Composition for recoloring skin

Abstract

The present invention relates to a composition for skin recoloration comprising a peptide inhibitor of MIA (Melanoma Inhibitory Activity) protein, at least one additional peptide and a pharmaceutically acceptable excipient. The invention also relates to application of the composition in prevention and / or treatment of vitiligo. The invention also relates to the cosmetic use of said composition for recoloring the skin.

Description

Technical Field

[0001] The present invention relates to the field of skin repigmentation. Background Art

[0002] Skin depigmentation is a common condition that can affect the skin on different parts of the body to varying degrees and can be caused by a variety of local and systemic conditions.

[0003] Skin depigmentation is commonly associated with patients with vitiligo, a depigmenting skin disorder characterized by the selective loss of melanocytes, resulting in the loss of pigmentation in affected areas of the skin.

[0004] Worldwide, the prevalence of vitiligo in adults and children is estimated to be 0.5-2%. Vitiligo is considered a disease that should not be ignored, and its psychological impact can be devastating, often placing a considerable burden on 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, in which the depigmented patches are usually bilateral and have some form of symmetry.

[0006] Vitiligo most commonly occurs on the face, fingers, backs of hands, flexor wrists, elbows, knees, calves, backs of ankles, armpits, groin area, anogenital area, navel, and nipples.

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

[0008] Common therapies currently available for the treatment of vitiligo include topical corticosteroids, topical calcineurin inhibitors (such as tacrolimus and pimecrolimus), photochemotherapy with psoralen combined with UVA radiation or kaline combined with UVA radiation, narrow-band UVB radiation, oral steroids, immunosuppressants, antioxidants, surgical melanocyte transplantation or depigmentation of remaining pigment islands, etc. (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 protein ("Melanoma Inhibitory Activity") has been considered as another target for vitiligo treatment. In particular, in the international patent application WO-A-2012 / 127352, a number of peptides and peptide derivatives as MIA inhibitors are proposed for the prevention and treatment of vitiligo.

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

[0011] Despite these suggestions in the prior art, there remains a need for more treatment options to effectively repigment the skin. Summary of the Invention

[0012] An object of the present invention is a composition comprising a MIA inhibitor peptide and at least another peptide.

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

[0014] Another aspect of the invention is the cosmetic, non-therapeutic use of said composition for skin repigmentation. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The results of the in vitro repigmentation assay of the reconstructed human pigmented epidermis (RHPE) described in Example 1 are shown. The increase in the amount of melanin produced by each test treatment compared to the control group is shown on the ordinate. On the abscissa, the grey bars show the results of the assay for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), the peptide of SEQ ID NO: 50 (B), and their combination (A + B). For comparison, the black bars represent the theoretical results expected for the A + B combination based on the additive effects obtained with A and B alone.

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

[0017] Figure 3The results of an in vitro repigmentation assay of reconstructed human pigmented epidermis (RHPE) described in Example 3 are shown, wherein samples were treated with a combination of the MIA inhibitor peptide of SEQ ID NO: 40 (A) and the peptide of SEQ ID NO: 50 (B) at varying weight ratios. The ordinate shows the increase in the amount of melanin produced by each test treatment compared to the control group. The abscissa shows the different tested combinations of A+B. The first column represents a 7.5:1 weight ratio of A:B, the second column represents an 11.2:1 weight ratio of A:B, and the third column represents a 22:1 weight ratio of A:B.

[0018] Figure 4 The results of the in vitro re-pigmentation test of reconstructed human pigmented epidermis (RHPE) described in Example 3 are shown. The increase in the amount of melanin produced by each test treatment compared to the control group is shown on the ordinate. On the abscissa, the grey bars show the results of the assay for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), the peptide of SEQ ID NO: 51 (C), and their combination (A + C). For comparison, the black bars represent the theoretical results expected for the A + C combination based on the additive effects obtained with A and C alone.

[0019] Figure 5 The results of the in vitro re-pigmentation test of reconstructed human pigmented epidermis (RHPE) described in Example 4 are shown. The increase in the amount of melanin produced by each test treatment compared to the control group is shown on the ordinate. On the abscissa, the grey bars show the results of the assay for samples treated with the MIA inhibitor peptide of SEQ ID NO: 40 (A), the peptide Pro-Pro (D), and their combination (A+D). For comparison, the black bars represent the theoretical results expected for the A+D combination based on the addition of the effects obtained with A and D alone. DETAILED DESCRIPTION

[0020] The object of the present invention is a composition comprising:

[0021] (a) an MIA inhibitor peptide of SEQ ID NO: 40;

[0022] (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 peptide Pro-Pro; and

[0023] (c) at least one pharmaceutically acceptable excipient.

