Nanoemulsions enabling improved bioavailability of active substances

Abstract

The present invention relates to a composition for topical application in the form of an oil-in-water or water-in-oil nanoemulsion comprising at least two distinct polyols, to its preparation process and to its use, particularly cosmetic and / or pharmaceutical.

Description

Title of the invention: NANOEMULSIONS ALLOWING IMPROVED BIOAVAILABILITY OF ACTIVE SUBSTANCES

[0001] The present invention relates to a composition comprising at least one active substance for topical application in the form of an oil-in-water or water-in-oil nanoemulsion comprising at least two distinct polyols, to its preparation process and to its use, in particular cosmetic and / or pharmaceutical.

[0002] Nanoemulsions are emulsions in which the droplets have a diameter of the order of a nanometer; they are of two types, oil-in-water (O / W) or water-in-oil (W / O). O / W emulsions consist of oil droplets dispersed in an aqueous medium, while W / O emulsions consist of small water droplets dispersed in an oily medium.

[0003] Thanks to the small size of their droplets, nanoemulsions have many advantageous properties: better apparent transparency, better bioavailability, good stability and high chemical reactivity.

[0004] Various nanoemulsions have already been described for dermatological or cosmetic applications, for example, WO2015 / 213631 describes a stable H / W nanoemulsion for the formulation of pharmaceutical or nutritional cosmetic active agents comprising an oily phase, an ionizable surfactant, a cosurfactant and water; US2012 / 0093882 proposes a pharmaceutical composition comprising a nanoemulsion composed in particular of soybean oil, water, Polysorbate 80 and glycerol; FR3061010 may also be cited which describes an H / W nanoemulsion comprising an oil, a surfactant, and optionally an adjuvant having emollient or moisturizing properties, this nanoemulsion finds applications for the treatment, care, makeup and / or cleansing of the skin and / or mucous membranes.

[0005] It remains, however, useful to propose nanoemulsions having improved properties, in particular, in terms of bioavailability and kinetics of release of active agents.

[0006] This is what the Applicant achieved by combining at least two particular polyols within a nanoemulsion.

[0007] The present invention thus relates to an oil-in-water or water-in-oil type nanoemulsion comprising:

[0008] - an aqueous phase;

[0009] - an oily phase;

[0010] - at least one surfactant; and

[0011] - at least two polyols distinct from one another, chosen from:

[0012] . diols and triols chosen from propanediol, glycerol, ethylhexylglycerin, propylene glycol, diethylene glycol and their derivatives;

[0013] . polysaccharides:

[0014] the polysaccharides are, preferably, mucopolysaccharides and glycosaminoglycans chosen from hyaluronic acid, heparin sulfate (HSGAGs), chondroitin sulfate, keratan sulfate, dermatan sulfate and their derivatives and polyglucosides chosen from alginic acid, alginates and esters of alginic acid, mannuronic acid, mucilages, glucans (starch, amylose, amylodextrin), galactans (agar-agar, carrageenans) and their derivatives;

[0015] preferably, the polysaccharides are chosen from rinulin, alginic acid, alginates and esters of alginic acid, mannuronic acid, glucans (starch, amilose, amilodextrin), galactans (agar-agar, carrageenans), mucilages, mucopolysaccharides or glycosaminoglycans chosen from hyaluronic acid, heparin sulfate (HSGAGs), chondroitin sulfate, keratan sulfate, dermatan sulfate and their derivatives;

[0016] still preferentially, the polysaccharides are oligosaccharides which are oligosides formed from less than 10 monosaccharide units linked by glycosidic bond; the oligosaccharides are preferably homopolysaccharides composed of a single type of sugar chosen from glucooligosaccharides, xylo-oligosaccharides, fructo-oligosaccharides, maltose, lactose, cyclo-dextrins, and their derivatives; most preferentially, the oligosaccharides are glucooligosaccharides;

[0017] . silanols:

[0018] Silanols are the homologues of organic alcohols in which the carbon atom carrying the alcohol function is replaced by a silicon atom.

[0019] The silanols are chosen from methylsilanetriol, dimethylsilanediol and their derivatives which can be partially condensed; preferably, the silanol is methylsilanetriol.

[0020] According to a particular embodiment, the polyols are chosen from diols and triols and from silanols.

[0021] According to another particular embodiment, the polyols are chosen from diols and triols and from oligosaccharides.

[0022] By aqueous phase is meant a phase consisting mainly of water purified by a purification technique such as reverse osmosis for example and which may contain other hydrophilic substances solubilized in water in quantities lower than those of water.

[0023] These hydrophilic substances can be active ingredients, surfactants, antioxidants, preservatives, or any other substance having a interest in improving the stability of the nanoemulsion or improving the stability and bioavailability of vectorized active ingredients.

[0024] By oily phase is meant a phase consisting mainly of mineral or synthetic oil, unmodified vegetable oil or modified vegetable oil or a combination of these different oils.

[0025] This oily phase may contain other solubilized lipophilic substances in quantities lower than that of the oil used.

[0026] These lipophilic substances may be active ingredients, surfactants, antioxidants, preservatives, or any other substance of interest for improving the stability of the nanoemulsion or improving the bioavailability of the vectorized active ingredients.

[0027] The surfactant, in particular non-ionic, anionic, cationic and / or zwitterionic, may be chosen from:

[0028] - sphingophospholipids such as sphingosine, ceramides, sphin- gomyelin, cerebrosides;

[0029] - glycerophospholipids such as natural lecithins from eggs, soy, wheat, sunflower, hydrogenated or non-hydrogenated lecithins;

[0030] - non-ionic polyoxyethylene systems such as polysorbates containing from 20 to 80 oxyethylene units and their derivatives; in particular polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (20) sorbitan monooleate and their derivatives;

[0031] - glycerol and polyglycerol esters containing from 2 to 20 glycerol units are- terified by one or more fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ricinoleic acid to form glyceryl esters, as well as their corresponding polyglyceryl esters;

[0032] - anionic surfactants such as lauryl sulfates, lauryl ether sulfates, do- decyl sulfates and their derivatives;

[0033] - cationic surfactants such as alkyltrimethyl ammonium salts, salts alkylbenzyldimethyl ammonium and their derivatives;

[0034] - zwitterionic surfactants such as cocamidopropyl betaines and their derivatives;

[0035] - any other structure having surfactant properties such as solvents protic agents of the diethylene glycol type and its derivatives which would be used for the purpose of improving the penetration of active substances carried by nanoemulsions in combination with the two substances of the polyol family.

[0036] Preferably, for Oil in Water nanoemulsions, the preferred surfactants are:

[0037] - glycerophospholipids such as phosphatidyl choline or soy lecithin (in hydrogenated or non-hydrogenated form);

[0038] Preferably, for Water in Oil nanoemulsions, the preferred surfactants are:

[0039] - Polyglyceryl-10 stearate and

[0040] - Polyglyceryl-4 Olivate / Polyricinoleate.

[0041] The nanoemulsion according to the invention may contain other optional ingredients such as: - stabilizing agents such as calcium sulfate or magnesium sulfate, - pH adjusters such as citric acid, sodium or potassium hydroxide, triethanolamine, tromethamine, di-potassium hydrogen phosphate, potassium di-hydrogen phosphate,... - preservatives such as ethylhexylglycerin, phenethyl alcohol, benzyl alcohol, dehydroacetic acid, gluconolactone, sodium benzoate, potassium sorbate, caprylyl glycol, chlorhexidine digluconate, chlorphenesin, benzalkonium chloride, etc.

