FR3080767A1 - EXTRACT FROM THEOBROMA COCOA BEANS TO COMBAT ROSACEA AND SKIN REDNESS - Google Patents

Abstract

The present invention relates to an extract of bean shells of Theobroma cacao or a cosmetic or dermatological composition containing such an extract and its applications in the fields of cosmetics and dermatology to prevent and / or fight against redness of the skin. The present invention relates in particular to an extract of cocoa bean shells or a cosmetic or dermatological composition comprising said extract for preventing and / or treating rosacea.

Description

TECHNICAL AREA

The present invention relates to an extract of Theobroma cocoa bean hulls and the compositions containing this extract for application in the fields of cosmetics and dermatology for combating skin redness.

More particularly, the present invention relates to an extract of Theobroma cocoa bean hulls and the compositions containing this extract for combating rosacea.

STATE OF THE PRIOR ART

The skin is the most extensive organ of the human body, almost 2m ² in area. It plays several fundamental roles including that of protection vis-à-vis the outside, thermal regulation, hormonal synthesis and it also has an immune function. The skin is made up of three superimposed layers which are the epidermis, in permanent renewal, the dermis and the hypodermis which ensures the fibrous framework. The color, texture and quality of the skin also has an undeniable psychosocial function.

Sensitive skin has in common to react quickly and excessively to a change in temperature, to cold, to the wind, to irritating hygiene or toilet products, to unsuitable care. Redness of the face is the prerogative of sensitive skin, this skin which is distinguished by an exacerbated reactivity of the skin and skin vessels. The redness is more or less intermittent, but always unpleasant and annoying.

Intermittent redness, also called "flush" is a reaction of acute vasodilation which can be due to a trivial or slightly "stressful" situation such as a questioning for a student, a job interview, an emotionally moving or confrontational conversation but also to a change in temperature which calls for the circulation of blood at the level of the face. Too hot a diet, alcoholic beverages or certain foods (spices, mustard, etc.) can also cause this redness.

Various factors can favor and aggravate these rednesses: external factors, like the cold or the sun which cause an acceleration of the cutaneous micro-circulation; internal factors such as emotions, consumption of coffee or spices; heredity: redness can appear in people with vasoreactive skin, a skin characteristic that can be familial; or even skin aging: from 25 years the skin is more sensitive to redness.

In the long run, the redness can become permanent, especially in the cheeks. This is called erythrosis which is a diffuse but permanent redness localized most often on the cheeks in the form of red patches.

Rosacea represents an aggravation of erythrosis with the appearance of small dilated vessels.

When pimples appear and the redness becomes permanent, this is called rosacea. It was formerly called "acne rosacea", because in addition to the redness, it also has pimples that remind acne of adolescents.

Rosacea is a common chronic and progressive inflammatory dermatosis linked to vascular relaxation. It is a condition that affects the small vessels of the face. It frequently affects people with fair skin and can have significant psycho-emotional consequences. The name of this pathology refers to the characteristic color that the face takes on during the illness. The general appearance of the face wrongly evoking a chronic excess of alcohol consumption, rosacea is a socially difficult disease to live with, in particular by women. Rosacea is a fairly common disease, since in France, 2 to 3% of the adult population is affected. Women are particularly affected, since there are two women for a man suffering from rosacea. It mainly affects the central part of the face and is characterized by reddening of the face or flushing, facial erythema, papules, pustules, telangiectasia and sometimes eye damage called ocular rosacea. In severe cases, especially in humans, the soft tissue in the nose can swell and produce a bulbous swelling called rhinophyma. Rosacea evolves, but not obligatorily, over several years by attacks aggravated by different stimuli such as temperature variations, alcohol, spices, sun exposure or emotions.

The mechanisms of rosacea are still very poorly understood today. Among the certainties of scientists, there is the vascular origin of the disease. The blood vessels are said to carry an abnormality of operation, in particular in subjects of the Nordic type with light skin, clear eyes and light hair. This geographic predisposition is found in France, where the disease is very rare in the south and much more frequent north of the Loire. On the other side of the Mediterranean, and particularly on black skin, the disease is practically non-existent.

