Wrinkle filling compositions of natural origin

Abstract

A wrinkle filling composition extracted from the combination of olive and myrtle leaves by a specific extraction method, and the use of the wrinkle filling composition to reduce or eliminate wrinkles and / or uneven skin by the application of the wrinkle filling composition, for example, in a cosmetic composition or preparation to areas of the skin in need of combatting the effects of aging, including wrinkles and uneven skin, as well as irregular in terms of texture: smoothing effect, not in terms of skin tone / color.

Description

[0001] Wrinkle Filling Compositions of Natural Origin Wrinkle filling compositions were achieved by extracting compounds from two types of plants, particularly Myrtus communis and Olea europaea leaves. These species are part of the Mediterranean flora since immemorial times and are associated to many cultures and religions, e.g., as sacred trees, that symbolize strength, eternity, youth and renewal. These plants produce active glycosides with antioxidant and healing properties, including myricitrin, oleuropein and verbascoside. WO2010112760 describes methods by which the extractions are achieved. The methods generally include extracting non-volatile natural compounds contained in a first solid material of natural origin, in particular a plant, in a dispersible form, with the help of a natural fatty substance or a mixture of natural fatty substances, in particular a vegetable oil or a mixture of vegetable oils, by the following steps: - at least one step a) of mixing and impregnating the first solid material in a dispersible form with the natural fatty substance at a temperature which is greater than the melting point of the fatty substance and under an atmosphere which is depleted or essentially depleted in oxygen, - at least one step b) of heating to a temperature between 80 and 200°C for a duration which is less than or equal to 10 minutes by a microwave, preferably of high-power microwaves, and under an atmosphere which is depleted or essentially depleted in oxygen, - at least one step c) of microdispersing the solid material, and possibly of rupturing the cells of the first material, into the natural fatty substance at a temperature which is greater than the melting point of the fatty substance and under an atmosphere which is depleted or essentially depleted in oxygen, by an ultrasonic cavitation treatment, step c) being able to be implemented before, during or after step b). The disclosure of WO2010112760 for its process of extraction is incorporated herein by reference. The extraction technology described above is used, preferably, with vegetable oil or olive oil, e.g., ω9, to lead to a new cosmetically usable composition product. The product is eco-processed, vegetal, 100% Mediterranean basin, COSMOS-certified and is totally safe and globally compliant.

[0002] The olive leaves are preferably organic, are preferably manually harvested, and preferably naturally dried.

[0003] The myrtle leaves are also preferably organic, and also preferably wild, and are harvested in accord with ecological and socially responsible harvesting practices.

[0004] Myrtle leaves (Latin name: Myrtus communis L.) and olive leaves (Latin name: Olea europaea L.) are used as plant material for the oily extract.

[0005] The INCI names are Myrtus Communis Leaf Extract (CAS No. 84082-67-7) and Olea Europaea (Olive) Leaf Extract (CAS No. 8060-29-5).

[0006] The terms oily extract or apolar extract or lipophilic extract of myrtle and olive are indiscriminately / interchangeably used in the description.

[0007] The oily extract of myrtle and olive is inspired by the theory of the polar paradox of antioxidants of PORTER and FRANKEL or physicochemical behavior of antioxidants in a continuous oil system and in a dispersed system allowing hydrophilic compounds (antioxidants or phenols for example) to become miscible in oily compounds containing , for example, phospholipids (molecules with polar functions) under physicochemical actions produced by ultrasound and microwaves.

[0008] More simply, it involves using an oil or a fatty substance, and in particular a vegetable oil, as a biologically active agro-solvent, to selectively extract molecules from a plant, in particular myrtle and olive, with high-performance technology based on physical principles, to obtain a concentrated oily complex, a stable vector ready to formulate.

[0009] The oily extract of myrtle and olive is obtained by a method of dynamic extraction which is made by energetic activation of the plant and the vector oil to have an active mass transfer, with a pump effect from the most concentrated medium to the least concentrated. The process combines multi-steps (cryo-grinding, ultrasound, microwaves, filtration) of short duration (each step <15min) and inerting in nitrogen and sheltered from light during the transformation limit the phenomena of oxidation.

[0010] The extraction is assisted by microwaves and ultrasounds which make it possible to gain in extraction efficiency (better yield, reduction in time and therefore in the energy required compared to traditional extraction (maceration)).

[0011] This makes it possible to open the plant cells, to disorganize the medium to make extractable molecules usually insoluble in oils, they become miscible with the oily support according to a dynamic rearrangement.

[0012] Such a method is in particular described in application W02010 / 112760.

[0013] In particular, the method comprises: at least one step a) of mixing and impregnating the solid raw material (the myrtle and olive leaves) with a natural fatty substance at a temperature above the melting point of the fatty substance and under an atmosphere devoid or essentially devoid of oxygen, at least one step b) of heating the mixture to high temperature for a very short time and under an atmosphere devoid or essentially devoid of oxygen, at least one step c) of micro-dispersion of the material to be extracted and possibly rupture of the cells of the raw material, in the natural fatty substance at a temperature above the melting point of the fatty substance and under an atmosphere devoid or essentially devoid of oxygen , it being possible for step c) to be carried out before, during or after step b).

[0014] According to a preferred embodiment, the method comprises:

[0015] - at least one step a) of mixing and impregnating the solid raw material in dispersible form with the natural fatty substance at a temperature above the melting point of the fatty substance and under an atmosphere devoid or essentially devoid of oxygen, - at least one step b) of heating the mixture to high temperature for a very short time and in an atmosphere devoid or essentially devoid of oxygen, using microwaves,

[0016] - at least one step c) of microdispersion of the material to be extracted and possibly of rupture of the cells of the raw material in the natural fatty substance at a temperature above the melting point of the fatty substance and under an atmosphere devoid or essentially devoid of oxygen, using ultrasound, step c) being able to be carried out before, during or after step b).

[0017] "Dispersible" means that the raw material is in a dissociated form capable of being finely dispersed, for example in a particulate and preferably pulverulent form.

[0018] This process makes it possible to simultaneously obtain a vegetable fatty substance and in particular a vegetable oil with a low level of oxidation and a high concentration of active molecules extracted, this thanks to the simultaneous implementation of a process carried out under an atmosphere devoid of or essentially devoid of oxygen, in particular nitrogen inerting, and of a process which uses the synergistic action of a short treatment at high temperature, in particular under microwaves, and of the microdispersion and possibly the rupture of the cells of the product to extract, in particular by ultrasonic cavitation.

