tester. La presente invention se rapporte a une composition cosmetiquetest. The present invention relates to a cosmetic composition
pour lutter contre la canitie comprenant au moins un agent mimetique de l'activite de la DOPAchrome for combating canities comprising at least one agent mimicking the activity of DOPAchrome
tautomerase (TRP-2).tautomerase (TRP-2).
s Le follicule pileux est une invagination tubulaire de l'epiderme qui s'enfonce jusqu'aux couches profondes du derme. La partie inferieure, ou bulbe pileux, comporte elle-meme une invagination dans laquelle se trouve la papille dermique. La partie inferieure du bulbe est une zone de proliferation cellulaire ou se trouvent les precurseurs des cellules keratinisees constituent le chevou. Les cellules en ascension issues de ces precurseurs se keratinisent progressivement dans la partie superieure du bulbe, et cet ensemble de s The hair follicle is a tubular invagination of the epidermis which sinks to the deep layers of the dermis. The lower part, or hair bulb, itself has an invagination in which the dermal papilla is found. The lower part of the bulb is an area of cell proliferation where the precursors of keratinized cells constitute the hair. The ascending cells from these precursors gradually keratinize in the upper part of the bulb, and this set of
cellules keratinisees formera la tige pilaire. keratinized cells will form the hair shaft.
La couleur des cheveux et des polls repose notamment sur la presence en quantites et ratios variables de deux groupes de melanines: les eumelanines (pigments bruns et lS noirs) et les pheomelanines (pigments rouges et jaunes). La pigmentation du cheveu et Hair color and polls are based in particular on the presence in variable quantities and ratios of two groups of melanins: eumelanins (brown pigments and black IS) and pheomelanins (red and yellow pigments). The pigmentation of the hair and
des polls requiert la presence de melanocytes au niveau du bulbe du follicule pileux. polls requires the presence of melanocytes in the bulb of the hair follicle.
Ces melanocytes vent dans un etat actif, c'est-a-dire qu'ils synthetisent des melanines. These melanocytes are in an active state, that is to say that they synthesize melanins.
Ces pigments vent transmis aux keratinocytes destines a former la tige pilaire ce qui conduira a la pousse d'un chevou ou d'un poll pigmente. Cette structure est appelee ci These pigments are transmitted to the keratinocytes intended to form the hair shaft which will lead to the growth of a pig or a pigmented poll. This structure is called ci
apres << unite folliculaire de pigmentation,,. after << follicular pigmentation unit ,,.
Chez les mammiferes, la melanogenese implique au moins trots enzymes: la tyrosinase, la DOPAchrome tautomerase (TRP-2, pour Tyrosinase Related Protein 2) et In mammals, melanogenesis involves at least three enzymes: tyrosinase, DOPAchrome tautomerase (TRP-2, for Tyrosinase Related Protein 2) and
la DHICAoxydase (TRP-1, pour Tyrosinase Related Protein 1). DHICAoxydase (TRP-1, for Tyrosinase Related Protein 1).
s La tyrosinase est ['enzyme qui initie la biosynthese des melanines. Wile est egalement s Tyrosinase is the enzyme that initiates the biosynthesis of melanins. Wile is also
decrite comme etant ['enzyme limitant de la melanogenese. described as being the enzyme limiting melanogenesis.
La TRP-2 catalyse la tautomerisation du DOPAchrome en acide 5,6Dibydroxyindole-2- TRP-2 catalyzes the tautomerization of DOPAchrome into acid 5,6 Dibydroxyindole-2-
carboxylique (DHICA). En ['absence de TRP-2, le DOPAchrome subit une carboxylic (DHICA). In the absence of TRP-2, DOPAchrome undergoes a
decarboxylation spontanee pour former le 5,6-dihydroxyindole (DHI). spontaneous decarboxylation to form 5,6-dihydroxyindole (DHI).
DHICA et DHI vent tous deux des precurseurs de pigments, TRP-1 oxyde les molecules de DHICA pour former des derives de quinones (Pawelek JM and Chakraborty AK. The enzymology of melanogenesis. In: Nordlund JJ, Boissy RE, Hearing VJ, King RA, Ortonne J-P. The Pigmentary System: Physiology and Pathophysiology. New York: Both DHICA and DHI are pigment precursors, TRP-1 oxidizes DHICA molecules to form quinone derivatives (Pawelek JM and Chakraborty AK. The enzymology of melanogenesis. In: Nordlund JJ, Boissy RE, Hearing VJ, King RA , Ortonne JP. The Pigmentary System: Physiology and Pathophysiology. New York:
Oxford university press; 1998. p. 391-400). Oxford university press; 1998. p. 391-400).
3s Les trots enzymes, tyrosinase, TRP-2 et TRP-1, apparaissent specifiquement impliquees dans la melanogenese. De plus, I'activite de ces trots enzymes a ete decrite comme 3s The enzyme trots, tyrosinase, TRP-2 and TRP-1, appear specifically involved in melanogenesis. In addition, the activity of these enzyme trots has been described as
necessaire a l'activite maximale de biosynthese des eumelanines. necessary for maximum activity of biosynthesis of eumelanins.
L'expression de TRP-2 a ete observee dans les polls de souris noires, a la fois dans les melanocytes actifs du bulbe et dans les melanocytes quiescents de la gaine epitheliale externe. De plus, il est connu que l'activite DOPAchrome tautomerase est augmentee s pendant la phase anagene chez la souris noire. Cependant aucune correlation claire n'a ete etablie entre ['expression de TRP-2 et l'intensite de la pigmentation (Sturm et al. The expression of TRP-2 was observed in the polls of black mice, both in the active melanocytes of the bulb and in the quiescent melanocytes of the outer epithelial sheath. In addition, it is known that DOPAchrome tautomerase activity is increased during the anagen phase in black mice. However, no clear correlation has been established between the expression of TRP-2 and the intensity of pigmentation (Sturm et al.
1995).1995).
Par ailleurs, TRP-2 a egalement ete decrite comme conferant aux melanocytes qui l'expriment une resistance a des agents endommageant l'ADN tel que le cis o diamminedichloroplatinum(ll) (Chu et al. 2000 et Pak et al. 2000). Ces resultats suggerent que TRP-2 serait aussi impliquee dans une fonction independante de la Furthermore, TRP-2 has also been described as conferring on melanocytes which express it resistance to DNA damaging agents such as cis o diamminedichloroplatinum (ll) (Chu et al. 2000 and Pak et al. 2000). These results suggest that TRP-2 would also be involved in a function independent of the
meianogenese, ['enzyme pourrait jouer un role cytoprotecteur. meianogenese, the enzyme could play a cytoprotective role.
Le cheveu et le poll subissent un cycle. Ce cycle comprend une phase de croissance (phase anagene), une phase de degenerescence (phase catagene) et une phase de repos (phase telogene) a la suite de laquelle une nouvelle phase anagene se developpera. En raison de ce cycle pilaire, I'unite folliculaire de pigmentation doit The hair and the poll go through a cycle. This cycle includes a growth phase (anagen phase), a degeneration phase (catagen phase) and a rest phase (telogen phase) after which a new anagen phase will develop. Because of this hair cycle, the follicular pigmentation unit must
egalement etre cycliquement renouvelee. also be cyclically renewed.
Ce processus a ete recemment decrit chez l'homme (Commo S. et Bernard B., 2000, Pigment Cell Res. 13:253-259). II a plus particulierement ete montre qu'au cours de la transition telogene-anagene, une partie des melanocytes inactifs contenus dans la capsule telogene prolifere, se positionne autour de la papille dermique du bulbe naissant et commence a exprimer des enzymes necessaires a la synthese de melanines. En parallele, I'autre partie des melanocytes reste inactive dans la region superieure du This process has recently been described in humans (Commo S. and Bernard B., 2000, Pigment Cell Res. 13: 253-259). It has more particularly been shown that during the telogen-anagen transition, a part of the inactive melanocytes contained in the proliferating telogene capsule, is positioned around the dermal papilla of the nascent bulb and begins to express enzymes necessary for the synthesis of melanin. In parallel, the other part of the melanocytes remains inactive in the upper region of the
follicule pileux.hair follicle.
Ces enzymes melanogenes seront exprimees dans les melanocytes du bulbe pendant toute la duree de la phase anagene mais ne seront plus exprimees pendant les phases catagene et telogene. Le cycle normal des melanocytes dans le follicule pileux humain requiert la presence de melanocytes quiescents dans la region superieure du follicule These melanogenic enzymes will be expressed in the melanocytes of the bulb throughout the duration of the anagen phase but will no longer be expressed during the catagen and telogen phases. The normal melanocyte cycle in the human hair follicle requires the presence of quiescent melanocytes in the upper region of the follicle.
pileux qui seront cycliquement actives pour regenerer ['unite folliculaire de pigmentation. hair which will be cyclically active to regenerate the follicular pigmentation unit.
11 est admis que la canitie (blanchissement naturel des cheveux) est associee a une diminution de melanine dans la tige pilaire. La cause de cette diminution n'est pas a ce jour elucidee. Plusieurs hypotheses vent avancees, elle pourrait etre liee a une diminution de l'activite melanogene, une alteration du transfert des melanines ou une It is accepted that canities (natural bleaching of the hair) are associated with a decrease in melanin in the hair shaft. The cause of this decrease has not yet been elucidated. Several hypotheses have been advanced, it could be linked to a decrease in melanogenic activity, an alteration in the transfer of melanins or a
diminution du nombre de melanocytes dans le bulbe (Tobin et Paus, 2001). decrease in the number of melanocytes in the bulb (Tobin and Paus, 2001).
Jusqu'a present, on pensait que des melanocytes quiescents etaient presents dans les follicules pileux de cheveux blancs (Takada et al. 1992, Horikawa et al. 1996, Jenner et Randall 2000). Or, la Demanderesse a constate que la progression de la canitie est associee a une diminution du nombre de melanocytes dans les bulbes pileux, qui, bien qu'en nombre restraint, synthetisent et transferent les melanines. La Demanderesse a egalement observe de fagon inattendue et surprenante que la population de melanocytes o quiescents de la region superieure du follicule pileux humain est egalement diminuee au Until now, quiescent melanocytes have been thought to be present in the hair follicles of white hair (Takada et al. 1992, Horikawa et al. 1996, Jenner and Randall 2000). However, the Applicant has found that the progression of canities is associated with a decrease in the number of melanocytes in the hair bulbs, which, although in limited numbers, synthesize and transfer the melanins. The Applicant has also unexpectedly and surprisingly observed that the population of quiescent melanocytes in the upper region of the human hair follicle is also decreased with
cours du processus de canitie, les cheveux blancs ne possedant plus que quelques - during the canities process, the white hair having only a few -
voire plus aucun - melanocytes, contrai rem ent a l' infundibul um et l'epiderme avoisinant ces chevoux blancs. Cette disparition affecte prematurement et specifiquement les or no longer any - melanocytes, contrary to the infundibul um and the epidermis surrounding these white ankles. This disappearance affects prematurely and specifically the
melanocytes contenus dans les cheveux. melanocytes contained in the hair.