It is common to classify rosacea into 4 types based on clinical characteristics according to Wilkin et al., J. Am. Acad. Dermatol., 46 (4): 584-587, 2002.

Primary characteristics such as flushing, persistent erythema, papules and pustules, telangiectasias and secondary characteristics such as burning or stinging sensations, plaques, dry skin, edema, ocular manifestations, phymatous changes in rosacea are often seen in combination. All these signs allow patients to be divided into these four types, but it is possible that patients simultaneously present characteristics suggestive of more than one type of rosacea.

Erythematotelangiectatic rosacea: it is mainly characterized by flushing and persistent central facial erythema. The presence of telangiectasias is common, but not essential to the diagnosis of this type. Central facial edema, burning and stinging sensations and roughness or flaking are also sometimes observed.

Papulopustular rosacea: it is characterized by a persistent central facial erythema and by transient papules and / or pustules distributed in the center of the face. However, papules and pustules can also affect peri-artificial regions, such as the perioral, perinasal or periocular areas. This type of rosacea is reminiscent of acne, but blackheads are absent. But rosacea and acne can coexist. Patients with this type of rosacea sometimes complain of burning and stinging sensations. This type is often observed before or at the same time as the previous type, including the presence of telangiectasias. The latter may be masked by persistent erythema and papules or pustules.

Phymatous rosacea: it manifests as thickening of the skin, nodules with an irregular surface and swelling. Rhinophyma is the most common presentation, but phymatous rosacea can affect other areas, such as the chin, forehead, cheeks or ears. In patients with this type of rosacea, the presence of enlarged and prominent follicular openings is sometimes reported in the affected area, as well as telangiectasias. This type is often observed before or at the same time as types 1 or 2. In case of rhinophyma, these additional stigmas are likely to be particularly pronounced in the nasal region.

Ocular or ophthalmic rosacea: the diagnosis of ocular rosacea should be considered when a patient has one or more of the following ocular signs and symptoms: watery or bloodshot appearance, feeling of a foreign body, burning or stinging, dryness, itching, photosensitivity, blurred vision, telangectiasis of the conjunctiva and the edge of the eyelid or erythema of the eyelid and periocular. Blepharitis, conjunctivitis and irregularity of the edges of the eyelid are other signs that may be detected. A chalazion or a chronic staphylococcal infection manifested by a stye and the cause of which is a dysfunction of the Meibomian glands is a frequent sign of eye disease linked to rosacea.The diagnosis of ocular rosacea is most often made when signs and skin symptoms are also detected.

Finally there are other rarer forms of rosacea, in particular granulomatous rosacea.

Despite its frequency, its causes are still unclear, and may involve several factors. Diet and climatic factors play a role in the disease and have an impact on these symptoms. Occasionally, in patients with rosacea, there is a dysfunction of the facial veins, which results in stagnation of blood in the vessels of the face, resulting in cascade of dilation of the vessels, edema and alteration of the endothelium.

Corticosteroids can also be incriminated, especially in 2 situations. The first is rosacea which is aggravated by the application of corticosteroids. The second is the appearance of the disease following long-term use of this type of medication, we even speak of steroid rosacea.

Oral treatments with tetracycline derivatives are problematic for several reasons but in particular for their non-negligible side effects. Oral administration of tetracyclines, such as doxycycline, can induce photosensitivity, even phototoxicity or gastrointestinal disorders.

Application WO2002 / 074290 describes the topical use of at least one non-steroidal anti-inflammatory compound for treating rosacea, these compounds can be combined with a nitro-imidazole compound. However, it is reported that the combination of this treatment induces significant side effects, in particular gastrointestinal and renal (Edwards, Br. J. Vener Dis., 56, 285-290, 1980).

There is therefore a need to have new active ingredients to combat skin redness and for the treatment of rosacea, that they can be used for long periods with side effects as limited as possible.

SUMMARY OF THE INVENTION

Surprisingly, the inventors discovered that an extract of Theobroma cocoa bean hulls had an agonist activity on the OC2B-adrenergic receptors (Example 1) but also inhibitory properties on the growth factor VEGF and anti inflammatory by inhibiting the production of IL8 (Example 2).

