EP3890698A1

EP3890698A1 - Garcinia mangostana extract for promoting hair growth

Info

Publication number: EP3890698A1
Application number: EP19839363.9A
Authority: EP
Inventors: Mathieu LETI; Marguerite LEVEQUE; Sylvie Daunes-Marion
Original assignee: Pierre Fabre Dermo Cosmetique SA
Current assignee: Pierre Fabre Dermo Cosmetique SA
Priority date: 2018-12-06
Filing date: 2019-12-04
Publication date: 2021-10-13
Also published as: FR3089413A1; US20210330725A1; CA3119556A1; JP2022510449A; KR20210102287A; WO2020115435A1; FR3089413B1; CN113164374A; SG11202105310SA

Abstract

The present invention relates to a garcinia mangostana extract and to compositions containing this extract for application in cosmetics and dermatology for promoting hair growth.

Description

Garcinia mangostana extract to promote hair growth

TECHNICAL AREA

The present invention relates to an extract of Garcinia mangostana L. and the compositions containing this extract for application in the fields of cosmetics and dermatology to promote hair growth, more particularly to stimulate hair regrowth.

STATE OF THE PRIOR ART

Hair care, not only for cosmetic purposes but also to prevent hair loss and to regenerate it, has always sought the spirit of research. Many theories have attempted to clarify the etiology of hair loss in baldness, alopecia, alopecia areata, etc., by blaming it on seborrhea, increased blood pressure. tissue on the cranial sphere, reduced blood supply, or certain endocrine or nervous disorders.

The hair follicle is a mini-organ anchored in the skin to the hypodermis, the main function of which is the production of a hair shaft. Their distribution is established during in utero growth and their number is genetically determined. The hair follicle is a dynamic structure that produces hair during the growth and tissue shaping cycle. This cycle is broken down into three phases:

During a growth phase (anagen), the cells of the dermal papilla (fibroblasts) send a signal to the stem cells of the bulb which allows their proliferation. Cells will transform and envelop the dermal papilla to form the sulfur matrix of the hair. They divide and differentiate into follicular keratinocytes, cells responsible for the structure of the hair. For the hair to be well structured, these keratinocytes need sulfur proteins, vitamin B6 and various minerals such as zinc, magnesium. The duration of this phase determines the length of the hair and depends on the proliferation and differentiation of the cells of the matrix at the base of the follicle.

- A regression phase (catagen), the matrix dies and as a result the dermal papilla is no longer in contact with this matrix. There is no longer any exchange between the cells. The follicle and the dermal papilla go up towards the epidermis.

- A resting phase (telogen), the cells of the dermal papilla and the bulb are intact and inactive. The hair falls out. For a new hair to develop, the cycle must be reinitiated. The hair is therefore constantly renewed and on the

100,000 to 150,000 hairs in a hair, the majority is in the growth phase. There is a normal and physiological loss of hair in the range of 60 to 100 per day for healthy hair. Beyond, the fall is said to be pathological, whether occasional or installed.

The term alopecia means partial or general loss of hair. Many factors can be involved in alopecia such as genetic factors, age, sex, diseases, stress, hormonal problems, side effects of drugs, scars. It is possible to distinguish several forms of alopecia:

Hereditary androgenetic alopecia, it is the most frequent; early hair loss occurs in genetically predisposed individuals and affects men in particular. It manifests itself by a decrease in the volume of the hair, even a baldness and affects 50% of men aged over 50 years.

Post-menopausal alopecia, this is the most common cause of baldness in women. Hair loss is more diffuse and widespread in women than in men. Diffuse female alopecia is a disorder that often starts at menopause and affects around 40% of women over the age of 70. The diffuse term illustrates that, unlike humans, hair loss affects the entire scalp, homogeneously.

Acute or reactive alopecia, it can be linked to drug treatment, stress, childbirth, significant food deficiencies, iron deficiency, hormonal disorders, it is a simultaneous and diffuse fall of a significant amount of hair.

Scar alopecia, it can be caused by skin problems (tumor, burning, alopecia areata), acute radiation, lupus erythematosus or parasites (ringworm, lichen).

Alopecia areata, it seems to be of auto immune origin and is characterized by an attack in more or less large plaques and in one or more places.

Congenital alopecia, rare, it corresponds to an absence of root or to abnormalities of the hair (mutations).

Alopecia is essentially linked to a disturbance of the capillary renewal which leads, initially, the acceleration of the frequency of the cycles at the expense of the quality of the hair then their quantity. The most frequent phenomenon is a reduction in the duration of the growth phase (anagen phase) in connection with a halt in cell proliferation. The consequence is a premature induction of the catagen phase and a greater number of hair follicles in the telogen phase and therefore a greater loss of hair. To fight against alopecia, it is therefore necessary to restart the hair cycle, for example by activating the anagen phase.

To date, various products have been proposed to combat alopecia, and in particular to induce or stimulate hair growth. Most combine several principles active ingredients that can provide a beneficial action on the biological parameters involved in hair loss. Among the most commonly encountered active ingredients, we can cite as examples: vitamins such as vitamins A, E, B5, B6, C, H and PP; trace elements such as zinc, copper, magnesium, silicon; protein derivatives such as peptides, sulfur amino acids (methionine, cystine, cysteine or derivatives); essential oils or extracts of plant origin of lipophilic or hydrophilic nature, the list of which is not exhaustive; antifungal agents such as piroctonolamine, undecyclinic derivatives, cyclopiroxolamine; chemical synthesis molecules known for their specific action at the level of androgen receptors or on the activity of 5-a reductases. Minoxidil or 2,4 diamino-6-piperidinopyrimidine 3-oxide is today a reference in the treatment of androgenic alopecia. Despite the many theories discussed on its mechanism of action, the latter is not clearly elucidated. In addition, its effectiveness remains limited, because even if there is a stabilization of hair loss in many clinical cases, there is a resumption of the alopeciant process as soon as treatment is stopped. Its restrictive daily use is probably the cause of undesirable side effects noted in patients using it for the long term such as localized skin reactions or systemic effects.

