Composition for re-pigmentation of the skin

Abstract

The present invention relates to a composition for skin re-pigmentation comprising a peptide inhibitor of MIA (melanoma-inhibiting activity) protein, at least one additional peptide, and a pharmaceutically acceptable excipient. The present invention also relates to the use of the composition for the prevention and / or treatment of vitiligo. The present invention also relates to the cosmetic use of the composition for skin re-pigmentation.

Description

Detailed description of the invention

[0001] [Technical field] This invention relates to the field of skin repigmentation.

[0002] [Current status of the technology] Skin depigmentation is a common condition that can affect various parts of the body's skin to varying degrees and can be caused by many localized and systemic conditions.

[0003] Typically, skin depigmentation is associated with vitiligo. Vitiligo is a depigmented skin disease characterized by the selective loss of melanocytes. As a result, vitiligo causes the loss of pigmentation in the affected areas of the skin.

[0004] Vitiligo is estimated to affect 0.5–2% of the global population, both in adults and children. Vitiligo is a condition that should not be taken lightly, as it is thought to have devastating psychological effects and often significantly impair daily life (Bergqvist C et al., Vitiligo: A Review, Dermatology 2020, 236, 571-592).

[0005] Non-segmental vitiligo (NSV) is the most common clinical form of the disease, and the depigmented skin patches are usually bilateral and symmetrical in some forms.

[0006] Vitiligo most commonly affects the face, fingers, back of the hands, flexor wrists, elbows, knees, shins, back of the ankles, armpits, groin, anal genitals, navel, and nipples.

[0007] Vitiligo is characterized by the loss of functional melanocytes, and multiple mechanisms, including metabolic abnormalities, oxidative stress, production of inflammatory mediators, cell shedding, and autoimmune responses, may be involved in this loss (Picardo et al., Vitiligo, Nat. Rev. Dis. Primers., 2015, 1, 15011).

[0008] Common treatments currently available for vitiligo include topical corticosteroids, topical calcineurin inhibitors such as tacrolimus and pimecrolimus, photochemotherapy with psoralen + UVA irradiation or kelin + UVA irradiation, narrowband UVB irradiation, oral steroids, immunosuppressants, antioxidants, surgical melanocyte transplantation, or depigmentation of residual pigmented lesions (Taieb A et al., Guidelines for the Management of Vitiligo: the European Dermatology Forum consensus, Br.J. Dermatol, 2013, 168 (1), 5-19).

[0009] MIA proteins (melanoma-inhibiting activity) have been suggested as another target for the treatment of vitiligo. In particular, international patent application WO-A-2012 / 127352 proposes numerous peptides and peptide derivatives that are MIA inhibitors for the prevention and treatment of vitiligo.

[0010] More recently, international patent application WO-A-2022 / 008251 has shown that a combination of snail secretion and the MIA inhibitory peptide disclosed in WO-A-2012 / 127352 provides a more effective treatment for vitiligo.

[0011] Despite the available proposals in the prior art, there is still a need for more therapeutic alternatives for effective skin re-pigmentation.

[0012] [Purpose of the invention] The object of the present invention is a composition comprising an MIA inhibitory peptide and at least one other peptide.

[0013] Another aspect of the present invention is the composition for use in the treatment of vitiligo.

[0014] Another aspect of the present invention is the cosmetic, non-therapeutic use of the composition for re-pigmenting the skin.

[0015] [Drawing description] Figure 1 shows the results of the in vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 1. The vertical axis represents the increase in melanin production for each test treatment compared to the control. On the horizontal axis, the gray column shows the assay results for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), samples treated with the peptide of SEQ ID NO: 50 (B), and samples treated with a combination of these (A+B). For comparison, the black column represents the expected theoretical result for combination A+B, based simply on the sum of the effects obtained separately for A and B.

[0016] Figure 2 shows the results of a similar assay described in Example 1, where the test samples were subjected to the same treatments (A, B, and A+B) and then irradiated additionally.

[0017] Figure 3 shows the results of the in vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 3. Samples were treated with different weight ratios of MIA inhibitor peptide (A) of SEQ ID NO: 40 and peptide (B) of SEQ ID NO: 50. The vertical axis represents the increase in melanin production for each test treatment compared to the control. The horizontal axis represents the different A+B combinations tested. The first column represents an A:B weight ratio of 7.5:1, the second column represents an A:B weight ratio of 11.2:1, and the third column represents an A:B weight ratio of 22:1.

[0018] Figure 4 shows the results of the in vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 3. The vertical axis represents the increase in melanin production for each test treatment compared to the control. On the horizontal axis, the gray column shows the assay results for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), samples treated with the peptide of SEQ ID NO: 51 (C), and samples treated with a combination of these (A+C). For comparison, the black column represents the expected theoretical result for combination A+C, based simply on the sum of the effects obtained separately for A and C.

[0019] Figure 5 shows the results of the in vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 4. The vertical axis represents the increase in melanin production for each test treatment compared to the control. On the horizontal axis, the gray column shows the assay results for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), samples treated with the Pro-Pro peptide (D), and samples treated with a combination of these (A+D). For comparison, the black column represents the expected theoretical result for combination A+D, based simply on the sum of the effects obtained separately for A and D.

[0020] [Detailed description of the invention] The subject of this invention is a composition comprising the following: (a) MIA inhibitory peptide of SEQ ID NO: 40; (b) at least one additional peptide selected from the group consisting of the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51, and the Pro-Pro peptide; and (c) at least one pharmaceutically acceptable excipient.

[0021] The compositions described above are particularly suitable for skin re-pigmentation. The authors of this invention have found that combining the MIA inhibitor peptide of SEQ ID NO: 40 with at least one other peptide selected from SEQ ID NOs: 50, 51, and Pro-Pro results in a significant synergistic effect in skin re-pigmentation. The remarkable re-pigmentation effect obtained with these combinations can improve the treatment of vitiligo compared to therapies previously available in the art.

[0022] In this specification and in the claims, singular expressions preceded by the articles "a," "an," or "the" generally include the plural form unless the context clearly indicates otherwise. Unless otherwise specified, all percentages are expressed in weight. Numbers preceded by the term "about" include a certain variation around such a value, i.e., a variation of ±5% of the stated quantity. Numerical ranges defined by lower and upper endpoints include the aforementioned endpoints and also include any narrower sub-ranges.