[0019] By 'atmosphere devoid or essentially devoid of oxygen', it is meant that one works under gas or inert atmosphere or under vacuum or partial vacuum.

[0020] The residual oxygen content, if any, must be low enough not to cause oxidation reactions sensitive to the temperature of the heat treatment.

[0021] One way to control the non-oxidation is by measuring the peroxide value of the final active ingredient at the end of the process. It has a low level of oxidation assessed by the peroxide index, which measures the concentration of hydroperoxides of fatty acids, called primary oxidation compounds, which can be formed in the oil in the presence of oxygen. This measurement is performed according to a recognized and standardized analytical method. The Myrtle and olive leaves extract generally has a peroxide value of less than 10 milli-equivalents of oxygen per kg and preferably less than 5 milli-equivalents of oxygen per kg at the production outlet. The extract is stable. Typically, its peroxide value remains below 5 mil li- equivalents of oxygen per kg after 6 months at +4°C / +6°C, at room temperature (about 25°C) and at 40°C.

[0022] The raw material is preferably ground beforehand at low temperature, between -20°C and -80°C (cryogrinding).

[0023] For example, this step can be carried out by freezing between -20 and -30° C and grinding (for example using a cutter mill) or by grinding under cryogenic conditions (for example between -70 and -80° C ). This ground material is in powder form.

[0024] In a particular embodiment, the temperature in step a) is advantageously between the natural fatty substance melting temperature and the melting temperature +20°C, preferably +10°C. Ambient temperature is perfectly suited for fatty substances, in particular oils, which are liquid at this temperature.

[0025] The duration of step a) can be between 1 and 48 hours, preferably between 5 and 30 hours.

[0026] In a particular embodiment, the temperature of step b) is between 60 and 200°C, preferably between 60 and 150°C. Heating at high temperature of very short duration means a treatment carried out in a time less than or equal to 10 minutes, preferably less than or equal to 5 minutes, preferably 1 to 5 minutes, and more preferably 1 to 3 minutes. , this duration corresponds to the time during which the treatment temperature is maintained once this temperature has been reached.

[0027] The temperature rise time is also very short, in particular less than or equal to 5 minutes, preferably 1 to 5 min, and more preferably 1 to 3 minutes.

[0028] Preferably, the heat treatment is provided by microwaves.

[0029] It is recommended to use a microwave generator with high useful power, preferably of the order of 10,000 Watts to 30,000 Watts per kilogram of mixture.

[0030] Stage c) allows both the microdispersion of the material to be extracted and, on cell tissues, the rupture of the cells, which promotes the dispersion of the extracted molecules in the natural fatty substance.

[0031] The term "microdispersion" means particles or solutes in suspension in the fatty substance.

[0032] The size of the particles or solutes is such that there is no settling over time, it is in particular between 0.1 and 10 pm. Step c) can be carried out using microwaves, but can also comprise or consist of treatment of the mixture by ultrasonic cavitation before, during or after step b).

[0033] Cavitation and dispersion under ultrasonic waves are preferably carried out in a closed reactor equipped with an ultrasound generator at low cavitation frequency, in particular less than 100 kHz and preferably of the order of 20 to 30 kHz. The duration of ultrasound treatment is in particular between 2 and 30 min, preferably between 10 and 20 min.

[0034] Steps b) and c) can be carried out simultaneously.

[0035] Advantageously, during step c) or just before, an oxygen scavenger or reducer compound, a compound making it possible to regenerate in reduced form the tocopherols of the oil as well as the phenolic compounds extracted from the oil by the process or a pro-oxidant metal chelator, these compounds helping to improve the oxidative stability of the final product.

[0036] As fatty substances that can be used as an extraction vector for the oily extract, mention may be made in particular of the following vegetable oils and fatty substances: vegetable oils such as: deodorized olive oil, jojoba oil (or liquid jojoba wax), deodorized oil Oleic sunflower, virgin sweet almond oil, virgin muscat rose oil, avocado oil, safflower oil, camelina oil, borage oil, grape seed oil, argan oil, nigella oil, pumpkin seed oil , or perilla oil, and mixtures thereof, butters such as: Murumuru butter, Mango butter, Shea butter, and mixtures thereof, vegetable waxes such as: Carnauba wax, beeswax, candelilla wax, jojoba wax, and mixtures thereof, and indeed mixtures of any of these in any combination.

[0037] Thus, preferably, the natural fatty substance is a vegetable oil chosen from deodorized olive oil, jojoba oil or liquid jojoba wax, deodorized sunflower oleic oil, virgin sweet almond oil, virgin muscat rose oil, avocado oil, safflower oil, camelina oil, borage oil, grape seed oil, argan oil, nigella oil, pumpkin seed oil, or perilla oil, and mixtures thereof.

[0038] Preferably used is deodorized olive oil. Deodorized olive oil (Latin name: Olea Europaea L.) mainly contains triglycerides which constitute oils and fats, have molecules formed by a glycerol residue and three fatty acid residues of different kinds, mainly oleic acid (C18) and palmitic acid (C16).

[0039] The INCI name for Deodorized olive oil is Olea Europaea Fruit Oil (INCI Europe) or Olea Europaea (Olive) Fruit Oil (INCI USA) (CAS No: 8001-25-0 / 84012-27-1).

[0040] According to a particular embodiment, the ratio between the Myrtle and olive leaves blend and the natural fatty substance in step a) is between 1:1 and 1:10, preferably between 1:4 and 1:8 expressed in mass / mass of fatty substances or in mass / volume of fatty substances.

[0041] Preferably, the weight ratio between the Myrtle and olive leaves blend and the oil in the starting mixture used in step a) ranges from 1:4 to 1:8 expressed in mass: mass of oil or mass: amount of oil. Preferably, a plant / oil weight ratio of 1:4 is used.

[0042] Preferably a blend of equal proportion of myrtle and olive leaves (50 / 50) are used by weight, but deviations from this ratio are possible, for example, 55 / 45 to 45 / 55, or even 60 / 40 to 40 / 60, including smaller deviations from equal amounts, e.g., 51 / 49 to 49 / 51, 48 / 52 to 52 / 48, 47 / 53 to 53 / 47 or 54 / 46 to 46 / 54.

[0043] Both the myrtle leaves and olive leaves are preferably dried.

