WO2020109445A1

WO2020109445A1 - Low molecular weight sulphated fucans in the treatment of atopic dermatitis

Info

Publication number: WO2020109445A1
Application number: PCT/EP2019/082861
Authority: WO
Inventors: Marie Françoise ARIES; Stéphane POIGNY; Hélène HERNANDEZ-PIGEON
Original assignee: Pierre Fabre Dermo-Cosmetique
Priority date: 2018-11-28
Filing date: 2019-11-28
Publication date: 2020-06-04
Also published as: FR3088824B1; FR3088824A1

Abstract

The present invention relates to the use of a low molecular weight sulphated fucan (1-25 kDa), and of a dermatological or dermo-cosmetic composition containing such a fucan, in the treatment and/or prevention of inflammatory dermatoses, in particular atopic dermatitis.

Description

LOW MOLECULAR SULPHATE FUCANES

IN THE TREATMENT OF ATOPIC DERMATITIS

TECHNICAL FIELD OF THE INVENTION

The present invention relates to low molecular weight sulfated fucans (l-25kDa), as well as a dermatological or dermo-cosmetic composition, for their use in the treatment and / or prevention of inflammatory dermatoses, in particular atopic dermatitis.

STATE OF THE PRIOR ART

Dermatoses are affections of the skin and mucous membranes, which are characterized by unsightly manifestations such as redness and flaking patches. Several pathologies are grouped under the name of inflammatory dermatoses. There may be mentioned, by way of non-limiting examples, atopic dermatitis, eczema, psoriasis, rosacea, lichen planus, prurigos, seborrheic dermatitis or even acne. These dermatoses very often result from inflammatory phenomena and immune disorders.

Atopic dermatitis is the cutaneous manifestation of atopy. It is a chronic inflammatory dermatosis, occurring on genetically determined grounds. 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 in the past three decades and 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 infancy and is characterized by rashes repeated for several years. It evolves by thrusts interspersed with spontaneous remissions. The lesions are characterized by significant skin dryness associated with inflammatory manifestations: erythematous papular, vesicular, scaly and very itchy rashes. On the plan Histological, atopic dermatitis is characterized, like many dermatoses, by an infiltration of lymphocytes, monocytes and eosinophilic polymorphonuclear cells around small vessels and capillaries; biochemically, it is characterized by the expression of cytokines such as Thymia Stromal

Lymphopoietin (TSLP), a major protein in triggering the inflammation associated with atopic dermatitis; moreover, it has been shown that chemokines, in particular interleukin 8 (IL8) and lipid mediators of inflammation such as prostaglandin 6KFlot (PGôKFlot), are strongly implicated in dermatoses such as atopic dermatitis and in chronic inflammatory diseases in general.

Eczema is a pruritic dermatosis characterized by an inflammation of the skin which is accompanied by redness, fine vesicles, dander and itching. It can start very early in life, it is even observed in infants. Affected people experience periods commonly known as "eczema flares", during which symptoms worsen. These relapses, of variable duration, are interspersed with periods of remission. Eczema is said to be a genetic disorder, but environmental factors such as the presence of chemical irritants or stress influence its onset.

Psoriasis, an inflammatory skin disease par excellence, is characterized by the appearance of thick, flaking patches of skin. These plaques are found in different places on the body, most often on the elbows, knees and scalp. This chronic disease progresses in cycles, with periods of remission. Psoriasis can be very unpleasant or even painful when it occurs on the palms of the hands, the soles of the feet or in the folds of the skin. There are several types of psoriasis, the most common form being plaque psoriasis or common psoriasis. The other forms are drops, erythrodermic and pustular psoriasis.

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. She touches people with fair skin frequently 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.

Lichen planus is a pruritic rash that affects adults only. It is an inflammatory skin condition of unknown origin. This dermatosis affects the skin, mucous membranes but also the hair and nails. These last two localizations are generally of chronic evolution and can leave irreversible after-effects, such as alopecia and destruction of the nails.