The present invention thus relates to an extract of Theobroma cocoa bean hulls for its use in the prevention and / or treatment of rosacea.

The present invention also relates to a cosmetic or dermatological composition comprising at least one extract of Theobroma cocoa bean shells and at least one cosmetically or dermatologically acceptable excipient for its use in the prevention and / or treatment of rosacea.

Preferably, this treatment or prevention is carried out topically, which considerably reduces any systemic side effect.

The present invention also relates to an extract of Theobroma cocoa bean hulls for its use in the prevention and / or treatment of skin rashes.

The present invention also relates to a cosmetic or dermatological composition comprising at least one extract of Theobroma cocoa bean shells and at least one cosmetically or dermatologically acceptable excipient for its use in the prevention and / or treatment of skin rashes.

The present invention also relates to the cosmetic use of an extract of Theobroma cocoa bean hulls to prevent and / or fight against skin redness.

The present invention also relates to the cosmetic use of a cosmetic or dermatological composition comprising at least one extract of the shell of Theobroma cocoa beans and at least one cosmetically or dermatologically acceptable excipient for preventing and / or combating skin redness.

The redness of the skin can be intermittent redness (i.e. flushes) or erythritis, these redness being particularly localized in the cheeks.

DEFINITIONS

By "extract of Theobroma cocoa bean hulls" is intended to denote the product of extraction of bean hulls from a

or more species of Theobroma cocoa. Through "Shells of Theobroma cocoa beans "means designate the seed coat hard and fine that envelops the bean of Theobroma cocoa.

By “extraction product” is meant the product obtained after extraction of the Theobroma cocoa bean shells with a solvent, called extraction solvent, (that is to say a liquid solution in the extraction solvent ) optionally in a concentrated or dry form after partial or total evaporation of the extraction solvent.

By “hydrophilic extract” is meant an extract obtained by the use of at least one hydrophilic solvent as extraction solvent. Preferably, it is an extract obtained by extraction using one or more hydrophilic solvents.

By "aqueous extract" means an extract obtained by the use of at least one aqueous solvent as extraction solvent. Preferably, it is an extract obtained by extraction using one or more aqueous solvents.

By "hydro-glycolic extract" means an extract obtained by the use of at least one hydro-glycolic solvent as extraction solvent. Preferably, it is an extract obtained by extraction using one or more hydro-glycolic solvents.

By “hydrophilic solvent” is meant a solvent chosen from the group consisting of water, C1 to C5 alcohols (for example ethanol), C3 to C5 glycols (for example butylene glycol), glycerol, l acetone, C1 to C5 alkyl esters (eg ethyl acetate, isopropyl acetate) and mixtures thereof.

By "aqueous solvent" is meant a solvent chosen from the group consisting of water alone and water in combination with one or more C1 to C5 alcohols (for example ethanol), one or more C3 to C5 glycols and combinations thereof.

By "hydro-glycolic solvent" is meant a mixture of water and at least one C3 to C5 glycol, in particular propylene glycol, butylene glycol, pentylene glycol or a combination of these. Advantageously, it is a water / butylene glycol mixture.

By “dry extract” is meant within the meaning of the present invention, an extract devoid of extraction solvent or support or containing it only in the non-significant trace state. Such a dry extract thus contains only material obtained from the shells of Theobroma cocoa beans. It may also contain insignificant traces of extraction solvent.

By “topical application” is meant an application to the skin, the mucous membranes and / or the integuments, in particular to the skin.

By the term "treatment" or "treating" rosacea is meant to decrease and / or inhibit the development of rosacea and / or at least one of its symptoms.

By the term "prevention" or "preventing" rosacea is meant to decrease and / or avoid the appearance of at least one of the symptoms of rosacea.

By "rosacea symptom" is meant persistent redness, burning and stinging sensations, flushing or telangiectasia.

By "skin rash" is meant more particularly intermittent skin rash (such as flushes or redness due to external factors such as cold or wind) or permanent (such as erythritis), more particularly localized in play.