11 appara'^t done necessaire de lutter contre la disparition des melanocytes des follicules pileux humains, processus affectant a la fois les melanocytes actifs des bulbes et les melanocytes quiescents de la region superieure des follicules pileux, pour lutter contre la canitie. Par ailleurs, la Demanderesse a egalement constate que ['enzyme TRP-2 n'est pas exprimee dans les melanocytes des follicules pileux humains pigmentes (bruns, noirs et roux) chez l'individu caucasien, asiatique et africain. Cette enzyme n'est detectee ni dans les melanocytes actifs du bulbe, ni dans les melanocytes quiescents de la region superieure du follicule pileux humain alors qu'elle est exprimee dans l'epiderme et l'infundibulum de l'individu caucasien, africain et asiatique. L'absence de TRP-2 est associee a la disparition precoce des melanocytes qui ne l'expriment pas, c'est-a-dire, les melanocytes quiescents de la region superieure du follicu le pi leux et les melanocytes It therefore appears necessary to combat the disappearance of melanocytes from human hair follicles, a process affecting both the active melanocytes of the bulbs and the quiescent melanocytes of the upper region of the hair follicles, in order to combat canities. Furthermore, the Applicant has also found that the enzyme TRP-2 is not expressed in the melanocytes of pigmented human hair follicles (brown, black and red) in the Caucasian, Asian and African individual. This enzyme is detected neither in the active melanocytes of the bulb, nor in the quiescent melanocytes of the upper region of the human hair follicle while it is expressed in the epidermis and infundibulum of the Caucasian, African and Asian individual. . The absence of TRP-2 is associated with the early disappearance of melanocytes which do not express it, that is to say, the quiescent melanocytes of the upper region of the filicular follicle and the melanocytes
actifs du bulbe.bulb assets.
La Demanderesse a identifie un moyen de maintenir la population de melanocytes du follicule pileux responsables de la pigmentation des cheveux, en effet, elle a montre qu'il etait possible de mimer lactivite TRP-2, elle a ainsi mis au point un moyen pour prevenir eVou limiter eVou stopper le developpement de la canitie et meme dtinduire la The Applicant has identified a means of maintaining the population of melanocytes of the hair follicle responsible for the pigmentation of the hair, in fact, it has shown that it is possible to mimic the TRP-2 activity, it has therefore developed a means for preventing You limit or you stop the development of canities and even destroy the
pigmentation des chevoux eVou des polls gris ou blancs. pigmentation of the ankles and gray or white polls.
Ainsi un premier objet de ['invention se rapporte a une composition cosmetique pour lutter contre la canitie comprenant dans un milieu cosmetiquement acceptable au moins Thus a first object of the invention relates to a cosmetic composition for combating canities comprising in a cosmetically acceptable medium at least
un agent mimetique de l'activite de la DOPAchrome tautomerase (TRP-2). a mimicry agent for the activity of DOPAchrome tautomerase (TRP-2).
On entend par agent mimetique de l'activite de la DOPAchrome tautomerase un compose capable de reproduire les effets de la DOPAchrome tautomerase sur le By mimetic agent of the activity of DOPAchrome tautomerase is meant a compound capable of reproducing the effects of DOPAchrome tautomerase on the
metabolisme et la survie des melanocytes. metabolism and survival of melanocytes.
L'agent mimetique de l'activite de la DOPAchrome tautomerase (TRP-2) pourra etre notamment choisi parmi les composes suivant: - molecules synthetiques mimetiques de SOD (Metaphore), par exemples, les complexes de manganese tels que decrits dans US 5637578, 5610293, 5874421; - composes anti-oxydants: tels que des derives de tetrahydro-5,6,7,8- naphtaneol-1, en particulier ceux decrits dans le brevet EP 0404640, des derives benzoheterocyles oxygenes (voir le brevet EP 0 685 473), des derives de cyclodextrines (voir le brevet EP 0 778287), des composes silices derives d'acide ascorbique (voir le brevet WO01/30784), de la pyrrolidone carboxylate de Iysine ou d'arginine (voir le brevet EP0511 118), des derives de benzylidene camphre ter-butyle (voir le brevet US 4, 952,391), des derives de benzylidene cyclanone (voir le brevet FR 2636531) , des o diorganopolysiloxanes modifies (voir le brevet EP 0 370 868), des derives lipophiles du benzylidene camphre (voir le brevet EP 0 390 681), des derives hydrophile du benzylidene cam ph re (voir le brevet EP 0 390 682), des derives de benzyl-cyclanone (voir le brevet EP 0 390 683), des polymeres anti-oxydants tels que decrits dans le brevet US4,281,192, des associations de mono- et diester d'acide cinnamique et de vitamine C (voir le brevet EP 0 664 290), des polyamines, telles que putrescine, spermidine, spermine, Di-amines, Tri-amines, Tetra-amines; le propyl gallate, la quercetine, le trolox, l'histidine, le tryptophane, la methionine, des chelateurs de metaux (21-aminosterodes), le complexe salen-manganese (par exemple: EUK-8), I'a-phenyl ter-butyl nitrol (PBN) (et composes derives) ou l'ebselen; - composes non anti-oxydants, tel que le MIF et ses analogues (Marcophage Migration The mimetic agent for the activity of DOPAchrome tautomerase (TRP-2) may be chosen in particular from the following compounds: - synthetic mimetic molecules of SOD (Metaphore), for example, manganese complexes as described in US 5637578, 5610293, 5874421; - antioxidant compounds: such as derivatives of tetrahydro-5,6,7,8- naphthaneol-1, in particular those described in patent EP 0404640, oxygenated benzoheterocyles derivatives (see patent EP 0 685 473), cyclodextrin derivatives (see patent EP 0 778 287), silica compounds derived from ascorbic acid (see patent WO01 / 30784), pyrrolidone carboxylate of Iysine or arginine (see patent EP0511 118), derivatives of benzylidene camphor ter-butyl (see patent US 4, 952,391), derivatives of benzylidene cyclanone (see patent FR 2636531), modified o diorganopolysiloxanes (see patent EP 0 370 868), lipophilic derivatives of benzylidene camphor (see patent EP 0 390 681), hydrophilic derivatives of benzylidene camphor (see patent EP 0 390 682), derivatives of benzyl-cyclanone (see patent EP 0 390 683), antioxidant polymers as described in patent US Pat. No. 4,281,192, combinations of mono- and diester of cinnamic acid and vitam ine C (see patent EP 0 664 290), polyamines, such as putrescine, spermidine, spermine, Di-amines, Tri-amines, Tetra-amines; propyl gallate, quercetin, trolox, histidine, tryptophan, methionine, metal chelators (21-aminosterodes), the salen-manganese complex (for example: EUK-8), a-phenyl ter -butyl nitrol (PBN) (and derivative compounds) or ebselen; - non-antioxidant compounds, such as MIF and its analogues (Marcophage Migration
Inhibiting Factor, voir Rosengren et al. Mol. Med., 1996, 2(1):143-9). Inhibiting Factor, see Rosengren et al. Mol. Med., 1996, 2 (1): 143-9).
La composition selon ['invention comprend une quantite d'agent mimetique de l'activite The composition according to the invention comprises a quantity of activity mimicry agent
de la DOPAchrome tautomerase comprise entre 0.001 % et 10 % en poids par volume. DOPAchrome tautomerase between 0.001% and 10% by weight by volume.
La composition selon ['invention peut etre administree par vole vale ou appliquee sur la The composition according to the invention can be administered by vale vale or applied to the
peau (sur toute zone cutanee du corps) eVou le cuir chevelu. skin (on any cutaneous area of the body) or the scalp.
Par vole vale, la composition selon ['invention peut contenir, le ou les agents mimetiques de l'activite de la DOPAchrome tautomerase composes actifs en solution s dans un liquide alimentaire tel qu'une solution aqueuse ou hydroalcoolique, eventuellement aromatisee. Ils peuvent egalement etre incorpores dans un excipient solide ingerable et se presenter par exemple sous forme de granules, de pilules, de comprimes ou de dragees. Ils peuvent egalement etre places en solution dans un By vale vale, the composition according to the invention may contain the agent or agents mimicking the activity of DOPAchrome tautomerase active compounds in solution s in a food liquid such as an aqueous or hydroalcoholic solution, possibly flavored. They can also be incorporated in a solid ingestible excipient and be presented for example in the form of granules, pills, tablets or dragees. They can also be placed in solution in a
liquide alimentaire conditionne lui-meme eventuellement dans des capsules ingerables. liquid food itself possibly packaged in ingestible capsules.
Selon le mode d'administration, la composition de ['invention peut se presenter sous Depending on the mode of administration, the composition of the invention may be presented in
toutes les formes galeniques normalement utilisees, particulierement en cosmetologie. all the dosage forms normally used, particularly in cosmetology.
Une composition preferee de ['invention est une composition cosmetique adaptee a une A preferred composition of the invention is a cosmetic composition suitable for a
application topique sur le cuir chevelu eVou la peau. topical application to the scalp and skin.
Pour une application topique, la composition utilisable selon ['invention peut etre notamment sous la forme d'une solution aqueuse, hydroalcoolique ou huileuse ou de dispersion du type lotion ou serum, d'emulsions de consistence liquide ou semi-liquide du type fait, obtenues par dispersion d'une phase grasse dans une phase aqueuse (H/E) ou inversement (E/H), ou de suspensions ou emulsions de consistence moue du type creme ou gel aqueux ou anhydres, ou encore de microcapsules ou microparticules, ou de dispersions vesiculaires de type ionique eVou non ionique. Wile peut ainsi se presenter sous forme d'onguent, de teinture, de creme, de pommade, de poudre, de timbre, de tampon imbibe, de solution, d'emulsion ou de dispersion vesiculaire, de lotion, s de gel, de spray, de suspension, de shampooing, d'aerosol ou de mousse. Wiles peuvent etre anhydres ou aqueuses. Wile peut egalement consister en des preparations solides For a topical application, the composition which can be used according to the invention may in particular be in the form of an aqueous, hydroalcoholic or oily solution or of a dispersion of the lotion or serum type, of liquid or semi-liquid consistency emulsions of the made type, obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O), or suspensions or emulsions of soft consistency of the aqueous or anhydrous cream or gel type, or alternatively of microcapsules or microparticles, or of vesicular dispersions of the ionic eVou nonionic type. Wile can thus be presented in the form of an ointment, tincture, cream, ointment, powder, patch, soaked tampon, solution, emulsion or vesicular dispersion, lotion, gel, spray. , suspension, shampoo, aerosol or foam. Wiles can be anhydrous or aqueous. Wile can also consist of solid preparations
constituent des savons ou des pains de nettoyage. constitute soaps or cleaning bars.