[0042] These ingredients can also be skin pH modifiers, ionic strength modifiers or surfactants or solvents. The substances with the best penetration are amphiphilic, that is to say both lipophilic and hydrophilic.

[0043] According to a particular embodiment, one of the at least two polyols is a diol or a triol chosen from propanediol, glycerol, propylene glycol, diethylene glycol, and their derivatives; preferably, it is glycerol.

[0044] According to this embodiment, the mass concentration ratio between the glycerol and the surfactant is preferably less than 5, and preferably less than 2.

[0045] Still according to this embodiment, the other of the at least two polyols is preferably chosen from:

[0046] - a silanol chosen from dimethylsilanediol, methylsilanetriol and their derivatives, preferably methylsilanetriol; when the polyols are glycerol and methylsilanetriol, the mass concentration ratio between glycerol and methylsilanetriol is preferably less than 200, and preferably less than 50;

[0047] - a polysaccharide chosen from glucans (starch, amilose amilodextrin), galactans (agar-agar, carrageenans), rinulin, hyaluronic acid, cyclodextrins, oligosaccharides chosen from glucooligosaccharide, xylooligosaccharide, fructooligosaccharide, and their derivatives; preferably, the polysaccharide is an oligosaccharide chosen from glucooligosaccharides, xylooligosaccharides, fructooligosaccharides, maltose, lactose, cyclodextrins and their derivatives; more preferably, it is a glucooligosaccharide.

[0048] When the polyols are glycerol and a glucooligosaccharide, the ratio of mass concentration between glycerol and glucooligosaccharide is preferably less than 10, and preferably less than 5.

[0049] When the polyol combination consists of glycerol and methylsilanetriol, the preferred surfactants are hydrogenated or non-hydrogenated soy lecithins.

[0050] When the polyol combination consists of glycerol and a glucooligosaccharide, the preferred surfactants are hydrogenated or non-hydrogenated soy lecithins for oil / water nanoemulsions and polyglyceryl-10 stearate for water / oil nanoemulsions.

[0051] The nanoemulsions according to the invention are characterized by a droplet size of less than 300 nm, preferably between 50 and 250 nm and most preferably of the order of 100 nm.

[0052] The size measurement is performed by the dynamic light scattering correlation method commonly referred to as DLS (Dynamic Light Scattering): the nanodroplets move randomly (Brownian motion) in the liquid medium with a speed that depends on the viscosity of the solvent. When the nanostructures pass through the LASER beam, the LASER photons are scattered in all directions. The photons scattered at a 90° angle are recovered in a photosensitive cell placed at a 90° angle. The intensity of each photon varies with the size of the nanostructures encountered. Photons of the same intensity are correlated and indicate the size of the nanostructure encountered. This can be measured by Malvern brand laser light scattering equipment.

[0053] The distribution of the droplets is such that the polydispersity index is less than 0.3 and preferably between 0.01 and 0.15.

[0054] The average size and size distribution are the two key parameters that determine the properties of nanoemulsions. The polydispersity index (PDI) reflects the measure of the extent of the size distribution. It takes into account the standard deviations from the average size.

[0055] In the context of the administration of active ingredients, phospholipid-based nanoemulsions (oil / water) with a polydispersity index (PDI) of less than 0.3 are considered acceptable and indicate a homogeneous population of phospholipid vesicles.

[0056] The PDI is calculated by the ratio of the intensity of the LASER photons from the median population to the intensity of all the other populations (see standard ISO 22412:2008).

[0057] The nanoemulsions according to the invention are liquid, in particular, they are not nanoparticles characterized in that they are solid, non-resorbable, persistent in the body, and non-bio-assimilable.

[0058] The present invention also relates to a cosmetic, pharmaceutical composition eutical or nutritional comprising the nanoemulsion according to the invention and at least one active substance.

[0059] By active substance is meant a cosmetic, pharmaceutical or nutraceutical active substance.

[0060] For example, substances regulating skin dysfunctions such as psoriasis, eczema, atopy, hyperseborrhea, acne, hyperpigmentation, hypopigmentation, hyperkeratosis, dryness, roughness, premature aging linked to inflammatory conditions and free radicals, protein glycosylation, protection against UV stress, chemical stress, pollution or other forms of stress.

[0061] Mention may also be made of cosmetic or pharmaceutical substances such as vitamins, hormones, enzymes, vasodilators or vasoconstrictors, anti-inflammatories, antiseptics, cholagogues, diuretics, anti-allergics, neuroleptics or any other active substance capable of being incorporated into the preparation of a nanoemulsion.

[0062] Without this list being limiting, the compositions according to the invention may comprise active substances such as, for example, vitamins A, B1, B2, B3, B5, B6, C, D3, E, K, PP, estrogen, androstane, escin, choline, salicylic acid, acetylsalicylic acid, glafenine, esculoside, dextro-propoxyphene (HÇ1), Piperazine, Diazepam, Oxazepam, Prometazine, Diclofenac, Ciclopirox olamine, Clotrimazole, Aciclovir, essential oils, perfume components, etc.

[0063] According to a particular embodiment, it is a cosmetic or pharmaceutical composition, such as a dermatological composition, intended to be administered topically.

[0064] The main advantage of these nanoemulsions according to the invention lies in the fact that the vectorization of active substances in the form of liquid nanoemulsions makes it possible to improve the bioavailability of these active substances.

[0065] Very advantageously, it has been observed that the vectorization of the active substance allows distribution in the dermal connective tissue without reaching the blood circulation. This unexpected feature is extremely important for the vectorization of active ingredients for which systemic exposure must be controlled or avoided, for example in the cosmetic context.

[0066] The improvement in bioavailability is particularly interesting when these active substances are hydrophobic and have great difficulty crossing the epidermal barrier.

[0067] Thus, according to a particular embodiment, the present invention relates to a composition comprising an oil-in-water type nanoemulsion comprising:

[0068] - an aqueous phase;

[0069] - an oily phase dispersed in the aqueous phase;

[0070] - one or more hydrophobic active substances;

[0071] - at least one surfactant; and

[0072] - at least two polyols distinct from each other, chosen from:

[0073] . diols and triols chosen from propanediol, glycerol, ethylhexylglycerin, propylene glycol, diethylene glycol, and their derivatives;

[0074] . silanols chosen from dimethylsilanediol, methylsilanetriol and their derivatives;

[0075] . polysaccharides chosen from inulin, alginic acid, alginates and esters alginic acid, mannuronic acid, glucans (starch, amilose, amilo-dextrin), galactans (agar-agar, carrageenans), mucilages, mucopolysac-charides or glycosaminoglycans chosen from hyaluronic acid, heparin sulfate (HSGAGs), chondroitin sulfate, keratan sulfate, dermatan sulfate and their derivatives; oligosaccharides chosen from glucooligosaccharide, xylo-oligosaccharide, fructo-oligosaccharide, maltose, lactose, cyclo-dextrins, and their derivatives; preferably, the polysaccharide is an oligosaccharide and preferably, the oligosaccharide is glucooligosaccharide.

[0076] According to another object, the present invention relates to the process for preparing the nanoemulsion according to the invention which comprises two stages:

[0077] 1. the preparation of an emulsion: the aqueous phase and the oily phase are heated separately to a temperature of 75°C and then mixed under vigorous stirring. This emulsion is then cooled. The droplet size is generally between 10 pm and 300 pm.

[0078] 2. strong shear treatment by microfluidic, ultrasound or technology equivalent.

[0079] This step consists of transmitting to the base emulsion a sufficient quantity of energy to obtain the division of the droplets until a droplet size of the order of 100 nm is reached.

