Polar wheat germ lipidate-based composition for the treatment of atopic dermatitis

Description

[0001] This patent application claims priority from French patent application FR 21 / 00391 filed on 01 / 15 / 2021. Field of invention

[0002] The present invention relates to a composition for the treatment of atopic dermatitis and, more specifically, for the treatment of atopic dermatitis resulting from an allergic reaction to dust mites in a subject. State of the art

[0003] Inflammatory skin diseases or inflammatory dermatoses are skin disorders accompanied by an inflammatory component. These diseases affect the skin and mucous membranes and are characterized by unsightly manifestations such as redness and / or scaling patches. Examples include, but are not limited to, atopic dermatitis, eczema, psoriasis, rosacea, and acne. Most often, these diseases result from immune disorders associated with inflammatory phenomena.

[0004] Atopic dermatitis is the cutaneous manifestation of atopy. It is a chronic inflammatory dermatosis, occurring on a genetically determined basis. It affects 15 to 30% of children and 2 to 10% of adults. Its prevalence is constantly increasing in industrialized countries; it has doubled or even tripled over the last three decades and it is now considered a major public health concern. Atopic dermatitis is often associated with other atopic disorders, such as allergic rhinitis and asthma. This condition most often appears during early childhood and is characterized by repeated eruptions over several years. It progresses in flare-ups interspersed with spontaneous remissions. The lesions are characterized by significant skin dryness associated with inflammatory manifestations: papular, vesicular, scaly, and very itchy erythematous eruptions.This condition is characterized by an inappropriate immune system response to environmental antigens, called allergens. In most cases, dust mites are the cause of the allergic reaction.

[0005] Dust mites are a taxon of arachnids with nearly 50,000 recorded species. These include dust mites, Dermatophagoides pteronyssinus Or Dermatophagoides farinae,are a species of house dust mite. They feed on organic detritus such as dead skin and thrive in a stable environment such as housing. The mite gut contains powerful digestive enzymes (notably proteases) that persist in feces and are major inducers of allergic reactions such as wheezing. These enzymes include peptidase 1, which is a cysteine ​​protease and is likely one of the major allergens of dust mites. Variants of this include Der p1, which is the peptidase 1 of the species Dermatophagoides pteronyssinus or Der f1 which is the peptidase 1 of the species Dermatophagoides farinae. Peptidase 1 activity causes disruption of the respiratory epithelium, the intestinal epithelium, and also the tight junctions of the skin.

[0006] Considering the complexity of atopic dermatitis, as well as the side effects associated with the treatments available for this pathology, there is a need for new compositions useful for the treatment and / or prevention of this pathology. Detailed description of the invention:

[0007] The inventors have now demonstrated that a polar lipid-based extract of wheat germ, which is rich in ceramides and digalactosyldiacylglycerides (DGDG), can inhibit the effect of dust mites on e-cadherin. in vitro And ex vivo, whereas ceramides alone from other sources show no effect.

[0008] Ceramides are sphingolipids resulting from the combination of a fatty acid with sphingosine via an amide bond. These molecules are abundant in cell membranes, where they are used to form sphingomyelins. It should be noted that ceramides do not only play a structural role in biological membranes, since they can also have lipid signaling functions. These functions include actions on cell differentiation, programmed cell death (apoptosis), and cell proliferation.

[0009] Galactoglycerolipids (i.e. monogalactosyldiacylglycerol, MGDG and digalactosyldiacylglycerides, DGDG) are the major lipids of chloroplast membranes, representing up to 80% of the plastid membrane composition.

[0010] Furthermore, the inventors have demonstrated that a combination of such oil extracted from wheat flour with oligofructans 'Ophiopogon japonicus allowed to obtain a synergistic effect on atopic dermatitis.

[0011] Accordingly, a first subject matter relates to a dermatological composition comprising at least one extract based on polar lipids of wheat germ for use in preventing and / treating atopic dermatitis resulting from an allergic reaction to dust mites in a subject.

[0012] Advantageously, for use in preventing and / or treating tight junction damage associated with atopic dermatitis following an allergic reaction to dust mites in a subject.

[0013] As for the subject, it is a mammal and preferably a human.

[0014] The composition according to the invention is applied to the affected skin surface at least once a day.

[0015] - The composition according to the invention is applied for at least one week to obtain the best effectiveness and, preferably, for at least one month.

[0016] According to a preferred embodiment, the composition according to the invention aims to prevent and / or treat atopic dermatitis resulting from an allergic reaction to peptidase 1 (Der p1 or Der f1) of dust mites in a subject.

