WO2021018682A1

WO2021018682A1 - Hybrid mineral-organic complex, and use thereof for maintaining the microbiological balance of the skin and/or of a cosmetic and/or dermopharmaceutical composition

Info

Publication number: WO2021018682A1
Application number: PCT/EP2020/070642
Authority: WO
Inventors: Han Athalin; Jean-Noël THOREL
Original assignee: Bionuclei
Priority date: 2019-07-26
Filing date: 2020-07-22
Publication date: 2021-02-04
Also published as: FR3099060B1; FR3099060A1; EP4003269A1; CN114667130A

Abstract

Disclosed is a hybrid mineral-organic complex comprising silica colloids covalently grafted with at least one antimicrobial peptide or its antimicrobial precursor.

Description

HYBRID MINERAL AND ORGANIC COMPLEX AND ITS USE

FOR MAINTAINING THE MICROBIOLOGICAL BALANCE OF THE SKIN AND / OR A COSMETIC AND / OR DERMOPHARMACEUTIOUS COMPOSITION

Field of the invention

The present invention relates to a hybrid complex and its use for maintaining the microbiological balance of the skin and / or a cosmetic or dermopharmaceutical composition via an activity of reducing or inhibiting bacterial proliferation.

Prior state of the art

The skin is made up of several layers: the epidermis which is the outermost layer, the dermis and the hypodermis constituting the deepest layer. This organ is the interface between the organism and the external environment. In particular, the epidermis plays a protective role against physical attacks (ultraviolet radiation, temperature, etc.), chemical (solvents, allergens, etc.) or even biological (pathogenic agents), this is the epidermal barrier concept.

To fight against pathogenic attacks, the epidermis has a primary immune defense mechanism. Thus, keratinocytes and Langerhans cells recognize pathogenic microorganisms and activate to eliminate them via phenomena of phagocytosis, presentation of microbial antigens to lymphocytes or the production of antimicrobial peptides.

This immunological component is supplemented by a second structural defense mechanism: the desquamation process which ensures the elimination of surface corneocytes and installed microorganisms.

In the following, the term "microorganism" refers to a living organism, invisible to the naked eye, corresponding to various forms of life including bacteria, fungi and archaebacteria.

The barrier function of the skin is also provided by an ecosystem made up of saprophytic bacterial flora. Saprophytic bacterial flora is natural and permanent on the surface of the skin. The number of bacteria on the surface of the skin is estimated to be between 10 ² and 10 ⁵ bacteria per cm ² of skin. The most represented species are staphylococci, in particular Staphyloccocns epider midis, with a negative and related coagulase (Micrococcus) and aerobic (Corynebacterium, Brevibacterium) or anaerobic (Cutibacterium acnes) coryneforms. These bacteria are established on the outermost layer of the epidermis, in this case the stratum corneum, where they adhere to the comeocytes, forming a protective biofilm.

This saprophytic bacterial flora therefore plays a barrier role since it occupies the adhesion sites of other microorganisms, possibly pathogenic, thus limiting their proliferation.

However, in the event of skin deterioration, as in the case of pathologies (atopic dermatitis, acne or psoriasis) or severe or repeated skin attacks, the deterioration of the skin barrier promotes the emergence of bacterial infections, viral and / or fungal skin.

At the same time, the skin can be the site of a proliferation of microorganisms brought on by contact with everyday products, in particular cosmetic products.

Traditional cosmetic compositions are liable to be contaminated by various microorganisms, both during their manufacturing process and during their use by a consumer.

The cosmetics industry therefore attaches great importance to maintaining the microbiological integrity of its products, both for consumer safety needs and to maintain good functionality and a good physicochemical aspect of their products.

By virtue of their use and storage technique, cosmetic products are subjected to temperature variations causing water evaporation-condensation cycles which can modify the concentration of the ingredients in the formulation. These products are also subject to variations in humidity during their distribution, storage and / or use. During their use, the products are contaminated by contact with the external environment or the skin. The risk is particularly pronounced in the case of products packaged in jars, which have a larger exposed surface and are, therefore, more accessible to airborne pathogenic microorganisms. In the absence of a suitable preservation system, cosmetic products are a substrate for the development of various microorganisms such as Enterobacter spp. (E. Cloacae or E. agglomerons), Pseudomonas spp. (P. pntida, P. aeruginosa or P. fluor escens), Bacillus spp. or even Staphylococcus spp. (S. aureus or S. saprophyticus).

Among the many parameters that influence the storage of cosmetics, the activity of water plays an important role. In order to develop in a cosmetic product, microorganisms must be in the presence of a certain amount of free water.

For the purposes of the invention, the term “free water” denotes water molecules not complexed with other molecules entering into the formulation of the composition. This amount of free water is called “water activity” and is denoted a _w .

The minimum value of a _w at which microorganisms grow depends on their species. However, a decrease in water activity will tend to slow the growth of these pathogens.