[0080] To provide this energy, microfluidic technology is preferably used with a system generating very high pressures of up to 2000 bars. The base emulsion circulates at very high speed in microchannels which generate friction, shear and cavitation forces allowing the division of the droplets into nanodroplets.

[0081] According to yet another object, the present invention relates to the use of a nanoemulsion as described above to improve the bioavailability of an active substance. Figures

[0082] [Fig.l] Particle size distribution spectrum of nanoemulsion 1 of example 1.

[0083] [Fig.2] Particle size distribution spectrum of nanoemulsion 2 of example 1.

[0084] [Fig.3] particle size distribution spectrum of nanoemulsion 3 of example 1.

[0085] [Fig.4] results of the Sebumetry test using Sebufix® Patches after 24 hours (part 2.1 of example 2).

[0086] [Fig.5] graph of the variation of the sebum occupancy rate at T24h (part 2.1 of example 2).

[0087] [Fig.6] histogram illustrating the theoretical and measured evolution of the occupancy rate of the sebum of formula 6 by transposing the effect measured with the formula 2 cream onto that measured for the formula 3 cream.

[0088] [Fig.7] results of the Sebumetry test using Sebufix® Patches after 24 hours (part 2.2 of example 2).

[0089] [Fig.8] graph of the variation of the sebum occupancy rate at T24h (part 2.2 of example 2).

[0090] [Fig.9] histogram illustrating the theoretical and measured evolution of the occupancy rate of the sebum of formula 5a by transposing the effect measured with the formula 2a cream onto that measured for the formula 3a cream. EXAMPLES

[0091] Example 1 - preparation and characterization of nanoemulsions according to the invention 1.1. Nanoemulsion 1

[0092] Nanoemulsion composed of POLYGLYCERYL-10 STEARATE, GLYCEROL and METHYLSILANETRIOL

[0093] The formula of nanoemulsion 1, expressed in INCI nomenclature, is as follows:

[0094] [Tables 1] NANOEMULSION 1 CENTESIMAL COMPOSITION in INCI NOMENCLATURE % GLYCERIN 35.00000 % AQUA 34.22650 % CAPRYLIC / CAPRIC TRIGLYCERIDE 25.00000 % POLYGLYCERYL-10 STEARATE 5.00000 % SILANETRIOL 0.34579 % ALCOHOL 0.1988% ACETIC ACID 0.1200% POTASSIUM HYDROXIDE 0.1089% TOTAL: 100.000%

[0095] TABLE 1 - Composition of nanoemulsion 1

[0096] The preparation process of this nanoemulsion is as follows:

[0097] Aqueous phase: - The methylsilanetriol solution is prepared in advance in the form of a complex containing the following elements: aqua, methylsilanetriol, potassium hydroxide, alcohol. - In the aqueous phase, the following elements are successively added while stirring: purified water, glycerin then the complex (methylsilanetriol, potassium hydroxide, alcohol).

[0098] Citric acid is added as a solution of 40% citric acid and 60% purified water.

[0099] This aqueous phase is heated to 75°C.

[0100] Oily phase: - In a separate container, pour the caprylic / capric triglyceride and heat it to a temperature of 75°C - Then add the polyglyceryl-10 stearate and maintain at 75°C until the oil phase is homogeneous.

[0101] The two phases are emulsified by slowly pouring the oily phase into the aqueous phase while maintaining the temperature at 75°C with vigorous stirring.

[0102] This emulsion is then slowly cooled with stirring to room temperature.

[0103] Citric acid is added as a solution of 40% citric acid and 60% purified water.

[0104] The emulsion obtained is then treated by very high pressure equipment at 2000 bars to obtain the nanoemulsion.

[0105] Characterization: This nanoemulsion has an average size of 162 nm with a polydispersity index of 0.139 ([Fig. 1]).

[0106] The protocol for verifying the stability of the nanoemulsion consists of making comparative organoleptic readings (visual appearance, color, odor) and comparative physicochemical measurements (pH, viscosity, centrifugation, size measurement).

[0107] These measurements are carried out from T0 then after 15 days at room temperature, then monthly after 1 month at 50°C, 6 months at 40°C, 6 months at room temperature.

[0108] The results obtained show that this nanoemulsion is perfectly stable over time. 1.2. Nanoemulsion 2

[0109] Nanoemulsion composed of GLYCEROPHOSPHOLIPID, GLYCEROL and METHYLSILANETRIOL.

[0110] The formula of nanoemulsion 2, expressed in INCI nomenclature, is as follows: [YES] [Tables2] NANOEMULSION 2 CENTESIMAL COMPOSITION in INCI NOMENCLATURE % AQUA 38.11984 % GLYCERIN 35.00000 % VITIS VINIFERA SEED OIL 17.50000 % CANNABIDIOL 5.00000 % HYDROGENATED LECITHIN 4.00000 % TOCOPHEROL 0.2000% SILANETRIOL 0.0657% CITRIC ACID 0.0560% ALCOHOL 0.0378% POTASSIUM HYDROXIDE 0.0207% TOTAL: 100.000%

[0112] TABLE 2 - Composition of nanoemulsion 2

[0113] The preparation process of this nanoemulsion is as follows:

[0114] Aqueous phase: - The methylsilanetriol solution is prepared in advance in the form of a complex containing the following elements: water, methylsilanetriol, potassium hydroxide, alcohol. - In the aqueous phase, the following elements are successively added while stirring: aqua, glycerin, the complex (methylsilanetriol, potassium hydroxide, alcohol) then citric acid in the form of a solution of 40% citric acid and 60% purified water.

[0115] This aqueous phase is heated to 75°C.

[0116] Oily phase:

[0117] It is necessary to place grape seed oil in the container first and heat to 75°C.

[0118] The following elements are then added successively: cannabidiol, hydrogenated lecithin, tocopherol.

[0119] The two phases are emulsified by slowly pouring the oily phase into the aqueous phase while maintaining the temperature at 75°C with vigorous stirring.

[0120] This emulsion is then slowly cooled with stirring to temperature ambient.

[0121] The emulsion obtained is then treated by very high pressure equipment at 2000 bars to obtain the nanoemulsion.

[0122] Characterization: This nanoemulsion has an average size of 123 nm with a polydispersity index of 0.11 ([Fig.2]). It is perfectly stable over time.

[0123] The protocol for verifying the stability of the nanoemulsion consists of making comparative organoleptic readings (visual appearance, color, odor) and comparative physicochemical measurements (pH, viscosity, centrifugation, size measurement).

[0124] These measurements are carried out from T0 then after 15 days at room temperature, then monthly after 1 month at 50°C, 6 months at 40°C, 6 months at room temperature. 1.3. Nanoemulsion 3

[0125] Nanoemulsion composed of GLYCEROPHOSPHOLIPID, GLYCEROL and GLUCOOLIGOSACCHARIDE

[0126] The formula of nanoemulsion 3, expressed in INCI nomenclature, is as follows:

[0127] [Tables3] NANOEMULSION 3 CENTESIMAL COMPOSITION in INCI NOMENCLATURE % GLYCERIN 35.00000 % AQUA 23.29200 % CAPRYLIC / CAPRIC TRIGLYCERIDE 17.50000 % ALPHA-GLUCAN OLIGOSACCHARIDE 15.00000 % CANNABIDIOL 5.00000 % HYDROGENATED LECITHIN 4.0000% TOCOPHEROL 0.2000% CITRIC ACID 0.0080% TOTAL: 100.000%

[0128] TABLE 3 - Composition of nanoemulsion 3

[0129] The preparation process of this nanoemulsion is as follows:

[0130] Aqueous phase:

[0131] The following elements are successively added to the aqueous phase with stirring: purified water, glycerin, glucooligosaccharide. This aqueous phase is heated to 75°C.

