Pro-pigmenting peptides

Holder (s): SEDERMA Simplified joint stock company.

Agent (s): SEDERMA Simplified joint stock company.

DESCRIPTION

The present invention relates to novel peptides, to compositions comprising them and to cosmetic, therapeutic or cosmeceutical uses of said peptides. It relates more particularly to peptides intended for the treatment of the skin and its integuments, of mammals, humans or animals, and more particularly still peptides for a pro-pigmenting treatment. It concerns the cosmetics, hygiene and personal care products, cosmeceuticals and dermopharmacy industries.

Peptides have an important signal function and coordinate many biochemical processes. They have therefore become essential and promising active ingredients, more particularly in the cosmetics industry where compounds capable of embellishing the skin and integuments, that is to say of improving them, are constantly being sought. general condition.

The present inventors were more particularly interested in searching for new peptides having pro-pigmenting activity, in particular at low levels, and peptides also having pro-collagen activity so as to provide peptides which may have dual pro-pigmenting activity. -pigmenting and pro-collagen.

A pro-pigmenting active ingredient will act mainly on the stimulation of the synthesis of melanin, the natural pigment of the skin, body hair, eyelashes, and hair (melanogenesis), so as to intensify the normal pigmentation of the skin and integuments without radiation solar or UV. It is the melanocytes in the epidermis that will produce melanin from the amino acid Tyrosine. Tyrosinase and other enzymes then intervene to transform tyrosine and form melanin.

Applications will include the repigmentation of white skin spots and the acceleration and intensification of tanning. A pro-pigmenting active can also be used for the prevention and repigmentation of hair, body hair, eyelashes, eyebrows (treatment of canities). The applications can be for cosmetic or dermatological purposes, for preventive or curative purposes, in particular a self-tanning treatment or for improving the uniformity of the complexion, a treatment intended to strengthen the phototype of people with fair skin and sensitive to the sun, a treatment for preparation of the skin before exposure to the sun, treatment of white spots in particular due to a partial melanocytic deficit.

State of the art

Dihydroxyacetone, also known as DHA or 1,3-dihydroxy-2-propanone, is a widely known pro-pigmenting active. Also known in cosmetics are tanning agents called TYR-OL ™ and TYR-EXCEL ™ proposed by Sederma and described respectively in patents FR 2 702 766 and W003 / 017966 based on Oleyl Tyrosine.

EP2049074 describes the use of a rice protein hydrolyzate as a pigmenting active. The hydrolyzate is characterized in that it comprises a mixture of peptides of which at least 50% have a molecular mass preferably between 300 and 3500 Da, that is to say from 3 to 30 amino acids approximately. Almost all of the natural amino acids are found in the hydrolyzate.

Furthermore, many peptides are described for an anti-aging or anti-aging activity via the stimulation of the proteins of the dermal extracellular matrix. Thus, for example, patent FR 2788777 describes the PR-OH and Pal-PR-OH peptides in anti-aging cosmetic compositions. Invention

The present invention provides peptides of general formula:

X - (Xaai) n - Pro * - Xaa₂ - Y (I)

With :

• n = 0, 1 or 2;

• Xaaj is:

a hydrophobic amino acid chosen from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Iso, I), Phenylalanine ( Phe, F), Proline (Pro, P) and analogs or derivatives thereof; or a polar amino acid chosen from Serine (Ser, S), Threonine (Thr, T), Tyrosine (Tyr, Y), Asparagine (Asp, N), Glutamine (Glu, Q) and derivatives and analogues thereof;

when n = 2, the two amino acids Xaai possibly being identical or different;

• Xaa₂ is :

a hydrophobic amino acid chosen from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Iso, I), Phenylalanine ( Phe, F), and analogs or derivatives thereof;

a basic amino acid selected from Arginine (Arg, R), Lysine (Lys, K) and Histidine (His, H) and derivatives and analogs thereof;

• at the N terminal end of the peptide, X is chosen from H, -CO-Ri and -SO₂-Ri;

• at the C terminal end of the peptide, Y is chosen from OH, ORi, NH₂, NHRi or NRiR₂, • Rj and R₂ being, independently of one another, chosen from an alkyl, aryl, aralkyl, alkylaryl, alkoxy and aryloxy group, possibly linear, branched, cyclic, polycyclic, unsaturated, hydroxylated, carbonylated, phosphorylated and / or sulfur-containing, said a group which may have in its backbone a heteroatom, in particular O, S and / or N;

• Pro * corresponding to Proline, an analogue or a derivative thereof;

excluding peptides in which X = H and Y = OH and excluding Pal-PR-OH.

The inventors have shown that such peptides exhibited cosmetic activity, which can be used alone or as a mixture to improve the appearance and general condition of the skin and of its integuments, and in particular for the treatment and / or prevention of signs. aging, and / or imperfections of the skin, and its integuments. The inventors have shown that the peptides according to the invention exhibited in particular a pro-pigmenting activity as well as for some a complementary activity stimulating the synthesis of collagen 1 advantageously making it possible to provide an active agent having a dual activity, propigmenting and procollagen, particularly activity. interesting for an anti-aging goal in particular (treatment of spots and wrinkles with the same active).

Some of the peptides also advantageously exhibit a property of keratinocyte differentiation, which makes it possible to envisage additional activity at the level of the epidermis (hydration, strengthening of the skin barrier). This activity also complements an overall anti-aging activity.

The peptides according to the invention advantageously exhibit pro-pigmenting activity even at a low ppm content, around 3 ppm for some and in any event below 20 ppm. The presence of a praline (or pyrrobdrne-2-carboxybc acid, following formula II) is an essential element of the invention. It induces a strong geometric constraint on the peptide backbone. This conformation imposes a "bent" (or hook) shape on the peptide. If the Praline is replaced by a more flexible amino acid such as for example by Glycine, the propigmenting activity disappears.

<img file="FR2998570B1_D0001.tif" />

Formula II (Praline)

The following structural formula III of the Pal-LPA-OH peptide according to the invention illustrates this bent structure by way of example:

<img file="FR2998570B1_D0002.tif" />

The present invention also covers derivatives or analogues of praline which are capable of also inducing such a bend. These derivatives or analogues are either:

1) from cycles of different size (eg: 4 or 6 dips);

2) resulting from the modification of the relative position (a or β) of the acid function (COOH) with respect to the nitrogen of the cycle.