Ces compositions vent preparees selon les methodes usuelles. These compositions are prepared according to the usual methods.
La composition utilisable selon ['invention peut en particulier etre une composition pour veins capillaires, et notamment un shampooing, une lotion de mise en plis, une lotion traitante, une creme ou un gel coiffant, une composition de teintures (notamment teintures d'oxydation) eventuellement sous forme de shampooings colorants, des lotions The composition which can be used according to the invention may in particular be a composition for capillary veins, and in particular a shampoo, a styling lotion, a treating lotion, a styling cream or gel, a composition of dyes (in particular oxidation dyes ) possibly in the form of coloring shampoos, lotions
restructurantes pour les cheveux, de masque. restructuring for hair, mask.
3s La composition cosmetique selon ['invention sera preferentiellement une creme, une 3s The cosmetic composition according to the invention will preferably be a cream, a
lotion capillaire, un shampooing ou un apres-shampooing. hair lotion, shampoo or conditioner.
Les quantites des differents constituents des compositions utilisables selon ['invention vent celles classiquement utilisees dans les domaines consideres. Lorsque la composition utilisable selon ['invention est une emulsion, la proportion de la phase grasse peut aller de 5% a 80% en poids, et de preference de 5% a 50% en poids par rapport au poids total de la composition. Les huiles, les cires, les emulsionnants et o les coemulsionnants utilises dans la composition sous forme d'emulsion vent choisis parmi ceux classiquement utilises dans le domaine cosmetique. L'emulsionnant et le co emulsionnant vent presents, dans la composition, en une proportion allant de 0,3% a % en poids, et de preference de 0,5 a 20% en poids par rapport au poids total de la The amounts of the various constituents of the compositions which can be used according to the invention are those conventionally used in the fields under consideration. When the composition which can be used according to the invention is an emulsion, the proportion of the fatty phase can range from 5% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the composition. Oils, waxes, emulsifiers and o coemulsifiers used in the composition in the form of a wind emulsion chosen from those conventionally used in the cosmetic field. The emulsifier and the co-emulsifier are present in the composition in a proportion ranging from 0.3% to% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the
composition. L'emulsion peut, en outre, contenir des vesicules lipidiques. composition. The emulsion may, in addition, contain lipid vesicles.
Lorsque la composition utilisable selon ['invention est une solution ou un gel huileux, la When the composition which can be used according to the invention is an oily solution or gel, the
phase grasse peut representer plus de 90% du poids total de la composition. fatty phase can represent more than 90% of the total weight of the composition.
Dans uns variante de ['invention, la composition sera telle que ['agent mimetique de I'activite de la DOPAchrome tautomerase est encapsule dans un enrobage tel que des microspheres, des nanospheres, des oleosomes ou des nanocapsules, ltenrobage sera choisi selon la nature chimique de ['agent mimetique de l'activite de la DOPAchrome tautomerase. s A titre d'exemple, les microspheres pourront etre preparees selon la methode decrite In a variant of the invention, the composition will be such that the mimicry agent for the activity of DOPAchrome tautomerase is encapsulated in a coating such as microspheres, nanospheres, oleosomes or nanocapsules, ltenrobing will be chosen according to the nature chemical of the mimetic agent of the activity of DOPAchrome tautomerase. s As an example, the microspheres can be prepared according to the method described
dans la demande de brevet EP 0 375 520. in patent application EP 0 375 520.
Les nanospheres pourront se presenter sous forme de suspension aqueuse et etre preparees selon les methodes decrites dans les demandes de brevet FR 0015686 et The nanospheres may be in the form of an aqueous suspension and be prepared according to the methods described in patent applications FR 0015686 and
FR 0101438.FR 0101438.
Les oleosomes consistent en une emulsion huile dans eau formee par des globules huileux pourvus d'un enrobage cristal iiquide lamellaire disperse dans une phase Oleosomes consist of an oil-in-water emulsion formed by oily globules provided with a lamellar liquid crystal coating dispersed in a phase
aqueuse (voir les demandes de brevet EP 0 641 557 et EP 0 705 593). aqueous (see patent applications EP 0 641 557 and EP 0 705 593).
L' agent m i m etiq ue de l'activite de la D O PAch rom e tautomerase pou rra au ssi etre encapsule dans des nanocapsules consistent en un enrobage lamellaire obtenu a partir d'un tensio-actif silicone (voir la demande de brevet EP 0 780 115), les nanocapsules pourront egalement etre preparees a base de polyesters sulfoniques hydrodispersibles The agent mim etiq ue of the activity of DO PAch rom e tautomerase can rs if encapsulated in nanocapsules consist of a lamellar coating obtained from a silicone surfactant (see patent application EP 0 780 115), the nanocapsules can also be prepared on the basis of water-dispersible sulfonic polyesters
s (voir la demande de brevet FR 0113337). s (see patent application FR 0113337).
L'agent mimetique de l'activite de la DOPAchrome tautomerase pourra egaiement etre complexe a la surface de globules huileux cationiques, quelques soit leur taille (voir les demandes de brevet EP 1 010 413, EP 1 010 414, EP 1 010 415, EP 1 010 41 6, The mimicry agent for the activity of DOPAchrome tautomerase may also be complex on the surface of cationic oily globules, whatever their size (see patent applications EP 1 010 413, EP 1 010 414, EP 1 010 415, EP 1 010 41 6,
EP 1 013 338, EP 1 016 453, EP 1 018 363, EP 1 020 219, EP 1 025 898, EP 1 013 338, EP 1 016 453, EP 1 018 363, EP 1 020 219, EP 1 025 898,
EP 1 120 101, EP 1 120 102, EP 1 129 684, EP 1 160 005 et EP 1 172 077). EP 1 120 101, EP 1 120 102, EP 1 129 684, EP 1 160 005 and EP 1 172 077).
L'agent mimetique de l'activite de la DOPAchrome tautomerase peut enfin etre complexe a la surface de nanocapsules ou nanoparticules pourvues d'un enrobage lamellaire (Voir S EP 0 447 318 et EP 0 557 489) et contenant un tensio-actif cationique a la surface (voir The mimicry agent for the activity of DOPAchrome tautomerase can finally be complex on the surface of nanocapsules or nanoparticles provided with a lamellar coating (See S EP 0 447 318 and EP 0 557 489) and containing a cationic surfactant the surface (see
les references citees precedemment pour les tensio-actifs cationiques). the references cited above for cationic surfactants).
En particulier, on preferera une composition telle que l'enrobage dans lequel ['agent mimetique de l'activite de la DOPAchrome tautomerase a un diametre inferieur ou egale a 10,um. Lorsque l'enrobage ne forme pas une vesicule spherique, on entend par In particular, a composition such as the coating in which the mimetic agent for the activity of DOPAchrome tautomerase has a diameter less than or equal to 10 μm will be preferred. When the coating does not form a spherical vesicle, the term “
diametre la dimension la plus grande de la vesicule. diameter the largest dimension of the vesicle.
De fa,con connue, la composition selon ['invention peut contenir egalement des adjuvants habituels dans le domaine cosmetique, tels que les gelifiants hydrophiles ou lipophiles, les additifs hydrophiles ou lipophiles, les conservateurs, les antioxydants, les solvents, les parfums, les charges, les filtres, les absorbeurs d'odeur et les matieres colorantes. Les quantites de ces differents adjuvants vent celles classiquement utilisees dans le domaine cosmetique, et par exemple de 0, 01% a 10% du poids total de la composition. Ces adjuvants, selon leur nature, peuvent etre introduits dans la phase As is known, the composition according to the invention may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, odor absorbers and coloring matter. The amounts of these various adjuvants are those conventionally used in the cosmetic field, and for example from 0.01% to 10% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced in the phase
o grasse, dans la phase aqueuse eVou dans les spherules lipidiques. o fatty, in the aqueous phase eVou in the lipid spherules.
Comme huiles ou cires utilisables dans ['invention, on peut citer les huiles minerales (huile de vaseline), les huiles vegetales (fraction liquide du beurre de karite, huile de tournesol), les huiles animales (perhydrosqualene), les huiles de synthese (huile de Purcellin), les huiles ou cires siliconees (cyclomethicone) et les huiles fluorees ss (perfluoropolyethers), les cires d'abeille, de carnauba ou paraffine. On peut ajouter a ces As oils or waxes which can be used in the invention, mention may be made of mineral oils (petroleum jelly oil), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils ( Purcellin oil), silicone oils or waxes (cyclomethicone) and ss fluorinated oils (perfluoropolyethers), beeswax, carnauba or paraffin. We can add to these
huiles des alcools gras et des acides gras (acide stearique). oils of fatty alcohols and fatty acids (stearic acid).
Comme emulsionnants utilisables dans ['invention, on peut citer par exemple le stearate de glycerol, le polysorbate 60 et le melange de PEG6/PEG-32/Glycol Stearate vendu As emulsifiers which can be used in the invention, there may be mentioned for example glycerol stearate, polysorbate 60 and the mixture of PEG6 / PEG-32 / Glycol Stearate sold
sous la denomination de Tefose 63 par la societe Gattefosse. under the name of Tefose 63 by the company Gattefosse.
Comme solvents utilisables dans ['invention, on peut citer les alcools inferieurs, As solvents which can be used in the invention, mention may be made of lower alcohols,
notamment ['ethanol et l'isopropanol, le propylene glycol. especially ethanol and isopropanol, propylene glycol.