For the remainder of the disclosure of the invention, the terms "compound", "component" and "ingredient" are used interchangeably.

To reduce the amount of water, in particular free water, in the formulations of traditional cosmetic products, a current solution is to add specific components such as humectants which make it possible to reduce the amount of free water by forming bonds. hydrogens between their hydrophilic functions and free water molecules.

Agents for modifying the rheology of the cosmetic formulation can also be used. These are, for example, gums (guar gum, xanthan gum etc.) which form a three-dimensional network and thus reduce the mobility of free water molecules. However, gums are in turn often a major source of bacterial and fungal contamination of the products in which they are incorporated. Each microorganism has an optimum growth pH, generally between 5 and 8. Another solution used in traditional compositions therefore consists in modifying the pH of the formulation so that it is less than 5. Consequently, the microorganisms are found in stress conditions unfavorable to any development. However, the addition of acidic compounds in a cosmetic composition is aggressive on the skin and can lead to skin irritation.

An alternative to the preserving solutions mentioned above consists in incorporating preservatives in the formulations. D can be synthetic preservatives, essential oils or even vegetable oils.

For the purposes of the invention, the term "preservative" denotes substances capable of inhibiting the development of microorganisms in cosmetic products. In Europe, all the preservatives authorized by the regulations as well as their limit concentrations for use are included in a list (Annex V of the European Directive on cosmetic products). However, several compounds that are not included in this list and are not considered authorized preservatives can contribute to the preservation of a cosmetic product.

The preservatives authorized by the European Directive are all of synthetic origin and have different physicochemical properties, activities and modes of action. These differences make it possible to adapt the choice of preservative (s) depending on the product to be formulated. The choice of preservative is based on various criteria such as spectrum of activity, efficacy at low concentration, solubility in water, compatibility with other ingredients or even safety and ease of use. .

However, the use of these preservatives poses a problem since they can be the cause of skin irritation and / or sensitization, endocrine disruption, allergies or even some preservatives are suspected of be carcinogenic products.

For example, parabens are among the authorized synthetic preservatives widely used in the cosmetics industry.

A paraben is an antimicrobial and antifungal agent essentially used in cosmetic compositions but also in food or pharmaceutical products. Their mode of action seems to be through the denaturation of the membranes microbial and fungal which would cause protein alterations. The spectrum of action of parabens includes Gram-positive bacteria, for example bacteria of the genus Staphylococcus, as well as some Gram-negative bacteria, such as P. aeruginosa. Parabens are also active on yeasts and molds. Their activity is, however, low on bacterial spores and zero on viruses or mycobacteria. This is the reason why they are most often used in combination with other types of preservatives.

However, parabens are suspected of disrupting the endocrine system by mimicking the properties of certain hormones and causing fertility problems or cancer. In addition, parabens are suspected to be predictors of obesity in children or to have allergenic and irritant effects.

Other ingredients are also used in formulations of traditional cosmetics for their natural antimicrobial properties. These are natural extracts derived from plant raw materials with antifungal and / or antibacterial properties.

For example, essential oils are used for their antimicrobial activity. In particular, the essential oils of thyme, savory or oregano contain thymol and carvacrol or the essential oil of clove contains Teugenol, which are compounds known for their effectiveness with respect to the proliferation of pathogenic microorganisms.

Despite their antimicrobial properties, the use of essential oils remains problematic in cosmetics due to their marked odor, the presence of allergens and contraindications in children or pregnant women.

At the same time, certain cosmetic formulations, soaps or even toothpastes contain antibiotics, such as triclosan, as antimicrobial agents. Triclosan is known to induce an increased risk of allergy, loss of muscle strength, damage to the immune system, and even to be a risk factor for liver cancer. In addition, scientists have found that triclosan is often in too small a quantity in consumer products to have a real antibacterial effect. On the other hand, bacteria exposed to this antibiotic come out stronger and are more resistant to antibiotics. In particular, in the presence of triclosan, bacteria, such as Escherichia coli (E. co / z), increase the activity of their stress response pathways and become even more resistant. This is a phenomenon of antibiotic resistance. It then takes four times more triclosan and eight times more quinolone (antibiotic used against these bacteria), to stop their proliferation.

There is therefore an obvious need to develop a new generation of compounds ensuring an inhibition or a decrease in the proliferation of microorganisms in a cosmetic composition and / or on the skin and which do not have the drawbacks of the ingredients of the prior art. .

Disclosure of the invention

The Applicant has developed a hybrid mineral and organic complex making it possible to reduce, decrease or even inhibit the proliferation of microorganisms in cosmetic compositions and / or on the skin.

The present invention solves the problems of the prior art mentioned above.

According to a first aspect, the invention relates to a hybrid mineral and organic complex comprising colloids of silica covalently grafted by means of a spacer arm with at least one peptide or its precursor.

Silica is naturally present in the form of silicon dioxide (S1O2) which is part of the composition of many minerals. It exists in the free state in different crystalline and amorphous forms, and in the combined state in silicates.