[0024] The composition is particularly suitable for skin repigmentation. The authors of the present invention have discovered that when the MIA inhibitor peptide of SEQ ID NO:40 is combined with at least one other peptide selected from SEQ ID NO:50, SEQ ID NO:51, and Pro-Pro, there is a significant synergistic effect in skin repigmentation. The superior repigmentation effect achieved by this combination can improve the treatment of vitiligo compared to treatments available in the prior art.

[0025] In this specification and claims, unless the context clearly indicates otherwise, singular expressions beginning with "a," "an," or "the" are generally intended to include the plural form. Unless otherwise specifically indicated, all percentages are expressed by weight. A numerical value preceded by the term "about" is also intended to include a certain variation around that value, i.e., ±5% of the variation or the amount. A numerical range defined by a lower limit and an upper limit is intended to include the stated endpoints and any narrower subranges.

[0026] Amino acids are represented herein using either the single-letter or three-letter codes in accordance with the IUPAC-IUB Biochemical Nomenclature Commission, as is well known to those skilled in the art, as described in Biochemical Nomenclature and Related Documents, 2nd edition, Portland Press, London, 1992 [ISBN 1-85578-005-4]. According to this nomenclature, peptides herein are designated by the N-terminus on the left side of the formula and by the C-terminus on the right side of the formula. Certain specific non-proteinogenic amino acids are designated herein as follows: D-phenylalanine is designated as DPhe, and norleucine is designated as Nle.

[0027] MIA inhibitor peptides

[0028] The MIA inhibitor peptide is a peptide having activity as an inhibitor of human melanoma inhibitory activity (MIA) protein.

[0029] The sequence of the MIA inhibitor peptide of SEQ ID NO: 40 contained in the composition of the present invention is as follows:

[0030] -SEQ ID NO:40FHWRYPLPLPGQ

[0031] This and other MIA inhibitor peptides are disclosed in International Patent Application WO-A-2012 / 127352, namely peptides having the sequences SEQ ID NO: 1 to SEQ ID NO: 49:

[0032] -SEQ ID NO:01 VPHIPPN

[0033] -SEQ ID NO:02 MPPTQVS

[0034] -SEQ ID NO:03 QMHPWPP

[0035] -SEQ ID NO:04 QPPFWQF

[0036] -SEQ ID NO:05 TPPQGLA

[0037] -SEQ ID NO:06 IPPYNTL

[0038] -SEQ ID NO:07 AVRPAPL

[0039] -SEQ ID NO:08 GAKPHPQ

[0040] -SEQ ID NO:09 QQLSPLP

[0041] -SEQ ID NO:10 GPPPSPV

[0042] -SEQ ID NO:11 LPLTPLP

[0043] -SEQ ID NO:12 QLNVNHQARADQ

[0044] -SEQ ID NO:13 TSASTRPELHYP

[0045] -SEQ ID NO:14 TFLPHQMHPWPP

[0046] -SEQ ID NO:15 VPHIPPNSMALT

[0047] -SEQ ID NO:16 RLTLLVLIMPAP

[0048] -SEQ ID NO:17 YNLPKVSSNLSP

[0049] -SEQ ID NO:18 MPPTQVSKFRLI

[0050] -SEQ ID NO:19 ANIDATPLFLRA

[0051] -SEQ ID NO:20 LLRTTETLPMFL

[0052] -SEQ ID NO:21 SALEPLV

[0053] -SEQ ID NO:22 GSPTPNA

[0054] -SEQ ID NO:23 APSHATH

[0055] -SEQ ID NO:24 TTVGHSD

[0056] -SEQ ID NO:25 THFSTFT

[0057] -SEQ ID NO:26 SLLLDTS

[0058] -SEQ ID NO:27 SVAMKAHKPLLP

[0059] -SEQ ID NO:28 NTIPGFASKSLD

[0060] -SEQ ID NO:29 VSNYKFYSTTSS

[0061] -SEQ ID NO:30 VSRHQSWHPHDL

[0062] -SEQ ID NO:31 HLNILSTLWKYR

[0063] -SEQ ID NO:32 HNASPSWGSPVM

[0064] -SEQ ID NO:33 SHPWNAQRELSV

[0065] -SEQ ID NO:34 HHWPFWRTLPLS

[0066] -SEQ ID NO:35 WHTKFLPRYLPS

[0067] -SEQ ID NO:36 NNTSFTVVPSVP

[0068] -SEQ ID NO:37 SHLSTWKWWQNR

[0069] -SEQ ID NO:38 FHWHPRLWPLPS

[0070] -SEQ ID NO:39 WHWTYGWRPPAM

[0071] -SEQ ID NO:40 FHWRYPLPLPGQ

[0072] -SEQ ID NO:41 WHWPLFIPNTTA

[0073] -SEQ ID NO:42 WHNGIWWHYGVR

[0074] -SEQ ID NO:43 HHLNYLWPWTRV

[0075] -SEQ ID NO:44 FWHRWSTFPEQP

[0076] -SEQ ID NO:45 WHMSYFWTRPPQ

[0077] -SEQ ID NO:46 FHLNWPSRADYL

[0078] -SEQ ID NO:47 WHKNTNWPWRTL

[0079] -SEQ ID NO:48 ALSPSQSHPVRS

[0080] -SEQ ID NO:49 GTQSTAIPAPTD

[0081] Within the meaning of the present invention, the MIA inhibitor peptide of sequence SEQ ID NO: 40 may optionally be acetylated (CH3-CO-) at the N-terminus and / or amidated at the C-terminus.

[0082] C-terminal amidation involves the formation of a terminal amide group of the formula -CONH2, -CONHR or -CONR2, where R is typically a short (e.g., C1-C4) alkyl group. The simplest and most common C-terminal amino group is -CO-NH2.

[0083] In one embodiment, the MIA inhibitor peptide of sequence SEQ ID NO: 40 is acetylated at the N-terminus and amidated at the C-terminus.

[0084] In another embodiment, the MIA inhibitor peptide of SEQ ID NO: 40 is neither acetylated nor amidated.

[0085] MIA inhibitor peptides can be prepared according to standard methods in peptide synthesis, typically by solid phase synthesis, or can be obtained commercially from a variety of sources.

[0086] In addition to the MIA inhibitor peptide of SEQ ID NO: 40, the composition of the present invention may further comprise one or more additional MIA inhibitory peptides, for example selected from the group consisting of SEQ ID NOs: 1-39 and SEQ ID NOs: 41-49.

[0087] In a preferred embodiment, the composition of the present invention comprises the peptide of SEQ ID NO: 40 as the only MIA inhibitor peptide in the composition.

[0088] The terms "MIA inhibitor peptide" and "MIA inhibitor" are used interchangeably herein to refer to the MIA inhibitor peptide of SEQ ID NO:40, unless the context indicates otherwise.

[0089] MIA inhibitory activity can be tested using standard methods, for example, a ligand binding assay using recombinant human MIA, as described in 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 as 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.

[0090] The MIA inhibitor peptide can be added to the composition as is, or can be encapsulated in different polymer materials, or combined with different carrier substances to improve its transdermal delivery through the stratum corneum to reach the target MIA protein in vitiligo melanocytes, which are located in the bottom layer of the epidermis, i.e., the basal layer, and are attached to the basement membrane.

[0091] Encapsulation techniques are known in the art for the delivery of active ingredients.

[0092] In one embodiment, the MIA inhibitor peptide is microencapsulated using liposome technology.

[0093] Liposomes are commonly used in skin preparations to improve the permeability of active substances through the skin layer. As is well known in the art, liposomes are spherical vesicles, typically between about 60nm and 300nm in size, most commonly consisting of phospholipids forming at least one phospholipid bilayer, but may also include other lipids. Liposomes contain a hydrophilic core, in which hydrophilic active substances can be encapsulated, while hydrophobic active substances are incorporated into the bilayer, so liposomes are suitable carriers for hydrophilic and lipophilic active substances (Knoth et al., Nanocarrier-Based Formulations:Production and Cosmeceutic Applications, in: Cosmetic Formulation.Principles and Practice, Benson HAE, Roberts MS, Rodrigues Leite-Silva V. and Walters KA, editors, CRC Press, 2019). Liposomes can be prepared by well-known techniques; generally, the preparation method includes mixing film-forming lipids in an organic phase, drying, then hydrating the lipids, and further reducing the size by different mechanical treatments (such as ultrasonic treatment, extrusion or homogenization).