3) resulting from substitutions on the cycle modifying its size and / or its polarity.

4) resulting from the combination of the previous items.

They can be represented by the following general formula IV:

COOH in any / \ (and OR β) any position y Q

NOT

Formula IV

The present invention preferably provides the following analogous compounds shown in the following Table 1 having a nitrogen in the ring such as proline (Cycle 5 and COOH in a):

<td>Compound name</td><td>Chemical structure</td>

<td>azetidine-2-carboxylic acid</td><td>Cycle at 4 and COOH at a</td>

<td>β-proline (or pyrrolidine-3-carboxylic acid)</td><td>Cycle at 5 and COOH at β</td>

<td>pipecolic acid</td><td>Cycle at 6 and COOH at a</td>

<td>nipecotic acid</td><td>Cycle at 6 and COOH at β</td>

<td>thio-proline (or thiazolidine-4-carboxylic acid)</td><td>Cycle at 5 and COOH at a + S at position 4</td>

<td>4-hydroxy-proline</td><td>Cycle at 5 and COOH at a + OH at position 4</td>

<td>3,4-dehydro-proline</td><td>Cycle at 5 and COOH at a + unsaturation 3-4</td>

Other compounds resulting from the substitution of proline by an R group are also possible. Nonlimiting examples are given in Table 2:

<td>Grouping R</td><td>Position</td>

<td>piperidin-4-yl</td><td>1 on nitrogen</td>

<td>phenyl; dimethyl</td><td> 3</td>

<td>phenyl; OH; NH₂; F; F₂; CF₃; benzyl; cyclohexyl; oxo; bromobenzyl; SH; phenoxy</td><td> 4</td>

<td>phenyl; dimethyl; oxo</td><td> 5</td>

<td>phenyl, cyclohexyl</td><td> 4+5</td>

Proline can also be replaced by substituted analogs having a 6-bond ring such as the examples given in Table 3 below:

<td>Compound name</td><td>Chemical structure</td>

<td>3-carboxy-morpholine</td><td>Cycle at 6 oxygenated + COOH in position 3</td>

<td>2-carboxy-morpholine</td><td>Cycle at 6 oxygenated + COOH in position 2</td>

<td>Tic (or 1,2,3,4-tetrahydroisoqumolme3-carboxylic acid) and its hydroxyl derivative</td><td>Cycle at 6 + COOH in position 2 on this cycle + phenyl in position 4 + 5</td>

<td>Tiq (or 1,2,3,4-tetrahydroisoqumolme1-carboxylic acid)</td><td>Cycle at 6 + COOH in position 6 on this cycle + indole in position 4 + 5</td>

According to the invention, preferably in formula I:

Pro * is Proline, a natural amino acid; and or

Xaaj is chosen from Alanine (Ala, A), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Iso, I), Proline (Pro, P), Serine (Ser , S), Tyrosine (Tyr, Y) and Glutamine (Glu, Q); more preferably chosen from Leucine (Leu, L), Proline (Pro, P), Serine (Ser, S) and Glutamine (Glu, Q); and or

Xaa₂ is selected from Alanine, (Ala, A), Arginine (Arg, R) and Methionine (Met, M).

According to other characteristics, according to the invention, preferably n = 0 or 1 so as to provide dipeptides and tripeptides, which are easier to synthesize and less expensive.

Thus, the dipeptides covered according to the invention based on Proline can be chosen from X-PA-Y, X-PV-Y, X-PM-Y, X-PL-Y, X-PI-Y, X-PF -Y, X-PR-Y, X-PK-Y and X-PH-Y.

The tripeptides covered according to the invention based on Proline can for their part be chosen from X-APA-Y, X-APV-Y, X-APM-Y, X-APL-Y, X-API-Y, X- APF-Y, X-APR-Y, X-APK-Y,

X-APH-Y, X-VPA-Y, X-VPV-Y, X-VPM-Y, X-VPL-Y, X-VPI-Y, X-VPF-Y, X-VPR-Y,

X-VPK-Y, X-VPH-Y, X-VPF-Y, X-VPR-Y, X-VPK-Y, X-VPH-Y, X-MPA-Y, X-MPV-Y, X- MPM-Y, X-MPL-Y, X-MPI-Y, X-MPF-Y, X-MPR-Y, X-MPK-Y, X-MPH-Y, X-LPA-Y, X-LPV- Y, X-LPM-Y, X-LPL-Y, X-LPI-Y, X-LPF-Y, X-LPR-Y, X-LPK-Y, X-LPH-Y, X-IPA-Y, X-IPV-Y, X-IPM-Y, X-IPL-Y, X-IPI-Y, X-IPF-Y, X-IPR-Y, X-IPK-Y, X-IPH-Y, X- FPA-Y, X-FPV-Y, X-FPM-Y, X-FPL-Y, X-FPI-Y, X-FPF-Y, X-FPR-Y, X-FPK-Y, X-FPH- Y, X-PPA-Y, X-PPV-Y, X-PPM-Y, X-PPL-Y, X-PPI-Y, X-PPF-Y, X-PPR-Y, X-PPK-Y, X-PPH-Y, X-SPA-Y, X-SPV-Y, X-SPM-Y, X-SPL-Y, X-SPI-Y, X-SPF-Y, X-SPR-Y, X-SPK-Y, X-SPH-Y, X-TPA-Y, X-TPV-Y, X-TPM-Y, X- TPL-Y, X-TPI-Y, X-TPF-Y, X-TPR-Y, X-TPK-Y, X-TPH-Y, X-YPA-Y, X-YPV-Y, X-YPM- Y, X-YPL-Y, X-YPI-Y, X-YPF-Y, X-YPR-Y, X-YPK-Y, X-YPH-Y,

X-NPA-Y, X-NPV-Y, X-NPM-Y, X-NPL-Y, X-NPI-Y, X-NPF-Y, X-NPR-Y, X-NPK-Y,

X-NPH-Y, X-QPA-Y, X-QPV-Y, X-QPM-Y, X-QPL-Y, X-QPI-Y, X-QPF-Y, X-QPR-Y,

X-QPK-Y, and X-QPH-Y.

More preferably, the peptide is chosen from X-SPR-Y, X-PPR-Y, X-QPA-Y, X-LPA-Y, XSPA-Y, X-PM-Y and X-PA-Y.

As examples of tetrapeptides, there may be mentioned X-AQPR-Y (SEQ ID NO: 1) and X-AQPK-Y (SEQ ID NO: 2).