According to a particular embodiment, the silicate used to produce the silica colloids according to the invention corresponds to tetraethylorthosilicate.

In practice, the silica according to the invention can be used in purified or isolated form, with a purity at least equal to 60%, preferably at least equal to 70%, advantageously at least equal to 80%, even more advantageously at least equal to at 90%, or even 95%, preferably at least 98%, advantageously 99% or even 100%. Silica colloids are modifiable at the surface, biocompatible and exhibit good dispersibility and stability in a hydrophilic medium.

It is possible to modify the size, shape, porosity and crystallinity of silica colloids according to the intended applications, for example, the biomedical, pharmaceutical or cosmetic fields. In addition, the variety of possible surface modifications allows control of different parameters such as dispersion, circulation and targeting capabilities of silica colloids.

According to the invention, colloids refer to particles in crystalline or amorphous form. In a liquid medium, for example in an aqueous medium, the colloids form a colloidal suspension.

The notion of colloid grafting is part of the general knowledge of those skilled in the art. Grafting corresponds to the formation of covalent bonds, for example, between a peptide or its precursor and the surface of silica colloids.

According to the invention, the covalent grafting is carried out by means of a spacer arm or "linker".

According to a particular embodiment, the spacer arm may comprise a function of ether, ester, phosphate or amide type, advantageously ether.

Advantageously, the spacer arm is a linear ether comprising 3 to 10 carbons, preferably 4 to 6 carbons.

According to the invention, the spacer arm has no particular affinity with the plasma membrane of the microorganism, preferably the bacterial plasma membrane.

Of course, grafting is not limited to grafting a single compound. It is the grafting of a molecule or a multitude of molecules of at least one type of compound onto each silica particle.

Colloids can be synthesized according to conventional techniques, for example by the Stöber process. In general, the colloids have an average size of the order of a few nanometers to a few tens of nanometers.

Thus, the colloids according to the invention have a size advantageously between 0.1 nm and 1000 nm, more advantageously between 0.3 nm and 100 nm, and even more advantageously of the order of 5 nm, the size being advantageously measured. by DLS.

The DLS technique (dynamic light diffraction) is a technique conventionally used to measure the size of colloids in a fluid.

According to a particular embodiment, the hybrid complex according to the invention comprises silica colloids covalently grafted with at least one peptide or its precursor which has antimicrobial activity.

The grafting of a peptide or its antimicrobial precursor onto the silica colloids is carried out by means of a spacer arm or "linker".

According to a particular embodiment, the grafting of the silica colloids with at least one peptide or its precursor, preferably a peptide or its antimicrobial precursor, is carried out by chemical reaction with alkoxysilanes or halosilanes, advantageously alkoxysilanes, for example, by the creation of a covalent bond by nucleophilic substitution between the terminal amine of the peptide or of its precursor and the reactive end of the spacer arm.

Preferably, the grafting of the silica colloids with at least one precursor or its peptide is carried out with (3-glycidyloxypropyl) trimethoxysilane.

Regarding the grafting of silica colloids with the spacer arm, this is a conventional reaction known to those skilled in the art. This reaction takes place between the surface of the silica colloids comprising Si — OH functions and the spacer arm, advantageously an alkoxysilane or a halosilane, preferably an alkoxysilane, even more advantageously (3-glycidyloxypropyl) trimethoxysilane.

For the purposes of the invention, the term “peptide” optionally denotes a polymer of amino acids. For the purposes of the invention, the term “peptide precursor or peptide precursor” denotes an amino acid, that is to say an amino acid monomer, which can be transformed into a peptide by peptide synthesis, naturally. , biotechnological or artificial. The peptides synthesized may be subject to modifications (for example, glycosylation, acylation and / or acetylation) capable of modulating their activities and / or properties.

For the purposes of the invention, the term “peptide or its antimicrobial precursor” denotes a peptide or its precursor whose properties make it possible to inhibit, slow down or reduce the growth of microorganisms such as bacteria, fungi, viruses, yeasts and / or protozoa.

According to a particular embodiment, the peptide or its precursor according to the invention is chosen from the group comprising: CM15 (SEQ ID NO: 1), lysine, drosocin, attacin, diptericin, melittin, cathelicidins, such as LL-37, defensins, such as human b-defensins- 1, -2 or -3 (or hBD-1, h-BD-2 or hBD-3) or plant defensins from Nicotiana alata (or NaDl or NaD2) and mixtures thereof.

According to a particular embodiment, the hybrid complex according to the invention comprises silica colloids grafted covalently with at least one peptide or its precursor, the complex has a colloid / peptide or precursor mass ratio of between 99.9 / 0 , 1 and 90/10, advantageously between 99/1 and 90/10, preferably between 93/7 and 94/6.