[0044] According to a preferred embodiment, in addition to the natural fatty substance for the extraction, at least an emulsifying agent is used as a co-extractant.

[0045] The co-extractant is introduced during step a) of the process described above.

[0046] The use of this co-extractant makes it possible to extract more polar compounds than in the oil alone. This co-extractant makes it possible in particular to extract polyphenols.

[0047] In the absence of a co-extractant, the content of total polyphenols in the oily extract of myrtle and olive leaves was 212 mg / kg eq.

[0048] Oleuropein, whereas in the presence of a co-extractant, the polyphenol content could be multiplied by 15 or even 40.

[0049] In particular, with polyglyceryl-3 diisostearate PG3DS (CAS No. 63705-03-3 / 66082-42-6 1 85666-92-8), the content of total polyphenols in the oily extract of myrtle and olive leaves was 4 205 mg / kg eq. Oleuropein and with Polyglyceryl-4 oleate PGMO (CAS No. 9007-48-1 / 71012-10-7), the content of total polyphenols in the oily extract of myrtle and olive leaves was 8 530 mg / kg eq. Oleuropein).

[0050] Thus, according to a particular embodiment, the co-extractant is an amphiphilic compound, chosen in particular from fatty acid esters of the "polyglyceryl" type such as polyglyceryl-3 diisostearate (PG3DS), polyglyceryl-4 oleate, polyglyceryl-6 dioleate or polyglyceryl-3 caprate.

[0051] Mention may also be made of glycerol stearate, or even phospholipids such as lecithins.

[0052] Preferably, polyglyceryl-3 diisostearate (PG3DS), or polyglyceryl-4 oleate, more preferably polyglyceryl-4 oleate (PGMO) is used.

[0053] According to a particular method, the oil / co-extractant weight ratio will advantageously be 95-75% oil / 5-25% co-extractant.

[0054] According to a preferred mode, the oily extract of myrtle and olive is obtained according to the following process: the fresh frozen leaves are ground, cryo-ground, then mixed with deodorized olive oil, preferably in the presence of a co -extractant, in particular in a dry plant / oil ratio ranging from 1:4 to 1:8, then various successive extraction steps are carried out by extraction using microwaves then by ultrasound.

[0055] A filtration step by centrifugation makes it possible to obtain a precious oil so the stability has been preserved because each step was carried out meticulously under nitrogen inerting.

[0056] Thus, according to a particular embodiment , the oily extract of myrtle and olive is obtained by an extraction process including the following steps: a) mixing and impregnating a powder of myrtle and olive leaves with the natural fatty substance, and preferably in the presence of a co-extractant, at a temperature above the melting point of said natural fatty substance and under an atmosphere devoid or essentially devoid of oxygen, b) heating the mixture thus obtained at a temperature of between 60 and 150° C., in an atmosphere devoid or essentially devoid of oxygen, in particular by using microwaves, c) the micro-dispersion of the leaves powder of myrtle and olive in the natural fatty substance at a temperature above the melting point of the fatty substance and under an atmosphere devoid or essentially devoid of oxygen, in particular using ultrasound, step c) possibly being carried out before, during or after step b).

[0057] Preferably, the natural fatty substance is an olive oil and the co-extractant is a polyglyceryl-4 oleate (PGMO).

[0058] According to a particular mode, step b) is carried out for a very short duration, in particular between 1 and 10 minutes.

[0059] An oily extract is thus obtained according to this process in the form of an oily solution, oily microdispersion or oily microemulsion.

[0060] According to a particular mode, the oily extract of myrtle and olive contains from 70% to 95% by weight of vegetable oil, preferably olive oil, from 5% to 25% by weight of myrtle and olive leaves, and from 5% to 15% by weight of co-extractant, preferably polyglyceryl-4 oleate, relative to the total weight of the extract.

[0061] The INCI name of this oily myrtle and olive extract is as follows:

[0062] European INCI name: Olea Europaea Fruit Oil (and) Polyglyceryl-4 Oleate (and) Myrtus Communis Leaf Extract (and) Olea Europaea Leaf Extract

[0063] INCI USA Name: Olea Europaea (Olive) Fruit Oil (and) Polyglyceryl-4 Oleate (and) Myrtus Communis Leaf Extract (and) Olea Europaea (Olive) Leaf Extract

[0064] It is known in the art that different extraction methods lead to different components being extracted from biological material and / or in different amounts and / or in different ratios and / or in different combination of components. For example, water or alcohol extraction would be expected to lead to the extraction of components or different amounts thereof that have a stronger affinity to be, e.g., dissolved in water, ethanol, etc., than extraction with oils or other solvents. Likewise different process parameters may favor the extraction of certain components more than of others, e.g., temperatures and / or pressures used and / or the amount of time given for various extraction steps, etc., as some components may not become soluble until certain physical parameters are met. Moreover, certain extraction methods may eliminate certain components, e.g., due to vaporization or even in some cases due to reactions with other components. Thus, many times the process of extraction especially regarding biological materials is a way to define the extract itself, especially if not characterized by chemical analysis for its components. In general, one would not assume in this art that two distinct extraction methods would yield the same product. A good publication on this issue is Yan et al., "The Influence of Different Extraction Techniques on the Chemical Profile and Biological Properties of Oroxylum indicum: Multifunctional Aspects for Potential Pharmaceutical Applications", Evidence-Based Complementary and Alternative Medicine, vol. 2022, Article ID 8975320, 17 pages, 2022.

[0065] Further evidence is provided that the extraction method used herein does not lead to the same extract as a comparative extract. In this regard, see the side-by-side extraction method comparison where Extract A (also identified as Fl : 0219.ol.AOC.06A) is prepared by the method disclosed in W02010112760 and Extract B (also identified as F2 : HA.ol.AE.01C) is a water conventional extract prepared from the same plant and which extract has exactly the same total polyphenol content (antioxidant molecules) as ingredient A. In ex vivo studies excised skin samples were tested with the two extracts concerning the restoration of the hydrophilic barrier of the skin as measured by T rans Epidermal Water Loss (TEWL). See the results in a graph form in Fig. 21. (Mean TEWL (g.m-2.h-l) for the 2 donors (n=6; mean ± SEM)) These results using an ex-vivo model of irritated skin, showed the effective property provided by the Extract A 0219.ol.AOC.06A to rapidly restore the hydrophilic barrier of the skin, while the comparative Extract B led to drastically different results, indeed opposite in the sense that the performance was worse than for the control, confirming that the two extracts were not the same and their activities were not the same either.