[0023] Amino acids are represented using either the one-letter code or the three-letter code according to the IUPAC-IUB Commission on Biochemical Nomenclature described in Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, 1992, London [ISBN1-85578-005-4], as is well known to those skilled in the art herein. In accordance with this nomenclature, the peptides herein represent the N-terminus on the left side of the formula and the C-terminus on the right side of the formula. Amino acids that do not form some specific proteins are represented herein as follows: D-phenylalanine is represented as DPhe, and norleucine is represented as Nle.

[0024] MIA inhibitory peptide An MIA inhibitory peptide is a peptide having an activity of inhibiting a human melanoma inhibitory activity (MIA) protein.

[0025] The sequence of the MIA inhibitory peptide of SEQ ID NO: 40 contained in the composition of the present invention is as follows: SEQ ID NO: 40 FHWRYPLPLPGQ This peptide and other MIA inhibitory peptides are disclosed in International Patent Application WO-A-2012 / 127352, that is, a group of peptides having SEQ ID NOs: 1 to SEQ ID NO: 49: SEQ ID NO: 01 VPHIPPN SEQ ID NO: 02 MPPTQVS SEQ ID NO: 03 QMHPWPP SEQ ID NO: 04 QPPFWQF SEQ ID NO: 05 TPPQGLA SEQ ID NO: 06 IPPYNTL SEQ ID NO: 07 AVRPAPL SEQ ID NO: 08 GAKPHPQ SEQ ID NO: 09 QQLSPLP SEQ ID NO: 10 GPPPSPV Sequence ID 11 LPLTPLP Sequence ID 12 QLNVNHQARADQ Sequence ID 13 TSASTRPELHYP Sequence ID 14 TFLPHQMHPWPP Sequence ID 15 VPHIPPNSMALT Sequence ID 16 RLTLLVLIMPAP Sequence ID 17: YNLPKVSSNLSP Sequence ID 18 MPPTQVSKFRLI Sequence ID 19 ANIDATPLFLRA Sequence ID 20 LLRTTETLPMFL Sequence ID 21 SALEPLV Sequence ID 22 GSPTPNA Sequence ID 23 APSHATH Sequence ID 24 TTVGHSD Sequence ID 25 THFSTFT Sequence ID 26 SLLLDTS Sequence ID 27 SVAMKAHKPLLP Sequence ID 28 NTIPGFASKSLD Sequence ID 29 VSNYKFYSTTSS Sequence ID 30 VSRHQSWHPHDL Sequence ID 31 HLNILSTLWKYR Sequence ID 32: HNASPSWGSPVM Sequence ID 33 SHPWNAQRELSV Sequence ID 34 HHWPFWRTLPLS Sequence ID 35 WHTKFLPRYLPS Sequence ID 36 NNTSFTVVPSVP Sequence ID 37 SHLSTWKWWQNR Sequence ID 38 FHWHPRLWPLPS Sequence ID 39 WHWTYGWRPPAM Sequence ID 40 FHWRYPLPLPGQ Sequence ID 41 WHWPLFIPNTTA Sequence ID 42 WHNGIWWHYGVR Sequence ID 43 HHLNYLWPWTRV Sequence ID 44 FWHRWSTFPEQP Sequence ID 45 WHMSYFWTRPPQ Sequence ID 46 FHLNWPSRADYL Sequence ID 47 WHKNTNWPWRTL Sequence ID 48 ALSPSQSHPVRS Sequence ID 49 GTQSTAIPAPTD In the sense of the present invention, the MIA inhibitory peptide of SEQ ID NO: 40 may optionally be acetylated (CH3-CO-) at the N-terminus and / or amidated at the C-terminus.

[0026] C-terminal amidation involves the formation of a terminal amide group of the formula -CONH2, -CONHR, or -CONR2, where R is typically a short-chain (e.g., C1-C4) alkyl group. The simplest and most common C-terminal amide group is -CO-NH2.

[0027] In one embodiment, the MIA inhibitory peptide of SEQ ID NO: 40 is acetylated at the N-terminus and amidated at the C-terminus.

[0028] In another embodiment, the MIA inhibitory peptide of SEQ ID NO: 40 is neither acetylated nor amidated.

[0029] MIA inhibitory peptides can be prepared typically by solid-phase synthesis according to standard peptide synthesis methods and may be commercially available from several sources.

[0030] In addition to the MIA inhibitory peptide of SEQ ID NO: 40, the composition of the present invention may also contain one or more additional MIA inhibitory peptides selected from, for example, SEQ ID NOs: 1-39 and 41-49.

[0031] In one preferred embodiment, the composition of the present invention comprises the peptide of SEQ ID NO: 40 as the sole MIA inhibitory peptide of the composition.

[0032] The terms “MIA inhibitory peptide” and “MIA inhibitor” are used interchangeably herein and refer to the MIA inhibitory peptide of SEQ ID NO: 40 unless otherwise indicated.

[0033] MIA inhibitory activity can be tested using standard methods such as ligand binding assays using recombinant human MIA, as described in, for example, Stoll et al., The extracellular human melanoma inhibitory activity (MIA) protein adopts an SH3 domain-like fold, EMBO J., 2001, 20(3), 340-349, or disclosed in Schmidt et al., Targeting melanoma metastasis and immunosuppression with a new mode of melanoma inhibitory activity (MIA) protein inhibition, 2012, PLoS ONE 7(5): e37941.

[0034] MIA inhibitory peptides can be added directly to the composition, or they may be encapsulated in different polymer materials or bound to different carrier materials to improve their transdermal delivery through the stratum corneum to reach target MIA proteins in vitiligo melanocytes located in the basal layer, the lowest layer of the epidermis, and attached to the basement membrane.

[0035] Encapsulation technology is well known in the art for the delivery of active ingredients.

[0036] In one embodiment, the MIA inhibitory peptide is microencapsulated using liposome technology.

[0037] Liposomes are commonly used in skin formulations to improve the penetration of active substances through the skin layer. As is well known in the art, liposomes are generally spherical vesicles with a size in the range of approximately 60 nm to 300 nm, and are most often composed of phospholipids forming at least one phospholipid bilayer, although they may also contain other lipids. Liposomes are suitable carriers for both hydrophilic and lipophilic active substances because they contain a hydrophilic core into which hydrophilic active substances can be encapsulated, while hydrophobic active substances are incorporated into the bilayer (Knoth et al., Nanocarrier-Based Formulations: Production and Cosmeceutic Applications, in: Cosmeceutic Applications, in: Cosmetic Formulation. Principles and Practice, Benson HAE, Roberts MS, Rodrigues Leite-Silva V. and Walters KA, editors, CRC Press, 2019). Liposomes may be prepared by known techniques, which generally involve mixing membrane-forming lipids in an organic phase, drying, then hydrating the lipids, and further reducing their size by different mechanical processes such as sonication, extrusion, or homogenization.