According to a particular embodiment, the invention relates to a hybrid complex comprising silica colloids grafted with at least one CM15 (CSC), the complex has a colloid / CM15 mass ratio of between 99.9 / 0.1 and 90 / 10, advantageously between 99/1 and 90/10, preferably between 93/7 and 94/6.

CM15 is a 15 amino acid multifunctional cationic peptide (or PCM) hybrid (SEQ ID NO: 1). In particular, CM15 is a hybrid peptide made up of 2 peptides, cecropin from the hemolymph of the butterfly Hyalophora cecropia and melittin.

According to the invention, the hybrid complex comprising CSCs has antimicrobial properties with a favorable efficacy / minimum inhibitory concentration ratio which reside, in particular, in the negative charges carried by the silica colloids. These negative charges are at the origin of a phenomenon of repulsion of the elements of the membrane of the microorganism, in particular the bacterial membrane, which is negatively charged. This phenomenon allows the hybrid complex to cross the membrane of the microorganism, such as a bacterium, and to access the plasma membrane, in particular the bacterial one, which leads to degradation of the microorganism.

According to the invention, the CSC hybrid complex allows CM15 to retain its initial conformation in solution and therefore to increase or improve its efficiency.

According to another particular embodiment, the hybrid complex according to the invention comprises colloids of silica grafted covalently with at least one lysine (CSL) as peptide precursor.

According to a particular embodiment, the invention relates to a hybrid complex comprising CSLs, the complex has a colloid / lysine mass ratio of between 99/1 and 90/10, advantageously between 95/5 and 94/6, preferably between 93/7 and 94/6.

Lysine is a positively charged amino acid in the composition of proteins. This amino acid is an important building block for a number of antimicrobial peptides. For example, cecropins are rich in lysine.

This amino acid is also part of the composition of homopolymers of lysine, called polylysines, which are variable in length (25 to 30 amino acids) and which may differ from each other in terms of stereochemistry and position of the bonds. Studies have shown that polylysines have antimicrobial properties.

The grafting of lysine onto the silica colloids according to the invention makes it possible to immobilize and electronically stabilize the lysines, which contributes to facilitating the penetration of the CSL into the plasma membrane of a microorganism, in particular the bacterial plasma membrane, to eliminate said microorganism.

According to another aspect, the invention relates to a cosmetic or dermopharmaceutical composition comprising a hybrid complex as described above. According to a particular embodiment, the invention relates to a cosmetic or dermopharmaceutical composition comprising CSCs and / or CSLs. Advantageously, the hybrid complex according to the invention, in particular CSCs and / or CSLs, represents between 0.001% and 2% by total weight of the composition, preferably between 0.01% and 1%, or alternatively between 0.1% and 1%.

The composition comprising the hybrid complex according to the invention, advantageously the CSCs and / or CSLs, can be provided in all the galenic forms normally used in cosmetics and dermatology, such as, for example, but in a nonlimiting manner, in the form of an optionally gelled aqueous solution, of a dispersion of the lotion type, of an O / W or vice versa W / O emulsion, more or less fluid, or of a multiple emulsion such as for example a triple emulsion / W or O / W / O), or in the form of a vesicular dispersion of ionic (liposomes) and / or nonionic type, of a two-phase composition devoid of emulsifiers and gelling agents whose immiscible phases separate for storage, foam, spray or mist.

According to a particular embodiment, the cosmetic or dermopharmaceutical composition comprising the hybrid complex according to the invention, advantageously the CSCs and / or CSLs, is in the form of an aqueous-based solution, a dispersion, a lotion or of an emulsion.

According to a particular embodiment, the cosmetic or dermopharmaceutical composition comprising the hybrid complex according to the invention, advantageously the CSCs and / or CSLs, is an aqueous solution comprising, in addition, at least one surfactant.

In a preferred embodiment, the surfactant is a nonionic surfactant chosen from the group comprising alkyl polyglucosides (APGs), polyglycerolated fatty alcohols, ethoxylated derivatives and polysorbates.

According to a particular embodiment, the alkyl polyglucosides contain an alkyl group comprising from 6 to 30 carbon atoms, preferably from 8 to 16 carbon atoms, and contain a hydrophilic group (glucoside) comprising, preferably, 1, 2 or 3 units of saccharide.

By way of example, as alkylpolyglucosides according to the invention, mention may be made of the compounds corresponding to the following INCI designations: - Sucrose stearate, marketed by the company SISTERNA under the name Sistema SP70-C

- decyl glucoside (or Alkyl-C9 / Cl 1-polyglucoside (1.4)) sold under the name MYDOL ™ 10 by the company KAO CHEMICALS, under the name PLANT AREN ™ 2000 UP by the company BASF, or also under the name ORAMIX NS ™ 10 by the company SEPPIC;

the caprylyl / capryl glucoside marketed under the name PLANT AC ARE ™ 810 UP by the company BASF;

- lauryl glucoside marketed under the names PLANTAREN ™ 1200 N and PLANTACARE ™ 1200 by the company BASF; and

- the coco-glucoside marketed under the name PLANTACARE ™ 818 / UP by the company BASF.