[0132] Oily phase:

[0133] It is necessary to place grape seed oil in the container of the oily phase as a priority and to heat to 75°C.

[0134] The following elements are then added successively: cannabidiol, hydrogenated lecithin, tocopherol.

[0135] The two phases are emulsified by slowly pouring the oily phase into the aqueous phase while maintaining the temperature at 75°C with vigorous stirring.

[0136] This emulsion is then slowly cooled with stirring to room temperature.

[0137] Citric acid is added as a solution of 40% citric acid and 60% purified water.

[0138] The emulsion obtained is then treated by very high pressure equipment at 2000 bars to obtain the nanoemulsion.

[0139] Characterization: This nanoemulsion has an average size of 73 nm with a polydispersity index of 0.07 ([Fig.3]).

[0140] It is perfectly stable over time.

[0141] The protocol for verifying the stability of the nanoemulsion consists of making comparative organoleptic readings (visual appearance, color, odor) and comparative physicochemical measurements (pH, viscosity, centrifugation, size measurement).

[0142] These measurements are carried out from T0 then after 15 days at room temperature, then monthly after 1 month at 50°C, 6 months at 40°C, 6 months at room temperature.

[0143] Example 2 - Comparative in vivo studies of the efficacy of the biological activity of CBD in different cream formulations

[0144] The efficacy of various formulations of a dermocosmetic cream containing Cannabidiol (CBD) in the form of a conventional emulsion and in the form of a nanoemulsion was evaluated. These formulations are prepared with different pairs of polyols.

[0145] The effectiveness of the formulations was studied in the context of a treatment against hyper seborrhea in acne-prone skin. The main objective of this study is to determine the effect of CBD in different formulations on the sebum level as well as the distribution of skin areas (spots) containing sebum.

[0146] 2.L Association of glycerol and methylsilanetriol

[0147] The composition of the formula body and the CBD concentration are identical for all the different formulations. The form of the CBD (emulsion or nanoemulsion) and the concentration of polyols are the only variables. Only the concentrations of Methylsilanetriol are different.

[0148] [Tables4] EMULSION NANOEMULSIONS Crème Formule 1 Crème Form ule 2 Crème Form ule 3 Crème Form ule 4 Crème Form ule 5 Crème Formu le 6 AQUA 67,35 % 66,68 % 67,38 % 67,21 % 66,98 % 66,67 % COCO-CAPRYLATE / CAPRATE 12,00 % 12,00 % 12,00 % 12,00 % 12,00 % 12,00 % GLYCERIN 7,50 % 7,50 % 7,50 % 7,50 % 7,50 % 7,50 % CETEARYL ALCOHOL / CETEARYL GLUCOSIDES 6,00 % 6,00 % 6,00 % 6,00 % 6,00 % 6,00 % TAPIOCA STARCH / POLYME-THTYLSILSESQUIOXANE 2,00 % 2,00 % 2,00 % 2,00 % 2,00 % 2,00 % VISTIS VINIFERA SEED OIL 1,75 % 1,75 % 1,75 % 1,75 % 1,75 % 1,75 % ETYLHEXYLGLYCERIN 1,20 % 1,20 % 1,20 % 1,20 % 1,20 % 1,20 % TOCOPHERYL ACETATE 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % CANNABIDIOL 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % SODIUM BENZOATE 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % HYDROGENATED LECITHIN 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % SCLEROTIUM GUM 0,30 % 0,30 % 0,30 % 0,30 % 0,30 % 0,30 % CITRIC ACID (40% Aqueous soin.Approximation to final pH5.5) 0.08% 0.25% 0.05% 0.12% 0.15% 0.26% TOCOPHEROL 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%. SILANETRIOL, POTASSUM HYDROXIDE, AQUA - 0.50% - 0.10% 0.30% 0.50% 100.00% 100.00% 100.00% 100.00% 100.00% 100.00%

[0149] TABLE 4 - Glycerol + Methylsilanetriol Association: Composition of the creams used for the sebumetry test

[0150] The final compositions of surfactant, CBD, glycerol and methylsilanetriol in the finished products are as follows:

[0151] [Tables5] Nanoemulsion No. Formula Emulsion or nanoemuls ion PHOSPHO LIPID CBD GLYCE ROL METHYLSILA NETRIOL Cream Formula 1 Emulsion 4.00% 0.50% 7.50% 0% Cream Formula 2 Emulsion 4.00% 0.50% 7.50% 0.173% Cream Formula 3 Nanoemuls ion 4.00% 0.50% 7.50% 0% Cream Formula 4 Nanoemuls ion 4.00% 0.50% 7.50% 0.035% Cream Formula 5 Nanoemuls ion 4.00% 0.50% 7.50% 0.104% Cream Formula 6 Nanoemuls ion 4.00% 0.50% 7.50% 0.173%

[0152] Table 5 - Association Surfactant + Glycerol + Methylsilanetriol: Composition of Creams

[0153] The mass concentration ratios of the constituents of the different nanoemulsions are as follows:

[0154] [Tableauxô] No. Formula Emulsion or nanoemulsion Glycerol / Surfactant concentration ratio Surfactant concentration ratio Methylsilanetri 01 Glycerol / Methylsilanetriol concentration ratio Formula 1 Emulsion 1.88 Formula 2 Emulsion 1.88 23.12 43.35 Formula 3 Nanoemulsion 1.88 Formula 4 Nanoemulsion 1.88 114.29 214.29 Formula 5 Nanoemulsion 1.88 38.46 72.12 Formula 6 Nanoemulsion 1.88 23.12 43.35

[0155] Table 6 - Association Surfactant + Glycerol + Methylsilanetriol: Concentration ratios in nanoemulsions Conditions of the study

[0156] The study was conducted on 8 volunteer individuals: 4 men and 4 women without makeup and with combination to oily skin type.

[0157] Application conditions: 2 mg / cm2.

[0158] Application areas: Forehead and chin. These areas are marked using a tracing on anatomical landmarks and identified using cutting so that measurements are taken on the same area at each time.

[0159] Sebum level measurement: T0, T30min T6h and T24h.

[0160] The software analyzes the image and determines the characteristics of the spots obtained (number, surface). The data obtained (the number of spots / cm2 and the total surface area of ​​the spots (mm2)) determine a sebum occupancy rate as a percentage of the surface analyzed (75 mm2 area).

[0161] The normalized variation of the sebum occupancy rate (TOS) corresponds to the difference between the normalized average sebum occupancy rate before application (T0) and the normalized average sebum occupancy rate 24 hours after application (T24h), this difference being divided by the initial occupancy rate (T0).