Comme gelifiants hydrophiles utilisables dans ['invention, on peut citer les polymeres carboxyvinyliques (carbomer), les copolymeres acryliques tels que les copolymeres 0 d'acrylates/alkylacrylates, les polyacrylamides, les polysaccharides tels que l'hydroxypropylcellulose, les gommes naturelles et les argiles, et, comme gelifiants lipophiles, on peut citer les argiles modifiees comme les bentones, les sels metalliques d'acides gras comme les stearates d'aluminium et la silice hydrophobe, ethylcellulose, polyethylene. Les compositions utilisables selon ['invention peuvent associer au moins un agent mimetique de l'activite de TRP-2 a d'autres agents actifs. Parmi ces agents actifs, on peut citer a titre d'exemple: - les agents modulant la differenciation et/ou la proliferation eVou la pigmentation des cellules de la peau tels que le retinol et ses esters, la vitamine D et ses derives, les oestrogenes tels que ltoestradiol, les modulateurs de l'AMPc tels que les derives de POMC, I'adenosine, ou la forskoline et ses derives, les prostaglandines et leurs derives, la triiodotrionine et ses derives; - des extraits de vegetaux tels que ceux d'lridacees ou de soja, extraits pouvant alors contenir ou non des isoflavones; - des extraits de micro-organismes; - les agents anti-radicaux libres tels que l'a-tocopherol ou ses esters, les superoxyde dismutases ou ses mimetiques, certains chelatants de metaux ou l'acide ascorbique et ses esters; - les anti-seborrheiques tels que certains acides amines soufres, I'acide 1 3-cis retinoque, I'acetate de cyproterone; - les autres agents de lutte contre les etats desquamatifs du cuir chevelu comme le zinc pyrithione, le disulfure de selenium, le climbazole, I'acide undecylenique, le Ketoconazole, la piroctone olamine (octopirox) ou la ciclopiroctone (ciclopirox); 3s en particulier, il pourra s'agir d'actifs stimulant la repousse et/ou favorisant le ralentissement de la chute des cheveux, on peut plus particulierement citer a titre non limitatif: - les esters d'acide nicotinique, dont notamment le nicotinate de tocopherol, le nicotinate de benzyle et les nicotinates d'alkyles en C1-C6 comme les nicotinates de methyle ou d'hexyle; s - les derives de pyrimidine, comme le 2,4-diamino 6-piperidinopyrimidine 3-oxyde ou "Minoxidil" decrit dans les brevets US 4,139,619 et US 4,596,812; - les agents inhibiteur de la lipoxygenase ou inducteur de la cyclooxydase favorisant la repousse des cheveux comme ceux decrits par la Demanderesse dans la demande de brevet europeen EP 0 648 488; - les agents antibacteriens tels que les macrolides, les pyranosides et les tetracyclines, et notamment l'Erythromycine; - les agents antagonistes de calcium, comme la Cinnarizine, la Nimodipine et la Nifedipine; - des hormones, telles que l'estriol ou des analogues, ou la thyroxine et ses sels; - des agents antiandrogenes, tels que l'oxendolone, la spironolactone, le diethylstilbestrol et la flutamide; - des inhibiteurs sterodiens ou non sterodiens des 5-x-reductases tels que coux decrits par la Demanderesse dans les demandes de brevet europeen EP 0 964 852 et EP 1 068 858 ou encore le finasteride; o - des agonistes des canaux potassiques dependent de l'ATP tels que la cromakalim et As hydrophilic gelling agents which can be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays , and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, ethylcellulose, polyethylene. The compositions which can be used according to the invention can combine at least one agent mimicking the activity of TRP-2 with other active agents. Among these active agents, there may be mentioned by way of example: - agents modulating the differentiation and / or proliferation and / or pigmentation of skin cells such as retinol and its esters, vitamin D and its derivatives, estrogens such as ltoestradiol, cAMP modulators such as POMC derivatives, adenosine, or forskolin and its derivatives, prostaglandins and their derivatives, triiodotrionine and its derivatives; - extracts of plants such as those of Irracees or soybeans, extracts which may or may not therefore contain isoflavones; - extracts of microorganisms; - anti-free radical agents such as α-tocopherol or its esters, superoxide dismutases or its mimetics, certain metal chelating agents or ascorbic acid and its esters; - anti-seborrheics such as certain sulfur amino acids, 1 3-cis retinoic acid, cyproterone acetate; - other agents for combating scalp conditions such as zinc pyrithione, selenium disulfide, climbazole, undecylenic acid, Ketoconazole, piroctone olamine (octopirox) or ciclopiroctone (ciclopirox); 3s in particular, it may be active stimulating regrowth and / or promoting the slowing down of hair loss, we can more particularly cite without limitation: - esters of nicotinic acid, including in particular nicotinate tocopherol, benzyl nicotinate and C1-C6 alkyl nicotinates such as methyl or hexyl nicotinates; s - pyrimidine derivatives, such as 2,4-diamino 6-piperidinopyrimidine 3-oxide or "Minoxidil" described in US patents 4,139,619 and US 4,596,812; agents for inhibiting lipoxygenase or inducing cyclooxidase promoting hair regrowth, such as those described by the Applicant in European patent application EP 0 648 488; - antibacterial agents such as macrolides, pyranosides and tetracyclines, and in particular Erythromycin; - calcium antagonist agents, such as Cinnarizine, Nimodipine and Nifedipine; - hormones, such as estriol or analogues, or thyroxine and its salts; - antiandrogenic agents, such as oxendolone, spironolactone, diethylstilbestrol and flutamide; - sterodian or non-sterodian inhibitors of 5-x-reductases such as coux described by the Applicant in European patent applications EP 0 964 852 and EP 1 068 858 or else finasteride; o - potassium channel agonists dependent on ATP such as cromakalim and
le nicorandil.nicorandil.
En particulier, I'utilisation selon ['invention d'un agent mimetique de l'activite DOPAchrome tautomerase est destinee a maintenir la population de melanocytes In particular, the use according to the invention of a mimetic agent for the activity DOPAchrome tautomerase is intended to maintain the population of melanocytes
quiescents des follicules pileux.quiescent hair follicles.
En particulier, I'objet de ['invention concerne l'utilisation d'un agent mimetique de l'activite de la DOPAchrome tautomerase pour prevenir eVou limiter eVou arreter le In particular, the object of the invention relates to the use of a mimetic agent for the activity of DOPAchrome tautomerase to prevent or limit or stop the
developpement de la canitie.development of canities.
L'objet de ['invention se rapporte aussi a l'utilisation d'un agent mimetique de i'activite de la DOPAchrome tautomerase pour favoriser la pigmentation naturelle des cheveux eVou des polls grist 3s Un autre objet de la presente invention se rapporte a un procede de traitement cosmetique de la canitie caracterise en ce qu'on applique sur la zone a traiter une composition comprenant au moins un agent mimetique de l'activite de la DOPAchrome tautomerase. L'invention se rapporte aussi a un procede de traitement cosmetique destine a favoriser la pigmentation naturelle des cheveux eVou des polls gris ou blancs caracterise en ce qu'on applique sur la zone a traiter une composition comprenant au moins un agent mimetique de l'activite de la DOPAchrome tautomerase: Les procedes de traitement de la canitie et de pigmentation des cheveux eVou des polls gris ou blancs peuvent egalement consister en ['ingestion d'une composition comprenant The object of the invention also relates to the use of a mimicry agent for the activity of DOPAchrome tautomerase to promote the natural pigmentation of the hair and pollutants. Another object of the present invention relates to a cosmetic treatment process for canities characterized in that a composition comprising at least one agent mimicking the activity of DOPAchrome tautomerase is applied to the area to be treated. The invention also relates to a cosmetic treatment process intended to promote the natural pigmentation of the hair and gray or white polls, characterized in that a composition comprising at least one activity-mimicking agent is applied to the area to be treated of DOPAchrome tautomerase: The methods of treatment of canities and pigmentation of hair and gray or white polls may also consist in [ingestion of a composition comprising
au moins un agent mimetique de l'activite de la DOPAchrome tautomerase. at least one mimicry agent for the activity of DOPAchrome tautomerase.
Les zones a traiter peuvent etre, par exemple et sans aucune limitation, le cuir chevelu, The areas to be treated can be, for example and without any limitation, the scalp,
les sourcils, la moustache eVou la barbe. eyebrows, mustache and beard.
Plus particulierement, les procedes de traitement cosmetique de la canitie et de pigmentation naturelle des cheveux eVou polls gris ou blancs consistent a appliquer une composition comprenant au moins un agent mimetique de l'activite de la DOPAchrome tautomerase choisi parmi: molecules synthetiques mimetiques de SOD (Metaphore), par exemples, les complexes de manganese tels que decrits dans US 5637578, 5610293, 5874421; - composes anti-oxydants: tels que des derives de tetrahydro-5,6,7,8naphtaneol-1, en particulier ceux decrits dans le brevet EP0404 640, des derives benzoheterocyles oxygenes (voir le brevet EP 0 685 473), des derives de cyclodextrines (voir le brevet EP 0 778 287), des composes silices derives d'acide ascorbique (voir le brevet WO01/30784), de la pyrrolidone carboxylate de Iysine ou d'arginine (voir le brevet EP0511 118), des derives de benzylidene camphre ter-butyle (voir le brevet US 4, 952,391), des derives de benzylidene cyclanone (voir le brevet FR 2636531) , des diorganopolysiloxanes modifies (voir le brevet EP 0 370 868), des derives lipophiles du benzylidene camphre (voir le brevet EP 0 390 681), des derives hydrophile du benzylidene camphre (voir le brevet EP 0 390 682), des derives de benzyl-cyclanone (voir le brevet EP 0 390 683), des polymeres anti-oxydants tels que decrits dans le brevet US4,281,192, des associations de mono- et diester d'acide cinnamique et de vitamine C (voir le brevet EP 0 664 290), des polyamines, telles que putrescine, spermidine, spermine, Di-amines, Tri-amines, Tetra-amines; le propyl gallate, la quercetine, le trolox, l'histidine, le tryptophane, la methionine, des chelateurs de metaux More particularly, the methods of cosmetic treatment of canities and natural pigmentation of gray or white polluted hair consist in applying a composition comprising at least one agent mimicking the activity of DOPAchrome tautomerase chosen from: synthetic molecules mimetics of SOD ( Metaphore), for example, manganese complexes as described in US 5637578, 5610293, 5874421; - antioxidant compounds: such as derivatives of tetrahydro-5,6,7,8naphtaneol-1, in particular those described in patent EP0404,640, oxygenated benzoheterocyles derivatives (see patent EP 0 685 473), derivatives of cyclodextrins (see patent EP 0 778 287), silica compounds derived from ascorbic acid (see patent WO01 / 30784), pyrrolidone carboxylate of Iysine or arginine (see patent EP0511 118), benzylidene derivatives ter-butyl camphor (see US patent 4, 952,391), benzylidene cyclanone derivatives (see patent FR 2636531), modified diorganopolysiloxanes (see patent EP 0 370 868), lipophilic benzylidene camphor derivatives (see patent EP 0 390 681), hydrophilic derivatives of benzylidene camphor (see patent EP 0 390 682), derivatives of benzyl-cyclanone (see patent EP 0 390 683), antioxidant polymers as described in patent US4 , 281.192, combinations of mono- and diester of cinnamic acid and vitamin C (see patent EP 0 664 290), polyamines, such as putrescine, spermidine, spermine, Di-amines, Tri-amines, Tetra-amines; propyl gallate, quercetin, trolox, histidine, tryptophan, methionine, metal chelators
(21-aminosterodes), le complexe salen-manganese (par exemple: EUK-8), I'[phenyl- (21-aminosterodes), the salen-manganese complex (for example: EUK-8), I '[phenyl-
ter-butyl nitrol (PBN) (et composes derives) ou l'ebselen; - composes non anti-oxydants, tel que le MIF et ses analogues (Marcophage Migration ter-butyl nitrol (PBN) (and derivative compounds) or ebselen; - non-antioxidant compounds, such as MIF and its analogues (Marcophage Migration
Inhibiting Factor, voir Rosengren et al. Mol. Med., 1996, 2(1):143-9). Inhibiting Factor, see Rosengren et al. Mol. Med., 1996, 2 (1): 143-9).