A prurigo is an intense pruritus of the skin with erythematous and vesicular papules with scratching lesions. It is most often an exaggerated sensitivity to insect bites, a sensitivity which prolongs abnormally long and which is frequent especially in young children.

Seborrheic dermatitis is a chronic inflammatory condition of the skin, which affects the areas rich in sebaceous glands, namely the scalp and the face. It is due to a yeast, Malassezia, present in the skin and which develops in the sebum. This affection evolves by pushes favored by the stress, the absence of sun and the pollution.

Acne is a common skin pathology, the result of inflammation of the pilosebaceous follicles due in large part to the colonization of Cutibacterium acnes in the infundibulum (Dréno et al., JEADV 2018, 32 (Suppl 2) 5-14 ).

In the case of mild conditions of inflammatory dermatosis, emollients and keratolytics are recommended. These treatments aim to make the lesions tolerable for the patient and they often have only a suspensive effect. For more severe conditions, these are anti inflammatory or corticosteroids capable of regulating the inflammation of the skin, which have been used for several years. All these treatments have significant side effects, sometimes very serious for the patients. Because of important side effects of the aforementioned existing treatments for skin or scalp disorders resulting from the activation state of the innate immune and epidermal inflammatory response of the skin, there is a real need for new cosmetic or therapeutic active agents and for new cosmetic or therapeutic compositions which can be used for the treatment of said skin or scalp disorders.

SUMMARY OF THE INVENTION

The object of the present invention is to meet these needs.

Indeed, the inventors have demonstrated, quite unexpectedly, that sulfated fucans of low molecular weight of l-25kDa have pharmacological activities of interest for the treatment and prevention of inflammatory dermatoses and more particularly of the atopic dermatitis.

A first object of the invention therefore relates to a low molecular weight sulfated fucan of l-25kDa for its use in the treatment and / or prevention of inflammatory dermatoses.

Another object of the invention relates to the use of a low molecular weight sulfated fucan of l-25kDa for the manufacture of a dermatological or dermo-cosmetic composition intended for the treatment and / or prevention of inflammatory dermatoses.

Another subject of the invention relates to the use of a low molecular weight sulfated fucan of l-25kDa for the treatment and / or prevention of inflammatory dermatoses.

Another subject of the invention relates to a method of treatment and / or prevention of an inflammatory dermatosis comprising the administration to a person in need of an effective amount of a low molecular weight sulfated fucan of l-25kDa. DEFINITIONS

Within the meaning of the present invention, the term “prevention” means avoiding the appearance of a disease, disorder or one or more signs and / or symptoms.

By the term "treatment" or "treating" an inflammatory dermatosis, it is intended to reduce and / or inhibit the development of an inflammatory dermatosis and / or at least one of its symptoms.

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

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

DETAILED DESCRIPTION

Sulphated fucans are polysaccharides that can be extracted from brown algae (Pheophyceae) or from marine invertebrates. The brown color of these algae results from the dominance of the xanthophyll pigment, fucoxanthin, which masks the other pigments (chlorophyll a and c, as well as beta carotene). All have a multicellular structure, but their dimensions vary from microscopic elements to very large specimens. The vast majority of brown algae are marine. There are approximately 2000 species of Pheophyceae. The algal polysaccharides form a large family within which we distinguish:

The reserve polysaccharides, they are stored inside the cell, in brown algae it is laminarin;

Low molecular weight polysaccharides, soluble in the medium, they pass through the membrane to regulate the osmotic pressure;

The polysaccharides of structure, that is to say those of the wall, called parietal polysaccharides, they comprise a skeletal phase, only of structure and made up of insoluble polysaccharides (cellulose, mannans, xylans). Cellulose significantly composes the wall of green algae up to 70% by dry weight, unlike brown algae (<20% by dry weight). The matrix or amorphous phase is water-soluble of a mucilaginous nature is sometimes associated with proteins, is of a very complex nature. The nature of the structural polysaccharides, embedded in this matrix where cation exchanges take place, is specific to each type of alga.