Furthermore, compositions comprising very diverse active agents are proposed in hair regrowth, these active agents possibly being, for example, derivatives of 2,4-diamino pyrimidine 3-oxide such as those described in the patent application.

EP0522964. Clinical studies have shown that PGF2ot analogues have the property of causing hair and eyelash growth in humans and animals (Johnstone, Am J Opht, 124 (4), 544-547, 1997). In humans, scalp tests have shown that a prostaglandin E2 analog, viprostol, has the property of increasing hair density. WO 98/33497 describes pharmaceutical compositions containing prostaglandins or derivatives of prostaglandins intended to promote hair growth.

Thus, despite the many options currently available, consumers still need new products to promote hair regrowth, which are natural and environmentally friendly, while being as effective as chemical active ingredients.

Recently, in experiments conducted on hair follicles of mice and humans, researchers (Harel et al., Sci. Adv. 2015; el500973) discovered that when applied to the skin, drugs that inhibit the family of enzymes Janus Kinase (JAK) promote rapid and dense growth of hair and hairs. Two JAK inhibitors are already approved by the Food and Drug Administration (FDA), one ruxolitinib for the treatment of blood diseases, the other tofacitinib for rheumatoid arthritis; they are both the subject of clinical studies in alopecia areata. During these studies, it was noted that a topical application of JAK inhibitors on the skin of mice resulted in hair regrowth, suggesting that in addition to their blocking effect of the autoimmune attack, they could exert a action on the hair follicles, bringing them out of their telogen phase. Mice treated for one of the two JAK inhibitors for 5 days showed new hair regrowth within 10 days, which demonstrates a rapid acceleration of the growth process, while no hair regrowth was observed in control mice over the same period.

In addition, Garcinia mangostana L. is a tropical tree native to Southeast Asia, today cultivated in many tropical countries for its edible fruit, the mangosteen, also called "fruit of the Gods" or "Queen of fruits" .

Garcinia mangostana L. is a dioecious tree that can reach 20 meters in height in the wild. Its leaves are smooth, shiny, leathery, elliptical to elliptical-oblong, measuring 14 to 25 cm by 5 to 10 cm. Their base is cuneiform to sub-rounded, the apex is short-acuminate. The male flowers, rare, are grouped by 2 to 9 at the end of twigs, while the female flowers, a little larger than the male flowers, are solitary or in pairs. The fruit consists of a thick pink to purplish pericarp, very dark at maturity, containing an edible white flesh and enveloping 4 to 5 seeds.

Mangosteen has been known for centuries in traditional Asian medicine for its antioxidant, anti-inflammatory and antibacterial activities. The pericarp in particular is used in case of skin infection, diarrhea, abdominal pain, urinary tract infection, or bruising. It can also be used in case of fever (Ovalle-Magallanes et al., Food Chem Toxicol 109: 102-122, 2017). We also observe in the West a strong craze for the mangosteen for ten years. Many fruit juices made from flesh and pericarp, food supplements and topical products containing mangosteen are marketed and recent clinical studies show their interest in various indications such as weight loss (Udani et al., Nutr J, 8 : 48, 2009) and periodontitis (Mahendra et al., J Investig Clin Dent, 8 (4), 2017). Mangosteen extracts are also found as active ingredients in several cosmetic references for their anti-aging or slimming properties.

The mangosteen pericarp is an important source of xanthones, the main ones being a-mangostine and g-mangostine (Ovalle-Magallanes et al., 2017). The mangosteen pericarp also contains tannins, anthocyanins and sugars. Extracts of fruits, and more particularly of mangosteen pericarp more or less enriched with xanthones have been the subject of numerous pharmacological studies, both in vitro and in vivo. The main activities highlighted are anti-tumor properties, in particular at the level of prostate, lung, breast and colon, anti-inflammatory, antioxidant, anti-diabetic, anti-hyperlipidemic and antibacterial.

Mangosteen extracts in combination with other extracts, forming a precise composition for topical use, have been the subject of several patent applications in the hair field. Patent application JP2016069334 relates to an extract of Garcinia mangostana in combination with hydrolysed silk in liquid form, and positioned as a protective agent for the hair against UV rays. Patent application CN103735453 relates to a composition intended to dye the hair. Patent application US2006210515 relates to a topical composition comprising a partially hydrolyzed fucoidan, which may be useful in hair regrowth. Natural components can be added to this composition, such as for example the mangosteen but no activity in the hair field is associated with it. The aim of a Thai study was to carry out a screening in order to identify plant extracts exhibiting 5a-reductase inhibiting activity, therefore useful for treating benign enlarged prostate and / or genetic alopecia. An ethanolic extract of Garcinia mangostana pericarp came out of this screening but no relationship between the content of total phenolic compounds and the 5a-reductase inhibitory activity could be established. The 5a-reductase inhibiting activity of Garcinia mangostana extracts has also been the subject of two patent applications. Application JP2000229857 attributes the inhibitory activity of 5a-reductase to xanthones, in particular a-mangostine. Xanthones can be extracted and isolated from plants of the family Hypericaceaes (Guttiferae), Gentianaceaes, Mulaceaes, Polygalaceaes, Lilyaceaes, and Plumaceaes. The preparation of a benzene extract of Garcinia mangostana L. is described. Application JP5017365 relates to several plant extracts, among which aqueous extracts or extracts obtained by hydrophilic organic solvents, such as for example a methanolic extract, of Garcinia mangostana and which can be formulated as topical application.