[0038] In another embodiment, the MIA inhibitor is encapsulated in microcapsules or nanocapsules made of biodegradable polymers well known in the art, such as those disclosed for the delivery of peptides of SEQ ID NOs. 1-49, including polyesters, polyamino acids, polyalkylcyanoacrylates, polyphosphazenes, or polyethylene oxides (WO-A-03 / 064457, cited above). Common polymers used for encapsulation are, for example, polyvinyl alcohol (PVA), polylactic acid (PLA), poly(lactic acid-coglycolic acid) (PLGA), or block copolymers thereof with poly(ethylene oxide) or poly(ethylene glycol). Other suitable biodegradable polymers include poly(propylene fumarate-coethylene glycol)[P(PF-co-EG)] block copolymer, polyanhydride, poly(fumarate-cosebacin) anhydride, alginates, dextran, chitosan, hydroxyapatite, collagen, fibrin, hyaluronic acid, carbomers, and mixtures thereof.

[0039] In another embodiment, the MIA inhibitory peptide is conjugated to nanoparticles, i.e., lipid nanoparticles, polymer nanoparticles, magnetic nanoparticles, or metal nanoparticles, which may act as carriers to facilitate the penetration of the MIA inhibitor through the stratum corneum.

[0040] In certain embodiments, MIA inhibitory peptides are conjugated to gold nanoparticles, which have been described as improving penetration through the skin (Gupta et al., J. Phys. Chem. B, 2016, 7133-7142). These nanoparticles have a gold core coated with the MIA inhibitory peptide. The MIA inhibitory peptide typically binds to the gold nanoparticles by electrostatic ionic bonding between the negative charge of the gold surface of the nanoparticle and the positive charge of the amino acid of the peptide (lysine, arginine, histidine, asparagine, or glutamine) having an amino group in its side chain. The gold nanoparticles have a size of less than 1000 nm, preferably including sizes of 50-200 nm. The conjugates may be prepared, for example, by reducing Au(III) to Au(0) with a reducing agent and treating the resulting gold nanoparticles with the MIA inhibitory peptide, as disclosed in international patent application WO-A-2019 / 185696.

[0041] The amount of SEQ ID NO: 40 in the composition of the present invention is typically between 0.0001% and 1%, preferably between 0.0005% and 0.1%, and more preferably between 0.001% and 0.05%, whether it is added in free form, encapsulated, or bound to a carrier, as disclosed above. Here, the percentage is expressed as the weight of the MIA inhibitory peptide of SEQ ID NO: 40 relative to the total weight of the composition.

[0042] Additional peptides The additional peptide (b) to be combined with the MIA inhibitory peptide of SEQ ID NO: 40 is selected from the following: Peptide of SEQ ID NO: 50, The peptide of SEQ ID NO: 51, and Pro-Pro peptide; Here: Sequence ID 50 is Nle-Ala-His-DPhe-Arg-Trp. Sequence ID 51 is His-DPhe-Arg-Trp.

[0043] The peptide of Sequence ID No. 50 is disclosed, for example, in international patent application WO-A-03 / 64458 for its melanotropic, anti-inflammatory, and / or anti-allergic uses.

[0044] In the sense of the present invention, the peptide of SEQ ID NO: 50 may optionally be acetylated at the N-terminus (CH3-CO-) and / or amidated at the C-terminus (-NH2).

[0045] In one embodiment, the peptide of SEQ ID NO: 50 contains an acetyl group at the N-terminus and an amide group (-NH2) at the C-terminus, and can be represented as Ac-Nle-Ala-His-DPhe-Arg-Trp-NH2.

[0046] As shown in Example 1 (and Figures 1 and 2), the combination of the MIA inhibitory peptide (SEQ ID NO: 40) and the peptide of SEQ ID NO: 50 resulted in a significant increase in melanin production in an in vitro assay performed using reconstituted human pigmented epidermis. The increase in melanin production was significantly higher than the effect expected from simply adding the effects of the individual peptides, indicating that the combination of the two peptides produces a synergistic effect.

[0047] The peptide of Sequence ID No. 51 is a melanocortin agonist, as described, for example, in Holder et al, J. Med. Chem., 2002, 45 (13), 2801-2810.

[0048] In the sense of the present invention, the peptide of SEQ ID NO: 51 has N-terminal lipidization, i.e., via an amide bond, a saturated or unsaturated C such as myristine or palmitine at its N-terminus. 12 ~C 18 The addition of a fatty acid and / or C-terminus amidation (-NH2) may be included. In one embodiment, the N-terminus of SEQ ID NO: 51 contains a palmitoyl group, and the C-terminus contains an amide group (-NH2).

[0049] As shown in Example 3 (and Figure 4), the combination of the MIA inhibitory peptide of SEQ ID NO: 40 and the peptide of SEQ ID NO: 51 resulted in a significant increase in melanin production in an in vitro assay performed using reconstituted human pigmented epidermis. This combination is clearly higher than the effect expected from simply adding the effects of the individual peptides.

[0050] Pro-Pro peptides are, for example, the secondary pigmentation peptides disclosed in international patent application WO-A-2014 / 080376.

[0051] In the sense of the present invention, the Pro-Pro peptide is N-terminal lipidization, i.e., saturated or unsaturated C such as myristine or palmitine via an amide bond. 12 ~C 18 The addition of a fatty acid and / or an amide group (-NH2) at the C-terminus may be included. In one embodiment, the N-terminus of the Pro-Pro peptide contains a palmitoyl group, CH3-(CH2) 14 It can be represented as -CO-Pro-Pro (palmitoyl-prolyl-proline).

[0052] As shown in Example 4 (and Figure 5), the combination of the MIA inhibitory peptide and Pro-Pro peptide of SEQ ID NO: 40 induced a significant increase in melanin production in an in vitro assay performed using reconstituted human pigmented epidermis. This combination is clearly higher than the effect expected from simply adding the effects of the individual peptides.

[0053] In one embodiment, the MIA inhibitory peptide is combined with the peptide of SEQ ID NO: 50.

[0054] In one embodiment, the MIA inhibitory peptide is combined with the peptide of SEQ ID NO: 51.

[0055] In one embodiment, the MIA inhibitory peptide is combined with a Pro-Pro peptide.

[0056] In one embodiment, the MIA inhibitory peptide is combined with at least two peptides selected from the group consisting of the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51, and the Pro-Pro peptide.