By the term “treatment” or “treat” or “fight” or “fight” skin rashes, it is intended to reduce and / or suppress the development of skin redness.

By the term “prevention” or “prevent” skin redness, it is intended to reduce and / or avoid the appearance of skin redness.

In the present invention, the term “cosmetically or dermatologically acceptable” is intended to denote that which is useful in the preparation of a cosmetic or dermatological composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for a cosmetic or dermatological use, in particular by topical application and / or by oral administration.

DETAILED DESCRIPTION

Also called cocoa or cocoa tree, the cocoa tree (Theobroma cacao) is a small evergreen tree of the genus Theobroma of the Sterculiaceae family according to the classic classification, or Malvaceae according to the phylogenetic classification. It produces edible beans with different flavors depending on the varieties of cocoa tree, from which cocoa, the basic product of chocolate, is made. The cocoa tree is a tropical species native to Mexico. It grows naturally in the Orinoco and Amazon basins at low altitude, at the foot of the Andes Cordillera. It is a tree that measures 10 to 15 meters high, cauliflower and evergreen. It blooms from three years and gives flowers, fruits and leaves all year round. It reaches its full yield 6 to 7 years after planting and lives up to 40 years. Only one flower in about 500 gives fruit. The tree can produce up to 100,000 flowers annually. At the same time, we find flowers and fruits on the tree. Its fruits, pods, are large, elongated berries. Each pod can weigh up to 400g and is 15 to 20cm long. They have the particularity of growing both on the friendly master branches also directly on the trunk of the tree. Their characteristics vary greatly from one population to another, but also within the same population. The ripening of the fruits lasts, depending on the genotypes, from 5 to 7 months. On average, a tree produces around 150 pods per year, which gives almost 6 kg of cocoa. The pods contain many seeds, from 25 to 75, grouped in spikes and called cocoa beans, rich in starch, fat and alkaloids. Each ripe seed is surrounded by a pulp called mucilage. The fresh beans collected in the pod are fermented and then dried to give what are called cocoa beans which will be used to prepare the cocoa itself. These beans contain a purple embryo provided with 2 large fleshy cotyledons, curled around a rest of albumen. The beans are protected by a hard seed coat, the shell, which completely envelops them. Cocoa beans are rich in xanthic bases and more particularly in theobromine and caffeine. In addition, the cocoa bean hulls have significant contents of polyphenols (anthocyanins, flavonoids).

According to one embodiment of the invention, the extract of Theobroma cocoa bean shells is a liquid extract, more particularly a hydrophilic extract, more particularly still an aqueous extract and even more particularly a hydro-glycolic extract.

This extract may in particular be obtained by extraction with at least one hydrophilic solvent, preferably with at least one aqueous solvent and even more preferably with at least one hydro-glycolic solvent.

According to a particular embodiment, this extract is obtained by extracting the shells of Theobroma cocoa beans, preferably previously crushed or ground, for example previously crushed, using one or more hydro-glycolic solvent (s) ( s), such as a water / butylene glycol mixture, for example in a water / butylene glycol ratio of 25/75 to 40/60.

The Theobroma cocoa bean shell extract according to the invention advantageously contains 45% to 65% by weight of caffeine relative to the weight of the dry extract. The Theobroma cocoa bean shell extract according to the invention will also advantageously contain 1.5% to 3.0% by weight of theobromine relative to the weight of the dry extract.

For example, the extract according to the present invention can be obtained by extraction of shells of Theobroma cocoa beans crushed using a water / butylene glycol mixture as extraction solvent, for example in a water / butylene glycol ratio from 25/75 to 40/60.

The bean extract of Theobroma cocoa beans obtainable by such an extraction example will advantageously contain 1.5 to 2.1% by weight of caffeine and 0.05 to 0.09% by weight of theobromine relative to the total weight of the extract. Such an extract advantageously contains 1 to 5%, in particular 2 to 4% by weight of dry extract. Such an extract may be used as it is (solution with the extraction solvent) or in the form of a concentrated extract or dry extract after partial or total evaporation of the extraction solvent.

