgo biloba, advantageously an extract of Ginkgo biloba comprising flavonoids; a meroterpene, advantageously bakuchiol; a polyol, advantageously chosen from xylitol, sorbitol and mannitol; a lipophilic antioxidant, advantageously chosen from propyl gallate, octyl gallate and dodecyl gallate; a keratolytic agent, advantageously chosen from salicylic acid, glycolic acid, citric acid, malic acid and lactic acid; ~ glycyrrhétinique acid or one of its derivatives or salts. 61 Composition according to one of the preceding claims, characterized in that it is in the form of a cream, a gel or a lotion. 7 / Composition according to one of claims 1 to 6 for its use in the prevention or treatment of acne. 8 / composition according to one of claims 1 to 6 for use as: - sebum regulating agent; and / or - fluidifying agent of sebum; and / or - agent capable of preventing the formation of atrophic scars of acne.
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    同族专利:
    公开号 | 公开日
    EP3364964A1|2018-08-29|
    EP3364964B1|2020-08-26|
    WO2017068424A1|2017-04-27|
    FR3042710B1|2019-12-13|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JP2000136131A|1998-08-26|2000-05-16|Fukuoka Prefecture|5alpha-reductase inhibitor|
    EP1484086A2|2003-05-09|2004-12-08|Dr. Scheller Cosmetics AG|Composition for preventing and curing the acne comprising zinc gluconate and copper gluconate|FR3091996A1|2019-01-24|2020-07-31|Les Laboratoires Brothier|HEALING COMPOSITION|FR2857266B1|2003-07-07|2007-09-21|Jean Noel Thorel|COMPOSITION FOR DERMATOLOGICAL AND / OR COSMETIC USE, COMPRISING AS ACTIVE INGREDIENT AT LEAST ONE LIPOPHILIC ANTIOXIDANT|
    ES2689715T3|2007-05-14|2018-11-15|Sytheon Ltd.|Compositions for skin treatment and methods|
    FR2981275B1|2011-10-18|2015-03-20|Jean Noel Thorel|MEROTERPENE-BASED COMPOSITION FOR OILY SKIN, ACNETIC SKIN OR ACNE-DENIED|WO2019166088A1|2018-02-28|2019-09-06|Symrise Ag|Tetraselmis extract|
    CN111995766A|2020-09-13|2020-11-27|仲恺农业工程学院|Method for preparing dihydromyricetin zinc nanoparticles based on vine tea extract and application thereof|
    法律状态:
    2016-10-31| PLFP| Fee payment|Year of fee payment: 2 |
    2017-04-28| PLSC| Publication of the preliminary search report|Effective date: 20170428 |
    2017-10-24| PLFP| Fee payment|Year of fee payment: 3 |
    2018-10-27| PLFP| Fee payment|Year of fee payment: 4 |
    2019-10-30| PLFP| Fee payment|Year of fee payment: 5 |
    2020-10-29| PLFP| Fee payment|Year of fee payment: 6 |
    2021-10-28| PLFP| Fee payment|Year of fee payment: 7 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1560091|2015-10-22|
    FR1560091A|FR3042710B1|2015-10-22|2015-10-22|COMPOSITION BASED ON DIHYDROMYRICETIN AND ZINC SALT FOR THE TREATMENT OF ACNE AND OILY SKIN|FR1560091A| FR3042710B1|2015-10-22|2015-10-22|COMPOSITION BASED ON DIHYDROMYRICETIN AND ZINC SALT FOR THE TREATMENT OF ACNE AND OILY SKIN|
    EP16806279.2A| EP3364964B1|2015-10-22|2016-10-25|Composition based on dihydromyricetin and a zinc salt for the treatment of acne and oily skin|
    PCT/IB2016/001634| WO2017068424A1|2015-10-22|2016-10-25|Composition based on dihydromyricetin and a zinc salt for the treatment of acne and oily skin|
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