[0057] In one embodiment, the MIA inhibitory peptide is combined with the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51, and the Pro-Pro peptide.

[0058] The weight ratio of the MIA inhibitory peptide (a) of SEQ ID NO:40 to the additional peptide (b) in the composition of the present invention is between 1:1 and 100:1, preferably between 2:1 and 50:1, where the additional peptide (b) is either the peptide of SEQ ID NO:50, the peptide of SEQ ID NO:51, or the Pro-Pro peptide.

[0059] If multiple additional peptides from SEQ ID NOs. 50, 51, or Pro-Pro are added to the composition, the weight ratio is related to the single weight ratio of SEQ ID NO. 40 MIA inhibitor peptide to each of the additional peptides.

[0060] When the composition of the present invention contains the peptide of SEQ ID NO: 50, the weight ratio of the MIA inhibitory peptide to the peptide of SEQ ID NO: 50 is preferably between 2:1 and 50:1, and more preferably between 5:1 and 25:1.

[0061] When the composition of the present invention contains the peptide of SEQ ID NO: 51, the weight ratio of the MIA inhibitory peptide to the peptide of SEQ ID NO: 51 is preferably between 2:1 and 60:1, more preferably between 10:1 and 50:1, and even more preferably between 20:1 and 40:1.

[0062] When the composition of the present invention contains a Pro-Pro peptide, the weight ratio of the MIA inhibitory peptide to the Pro-Pro peptide is preferably between 1:1 and 10:1, and more preferably between 2:1 and 5:1.

[0063] Optional additional ingredients Optionally, the composition of the present invention may contain snail secretions as an additional active ingredient.

[0064] Snail secretion, also known as snail mucus, is a type of mucus or bodily fluid secreted from glands in the feet of snails (gastropods). This mucus is a complex mixture of water and substances including proteoglycans, glycosaminoglycans, glycoprotein enzymes, hyaluronic acid, copper peptides, antimicrobial peptides, and metal ions, with allantoin, collagen, elastin, and glycolic acid being the main components (Cillia et al., Antimicrobial properties of terrestrial snail and slug mucus, J. Complement.Integr.Med., 2018, 15(3)).

[0065] This secretion can be collected and recovered from living snails, for example, as disclosed in patent US5538740 or US patent application US-A-2018 / 0064635. Generally, the secretion is collected and filtered after subjecting gastropods to specific stress conditions.

[0066] Snail secretions are generally in liquid form, with a pH typically in the range of 5 to 8, a density generally of about 1.0 to 1.1 mg / ml, and the dry residue is generally between 0.1% and 3%, preferably between 0.2% and 2%, more preferably between 0.25% and 1%, and even more preferably between 0.3% and 0.7%. The protein content is generally in the range of 0.1 to 3 mg / ml.

[0067] Snail secretions are commercially available from several suppliers, such as the Spanish company Cobiosa (marketed as product Poly-Helixan PF) or the Italian company CENTISIA Laboratorio di Fitocosmesi di Bruno Dott.ssa Laura Francesca & C. sas (marketed as Prodotto 580038).

[0068] To obtain this secretion, among others, Achatina fulica, Cornu aspersum (or Helix aspersa or Cryptomphalus aspersa or Cantareus aspersus), Helix pomatia, Helix hortensis, Helix nemoralis, Helix cardidula, Helix tchthyomma, Helix fructicola, Helix strigella, Helix fruticum, Helix bidens, Helix arbostorum, Helix aculeata, Helix pulchella, Helix fructicola, Helix strigella, Helix fruticum, Helix bidens, Helix arbostorum, Helix rotundata, Helix aculeata, Helix pulchella, Helix personata, Helix holoserica, Helix aperta, Helix Various types of gastropods may be used, including Helix parnassia, Helix alonensis, Helix candidissima, Helix pisana, or Helix gualteviana. In certain embodiments, snail secretions are obtained from Cornu aspersum, also known as Helix aspersa, Cryptomphalus aspersa, or Cantareus aspersus.

[0069] The medicinal and cosmetic uses of snail secretions have been disclosed in the art, for example, as antimicrobial agents, wound healers, skin protectants, or anti-aging agents.

[0070] The combined use of MIA inhibitory peptides and snail secretions is disclosed in international patent application WO-A-2022 / 008251.

[0071] The amount of snail secretion in the composition of the present invention, if present, is typically between 0.5% and 15%, preferably between 1% and 10%, more preferably between 2% and 8%, and even more preferably about 5%, where the percentage is expressed as the weight of snail secretion relative to the total weight of the composition.

[0072] composition The composition of the present invention comprises at least one pharmaceutically acceptable excipient.

[0073] The term "pharmaceutically acceptable excipients" refers to components of a pharmaceutical or cosmetic composition that are not active ingredients. These components are useful for preparing the composition and are generally safe and non-toxic for human pharmaceutical or cosmetic use. In particular, since the compositions of the present invention are typically intended for external use, applied topically to the skin of an affected area, the pharmaceutically acceptable excipients are especially "dermatologically acceptable," i.e., suitable for use in contact with human skin tissue and non-toxic.

[0074] In one embodiment, the composition according to the present invention is for topical administration and is spread on the skin of the area to be treated, i.e., an area exhibiting depigmentation, typically vitiligo depigmentation, or an area prone to depigmentation. Topical administration, dermal administration, or cutaneous administration are used interchangeably herein.

[0075] Any type of formulation suitable for topical administration can be used. Typically, the compositions of the present invention are in the form of, for example, creams, gels, cremigels, lotions, pastes, foams, solutions, suspensions, emulsions, or stick formulations, which are well known in the art. For example, cremigel differs from cream in that it is an intermediate formulation between cream and gel. However, cremigel is opaque like cream and usually appears white.

[0076] Suitable carriers may be, for example, anhydrous substances as mixtures of fats, waxes, animal and vegetable oils, and solid and liquid hydrocarbons. Alternatively, the carrier may be water or an aqueous solution of a hydrophilic substance. Preferably, the carrier may be in the form of an emulsion. The emulsion may typically be an oil-in-water emulsion, a water-in-oil emulsion, a water-in-oil-in-water emulsion, an oil-in-oil-in-water emulsion, or a water-in-silicone emulsion. The emulsion may generally be described as having a continuous aqueous phase (oil-in-water and water-in-oil-in-water) or a continuous oil phase (water-in-oil and oil-in-oil-in-water). The oil phase may contain silicone oils, non-silicone oils such as paraffinic hydrocarbons, fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, or cetostearyl alcohol), fatty acids (e.g., stearic acid, oleic acid), fatty acid esters (e.g., isopropyl myristate, isopropyl palmitate), waxes or vegetable oils (e.g., castor oil, canola oil, cottonseed oil, jojoba oil, or peanut oil), or mixtures thereof. The aqueous phase may contain water or an aqueous solution of a hydrophilic substance such as an alcohol (e.g., ethanol, isopropyl alcohol), a polyol (e.g., glycerol, sorbitol), an α-hydroxy acid, an amino acid, a protein hydrolysate, a monosaccharide, or a polysaccharide.