According to a first aspect, the invention relates to an extract of Theobroma cocoa bean shells, in particular as defined above, for its use in the treatment and / or prevention of rosacea.

The invention also relates to the use of an extract of Theobroma cocoa bean hulls, in particular as defined above, for the manufacture of a medicament intended for the prevention and / or treatment of rosacea.

The invention also relates to a method for the prevention and / or treatment of rosacea comprising the administration to an individual in need of an effective amount of an extract of Theobroma cocoa bean hulls, in particular as defined above. above.

In a particular embodiment, the invention thus aims to provide a treatment for rosacea, which in particular reduces the side effects for the patient. Preferably, this treatment is carried out topically, which considerably reduces any systemic side effect.

Rosacea can be selected from the group consisting of erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea.

According to a second aspect, the present invention also relates to an extract of the shell of Theobroma cocoa beans, in particular as defined above, for its use in the prevention and / or treatment of skin rashes.

The invention also relates to the use of an extract of Theobroma cocoa bean hulls, in particular as defined above, for the manufacture of a medicament intended for the prevention and / or treatment of skin rashes.

The invention also relates to a method for preventing and / or treating redness of the skin comprising the administration to an individual in need of an effective amount of an extract of the Theobroma cocoa bean shell, in particular as defined above. above.

The present invention also relates to the cosmetic use of an extract of the shell of Theobroma cocoa beans, in particular as defined above, to prevent and / or fight against skin redness.

The present invention thus also relates to a cosmetic method for preventing and / or combating skin redness comprising the use, preferably by topical application, of an extract of the shells of Theobroma cocoa beans, in particular as defined above.

The use of the shell extract of Theobroma cocoa beans according to the invention is preferably topically.

Skin rashes are as defined above. Preferably, the redness of the skin is localized on the cheeks.

According to a third aspect, the present invention also relates to a cosmetic or dermatological composition comprising at least one extract of the shell of Theobroma cocoa beans, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient, for its use in the treatment and / or prevention of rosacea.

The invention also relates to the use of a cosmetic or dermatological composition comprising at least one extract of Theobroma cocoa bean shell, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient, for the manufacture of 'a medicine intended for the prevention and / or treatment of rosacea.

The invention also relates to a method for the prevention and / or treatment of rosacea comprising the administration to an individual in need of an effective amount of a cosmetic or dermatological composition comprising at least one extract of Theobroma bean shells cocoa, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient.

According to a particular embodiment, the composition according to the invention is in a form suitable for topical application.

According to a fourth aspect, the present invention also relates to a cosmetic or dermatological composition comprising at least one extract of the shell of Beans of Theobroma cacao, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient, for its use in the treatment and / or prevention of skin redness.

The invention also relates to the use of a cosmetic or dermatological composition comprising at least one extract of Theobroma cocoa bean shell, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient, for the manufacture of '' a medicine intended for the prevention and / or treatment of redness of the skin.

The invention also relates to a method for preventing and / or treating skin rash comprising administering to an individual in need of an effective amount of a cosmetic or dermatological composition comprising at least one extract of Theobroma bean shells cocoa, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient.

The subject of the present invention is also the cosmetic use of a cosmetic or dermatological composition comprising at least one extract of the shell of Theobroma cocoa beans, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient, for prevent and / or fight against redness of the skin.

The present invention thus also relates to a cosmetic method for preventing and / or combating skin redness comprising the use, preferably by topical application, of a cosmetic or dermatological composition comprising at least one extract of the shells of Theobroma cocoa beans, in particular as defined above, with at least one cosmetically or dermatologically acceptable excipient.

The use of the cosmetic or dermatological composition according to the invention is preferably topically.

Skin rashes are as defined above. Preferably, the redness of the skin is localized on the cheeks.

The cosmetic or dermatological compositions according to the third or fourth aspect of the invention may be in the forms which are usually known for topical administration, that is to say in particular lotions, foams, gels, dispersions, emulsions , sprays, serums, masks or creams, jellies, in particular micellar jellies, with excipients allowing in particular skin penetration in order to improve the properties and accessibility of the active principle. Advantageously, it will be a cream, an emulsion, or a jelly.