Thus, to date no bibliographic data mentions that an extract of Garcinia mangostana L. can have an activity in hair regrowth.

SUMMARY OF THE INVENTION

Surprisingly, the inventors have discovered that an extract of Garcinia mangostana L. has pharmacological activities of interest for promoting hair growth, in particular for promoting hair regrowth by acting in particular on this JAK target. These activities are detailed in Examples 11 to 13.

The invention therefore relates to the treatment of hair loss to the extent that the extract of Garcinia mangostana L. acts on the biological functions or mechanisms at the origin of hair growth.

More particularly, the invention relates to an hydroalcoholic extract of Garcinia mangostana and a dermatological composition comprising said extract with at least one dermatologically acceptable excipient for its use in the prevention or treatment of alopecia by promoting hair growth.

The invention also relates to the non-therapeutic use of an hydroalcoholic extract of Garcinia mangostana to promote hair regrowth. The invention relates to a cosmetic composition for promoting hair growth, in particular for promoting hair regrowth comprising at least one hydroalcoholic extract of Garcinia mangostana with at least one dermatologically acceptable excipient.

Definitions

In the present invention, the plant Garcinia mangostana L. could be designated in an abbreviated manner by the term Garcinia mangostana.

By "Garcinia mangostana extract" means the product of extraction of all or part of the Garcinia plant mangostana.

By “extraction product” is meant the product obtained after extraction of part of the plant, with a solvent, called extraction solvent, that is to say a product present in the extraction solvent which may then optionally be in a concentrated or dry form after partial or total evaporation of the extraction solvent. It can be a dry extract.

By “dry extract” is understood within the meaning of the present, 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 from Garcinia mangostana. It may also contain insignificant traces of extraction solvent.

By “approximately”, it is meant in the present invention that the value concerned can be lower or higher by 10%, in particular by 5%, in particular by 1%, relative to the value indicated. This definition applies in particular when defining the content by weight of alpha-mangostine relative to the weight of the dry extract.

By “hydrophilic solvent” is meant a solvent chosen from the group consisting in particular of water, subcritical water, water-miscible alcohols such as, for example, ethanol, C3 to C5 glycols, glycerol , acetone, and mixtures thereof.

By “non-polar solvent” is meant within the meaning of the present invention, a solvent chosen for example from heptane, hexane, limonene, halogenated hydrocarbons (chloroform, dichloromethane), supercritical CO ₂ , a CO mixture ₂ supercritical and ethanol.

By "moderately polar solvent" is meant within the meaning of the present invention, a solvent chosen from the group consisting in particular of C1 to C5 alcohols, glycols such as propylene glycol, butylene glycol, butanediol, or pentylene glycol, glycerol, acetone, alkyl esters such as ethyl acetate, isopropyl acetate, solvents miscible with water (a hydro-alcoholic mixture or an acetone / water mixture for example). Also included in this group are hydrotropic type alternative solvents (amphiphilic molecules soluble in water and which, from a sufficient concentration, can extract moderately polar compounds as described in the characterization of the extract).

By "hair and hair" is meant the hair, the hair, the eyebrows, the eyelashes and / or the coat, preferably the hair.

By "dander" means the hair, the hair, the eyebrows, the eyelashes, and / or the nails, preferably the hair.

By "alopecia" is meant the total or partial loss of hair and / or body hair, for example linked to the reduction of hair growth and / or the acceleration of hair loss and / or body hair. This term includes but is not limited to androgenetic alopecia, post-menopausal alopecia, reactive alopecia, cicatricial alopecia, alopecia areata, and congenital alopecia. The consequences of alopecia are a temporary or permanent and partial or total absence of hair and / or body hair.

By the term "treating" alopecia is meant stopping alopecia, reducing alopecia and / or alleviating alopecia. Thus, "treating" alopecia includes limiting hair loss and / or body hair and / or promoting hair growth and / or body hair, increasing the density of hair follicles and / or regulating the phases of the hair follicle cycle. .

By the term "preventing" alopecia is meant to reduce the risk of developing alopecia, or to slow the progression of alopecia in a mammal, preferably a man who is likely to develop alopecia.

By the term "limit" is meant to brake, reduce, decrease and / or stop.

By the term "promote" is meant to increase, increase, promote, amplify and / or accelerate. In the present invention, the expression “

"Cosmetically or dermatologically acceptable" which is useful in the preparation of a cosmetic, dermatological composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for cosmetic or dermatological use, in particular by topical application in the hair and / or scalp.

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

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the invention relates to an extract of Garcinia mangostana for its use for promoting hair growth, more particularly for promoting hair regrowth.

In the context of the present invention, the extract of Garcinia mangostana is obtained from one or more parts of the Garcinia mangostana plant chosen from the aerial parts such as the fruit, the pericarp of the fruit, the pulp of the fruit, seeds, leaves, stems and / or bark.

In a particular embodiment of the invention, the extract is obtained from the fruits and / or pericarp of the fruit of Garcinia mangostana. Advantageously, the extract is obtained from the pericarp of the fruit of Garcinia mangostana.

In a particular embodiment of the invention, the extract is obtained from a culture of Garcinia mangostana cells.

The extract is a hydro-alcoholic extract, in particular a hydro-ethanolic extract.

According to a preferred embodiment, the extract according to the invention can be obtained by a process such as described below.

The Garcinia mangostana plant or part of it can be fresh or dry, whole, cut or crushed and then subjected to an extraction stage.