By way of example, as polyglycerolated fatty alcohol according to the invention, mention may be made of the raw materials Tegosoft ™ PC 41, TegoSolve ™ 90MB marketed by the company EVONIK and corresponding respectively to the INCI designations Polyglyceryl-4 Caprate and Polyglyceryl-6 Caprylate ( and) Polyglyceryl-4 Caprate.

Advantageously, the composition comprising the hybrid complex according to the invention, advantageously CSCs and / or CSLs, comprises between 0.5% and 20% by total weight of the surfactant composition, preferably between 1% and 10% or alternatively between 1% and 5%.

According to a particular embodiment, the composition comprising the hybrid complex according to the invention, advantageously CSCs and / or CSLs, is free from ethoxylated derivatives, preferably from surfactants derived from polyethylene glycol (PEG).

According to another embodiment, the composition according to the invention comprises a hybrid mineral and organic complex comprising silica colloids covalently grafted by means of a spacer arm with at least one peptide or its precursor, advantageously CSCs and / or CSL, and at least one preservative.

Any preservative, authorized or not authorized by the regulations (Annex V of the European Directive on cosmetic products), suitable for use in cosmetic or dermatological compositions can be used in the formulation of a composition comprising the hybrid complex according to the invention, advantageously CSC and / or CSL. According to a particular embodiment, the preservatives according to the invention are alkanediols.

Preferably, the preservatives according to the invention are 1,2-alkanediols or 1,3-alkanediols.

According to a particular embodiment, the alkanediol is chosen from the group comprising the compounds corresponding to the following INCI designations: propylene glycol, 1,3-propanediol, 2-methyl-l, 3-propanediol, 1,2-pentanediol, 1 , 2-hexanediol, caprylyl glycol, 1,2-decanediol, hexylene glycol and mixtures thereof.

These preservatives are available from several cosmetic raw material suppliers.

For example, we can cite:

the EVO-100 ™ marketed by the company ARCHER DANIELS MIDLAND COMPANY and corresponding to the INCI designation propylene glycol;

ZEMEA ™ marketed by the company DUPONT-TATE & LYLE BIOPRODUCTS and corresponding to the INCI designation 1,2-propanediol; DUB DIOL ™ marketed by the company TEARTNERTE DUBOIS and corresponding to the INCI designation 2-methyl-l, 3-propanediol;

Hydrolite-5 ™, Hydrolite-6 ™, Hydrolite-8 ™ and SymClariol 344028 ™ sold by the company SYMRISE and corresponding respectively to the INCI designations 1,2-pentanediol, 1,2-hexanediol, caprylyl glycol and 1,2 - decanediol;

- Hexasol ™ marketed by the company ARKEMA and corresponding to the INCI designation hexylene glycol.

According to another embodiment, the preservative is a quaternary ammonium chosen from the group comprising behentrimonium chloride, cetrimonium bromide, myrtrimonium bromide, cetrimonium chloride, laurtrimonium bromide, laurtrimonium chloride , steartrimonium bromide, steartrimonium chloride, benzethonium chloride, benzalkonium chloride and mixtures thereof. According to a particular embodiment, the preservative corresponding to a quaternary ammonium is cetrimonium bromide and / or myrtrimonium bromide, advantageously cetrimonium bromide.

By way of example, cetrimonium bromide is marketed by the company MERCK under the trade name RONACARE ™ CETRIMONIUM BROMIDE and myrtrimonium bromide is marketed by the company COSPHATECH LLC under the trade name iBact Cetrimide ™.

Other preservatives suitable for use in the composition comprising the hybrid complex according to the invention, advantageously CSC and / or CSL, are, for example:

- potassium sorbate (INCI), sodium benzoate (INCI) and benzyl alcohol (INCI) sold by the company AZELIS UK under the name Paratexin ™ KS, Paratexin ™ SB G and Paratexin ™ B A, respectively;

- p-anisic acid (INCI) and levulinic acid (INCI) sold by the company COSPHATEC GMBH under the name Cosphaderm ™ and Cophaderm ™ LA-T, respectively;

- dehydroacetic acid (INCI) and polyaminoprypyl guanide (INCI), sold by the company LONZA under the names Geogard ™ 111A and Cosmocil ™ CQ, respectively;

- phenoxyethanol (INCI) marketed by the company CLARIANT INTERNATIONAL LTD under the name Phenoxetol ™.

According to a particular embodiment, the composition comprising the hybrid complex according to the invention, advantageously CSCs and / or CSLs, comprises between 0.001% and 5% by total weight of the composition of preservative, advantageously between 0.01% and 2%, preferably between 0.1% and 1%.