[0017] Wheat germ (or wheat flour) polar lipid extract can be found in the form of an oil, an emulsion, or a powder.

[0018] In the case of a powder, such extracts are available from HITEX (LIPOWHEAT POWDER), ENNAGRAM (CENNAMIDE water-dispersible powder), EPI France (WHEAT CERASOMES POWDER) and from SEPPIC (CERAMOSIDES powder).

[0019] In the context of an oil, such extracts simply correspond to wheat germ oil. Now, such extracts are available from HITEX (LIPOWHEAT OIL), ENNAGRAM (CENNAMIDE "wheat lipids at 15% CERs"), EPI France (WHEAT CERASOMES OIL) and SEPPIC (CERAMOSIDES oil).

[0020] In the context of an emulsion, again it is simply an emulsified wheat germ oil. Now, such extracts are available from ENNAGRAM (CENNAMIDE "water soluble emulsion at 5% CERs") and from EPI France (WHEAT CERASOMES EMULSION) and from SEPPIC (CERAMOSIDES oil).

[0021] Preferably, the extract is in powder form.

[0022] Such a powder then comprises nearly 50% ceramides (glycosphingolipids and glycolipids) and nearly 40% digalactosyldiacylglycerides.

[0023] Advantageously, the powder used has a ceramide content of 40% or more (by weight relative to the total weight of the oil), preferably 50% or more.

[0024] Advantageously, the powder used has a digalactosyldiacylglyceride content of 30% or more (by weight relative to the total weight of the oil), preferably 40% or more.

[0025] Methods for obtaining such an extract, whether in the form of an oil, an emulsion or a powder, are known to those skilled in the art.

[0026] Extraction methods are notably in patents FR 2 886 846 B1 or FR 2 779 646.

[0027] Synthetically, the oil corresponds to the total oily fraction of wheat germ (preferably in the form of flour to facilitate extraction) which is extracted using solvents capable of solubilizing lipids. Such a solvent is typically an alcohol such as methanol, isopropanol, 1-butanol or ethanol. Such an extraction is typically carried out under stirring and, advantageously using the beneficial effect of temperature, the value of which is chosen according to the solvent used. The result of this extraction step is a heterogeneous mixture consisting of the exhausted solid of lipids and the extraction solution. It is therefore important to collect the liquid phase by separating the solid phase from it (screening, decantation, filtration, etc.). This separation can be done with the prior addition of an adjuvant capable of fixing water and retaining proteins such as diatomaceous earth.

[0028] The oil can be obtained simply by distillation of the filtrate obtained. This wheat flour (germ) oil then generally comprises around 15% ceramides and 15% digalactosyldiacylglycerides. In the context of an emulsion, this oil is simply emulsified using techniques well known to those skilled in the art and the proportion of ceramides and digalactosyldiacylglycerides then drops to around 5% (due to the addition of water and emulsifiers leading to their dilution).

[0029] Now, and in the case where one would like a powder corresponding to an "enriched" polar lipid extract, it is simply necessary to use the difference in solubility of these polar lipids compared to the apolar lipids. To do this, it is possible to directly precipitate the polar lipids by adding to the oil a solvent in which they are not soluble (e.g. acetone) as described in patent FR 2 779 646 B1. It is also possible, and starting from the filtrate (and not from the distillate which constitutes the oil), to carry out a liquid / liquid extraction using a two-phase system with two immiscible solvents, one of which does not solubilize the polar lipids (e.g. heptane / methanol) as described in patent FR 2 886 846 B1. Polar lipids are preferentially maintained in one of the phases and successive extractions thus allow an enrichment in polar lipids before evaporating the solvent.

[0030] Advantageously, the content of the composition according to the invention in extract, whether in the form of oil, emulsion or powder, is between 0.01 and 15% (by weight relative to the total weight of the composition).

[0031] In the case of a powder, the content is preferably between 0.1 and 0.5%.

[0032] The composition according to the invention is intended for topical application to the skin, in particular the skin of the face and body. As such, the composition according to the invention takes the form of a cream, a serum, a milk, a lotion or a gel.

[0033] Preferably, the composition according to the invention will take the form of a cream.

[0034] According to another preferred embodiment, the composition according to the invention further comprises at least oligofructans d 'Ophiopogon japonicus.

[0035] Ophiopogon japonicusor Japanese lily of the valley, is a perennial herbaceous plant found naturally in China, Japan, India and Vietnam.

[0036] By oligofructans d 'Ophiopogon japonicus, we mean the polysaccharides present in tubers, which are mainly fructans.