Three main types of structural polysaccharides are derived from brown algae: fucans, ascophylans and alginates. Ascophylans are polysaccharides rich in uronic acids and carrying ramifications of the xylose or fucose type. The alginates which represent the major matrix mucilage of brown algae, are in the form of alginic acids, they are composed of two monosaccharide units, namely bD-mannuronic acid and aL-guluronic acid. Finally, fucans, or fucoidans, constitute a heterogeneous family of polymers based on L-fucose units linked in a- (1,2) and sulfated in 4, the composition of which varies from molecules rich in fucose to molecules more poor in this ose with large proportions of galactose, xylose or uronic acid. It also happens frequently that certain brown algae contain a mixture of fucans of different compositions within them. Fucans, once extracted, generally have a molecular weight greater than 500,000 kDa. Many techniques exist for depolymerizing fucans in order to obtain fucans having a molecular weight of 1 to 25 kDa. The lysis of fucan can be obtained in various ways well known to those skilled in the art. Mention may be made of acid hydrolysis by the action of sulfuric acid, radiolysis in particular by gamma rays, enzymatic hydrolysis, lysis by physical processes such as sonication. Preferably, the fucane does not undergo an additional demineralization step. According to the present invention, the fucans have a molecular weight ranging from 1 to 25 kDa, more particularly from 5 to 25 kDa, in particular from 5 to 15 kDa.

According to a particular embodiment, the low molecular weight sulfated fucan is as described in WO2010 / 086197.

We can cite the commercial specialty Ascophyscient® of Solabia extracted from the alga Ascophyllum nodosum, but also Fucoreverse ^tm from the company Lessonia.

Fucans are mainly exploited in a potential biomedical interest for their antithrombotic, antiviral or even anticoagulant activities.

The sulfated fucans according to the invention are useful for the treatment and / or prevention of inflammatory dermatoses.

Preferably, the inflammatory dermatoses are chosen from atopic dermatitis, eczema, psoriasis, rosacea, lichen planus, prurigos, seborrheic dermatitis and acne. Preferably, it is atopic dermatitis. Another object of the present invention relates to a dermatological or dermo-cosmetic composition comprising, as active principle, at least one low molecular weight sulfated fucan as defined above with at least one dermatologically or dermo-cosmetically acceptable excipient, for its use in the treatment and / or prevention of inflammatory dermatoses such as atopic dermatitis.

Another object of the present invention relates to the use of a dermatological or dermocosmetic composition comprising as active principle at least one sulfated fucan of low molecular weight as defined above with at least one dermatologically or dermo- excipient cosmetically acceptable, in the treatment and / or prevention of inflammatory dermatoses such as atopic dermatitis.

Another subject of the invention relates to a method of treatment and / or prevention of inflammatory dermatosis such as atopic dermatitis comprising administration to a person needing an effective amount of a dermatological or dermo-cosmetic composition comprising, as active principle, at least one low molecular weight sulfated fucan as defined above with at least one dermatologically or dermo-cosmetically acceptable excipient.

In a particular embodiment, the composition according to the invention is used in the treatment and / or prevention of an inflammatory dermatosis chosen from atopic dermatitis, eczema, psoriasis, rosacea, lichen planus, prurigos , seborrheic dermatitis and acne.

Preferably, the composition according to the invention is used in the treatment and / or prevention of atopic dermatitis.