The composition comprising the hybrid complex according to the invention, advantageously CSCs and / or CSLs, can also comprise at least one dermocosmetic active principle such as, for example:

- lysine azeilate or a derivative thereof or a salt of azelaic acid;

- Andrographolide, in particular the extract of Andrographis paniculata corresponding to the INCI designation Andrographis paniculata leaf extract; native ascorbic acid (vitamin C) or its derivatives, in particular the derivatives corresponding to INCI Ascorbyl Glucoside, Ethyl ascorbic acid, Ascorbyl methylsilanol pectinate, Sodium ascorbyl phosphate and Ascorbyl tetraisopalmitate, advantageously ascorbyl glucoside;

arbutin or a plant extract containing it, in particular bearberry extract corresponding to the INCI designation Arctostaphylos uva-ursi leaf extract; glabridin or a plant extract containing it, in particular the liquorice extracts corresponding to the INCI designation Glycyrrhiza glabra root extract, Glycyrrhiza inflata root extract, Glycyrrhiza uralensis root extract;

biomimetic peptides corresponding to the INCI designations hexapeptide 2 and / or nonapeptide-1;

an aqueous extract of an alga called Palmaria palmata, in particular the extract corresponding to the INCI designation Palmaria palmata extract;

4-n-butylresorcinol;

vitamin PP, also called niacinamide or nicotinamide, and its derivatives;

at least one polyol chosen in particular from xylitol, rhamnose, mannitol and their mixtures;

fructoligosaccharides;

an extract of the algae Laminaria ochroleuca, Blidingia minima and / or Laminaria saccharina;

an extract of the plant Zanthoxylum alatum;

panthenol;

vitamin E or one of its hydrophilic or lipophilic derivatives, or one of their salts, advantageously tocotrienol or tocopherol;

salicylic acid or a derivative of it;

an extract of cade wood;

an extract from Boldo;

an extract from Meadowsweet;

an agent limiting immunosuppression, advantageously vitamin PP; a protective agent for the p53 protein, advantageously epigallocathechin gallate (EGCG);

an extract of karanja oil from Pongamia glabra;

GATR (adenosine-5 tri-phosphate), Gp4G (diguanosine tetraphosphate) or Ap4A (diadenosine tetraphosphate),

a peptide extract of soya and / or wheat and mixtures thereof;

an amino acid or an amino acid derivative selected from the group consisting of ectoin, creatine, ergothioneine, camosine, tyrosine, decarboxycamosine, glutamine and their salts;

- an aqueous cucumber extract corresponding to the INCI designation Cucumis sativus (Cucumber) Fruit Extract;

- or their mixtures.

Advantageously, the composition comprising the hybrid complex according to the invention, advantageously the CSCs and / or CSLs, further comprises between 0.001% and 10% by total weight of the composition of dermocosmetic active principles, advantageously between 0.01% and 5%, preferably between 0.1% and 1%.

The composition comprising the hybrid complex according to the invention, advantageously the CSCs and / or CSLs, can also comprise the adjuvants customary in the field considered, such as hydrophilic or lipophilic thickeners or gelling agents, hydrophilic or lipophilic additives, antioxidants, perfumes, fillers, pigments, UV filters, odor absorbers, dyes, moisturizers, vitamins, essential fatty acids, liposoluble polymers in particular hydrocarbons, opacifiers, stabilizers, sequestrants, conditioners propellants, fatty substances, organic solvents, silicones, thickeners, softeners, anionic, cationic, non-ionic or amphoteric polymers, anti-foaming agents, hair conditioning agents such as proteins, vitamins , dyes, pearlescent agents, sun filters and in particular hydrophilic sun filters, electrolytes, stabilizing agents isants, buffers such as, for example, citric acid / sodium citrate buffer.

According to another aspect, the invention relates to the use of a hybrid complex as described above as an agent for sanitizing the skin.

According to the invention, the hybrid complex as a skin cleansing agent makes it possible to:

- maintain and rebalance the skin microbiome;

- decrease or inhibit the proliferation of pathogenic bacteria; and or

- eliminate pathogenic bacteria.

According to another aspect, the invention relates to the use of a hybrid complex as described above as an agent for cleaning up a cosmetic or dermopharmaceutical composition. According to the invention, the hybrid complex as a sanitizing agent for a composition makes it possible to:

- protect said composition from bacterial contamination;

- decrease or inhibit the proliferation of pathogenic bacteria; and or

- eliminate pathogenic bacteria.

In other words, the invention relates to the use of a hybrid complex as described above as an agent for sanitizing the skin and / or a cosmetic or dermopharmaceutical composition.

According to a particular embodiment, the hybrid complex is used to reduce, decrease or inhibit the proliferation of pathogenic bacteria on the skin and / or in a cosmetic or dermopharmaceutical composition. The invention and the advantages resulting therefrom will emerge better from the following figures and examples given in order to illustrate the invention and not in a limiting manner.

[Fig. 1] Figure 1 shows a comparison of the antimicrobial activity of the hybrid complex corresponding to CSCs according to the invention compared to that of CM 15 alone.