According to other preferred characteristics of the invention:

Ri and / or R₂ is an alkyl chain of 1 to 24 carbon atoms, preferably 3 to 24 carbon atoms; and or

X is an acyl group CO-Ri and Y is chosen from OH, OMe, OEt and NH₂, preferably OH; X is preferably chosen from an octanoyl (C₈), decanoyl (Cio), lauroyl (Ci₂), myristoyl (Ο_Μ), palmitoyl (Cie), stearoyl (Ci₈), biotinoyl, elaidoyl, oleoyl and lipoyl; more preferably chosen from a lauroyl (Ci₂), myristoyl (0¼) and palmitoyl (C ^); and / or Y is OH and X is selected from palmitoyl (Ci₆), myristoyl (C_M) and lauroyle (C_î2); and / or more preferably the peptide is chosen from Pal-SPR-OH, Pal-PPR-OH, Pal-QPA-OH, PalLPA-OH, Myr-SPA-OH, Pal-PM-OH and Pal-PA- OH.

The peptides according to the invention can be optically pure, or consist of the L or D isomers or of a mixture thereof. L isomers which are those naturally occurring may be preferred.

The peptides can be in the form of salts, in particular hydrochloric salt.

In addition, the peptides according to the invention can constitute a larger peptide fragment, containing more amino acids than the active “core” di-, tri- or tetra-peptide according to the invention.

The present invention also covers derivatives (with modification and / or addition of a chemical function but without change in the carbon skeleton) and the like (with modification and / or addition of a chemical function but in addition with a change in the backbone. carbonaceous), complexes with other species such as a metal ion (eg copper, zinc, manganese, magnesium, and others).

The present invention also provides a composition, in particular topical, comprising at least one peptide according to the invention in a physiologically acceptable medium. Depending on the excipient and the dosage of peptide, this composition will for example constitute a concentrated active ingredient or a less concentrated final composition intended directly for the patient.

By “physiologically acceptable medium” is meant according to the present invention, without being limiting, an aqueous or hydroalcoholic solution, a water-in-oil emulsion, an oil-in-water emulsion, a microemulsion, an aqueous gel, an anhydrous gel, a water-in-oil emulsion. serum, a dispersion of vesicles, a powder.

“Physiologically acceptable” means that the compositions are suitable for topical or transdermal use, in contact with the mucous membranes, nails, scalp, hair, hair and skin of mammals and more particularly human, compositions which can be ingested or injected into the skin, without risk of toxicity, incompatibility, instability, allergic response, and others. This “physiologically acceptable medium” forms what is conventionally called the excipient of the composition.

The peptides according to the invention can be solubilized in a lipophilic or hydrophilic matrix with, where appropriate, a solubilizer, depending on the future application.

The peptide can be combined with other active ingredients at effective concentrations which can act synergistically or in reinforcement to achieve the desired effects described for the invention, such as the following agents: filtering radiation, in particular UVA UVB, moisturizing, calming, muscle relaxant, slimming, restructuring, firming, plumping, tightening, acting on microcirculation, acting on inflammation, on free radicals, vitamins, anti-wrinkles, etc.

The composition according to the invention can be applied to the face, body, décolleté, scalp, hair, eyelashes, body hair, in any form or vehicles known to those skilled in the art, in particular in the form of a solution, dispersion, emulsion, paste or powder, individually or as a premix or be conveyed individually or as a premix by vectors such as macrocapsules, microcapsules or nanocapsules, macrospheres, microspheres, or nanospheres, liposomes, oleosomes or chylomicrons, macroparticles, microparticles or nanoparticles, macro-sponges, micro-sponges or nano-sponges, micro-emulsions or nano-emulsions, or adsorbed on powdery organic polymers, talcs, bentonites, spores or exins and other mineral or organic supports.

In cosmetics in particular, applications can be offered in particular in ranges of skin care for the face, body, hair and body hair and ranges of make-up-care, in particular the eyelashes and eyebrows.

In general, the peptides according to the present invention can be used in any form, in a form linked, incorporated or adsorbed on macro-, micro-, and nanoparticles, or on macro-, micro- and nanocapsules. , for the treatment of textiles, natural or synthetic fibers, wools, and all materials intended to come into contact with the skin and which can be used in clothing, day or night underwear, handkerchiefs, or tissues, in order to exert its cosmetic or therapeutic effect through this skin / textile contact and allow continuous topical delivery.

The CTFA (“International cosmetic ingredient dictionary &amp; handbook (13th Ed. 2010) published by“ the Cosmetic, Toiletry, and Fragrance Association, Inc. ”, Washington, DC) describes a wide variety, without limitation, of cosmetic and pharmaceutical ingredients. commonly used in the skin care industry, which are suitable for use as additional ingredients in the compositions according to the present invention.

Other additional skin care actives which are particularly useful can be found in Sederma's sales literature and at www.sederma.fr.

The following commercial assets may also be mentioned by way of example: betaine, glycerol, Actimoist Bio 2 ™ (Active organics), AquaCacteen ™ (Mibelle AG Cosmetics), Aquaphyline ™ (Silab), AquaregulK ™ (Solabia), Carciline ™ (Greentech), Codiavelane ™ (Biotech Marine), Dermaflux ™ (Arch Chemicals, Inc), Hydra'Flow ™ (Sochibo), Hydromoist L ™ (Symrise), RenovHyal ™ (Soliance), Seamoss ™ (Biotech Marine), Argireline ™ (trade name for acetyl hexapeptide-3 from Lipotec), spilanthol or an extract of Acmella oleracea known as Gatuline Expression ™, an extract of Boswellia serrata known under the name Boswellin ™, Deepaline PVB ™ (Seppic), Syn-AKE ™ (Pentapharm), Ameliox ™, Bioxilift ™ (Silab), PhytoCellTec ™ Argan (Mibelle), Papilactyl D ™ (Silab), Preventhelia ™ (Lipotec), Subliskin ™ (Sederma), Venuceane ™ (Sederma), Moist 24 ™ (Sederma), Vegesome Moist 24 ™ (Sederma), Essenskin ™ (Sederma), Juvinity ™ (Sederma), Revidrat ™ (Sederma) , Resistem ™ (Sederma), Chronodyn ™ (Sederma), Kombuchka ™ (Sederma), Chromocare ™ (Sederma), Calmosensine ™ (Sederma), Glycokin factor S ™ (Sederma), Biobustyl ™ (Sederma), Idealift ™ (Sederma), Ceramide 2 ™, Ceramide A2 ™ and Ceramide HO3 ™ (Sederma), Legance ™ (Sederma), Intenslim ™ (Sederma), Prodizia ™ ( Sederma), or mixtures thereof.