In a particular embodiment, the dermatological or dermo-cosmetic composition according to the invention comprises 0.0001 to 0.1%, preferably 0.0005 to 0.06%, more preferably from 0.001 to 0.05% by dry weight of low molecular weight sulfated fucan according to the invention relative to the total weight of the composition. Advantageously, the dermatological or dermo-cosmetic composition according to the invention comprises 0.03% by dry weight of low molecular weight sulfated fucan according to the invention relative to the total weight of the composition. In the embodiments described above, the dermatological or dermo-cosmetic composition according to the invention is advantageously devoid of any galactan, that is to say of a polysaccharide consisting exclusively of galactose monomers, and preferably is devoid of any polysaccharide other than the at least one sulfated fucan of low molecular weight as defined above, that is to say that the only polysaccharides present in the dermatological or dermo-cosmetic composition according to the invention are a fucan low molecular weight sulfate as defined above or a mixture of low molecular weight sulfated fucans as defined above. Preferably, the dermatological or dermo-cosmetic composition according to the invention comprises, as active principle, a sulfated fucan of low molecular weight as defined above as the only polysaccharide with at least one dermatologically or dermo-cosmetically acceptable excipient. More preferably, the dermatological or dermo-cosmetic composition according to the invention comprises, as the sole active principle, a sulfated fucan of low molecular weight as defined above with at least one dermatologically or dermo-cosmetically acceptable excipient.

The compositions according to the invention are advantageously intended for topical application, in particular by application to the skin.

The compositions according to the invention may thus be presented in the forms which are usually known for topical administration, that is to say in particular lotions, foams, gels, dispersions, emulsions, sprays, serums , balms, masks or creams.

Advantageously, it will be a milk, a cream, or a balm. The invention thus relates to dermatological or dermo-cosmetic compositions according to one of the embodiments of the present invention, characterized in that they are in their own form and suitable for topical application.

These compositions generally contain, in addition to the fucan 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, stabilizing agents, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, matting agents, chemical or mineral filters, hydrating agents or thermal waters, etc. The following example illustrates the invention without limiting its scope. EXAMPLE

Effects of fucans in skin inflammation

Atopic dermatitis or atopic eczema is a chronic inflammatory disease progressing by cycle with phases of remission. Lesions of atopic dermatitis are mainly due to the activation of T cells specific to allergens. This immune response is probably due to the penetration of environmental allergens into the skin. A disruption of the skin barrier and therefore a dispersion of allergens are linked to the induction of a specific immune response and eczema lesions. Two complementary hypotheses are proposed to explain the origin of the disease. The first hypothesis is that a damage to the barrier function of the skin would allow allergens to enter and cause immune sensitization. The second hypothesis is that atopy is a dysfunction of the immune system leading to an imbalance in the Thl / Th2 balance in favor of Th2 and the production of IgE specific to allergens. For all these reasons, atopic dermatitis is considered to be a complex disease involving several mechanisms.

In this study, the effects of a low molecular weight sulfated fucan according to the invention are evaluated in a model mimicking an environment of atopic dermatitis, on stimulated human keratinocytes.

Methods

The study is carried out on normal human epidermal keratinocytes cultured under standard conditions (37 ° C, 5% CO2). The culture medium is standard (keratinocyte-SFM supplemented with Epidermal Growth Factor (EGF) 0.25ng / ml, pituitary extract 25pg / ml and gentamycin 25pg / ml). The test medium is the same without growth factor.

To simulate an atopic dermatitis environment, the keratinocytes are pre-incubated for 1 hour in the medium containing or not containing (control) the compounds to be tested, the vehicle (water) or the positive controls, that is to say desonide (based corticosteroid) to ImM and Tacrolimus (immunosuppressant) to ImM. The low molecular weight sulfated fucan tested in this study is the Ascophyscient® compound from Solabia with a molecular weight of 5-15 kDa, centered on 10 kDa. After this pre-incubation, the keratinocytes are stimulated by a mixture of TLR ligands (Poly I: C and PamC3) and inflammatory cytokines (IL4 and IL13) added to the cells. An unstimulated control condition is also performed in parallel. The cells are incubated either for 5 hours or for 24 hours.

Culture supernatants are harvested, centrifuged and frozen at -80 ° C. TSLP and IL8 are quantified by ELISA. The TSLP cytokine is major in atopic dermatitis (Indra AK, Expert Rev Proteomics 2013, 10 (4), 309-311).

Four independent experiments are carried out. Statistical analysis is determined by a one-way ANOVA followed by the Dunnett post test.