[0077] Emulsifiers, which are common components of lotions, are surfactants, and include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. Nonionic surfactants include, in particular, ethoxylated fatty alcohols, ethoxylated fatty acid esters, alkyl glucosides or alkyl oligoglucosides, ethoxylated sorbitan fatty acid esters, monoglycerin / polyglycerin fatty acid esters, ethoxylated glycerin monoesters, ethoxylated polyglyceryl esters, alkyldimethylamine oxide, or poloxamer. Anionic surfactants include alkaline soaps, alkyl sulfates, alkyl ether sulfates, alkyl sulfosuccinates, alkyl phosphates, acyl sarcosinates, or acyl isethionates. Cationic surfactants include quaternary ammonium salts or pyridine salts. Amphoteric surfactants include imidazoline derivatives, betaine, amide betaine, and sulfobetaine.

[0078] Other common ingredients in formulations include, for example, emollients, humectants, preservatives, viscosity modifiers, antioxidants, pH adjusters, UV filters, chelating agents, fragrances, and colorants. Common emollients include, for example, paraffinic hydrocarbons, silicones, fatty alcohols, fatty acids, fatty acid-alcohol esters, triglycerides, ceramides, phospholipids, and waxes. Humidifiers include polyhydroxy alcohols, proteins, and hydroxy acids. Common preservatives include sorbic acid and its salts, benzoic acid and its salts, parabens, imidazolidinyl urea, diazolidinyl urea, DMDM ​​hydantoin, sodium hydroxymethylglycinate, methylchloroisothiazolinone / methylisothiazolinone, benzyl alcohol, and 2-phenoxyethanol. Other additives may also be added to adjust the viscosity of the formulation, such as xanthan gum, gellan gum, acacia, carrageenan, chitosan, collagen, tragacanth, pectin, starch derivatives, carbomer, cellulose derivatives (e.g., hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, or carboxymethylcellulose), polyamide, glutamic acid, colloidal silica, or wax (e.g., beeswax or vegetable wax).

[0079] Some components in the composition may act as penetration enhancers to promote the penetration of active ingredients into the entire stratum corneum. Common penetration enhancers include, for example, short-chain alcohols such as ethanol or isopropyl alcohol, long-chain alcohols such as decanol, hexanol, lauryl alcohol, myristyl alcohol, octanol, octyldodecanol or oleyl alcohol, cyclic amides such as azone, esters such as ethyl acetate, octyl salicylate, badimate O, ethyl oleate, glyceryl monooleate, glyceryl monocaprate, glyceryl tricaprylate, isopropyl myristate, isopropyl palmitate, propylene glycol monolaurate or propylene glycol monocaprylate, and Transcutol®. Any ether alcohol, fatty acids such as lauric acid, linoleic acid, linolenic acid, myristic acid, oleic acid, palmitic acid, stearic acid or isostearic acid, glycols such as dipropylene glycol, propylene glycol, 1,2-butylene glycol or 1,3-butylene glycol, pyrrolidones such as N-methyl-2-pyrrolidone or 2-pyrrolidone, sulfoxides such as decyl methyl sulfoxide or dimethyl sulfoxide, anionic surfactants, cationic surfactants, nonionic surfactants, terpenes such as eugenol D-limonene, menthol, menthone, farnesol or neridol (e.g., Lane This is disclosed in ME, Skin penetration enhancers, Int. J. Pharm., 2013, 447, 12-21 or Haque et al., Chemical enhancer: a simplistic way to modulate barrier function of the stratum corneum, Adv. Pharm. Bull., 2018, 8(2), 169-179.

[0080] The compositions of the present invention typically have a weakly acidic pH close to the physiological pH of the skin. Common acid modifiers are organic acids, including hydroxy acids and fatty acids. Some of the most common pH modifiers in cosmetic lotions are hydroxy acids such as lactic acid or citric acid.

[0081] A single excipient can perform multiple functions. The ingredients cited above, as well as many other suitable dermatological excipients, are well known to those skilled in the art of topical compositions. Such ingredients are commercially available from several companies, such as Commercial Quimica Masso, SA, Evonik, DuPont, or Dow Corning.

[0082] The preparation of topical compositions is carried out according to procedures well known to those skilled in the art of formulating dermatological compositions, and generally involves a simple step of mixing the components and optionally heating them.

[0083] For example, a cream can typically be prepared by heating the oil phase and the aqueous phase separately to a temperature of approximately 60-80°C and mixing them under stirring to prepare an emulsion.

[0084] The main components of the compositions and the procedures for preparing them are described, for example, in the book *Cosmetic Formulation: Principles and Practice*, by Benson HAE, Roberts MS, Rodrigues Leite-Silva V, and Walters KA, CRC Press, 2019, or in other similar references. Furthermore, regulated cosmetic substances and components are disclosed in the European Commission's database "CosIng" (https: / / ec.europa.eu / growth / tools-databases / cosing).

[0085] Typically, for example, a cream, gel, or lotion-based formulation is first prepared using standard ingredients and procedures well known in the art, then the MIA inhibitory peptide, additional peptides, and snail secretions (if present) are added and thoroughly mixed, and finally the pH of the composition is adjusted.

[0086] Use of the composition As demonstrated in the in vitro repigmentation assay of the examples, the combination of the MIA inhibitory peptide and additional peptide defined above is remarkably effective in repigmenting the skin.

[0087] Therefore, another aspect of the present invention is the composition of the present invention for use in the prevention and / or treatment of vitiligo.

[0088] Another aspect of the present invention is a method for the prevention and / or treatment of vitiligo in a patient in need, comprising the procedure of applying a therapeutically effective amount of the composition of the present invention.

[0089] The compositions of the present invention can also be used for cosmetic, non-therapeutic re-pigmentation of small areas of skin that have become depigmented and whitened, not specifically defined as vitiligo.

[0090] Therefore, another aspect of the present invention is the cosmetic, non-therapeutic use of the compositions of the present invention for the re-pigmentation of skin.