Les procedes de traitement cosmetique pour lutter contre la canitie et/ou pour stimuler la pigmentation naturelle des cheveux eVou des polls gris ou blancs peut par exemple consister a appliquer la composition sur les cheveux et le cuir chevelu, le soir, garder la composition toute la nun' et eventuellement effectuer un shampooing le matin ou laver les cheveux a ['aide de cette composition et a laisser a nouveau en contact quelques minutes avant de rincer. La composition conforme a ['invention s'est revelee particulierement interessante lorsqu'elle est appliquee sous forme de lotion capillaire, The cosmetic treatment methods for combating canities and / or for stimulating the natural pigmentation of the hair and gray or white polls may for example consist in applying the composition to the hair and the scalp, in the evening, keeping the composition throughout. nun 'and possibly perform a shampoo in the morning or wash the hair using this composition and leave to contact again for a few minutes before rinsing. The composition in accordance with the invention has been found to be particularly interesting when it is applied in the form of a hair lotion,
eventuellement rincee ou meme sous forme diun shampooing. optionally rinsed or even in the form of a shampoo.
Dans un autre de ses objets, la presente invention se rapporte a une methode d'identification d'un agent mimetique de l'activite de la DOPAchrome tautomerase consistent a determiner la capacite d'un compose a diminuer ['induction d'une mort cellulaire dans des melanocytes n'exprimant pas la DOPAchrome tautomerase en reference a une population de melanocytes qui expriment la DOPAchrome tautomerase, o la methode comprend les etapes suivantes: a- mise en pre-culture d'une population de melanocytes; b- separation en deux populations de la population de melanocytes obtenue a ['issue de l'etape (a), appelees respectivement MelA et Mel-B, mise en culture de Mel-A dans un milieu A ou les melanocytes n'expriment pas la DOPAchrome tautomerase et de Mel-B dans un milieu B contenant un facteur favorisant ['expression de la DOPAchrome tautomerase; c- exposition de la population Mel-A a une condition induisant l'apoptose ou la senescence en culture en presence (population Mel-A(+)) ou en ['absence (population Mel-A(-)) d'un compose pour lequel on souhaite tester l'activite mimetique de la DOPAchrome tautomerase; d- exposition de la population Mel-B a une condition induisant l'apoptose ou la senescence en culture identique a la condition choisie a l'etape (c) en ['absence du compose pour lequel on souhaite tester l'activite DOPAchrome tautomerase; e- comparaison des reponses apoptotique ou senescente de la population Mel-A(+) avec Mel-A(-) et de Mel-A(+) avec Mel-B; f- selection des composes pour lesquels la reponse est telle que la cytotoxicite observee dans l'essai Mel-A(+) est moindre que celle observee dans l'essai Mel-A(-), et la cytotoxicite observee dans l'essai Mel-A(+) est proche de celle observee dans l'essai Mel-B. Dans un mode de realisation particulier selon ['invention, les melanocytes vent mis en culture a l'etape (a) dans du milieu M2 (PromoCell, Heidelberg, D). La mise en culture de l'etape (a) peut etre realisee selon differentes modalites: - dans un systeme de culture monocouche ou les cellules vent ensemencees a meme le 0 plastique; - les cellules peuvent aussi etre ensemencees sur un ou plusieurs composes de matrice extra-cellulaire, tels que collagene, elastine, fibronectine, laminine; - les cellules peuvent etre cultivees dans un systeme tridimensionnel, tel qu'un cheveu In another of its objects, the present invention relates to a method of identifying a mimic agent for the activity of DOPAchrome tautomerase, consisting in determining the ability of a compound to decrease the induction of cell death. in melanocytes which do not express DOPAchrome tautomerase with reference to a population of melanocytes which express DOPAchrome tautomerase, where the method comprises the following steps: a- pre-culture of a population of melanocytes; b- separation into two populations of the melanocyte population obtained at the end of step (a), called respectively MelA and Mel-B, culturing of Mel-A in medium A where the melanocytes do not express DOPAchrome tautomerase and Mel-B in medium B containing a factor favoring the expression of DOPAchrome tautomerase; c- exposure of the Mel-A population to a condition inducing apoptosis or senescence in culture in the presence (Mel-A population (+)) or in the absence (Mel-A population (-)) of a compound for which one wishes to test the mimetic activity of DOPAchrome tautomerase; d- exposure of the Mel-B population to a condition inducing apoptosis or senescence in culture identical to the condition chosen in step (c) in the absence of the compound for which it is desired to test the DOPAchrome tautomerase activity; e- comparison of the apoptotic or senescent responses of the Mel-A (+) population with Mel-A (-) and of Mel-A (+) with Mel-B; f- selection of the compounds for which the response is such that the cytotoxicity observed in the Mel-A (+) trial is less than that observed in the Mel-A (-) trial, and the cytotoxicity observed in the Mel trial -A (+) is close to that observed in the Mel-B test. In a particular embodiment according to the invention, the melanocytes are cultured in step (a) in M2 medium (PromoCell, Heidelberg, D). The cultivation of step (a) can be carried out according to different methods: - in a monolayer culture system where the wind cells are seeded with even the plastic; - the cells can also be seeded on one or more extracellular matrix compounds, such as collagen, elastin, fibronectin, laminin; - cells can be grown in a three-dimensional system, such as a hair
disseque, un cheveu arrache, une peau reconstruite in vitro. disc, a hair plucked, skin reconstructed in vitro.
Cette etape a est mise en ceuvre pendant un temps compris entre 2 et 18 heures This step has been implemented for a time between 2 and 18 hours
necessaire a ['adherence des cellules. necessary for cell adhesion.
Pour la realisation des etapes suivantes, le milieu de culture de l'etape (a) est ensuite remplace par un milieu approprie au test: - pour l'etape (b)' il s'agit d'un milieu ne favorisant pas ['expression de TRP-2 ou bien d'un milieu contenant un facteur reprimant ['expression de la DOPAchrome tautomerase pour la population Mel-A, ce facteur pouvant etre un facteur neutralisant les ARN messagers codant pOur la TRP2 (methode anti-sens, siRNA) a ['aide de sequences For the realization of the following stages, the culture medium of stage (a) is then replaced by a medium suitable for the test: - for stage (b) 'it is a medium which does not favor [' expression of TRP-2 or of a medium containing a factor repressing the expression of DOPAchrome tautomerase for the Mel-A population, this factor possibly being a factor neutralizing the messenger RNA coding for TRP2 (antisense method, siRNA ) using sequences
nucleotidiques appropriees.appropriate nucleotides.
- pour l'etape (c), il s'agit d'un milieu favorisant ['expression de TRP2, ce milieu peut - for step (c), it is a medium favoring the expression of TRP2, this medium can
egalement contenir un facteur induisant ['expression de la DOPAchrome tautomerase. Par exemple, ce facteur peut etre choisi parmi: I'Hexamethylene also contain a factor inducing the expression of DOPAchrome tautomerase. For example, this factor can be chosen from: Hexamethylene
Bisacetamide (HMBA),Bisacetamide (HMBA),
la glycyrrhizine, diethylstilbestrol, estradiol, lL1cc. glycyrrhizin, diethylstilbestrol, estradiol, lL1cc.
L'expression de TRP2 peut aussi etre obtenue apres transfection de la region codante du gene humain de TRP-2 (par exemple tel que decrit dans genebank n S69231, n NM_001922, n AJ000503) dans n'importe quei vecteur approprie (exemple: pcDNA Vector, invitrogen, Groningen, CH, N). Dans ce cas le test peut-etre realise sur melanocytes ou sur tout autre type de cellules de mammiferes (exemple: fibroblastes, keratinocytes). Pour la realisation des etapes (d) et (e), les populations Mel-A et Mel-B vent exposees a une condition induisant l'apoptose ou la senescence en culture, il pourra s'agir, par The expression of TRP2 can also be obtained after transfection of the coding region of the human gene for TRP-2 (for example as described in genebank n S69231, n NM_001922, n AJ000503) in any suitable vector (example: pcDNA Vector, invitrogen, Groningen, CH, N). In this case, the test can be performed on melanocytes or on any other type of mammalian cell (example: fibroblasts, keratinocytes). For the realization of stages (d) and (e), the populations Mel-A and Mel-B may be exposed to a condition inducing apoptosis or senescence in culture, it may be, by
exemple, d'un facteur pro-apoptotique (TNF a), de ['absence d'un facteur de survie (IGF- example, a pro-apoptotic factor (TNF a), the absence of a survival factor (IGF-
1), d'un traitement par le cis-platine (Pak B.J. et al., 2000, Melanoma Res. 10:499-505) OU l'oxaliplatine, d'un agent toxique (cyclophosphamide), d'une exposition aux rayonnements ultraviolets, d'un stress oxydatif (H2O2, diethylmaleate) (voir Vaux D.L. & 1), treatment with cis-platinum (Pak BJ et al., 2000, Melanoma Res. 10: 499-505) OR oxaliplatin, a toxic agent (cyclophosphamide), exposure to radiation ultraviolet, oxidative stress (H2O2, diethylmaleate) (see Vaux DL &
Strasser A., 1996, Proc.Natl.Acad.Sci. 93:2239-2244). Strasser A., 1996, Proc.Natl.Acad.Sci. 93: 2239-2244).