[0066] See Fig. 22 showing chromatographic data establishing that the extraction of the two plants in accord with W02010112760 leads to the extraction of compounds from both plants (comparison is made to each extract separately). In the HPLC chromatographic profile at 280 nm in black: myrtle leaf / in blue: olive leaf / in red: the extract from the combination.

[0067] See also some corresponding tabulated results as follows showing that certain compounds were present in the combined extract that were present in only one of the individually extracted plant: OA.ol.MOPM.Ol = Myrtle leaf extract OA.ol.OOPM.02 = Olive leaf extract

[0068] OA.ol.MOOPM.03 = Extract with both plants

[0069] The combined extract contain: gallic acid, hydroxytyrosol, myricitrin, oleuropein and myricetin. Gallic acid, myricitrin and myricetin are mainly extracted from myrtle leaves. Hydroxytyrosol and oleuropein from olive leaves.

[0070] Main compounds of myrtle and olive extract are: oleuropein and myricitrin.

[0071] Noted is that the sizes of the various peaks of the combination independently from each other do not always correspond to the sizes of the peaks expectable from the mere addition of the two extracts separately, indicating that the relative amounts of certain compounds extracted versus other compounds extracted is not the same as if the two individually extracted plants were merely combined. This is likely due to the competition between the different molecules when the plants are extracted simultaneously and by the particular process described herein. And as such, a unique composition is achieved at least regarding the amounts of various components.

[0072] For example, note the results below showing a synergistic result in terms of total polyphenols contents and antioxidant efficacies:

[0073] Antioxidant efficacy - in tubo test - CAT test:

[0074] Principle of the test

[0075] The CAT (Conjugated Autoxidizable Triene) assay is one of the spectrophotometric tests allowing the evaluation of the total antioxidant capacity of samples [3], The CAT test measures the ability of a product to scavenge free radicals, an indication of an anti-aging activity. The CAT test is well-adapted to oil-based products.

[0076] This test evaluates the ability of a product to block oxidative radical reactions. It measures by UV spectrophotometry, the damage caused by free radicals on an oxidizable substrate. The presence of antioxidants in a tested product prevents the free radicals acting on the oxidizable substrate.

[0077] 2,2'- azobis-2-amidinopropane dihydrochloride (AAPH) is used to generate Reactive Oxygen Species (ROS), and tung oil is used as an oxidizable substrate. Trolox® (6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid), a vitamin E analogue, is used as the external reference and the CAT results are expressed in Trolox® equivalents per unit weight of sample.

[0078] [3] M. Laguerre et al. Conjugated autoxidizable triene (CAT) assay: A novel spectrophotometric method for determination of antioxidant capacity using triacylglycerol as ultraviolet probe. Analytical Biochemistry., 2008 ; 380:282-290.

[0079] The wrinkle filling compositions activate natural skin healing pathways and counter-balance skin aging signs. As a result, the skin's surface appear less irregular and less wrinkled.

[0080] Aged skin is characterized by wrinkles and uneven roughened skin. The aged wrinkled skin contains aged keratinocytes, aged basal stem cells, shortened collaged fibers, senescent fibroblasts, disordered elastin fibers, aged hair follicle stem cells, and is showing a slowdown of epidermis regeneration and depletion of dermis. Moreover, reactive oxygen species are generally constantly contributing to skin aging and wrinkle formation. See Fig. 1 depicting some of these effects in the aged wrinkled skin.

[0081] The wrinkle filling compositions combat wrinkles by a variety of effect, including boosting cell defenses, for example, by providing protection from oxidative stress. See Fig. 2. Furthermore, these compositions achieve mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and the proliferation / differentiation of hair follicle stem cells. See Fig.

[0082] 3.

[0083] The compositions additionally lead to epidermal regeneration, which affect migration / proliferation of keratinocytes. See Fig. 4.

[0084] Moreover, the compositions affect dermal remodeling by the migration / proliferation of fibroblasts and the synthesis of ECM (collagen fibers). See Fig. 5

[0085] The final result is the filling of skin wrinkles as a result of the various effects the wrinkle filling compositions that result is visibly younger skin. The skin therefore is healthier and the wrinkles disappear or are at least diminished in depth and size. The internal effects include the presence of active keratinocytes, active basal stem cells, which in sum are part of the restructured epidermis, and the presence of new collagen fibers, proliferative fibroblasts, structured elastin fibers and proliferative and differentiated hair follicle stems cells, all in the remodeled dermis. See Fig. 6.

[0086] In sum, the wrinkle filling compositions activate healing mechanisms from the inside for visibly younger skin from the outside.

[0087] Thus, a graphical representation is provided in Fig. 1-6 from the aged wrinkled uneven skin being affected by a variety of processes that leads to skin that is outwardly visibly less wrinkled and more even and therefore younger appearing, while internally several aspects of skin aging have been not only slowed, but even reversed.

[0088] Efficacy tests have been used to measure the effectiveness of the wrinkle filling compositions.

[0089] In the first efficacy test, a mature skin explant (54 years old) was taken and treated with a 1% composition of the wrinkle filling composition and compared to untreated skin. The observed effects included boost of cells defenses, mobilization of epidermal stem cells, epidermal regeneration and dermal remodeling. In a second efficacy test, 21 women of ages 44 to 60 years old participated who had mature skin presenting wrinkles and roughness. The treatment with a 1% composition of the wrinkle filling composition was compared to treatment with a placebo twice daily for 14 and 28 days. The results led to skin resurfacing action, including the removal of skin roughness, wrinkle filler effect, including the reduction of the number, surface area and length of wrinkles. The perceptible benefits were reported by self-evaluation.

[0090] In more detail concerning the Ex vivo efficacy:

[0091] 54 years-old skin explants were left untreated or topically treated with 1% of the wrinkle filling composition twice a day for 3 days.

[0092] Gene expression was studied after mRNA extraction and RT-qPCR analysis.

[0093] Protein expression was measured by immunostaining.

[0094] The results confirm that the wrinkle filling composition activates genes expression involved in 4 different biological pathways inspired from skin healing ability:

[0095] • Boost of cell defense

[0096] • Mobilization of epidermal stem cells

[0097] • Epidermal regeneration

[0098] • Dermal remodeling

[0099] Efficacy confirmed at protein level.