Among the plant extracts which can be combined with a peptide according to the invention, there may also be mentioned in particular extracts of ivy, for example of climbing ivy (Hedera Hélix), of Bupleurum chinensis, of Bupleurum Falcatum, of arnica ( Arnica Montana L), rosemary (Rosmarinus officinalis N), marigold (Calendula officinalis), sage (Salvia officinalis L), ginseng (Panax ginseng), ginko biloba, St. John's wort (Hyperycum Perforation), butcher's broom (Ruscus) aculeatus L), ulmar (Filipendula ulmaria L), orthosiphon (Orthosiphon Stamincus Bentli), algae (Fucus Vesiculosus), birch (Betula alba), green tea, kola nuts (Cola Nipida), horse chestnut trees India, bamboo, Centella asiatica, heather, wrack, willow, piloselle, extracts of escin, extracts of cangzhu, extracts of chrysanthellum indicum, of plants of the genus Armeniacea, Atractylodis Platicodon, Sinnomenum, Pharbitidis, Flemingia, of Coleus like C. Forskohlii, C. blumei, C. esquirolii, C. scutellaroides, C. xanthantus and C. Barbatus, as an extract of rootiness of Coleus barbatus, extracts of Horehound, Guioa, Davallia, Terminalia, Barringtonia, Tréma, antirobia, cecropia, argania, dioscoreae such as Dioscorea opposita or Mexican, extracts of Ammi visnaga, of Siegesbeckia, in particular Siegesbeckia orientalis, plant extracts from the Ericaceae family, in particular extracts of blueberries (Vaccinium angustifollium) of Arctostaphylos uva ursi, aloe vera, plants containing sterols (in particular phytosterols), of Manjistha (extract of plants of the genus Rubia, in particular Rubia Cordifolia), of Guggal (extract of plants of the genus Commiphora, in particular Commiphora Mukul), an extract of kola, chamomile, purple treffle, Piper methysticum (Kava Kava from Sederma), Bacopa monieri (Bacocalmine ™, Sederma) and sea whip, Glycyrrhi-.a glabra, mulberry, melaleuca (tea tree), Larrea divaricata, of Rabdosia rubescens, of Euglena gracilis, of Fibraurea recisa Hirudinea, of Chaparral Sorghum, of sunflower flower, of Enantia chlorantha, of Mitracarp of the genus Spermacocea, of Buchu barosma, of Lawsonia inermis L., of Adiantium Capillus-Veneris L., of Chelidonium majus, from Luffa cylindrical, from "Japanese Mandarin" (Citrus reticulata Blanco var. unshiu), Camellia sinensis, Imperata cylindrical, Glaucium Flavum, Cupressus Sempervirens, Polygonatum multiflorum, loveyly hemsleya, Sambucus Nigra, Phaseolus lunatus, Centaurium, Macrocystis Pyrifera, Turnera Diffarrhusa asphodelo Anemia, of Portulaca pilosa, of Humulus lupulus, of Arabica coffee, of Paraguariensis, of Globularia Cordifolia, of Oxydendron arboreum and of Zingiber zerumbet smith.

Compositions according to the present invention may include other peptides, including, but not limited to, di-, tri-, tetra-, penta- and hexapeptides and their derivatives. According to a particular embodiment, the concentration of the additional peptide, in the composition, varies between 1x10⁷% and 20%, preferably between lxl0⁶% and 10%, preferably between lxl0⁵% and 5%, by weight. The term "peptide" denotes herein peptides containing 10 amino acids or less, their derivatives, isomers and complexes with other species such as a metal ion (eg copper, zinc, manganese, magnesium, and others). The term peptides refers to both natural peptides and synthetic peptides. It also refers to compositions which contain peptides and which occur in nature, and / or which are commercially available.

Nonlimiting examples of dipeptides which can be used in the context of the present invention include Carnosine (beta-AH), YR, VW, NL, DL, KT, KC, CK, KP, KK or TT. Non-limiting examples of tripeptides include RKR, HGG, GKH, GGH, GHG, KLK, KPK, KMOK, KM0₂K or KAvaK. Non-limiting examples of tetrapeptides are RSRK (SEQ ID NO: 3), GQPR (SEQ ID NO: 4) or KTLK (SEQ ID NO: 5). A non-limiting example of a pentapeptide is KTTKS (SEQ ID NO: 6) and of hexapeptides the GKTTKS (SEQ ID NO: 7) and VGVAPG (SEQ ID NO: 8).

Other peptides which can be used in the context of the present invention can be chosen from, without this list being limiting: lipophilic derivatives of peptides, preferably palmitoyl derivatives, and complexes with the metal ions mentioned above (eg copper complex HGG tripeptide). Preferred dipeptides include, for example, N-Palmitoyl-beta-Ala-His, N-Acetyl-Tyr-Arg-hexadecylester (Calmosensine ™, Idealift ™, Sederma), Pal-KT, Pal-RT (Sederma). Preferred tripeptides include in particular N-Pal-Gly-Lys-His, (Pal-GKH, Sederma), the copper derivative of HGG (Lamin ™, Sigma), lipospondin (N-Elaidoyl-KLK) and its substitution analogs. conservative, N-Acetyl-RKR-NH₂ (Peptide CK +), N-Biot-GHK (Sederma), Pal-KMO₂K (Sederma) and their derivatives. Tetrapeptide derivatives which can be used in the context of the present invention include, without being limited thereto, N-Pal-GQPR (Sederma) (SEQ ID NO: 9), Ela-KTLK (SEQ ID NO: 10). Usable pentapeptide derivatives are, without being limited thereto, N-Pal-KTTKS (SEQ ID NO: 11) (MATRIXYL ™, Sederma), N-Pal-Tyr-Gly-Gly-PheX (SEQ ID NO: 12) with X being Met or Leu or a mixture thereof. Usable hexapeptide derivatives include, but are not limited to: N-Pal-VGVAPG (SEQ ID NO: 13), Pal-GKTTKS (SEQ ID NO: 14) and derivatives. Mention may also be made of the mixture Pal-GHK and Pal-GQPR (SEQ ID NO: 9) (Matrixyl ™ 3000, Sederma).