[Fig. 2] Figure 2 shows a comparison of the antimicrobial activity of the hybrid complex corresponding to CSLs according to the invention compared to that of lysine alone. EXAMPLES OF EMBODIMENT OF THE INVENTION

1 / Summary of CSLs according to the invention

The composition used in the synthesis of the CSLs according to the invention is shown in Table 1. [Table 1]

Step 1: B is solubilized in A at 60 ° C for 20 minutes. Step 2: C is integrated into the solution obtained in step 1 and the mixture is heated to 60 ° C and stirred for 20 hours.

Step 3: The suspension obtained in step 2 is cooled to room temperature and then filtered under vacuum on a 0.4 μm filter.

Step 4: D is added to the reaction mixture from step 3, then the reaction is maintained at 40 ° C for 16h.

Step 5: The silica colloids grafted covalently with lysine (CSL) according to the invention are obtained after a step of purification by dialysis of the mixture according to step 4, first against a solution of E at 5 g / L for 15h with 3 changes of counter solvent, then for 15h against A with 3 changes of counter solvent. The dialysis membrane used has an exclusion limit of 3.5kDa. The dust is removed by filtration through a 0.2 μm cellulose acetate filter.

2 / Summary of CSCs according to the invention

The composition used in the synthesis of CSCs according to the invention is shown in Table 2. [Table 2]

Step 1: B is solubilized in A at 60 ° C for 20 minutes. The pH of the solution is approximately 10.3.

Step 2: C is integrated into the solution obtained in step 1 and the mixture is heated to 60 ° C and stirred for 20 hours.

Step 3: The suspension obtained in step 2 is cooled to room temperature and then filtered under vacuum through a 0.4 μm filter.

The solution is then dialyzed with a lkDa exclusion limit dialysis membrane first against a 5g / L solution of D for 15h with 3 changes of counter solvent, then for 15h against A with 3 changes of counter solvent.

The pH of the solution obtained after dialysis is between 8 and 9.5 and is then adjusted between 7.5 and 8 by adding a necessary amount of a 0.1M HCl solution.

Step 4: For chemical grafting, E, then F are added in the dark to the solution obtained in step 3 and the reaction is kept at 40 ° C for 16 hours in the dark.

Step 5: The silica colloids covalently grafted with CM15 (CSC) according to the invention are obtained after a step of purification by dialysis of the mixture according to step 4 against A for 15 h. The dialysis membrane used has an exclusion limit of 3.5kDa. The dust is removed by filtration through a 0.2 μm cellulose acetate filter. 3Æevaluation of the antimicrobial properties of the hybrid CSC and CSL complexes according to the invention

The antimicrobial power of the hybrid CSC and CSL complexes according to the invention is determined in vitro according to the principle of ATPmetry.

This technique consists of measuring the amount of ATP present in samples.

All living organisms contain GATR. ATP is quantified by a bioluminescence reaction using the enzyme luciferase. This enzyme catalyzes the reaction between luciferin (substrate), G ATP (cofactor) and oxygen, which is responsible for the emission of photons.

This is because each ATP molecule consumed in the reaction produces a photon of light. The production of light from this reaction is therefore directly proportional to the amount of biological energy (ATP) present in the sample.

The amount of ATP measured is converted to the amount of microorganisms by considering the consensus that a bacterium, for example E. coli, contains 0.001 pg of ATP.

The evaluation of the antimicrobial properties of the CSC and CSL hybrid complexes was carried out using an ATPmetry kit comprising a lysis buffer making it possible to extract cellular T ATP, a resin making it possible to capture substances that could interfere with the test, a buffer stabilization agent of dissolved GATR (not extracted from living cells) before quantification, a standard solution of ATP and luciferase.

The amount of ATP measured after treatment with the lysis buffer and the resin corresponds to the total amount of ATP contained in the sample. Subtracting the value obtained for dissolved ATP from that for total ATP makes it possible to obtain the concentration of cellular ATP from which we can deduce the concentration of living biomass present in the sample analyzed.

The analyzes were carried out in the presence of the CM15 peptide alone, of lysine alone or of a solution comprising CSCs or CSLs according to the invention. a / Preparation of samples

1.5 mL of each sample studied are placed in 5 mL glass vials. All samples are then contaminated with a glucose solution (method 1) or by skin contact (method 2).

- Method 1 - glucose contamination: an aqueous solution of glucose at 1 g / L is prepared and stored for 3 days at room temperature so as to promote microbial development. This solution is then added to the samples to be tested at a concentration of 25% by weight of the sample.

- Method 2 - contamination by skin contact: 100 μL of sample to be tested are taken and brought into contact with the palm of an individual's hand (aspiration and reflux 3 times). The skin contains between 10 ² and 10 ⁵ bacteria per cm ² . These bacteria belong to the resident flora (non-pathogenic bacteria) or to the transient flora (potentially pathogenic bacteria). Unlike method 1, this contamination technique makes it possible to ensure that the samples contain a maximum of bacteria that may come into contact with cosmetic or dermopharmaceutical preparations. b / Determination of the amount of ATP in the samples

Determination of the total amount of ATP

40 μl of sample are mixed with 40 μl of lysis buffer. After one minute of incubation at room temperature, 50 μL of this mixture are placed in 200 μL of resin. After homogenization of the mixture, the luminescence of the supernatant is analyzed by taking a volume of 10 μL of the mixture added to 10 μL of luciferase in a 384-well plate.