Pour la realisation de l'etape (f), on pourra utiliser les methodes de revelation de 0 I'apoptose ou de senescence suivantes: - la reponse apoptotique peut etre determinee par toute methode permettant de reveler l'apoptose cellulaire, par exemple, identification de la fragmentation de l'ADN apres electrophorese sur gel d'agarose, marquage des fragments d'ADN par la methode du "TUNEL" (Gavrieli Y et al. J Cell Biol 1992; 119:493-501), revelation de l'anexine V l5 (ApoAlert Annexin V Apoptosis Kit (i996) CLONTECHniques Xl(3):9-11 (BD Biosciences, Belgium mesure de l'activite de caspase (ApoAlert Caspase Assay Kit (BD For carrying out step (f), the following methods of revealing apoptosis or senescence may be used: - the apoptotic response can be determined by any method allowing the detection of cellular apoptosis, for example, identification of DNA fragmentation after electrophoresis on agarose gel, labeling of DNA fragments by the "TUNEL" method (Gavrieli Y et al. J Cell Biol 1992; 119: 493-501), revelation of the anexine V l5 (ApoAlert Annexin V Apoptosis Kit (i996) CLONTECHniques Xl (3): 9-11 (BD Biosciences, Belgium measurement of caspase activity (ApoAlert Caspase Assay Kit (BD
Biosciences, Belgium).Biosciences, Belgium).
- la reponse senescente peut etre determinee par toute methode permettant de reveler la senescence cellulaire, par exemple, determination d'un raccourcissement des telomeres, mesure de l'activite de la telomerase (TRAPeze kit, Intergen), determination de la diminution du taux de cycline E, determination de la diminution du taux de proteine P105 Rb phosphorylee (Bandyopadhyay D et al. Experimental Gerontology 2001; 36:1265-1275), mesure de l'activite beta-Galactosidase (Dimri GP et al. PNAS - the senescent response can be determined by any method making it possible to reveal cellular senescence, for example, determination of a shortening of telomeres, measurement of the activity of telomerase (TRAPeze kit, Intergen), determination of the decrease in the rate of cyclin E, determination of the decrease in the level of protein P105 Rb phosphorylee (Bandyopadhyay D et al. Experimental Gerontology 2001; 36: 1265-1275), measurement of beta-Galactosidase activity (Dimri GP et al. PNAS
1995;92:9363-9367)1995; 92: 9363-9367)
L'invention se rapporte aussi a l'utilisation d'un agent mimetique de l'activite de la DOPAchrome tautomerase susceptible d'etre identifie par la methode decrite ci-dessus dans un procede de traitement cosmetique pour prevenir eVou limiter eVou arreter le developpement de la canitie eVou pour favoriser la pigmentation naturelle des cheveux The invention also relates to the use of a mimetic agent for the activity of DOPAchrome tautomerase capable of being identified by the method described above in a cosmetic treatment process to prevent or limit or stop the development of eVou canity to promote natural hair pigmentation
eVou des polls gris ou blancs.eVou gray or white polls.
L'invention se rapporte enfin a l'utilisation d'un agent mimetique de l'activite de la DOPAchrome tautomerase susceptible d'etre identifie par la methode decrite ci-dessus pour la preparation d'une composition cosmetique destinee a prevenir eVou limiter eVou arreter le developpement de la canitie eVou a favoriser la pigmentation naturelle des The invention finally relates to the use of a mimetic agent for the activity of DOPAchrome tautomerase capable of being identified by the method described above for the preparation of a cosmetic composition intended to prevent or limit or stop the development of canities eVou to promote the natural pigmentation of
chevoux eVou des polls gris ou blancs. chevou eVou gray or white polls.
Fioums: FIoure 1: cUe 1igure mssamble d#1Arntes photogrsphies raprAsontant IB disthbuton da mAlanocas dans la 1011iculO pilOux lors da Is phase sragAna vlsualisAa au mroscopa. LAgandas: (A) ast una sAria da clichAs da la gsina AplthAliala aarna grossia 40 fois, (B) ast una sAda da cHchAs da la gaina dphANsla aarna (cantrds sur la tige) grossle 20101s et (C) -__d. o (1) reprAsanta un chaveu hAs foncA, (2) un chavau moddrAmant gment6, (3) (5) des Fioums: FIoure 1: cUe 1igure mssamble d # 1Arntes photogrsphies raprAsontant IB disthbuton da mAlanocas in 1011iculO pilOux during Is sragAna vlsualisAa phase at mroscopa. LAgandas: (A) ast una sAria da clichAs da la gsina AplthAliala aarna grossia 40 times, (B) ast una sAda da cHchAs da la gaina dphANsla aarna (cantrds on the stem) grossle 20101s and (C) -__ d. o (1) representing a chavis man who has fun, (2) a moderated loving chavis, (3) (5)
chevoux de dlUArentes nuances de ghs et (6) un chevou anc. chevou de dlUArentes shades of ghs and (6) an chevou anc.
Fioure 2: Ces photographs permeMent de suaNser [expression de TRP-2 dans s Fioure 2: These photographs allow us to know [expression of TRP-2 in s
mblanoces de l'Aplderme du chevou (gaine dpithAllale eerne et bulbe pileu. mblanoces of the Aplderme du chevou (sheath dpithAllale eerne and hair bulb.
Rude immunohilue anal6e en mms=e =-ca ser Floure 3: Ces photographies reprdsentent les rdsu#sts obtenus sprds Is mise en uvre Rough immunohilue anal6e in mms = e = -ca ser Floure 3: These photographs represent the results obtained # stds sprds Is implemented
des essais da Waarn Blot dAcrits I'exempla 2B. Waarn Blot's essays of Example 2B.
ExemDIe 1 - rvAlation ImmunchiochEmioue des mAlanoces dens les 1011icules olleux diMArents s1ndes de blanchisseme. nar marousue de la jro16ine nel us da l us ux il r da -as lu 8 donnaum EXAMPLE 1 - Revision Immunochemistry of the mAlanoces in the 1011 ollous particles which are very white. nar marousue de la jro16ine nel us da l us ux il r da -as lu 8 donnaum
71 srs ont AtA dtudiAs.71 srs have AtA students.
A - Protocole d'isolemen1 des 1011icules Dlleux entlers (Commo S and Bernard BA Pmen1 CeM Res 2000;13:253-259) ]o Des 1ragments de ops son1 incubAs dans la dpase (2,4 U/ml, BoehNnger annheim, D) Is nuR +04 C. Les chavaux vent ansu#a olAs rsa da pincas sous binoculalras. B - Protocole d'immunomarouaoe sur follicules Dlleux entiers (Commo S and Bernard BA 3 Pment Ce" Res 2000;13:253-25g) Les chevcux enDers son1 f6s dans l'hanol O'C pcodan1 10 mu10s. Chaque 61spe des procAdures de fxshon e1 de mauage est suio de vages au tampon phosphe (pH 7,4 (PBS)een20 0,06. Sau1 prA3sn, 10utes s Atapes se 10nt tempArature ambiante. Les pAmdases endogAnes de l'dchantHon son1 neutraRsdes en cuban1 FAchanDRon dans une so1n de pAroxyde dydrogAne OJ pendant 10 minutes. Pour bloquer les sltes de 1ix10n non spAclTiques, I'dchan11110n e incubA avec du laR AcrAmA 1, 15 minutes. L'anDcorps (Ac) pdmre NKl-beteb reconnaissan1 A - Protocol for the isolation of the 1011 particles from two entlers (Commo S and Bernard BA Pmen1 CeM Res 2000; 13: 253-259)] o Oprements of ops are incubated in dpase (2.4 U / ml, BoehNnger annheim, D ) Is nuR +04 C. Chavaux vent ansu # a olAs rsa da pincas sous binoculalras. B - Protocol of immunomarouaoe on whole follicles Dlleux (Commo S and Bernard BA 3 Pment Ce "Res 2000; 13: 253-25g) Chevcux enDers son1 f6s ethanol O'C pcodan1 10 mu10s. Each 61spe procedures fxshon e1 mauage is suio de vages with a phosphate buffer (pH 7.4 (PBS) een20 0.06. Sau1 prA3sn, 10utes s Steps are 10nt ambient temperature. The endogenous pAdases of the dchantHon son1 neutraRsdes en cuban1 FAchanDRon Hydrogen OJ hydroxide for 10 minutes To block non-spastic slices of 1ix10n, I'dchan11110n e incubated with AcrAmA laR 1, 15 minutes. The antibody (Ac) for NKl-beteb recognized
spAcTuement k'p-e pkdeLl7 (donosan, Pads, F) est duA au 1/40 dans du PBS - spAcTuement k'p-e pkdeLl7 (donosan, Pads, F) is 1/40 duA in PBS -
Tween 0,059t, con10nan1 10}S de sArum norm (X0907, DAKO, Trappes, F). Ac o pmre est incubA 18 heures sur les chevoux +04 C. LAc socondake coupld la blohne (E-433, DAKO, Trappes, F) es1 6 au 1400 e1 locubA 30 minu1es. Le cheveu es1 ensu#e cubA en prdsence de reptav1ne-bioline-pAmdase (K- Oj77, DAKO, Tween 0.059t, con10nan1 10} S of normal sArum (X0907, DAKO, Trappes, F). Ac o pmre is incubated at 18 hours on ankles +04 C. LAc socondake coupled with blohne (E-433, DAKO, Trappes, F) es1 6 to 1400 e1 locubA 30 minutes. The hair is ensu # e cubA in the presence of reptavene-bioline-pAmdase (K- Oj77, DAKO,
Trappes, F), e1 1inalemen1 llmmunomarquage es1 rAvAld en prAnce de 3amino-g- Trappes, F), e1 1inalemen1 llmmunmarking es1 rAvAld by 3 amino-g-
61hylcarbazole (AEC) (AEC kib101, Sigma, Ssin1 Ouentin Fallavier, F). 61hylcarbazole (AEC) (AEC kib101, Sigma, Ssin1 Ouentin Fallavier, F).