Preferred commercially available compositions containing a tripeptide or derivative include Biopeptide-CL ™, Maxilip ™ or Biobustyl ™ from Sederma. Preferred compositions, commercially available, sources of tetrapeptides include: RIGIN ™, Eyeliss ™, Matrixyl ™ Reloaded and Matrixyl 3000 ™, which contain between 50 and 500 ppm of palmitoyl-GQPR (SEQ ID NO: 9) and an excipient, offered by Sederma.

The following commercial peptides may also be mentioned as additional active ingredients: Vialox ™, Syn-ake ™ or Syn-Coll ™ (Pentapharm), Hydroxyprolisilane CN ™ (Exsymol), Argireline ™, Leuphasyl ™, Aldenine ™, Trylgen ™, Eyeseryl ™, Serilesine ™ or Decorinyl ™ (Lipotec), Collaxyl ™ or Quintescine ™ (Vincience), BONT-L-Peptide ™ (lnfinitec Activos), Cytokinol ™ LS (Serobiological Laboratories / Cognis), Kollaren ™, IP2000 ™ or Meliprene ™ (European Institute of Cellular Biology), Neutrazen ™ (Innovations), ECMProtect ™ (Atrium Innovations), Timp-Peptide ™, ECM Moduline ™ (Infinitec Activos).

The present invention also also provides a method of topical cosmetic, cosmeceutical or dermopharmaceutical treatment for improving the appearance and general condition of the skin and its integuments, comprising topical application to the skin of a subject. which needs an effective amount of a peptide according to the invention or of a composition according to the invention comprising said peptide as defined above.

By “topical treatment” or “topical use” is meant an application which is intended to act at the place where it is applied: skin, mucous membrane, integuments.

The peptide or the composition according to the invention can be applied locally to the targeted areas. The "effective" amount depends on various factors, such as the age, condition of the patient, the severity of the disorder or pathology and the mode of administration. An effective amount means a non-toxic amount sufficient to achieve the desired effect.

In a cosmetic composition according to the invention, the peptides, in order to be present in an effective amount, are generally found in proportions of between 0.000001% and 15% relative to the total weight of the composition, more preferably between 0.0001 % and 5%, depending on the destination of the composition and the desired effect more or less pronounced. The peptides can be present in the compositions according to the invention in variable relative proportions, in equivalent amounts, or on the contrary in different proportions.

All the percentages and ratios used in the present application are by weight of the total composition and all measurements are made at 25 ° C unless specified otherwise.

For example, for a cosmetic treatment of the face, the European Directive on Cosmetics has set a standard amount of application of a cream of 2.72 mg / cm²/ day / person and for a body lotion of 0.5 mg / cm²/ day / person.

According to other particularities, the cosmetic treatment method according to the invention can be combined with one or more other treatment methods targeting the skin, such as, for example, treatments by light therapy, by heat or by aromatherapy.

According to the invention, it is possible to provide devices with several compartments or kits intended for the implementation of the method described above, and which could comprise, by way of example, and without this being limiting, in a first compartment a composition containing a peptide of the invention and in a second compartment an additional excipient and / or active, the compositions contained in said first and second compartments being considered here as a combination composition for simultaneous, separate or spread out use, in particular in one of the treatments defined above.

The treatment method according to the invention is more particularly suitable for treatment: propigmenting;

with a view to preventing and / or treating the loss of pigmentation of the skin and of its integuments (hair, eyelashes, eyebrows or hair), in particular with a view to treating white skin spots and / or canities;

with a view to improving the skin phototype of a person with white and / or sensitive skin, in particular with a view to preparing the skin and its integuments for exposure to the sun, self-tanner; accelerating tanning;

with a view to preventing and / or treating the defect of unification of the complexion;

for preventing and / or treating the loss of collagen in the extracellular matrix of the skin or for stimulating the synthesis of collagen with a view to a volumizing effect; to prevent and / or treat the loss of hydration of the skin, in particular by improving the skin barrier; and / or for an anti-aging treatment, in particular anti-wrinkles and fine lines, moisturizer and unifying the complexion.

Other applications are of course conceivable, for example slimming, treatment of loss of elasticity, detoxification, anti-glycation, anti-free radicals, anti-oxidants, tensors, anti-fatigue, anti-puffiness and / or dark circles, calming, firming, action on hair growth, action on complexion radiance, etc. as a preventive or curative measure.

The examples which follow describe and illustrate certain aspects of the invention. They should not be seen as limiting disclosure, as they mainly provide information useful for its understanding and implementation.

A) Example of synthesis of a peptide according to the invention, Pal-PA-OH:

The Pal-PA-OH peptide is prepared by peptide synthesis. Proline is acylated on its amine function with an activated palmitic acid derivative (palmitoyl chloride for example) in the presence of base to obtain palmitoyl-proline. It is then activated on its terminal acid function with a coupling agent (DCC (diclyclohexylcarbodiimide) / NHS (N-hydroxysuccinimide) or HBTU (2- (lH-benzotriazole-l-yl) -l, 1, 3, 3-tetramethyluronium hexafluorophosphate) / HOBT (1hydroxy-benzotriazole)) to react with alanine. After precipitation, washing and drying, the product palmitoyl-prolyl-alanine is obtained in solid form.

B) Preparation of a composition according to the invention comprising the Pal-PA-OH peptide of Example A).

Starting products:

pure Pal-PA-OH peptide, synthesized according to the synthetic method explained above;

Excipient: mixture of fatty esters, chosen so as to form an oily matrix, for example intended to form a composition without water for the subsequent formulation of cosmetic compositions without water.

Procedure: The Pal-PA-OH peptide is mixed with the excipient and placed under gentle stirring and heating until solubilization and total clarity.

C) In vitro evaluations

The peptides according to the invention exhibit a certain number of remarkable effects presented below. Peptides prepared according to A) above and dissolved in a fatty excipient to form compositions according to example B) were tested in vitro and showed pro-pigmenting activities and for certain pro-collagen which are presented below. . Comparative tests are also presented below.