A method of preparing an extract according to the invention comprises a step of extracting all or part of the Garcinia mangostana plant with an alcohol / water mixture.

In one embodiment of the invention, the extraction solvent is an alcohol / water mixture, in which the alcohol may be a C3 to C5 glycol or a C1 to C5 alcohol.

Advantageously, the alcohol / water mixture is characterized by an alcohol / water proportion of 9: 1 to 7: 3 (v / v). Even more advantageously, the alcohol / water mixture is characterized by an alcohol / water proportion of 9: 1 (v / v).

Advantageously, it will be an ethanol / water mixture.

Even more advantageously, this ethanol / water mixture will be characterized by an ethanol / water proportion of 9: 1 to 7: 3 (v / v).

And even more advantageously, this ethanol / water mixture will be characterized by an ethanol / water proportion of 9: 1 (v / v).

According to another particular embodiment of the invention, the extraction is carried out with stirring or statically, at reflux, at room temperature, or at a temperature between room temperature and reflux. It can be assisted by ultrasound, by microwave, by flash flash or by extrusion, in a weight ratio of plant / volume of solvent which can vary from 1/3 to 1/30, for a period of 1 minute to 48 hours. The extraction can be renewed 2 to 3 times.

According to another particular embodiment of the invention, the marc is then separated from the extract by centrifugation or filtration in order to recover a clear liquid phase free of particles. The liquid phase representing the extract can be more or less concentrated, up to a dry extract. In another embodiment of the invention, a support can be added during the concentration step so as to obtain an extract containing 1 to 75% of dry extract. The support can be maltodextrin, lactose, silica, glycerin, glycol, vegetable oil, hydrotrope, a water / solubilizer or water / surfactant mixture, or any other cosmetologically acceptable support and solubilizes the extract. , preferably of biobased origin such as for example biobased glycols (1, 2-pentanediol; 1, 3-butanediol; 1,3-propanediol ...), esterified fatty acids and also hydrotropes such as for example alkyl glycosides ( Sepiclear, Apyclean, APXC4 ...).

According to a particular embodiment of the invention, the extract of Garcinia mangostana can be discolored, for example on activated carbon. Advantageously, the extract of Garcinia mangostana is not discolored.

The hydroalcoholic extract of Garcinia mangostana according to the present invention induces an inhibition of the JAK-STAT signaling pathway. Furthermore, the hydroalcoholic extract of Garcinia mangostana according to the present invention inhibits the synthesis of melanin.

According to a second aspect, the present invention relates to a dermatological or cosmetic composition comprising at least one extract of Garcinia mangostana with at least one excipient dermatologically or cosmetically acceptable for its use for promoting hair growth, more particularly for promoting hair regrowth.

Advantageously, the extract included in the dermatological or cosmetic composition is as described above.

According to a particular embodiment of the invention, the cosmetic or dermatological composition comprising at least one extract of Garcinia mangostana as described above and at least one cosmetically or dermatologically acceptable excipient comprises from 0.001 to 5% by weight, preferably 0.002 to 2% by weight, preferably from 0.005 to 1% by weight, more preferably from 0.01 to 0.5% of extract of Garcinia mangostana, by weight of dry extract relative to the total weight of the composition.

The invention preferably relates to a cosmetic or dermatological composition according to the invention which is in a clean form and suitable for topical application, in particular on the scalp and / or hair.

The cosmetic or dermatological composition according to the invention can thus be presented in the forms which are usually known for topical administration, that is to say in particular lotions, shampoos, balms, mousses, gels, dispersions , emulsions, sprays, serums, masks or creams, with excipients allowing in particular penetration to improve the properties and accessibility of the active ingredient.

Advantageously, the composition according to the invention can be in the forms which are usually known for topical administration on the hair and the scalp, that is to say in particular a shampoo, a conditioner, a hair cream, a hair lotion, mask or spray without rinsing.

A distinction is thus made between formulated products which can be rinsed and formulated products which do not require rinsing.

Preferably, the composition according to the invention has a light texture which also allows optimal penetration without greasing the hair and / or the hair, or the scalp.

In a particular embodiment of the invention, the composition according to the invention is characterized in that it is in a form suitable for oral administration.

According to another embodiment of the invention, the composition according to the invention can also be in the forms which are usually known for oral administration, that is to say in particular tablets, capsules, powders, granules and oral solutions or suspensions. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

A preparation in capsules can be obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard capsules.

The composition according to the invention, administered for example topically or orally, generally contains, in addition to the extract as described above, a physiologically acceptable medium, generally based on water or solvent, for example alcohols, ethers or glycols. It can also contain surfactants, complexing agents, preservatives, stabilizing agents, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, moisturizers or thermal waters, etc.

From the first administrations, for example topically or orally, of the composition according to the invention, the hair will regain strength and vitality.

According to the first or second aspect of the invention, the extract as described above or the composition as described above can therefore be used to promote hair growth, more particularly to promote hair regrowth .

In a particular embodiment, the extract of Garcinia mangostana as described above is the only active principle for promoting hair growth, more particularly for promoting hair regrowth.

According to a particular embodiment of the invention, the extract of Garcinia mangostana as described above is characterized by a content of 0.5 to 80%, particularly from 5 to 80%, more particularly from 10 to 60% or even more particularly about 15% by weight of alpha-mangostine relative to the weight of the dry extract.

According to one embodiment of the invention, the extract of Garcinia mangostana as described above or the cosmetic or dermatological composition comprising at least one extract of Garcinia mangostana and at least one cosmetically or dermatologically acceptable excipient as described above above, is intended to be applied topically and / or orally, preferably topically.

The cosmetic or dermatological extract or composition as described above can be used in an individual who has undergone a hair micro-transplant.