En comparsn1 les dhAs (B1) (BS) de Dgure 1, on conste que Is dimlnuton de pigmen110n du chevou os1 sssocid uno diminution do mAlanino dans le bulbe o1 d une muDon de mAlanoces dans bue ok C1 CS). Le cheveu snc don1 la By comparing the dhAs (B1) (BS) of Dgure 1, we can see that Is dimlnuton of pigmen110n from the ankle os1 sssocid a decrease of mAlanino in the bulb o1 of a muDon of mAlanoces in bue ok C1 CS). Snc don1 hair
tge es1 dApouue de mAlane (B6) ne conDen1 pas de md!snocp dans le bue (C6) . tge es1 dApouue de mAlane (B6) does not contain md! snocp in the bue (C6).
Les cheveux gHs e1 snQ conDennont uno qusnttA vahab de md#snocytes dans psle hauto do Is galne AplthAllale eorno, coUe quanti16 pouvan1 mAmo 61ro nullo dans The gHs e1 snQ hair contains one or more vahab of md # snocytes in psle hauto do Is galne AplthAllale eorno, cost quanti16may1 mAmo 61ro nullo in
css du chevou snc (A3 6) Is diMAronce dos chevoux gmen1As (A1 e1 2). css du chevou snc (A3 6) Is diMAronce dos chevoux gmen1As (A1 e1 2).
: Exemole 2 - mlse en idence de l'exoresslon diM6ren1lelle de le DOPhrome 1au10mArase dans Ies mAlanoces de follicules olleux de l'6niderme chez : Example 2 - Evidence for the diM6ren1elle exoresslon of DOPhrome 1au10mArase in mAlanoces of oily epidermal follicles in
l'lndlvidu caucaslen.the lndlvidu caucaslen.
A- Uudo lmmunohls1010gioue snslvsde on microscopic con10calo Issor 30. A. 1 - Oen110n de coupes conQeldes de folllcule Dileux (Commo S sod Bernard BA Pment CeM Res 2000;13:253-25g) Un 1ragment de biopsle de scalp contenan1 des 10111culds plleux es1 lnclus dans du tssue-Tek-OC1 (ls, NspeiHo, IL, USA) et ensuLo congold sur do la carbo-glaco. La biopsio congelde e onsuite coupAe (7 pm) I'aide d'uno costst (C3050, Lolcs, A- Uudo lmmunohls1010gioue snslvsde on microscopic con10calo Issor 30. A. 1 - Oen110n de coupes conQeldes de folllcule Dileux (Commo S sod Bernard BA Pment CeM Res 2000; 13: 253-25g) A 1ragment of scalp biopsle containing 10111cul lncluded in tssue-Tek-OC1 (ls, NspeiHo, IL, USA) and ensuLo congold on do la carbo-glaco. The frozen biopsy was then cut (7 pm) using uno costst (C3050, Lolcs,
Ruell-slmsison, F).Ruell-slmsison, F).
A.2 - Protocole d'isolement des follicules nileux entiers et des lambeaux enitheliaux de ceau (Commo S and Bernard BA Pigment Cell Res 2000;13:253259) Des fragments de biopsie vent incubes dans la dispase (2,4 U/ml, Boehringer Mannheim, D) la nun' a +04 C. Le compartiment epithelial est separe du derme a ['aide de pieces sous binoculaire. Les structures epitheliales vent ensuite micro-dissequees A.2 - Protocol for the isolation of whole nile follicles and enithelial flaps of the skin (Commo S and Bernard BA Pigment Cell Res 2000; 13: 253259) Biopsy fragments are incubated in the dispase (2.4 U / ml, Boehringer Mannheim, D) la nun 'at +04 C. The epithelial compartment is separated from the dermis using binocular pieces. The epithelial structures are then micro-dissected
pour separer les follicules pileux et l'epiderme, puis triees. to separate the hair follicles and the epidermis, then sorted.
A.3 - Protocole d'immunomarquane sur follicules pileux entiers. Iambeau de neau et coune conaelee Les cheveux entiers, les lam beaux epitheliaux de peau et les coupes congelees vent fixes dans ['ethanol a-20 C pendant 10 minutes. Chaque etape des procedures de fixation et de marquage est suivie de iavages au tampon phosphate (pH 7,4 (PBS)) Tween20 0,05%. Sauf precision, toutes les etapes se font a temperature ambiante. Les peroxydases endogenes de l'echantillon vent neutralisees en incubant l'echantillon dans une solution de peroxyde d'hydrogene a 0,1% pendant 10 minutes. Pour bloquer les sites de fixation non specifiques, I'echantillon est incube avec du fait ecreme 1%, 15 minutes. Les anticorps (Ac) primaires vent dilues dans du PBS - Tween 0,05%, contenant 10 % de serum normal (X0907, DAKO, Trappes, F). Les Ac primaires NK1 beteb reconnaissant specifiquement la proteine pMel-17 (1/40, Monosan, Paris, F), et aPEP8h (1/2000, Dr VJ.Hearing, NIH, Bethesda, MD, USA) reconnaissant specifiquement la proteine TRP2 humaine (Virador et al. 2001) vent incubes simultanement 18 heures a +04 C sur les cheveux entiers et les lambeaux epitheliaux de peau, et 30 minutes a temperature ambiante sur les coupes congelees. L'Ac secondaire de chevre dirige contre les immunoglobulines (Ig) G2b couple a la Cy3 (M32410, TEBU, le Perray en Yveline, F) est dilue au 1/80, et l'Ac secondaire dirige contre les Ig couple a la Cy5 (111-175-144, Jackson Immunoresearch Lab. Inc. West Grove, PA, USA) est dilue au 1/500 vent incubes simultanement 30 minutes sur les echantillons. Les immunomarquages vent analyses en microscopic confocale laser A.3 - Immunomarquane protocol on whole hair follicles. Fillet of lamb and conaelée coune Whole hair, beautiful skin epithelial lam and frozen cuts are fixed in ethanol at -20 C for 10 minutes. Each step of the fixing and labeling procedures is followed by washing with phosphate buffer (pH 7.4 (PBS)) Tween20 0.05%. Unless otherwise specified, all steps are carried out at room temperature. The endogenous peroxidases in the sample are neutralized by incubating the sample in a 0.1% hydrogen peroxide solution for 10 minutes. To block non-specific binding sites, the sample is incubated with 1% skim, 15 minutes. The primary antibodies (Ac) are diluted in 0.05% PBS - Tween, containing 10% normal serum (X0907, DAKO, Trappes, F). Primary NK1 beteb Ac specifically recognizing the protein pMel-17 (1/40, Monosan, Paris, F), and aPEP8h (1/2000, Dr VJ.Hearing, NIH, Bethesda, MD, USA) specifically recognizing the human TRP2 protein (Virador et al. 2001) are incubated simultaneously for 18 hours at +04 C on whole hair and epithelial skin flaps, and 30 minutes at room temperature on frozen sections. Goat secondary Ac directed against immunoglobulins (Ig) G2b coupled to Cy3 (M32410, TEBU, Perray en Yveline, F) is diluted to 1/80, and secondary Ac directed against Ig coupled to Cy5 (111-175-144, Jackson Immunoresearch Lab. Inc. West Grove, PA, USA) is diluted to 1/500 wind incubations simultaneously on the samples for 30 minutes. Immunolabelling wind analyzes in laser confocal microscopy
(LSM510, Carl Zeiss, Oberkochen, D). (LSM510, Carl Zeiss, Oberkochen, D).
Conclusion des observations: on constate sur la figure 2 la presence de TRP-2 dans les melanocytes de l'epiderme, en revanche, cette enzyme n'est exprimee ni dans les melanocytes de la gaine epitheliale du follicule pileux, ni dans les melanocytes du bulbe pileux. B - etude biochimioue par analvse en Western Blot B.1 - Protocole d'extraction de proteine de follicules nileux humains et de melanocvtes (Commo S et al. Differentiation 2000;66:157-164) - Extraction proteique a partir de bulbes pileux: les follicules pileux vent isoles apres traitement de biopsies de scalp a la dispase (2,4 U/ml, Boehringer Mannheim, D) la nun' a +04 C. Apres isolement, les follicules pileux vent micro-disseques pour isoler la partie du bulbe pileux. 80 bulbes pileux ainsi isoles vent places dans un tampon de Iyse Conclusion of the observations: we note in Figure 2 the presence of TRP-2 in the melanocytes of the epidermis, on the other hand, this enzyme is expressed neither in the melanocytes of the epithelial sheath of the hair follicle, nor in the melanocytes of the hair bulb. B - biochemical study by Western Blot analysis B.1 - Protocol for the extraction of protein from human nile follicles and melanocytes (Commo S et al. Differentiation 2000; 66: 157-164) - Protein extraction from hair bulbs: the hair follicles are isolated after treatment of scalp biopsies at the dispase (2.4 U / ml, Boehringer Mannheim, D) at +04 C. After isolation, the hair follicles are micro-disks to isolate the part of the hair bulb. 80 hair bulbs isolated in this way placed in a Iyse tampon
approprie pour extraction proteique et analyse en western blot. suitable for protein extraction and western blot analysis.
o - Extraction proteique a partir de culture de melanocytes: Les melanocytes cultives en milieu M2 (PromoCell, Heidelberg, D) vent Iyses avec un meme tampon de Iyse o - Protein extraction from melanocyte culture: Melanocytes cultivated in M2 medium (PromoCell, Heidelberg, D) are lysed with the same Iyse buffer
approprie pour extraction proteique et analyse en westem blot. suitable for protein extraction and westem blot analysis.
Le Westem blot (voir protocole dans Maniatis et al.) est realise avec les anticorps suivants: aPEP8h, anticorps polyclonal specifique de la TRP-2 humaine donne par Dr VJ Hearing (NIH, Bethesda, USA), et T311, anticorps monoclonal specifique de la The Westem blot (see protocol in Maniatis et al.) Is carried out with the following antibodies: aPEP8h, polyclonal antibody specific for human TRP-2 given by Dr VJ Hearing (NIH, Bethesda, USA), and T311, monoclonal antibody specific for the
tyrosinase humaine (Novocastra, New Castle, UK). human tyrosinase (Novocastra, New Castle, UK).
On observe (figure 3) que la tyrosinase est detectee dans les extraits de bulbe pileux. It is observed (FIG. 3) that tyrosinase is detected in the extracts of the hair bulb.
o L'enzyme n'est pas detectee dans les extraits de gaine epitheliale externe. L'expression de la tyrosinase est regulee. Cette enzyme n'est pas ou peu exprimee dans les melanocytes inactifs (ne produisant pas de melanine), c'est le cas des melanocytes o The enzyme is not detected in the extracts of the outer epithelial sheath. The expression of tyrosinase is regulated. This enzyme is not or little expressed in inactive melanocytes (not producing melanin), this is the case of melanocytes
contenus dans le scalp inter folliculaire d'individu caucasien. contained in the inter follicular scalp of a Caucasian individual.