[0037] Advantageously, the content of the composition according to the invention oligofructans of Ophiopogonjaponicus is between 0.01 and 5% (by weight relative to the total weight of the composition), preferably it is between 0.05 and 1% and, particularly preferably, between 0.3 and 0.7%.

[0038] In general, the composition according to the invention may comprise numerous types of adjuvants or active ingredients used in pharmaceutical or cosmetic formulations, preferably dermatological, whether fatty substances, organic solvents, thickeners, gelling agents, softeners, antioxidants, opacifiers, stabilizers, foaming and / or detergent surfactants, emollients, superfatting agents, perfumes, ionic or non-ionic emulsifiers, fillers, sequestering agents, chelators, preservatives, essential oils, coloring materials, pigments, hydrophilic or lipophilic active ingredients, humectants, such as for example glycerin or glycols, preservatives, colorants, cosmetic active ingredients, mineral and / or organic sunscreens, mineral fillers, synthetic fillers, silicone elastomers, or plant extracts or lipid vesicles,or any other ingredient usually used in cosmetics.,

[0039] Examples of oils include paraffins, isoparaffins, white mineral oils, vegetable oils (from flowers, fruits, vegetables, trees, cereals, oilseeds, etc.), animal oils, synthetic oils, silicone oils and fluorinated oils;and more particularly: oils of vegetable origin, such as sweet almond oil, coconut oil, castor oil, jojoba oil, olive oil, rapeseed oil, peanut oil, sunflower oil, wheat germ oil, corn germ oil, soybean oil, cottonseed oil, alfalfa oil, poppy seed oil, pumpkin oil, evening primrose oil, millet oil, barley oil, rye oil, safflower oil, candlenut oil, passionflower oil, hazelnut oil, palm oil, shea butter, apricot kernel oil, calophyllum oil, sisymbra officinalis oil, avocado oil, calendula, oils from flowers or vegetables; ethoxylated vegetable oils; oils of animal origin, such as squalene, squalane; mineral oils, such as paraffin oil, vaseline oil and isoparaffins;synthetic oils, including fatty acid esters such as butyl myristate, propyl myristate, cetyl myristate, isopropyl palmitate, butyl stearate, hexadecyl stearate, isopropyl stearate, octyl stearate, isocetyl stearate, dodecyl oleate, hexyl laurate, propylene glycol dicaprylate;esters derived from lanolic acid, such as isopropyl lanolate, isocetyl lanolate, monoglycerides, diglycerides and triglycerides of fatty acids such as glycerol triheptanoate, alkylbenzoates, polyalphaolefins, polyolefins such as polyisobutene, synthetic isoalkanes such as isohexadecane, isododecane, perfluorinated oils and silicone oils. Among the latter, we can more particularly cite dimethylpolysiloxanes, methylphenylpolysiloxanes, silicones modified by amines, silicones modified by fatty acids, silicones modified by alcohols, silicones modified by alcohols and fatty acids, silicones modified by polyether groups, modified epoxy silicones, silicones modified by fluorinated groups, cyclic silicones and silicones modified by alkyl groups.;

[0040] Other fats that may be mentioned are linear or branched, saturated or unsaturated fatty alcohols, mixtures of linear and / or branched, saturated and / or unsaturated fatty alcohols, or linear or branched, saturated or unsaturated fatty acids, mixtures of linear or branched, saturated or unsaturated fatty acids.

[0041] Among the thickening and / or emulsifying polymers that can be used, there are, for example, homopolymers or copolymers of acrylic acid or acrylic acid derivatives, homopolymers or copolymers of methacrylic acid or methacrylic acid derivatives, homopolymers or copolymers of acrylamide, homopolymers or copolymers of acrylamide derivatives, homopolymers or copolymers of acrylamidomethyl propanesulfonic acid, homopolymers or copolymers of vinyl monomers, homopolymers or copolymers of trimethylaminoethylacrylate chloride, hydrocolloids of plant or biosynthetic origin such as, for example, xanthan gum, karaya gum, carrageenans, alginates; silicates; cellulose and its derivatives; starch and its hydrophilic derivatives; polyurethanes.