According to a particular embodiment of the invention, the extract of Garcinia mangostana as described above or the composition as described above makes it possible to prevent or treat alopecia, which can be chosen from the group consisting of androgenetic alopecia, reactive alopecia, post-menopausal alopecia and areata alopecia.

The subject of the invention is an extract of Garcinia mangostana or a dermatological composition comprising at least one extract of Garcinia mangostana with at least one dermatologically acceptable excipient, as defined above, for their use in prevention and / or in treatment alopecia, said alopecia can be chosen from the group consisting of reactive alopecia and alopecia areata.

The subject of the invention is also the use of an extract of Garcinia mangostana or of a dermatological composition comprising at least one extract of Garcinia mangostana with at least one dermatologically acceptable excipient, as defined above, for the manufacture of 'A pharmaceutical or dermatological composition intended for the promotion of hair growth, in particular for the prevention and / or treatment of alopecia, for example reactional alopecia and alopecia areata. The invention also relates to the use of an extract of Garcinia mangostana or of a dermatological composition comprising at least one extract of Garcinia mangostana with at least one dermatologically acceptable excipient, as defined above, for promoting growth capillary, especially to promote hair regrowth, in particular for the prevention and / or treatment of alopecia, for example reactive alopecia and alopecia areata.

A subject of the invention is also a method for promoting hair growth, in particular for preventing and / or treating alopecia, for example reactional alopecia and alopecia areata, comprising administration to a patient in needing an effective amount of an extract of Garcinia mangostana or of a cosmetic or dermatological composition comprising at least one extract of Garcinia mangostana with at least one cosmetically or dermatologically acceptable excipient, as defined above.

The invention also relates to a cosmetic (non-therapeutic) use of the extract as described above according to a mode described above or of the cosmetic or dermatological composition as described above according to a mode described above, for care of hair and / or scalp, and / or to promote hair growth, more particularly to promote hair regrowth, and / or to increase the density of the hair follicles and / or to obtain more covering hair and / or to promote follicular regeneration and / or to combat alopecia, said alopecia being able to be chosen from androgenetic alopecia and post-menopausal alopecia.

The invention also relates to a non-therapeutic cosmetic method for hair and / or scalp care, and / or for promoting hair growth, more particularly for promoting hair regrowth, and / or for increasing the density of hair follicles. and / or to obtain more covering hair and / or to promote the follicular regeneration and / or to fight against alopecia, said alopecia being able to be chosen from androgenetic alopecia and post-menopausal alopecia.

A subject of the invention is also a non-therapeutic cosmetic method for promoting hair growth, more particularly for promoting hair regrowth, in particular for preventing and / or treating alopecia, for example androgenetic alopecia and post menopausal alopecia, comprising the use of an extract of Garcinia mangostana or of a cosmetic or dermatological composition comprising at least one extract of Garcinia mangostana with at least one cosmetically or dermatologically acceptable excipient, as defined above.

EXAMPLES

The following examples illustrate the invention without limiting its scope.

The first ten examples relate to the preparation of an extract used for the invention.

EXAMPLE 1 Extraction at reflux with ethanol 90%

377 grams of dry ground pericarps of Garcinia mangostana are extracted at reflux with stirring with 3.8 liters of an ethanol / water 90:10 (v / v) mixture for 1 hour in a reactor. The extract is then filtered on a K900 filtration plate and the solvent is evaporated so as to obtain 100 grams of an orange powder with a mass yield of 26%. The dry extract obtained contains 15.9% by weight of alpha-mangostine.

Example 2 Extraction under reflux with 90% ethanol followed by placing on a support

200 grams of dry ground pericarps of Garcinia mangostana are extracted at reflux with stirring with 2 liters of a 90:10 ethanol / water mixture (v / v) for 1 hour in a reactor.

The extract is then filtered on a K900 filtration plate and is dried over maltodextrin so as to obtain 142 grams of extract in the form of an orange-beige powder. The extract contains 75% maltodextrin and 3.5% alpha-mangostine by weight of the extract.

Example 3 Extraction at reflux with 90% ethanol followed by placing on a support

1000 grams of dry ground pericarps of Garcinia mangostana are extracted at reflux with stirring with 10 liters of a 90:10 ethanol / water mixture (v / v) for 1 hour in a reactor. The extract is then filtered on a K900 filtration plate and is dried over 1, 2-pentanediol so as to obtain 747 grams of extract in the form of a dark viscous liquid. The extract contains 70% of 1,2-pentanediol and 4.9% of alpha-mangostine by weight of the extract. EXAMPLE 4 Extraction at Reflux with Hexane

17 grams of dry ground pericarps of Garcinia mangostana are extracted at reflux with stirring with 170 milliliters of hexane for 1 hour in a reactor. The extract is then filtered on a K900 filtration plate and the solvent is evaporated so as to obtain 200 milligrams of an orange-yellow paste with a mass yield of 1.2%. The dry extract obtained contains 75.0% by weight of alpha-mangostine.

EXAMPLE 5 Extraction with 96% ethanol assisted by ultrasound 36 grams of dry ground pericarps of Garcinia mangostana are brought into contact with 350 milliliters of 96% ethanol and then extracted under the action of ultrasound (20 kHz) for 3 times a minute at 100% amplitude. The extract is then filtered on a K900 filtration plate and the solvent is evaporated so as to obtain 7.9 grams of a purplish red powder with a mass yield of 22%. The dry extract obtained contains 16.4% by weight of alpha-mangostine.