[0100] Regarding the boost of cell defenses, the wrinkle filling composition significantly regulates gene expression of SOD2 (+65%*). Thus, SOD2 is upregulated. (Gene expression studied after mRNA extraction and RT-qPCR analysis. Student's test: vs untreated explant, significant with * p<0.05.) Furthermore, the wrinkle filling composition led to the stimulation of skin defense from oxidative stress and the protection from cellular damages, and encourages the natural processes of skin and resurfacing. Regarding the mobilization of epidermal stem cells, the wrinkle filling composition significantly regulates gene expression of CD200 (+116%*), KRT15 (-73%**) and LRIG1 (-49%**). Thus, CD200 is upregulated while KRT15 and LRIG1 are downregulated. (Gene expression studied after mRNA extraction and RT- qPCR analysis. Student's test: vs untreated explant, significant with * 0.05<p<0.1, ** p<0.05).

[0101] Additionally, basal stem cells stimulation is up ('f CD200), hair follicle stem cells are observed to have differentiation of suprabasal cells in the bulge region ('f CD200 / 4 / KRT15) and proliferation of cells of the junctional zone (4 / LRIG1). The initiation of epidermis regeneration is achieved.

[0102] The mobilization of epidermal stem cells is observed when compared from untreated explant (left side of figure) to treatment with 1% wrinkle filling composition where the results are, of example, 19% stimulation of CD200 or 92% stimulation of CD200 (see Fig. 7). (Proteinexpression measuredby immunostainingin epidermis. E: epidermis, D: dermis. In blue: cellular nucleus, in red: K17. Student'stest: vs untreatedexplant, significantwith* p<0.001)

[0103] Regarding epidermal regeneration, the wrinkle filling composition significantly regulates gene expression of FGF2 (+74%**), IL1 (+274%**), IL6 (+188%**), KRT16 (+49%*), KRT17 (+264%**), MMP19 (+50%**) and MYO5B (+58%*). Thus, FGF2, IL1, IL6, KRT16, KRT17, MMP19 and MYO5B are all upregulated. (Gene expression studied after mRNA extraction and RT-qPCR analysis. Student's test: vs untreated explant, significant with * 0.05<p<0.1, ** p<0.05.) Additionally, keratinocytes show migration ('t FGF2, IL1, IL6, KRT16, KRT17, MMP19, MYO5B), the cell size / number balance ('T MYO5B), the proliferation (4sFGF2, IL1, MMP19), and reorganization of the epidermis in structured and dense layers is observed. Reinforced epidermis cohesion and thickness is achieved.

[0104] See Fig. 8 regarding epidermal regeneration showing K17 expression in the untreated explant (left side of figure) with treatment with 1% wrinkle filling composition where the results are, of example, 42% stimulation of K17 or 85% stimulation of K17. (Proteinexpression measuredby immunostainingin epidermis. E: epidermis, D: dermis. In blue: cellular nucleus, in red: K17. Student'stest: vs untreatedexplant, significantwith* p<0.001)

[0105] Regarding dermal remodeling, the wrinkle filling composition significantly regulates gene expression of IL6 (+188%**), ADAMST1 (+44%*), MMP19 (+50%**), MYO5B (+58%*), HAS2 (+163%*) and RELA (- 30%**). Thus, IL6, ADAMST1, MMP19, MYO5B, HAS2 are upregulated, while RELA is downregulated. (Gene expression studied after mRNA extraction and RT-qPCR analysis. Student's test: vs untreated explant, significant with * 0.05<p<0.1, ** p<0.05) Furthermore, fibroblasts: migration (4sIL6, ADAMST1, MMP19, MY05B), proliferation IL6), protection from apoptosis ('f HAS2); and stimulation of the production of extracellular matrix and collagen I was observed (4 / RELA) as well as support of epidermis structure. In sum, the restoration of dermis resistance and elasticity was observed.

[0106] Regarding dermal remodeling, the wrinkle filling composition stimulates HAS2 protein expression. See See Fig. 9 showing untreated explant (left side of figure) with treatment with 1% wrinkle filling composition where the results are, of example, 17% stimulation of HAS2 or 42% stimulation of HAS2. (Proteinexpression measuredby immunostainingin epidermis. E: epidermis, D: dermis. In blue: cellular nucleus, in red: HAS2. Student'stest: vs untreatedexplant, significantwith* 0.05<p<0.1)

[0107] The summary of skin healing properties for anti-aging efficacy of the wrinkle filling composition (identified as FILL oleoactif® in the figure) is provided in Fig. 10. This figure shows that the activities of the wrinkle filling composition lead to the restoring of younger skin defenses and architecture. (Gene expression studiedaftermRNAextraction and RT-qPCRanalysis. Student'stest: vs untreatedexplant, significantwith* 0.05<p<0.1, ** p<0.05)

[0108] A clinical study was conducted to demonstrate the efficacy of the wrinkle filling composition.

[0109] The study design is: Randomized; Versus placebo; Hemi-face; Mature skin presenting wrinkles and roughness; 21 Caucasian volunteers; Women; 44 to 60 years old; 1% wrinkle filling composition; Twice daily application; 14 days and 28 days.

[0110] The study evaluated the skin resurfacing action of the wrinkle filling composition. High-resolution digital photographs of hemiface were taken with VISIA® at Day 1 (baseline), Day 14 and Day 29. Analysis was done with VISIA® software to quantify the skin roughness.

[0111] The results indicated that the wrinkle filling composition significantly removes skin roughness from 14 days of application. The efficacy is confirmed after 28 days of use. Effectiveness: > 90% at Day 14, 100% at Day 29. See Fig. 11, where gray bar is placebo and purple bar showing -16% and -22% are the results of the wrinkle filling composition. (Student'st-test: vs DI (baseline), significant with * 0.05<p<0.1, ** pcO.Ol, *** p<0.0005. One-wayANOVA test: vs placebo, significant with # p<0.05)

[0112] The skin resurfacing action of the wrinkle filling composition on the cheek is visibly smoothed, i.e., skin roughness is removed after 14 days of application. See Fig. 12. (High-resolution digital photographs taken with VISIA® - 3D)