[0042] Among the polyelectrolyte polymers that can be used in the production of a gelled aqueous phase suitable for use in the preparation of W / O, O / W, W / O / W or O / W / O emulsions, or of an aqueous gel comprising SEPIBIO ™< POTENTILLA 217, there are, for example, copolymers of acrylic acid and 2-methyl-[(1-oxo-2-propenyl)amino] 1-propane sulfonic acid (AMPS), copolymers of acrylamide and 2-methyl-[(1-oxo-2-propenyl)amino] 1-propane sulfonic acid, copolymers of 2-methyl-[(1-oxo-2-propenyl)amino] 1-propane sulfonic acid and (2-hydroxyethyl)acrylate, homopolymer of 2-methyl-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid, acrylic acid homopolymer, copolymers of acryloyl ethyl trimethyl ammonium chloride and acrylamide, copolymers of AMPS and vinylpyrrolidone, copolymers of AMPS and N,N-dimethylacrylamide., terpolymers of AMPS, acrylic acid and N,N-dimethylacrylamide, copolymers of acrylic acid and alkyl acrylates whose carbon chain comprises between ten and thirty carbon atoms, copolymers of AMPS and alkyl acrylates whose carbon chain comprises between ten and thirty carbon atoms.

[0043] Among the waxes that can be used in the compositions according to the invention, mention may be made, for example, of beeswax, carnauba wax, Candelilla wax, Ouricoury wax, Japan wax, China wax, rice bran wax, Montan wax, cork or sugar cane fiber wax, paraffin waxes, lignite waxes, microcrystalline waxes, lanolin wax, ozokerite, polyethylene wax, hydrogenated oils, silicone waxes, alkenone waxes, vegetable waxes, fatty alcohols and fatty acids that are solid at room temperature, and glycerides that are solid at room temperature.

[0044] Among the emulsifiers that can be used in the compositions according to the invention, mention may be made of: optionally alkoxylated alkylpolyglycoside fatty esters; alkoxylated fatty esters; fatty chain polyalkylene glycol carbamates; fatty acids, ethoxylated fatty acids, sorbitol fatty acid esters, ethoxylated fatty acid esters, polysorbates, polyglycerol esters, ethoxylated fatty alcohols, sucrose esters, alkylpolyglycosides, sulfated and phosphated fatty alcohols or mixtures of alkylpolyglycosides and fatty alcohols; combinations of emulsifying surfactants chosen from alkylpolyglycosides; combinations of alkylpolyglycosides and fatty alcohols, polyglycerol or polyglycol or polyol esters.

[0045] Among the surfactants that can be used in the compositions according to the invention, mention may be made of: topically acceptable anionic, cationic, amphoteric or non-ionic surfactants usually used in this field of activity.

[0046] Among the anionic surfactants that can be used in the compositions according to the invention, mention will be made in particular of alkali metal salts, alkaline earth metal salts, ammonium salts, amino acid salts, amino alcohol salts of the following compounds: alkyl ether sulfates, alkyl sulfates, alkylamidoether sulfates, alkylarylpolyether sulfates, monoglyceride sulfates, alpha-olefinsulfonates, paraffin sulfonates, alkylphosphates, alkyletherphosphates, alkylsulfonates, alkylamidesulfonates, alkylarylsulfonates, alkylcarboxylates, alkylsulfosuccinates, alkylethersulfosuccinates, alkylamidesulfosuccinates, alkylsulfoacetates, alkylsarcosinates, acylisethionates, N-acyltaurates, acyllactylates.

[0047] Among the amphoteric surfactants that can be used in the compositions according to the invention, mention may be made of alkylbetaines, alkylamidobetaines, sultaines, alkylamidoalkylsulfobetaines, imidazoline derivatives, phosphobetaines, amphopolyacetates and amphopropionates.

[0048] In order to further potentiate the activity obtained by the composition according to the invention, it may be combined with other active ingredients, in particular those known for their anti-aging, firming, restructuring, stimulating, energizing, anti-wrinkle, relaxing, moisturizing, antimicrobial, sebum-regulating, purifying, soothing, relaxing, decontracting, anti-stress, lightening, immunomodulating, cell renewal stimulating, lifting, plumping, complexion radiance improving action, etc.

[0049] According to a second object, the composition described above is used in a method which aims to prevent and / or treat atopic dermatitis following an allergic reaction to dust mites in a subject and comprises a step of administering a therapeutically effective amount of the latter to a skin surface of said subject.

[0050] By "therapeutically effective amount" is meant an amount sufficient to achieve the desired biological effect.

[0051] Advantageously, the method according to the invention aims to prevent and / or treat atopic dermatitis resulting from an allergic reaction to peptidase 1 (Der p1 or Der f1) of dust mites in a subject.