Example 6 Extraction under reflux with ethanol 96%

20 grams of dry ground pericarps of Garcinia mangostana are extracted at reflux with stirring with 200 milliliters of 96% ethanol for 1 hour in a reactor. The extract is then filtered on a K900 filtration plate and the solvent is evaporated so as to obtain 5.3 grams of a purplish red powder with a mass yield of 26%. The dry extract obtained contains 16.0% by weight of alpha-mangostine.

Example 7: Hydrotropic extraction with a 1.5M aqueous solution of heptylglucosides

26 grams of dry ground pericarps of Garcinia mangostana are extracted for 2 hours at 40 ° C with stirring with 260 milliliters of an aqueous solution of heptylglucosides 1.5M.

After filtration on a K900 filtration plate, the filtrate is acidified to pH = 2 and then diluted with 11 volumes of acidified water to pH = 2. After centrifugation, the pellet is taken up and dried so as to obtain an orange-colored paste with a mass yield of 7.3%. The dry extract obtained contains 17.0% by weight of alpha-mangostine.

Example 8: Hydrotropic extraction with a 25% aqueous solution of butyl xylosides

20 grams of dry ground pericarps of Garcinia mangostana are extracted for 2 hours at room temperature with stirring with 200 milliliters of an aqueous solution of butyl xylosides at 25% by mass. After filtration on a K900 filtration plate, the filtrate is diluted with 2 volumes of water. After centrifugation, the pellet is recovered. The supernatant is diluted with 2 volumes of water. After centrifugation, the pellet is recovered and combined with the previous pellet, so as to obtain the dry extract of Garcinia mangostana in the form of a brown powder with a mass yield of 4.9%. The dry extract obtained contains 53.0% by weight of alpha-mangostine.

Example 9: Hydrotropic extraction with an aqueous solution of butyl xylosides (APXC4) assisted by extrusion

670 grams of dry pericarps of Garcinia mangostana are introduced into the first sheath of a Clextral BC45 twin-screw extruder with a flow rate of 40 kg / h. Then introduced an aqueous solution of butyl xylosides at 26% by mass with a flow rate of 120 kg / h. The temperature applied to the different sleeves is 60 ° C. After one minute, the pericarp extract of Garcinia mangostana is recovered at the extruder outlet thanks to a filtering sleeve allowing a solid / liquid separation. After clarification, the solution is diluted with 2 volumes of water. After centrifugation, the pellet is recovered. The supernatant is diluted with 2 volumes of water. After centrifugation, the pellet is recovered and combined with the previous pellet, so as to obtain the dry extract of Garcinia mangostana in the form of an orange paste with a mass yield of 0.4%. The dry extract obtained contains 50.0% by weight of alpha-mangostine.

Example 10 Extraction by Supercritical C0 ₂

470 grams of ground dried pericarps of Garcinia mangostana are extracted for 2 hours at 50 ° C and under 50 bars with supercritical C0 ₂ , the flow rate of which is 10 kg / h. The extract is then dissolved in ethanol then filtered through a K900 filtration plate and the solvent is evaporated so as to obtain 3.4 grams of an orange-yellow paste with a mass yield of 0.7%. The dry extract obtained contains 9.45% by weight of alpha-mangostine.

The marc (466 grams) is then extracted for 1 hour at 50 ° C. and under 50 bars with supercritical CO ₂ with co-solvent for ethanol (flow rates of 10 kg / h and 1 kg / h, respectively). The extract is filtered on a K900 filtration plate and the solvent is evaporated so as to obtain 2.3 grams of an orange-yellow paste with a mass yield of 0.5%. The dry extract obtained contains 22.3% by weight of alpha-mangostine.

Example 11 Evaluation of an Extract of Garcinia Mangostana on the Inhibition of Human JAK1, JAK2 and JAK3

JAK-STAT is a transduction signaling pathway that regulates growth, survival, differentiation and resistance to pathogens. This pathway mediates the effects of cytokines, interferons and growth factors. In mammals the JAK family consists of four members: JAKl, JAK2, JAK3 and TYK2. It is shown in a study carried out on mouse hair follicles, that the JAK-STAT pathway is dynamically regulated in the hair cycle; in fact, the JAK-STAT pathway is activated during the catagen and telogen phases and repressed at the start of the anagen phase. In addition, it has been demonstrated in mice that topical treatment in the telogen phase with inhibitors of the JAK-STAT pathway, including tofacitinib (JAK1 / 3>JAK2> TYR2) and ruxolitinib (JAK1 / 2>TYR2> JAK3 ), resulted in a rapid reentry at the start of the anagen phase (Harel et al., 2015 Sci. Adv. 1, el500973). In this same study it is also shown that the inhibition of JAK-STAT in human hair follicles increases hair growth ex vivo. These data suggest that the JAK-STAT signaling pathway may be a new target for stimulating hair growth.

The purpose of this example is to assess whether an extract of Garcinia mangostana can inhibit the JAK-STAT signaling pathway. This inhibition is evaluated on recombinant human proteins JAKl, JAK2 or JAK3.

Methods

An extract of Garcinia mangostana according to Example 1 is diluted in DMSO and is tested at various concentrations (0.1 - 1000 pg / ml). Positive controls (Tofacitinib and Ruxolitinib) are also evaluated in this test.

The products to be tested are incubated with a recombinant human protein JAKl, JAK2 or JAK3 with a reaction buffer (Tris / HCl for JAKl, MOPS (3-morpholino-1-propanesulfonic acid) for JAK2 and JAK3), EDTA and the specific peptide substrates. The phosphorylation reaction is then initiated by the addition of a mixture of magnesium acetate and radiolabelled ATP (45 mM for JAK1 and JAK2 and 10 mM for JAK3). After incubation for 40 minutes at room temperature, the reaction is stopped by adding phosphoric acid. Four washes with phosphoric acid and one with methanol are carried out to elute the small molecules including the labeled ATP. Finally the radioactivity of the substrate specific phosphorylated is counted. The compounds are tested on 3 separate experiments and for each experiment, duplicates are made.