These compositions generally contain, in addition to the compounds of the extract according to the present invention, a physiologically acceptable medium, generally based on water or on a solvent, for example alcohols, ethers or glycols. They may also contain surfactants, complexing agents, preservatives, stabilizers, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, matting agents, chemical or mineral filters, hydrating agents, thermal waters, etc.

Advantageously, the compositions according to the present invention will comprise 0.1 to 5% by weight, preferably 0.5 to 4% by weight, more preferably 0.5 to 3% by weight, more preferably 1 to 2% by weight of the shell extract of Theobroma cocoa beans relative to the total weight of the composition. Preferably, the compositions according to the present invention will comprise 1% by weight of the shell extract of Theobroma cocoa beans relative to the total weight of the composition. In an equally preferred manner, the compositions according to the present invention will comprise 2% by weight of the shell extract of Theobroma cocoa beans relative to the total weight of the composition. In another equally equally preferred manner, the compositions according to the present invention will comprise 3% by weight of extract of the shell of Theobroma cocoa beans relative to the total weight of the composition. The shell extracts of Theobroma cocoa beans used in the compositions according to the invention will advantageously comprise a dry extract content of 1% to 5%, preferably from 2% to 4%, by weight relative to the total weight of l 'extract.

According to another embodiment, the compositions according to the present invention will comprise 0.001 to 0.25%, preferably 0.005 to 0.20%, more preferably 0.005 to 0.15%, even more preferably 0.01 to 0.10% extract of the shell of Theobroma cocoa beans by weight of dry extract relative to the total weight of the composition. The shell extracts of Theobroma cocoa beans used in the compositions according to the invention will advantageously comprise a dry extract content of 1% to 5%, preferably from 2% to 4%, by weight relative to the total weight of l 'extract.

Such compositions can be made according to methods well known to those skilled in the art.

The following examples illustrate the invention without limiting its scope.

EXAMPLE 1 Pharmacological Test of an Extract of Theobroma Cocoa Bean Hulls for Its 0C2-Adrenergic Activity

Rosacea is a chronic disorder characterized by inflammation and vascular abnormalities in the skin of the face. Skin biopsies in patients with rosacea are characterized by perivascular infiltrates associated with vasodilation. OC2-adrenergic receptor agonists exhibit vasoconstrictor activity. New approaches are expected for the treatment of facial erythema of rosacea. A recent approach has been to reduce erythema by vasoconstriction of the cutaneous blood vessels by targeting the two α-adrenergic receptors with oxymetazoline (selective αι-adrenergic receptors, Shanler and Ondon, Arch Dermatol, 143 (11), pp 1369-1371, 2007) and brimonidine (selective for OC2-adrenergic receptors, Fowler et al., J. Drugs dermatol. 12 (6), pp 650-656, 2013) by their agonist effects. The 0C2-adrenergic receptors belong to the large family of receptors with 7 transmembrane domains coupled to the G proteins. The agonists for the “2adrenergic receptors cause an increase in the activity of adenylate cyclase resulting in an increase in intracellular cAMP.

The purpose of this test is to evaluate the effects of an extract of Theobroma cocoa bean hulls on the activity of human a2-adrenergic receptors expressed in HEK-293 cells. This activity is measured by the production of cAMP.

Protocol

The study was carried out on HEK-293 cells transfected with the human a2-adrenergic receptor. A specific agonist of this subtype is added to the incubation medium, this is dexmedetomidine at 3 μΜ which will serve as a positive control. The resulting production of cAMP is then quantified by the HTRF® (Homogeneous Time-Resolved Fluorescence) detection method. The results presented come from 3 independent experiments.

The extract tested in this study was obtained by hydroglycolic extraction of shell of Theobroma cocoa beans using a water / butylene glycol mixture as extraction solvent. This extract comprises approximately 69.2% of butylene glycol, 27.5% of water and 3.3% of dry extract. It is a Caobromine® UP commercial material, sold by the company Solabia. The INCI name for this material: Butylene glycol / Aqua / Theobroma cocoa. The Theobroma cocoa CAS number is: 84649-99-0.