[0091] Another aspect of the present invention is a method for re-pigmenting the skin to a subject requiring it, comprising the treatment of applying an effective amount of the composition of the present invention.

[0092] The cosmetic use of skin re-pigmentation should be understood as a procedure aimed at partially or completely restoring the original pigmentation of depigmented or dilated skin lesions in a subject.

[0093] Similarly, the treatment of vitiligo should be understood as a procedure aimed at improving vitiligo symptoms, that is, partially or entirely restoring the original pigmentation of the depigmented or dilated skin patches in the subject.

[0094] In one embodiment, the prevention and / or treatment of vitiligo relates to the prevention and / or treatment of non-segmental vitiligo.

[0095] Prevention of vitiligo is aimed at preventing the onset of vitiligo symptoms. For example, by detecting the presence of MIA protein in melanocytes, early diagnosis can be made before the symptoms appear, or subjects known to be susceptible to vitiligo can be targeted based on whether they have some known genetic factors that make them prone to this disease. Prevention of vitiligo also includes treatment for patients who have previously suffered from vitiligo and recovered from this disease, that is, patients who have achieved repigmentation of vitiliginous depigmented skin, to prevent them from suffering from vitiligo symptoms again.

[0096] Typically, the compositions of the present invention are administered topically, that is, spread over vitiligo or depigmented skin patches.

[0097] In one embodiment, the compositions of the present invention can be delivered transdermally, for example, using iontophoresis, ultrasound or microneedles (Escobar-Chavez et al., Microneedles: a valuable physical enhancer to increase transdermal drug delivery, J. Clin.Pharmacol., 2011, 51(7), 964-977).

[0098] The amount of the composition considered to be "effective" for the treatment or prevention of vitiligo, or for cosmetic, non-therapeutic skin repigmentation, can vary widely depending on many factors, such as the severity and progression stage of the pigmentation state, or the specific formulation used. This amount can be easily adjusted by a skilled practitioner in each case. Generally, the amount of the topical composition applied to the affected skin is from about 0.1 mg of the composition per unit surface area (mg / cm 2 ) of the skin to about 100 mg / cm 2 , preferably in the range of about 5 mg / cm 2 to about 10 mg / cm 2 .

[0099] The composition of the present invention may be applied topically once or more times a day, for example, twice, three or four times a day. The composition is typically applied by spreading it over the skin, only on the affected area of ​​skin. The duration of treatment can be adjusted according to the progression of hyperpigmentation. Typically, treatment may be maintained for several weeks, for example, one, two, three or four weeks, or for several months, for example, one to twelve months, or longer, depending on the severity and progression of the depigmentation symptoms. The duration of treatment can be easily adjusted by a skilled practitioner.

[0100] Advantageously, treatment with the compositions of the present invention may be combined with phototherapy, for example, simple sunlight exposure or the use of a sunbathing bed, to stimulate the formation and migration of melanocytes and promote re-pigmentation.

[0101] Accordingly, another aspect of the present invention is a method for the prevention and / or treatment of vitiligo in a patient in need, comprising the procedure of applying a therapeutically effective amount of the composition of the present invention and exposing the treated skin area to the phototherapy.

[0102] As used herein, the terms “phototherapy” or “light therapy” include exposure to sunlight or exposure to radiation of specific wavelengths, such as UV radiation, including UVA and UVB radiation. Thus, “phototherapy” can be carried out by simple exposure to sunlight, the use of a sunbathing bed, or the use of a light-emitting device, in particular a UV radiation device.

[0103] The duration of phototherapy is not fixed and may vary from, for example, about 2 minutes to 2 hours daily, or every other day, or 2 or 3 times a week, or from other appropriate options.

[0104] Vitiligo, or general depigmentation of the skin, can affect any area of ​​the skin, so the composition may be applied to any area of ​​the affected (depigmented) skin. The areas of skin most commonly affected, and therefore most likely to require treatment, are the hands and face, around the body openings (eyes, nostrils, mouth, navel and genital area), and the inside of folded parts of the body such as the armpits and groin.

[0105] In one embodiment, the use of the composition of the present invention for treating common skin depigmentation, particularly vitiligo, may be combined with the use of antioxidants, especially when the treatment is combined with phototherapy, in order to reduce the potential adverse effects of radiation exposure.

[0106] Antioxidants are typically used orally. Suitable antioxidants include, among others, vitamin E, vitamin C, carotenoids (such as lycopene), beta-carotene, alpha-carotene, green tea extract, zinc, selenium, Polypodium leucotomos extract, or combinations thereof.

[0107] These can be formulated, for example, using standard excipients and preparation processes known in the art, typically as oral dietary supplements such as tablets, powders, or capsules.

[0108] Another aspect of the present invention is a method for the prevention and / or treatment of vitiligo in a patient in need, comprising the treatment of applying a therapeutically effective amount of the composition of the present invention, the treatment of exposing the treated skin area as phototherapy, and the treatment of administering an antioxidant to the patient.

[0109] The present invention can be defined according to the following embodiments.

[0110] 1. A composition, (a) MIA inhibitory peptide of SEQ ID NO: 40; (b) at least one additional peptide selected from the group consisting of the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51, and the Pro-Pro peptide; and (c) A composition comprising at least one pharmaceutically acceptable excipient.

[0111] 2. The composition according to Embodiment 1, characterized in that the MIA inhibitory peptide of SEQ ID NO: 40 is acetylated at the N-terminus and / or amidated at the C-terminus, more preferably acetylated at the N-terminus and amidated at the C-terminus.

[0112] 3. The composition according to Embodiment 2, characterized in that the C-terminal amide group is selected from -CONH2, -CONHR, and -CONR2, where R is a C1-C4 alkyl group, preferably -CO-NH2.

[0113] 4. The composition according to Embodiment 1, characterized in that the MIA inhibitory peptide of Sequence ID No. 40 is neither acetylated nor amidated.

[0114] 5. The composition according to any one of Embodiments 1 to 4, characterized in that the MIA inhibitory peptide is encapsulated or bound to carrier nanoparticles.

[0115] 6. The composition according to any one of Embodiments 1 to 5, characterized in that the amount of MIA inhibitory peptide in the composition is between 0.0001% and 1%, preferably between 0.0005% and 0.1%, and more preferably between 0.001% and 0.05%, where the percentage is expressed as the weight of the MIA inhibitory peptide relative to the total weight of the composition.

[0116] 7. The composition according to any one of Embodiments 1 to 6, characterized by containing the peptide of Sequence ID No. 50.