1. Pro-pigmenting activity (Melanogenesel

a) B16 cell test

Mouse melanomas (B16 cells) are cultured in their maintenance medium (DMEMc + 10% FCS) in the presence of the products and positive references from the literature for 48 hours. At the end of the contact, the melanins are extracted from the cells and assayed by spectrophotometry. In parallel, the residual tyrosinase (dopa oxidase) activity of the cells is assayed by spectrophotometry in the presence of one of the substrates of the enzyme: L-DOPA. An estimate of the viability of the cells is also carried out at the end of the culture using a protein assay by the BCA method.

b) Test on human melanocytes

Normal human melanocytes (HEMn cells) are inoculated in their maintenance medium and then brought into contact with the products and the positive controls (references in the literature) in a test medium suitable for culturing the melanocytes for 10 days. At the end of the contact, the melanins are extracted from the cells and assayed by spectrophotometry. In parallel, the residual tyrosinase (dopa oxidase) activity of the cells is assayed by spectrophotometry in the presence of one of the substrates of the enzyme: L-DOPA. An estimate of the viability of the cells is also carried out at the end of culture using a protein assay by the BCA method.

e) Pigmentation results

<td>Peptides</td><td>on Wheat cells</td><td>on human melanocytes</td>

<td>IBMX (isobutyl-methyl-xanthine)</td><td> +++</td><td> +++</td>

<td>Pal-AQPR-OH (SEQ ID NO: 15)</td><td> +++</td><td></td>

<td>Pal-AQPK-OH (SEQ ID NO: 16)</td><td> +++</td><td></td>

<td>Pal-QPR-OH</td><td> ++</td><td></td>

<td>Pal-YPR-OH</td><td> ++++</td><td> ++</td>

<td>Pal-SPR-OH</td><td> ++++</td><td> ++</td>

<td>Pal-LPR-OH</td><td> ++++</td><td> +++</td>

<td>Myr-LPR-OH</td><td></td><td> ++</td>

<td>Lau-LPR-OH</td><td></td><td> +++</td>

<td>H-LPR-OH</td><td></td><td> =0</td>

<td>Pal-APR-OH</td><td> +++</td><td></td>

<td>Pal-PPR-OH</td><td> +++</td><td></td>

<td>Pal-QPK-NH₂</td><td> ++</td><td></td>

<td>Pal-QPH-OH</td><td> +++</td><td></td>

<td>Pal-QPM-OH</td><td> +++</td><td></td>

<td>Pal-QPA-OH</td><td> +++</td><td> ++</td>

<td>Pal-LPA-OH</td><td> +</td><td> ++</td>

<td>Myr-DPA-OH</td><td></td><td> =0</td>

<td>Pal-SPA-OH</td><td></td><td> ++</td>

<td>Pal-PPA-OH</td><td></td><td> +</td>

<td>Pal-DPA-OH</td><td></td><td> =0</td>

<td>Myr-SPA-OH</td><td></td><td> ++</td>

<td>Pal-LGA-OH</td><td></td><td> =0</td>

<td>Pal-LPM-OH</td><td> +</td><td></td>

<td>Pal-IPM-OH</td><td> +</td><td></td>

<td>Pal-FPM-OH</td><td> =0</td><td></td>

<td>Pal-MPL-OH</td><td> +++</td><td></td>

<td>Pal-PR-OH</td><td> +++</td><td> +</td>

<td>Myr-PR-OH</td><td></td><td> +</td>

<td>Pal-PM-OH</td><td> +++</td><td> +</td>

<td>Pal-PA-OH</td><td></td><td> +++</td>

<td>H-PA-OH</td><td></td><td> =0</td>

<td>Pal-GA-OH</td><td></td><td> =0</td>

The results clearly show a greater or lesser pro-pigmenting activity for a representative panel of peptides according to the invention.

The table also gives comparative results:

It is seen that Pal-LGA-OH and Pal-GA-OH do not exhibit pro-pigmenting activity compared to Pal-LPA-OH and Pal-PA-OH which shows that when one substitutes the Proline by more flexible amino acid, here Glycine, the pro-pigmenting activity is annihilated.

It is also seen that the Myr-DPA-OH and Pal-DPA-OH, comprising an acid Xaaj (aspartic acid Asp (D)) also do not exhibit pro-pigmenting activity.

Furthermore, it can be seen that Pal-FPM-OH, comprising a nonpolar Xaaj (Phenylalanine Phe 10 (F)) also does not exhibit pro-pigmenting activity.

Finally, we see that H-LPR-OH and H-PA-OH have no pro-pigmenting activity unlike Pal-LPR-OH and Pal-PA-OH respectively, which shows the importance of '' have peptides having an X or Y substitution.

2. Dual pro-pigmenting and pro-collagen activity Normal human fibroblasts are seeded and brought into contact with the peptides to be tested for 6 days in DMEMc + 5% FCS. After contact, the mats are fixed and the collagen 1 fibers are visualized by immunostaining using a specific antibody. Quantification is then carried out by image analysis. The positive control is TGF β 10⁶%.

<td>Peptide</td><td>Melanogenesis on Wheat cells</td><td>Melanogenesis on Human melanocytes</td><td>Colll</td>

<td>Pal-SPR-OH</td><td> ++++</td><td> ++</td><td> +</td>

<td>Pal-PPR-OH</td><td> +++</td><td></td><td> +</td>

<td>Pal-QPA-OH</td><td> +++</td><td> ++</td><td> +</td>

<td>Pal-LPA-OH</td><td> +</td><td> ++</td><td> +++</td>

<td>Myr-SPA-OH</td><td></td><td> ++</td><td> ++</td>

<td>Pal-PM-OH</td><td> +++</td><td> +</td><td> ++</td>

<td>Pal-PA-OH</td><td></td><td> +++</td><td> ++</td>

3. Activity on keratinocytes

Human keratinocytes are brought to just confluence in a KSFMc medium. The contact with the active ingredients and therefore their evaluation is then done in a KSFMc medium alone or with calcium (0.8mM) * The visual evaluation of the differentiation is done after 2, 4/5 and 7 days of contact.

* Calcium differentiation allows the creation of a binding structure between cells which leads to better attachment of the basal mat.

<td>Peptide</td><td>Differentiation of keratinocytes</td>

<td>Pal-KT - positive control</td><td>+++ at 2.5 ppm</td>

<td>Pal-FPR</td><td>+ to 10 ppm</td>

<td>Pal-SPR</td><td>+ to 10 ppm</td>

<td>Pal-PA</td><td>+ to 2 ppm</td>

<td>Pal-FPA</td><td>++ at 3ppm</td>

D) GALENIC

Active ingredient according to the invention:

Formula containing a peptide according to the invention either in a hydrophobic excipient as in the preceding examples or in a hydrophilic excipient.