Results

The concentrations of cAMP produced by stimulation of the a2-adrenergic receptor with the extract according to the invention and dexmedetomidine are shown in Table 1 below.

Extract c the hull of beans Dexmedet Theobroma cocoa Control 0.01% 0.1% 0.3% 3μΜ Avg AMPc 8 9 18 33 33 SEM 1 1 4 7 9 % effect / 0 4 39 96 100 Dexmedet stats - P> 0.05 P> 0.05 P <0.01 P <0.01

Dexmedet: Dexmedetominidine; Avg: average; SEM: standard error to the mean.

Treatment of the cells with the reference compound Dexmedetomidine at 3 μΜ results in an 0C2Badrenergic agonist response, by inducing a large production of cAMP. This result was expected and validates this experience.

Treatment of the cells with a shell extract of Theobroma cocoa beans tested at 0.01, 0.1% and 3% w / v shows an a2-adrenergic agonist response which appears concentration-dependent. The a2B-adrenergic agonist effect of this 0.3% extract (statistically significant) is even comparable to that of the reference compound tested at 3μΜ.

The inventors thus demonstrate that an extract of Theobroma cocoa bean hulls has a vasoconstrictor activity making it possible to reveal anti-redness properties.

Example 2 Pharmacological Test of an Extract of Theobroma Cocoa Bean Hulls for Its Anti-VEGF and IL-8 Activity

The growth factor VEGF (Vascular Endothelial Growth Factor) is a dimeric glycoprotein, mitogenic for endothelial cells. It plays a key role in the physiological or pathological process of angiogenesis. VEGF increases vascular permeability, stimulates the migration and proliferation of endothelial cells and induces neovascularization. VEGF is secreted by several cell types, such as endothelial cells, lymphocytes and monocytes but also keratinocytes. Its biological effects are mediated by the VEGF-R1 and VEGF-R2 receptors. The cutaneous vascular network in adults is remarkably stable and does not activate angiogenesis. However, during pathological processes such as inflammatory skin diseases, the skin has the power to initiate a return to homeostasis very quickly and effectively. Abnormal regulation of angiogenesis is involved in the pathogenesis of several diseases including rosacea. This angiogenesis process is associated with the inflammatory response where VEGF plays a crucial role in particular in the recruitment of inflammatory cells from the blood to the inflamed tissue. In humans, in normal skin, keratinocytes secrete VEGF and express VEGF-R while in inflammatory skin diseases, VEGF and its receptor are overexpressed.

Rosacea is a chronic skin disease whose etiology remains poorly understood. Rosacea is characterized by vascular and inflammatory abnormalities of the skin of the face and the ocular surface. VEGF and its receptor are expressed in skin biopsies of patients with rosacea showing the probable importance of this growth factor in this pathology. Biopsies are characterized by a perivascular infiltrate associated with vasodilation. The endothelium expresses the two VEGF receptors. Although VEGF is present in the epidermis and endothelium, VEGF is not expressed by the endothelium but rather by the infiltration of inflammatory immune cells such as lymphocytes and macrophages. The VEGF pathway may contribute to the vascular changes and immune infiltration seen in rosacea.

The aim of this study is to assess the possible effects of a shell extract of Theobroma cocoa beans on the release of IL8 and VEGF (Steinhoff et al., JAAD, 69: S1526, 2013).

Protocol

Normal human keratinocytes were obtained from pieces of skin obtained from surgical waste from mammary or abdominal plasties. The keratinocytes thus obtained are placed in culture on 12 or 24 well plates and are exposed for one hour to the compounds to be tested, then placed for 5 or 2 4 h in an environment of rosacea type. Based on the article by Steinhoff et al., JAAD, 69: S15-26, 2013, the rosacea environment is mimicked by the mixture of: an inflammation mediator chosen from TNF activating agents, a mediator of innate immunity chosen from activating agents for TRP receptors (TRPV1, TRPA1) and a bacterial component which is the peptide LL37. The culture supernatant is then removed, centrifuged and frozen at -20 ° C. VEGF and IL-8 productions are quantified by ELISA (Enzyme-Linked Immunosorbent Assay). A percentage inhibition of the production of VEGF and IL-8 after exposure to the various compounds tested is calculated. Statistical analysis is performed using a one-way analysis of variance (ANOVA) followed by the Dunnett test.