[0162] The normalized variation of the sebum occupancy rate, expressed as a percentage, is as follows:

[0163] Normalized variation of TOS (%) = (TOS T24h - TOS To) / TOS Tox 100

[0164] Results of the sebumetry test using Sébufix® Patches Cream No. Formula Emulsion or Nanoemulsion Concentration Methylsilane etriol (%) Variation of exposure time VARIATION Number of spots VARIATION Total spot area [mm2] Number of spots / c m2 VARIATION NORMA LISEE Emulsion occupancy rate [10%] T0 / T30mi n -11 - 5 mm2 -11 - 5.30 % T0 / T6h + 262 + 486 mm2 + 262 + 486.10 % T0 / T24h + 206 + 517 mm2 + 204 + 513.00 % Emusion 30 % T0 / T20 107 n + 5 + 68 mm2 + 5 + 67.85 % T0 / T6h -10 + 61 mm2 -10 + 61.34 % T0 / T24h + 59 + 81 mm2 + 59 + 80.66 % 3 Nanoemulsions ion 0% T0 / T0 / 30 + 365 + +7 185 + 735.54 % T0 / T6h + 97 + 208 mm2 + 97 + 208.19 % T0 / T24h + 22 + 135 mm2 + 22 + 135.00 % 4 Nanoemulsion ion 0.035 % T0 + T0 + 161 mm + 161 mm 61 + 166.72 % T0 / T6h + 79 + 183 mm2 + 79 + 183.40 % T0 / T24h + 92 + 84 mm2 + 92 + 83.77 % 5 Ion nanoemuls 0.104% T0 / T30mi n + 153 + 464 mm2 + 153 + 464.49% T0 / T6h + 40 + 55 mm2 + 40 + 55.10% T0 / T24h -2 -1 mm2 -2 -1.29% 6 Ion nanoemuls 0.173% T0 / T30mi n + 17 + 107 mm2 + 17 + 107.30% T0 / T6h -36 -41 mm2 -36 - 40.80% T0 / T24h -62 -36 mm2 -62 - 36.20%

[0166] Table 7 - Formulations at 0.50% CBD and Associations of Glycerol (7.50%) and Methylsilanetriol: Variation in the sebum occupancy rate at T30mn, T6h, T24h

[0167] Under the experimental conditions of the Sébufix® test, 24 hours after the application of the 6 formulas studied, the results obtained are as follows: Formula 1 Cream (CBD emulsion + Glycerol):

[0168] 24 hours after application, formula 1 causes an increase in the rate sebum occupancy of +513%; which is a very poor result. The objective of regulating sebaceous flow is not achieved.

[0169] Formula 2 Cream (CBD emulsion + Glycerol + 0.173% Methylsilanetriol):

[0170] 24 hours after application, formula 2 also causes an increase in sebum rate of +80%. The objective of reducing sebaceous flow is not achieved. But this increase is lower than that obtained with formula 1.

[0171] Even if the objective of regulating sebaceous flow is not achieved, the glycerol + methylsilanetriol combination provides a significant improvement linked to the incorporation of methylsilanetriol.

[0172] Formula 2 provides a reduction in sebum occupancy rate of 84% compared to formula 1. Formula 3 Cream (CBD Nanoemulsion + Glycerol):

[0173] 24 hours after application, formula 3 containing nanoemulsified CBD provides a variation in sebum occupancy rate of +135%.

[0174] The objective of reducing sebaceous flow has still not been achieved, but this variation nevertheless demonstrates the interest of the nanoemulsion form since it reduces the occupancy rate by 26% compared to formula 1 containing CBD in emulsion form, which confirms the interest of the nanoemulsion.

[0175] Formula 4 Cream (CBD Nanoemulsion + Glycerol + 0.035% Methylsilanetriol):

[0176] 24 hours after application of Formula 4, containing 0.035% methylsilanetriol silanol provides a variation in the occupancy rate of +83.77%.

[0177] This variation demonstrates the benefit of adding methylsilanetriol to the formulation even if the objective of reducing sebaceous flow is not achieved. Thanks to the presence of methylsilanetriol, the reduction in the sebum occupancy rate is 62% compared to Formula 3.

[0178] Formula 5 Cream (CBD Nanoemulsion + Glycerol + 0.104% Methylsilanetriol):

[0179] 24 hours after application of Formula 5 allows to obtain an occupancy rate sebum by -1.29%. This negative variation confirms the interest of methylsilanetriol.

[0180] Although this negative variation is quite small, it is nevertheless very significant compared to the variation in formula 4 and suggests that the objective of reducing sebaceous flow could be achieved by increasing the concentration of methylsilanetriol.

[0181] Formula 6 Cream (CBD Nanoemulsion + Glycerol + 0.173% Methylsilanetriol):

[0182] 24 hours after application of Formula 6 allows to obtain a very strong di reduction of the variation of the sebum occupancy rate by -36%.

[0183] Thanks to the concentration of 0.173% of methylsilanetriol, the reduction in the sebum occupancy rate is 2790% compared to Formula 5. The objective of reducing sebaceous flow is achieved.

[0184] Conclusion of study 2.1 relating to the glycerol + methylsilanetriol association:

[0185] [Fig.4] illustrates the graphical representation of the results of the Sebumetry test at using Sebufix® Patches after 24 hours.

[0186] After 24 hours, the activity of Formula 3 containing nanoemulsified CBD is significantly greater than the activity of Formula 1 containing emulsified CBD.

[0187] This observation demonstrates the effectiveness of the nanoemulsion form through the prolonged release effect of the nanoemulsified CBD in formula 3.

[0188] At the identical concentration of 0.173% in methylsilanetriol for formula 2 and formula 6, formula 6 gives an occupancy rate of -36% while formula 2 gives an occupancy rate of +80%.

[0189] The very low occupancy rate observed on subjects treated with formula 6 compared to formula 2 is due to the nanoemulsion form coupled with methylsilanetriol.

[0190] This nanoemulsion + glycerol + methylsilanetriol coupling ensures a complementary effect on the effectiveness of regulating sebaceous flow.

[0191] Formulas 4, 5 and 6 show increasing effectiveness in reducing the sebum occupancy rate.

[0192] The linearity of the results obtained with formulas 4, 5, 6 seems to indicate that this complementarity is expressed linearly as a function of the concentrations of the methylsilanetriol concentration in the methylsilanetriol concentration range studied ([Fig.5]).

[0193] Interpretation of the results of the Sebumetry test using Sebufix® Patches obtained after 24 hours.

[0194] Evaluation of the complementarity of the nanoemulsion + Glycerol + Methylsilanetriol coupling on the effectiveness of the reduction of the sebum occupancy rate 24 hours after application.

[0195] At a constant glycerol concentration, we can evaluate the complementarity of the coupling (nanoemulsion + Glycerol + Methylsilanetriol) on the effectiveness of the reduction of the sebum occupancy rate 24 hours after application.

[0196] [Tables8] Cream Formula Number Time Variation Sebum Occupancy Rate Variation [%] CREAM FORMULA 1 CBD Emulsion 0.50% + Glycerol 7.50% T0 / T24h + 513.0% CREAM FORMULA 2 CBD Emulsion 0.50% + Glycerol 7.50% + MeSi(OH)3 0.173% T0 / T24h + 80.7% Effect of Methylsilanetriol on Sebum Occupancy Rate T0 / T24h - 84.3% CREAM FORMULA 3 CBD Nanoemulsion 0.50% + Glycerol 7.50% T0 / T24h + 135.0% Transposition of the reduction factor to CREAM FORMULA 3 CBD Nanoemulsion 0.50% + Glycerol 7.50% Expected Occupancy Rate (calculated) T0 / T24h Calculated + 21.2% CREAM FORMULA 6 Actual experimental occupancy rate CBD Nanoemulsion 0.50% + Glycerol 7.50% + MeSi(OH)3 0.173% T0 / T24h Experimental -36.20%

[0197] Table 8 - Transposition of the silanol effect of Formula 2 Cream to the cream