The inhibition curves are constructed and CI ₀ values are calculated for each JAK subtype. A CI ₀

(50% inhibitory concentration) corresponds to the concentration of a compound which inhibits 50% of the effect observed.

The IC ₅₀ values, in pg / ml, of each JAK1, JAK2 and JAK3 recombinant protein as a function of the incubated test product are presented in Table 1 below:

[Table 1]

Gar eat. : Garcinia mangostana

The results obtained with the reference compounds (Ruxolitinib and Tofacitinib) are in accordance with those expected. Indeed, these two compounds strongly inhibit JAK-STAT activity (between 97% and 100% of maximum inhibition, with very low IC ₅₀ values (of the order of nanograms per milliliter).

Ruxolitinib shows a greater affinity for JAK1 or JAK2 than for JAK3. While Tofacitinib has more affinity for JAK1 or JAK3 than for JAK2. These expected results validate this test.

Garcinia mangostana extract shows strong inhibition of JAK1 (100% maximum inhibition) with an IC ₅₀ value of 6.6 pg / ml, strong inhibition of JAK2 (100% maximum inhibition) with a value slightly higher IC ₅₀ of 46.2 pg / ml, and also strong inhibition for JAK3 (100% maximum inhibition) with an IC ₅₀ value of 1.4 pg / ml.

This test demonstrates that Garcinia mangostana extract induces an inhibition of tyrosine kinase activity (with a stronger affinity for JAK1 and JAK3 than for JAK2), revealing a pharmacological activity of interest for promoting capillary growth.

Example 12 Confirmation of the Inhibitory Activity of the JAK-STAT Pathway of a Garcinia Mangostana Extract at the Cellular Level

The purpose of this example is to confirm the inhibitory activity of an extract of Garcinia mangostana from the JAK-STAT signaling pathway on a cellular model, the follicular keratinocytes of the external epithelial sheath of the hair follicle (ORS Outer Root Sheath model) . In this model, interleukin IL-6 is used to activate the JAK1 / 2-STAT3 pathway by activating the IL-6 and GP130 receptors, which are both expressed in this epithelial sheath of the hair follicles. . IL-6 is a cytokine which acts as an inhibitor of the hair growth cycle, its overexpression in a transgenic mouse model leads to delayed hair growth. Furthermore, in androgenetic alopecia IL-6 would be overexpressed in the cells of the dermal papilla under the influence of androgens (Kwack et al., 2012, J Invest Dermatology 132 (1) 43-9). It has also been reported that IL-6 delays the growth of the hair follicle in humans.

Method

The study is carried out on follicular keratinocytes of the external epithelial sheath of the hair follicle (ORS Outer Root Sheath model). The keratinocytes are cultured in a 96-well plate in an adequate medium (CnT-PR from Cellntec). Twenty-four hours later, the cells are washed with an alkaline phosphate buffer (PBS) and the medium is changed by CnT-PR-H medium (standard maintenance medium for human primary keratinocytes). After 48 hours, the cells are treated for 1 hour with the compounds to be tested (extract of Garcinia mangostina at 10 and 30 μg / ml diluted in DMSO) and the reference compounds (Ruxolutinib and Tofacitinib at 5 mM both, diluted in DMSO). The extract of Garcinia mangostana tested is an extract according to Example 1 of the present invention. Then the stimulation treatment with IL-6 is carried out at 100 ng / ml for 15 minutes.

All conditions are tested on cells from n = 3 separate donors. Garcinia mangostana extracts are tested on n = 3 separate experiments, the control and stimulation conditions and with the reference compounds are performed on n = 6 experiments. For each experiment, the data are produced in triplicate.

The activity of JAK is estimated by evaluating the level of phosphorylation of the STAT3 protein. Statistical analysis is performed by a parametric test after checking the normality and equivalence of the variance, otherwise a non-parametric test is chosen.

Results

The results are summarized in the following table 2:

[Table 2]

esm: standard error to the mean; % inh: percentage of inhibition; Gare mang: Garcinia mangostina extract.

Treatment of keratinocytes with IL-6 induces a significant increase in the level of phosphorylation of STAT3, this increase reaches 19% and is statistically significant (P <0.01). Reference compounds (Ruxolutinib and Tofacitinib tested at 5 mM) significantly reduce the phosphorylation level of STAT3, respectively by 90% and 59%, P <0.05 for the two compounds. These expected results validate the test.

The extract of Garcinia mangostana at the two concentrations tested significantly and very markedly inhibits the level of phosphorylation of STAT3 induced by stimulation with IL-6.

The inventors thus highlight the interest of an extract of Garcinia mangostana in the promotion of hair regrowth.

EXAMPLES 13 Evaluation of an Garcinia Mangostana Extract on the Synthesis and Release of Versican

The anchoring of the hair follicles results from a complex organization, composed of proteoglycans, matrix proteins like collagen and anchoring structures such as desmosomes and hemidesmosomes. Proteoglycans participate in cell adhesion to the extracellular matrix, in the adhesion of cells to each other, as well as in cell differentiation. Desmosomes also mediate cell-cell adhesion and allow the anchoring of the network of intermediate filaments to the plasma membrane. A study shows that mutations in proteins of the anchoring of hair follicles and more specifically in proteins of desmosomes results in hypotrichosis in mice but also in humans (Nagasawa et al., Dermatol Ther (Heidelb), 2016, 6: 59-68). Hypotrichosis is a disease of both the skin and the scalp that means stopping all hair growth. In addition, it is reported that androgenetic alopecia is associated with miniaturization of the hair follicle and ultimately a loss of anchoring properties.