The same extract as for Example 1 was used.

Results

The results are summarized in Table 2 below:

compounds Conc Inhibition percentage VEGF IL-8 5 hrs 24h 24h Reference 25μΜ 70 ** 83 ** 25 ** Ext cocoa bean shells 0.1% w / v 47 ** 75 ** 57 ** 0.3% w / v 49 ** 78 ** 86 **

Ext cocoa bean shell: extract of cocoa bean shell

Theobroma cocoa; Conc: concentration.

** p <0.01 versus control.

Doxycycline is used as a reference inhibitor on the production of VEGF, the results are convincing, the use of doxycycline made it possible to validate this test.

The shell extract of Theobroma cocoa beans tested at two concentrations strongly and statistically inhibits the production of VEGF after 5 h and 24 h of stimulation. Likewise, the production of the inflammatory cytokine IL-8 is reduced statistically and concentration-dependent by the shell extract of Theobroma cocoa beans.

Thus, by anti-VEGF activity, the extract of Theobroma cocoa bean hulls has a vascular, anti-redness component, reducing the vasodilation of the blood vessels of the face and reducing angiogenesis.

Similarly, the extract of Theobroma cocoa bean hulls inhibits the protein expression of IL8 in vitro on cells stimulated by an environment of rosacea type, demonstrating anti-inflammatory activity.

EXAMPLES 3 Preparation of an Extract According to the Invention

An extract according to the invention can be obtained by extracting shells of Theobroma cocoa beans crushed by a mixture of butylene glycol and water, then filtration.

Composition obtained:

Claims (1)

Extract of shell s beans Theobroma cocoa for its use in the treatment and / or prevention of Rosacea. Theobroma cocoa bean shell extract for its use according to claim 1, characterized in that rosacea is selected from the group consisting of erythematotelangiectatic rosacea, papule-pustular rosacea, phymateu.se rosacea, and ocular rosacea. Extract of shells of beans Th eo.br orna. cocoa for its use in the treatment and / or the pre ven t ion rash had year s. Extract of shells of beans Theobroma. cocoa for its Use according to any one of Claims 1 to 3, characterized in that the said extract is intended to be applied topically. Theobroma cocoa bean shell extract for its use according to any one of claims 1 to 4, characterized in that the extract is an aqueous extract. Theobroma cocoa bean shell extract for its use according to any one of claims 1 to 5, characterized in that the extract is a hydroglycolic extract. Cosmetic use, preferably topically, of an extract of Theobroma bean hulls. cocoa to prevent and / or fight intermittent skin rash. 8. Cosmetic use according to claim 7, characterized in that the extract of Theobroma cocoa bean shells is an aqueous extract, such as a hydroglycolic extract. Dermatological or cosmetic composition comprising at least one extract of Theobroma cocoa bean hulls with at least one dermatologically or cosmetically acceptable excipient for its use in the treatment and / or prevention of rosacea. Dermatological or cosmetic composition for its use according to claim 9, characterized in that rosacea is chosen from the group consisting of erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea. Dermatological or cosmetic composition for its use in the treatment and / or prevention of skin redness. smetic dermatolooicue for 1 a reven 11, characterized in that it comprises 0.1 to 5% by weight, preferably 0.5 to 4% by weight of the shell extract of Theobroma cocoa beans relative to the total weight of the composition. Dermatological or cosmetic composition for its use according to any one of Claims 9 to 12, characterized in that it is intended for topical application. Dermatological or cosmetic composition for its use according to any one of Claims 9 to 13, characterized in that the extract of shell beans of Theobroma cocoa is an aqueous extract, such as a hy dr o g1yc ο1i que extract. Cosmetic use, preferably topical, dermatological or cosmetic composition comprising at least one shell extract of Theobroma cocoa beans with at least one dermatologically or cosmetically acceptable excipient for preventing and / or combating intermittent skin redness.