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205] Formula 3 Effect of methylsilanetriol 24 hours after application, - Formula 1 cream containing glycerol but not containing methylsilanetriol provides a variation in occupancy rate of 513%. - Formula 2 cream containing glycerol and 0.173% methylsilanetriol provides a variation in sebum occupancy rate of +81%. Formula 2 cream therefore reduces the sebum occupancy rate of formula 1 by 84%. This ratio characterizes the effectiveness of coupling glycerol with methylsilanetriol. - Formula 3 cream containing glycerol but not containing methylsilanetriol provides a variation in sebum occupancy rate of 135%. If we transpose this methylsilanetriol effect (-84%) to Formula 3 cream (containing glycerol but not containing methylsilanetriol) to be in the same configuration as Formula 6 (with glycerol and 0.173% methylsilanetriol), we should obtain a calculated sebum occupancy rate of +21%. - Formula 6 cream containing glycerol and 0.173% methylsilanetriol provides a variation in sebum occupancy rate of -36%. The difference between the calculated and actual sebum occupancy rates is -57%. This difference was unexpected. Formula 6 cream is therefore more effective in reducing sebaceous flow than expected ([Fig.6]). [Tables 9] REDUCTION IN SEBUM OCCUPATION RATE T0 / T24h CREAM FORMULA 2 ACTUAL EFFECT of methylsilanetriol (Cream formula 2) on CBD EMULSION (compared to formula 1) -84.28% CREAM FORMULA 6 EXPECTED EFFECT of methylsilanetriol on CBD NANOEMULSION (from the result of formula 3) -84.28% CALCULATED OCCUPANCY RATE for CBD NANOEMULSION (formula 6, theoretical rate calculated based on the result of formula 3) 21.23% ACTUAL OCCUPANCY RATE for CBD NANOEMULSION (formula 6) -36.20% UNEXPECTED REDUCTION observed for CBD NANOEMULSION (formula 6) -57.43% Table 9 - Formula 6 Cream: Comparison of transposed values ​​and values real

[0206] This study highlighted an unexpected improvement in the efficacy of the nanoemulsion of the active ingredient studied by adding the polyol couple glycerol + methylsilanetriol to this nanoemulsion.

[0207] This unexpected result results from an improvement in the bioavailability of the active ingredient in the form of nanoemulsion as well as the action of the polyol pair (glycerol + methylsilanetriol) which very probably improves its stability as well as its prolonged release.

[0208] 2.2. Association of glycerol and glucooligosaccharide

[0209] Following the same approach as in point 2.1, several formulations, in which only the form of CBD (emulsion or nanoemulsion) and the concentration of glucooligosaccharide (glucose polysaccharide containing less than 10 glucose units, GOS) vary, are tested as part of a treatment against hyper seborrhea in acne-prone skin.

[0210] As with the previous study, only the results obtained 24 hours after application were taken into consideration because, in the context of research on the reduction of hyperseborrhea for an anti-acne treatment, the results obtained after a very short time are not relevant.

[0211] As stated previously, immediate elimination of sebum does not allow us to predict the actual effectiveness of a treatment.

[0212] [TableauxlO] EMULSIONS NANOEMULSIONS Crème FORMU LE la Crème FORMU LE 2a Crème FORMU LE 3a Crème FORMU LE 4a Crème FORMU LE 5a AQUA 67,43 % 65,43 % 67,38 % 65,82 % 65,35 % COCO-CAPRYLATE / CAPRA TE 12,00 % 12,00 % 12,00 % 12,00 % 12,00 % GLYCERIN 7,50 % 7,50 % 6,00 % 7,50 % 7,50 % CETEARYL ALCOHOL / CETARYL GLUCOSIDE 6,00 % 6,00 % 7,50 % 6,00 % 6,00 % TAPIOCA STARCH / POLY-METHTYLSILSESQUIOXAN E 2,00 % 2,00 % 2,00 % 2,00 % 2,00 % CAPRYLIC / CAPRIC TRIGLYCERIDE 1,75 % 1,75 % 1,75 % 1,75 % 1,75 % ETHYLHEXYLGLYCERIN 1,20 % 1,20 % 1,20 % 1,20 % 1,20 % CANNABIDIOL 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % TOCOPHERYL ACETATE 0,50 % 0,50 % 0,50 % 0,50 % 0,50 % HYDROGENATED LECITHIN 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % SODIUM BENZOATE 0,40 % 0,40 % 0,40 % 0,40 % 0,40 % SCLEROTIUM GUM 0,30 % 0,30 % 0,30 % 0,30 % 0,30 % TOCOPHEROL 0,02 % 0,02 % 0,02 % 0,02 % 0,02 % CITRIC ACID Aqueous soin.Approximation to final pH5.5) 0.00% 0.00% 0.05% 0.11% 0.08% GLUCOOLIGOSACCHARIDE - 2.00% - 1.50% 2.00% 100.00% 100.00% 100.00% 100.00% 100.00%.

[0213] TABLE 10 - Glycerin + Glucooligosaccharide Association: Composition of the creams used for the sebumetry test

[0214] The final compositions of surfactant, CBD, glycerol and glucooligosaccharide in the finished products are as follows:

[0215] [T ables 11] No. Formula Emulsion or Nanoemuls ion PHOSPHOLI PIDE CBD GLYCERO L GLUCO-OLIGOSACC HARIDE Cream Formula la Emulsion 4.00% 0.50% 7.50% 0% Cream Formula 2a Emulsion 4.00% 0.50% 7.50% 2.00% Cream Formula 3a Nanoemulsi on 4.00% 0.50% 7.50% 0% Cream Formula 4a Nanoemulsi on 4.00% 0.50% 7.50% 1.50% Cream Formula 5a Nanoemulsi on 4.00% 0.50% 7.50% 2.00%

[0216] Table 11 - Glycerin + Glucooligosaccharide Association: Composition of Creams

[0217] The mass concentration ratios of the constituents of the different nanoemulsions are as follows:

[0218] [Tableauxl2] Formula No. Emulsion or Nanoemulsion Glycerol / Surfactant concentration ratio Surfactant concentration ratio Glu-cooligosaccharide Glycerol / Glucooligosaccharide concentration ratio Cream Formula 1a Emulsion 1.88 Cream Formula 2a Emulsion 1.88 2.00 3.75 Cream Formula 3a Nanoemulsion 1.88 Cream Formula 4a Nanoemulsion 1.88 2.67 5.00 Cream Formula 5a Nanoemulsion 1.88 2.00 3.75

[0219] Table 12 - Association Surfactant + Glycerin + Glucooligosaccharide: Concentration ratios in nanoemulsions

[0220] Results of the sebumetry test using Sébufix® Patches 24 hours after application

[0221] The study conditions are as described in paragraph 2.1.

[0222] [Tables 13] Cream No. Formulation Emulsion or Nanoemulsion Concentration Gluco-oligo or sac-chararide (%) Variation of exposure time VARIATION Number of spots VARIATION Total spot area [mm2] Number of spots / c m2 VARIATION STANDARD LIS Coverage Rate [%] Emulsion Form 0% T0 / T30mi n 89 + 0.052 mm2 + 103 + 5.95% T0 / T6h 10 + 0.001 mm2 + 11 + 5.82% T0 / T24h 20 + 0.006 mm2 + 257% Cream Form 29 Emulsion 2.00 % T0 / T30mi n 15 + 0.024 mm2 + 18 + 2.90% T0 / T6h 0 - 0.001 mm2 - 1 + 2.90% T0 / T24h 26 + 0.002 mm2 + 29 + 41% Cream Formula 33 ion 0% T0 / T30mi n -17 - 0.001 mm2 - 19 - 0.12% T0 / T6h -7 - 0.001 mm2 - 8 + 0.00% T0 / T24h -19 - 0.001 mm2 -22 + 0.20% Lemon Cream, Formula 140% i T0 / T30mi n 154 + 0.121 mm2 + 188 + 13.88% T0 / T6h 50 + 0.017 mm2 + 58 + 16.72% T0 / T24h 13 - 0.004 mm2 + 15 - 5.56% Cream Formula 5a Nanoemuls ion 2.00% T0 / T30mi n -14 - 0.001 mm2 - 17 - 0.10% T0 / T6h -13 - 0.001 mm2 - 15 - 0.03% T0 / T24h -44 - 0.004 mm2 -50 -53.81%

[0223] Table 13 - 0.50% CBD formulations - 7.50% Glycerol + Glu-cooligosaccharide combination. Variation in occupancy rate at T30mn, T6h, T24h

[0224] As explained above, the results obtained 24 hours after application are those to be considered.