Proteoglycans are made up of a combination of glycosaminoglycans, which are anionic polysaccharides and basic proteins. Each basic protein is preferably associated with a specific glycosaminoglycan chain. Glycosaminoglycans are classified into chondroitin sulfate, heparan sulfate, keratin sulfate or dermatan sulfate depending on their chemical structure. It is shown that there is a variable distribution of the components of these proteoglycans depending on the location and the state of growth of the hair. The dermal papilla contains an important level of basic protein and a wide variety of glycosaminoglycans. These glycosaminoglycans are known to bind and modulate a large number of biomolecules involved in cell differentiation or proliferation. We can mention FGF (Fibroblast Growth Factor), VEGF (Vascular Endothelial Growth Factor), Shh (Sonic HedgeHog), BMPs (Bone Morphogenetic Protein), Wnt (Wingless Integration site) and HGF (Hepatocyte Growth Factor). All these factors are well known to be involved in the morphogenesis of the hair follicle. This network by forming a microenvironment specific to the hair follicle also acts as a reservoir of modulators and growth factors and is therefore involved in the homeostasis of the hair follicle and in the regulation of the proliferation and differentiation of follicular cells.

Versican is a large proteoglycan from the chondroitin sulfate family. It is produced by fibroblasts, smooth muscle cells and keratinocytes and is involved in skin maintenance and firmness. It is involved in cell adhesion within the extracellular matrix. It plays a significant role in cell migration, proliferation and differentiation. Versican is expressed in the dermal papilla of the hair follicle, in the proximal part of the sheath of connective tissue, with a gradual decrease towards the distal part. The expression of its specific gene in the dermal papilla is important during the anagen phase and decreases from the start of the catagen phase. Its expression is regulated by the b-catenin signaling pathway. This specific expression of Versican shows its importance in the growth phase of the hair.

The purpose of this example is to assess whether an extract of Garcinia mangostana can influence the synthesis and release of Versican, an anchoring component of the hair follicle. Method

The experiments are performed on human dermal papilla cells from the hair follicles of three donors. The cells are seeded in 96-well plates and cultured for 24 h with the necessary supplements. The cells are then treated for 48 h with the products to be tested (extract of Garcinia mangostana at 3 or 10 g / ml diluted in DMSO). The extract of Garcinia mangostana tested is an extract according to Example 1 of the present invention. At the end of the incubation, the supernatants are collected and an ELISA test is carried out to evaluate the synthesis and the release of Versican. All the experimental conditions are carried out with n = 3 donors and n = 3 technical replicas. The amount of Versican in the supernatants is measured using a specific ELISA kit according to the supplier's instructions (Cusabio).

Results

The Versican concentrations measured in the supernatants are shown in Table 3 below:

[Table 3]

esm: standard error to the mean; Stats: the inter-group comparison is performed by an ANOVA with repeated measurements followed by a Dunnett post test. Treatment of the cells of the dermal papilla with an extract of Garcinia mangostana at 10 pg / ml also induces a strong statistically significant activation (P 0.01) of the synthesis and of the release of Versican. A lower concentration of an extract of Garcinia mangostana at 3pg / ml, is not enough to activate this target. Garcinia mangostana extract inhibits JAK-STAT activity with IC ₅₀ values of the order of

I at 46 pg / ml depending on the subtype as set out in Example 10.

It is therefore not illogical that a concentration higher than 3pg / ml is necessary to significantly increase the synthesis and the release of a proteoglycan since the activation of Versican is not in connection with the inhibition of the JAK pathway. / STAT.

Claims

1. Garcinia mangostana hydroalcoholic extract for its use in the prevention or treatment of alopecia by promoting hair growth.

2. Extract for its use according to claim 1, characterized in that said extract is an extract of pericarp from the fruit of Garcinia mangostana.

3. Extract for its use according to any one of claims 1 and 2, characterized in that said extract is intended to be applied topically.

4. Extract for its use according to any one of claims 1 to 3 in which the alopecia is chosen from the group consisting of androgenetic alopecia, reactive alopecia, post-menopausal alopecia and alopecia areata.

5. Non-therapeutic use of a hydroalcoholic extract of Garcinia mangostana to promote hair regrowth.

6. Dermatological composition comprising at least one hydroalcoholic extract of Garcinia mangostana with at least one dermatologically acceptable excipient for its use in the prevention or treatment of alopecia by promoting hair growth.

7. Dermatological composition for its use according to claim 6, characterized in that the extract of Garcinia mangostana is an extract of pericarp from the fruit of Garcinia mangostana.

8. Dermatological composition for its use according to any one of claims 6 and 7, characterized in that it comprises 0.001 to 5%, preferably 0.005 to 1% of extract of Garcinia mangostana by weight of dry extract relative to the total weight of the composition.

9. Dermatological composition for its use according to any one of claims 6 to 8, characterized in that the composition is intended for topical application.

10. Dermatological composition for its use according to any one of claims 6 to 9 in which the alopecia is chosen from the group consisting of androgenetic alopecia, reactive alopecia, post-menopausal alopecia and areata alopecia .

11. Cosmetic composition for promoting hair growth, in particular for promoting hair regrowth comprising at least one hydroalcoholic extract of Garcinia mangostana with at least one dermatologically acceptable excipient.

12. Cosmetic composition according to claim 11 in which the hydroalcoholic extract of Garcinia mangostana is the only active principle for promoting hair growth.

13. Non-therapeutic use of a cosmetic composition comprising at least one hydroalcoholic extract of Garcinia mangostana with at least one cosmetically acceptable excipient to promote hair regrowth.