[0117] 8. The composition according to Embodiment 7, characterized in that the peptide of Sequence ID No. 50 is acetylated at the N-terminus (CH3-CO-) and / or amidated at the C-terminus (-NH2), preferably acetylated at the N-terminus and amidated at the C-terminus (Ac-Nle-Ala-His-DPhe-Arg-Trp-NH2).

[0118] 9. The composition according to any one of Embodiments 1 to 8, characterized by containing the peptide of Sequence ID No. 51.

[0119] 10. The composition according to Embodiment 9, characterized in that the N-terminus of the peptide of Sequence ID No. 51 contains a palmitoyl group and the C-terminus contains an amide group (-NH2).

[0120] 11. The composition according to any one of Embodiments 1 to 10, characterized by containing a Pro-Pro peptide.

[0121] 12. The composition according to Embodiment 11, characterized in that the N-terminus of the Pro-Pro peptide contains a palmitoyl group (palmitoyl-prolyl-proline).

[0122] 13. The composition according to any one of Embodiments 1 to 12, characterized in that the weight ratio of the MIA inhibitory peptide (a) to the additional peptide (b) is between 1:1 and 100:1, preferably between 2:1 and 50:1.

[0123] 14. The composition according to Embodiment 7 or 8, characterized in that the weight ratio of the MIA inhibitory peptide to the peptide of Sequence ID No. 50 is between 2:1 and 50:1, preferably between 5:1 and 25:1.

[0124] 15. The composition according to Embodiment 9 or 10, characterized in that the weight ratio of the MIA inhibitory peptide to the peptide of Sequence ID No. 51 is between 2:1 and 60:1, preferably between 10:1 and 50:1, and more preferably between 20:1 and 40:1.

[0125] 16. The composition according to Embodiment 11 or 12, characterized in that the weight ratio of the MIA inhibitory peptide to the Pro-Pro peptide is between 1:1 and 10:1, preferably between 2:1 and 5:1.

[0126] 17. The composition according to any one of Embodiments 1 to 16, characterized in that the composition contains snail secretions.

[0127] 18. The composition according to Embodiment 17, characterized in that the amount of snail secretion in the composition is between 0.5% and 15%, preferably between 1% and 10%, more preferably between 2% and 8%, and even more preferably about 5%, where the percentage is expressed as the weight of the snail secretion relative to the total weight of the composition.

[0128] 19. The composition according to any one of Embodiments 1 to 18, characterized in that it is for local administration.

[0129] 20. The composition according to Embodiment 19, characterized in that it is selected from creams, gels, cremigels, lotions, pastes, foams, solutions, suspensions, emulsions, and sticks, preferably selected from creams, gels, and cremigels, and more preferably selected from creams and gels.

[0130] 21. A composition according to any one of Embodiments 1 to 20 for use in the prevention and / or treatment of the vitiligo.

[0131] 22. The composition for use according to Embodiment 21, characterized in that the vitiligo is non-segmental vitiligo.

[0132] 23. Cosmetic and non-therapeutic use of any one of the compositions described in Embodiments 1 to 20 for the re-pigmentation of skin.

[0133] 24. A method for the prevention and / or treatment of vitiligo in a patient in need, comprising the procedure of applying a therapeutically effective amount of the composition described in any one of Embodiments 1 to 20.

[0134] 25. A method for the prevention and / or treatment of vitiligo in a patient in need, comprising the procedure of applying a therapeutically effective amount of the composition described in any one of Embodiments 1 to 20 and the procedure of exposing the treated skin area as phototherapy.

[0135] 26. The method according to Embodiment 25, wherein the phototherapy involves exposure to sunlight or radiation of a specific wavelength, such as UV radiation including UVA and UVB radiation.

[0136] 27. The method according to Embodiment 25 or 26, comprising the additional treatment of administering an antioxidant to the patient.

[0137] 28. The method according to any one of embodiments 24 to 25, wherein the vitiligo is non-segmental vitiligo.

[0138] [Examples] Example 1: In vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) treated with a combination of MIA inhibitory peptide and the peptide of SEQ ID NO: 50. To analyze the re-pigmentation effect, we used a reconstructed epidermal model based on a polycarbonate filter (SkinEthic® RHPE, available from Episkin) on which melanocytes and keratinocytes were added.

[0139] Tissue samples were treated with the test composition for 6 days (days 1-6). After each administration, the samples were incubated at 37°C, and melanin extraction was performed after 6 days of treatment (day 7). Untreated samples were also included in the assay as a control. Cell viability was also evaluated.

[0140] After processing, each sample filter was immersed in 800 μl of Solvable® (Perkin Elmer) and heated overnight at 63°C to extract melanin. The optical density of the supernatant of 300 μl of the extract was measured at 405 nm using synthetic melanin as a reference. Six samples were used for each treatment, and the average value was calculated.

[0141] The test procedure is as follows:

[0142] [Table 1]

[0143] The peptide of SEQ ID NO: 50 used in this assay had its N-terminus acetylated.

[0144] Another similar assay was performed using the same procedure, but the sample was irradiated simultaneously. In this second assay, the sample was irradiated with 300 W / m² of light. 2 , 150 J / m 2 The device was irradiated three times on consecutive days (days 2, 3, and 4 of the assay).

[0145] For each treatment, the increase in the amount of melanin produced compared to the control (0) was calculated. To analyze the possibility of synergistic effects, the experimental increase in melanin in the combined treatment (A+B) was compared to the theoretical increase expected if a simple additive effect was obtained.

[0146] The results are shown below (using the median of 6 samples, SE represents the standard error):

[0147] [Table 2]

[0148] The results shown in the table above are represented in Figure 1, where the gray bars represent experimental results and the black bars represent theoretical results for the combinations.

[0149] The results of the assays irradiated onto the samples are shown in the table below (using the median of 6 samples):

[0150] [Table 3]

[0151] The results shown in the table above are represented in Figure 2, where the gray bars represent experimental results and the black bars represent theoretical results for the combinations.

[0152] In both irradiated and unirradiated assays, a synergistic effect of increased melanin production by the combination of both peptides was observed. This is because the increase obtained by the combination is significantly higher than the increase expected from the sum of the individual effects of the two peptides.

[0153] Example 2: In vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) treated with MIA inhibitory peptide and the peptide of SEQ ID NO: 50 in different ratios. Using the same reconstituted epidermal model, another in vitro repigmentation assay was performed using the same procedure as disclosed in Example 1. In this case, the assay was performed without irradiation.

[0154] The assay used the same peptide combination as in Example 1, as summarized in the table below, but in different weight ratios:

[0155] [Table 4]

[0156] The results are as follows (using the median of 6 samples):

[0157] [Table 5]

[0158] The results of the table above are shown in Figure 3.