[0225] [Tablesl4] GLYCEROL + GLUCOOLIGOSACCHARLDE: TABLE OF VARIATION OF THE RATE OF SEBUM after 24 hours Cream N°Form ule Emulsion or Nanoemulsion Concentration Gluco-olig or sac-chararide (%) VARIATION OF EXPOSURE TIME Total spot area [mm2] VARIA TION Number of spots / cm2 VARIAT ION Occupancy rate [%] Cream Cheese and Emulsion 0% T0 / T24h 20 + 0.006 mm2 + 22 + 75.97% Cream Cheese and Emulsion 20% T0 / 2020 0.002 mm2 + 29 + 41.27% Cream Cheese and 3a Nanoemulsions ion 0% T0 / T24h -19 - 0.001 mm2 -22 + 0.20% Cream Cheese and 4a Nanoemulsions ion 1.50% T0 / T024h - 10.02 mm - 5.56% Creme Cheese and 5a Nanoemulsions ion 2.00 % T0 / T24h -44 - 0.004 mm2 -50 -53.81%

[0226] Table 14 - Glycerin + Glucooligosaccharide: Sebum Occupancy Rate Variation at T24h

[0227] The [Fig.7] illustrates the results of the Sebumetry test using the Sebufix® Patches after 24h.

[0228] Interpretation of the results of the Sebumetry test using Sebufix® Patches obtained after 24 hours Formula Cream (CBD emulsion + Glycerol):

[0229] 24 hours after application, the formula causes an increase in the rate sebum occupancy of +76%; which is a very poor result. The objective of regulating sebaceous flow is not achieved.

[0230] Formula 2a Cream (CBD emulsion + Glycerol + GOS 2.00%):

[0231] 24 hours after application, the formula also causes an increase in sebum rate of +41% but this increase is lower than that obtained with formula I.

[0232] Even if the objective of regulating sebaceous flow is not achieved, the glycerol + oligosaccharide association provides a significant improvement linked to the incorporation of glucooligosaccharide.

[0233] Formula 2a provides a 54% reduction in sebum occupancy rate compared to formula 1a. Formula 3a Cream (CBD nanoemulsion + Glycerol):

[0234] 24 hours after application, formula 3a containing nanoemulsified CBD provides a variation in the sebum occupancy rate of +0.2%. This variation being very small, we can therefore consider that this formula does not change the initial hyperseborrheic state.

[0235] However, it is noted that the activity of formula 3a containing nanoemulsified CBD is significantly greater than the activity of Formula 1a containing emulsified CBD, which confirms the interest of the nanoemulsion form.

[0236] It should be noted that formula 3a provides a very low variation in the sebum occupancy rate from the start of application (after 30 min); this variation remains stable after 6 hours and after 24 hours.

[0237] Formula 4a Cream (CBD nanoemulsion + Glycerol + GOS 1.50%):

[0238] 24 hours after application, formula 4a provides a variation of -5.56% of the rate sebum occupation. This variation is quite small but it is nevertheless negative and highlights the better activity of formula 4a compared to formula 3a and compared to all the previous formulas.

[0239] Formula 4a confirms that the association nanoemulsion + glycerol + glucooligosaccharide is of interest in achieving the desired objective, the reduction of the sebum occupancy rate.

[0240] Formula 5a Cream (CBD emulsion + Glycerol + GOS 2.00%):

[0241] 24 hours after application, formula 4a provides a variation of -53.81% of the rate sebum occupation. This negative variation is significant and highlights the greater effectiveness of formula 5a compared to formulas 4a and 3a. Formula 5a therefore provides the best results compared to all previous formulas.

[0242] Formula 5a cream also highlights the need to have, when the glycerol concentration is 7.50% in the cream, a minimum concentration of 2.00% glucooligosaccharide to obtain a significant result in reducing the sebum occupancy rate.

[0243] Conclusion of study 2.2 relating to the glycerol + glucooligosaccharide association:

[0244] [Fig.8] illustrates the graphic representation of the results of the Sebumetry test using Sebufix® Patches after 24 hours.

[0245] After 24 hours, the activity of the Formula 3a Cream containing the nanoemulsified CBD is significantly greater than the activity of the Formula 1a Cream containing the emulsified CBD.

[0246] This observation demonstrates the effectiveness of the nanoemulsion form by the prolonged release effect of the nanoemulsified CBD in formula 3a.

[0247] At the identical concentration of 2.00% glucooligosaccharide for formula 2a and formula 5a, formula 5a gives an occupancy rate of -54% while formula 2a gives an occupancy rate of +41%.

[0248] The very low occupancy rate observed on subjects treated with formula 5a compared to Formula 2a is due to the nanoemulsion form in the presence of the glycerol + oligosaccharide couple.

[0249] This nanoemulsion + glycerol + glucooligosaccharide coupling ensures a complementary effect on the effectiveness of regulating sebaceous flow.

[0250] Formulas 3a, 4a and 5a show increasing effectiveness in reducing the sebum occupancy rate.

[0251] The results obtained with formulas 3a, 4a and 5a seem to indicate that this complementarity is expressed in a less linear manner as a function of the concentrations of the glucooligosaccharide concentration than with methylsilanetriol in the glucooligosaccharide concentration range studied ([Fig.9]).

[0252] Interpretation of the results of the Sebumetry test using Sebufix® Patches obtained after 24 hours: evaluation of the complementarity of the nanoemulsion + glycerol + glucooligosaccharide coupling on the effectiveness of the reduction of the sebum occupancy rate 24 hours after application.

[0253] At constant glycerol concentration, the complementarity of the coupling (nanoemulsion + Glycerol + glucooligosaccharide) on the effectiveness of the reduction of the sebum occupancy rate 24 hours after application is evaluated.

[0254] [Tables 15] Cream Formula Number Time Variation Sebum Occupancy Rate Variation [%] CREAM FORMULA CBD Emulsion 0.50% + Glycerol 7.50% T0 / T24h + 76.0% CREAM FORMULA 2a CBD Emulsion 0.50% + Glycerol 7.50% + glucooligosaccharide 2.00% T0 / T24h + 41.3% Effect of glucooligosaccharide on sebum occupancy rate T0 / T24h - 45.7% CREAM FORMULA 3a CBD Nanoemulsion 0.50% + Glycerol 7.50% T0 / T24h + 0.2% Transposition of reduction factor to formula 3 CBD Nanoemulsion 0.50% + Glycerol 7.50% Expected (calculated) occupancy rate T0 / T24h + 0.1% CREAM FORMULA 5a: Actual experimental occupancy rate CBD Nanoemulsion 0.50% + Glycerol 7.50% + glucooligosaccharide 2.00% T0 / T24h - 53.8%

[0255] Table 15 - Transposition of the glucooligosaccharide effect of Formula 2a Cream to Formula 3 Cream Effect of glucooligosaccharide

[0256] 24 hours after application,

[0257] - The cream formula contains 7.50% glycerol but does not contain glucoo ligosaccharide provides a variation in occupancy rate of +76%.