[0113] The results indicated that the wrinkle filling composition has a winkle filler effect. In this regard, Silicone resin impressions (SILFLO®) of crow's feet wrinkles are obtained at Day 1 and Day 29. Negative replica of skin wrinkles are studied by QUANTIRIDES® software (video image analysis system). After 28 days of use, the wrinkle filling composition significantly reduces the number, the surface and the length of crow's feet wrinkles. In sum, wrinkles are filled compared to placebo. See Fig. 13, where gray bar is placebo and purple bar showing -49%, -45 and -41% are the results of the wrinkle filling composition concerning wrinkles reduction. ( Wilcoxon test: vs DI (baseline), significant with * p<0.05, ** p<0.0001)

[0114] Further see Fig. 14, clearly showing the winkle filler effect of the 1% wrinkle filler composition visibly showing reduction of wrinkles. (Negative replica of crow's feet wrinkles obtained with Quantirides®software (video image analysis))

[0115] See also Fig. 15, clearly showing in another case the winkle filler effect of the 1% wrinkle filler composition visibly showing reduction of wrinkles. (Negative replica of crow's feet wrinkles obtained with Quantirides'-software (video image analysis))

[0116] Furthermore see Fig. 16, clearly showing the winkle filler effect of the 1% wrinkle filler composition visibly showing reduction of wrinkles. (High-resolution digital photographs taken with VISIA®)

[0117] Also see Fig. 17, clearly showing in another case the winkle filler effect of the 1% wrinkle filler composition visibly showing reduction of wrinkles. (High-resolution digital photographs taken with VISIA®) Also see Fig. 18, clearly showing in yet another case the winkle filler effect of the 1% wrinkle filler composition visibly showing reduction of wrinkles. (High-resolution digital photographs taken with VIS I A®)

[0118] The perceptible benefits of the use of the wrinkle filler composition are numerous, and include, a 100% reporting of a feeling of a pleasant effect during application. 95% of users appreciated the cream texture, and 100% like the cream color. Additionally noted is that 86% of users reported wanting to use the cream again, and 81% indicated that they would recommend the product to others.

[0119] The perceptible benefits are quantified in Fig. 19, concerning winkles filled in (crow's feet) and antiaging effect, where gray bar is placebo and purple bar showing +8% and +32% and also +17% and +22% are the results of the wrinkle filling composition. And Fig. 20 provides effectiveness results concerning tightening effect, skin softer to the touch, skin irregularities reduced, and expression lines less visible. (Benefits noted by the 21 panelists. (1) % of volunteers that agree after 4 weeks. (2) ScoringthroughlO- degree visualscale. One-wayANOVA test: vs DI (baseline), significant with * 0.05<p<0.1, ** p<0.005)

[0120] The demonstrated effects of the wrinkle filling composition include boost of cell defense, mobilization of epidermal stem cells, epidermal regeneration, dermal remodeling, skin resurfacing action and wrinkle filler effect, and method of use for each of these indications is included.

[0121] The wrinkle filling composition can be used, e.g., in day and night skin care compositions; for mature skin presenting wrinkles and roughness; for smoothing care; for anti-aging care; in mattifying products; in leave-on mask or serum or primer; or in make-up or anhydrous formulations.

[0122] Additionally, the wrinkle filling composition can be provided into various make-up compositions, powders, lotions, creams, lipsticks, eyeliners, or can be provided into self-care compositions, such as moisturizing lotions, face creams, UV protectant creams or sprays, hand or body creams, gels, spray on compositions, oils, various face masks, including applied onto a substrate first that is applied to the face or for direct application as a composition onto the face, masques, night creams and / or eye creams.

[0123] The wrinkle filling composition is preferably administered topically to areas of the skin in need of the various effects on the skin disclosed herein, e.g., to diminish or remove wrinkles and / or unevenness in the skin, e.g., due to aging. Administration is typically once or twice daily, but it can be more times, e.g., 3-4 times, or it can be less, e.g., once or twice every other day. Administration is preferably for a duration of at least one week, preferably two weeks, three weeks, 4 weeks, 5 weeks, 6 weeks, or even indefinitely.

[0124] In view of the demonstrated biological effects on the dermis and epidermis and also effects at the clinical level through studies on volunteers one can target administration to various levels of the skin by the use of appropriate vehicles, including penetrating agents. For example, one may target the epidermis in case that layer of the skin may be in need of reparation or protection by administering in a vehicle that keeps the wrinkle filling composition on the top layer of the skin. Alternatively, one can use a composition that favors the penetration of the composition further down into the skin into the dermis layer.

[0125] The amount of the wrinkle filling composition is preferably 0.1% to 10%, preferably 0.2% to 5 %, even more preferably 0.5 to 2%, highly preferably 0.75 to 1.5 %, including 1.0% and 1.25%, all by weight.

[0126] Mask leave-on

[0127] Phase IMiCl None PNH / USAN] (Other Information) Trade Name % Bstch <

[0128] Wt Serum Note that Myrtle-Olive Oleoactif® in the list is the wrinkle filling composition described herein.

[0129] This serum has a light touch, and the activating Serum enhances the authentic beauty and health of skin.

[0130] This formulation counters premature skin aging with strong energizing action, and erases the effect of time by smoothing, moisturizing, and minimizing wrinkles. The unique texture makes the daily use of this Activating Serum a comforting, calming reprieve for skin. Brief Description of the Drawings:

[0131] Fig. 1: shows some effects of aged wrinkled skin;

[0132] Fig. 2: shows that the wrinkle filling compositions combat wrinkles by a variety of effect, including boosting cell defenses, for example, by providing protection from oxidative stress;

[0133] Fig. 3: shows that the compositions achieve mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and the proliferation / differentiation of hair follicle stem cells;

[0134] Fig. 4: shows that the compositions additionally lead to epidermal regeneration, which affect migration / proliferation of keratinocytes;

[0135] Fig. 5: shows that the compositions affect dermal remodeling by the migration / proliferation of fibroblasts and the synthesis of ECM (collagen fibers);

[0136] Fig. 6: shows the filling of skin wrinkles as a result of the various effects the wrinkle filling compositions that result is visibly younger skin;

[0137] Fig. 7: shows that the mobilization of epidermal stem cells is observed when compared from untreated explant;

[0138] Fig. 8: shows epidermal regeneration showing K17 expression;

[0139] Fig. 9: shows stimulation of HAS2 protein expression;

[0140] Fig. 10: shows the summary of skin healing properties for anti-aging efficacy of the wrinkle filling composition;

[0141] Fig. 11: shows significantly removal of skin roughness;