Different formulations are described below. Additional cosmetic active ingredients, where appropriate supporting and / or complementing the activity of the active ingredient according to the invention, can be added in the appropriate phase according to their hydrophobic or hydrophilic nature. These ingredients can be of any category according to their function (s), the place of application (body, face, neck, bust, hands, hair, eyelashes, eyebrows, body hair, etc.), the desired final effect. and the targeted consumer, for example anti-aging, anti-wrinkle, moisturizer, anti-dark circles, firming, anti-glycation, slimming, soothing, muscle relaxant, anti-redness, anti-stretch marks, etc. They are mentioned above in the description.

1) Cream form

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A Sorbitan Stearate</td><td> 3,00</td>

<td>Cyclopentasiloxane (and) Cyclohexasiloxane</td><td> 2,00</td>

<td>Ethylhexyl Palmitate</td><td> 3,00</td>

<td>Glyceryl Stearate (and) PEG-100 Stearate</td><td> 3,00</td>

<td>Ethylhexyl Methoxycinnamate</td><td> 1,00</td>

<td>Ethylhexyl Dimethyl PABA</td><td> 1,00</td>

<td>Phase B Demineralized Water</td><td>Qsp 100</td>

<td>Ultrez 10 (Carbomer)</td><td> 0,40</td>

<td>Phase C Glycerine Conservative</td><td>5.00 qs</td>

<td>Phase D Peptide according to the invention in a fatty excipient</td><td> 2,00</td>

<td>Phase E Potassium Sorbate (Potassium Sorbate)</td><td> 0,10</td>

<td>Phase F Sodium Hydroxide 30% (Sodium Hydroxide)</td><td> 0,60</td>

<td>Demineralized Water</td><td> 6,00</td>

<td>Phase G Perfume</td><td> 0,10</td>

<td>Protocol: Weigh phase A and heat it to 75 ° C in a water bath. Weigh the p</td><td>shave B and let swell</td>

for 20 minutes. Melt phase C until dissolved and add it to phase B. Heat phase (B + C) to 75 ° C in a water bath. Pour phase A into phase (B + C) with Staro stirring. Extemporaneously, add phase D to phase (A + B + C). At approximately 45 ° C add phase E and neutralize with phase F. Homogenize well. At 35 ° C, add phase G. Homogenize well. pH: 6.20.

Examples of ingredients that can be added to this formulation:

• CALMOSENSINE ™: calming active ingredient marketed by Sederma (WO1998 / 07744) containing the lipo-dipeptide Tyr-Arg. It reduces feelings of discomfort.

· NG Birch Sap ™: invigorating and moisturizing active ingredient marketed by Sederma.

• Shea butter: with nourishing and protective properties for the treatment of skin damaged by the environment.

2) Oil form, especially for spray

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A Crodamol GTCC (Capric / Caprylic Triglyceride)</td><td>Qsp 100</td>

<td>Ethylhexyl Dimethyl PABA</td><td> 2,00</td>

<td>Ethylhexyl Methoxycinnamate</td><td> 2,00</td>

<td>Crodamol OS (Ethylhexyl Stearate)</td><td> 20,00</td>

<td>Tocopherol Acetate</td><td> 0,20</td>

<td>Phase B Peptide in a fatty excipient</td><td> 2,00</td>

<td>Phase C Perfume</td><td> 0,05</td>

Protocol: Weigh phase A and stir by helix. Add phase B to phase A with helix stirring. Homogenize well. Add phase C to phase (A + B).

Examples of ingredients that can be added to this formulation:

• REVIDRAT ™: active agent marketed by Sederma (WO 2011/086532), which in particular improves the cohesion of the epidermis and its hydration.

• REN OV AGE ™: global anti-aging active ingredient marketed by Sederma (W02006 / 020646).

3) Gel form

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A Demineralized Water</td><td>Qsp 100</td>

<td>Ultrez 10 (Carbomer)</td><td> 0,20</td>

<td>Phase B PEG 400</td><td> 5,00</td>

<td>Preservatives</td><td>qs</td>

<td>Phase C Dimethicone</td><td> 4,00</td>

<td>Pemulen TR2 (Acrylates / C 10-30 Alkyl Acrylate Cross Polymer)</td><td> 0,20</td>

<td>Phase D Tween 20 (Polysorbate 20)</td><td> 1,00</td>

<td>Peptide in a fatty excipient</td><td> 2,00</td>

<td>Phase E Potassium Sorbate (Potassium Sorbate)</td><td> 0,10</td>

<td>Phase F Sodium Hydroxide 30% (Sodium Hydroxide)</td><td> 0,60</td>

<td>Demineralized Water</td><td> 5,00</td>

<td>Phase G Perfume</td><td> 0,10</td>

Protocol: Disperse Ultrez 10 in water and let swell for 15 minutes. Heat phase

B until dissolved and add to phase A. Weigh and mix phase C. Mix phase D and add to phase C; Homogenize well. Add phase (C + D) to phase (A + B). Then add phase E. Let swell for 1 hour. Homogenize well. Neutralize with phase F. Finally, add phase G. pH: 6.10.

Examples of ingredients that can be added to this formulation:

• RESISTEM ™: anti-aging ingredient marketed by Sederma (WO 2012/104774), helping the skin to build its own anti-aging defense system, based on an extract obtained by cell culture of the Globularia cordifolia plant.

• AQUALANCE ™: active osmoprotective moisturizing ingredient marketed by Sederma (W02009 / 104118) composed of homarin and erythritol.

• LEGANCE ™: active anti-aging ingredient marketed by Sederma, corresponding to an extract of Zingiber zerumbet Smith obtained by supercritical CO2 in a water-soluble excipient and titrated in zerumbone. It is an overall anti-aging ingredient for the legs. It improves their appearance and comfort by reducing water retention, improving mrcrocirculation and refining adipose tissue.

• BODYFIT ™: active ingredient marketed by Sederma (WO 2004/024695) slimming / firming.

• PRODIZIA ™: active ingredient marketed by Sederma which fights the cutaneous signs of fatigue caused by glycation and glycoxidation.

· JUVINITY ™: active marketed by Sederma (WO 2011/125039) which reduces the signs of aging on the face and décolleté, smoothes wrinkles, restructures and densifies the dermis.