Determination of the amount of dissolved ATP

33 µL of sample are mixed with 300 µL of stabilizing buffer. After homogenization and incubation for one minute at room temperature, the luminescence of the solution is analyzed by removing a volume of 10 μL of sample mixed with 10 μL of luciferase in a 384-well plate.

The amount of ATP was initially quantified after contamination (T0). The samples are placed in a climatic chamber at 40 ° C and 75% relative humidity for 3 days. Then, a new quantification of GATR is carried out (T3 = T3 days after contamination).

The values obtained in cellular ATP are converted into microorganism equivalent. c / Comparison of the antimicrobial activity of SCCs compared to CM15 alone

The antimicrobial activity of the CSCs according to the invention, at a concentration of 1.10 ³ ; 1.10 ⁴ or 1.10 ⁵ mg / mL, is compared with that of CM 15 alone (that is to say in free form, not grafted) used at the same concentrations.

The results are shown in Figure 1.

The data show that CM 15 alone has no antimicrobial effect, regardless of the concentration of CM15 used.

Conversely, the use of CSCs significantly inhibits bacterial proliferation by 75.5%; 70.6% and 87.7%, respectively at concentrations of 1.10 ³ ; 1.10 ⁴ or 1.10 ⁵ mg / mL. d / Comparison of the antimicrobial activity of CSL compared to lysine alone

The antimicrobial activity of CSLs according to the invention, at a concentration of 0.5; 0.2 or 0.05 mg / mL, is compared to that of lysine alone (i.e. in free, ungrafted form) used at the same concentration.

The results are shown in Figure 2.

The data show that at a concentration of 0.5 mg / mL or 0.2 mg / mL, CSLs have the same inhibitory power against bacterial overgrowth as lysine alone.

Conversely, the use of CSLs at a concentration of 0.05 mg / mL significantly inhibits bacterial proliferation by 70%, while lysine alone has no inhibiting effect on this proliferation. 4Æexamples of composition - Micellar waters. foaming hygienes and emulsions comprising CSL or CSC according to the invention

The percentages indicated are given by weight of product relative to the total weight of the composition in the tables below.

The formulation of the composition of a micellar water comprising the CSLs according to the invention is shown in Table 3.

Table 3]

The formulation of the composition of a micellar water comprising the CSCs according to the invention is shown in Table 4.

Table 4]

The formulation of a composition corresponding to a foaming hygiene (shower gel) comprising the CSLs according to the invention is shown in Table 5.

Table 5]

The formulation of a cosmetic O / W emulsion comprising the CSLs according to the invention is shown in Table 6.

Table 6]

Claims

1. A hybrid mineral and organic complex comprising colloids of silica covalently grafted by means of a spacer arm with at least one antimicrobial peptide or its antimicrobial precursor.

2. Hybrid complex according to claim 1, characterized in that the spacer arm comprises a function of ether, ester, phosphate or amide type, advantageously ether, preferably is a linear ether comprising 3 to 10 carbons, advantageously 4 to 6 carbons.

3. Hybrid complex according to one of the preceding claims, characterized in that the at least one peptide or its precursor is chosen from the group comprising: CM15 (SEQ ID NO: 1), lysine, drosocin, attacin , diptericin, melittin, defensins, cathelicidins and their mixtures.

4. Hybrid complex according to one of claims 1 to 3, characterized in that the colloid / peptide or precursor mass ratio is between 99.9 / 0.1 and 90/10, advantageously between 93/7 and 94/6 .

5. Cosmetic or dermopharmaceutical composition comprising a hybrid complex according to one of claims 1 to 4.

6. Cosmetic or dermopharmaceutical composition according to claim 5, characterized in that the hybrid complex represents between 0.001% and 2% by total weight of the composition, preferably between 0.01% and 1%.

7. Cosmetic or dermopharmaceutical composition according to claim 5 or 6, characterized in that it is in the form of an aqueous-based solution, of a dispersion of a lotion or of an emulsion.

8. Cosmetic or dermopharmaceutical composition according to one of claims 5 to 7, characterized in that it is free of surfactants derived from polyethylene glycol.

9. Use of a hybrid complex according to one of claims 1 to 4 or of a cosmetic or dermopharmaceutical composition according to one of claims 5 to 8, as an agent for sanitizing the skin and / or a cosmetic or dermopharmaceutical composition.

10. Use according to claim 9, for reducing, reducing or inhibiting bacterial proliferation on the skin and / or in a cosmetic or dermopharmaceutical composition.