[0142] Fig. 12: shows skin resurfacing action of the wrinkle filling composition;

[0143] Fig. 13: shows significant reduction of the number, the surface and the length of crow's feet wrinkles;

[0144] Fig. 14: shows visible reduction of wrinkles;

[0145] Fig. 15: shows reduction of wrinkles;

[0146] Fig. 16: shows reduction of wrinkles;

[0147] Fig. 17: shows reduction of wrinkles;

[0148] Fig. 18: shows reduction of wrinkles;

[0149] Fig. 19: shows winkles filled in (crow's feet) and anti-aging effect;

[0150] Fig. 20: shows effectiveness results concerning tightening effect, skin softer to the touch, skin irregularities reduced, and expression lines less visible; Fig. 21: shows results for ex vivo studies on excised skin samples tested with two extracts concerning the restoration of the hydrophilic barrier of the skin as measured by Trans Epidermal Water Loss (TEWL);

[0151] Fig. 22: shows chromatographic data; Fig. 23: shows chromatographic data.

[0152] Thus, in summary, in various aspects, the invention includes:

[0153] In a 1st aspect, a wrinkle filling composition

[0154] - which has been prepared by a process comprising extracting the wrinkle free composition with a vegetable oil, preferably olive oil, and advantageously in addition an emulsifying agent as co-extractant, characterized in that the co-extractant is an amphiphilic compound, chosen in particular from fatty acid esters preferably polyglyceryl-4 oleate, from a combination of myrtle leaves and olive leaves, wherein the process comprises the following steps: a) mixing and impregnating a powder of myrtle and olive leaves with the natural fatty substance, and preferably in the presence of a co-extractant, at a temperature above the melting point of said natural fatty substance and under an atmosphere devoid or essentially devoid of oxygen, b) heating the mixture thus obtained at a temperature between 60 and 150°C, under an atmosphere devoid or essentially devoid of oxygen, in particular using microwaves, c) the micro-dispersion of the powder of myrtle and olive leaves in the natural fatty substance at a temperature above the melting point of the fatty substance and in an atmosphere devoid or essentially devoid of oxygen, in particular using ultrasound, step c) possibly being carried out before, during or after step b); or

[0155] - which is characterized by the chromatograph depicted in Fig. 22, red line or Fig. 23

[0156] In a 2nd aspect, a cosmetic or self-care composition comprising 0.1 to 5.0 % by weight of the wrinkle free composition according to the 1st aspect and one or more cosmetically of self-care compositionally acceptable carriers.

[0157] In a 3rd aspect, a method for reducing the signs of aging skin, including wrinkles and / or uneven skin, comprising applying an effective amount of the wrinkle filling composition of the 1st aspect to the skin of a subject in need thereof in areas of the skin having wrinkles and / or uneven skin. In a 4th aspect, a method according to the 3rd aspect, wherein administration is for 14 days once or twice daily.

[0158] In a 5th aspect, a method according to the 3rd aspect, wherein the reduction of crow's feet wrinkles is achieved.

[0159] In a 6th aspect, a cosmetic or self-care composition according to the 2nd aspect, which is in the form of a mask or serum.

[0160] In a 7th aspect, a method for regulating genes in the skin, comprising applying an effective amount of the wrinkle filling composition of the 1st aspect to the skin of a subject in need thereof in areas of the skin having wrinkles and / or uneven skin, wherein the following genes are regulated as follows SOD2 is upregulated,

[0161] CD200 is upregulated and KRT15 and LRIG1 are downregulated,

[0162] FGF2, I LI, IL6, KRT16, KRT17, MMP19 and MYO5B are upregulated, and / or

[0163] IL6, ADAMST1, MMP19, MYO5B, HAS2 are upregulated, and RELA is downregulated.

[0164] In an 8th aspect, a method for boosting cell defenses of the skin, for example, by providing protection from oxidative stress, comprising administering to the skin of a subject an effective amount of a composition according to the 1st aspect.

[0165] In a 9th aspect, a method for mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and / or the proliferation and / or differentiation of hair follicle stem cells, comprising administering to the skin of a subject an effective amount of a composition according to the 1st aspect.

[0166] In a 10th aspect, a method for epidermal regeneration, which affect migration and / or proliferation of keratinocytes, comprising administering to the skin of a subject an effective amount of a composition according to the 1st aspect. In a 11th aspect, a method for dermal remodeling by the migration and / or proliferation of fibroblasts and / or the synthesis of ECM, for example, collagen fibers, comprising administering to the skin of a subject an effective amount of a composition according to the 1st aspect.

[0167] In a 12th aspect, a wrinkle filling composition according to the 1st aspect,

[0168] - which has been prepared by a process comprising extracting the wrinkle free composition with a vegetable oil, preferably olive oil, and advantageously in addition an emulsifying agent as co-extractant, characterized in that the co-extractant is an amphiphilic compound, chosen in particular from fatty acid esters preferably polyglyceryl-4 oleate, from a combination of myrtle leaves and olive leaves, wherein the process comprises the following steps: a) mixing and impregnating a powder of myrtle and olive leaves with the natural fatty substance, and preferably in the presence of a co-extractant, at a temperature above the melting point of said natural fatty substance and under an atmosphere devoid or essentially devoid of oxygen, b) heating the mixture thus obtained at a temperature between 60 and 150°C, under an atmosphere devoid or essentially devoid of oxygen, in particular using microwaves, c) the micro-dispersion of the powder of myrtle and olive leaves in the natural fatty substance at a temperature above the melting point of the fatty substance and in an atmosphere devoid or essentially devoid of oxygen, in particular using ultrasound, step c) possibly being carried out before, during or after step b).

[0169] In a 13th aspect, the wrinkle filling composition according to the 1st aspect, which is characterized by the chromatograph depicted in Fig. 22, red line or Fig. 23.

[0170] In a 14th aspect, the wrinkle filling composition of the 1st aspect for use in the reduction of the signs of aging skin, including wrinkles and / or uneven skin.

[0171] In a 15th aspect, the wrinkle filling composition of the 1st aspect for use in the reduction of crow's feet wrinkles.

[0172] In a 16th aspect, the wrinkle filling composition of the 1st aspect for use in the regulating genes in the skin, characterized in that the following genes are regulated as follows SOD2 is upregulated,

[0173] CD200 is upregulated and KRT15 and LRIG1 are downregulated, FGF2, IL1, IL6, KRT16, KRT17, MMP19 and MY05B are upregulated, and / or

[0174] IL6, ADAMST1, MMP19, MY05B, HAS2 are upregulated, and RELA is downregulated.