Results

The production by normal human epidermal keratinocytes of TSLP measured at 5 and 24 hours is shown in Tables IA and IB below.

[Table IA]

Avg: average; EC: standard deviation; Inh: inhibition; [Table IB]

Avg: average; EC: standard deviation; Inh: inhibition. Stimulation of keratinocytes by a cocktail of agents

(Poly I: C, PamC3, IL4 and IL13) to mimic an environment of atopic dermatitis does induce an increased production of TSLP at 5 hours and an even more marked production at 24 hours. The two compounds used as positive controls significantly inhibit the production of TSLP at 5 and 24 hours. These results make it possible to perfectly validate this pharmacological test.

The fucans according to the present invention completely inhibit the production of TSLP measured at 5 hours at 30, 100 and 300 pg / ml (Table 1D). For the measurement of TSLP at 24 hours, lower concentrations of the fucans according to the invention were therefore added to the protocol. The inventors demonstrate that the fucans according to the present invention significantly inhibit the production of TSLP (73% inhibition, P <0.01 versus the stimulated condition) from 3 pg / ml. From 10 pg / ml and up to 300 pg / ml of the fucans according to the invention, the production of TSLP due to pharmacological stimulation to mimic an environment of atopic dermatitis is completely annihilated (Table IB). The inhibitory effect of fucans according to the invention seems to be concentration-dependent.

The production by normal human epidermal keratinocytes of interleukin 8 (IL8) measured at 24 hours is shown in Table 2 below.

[Table 2]

Avg: average; EC: standard deviation; Inh: inhibition.

The stimulation of keratinocytes by the cocktail of agents to mimic an environment of atopic dermatitis induces a massive production of interleukin 8 (more than 300 times the production measured under control conditions). Desonide (1 mM) significantly inhibits the production of IL8 (more than 50% reduction), on the other hand Tacrolimus does not induce a reduction in this production of IL8. All of these results validate the test but the fact that a reference compound does not decrease this production of IL8, shows that it is not so easy to inhibit the release of this interleukin.

The fucans according to the invention decrease in a concentration-dependent manner the production of IL8 induced by an environment of atopic dermatitis. From 3 g / ml of fucans according to the invention, the inventors show that the release of IL8 is already reduced by 50% (Table 2). From 10 pg / ml and up to 300 pg / ml, the inhibition of the release of this cytokine is complete, showing that the fucans according to the invention are very effective in reducing these selective cytokines of atopic dermatitis.

Conclusion of these studies

The inventors have thus shown that normal human epidermal keratinocytes produce a large amount of TSLP and IL8 after 5 and 24 hours of stimulation with a cocktail of agents (Poly I: C, PamC3, IL4 and IL13) mimicking an environment of atopic dermatitis. In this model, the inventors demonstrate that the low molecular weight fucans according to the invention are very effective and, even at very low concentrations, are capable of preventing this release of inflammatory cytokines and in particular TSLP, a key marker in the development of atopic dermatitis, demonstrating a protective role in this pathology.

Claims

1. Low molecular weight sulfated fucan, 1 to 25kDa, for use in the treatment and / or prevention of atopic dermatitis.

2. Low molecular weight sulfated fucan for its use according to claim 1, characterized in that it has a molecular weight of 5 to 25 kDa.

3. Dermatological or dermo-cosmetic composition comprising as active principle at least one sulfated fucan of low molecular weight, from 1 to 25 kDa, with at least one dermatologically or dermo-cosmetically acceptable excipient, for its use in the treatment and / or prevention of atopic dermatitis.

4. Dermatological or dermo-cosmetic composition for its use according to claim 3, characterized in that the sulfated fucan of low molecular weight has a molecular weight of 5 to 25 kDa.

5. Dermatological or dermo-cosmetic composition for its use according to any one of claims 3 and 4, characterized in that the sulfated fucan of low molecular weight is the only polysaccharide.

6. Dermatological or dermo-cosmetic composition according to any one of claims 3 to 5, characterized in that it is in a form suitable for topical application.