[0159] Example 3: In vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) treated with a combination of MIA inhibitory peptide and the peptide of SEQ ID NO: 51. In this example, the same reconstituted epidermal model was used, specifically based on a polycarbonate filter (SkinEthic® RHPE, available from Episkin) on which melanocytes and keratinocytes were added, and the same protocol as disclosed in Example 1 was used.

[0160] The processes tested were as follows:

[0161] [Table 6]

[0162] For each treatment, the increase in melanin production compared to the control (0) was calculated. To analyze the possibility of synergistic effects, the experimental increase in melanin in the combined treatment (A+C) was compared to the theoretical increase expected if a simple additive effect was obtained.

[0163] The results are shown below (using the median of 6 samples):

[0164] [Table 7]

[0165] The results shown in the table above are represented in Figure 4, where the gray bars represent experimental results and the black bars represent theoretical values ​​expected with simple additive effects.

[0166] The synergistic effect of the combination of both peptides, resulting in increased melanin production, was observed again. This is because the increase from the combination was significantly higher than the increase expected from the sum of the effects of both peptides.

[0167] Similar assays using irradiation were also performed, yielding similar results.

[0168] Example 4: In vitro repigmentation assay in reconstituted human pigmented epidermis (RHPE) treated with a combination of MIA inhibitory peptide and Pro-Pro peptide. In this example, the same reconstituted epidermal model was used, specifically based on a polycarbonate filter (SkinEthic® RHPE, available from Episkin) on which melanocytes and keratinocytes were added, and the same protocol as disclosed in Example 1 was used.

[0169] The processes tested were as follows:

[0170] [Table 8]

[0171] In particular, the Pro-Pro peptide used in this assay had a palmitoyl group at its N-terminus, i.e., palmitoyl-prolyl-proline.

[0172] For each treatment, the increase in melanin production compared to the control (0) was calculated. To analyze the possibility of synergistic effects, the experimental increase in melanin in the combined treatment (A+D) was compared to the theoretical increase expected if a simple additive effect were obtained.

[0173] The results are shown below (using the median of 6 samples):

[0174] [Table 9]

[0175] The results shown in the table above are represented in Figure 5, where the gray bars represent experimental results and the black bars represent theoretical values ​​expected with simple additive effects.

[0176] A synergistic effect is again observed in the increase of melanin production by the combination of the two peptides. This is because this combination results in a significantly higher increase in melanin production than would be expected from the sum of the effects of the two peptides.

[0177] Example 5: Preparation of the composition of the present invention Four compositions (A, B, C, and D) according to the present invention were prepared using the components shown in the table below:

[0178] [Table 10]

[0179] The peptide components of the composition (D2, D3a, D3b, and D3c) were added as aqueous solutions or water / glycerin solutions containing approximately 0.1 wt%, 0.02 wt%, 0.002 wt%, and 0.6 wt% of the peptides, respectively.

[0180] To prepare the composition, the first components A1-A6 were heated to approximately 70°C-75°C and thoroughly mixed to obtain the first liquid phase ("Phase A"). Components B1-B8 were mixed separately to form solutions, which were heated to approximately 70°C-75°C. Phase A was added to this solution and emulsified for approximately 3 minutes using an 8000 rpm high-shear Ultra-Turrax mixer, and then the emulsion was stirred for approximately 15 minutes using a 300 rpm blade mixer. Components C1-C3 were added at 60°C, the mixture was cooled to room temperature, and finally components D1, D2, D3a / D3b / D3c and D4 were added. The final pH of the composition was confirmed to be in the range of 5.5-6.5 (otherwise adjusted with 10% citric acid or 10% NaOH). [Brief explanation of the drawing]

[0181] [Figure 1] These are the results of the in vitro re-pigmentation assay in reconstituted human pigmented epidermis (RHPE) described in Example 1. [Figure 2] These are the results of a similar assay, as described in Example 1. [Figure 3] This shows the results of an in vitro re-pigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 3. [Figure 4] These are the results of the in vitro re-pigmentation assay in reconstituted human pigmented epidermis (RHPE) as described in Example 3. [Figure 5] These are the results of the in vitro re-pigmentation assay in reconstituted human pigmented epidermis (RHPE) described in Example 4.

Claims

1. (a) MIA inhibitory peptide of SEQ ID NO: 40, (b) At least one additional peptide selected from the group consisting of the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51, and the Pro-Pro peptide, (c) at least one pharmaceutically acceptable excipient, A composition containing the following:

2. The composition according to claim 1, characterized in that the amount of MIA inhibitory peptide in the composition is between 0.0001% and 1%, preferably between 0.0005% and 0.1%, and more preferably between 0.001% and 0.05%, where the percentage is expressed as the weight of the MIA inhibitory peptide relative to the total weight of the composition.

3. The composition according to claim 1 or 2, characterized by containing the peptide of Sequence ID No.

50.

4. The composition according to any one of claims 1 to 3, characterized by containing the peptide of Sequence ID No.

51.

5. A composition according to any one of claims 1 to 4, characterized by containing a Pro-Pro peptide.

6. The composition according to any one of claims 1 to 5, characterized in that the weight ratio of the MIA inhibitory peptide (a) to the additional peptide (b) is between 1:1 and 100:

1.

7. The composition according to claim 6, characterized in that the weight ratio of the MIA inhibitory peptide (a) to the additional peptide (b) is between 2:1 and 50:

1.

8. The composition according to any one of claims 1 to 7, characterized in that the composition contains snail secretions.

9. The composition according to claim 8, characterized in that the amount of snail secretion in the composition is between 0.5% and 15%, preferably between 1% and 10%, more preferably between 2% and 8%, and even more preferably about 5%, where the percentage is expressed as the weight of the snail secretion relative to the total weight of the composition.

10. The composition according to any one of claims 1 to 9, characterized in that it is for local administration.

11. The composition according to claim 10, characterized in that it is selected from a cream, gel, cremigel, lotion, paste, foam, solution, suspension, emulsion, lotion, and stick.

12. The composition according to claim 11, characterized in that it is selected from a cream, a gel, and a cremigel, and preferably selected from a cream and a gel.

13. A composition according to any one of claims 1 to 12 for use in the prevention and / or treatment of vitiligo.

14. The composition for use according to claim 13, characterized in that the vitiligo is non-segmental vitiligo.

15. Cosmetic and non-therapeutic use of the composition according to any one of claims 1 to 12 for the re-pigmentation of the skin.

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