[0175] In a 17th aspect, the wrinkle filling composition of the 1st aspect for use in the boosting of cell defenses of the skin, for example, by providing protection from oxidative stress.

[0176] In a 18th aspect, the wrinkle filling composition of the 1st aspect for use in the mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and / or the proliferation and / or differentiation of hair follicle stem cells.

[0177] In a 19th aspect, the wrinkle filling composition of the 1st aspect for use in epidermal regeneration, which affect migration and / or proliferation of keratinocytes.

[0178] In a 20th aspect, the wrinkle filling composition of the 1st aspect for use in dermal remodeling by the migration and / or proliferation of fibroblasts and / or the synthesis of ECM, for example, collagen fibers.

Claims

Claims:

1. A wrinkle filling composition- which has been prepared by a process comprising extracting the wrinkle free composition with a vegetable oil, preferably olive oil, and advantageously in addition an emulsifying agent as co-extractant, characterized in that the co-extractant is an amphiphilic compound, chosen in particular from fatty acid esters preferably polyglyceryl-4 oleate, from a combination of myrtle leaves and olive leaves, wherein the process comprises the following steps: a) mixing and impregnating a powder of myrtle and olive leaves with the natural fatty substance, and preferably in the presence of a co-extractant, at a temperature above the melting point of said natural fatty substance and under an atmosphere devoid or essentially devoid of oxygen, b) heating the mixture thus obtained at a temperature between 60 and 150°C, under an atmosphere devoid or essentially devoid of oxygen, in particular using microwaves, c) the micro-dispersion of the powder of myrtle and olive leaves in the natural fatty substance at a temperature above the melting point of the fatty substance and in an atmosphere devoid or essentially devoid of oxygen, in particular using ultrasound, step c) possibly being carried out before, during or after step b); or- which is characterized by the chromatograph depicted in Fig. 23.

2. A cosmetic or self-care composition comprising 0.1 to 5.0 % by weight of the wrinkle free composition according to claim 1 and one or more cosmetically of self-care compositionally acceptable carriers.

3. A method for reducing the signs of aging skin, including wrinkles and / or uneven skin, comprising applying an effective amount of the wrinkle filling composition of claim 1 to the skin of a subject in need thereof in areas of the skin having wrinkles and / or uneven skin.

4. A method according to claim 3, wherein administration is for 14 days once or twice daily.

5. A method according to claim 3, wherein the reduction of crow's feet wrinkles is achieved.

6. A cosmetic or self-care composition according to claim 2, which is in the form of a mask or serum.

7. A method for regulating genes in the skin, comprising applying an effective amount of the wrinkle filling composition of claim 1 to the skin of a subject in need thereof in areas of the skin having wrinkles and / or uneven skin, wherein the following genes are regulated as followsSOD2 is upregulated,CD200 is upregulated and KRT15 and LRIG1 are downregulated,FGF2, I LI, IL6, KRT16, KRT17, MMP19 and MYO5B are upregulated, and / orIL6, ADAMST1, MMP19, MYO5B, HAS2 are upregulated, and RELA is downregulated.

8. A method for boosting cell defenses of the skin, for example, by providing protection from oxidative stress, comprising administering to the skin of a subject an effective amount of a composition according to claim 1.

9. A method for mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and / or the proliferation and / or differentiation of hair follicle stem cells, comprising administering to the skin of a subject an effective amount of a composition according to claim 1.

10. A method for epidermal regeneration, which affect migration and / or proliferation of keratinocytes, comprising administering to the skin of a subject an effective amount of a composition according to claim 1.

11. A method for dermal remodeling by the migration and / or proliferation of fibroblasts and / or the synthesis of ECM, for example, collagen fibers, comprising administering to the skin of a subject an effective amount of a composition according to claim 1.

12. A wrinkle filling composition according to claim 1,- which has been prepared by a process comprising extracting the wrinkle free composition with a vegetable oil, preferably olive oil, and advantageously in addition an emulsifying agent as co-extractant, characterized in that the co-extractant is an amphiphilic compound, chosen in particular from fatty acid esters preferably polyglyceryl-4 oleate, from a combination of myrtle leaves and olive leaves, whereinthe process comprises the following steps: a) mixing and impregnating a powder of myrtle and olive leaves with the natural fatty substance, and preferably in the presence of a co-extractant, at a temperature above the melting point of said natural fatty substance and under an atmosphere devoid or essentially devoid of oxygen, b) heating the mixture thus obtained at a temperature between 60 and 150°C, under an atmosphere devoid or essentially devoid of oxygen, in particular using microwaves, c) the micro-dispersion of the powder of myrtle and olive leaves in the natural fatty substance at a temperature above the melting point of the fatty substance and in an atmosphere devoid or essentially devoid of oxygen, in particular using ultrasound, step c) possibly being carried out before, during or after step b).

13. A wrinkle filling composition according to claim 1, which is characterized by the chromatograph depicted in Fig. 22, red line.

14. The wrinkle filling composition of claim 1 for use in the reduction of the signs of aging skin, including wrinkles and / or uneven skin.

15. The wrinkle filling composition of claim 1 for use in the reduction of crow's feet wrinkles.

16. The wrinkle filling composition of claim 1 for use in the regulating genes in the skin, characterized in that the following genes are regulated as followsSOD2 is upregulated,CD200 is upregulated and KRT15 and LRIG1 are downregulated, FGF2, I LI, IL6, KRT16, KRT17, MMP19 and MYO5B are upregulated, and / or IL6, ADAMST1, MMP19, MYO5B, HAS2 are upregulated, and RELA is downregulated.

17. The wrinkle filling composition of claim 1 for use in the boosting of cell defenses of the skin, for example, by providing protection from oxidative stress.

18. The wrinkle filling composition of claim 1 for use in the mobilization of epidermal stem cells, which positively affect the activation of basal stem cells and / or the proliferation and / or differentiation of hair follicle stem cells.

19. The wrinkle filling composition of claim 1 for use in epidermal regeneration, which affect migration and / or proliferation of keratinocytes.

20. The wrinkle filling composition of claim 1 for use in dermal remodeling by the migration and / or proliferation of fibroblasts and / or the synthesis of ECM, for example, collagen fibers.

Images