[0052] The invention will be better understood in light of the following examples, which are given purely for illustrative purposes and are not intended to limit the scope of the invention, defined by the appended claims. Examples Example 1: Preparation of a composition according to the invention:

[0053] For this study in vitro, 3 ceramides named HP ceramides (SEPPIC, powder), Y30 ceramides (DOOSAN) and DS ceramides (DOOSAN) were tested.

[0054] For this purpose, keratinocytes extracted from foreskin were cultured either in KGM keratinocyte culture medium (LONZA) according to the conditions defined by the manufacturer. These keratinocytes were cultured in the presence or absence of dust mite extracts (HDM) at 100 / µg / ml for 24h, but also in the presence or absence of ceramides at different concentrations (1 / 20, 1 / 50 and 1 / 100).

[0055] Then the keratinocytes were collected and the expression level of the junction protein E-cadherin and the metalloproteinase MMP-9 were determined by immunofluorescence and western blotting. All these experiments were carried out three times.

[0056] The results confirmed the decrease in the expression level of e-cadherin in the presence of dust mite (HDM) extracts. The results also showed that DS ceramides and Y30 ceramides showed no effect on the decrease in this expression level of e-cadherin in the presence of dust mite (HDM) extracts.

[0057] In contrast, and unexpectedly, HP ceramides (SEPPIC) showed a clear inhibition of the effect of HDM on the expression level of e-cadherin. Indeed, in the presence of HDM and the 3 concentrations of HP ceramides, the level of E-cadherin remained stable.

[0058] Determining the mechanism involved in these results revealed that HDM increases the expression level of the metalloprotease MMP9, which increase is inhibited by HP ceramosides. It therefore appears that the combination of ceramides and digalactosyldiacylglycerides (DGDG) present in this active ingredient (corresponding to oil extracted from wheat flour) allows this surprising effect to be obtained, allowing the maintenance of normal tight junctions in the presence of HDM.

[0059] Similar results were obtained using other sources of wheat germ polar lipid extract (WHEAT CERASOMES OIL, EPI) as well as with wheat germ oil.

[0060] The results also showed that the addition of AD-Resyl made it possible to potentiate the effectiveness of ceramide HP. Example 2: Effectiveness of the composition according to the invention...:

[0061] Skin biopsies of 4 mm diameter from 3 healthy volunteers were taken.

[0062] These biopsies were incubated in the presence or absence of dust mite (HDM) extracts at 100 / µg / ml for 30 minutes. The biopsy was then covered with a cream comprising 0.08 or 0.1% HP ceramide and re-cultured for 24 hours in the presence or absence of HDM.

[0063] The results showed that at both concentrations, HP ceramides helped preserve the structural integrity of the skin unlike the controls.

Claims

1. A dermatological composition comprising at least one extract based on polar lipids of wheat germ for use in preventing and / or treating atopic dermatitis resulting from an allergic reaction to dust mites in a subject.

2. The dermatological composition for use according to claim 1, characterized in that it aims to prevent and / or treat the alteration of tight junctions associated with atopic dermatitis resulting from an allergic reaction to dust mites in a subject.

3. The dermatological composition for use according to claim 1, characterized in that this atopic dermatitis results from an allergic reaction to peptidase 1 (Der p1 or Der f1) of dust mites.

4. The dermatological composition for use according to any one of the preceding claims, characterized in that the subject is a human.

5. The dermatological composition for use according to any one of the preceding claims, characterized in that said extract is in the form of an oil, an emulsion, or a powder.

6. The dermatological composition for use according to the preceding claim, characterized in that said extract is in the form of a powder.

7. The dermatological composition for use according to the preceding claim, characterized in that said extract has a ceramide content of 40% or more (by weight relative to the total weight of the oil), preferably of 50% or more.

8. The dermatological composition for use according to claim 6, characterized in that said extract has a digalactosyldiacylglycerides content of 30% or more (by weight relative to the total weight of the oil), preferably of 40% or more.

9. The dermatological composition for use according to any one of the preceding claims, characterized in that the extract content of the composition according to the invention is comprised between 0.01 and 15% (by weight relative to the total weight of the composition).

10. The dermatological composition for use according to any one of the preceding claims, characterized in that it further comprises oligofructans of Ophiopogon japonicus.

11. The composition for use according to the preceding claim, characterized in that the oligofructans of Ophiopogon japonicus are the polysaccharides present in its tubers.

12. The composition for use according to any one of claims 10 or 11, characterized in that the content of oligofructans of Ophiopogon japonicus is comprised between 0.01 and 5% (by weight relative to the total weight of the composition), preferably it is comprised between 0.05 and 1% and, particularly preferably, between 0.3 and 0.7%.