4) Compact powder form

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A Talc</td><td>Qsp 100</td>

<td>Kaolin</td><td> 2.00</td>

<td>Calcium Stearate</td><td> 1.00</td>

<td>Mica</td><td> 4.00</td>

<td>Silica</td><td> 1.00</td>

<td>Bismuth Oxychloride</td><td> 2.00</td>

<td>Potassium Sorbate</td><td>qs</td>

<td>Phenoxyethanol</td><td>qs</td>

<td>Phase B Unipure Black LC 989 HLC [CI 77499 (and) Hydrogenated Lecithin]</td><td> 0.20</td>

<td>Unipure Red LC 381 HLC [CI 77491 (and) Hydrogenated Lecithin]</td><td> 0.60</td>

<td>Unipure Yellow LC 182 HLC [CI 77492 (and) Hydrogenated Lecithin]</td><td> 1.00</td>

<td>Covapearl Star Gold 2302 AS [CI 77891 (and) CI 77491 (and) Synthetic</td><td> 0.50</td>

<td>Fluorphlogopite (and) Triethoxycaprylylsilane] Covapearl Brown 838 HLC [CI 77491 (and) Mica (and) Hydrogenated</td><td> 1.00</td>

<td>Lecithin) Covapearl Dark Blue 637 [CI 77510 (&amp;) CI 77891 (&amp;) Mica]</td><td> 0.10</td>

<td>Phase C Crodamol PTIS-LQ- (MV) [Pentaerythrityl Tetraisostearate]</td><td> 4,00</td>

<td>Peptide according to the invention in a fatty matrix</td><td> 2,00</td>

<td>Phase D Perfume</td><td> 0,30</td>

Protocol: Weigh phase A and mix. Weigh phase B and pour it into phase B. Pour A + B into the blender and mix. Add phase C to A + B several times and mix each time. Add phase D. Check homogeneity at each step.

Example of an ingredient that can be added to this formulation:

• VEGESOME MOIST 24 ™. an ingredient marketed by Sederma specially designed for the formulation of moisturizing makeup powders; it is a powder composed of 25 μm hollow particles (exins of Lycopodium clavatum) loaded with an extract

at.' Imperata cylindrica having moisturizing properties.

5) Cream form

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A</td><td></td>

<td>Arlacel 170 (Glyceryl Stearate (and) PEG-100 Stearate)</td><td> 5,50</td>

<td>Abil Wax 2434 (Stearoxy Dimethicone)</td><td> 3,00</td>

<td>Acetulan (Cetyl Acetate (and) Acetylated Lanolin Alcohol)</td><td> 1,50</td>

<td>Crodacol C 90 (Cetyl Alcohol)</td><td> 1,50</td>

<td>Ore Oil</td><td> 3,00</td>

<td>Shea butter</td><td> 5,00</td>

<td>Unsaponifiable Shea</td><td> 1,00</td>

<td>Parsol MCX (Ethylhexyl Methoxicinnamate)</td><td> 3,50</td>

<td>Phase B Demineralized Water</td><td>Qs 100</td>

<td>Phase C</td><td></td>

<td>Carbopol 940 (Carbomer)</td><td> 0,20</td>

<td>Phase D Demineralized Water</td><td> 2,00</td>

<td>Triethanolamine 99% (Triethanolamine)</td><td> 0,20</td>

<td>Phase E</td><td></td>

<td>Propylene glycol Mixed Parabens</td><td> 0,10</td>

<td>Phase F Sodium Hydroxide 30% (Sodium Hydroxide)</td><td> 5,00</td>

<td>Demineralized Water</td><td>qs</td>

<td>Phase G Peptide according to the invention in a hydrophilic matrix</td><td> 2,00</td>

Protocol: Weigh phase A and heat it to 75 ° C in a water bath. Weigh phase B and let swell for 20 minutes. Melt phase C until dissolved and P add to phase B. Heat phase (B + C) to 75 ° C in a water bath. Pour phase A into phase (B + C) with Staro stirring. 5 Extemporaneously, add phase D to phase (A + B + C). At approximately 45 ° C add phase E and neutralize with phase F. Homogenize well. At 35 ° C, add phase G. Homogenize well.

pH: 6.20.

Examples of ingredients that can be added to this formulation:

• SUBLISKIN ™: active ingredient marketed by Sederma (W02009 / 055663) which moisturizes and smoothes the skin while allowing it to resist external aggressions.

• VENUCEANE ™: active ingredient marketed by Sederma (W02002 / 066668) which prevents visible signs of photoaging (spots, wrinkles, dryness, etc.), protects cellular structures from UV damage and strengthens the integrity of the skin .

• MATRIXYL synthe'6 ™: active anti-wrinkle ingredient based on peptides marketed by

Sederma (W02010 / 082175) which helps repair skin damage caused by aging.

• KOMBUCHKA ™: active ingredient acting on the radiance of the complexion, marketed by Sederma (W02004 / 012650).

• INTENSLIM ™: active slimming ingredient marketed by Sederma. It is a synergistic combination of extracts of Globularia cordifolia obtained by plant cell culture, Zingiber zerumbet Smith titrated in zerumbone and plant caffeine obtained by CO extraction₂ supercritical.

6) Repigmenting hair lotion

<td>Ingredient (INCI name)</td><td>% in weight</td>

<td>Phase A Demineralized Water</td><td>Qsp 100</td>

<td>Ethanol</td><td> 50,00</td>

<td>Phase B Methyl Paraben</td><td> 0,20</td>

<td>Butylene Glycol</td><td> 2,00</td>

<td>Phase C Tween 20 [Polysorbate 20]</td><td> 1,50</td>

<td>Fragrance</td><td> 0,10</td>

<td>Phase D Peptide according to the invention</td><td> 3,00</td>

Protocol: Weigh phase A. Weigh and melt phase B. Cool phase B. Mix phase B with phase A with propeller stirring. Mix phase C and add it to phase A + B.

Add phase D to phase A + B + C. pH: 6.70.

Example of an ingredient that can be added to this formulation:

PROCAPIL ™: active ingredient for anti-hair loss marketed by Sederma (W02009 / 055663) which combines a vitamin matrikine (biotinyl-GHK), apigenin (a flavonoid extracted from citrus) and oleanolic acid (extract of the roots of Loveyly Hemsleyà).