[0258] - Formula 2a cream containing glycerol and 2.00% glucooligosaccharide provides a variation in the sebum occupancy rate of +41%.

[0259] Formula 2a cream therefore reduces the sebum occupancy rate of formula 1a cream by 46%.

[0260] This report characterizes the efficiency of the coupling of glycerol with glucooligosaccharide.

[0261] - Formula 3a cream containing glycerol but not containing glucooligo- saccharide provides a variation in the sebum occupancy rate of +0.2%.

[0262] If we transpose this glucooligosaccharide effect, -45.7%, to Formula 3a cream (containing glycerol but not containing methylsilanetriol) to be in the same configuration as Formula 5a (with glycerol and 2.00% glucooligosaccharide), we should obtain a calculated sebum occupancy rate of +0.1%.

[0263] - However, the formula 5a cream containing glycerol and 2.00% glucooligosaccharide provides a variation in the sebum occupancy rate of -54%.

[0264] The difference between the calculated and actual sebum occupancy rates is 54%.

[0265] This difference was unexpected.

[0266] Formula 5a cream is therefore more effective than expected in reducing sebaceous flow ([Fig.9]).

[0267] [Tables 16] REDUCTION IN SEBUM OCCUPATION RATE T0 / T24h FORM ULE2a ACTUAL EFFECT of GOS on CBD EMULSION (compared to formula 1a): -45.67% FORM ULE5a EXPECTED EFFECT of GOS on CBD NANOEMULSION (from the result of formula 3a): -45.67% CALCULATED OCCUPANCY RATE for CBD NA NOEMULSION (formula 5a, theoretical rate): 0.11% ACTUAL OCCUPANCY RATE for CBD NA NOEMULSION (formula 5a): -53.81% ADDITIONAL REDUCTION observed for CBD NANOEMULSION (formula 5a) -53.92%

[0268] Table 16 - Formula 5a cream: Comparison of transposed values ​​and actual values

[0269] This study highlighted an unexpected improvement in the efficacy of the nanoemulsion of the active ingredient studied by adding the polyol pair glycerol + glucooligosaccharide to this nanoemulsion.

[0270] This unexpected result results from an improvement in the bioavailability of the active ingredient in the form of nanoemulsion as well as the action of the polyol pair (glycerol + glucooligosaccharide) which very probably improves its stability as well as its prolonged release.

[0271] Overall conclusion on clinical sebumetry studies.

[0272] These results indicate the complementarity of the association of the nanoemulsion of the active ingredient with a pair of polyols.

[0273] For the same active ingredient, the behaviors of 2 different pairs of polyols (Glycerol + methylsilanetriol) and (Glycerol + Glucooligosaccharide) are very similar.

[0274] Identical results were obtained with both polyol pairs.

[0275] In both studies,

[0276] - The activity of CBD on the regulation of hyper seborrhea is better expressed under nanoemulsion form containing a single polyol than in the form of an emulsion containing a single polyol,

[0277] - The activity of CBD is better expressed when the emulsion contains two polyols,

[0278] - The activity of CBD is better expressed when the nanoemulsion contains two polyols,

[0279] - In the 2 clinical studies, it is observed that the differential activity of CBD observed between the nanoemulsion containing 1 polyol and the nanoemulsion containing 2 polyols is greater than that observed between the emulsion containing 1 polyol and the emulsion containing 2 polyols.

Claims

Claims

1. Nanoemulsion of oil-in-water or water-in-oil type comprising: - an aqueous phase; - an oily phase; - at least one surfactant; and - at least two polyols distinct from one another, chosen from: . diols and triols chosen from propanediol, glycerol, ethylhexyl glycerin, propylene glycol, diethylene glycol, and their derivatives; . silanols chosen from dimethylsilanediol, methylsilanetriol and their derivatives; . polysaccharides chosen from inulin, alginic acid, alginates and esters of alginic acid, mannuronic acid, glucans (starch, amilose, amilodextrin), galactans (agar-agar, carrageenans), mucilages, mucopolysaccharides or glycosaminoglycans chosen from hyaluronic acid, heparin sulfate (HSGAGs), chondroitin sulfate, keratan sulfate, dermatan sulfate and their derivatives; .oligosaccharides chosen from glucooligosaccharides, xylooligosaccharides, fructo-oligosaccharides, maltose, lactose, cyclodextrins, and their derivatives.

2. Nanoemulsion according to claim 1, characterized in that the surfactant of non-ionic, anionic, cationic or switterionic type is chosen from: - sphingophospholipids; - glycerophospholipids; - polyoxyethylene non-ionic systems; - glycerol and polyglycerol esters containing from 2 to 20 glycerol units esterified by one or more fatty acids of the lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, ricinoleic acid type.

3. Nanoemulsion according to claim 1 or claim 2, characterized in that one of the at least two polyols is a diol or a triol chosen from propanediol, glycerol, propylene glycol, diethylene glycol and their derivatives.

4. Nanoemulsion according to claim 3, characterized in that one of the at least two polyols is glycerol.

5. Nanoemulsion according to claim 4, characterized in that the ratio mass concentration between glycerol and surfactant is less than 5, and preferably less than 2.

6. Nanoemulsion according to any one of claims 3 to 5, characterized in that the other of the at least two polyols is chosen from: - a silanol chosen from dimethylsilanediol, methylsilanetriol, and their derivatives; - an oligosaccharide chosen from glucooligosaccharides, xylooligosaccharides, fructo-oligosaccharides, maltose, lactose, cyclodextrins and their derivatives.

7. Nanoemulsion according to claim 6, characterized in that the polyols are glycerol and methylsilanetriol and in that the mass concentration ratio between glycerol and methylsilanetriol is preferably less than 200, and preferably less than 50.

8. Nanoemulsion according to claim 6, characterized in that the polyols are glycerol and a glucooligosaccharide and in that the mass concentration ratio between the glycerol and the glucooligosaccharide is preferably less than 10, and preferably less than 5.

9. Nanoemulsion according to any one of the preceding claims, characterized in that the size of the droplets of the dispersed phase of said nanoemulsion is less than 300 nm, preferably between 50 and 250 nm and most preferably of the order of 100 nm.

10. Nanoemulsion according to any one of the preceding claims, characterized in that the droplet size distribution is between 50 nm and 250 nm and such that the polydispersity index is between 0.01 and 0.

15.

11. Cosmetic, pharmaceutical or nutritional composition comprising the nanoemulsion according to any one of claims 1 to 10 and at least one active substance.

12. Composition according to claim 11, characterized in that it is intended to be administered topically.

13. Composition according to claim 11 or claim 12, such that said nanoemulsion is of the oil-in-water type and comprises: - an aqueous phase; - an oily phase dispersed in the aqueous phase; - one or more hydrophobic active substances; - at least one surfactant; and - at least two polyols distinct from each other, chosen from: . diols and triols chosen from propanediol, glycerol, ethylhexylglycerin, propylene glycol, diethylene glycol, and their derivatives; . silanols chosen from dimethylsilanediol, methylsilanetriol and their derivatives; . oligosaccharides chosen from glucooligosaccharides, xylooligosaccharides, fructo-oligosaccharides, maltose, lactose, cyclodextrins, and their derivatives.

14. Use of the nanoemulsion according to any one of claims 1 to 10 for improving the bioavailability of an active substance.

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