Par ailleurs, la DOPAchrome tautomerase (TRP-2) n'est detectee ni dans les extraits de bulbe ni dans les extraits de gaine epitheliale externe. L'expression de la TRP-2 ne suit pas celle de la tyrosinase et ['induction de la melanogenese, elle n'est pas exprimee In addition, DOPAchrome tautomerase (TRP-2) is detected neither in bulb extracts nor in outer epithelial sheath extracts. The expression of TRP-2 does not follow that of tyrosinase and the induction of melanogenesis is not expressed
dans les melanocytes actifs des bulbes pileux. in the active melanocytes of the hair bulbs.
ExemnIe 3 - Comnositions - lotion caPillaire Agent mimetique de l'activite de la DOPAchrome tautomerase 0,5 g Propylene glycol 20 g Ethanol 95 30 g Eau qsp 100 g Cette lotion est appliquee quotidiennement sur les zones a traiter et de preference sur EXEMPTION 3 - COMPOSITIONS - CAPILLARY LOTION Mimic agent for the activity of DOPAchrome tautomerase 0.5 g Propylene glycol 20 g Ethanol 95 30 g Water qs 100 g This lotion is applied daily to the areas to be treated and preferably on
['ensemble du cuir chevelu pendant au moins 10 jours et preferentiellement 1 a 2 mois. ['whole scalp for at least 10 days and preferably 1 to 2 months.
s On constate alors une diminution de ['apparition des cheveux blancs ou gris et une repigmentation des cheveux grist - shampooina traitant Agent mimetique de l'activite de la DOPAchrome tautomerase 1,5 g Polyglyceryl 3hydroxylarylether 26 g Hydroxy propyl cellulose vendue sous la denomination de Klucell G par la societe Hercules 2 g Conservateurs ps Ethanol 95 50 g Eau qsp 100 g Ce shampooing est utilise a chaque ravage avec un temps de pose d'environ d'une minute. Un usage prolonge, de ltordre de deux mods, conduit a la repigmentation o progressive des cheveux grist Ce shampocing peut egalement etre utilise a titre preventif afin de retarde le s There is then a decrease in the appearance of white or gray hair and a repigmentation of gray hair - shampooina treating Mimetic agent for the activity of DOPAchrome tautomerase 1.5 g Polyglyceryl 3hydroxylarylether 26 g Hydroxy propyl cellulose sold under the name of Klucell G by the company Hercules 2 g Preservatives ps Ethanol 95 50 g Water qs 100 g This shampoo is used for each devastation with an exposure time of approximately one minute. Prolonged use, in the order of two mods, leads to the gradual repigmentation or gray hair This shampoo can also be used as a preventive measure in order to delay the
blanchiment des cheveux.bleaching hair.
- Gel traitant Agent mimetique de l'activite de la DOPAchrome tautomerase 0,75 g Huiles essentielles d'Eucalyptus 1 g Econozole 0,2 g Lauryl polyglyceryl 6 cetearyl glycoether 1,9 g Conservateurs qs Carbopol 934P vendu par la societe BF Goodrich Corporation 0,3 g Agent de neutralisation qs pH 7 Eau qsp 100 g Ca gel fist applique sur les zones Cager dGux 10 par Tour (main at sob) sac On masso rmlnsL Apes Dais mom dppcion, on obsess uno mpigmclon dos - Treatment gel Mimetic agent for DOPAchrome tautomerase activity 0.75 g Eucalyptus essential oils 1 g Econozole 0.2 g Lauryl polyglyceryl 6 cetearyl glycoether 1.9 g Preservatives qs Carbopol 934P sold by the company BF Goodrich Corporation 0 , 3 g Neutralizing agent qs pH 7 Water qs 100 g Ca fist gel applied to Cager dGux 10 areas per turn (main at sob) bag On masso rmlnsL Apes Dais mom dppcion, on obsess uno mpigmclon dos
pods ou chovoux de zonotmlt6G.zonotmlt6G pods or chovoux.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0207137AFR2840531B1 (en) | 2002-06-11 | 2002-06-11 | COSMETIC COMPOSITION COMPRISING A MIMETIC AGENT FOR THE ACTIVITY OF DOPACHROME TAUTOMERASE (TRP-2) FOR COMBATING CANITIS |
| PCT/FR2003/001729WO2003103616A2 (en) | 2002-06-11 | 2003-06-10 | Use of an agent mimicking dopachrome tautomerase (trp-2) activity as protective agent for hair follicle melanocytes and uses thereof |
| AU2003255653AAU2003255653A1 (en) | 2002-06-11 | 2003-06-10 | Use of an agent mimicking dopachrome tautomerase (trp-2) activity as protective agent for hair follicle melanocytes and uses thereof |
| ES03757134TES2431309T3 (en) | 2002-06-11 | 2003-06-10 | Use of a sale-manganese complex as a protective agent for hair follicle melanocytes, and cosmetic applications |
| EP03757134.6AEP1515688B1 (en) | 2002-06-11 | 2003-06-10 | Use of salen-manganese complexes as protective agents for hair follicule melanocytes and cosmetic uses thereof |
| JP2004510737AJP2006512285A (en) | 2002-06-11 | 2003-06-10 | Use and use of agents that mimic dopachrome isomerase (TRP-2) activity as protective agents for hair follicle melanocytes |
| CA002487945ACA2487945A1 (en) | 2002-06-11 | 2003-06-10 | Use of an agent mimicking dopachrome tautomerase (trp-2) activity as protective agent for hair follicle melanocytes and uses thereof |
| US11/009,153US7585514B2 (en) | 2002-06-11 | 2004-12-13 | Administration of agents mimicking DOPAchrome tautomerase (TRP-2) activity for protecting hair follicle melanocytes |
| JP2007035444AJP2007190023A (en) | 2002-06-11 | 2007-02-15 | Use and use of agents that mimic dopachrome isomerase (TRP-2) activity as protective agents for hair follicle melanocytes |
| JP2007212400AJP4971072B2 (en) | 2002-06-11 | 2007-08-16 | Use and use of agents that mimic dopachrome isomerase (TRP-2) activity as protective agents for hair follicle melanocytes |
| US12/541,398US8445004B2 (en) | 2002-06-11 | 2009-08-14 | Administration of agents mimicking dopachrome tautomerase (TRP-2) activity for protecting hair follicle melanocytes |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0207137AFR2840531B1 (en) | 2002-06-11 | 2002-06-11 | COSMETIC COMPOSITION COMPRISING A MIMETIC AGENT FOR THE ACTIVITY OF DOPACHROME TAUTOMERASE (TRP-2) FOR COMBATING CANITIS |
| Publication Number | Publication Date |
|---|---|
| FR2840531A1true FR2840531A1 (en) | 2003-12-12 |
| FR2840531B1 FR2840531B1 (en) | 2004-10-29 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR0207137AExpired - LifetimeFR2840531B1 (en) | 2002-06-11 | 2002-06-11 | COSMETIC COMPOSITION COMPRISING A MIMETIC AGENT FOR THE ACTIVITY OF DOPACHROME TAUTOMERASE (TRP-2) FOR COMBATING CANITIS |
| Country | Link |
|---|---|
| ES (1) | ES2431309T3 (en) |
| FR (1) | FR2840531B1 (en) |
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| WO2013178749A1 (en) | 2012-06-01 | 2013-12-05 | Galderma Research & Development | Lipid nanocapsules comprising a retinoid, nanodispersion and composition containing same, method of producing same and use thereof in dermatology |
| WO2015082660A1 (en) | 2013-12-04 | 2015-06-11 | Galderma Research & Development | Lipid microcapsules preferably comprising a lipophilic active substance and composition containing same, method for the production thereof, and use of same in dermatology and in cosmetics |
| WO2016193588A1 (en) | 2015-05-29 | 2016-12-08 | Galderma Research & Development | Compositions comprising at least one dispersed active principle and lipid microcapsules |
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| US5965157A (en)* | 1993-04-02 | 1999-10-12 | Anticancer Inc. | Method to provide for production of hair coloring pigments in hair follicles |
| JPH072677A (en)* | 1993-06-18 | 1995-01-06 | Toyo Seito Kk | Peroral hair-growing agent |
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| EP0778287A1 (en)* | 1995-12-04 | 1997-06-11 | L'oreal | Cyclodextrin derivatives |
| EP0862910A2 (en)* | 1997-02-10 | 1998-09-09 | Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) | Use of retinoids as skin pigmentation inducing agent |
| WO1999039728A2 (en)* | 1998-02-04 | 1999-08-12 | Trustees Of Boston University | Methods of inducing hair growth and coloration |
| WO2001030784A1 (en)* | 1999-10-26 | 2001-05-03 | L'oreal | Silicon compounds derived from ascorbic acid |
| Title |
|---|
| DATABASE WPI Week 199511, Derwent World Patents Index; AN 1995-077960, XP002231404* |
| DATABASE WPI Week 199939, Derwent World Patents Index; AN 1992-189207, XP002231405* |
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| EP2113286A1 (en) | 2008-04-30 | 2009-11-04 | L'Oreal | Uses of the BNIPXL-beta in early canities |
| WO2011079971A3 (en)* | 2009-12-18 | 2012-06-14 | Henkel Ag & Co. Kgaa | Cosmetics containing euk-134 and/or euk-118 and at least one cosmetic care substance |
| WO2013178749A1 (en) | 2012-06-01 | 2013-12-05 | Galderma Research & Development | Lipid nanocapsules comprising a retinoid, nanodispersion and composition containing same, method of producing same and use thereof in dermatology |
| WO2015082660A1 (en) | 2013-12-04 | 2015-06-11 | Galderma Research & Development | Lipid microcapsules preferably comprising a lipophilic active substance and composition containing same, method for the production thereof, and use of same in dermatology and in cosmetics |
| WO2016193588A1 (en) | 2015-05-29 | 2016-12-08 | Galderma Research & Development | Compositions comprising at least one dispersed active principle and lipid microcapsules |
| Publication number | Publication date |
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| FR2840531B1 (en) | 2004-10-29 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PLFP | Fee payment | Year of fee payment:15 | |
| PLFP | Fee payment | Year of fee payment:16 |