[0094] In another embodiment, the MIA inhibitor is encapsulated in microcapsules or nanocapsules made of biodegradable polymers, as are known in the art, for example, as disclosed for the delivery of peptides of sequences 1 to 49 (WO-A-03 / 064457, supra), including polyesters, polyamino acids, polyalkyl cyanoacrylates, polyphosphazenes or polyethylene oxides. Common polymers used for encapsulation are, for example, polyvinyl alcohol (PVA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) or block copolymers thereof with polyethylene oxide or polyethylene glycol. Other suitable biodegradable polymers are poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG)] block copolymers, polyanhydrides-poly(fumaric acid-co-sebacic acid) anhydrides, alginate, dextran, chitosan, hydroxyapatite, collagen, fibrin, hyaluronic acid, carbomer and mixtures thereof.

[0095] In another embodiment, the MIA inhibitor peptide is conjugated to nanoparticles, ie, lipid nanoparticles, polymer nanoparticles, magnetic nanoparticles or metal nanoparticles, which can serve as carriers to facilitate the penetration of the MIA inhibitor into the stratum corneum.

[0096] In a specific embodiment, the MIA inhibitor peptide is combined with gold nanoparticles, which are described as improving skin penetration (Gupta et al., J. Phys. Chem. B, 2016, 7133-7142). These nanoparticles have a gold core coated with the MIA inhibitor peptide. The MIA inhibitor peptide is typically bound to the gold nanoparticles through an electrostatic ionic bond between the negative charge on the surface of the gold nanoparticle and the positive charge of the amino acid (lysine, arginine, histidine, asparagine or glutamine) of the peptide carrying an amino group in the side chain. The size of the gold nanoparticles is less than 1000 nm, preferably 50 nm to 200 nm. For example, as disclosed in international patent application WO-A-2019 / 185696, the conjugate can be prepared by reducing Au (III) to Au (0) with a reducing agent and treating the obtained gold nanoparticles with the MIA inhibitor peptide.

[0097] As described above, if the MIA inhibitor peptide of SEQ ID: 40 is added in free form or encapsulated or bound to a carrier, its amount in the composition of the present invention is generally 0.0001% to 1%, preferably 0.0005% to 0.1%, more preferably 0.001% to 0.05%, wherein the percentages are expressed as the weight of the MIA inhibitor peptide of SEQ ID: 40 relative to the total weight of the composition.

[0098] Additional peptide

[0099] The additional peptide (b) that binds to the MIA inhibitor peptide of SEQ ID NO: 40 is selected from the group consisting of:

[0100] - a peptide of SEQ ID NO: 50,

[0101] - a peptide of SEQ ID NO: 51, and

[0102] -Peptide Pro-Pro;

[0103] in:

[0104] -SEQ ID NO: 50 is Nle-Ala-His-DPhe-Arg-Trp

[0105] - SEQ ID NO: 51 is His-DPhe-Arg-Trp.

[0106] For example, the peptide of SEQ ID NO: 50 is disclosed in International Patent Application WO-A-03 / 64458 for its melanin-stimulating, anti-inflammatory and / or anti-allergic uses.

[0107] Within the meaning of the present invention, the peptide of SEQ IDE NO: 50 may optionally be acetylated at the N-terminus (CH3-CO-) and / or amidated at the C-terminus (-NH2).

[0108] In one embodiment, the peptide of SEQ ID NO: 50 includes an acetyl group at the N-terminus and an amide group (—NH 2 ) at the C-terminus and can be represented as Ac-Nle-Ala-His-DPhe-Arg-Trp-NH 2 .

[0109] As in Example 1 (and Figure 1 and Figure 2 ), in an in vitro assay using reconstructed human pigmented epidermis, the combination of a MIA inhibitor peptide (SEQ ID NO: 40) and a peptide of SEQ ID NO: 50 resulted in a significant increase in melanin production. The combination of the two peptides provided a synergistic effect, as the increase in melanin production was significantly greater than would be expected from the addition of a single peptide alone.

[0110] The peptide of SEQ ID NO: 51 is a melanocortin agonist as described in Holder et al., J. Med. Chem., 2002, 45(13), 2801-2810.

[0111] Within the meaning of the present invention, the peptide of SEQ ID NO: 51 may include an N-terminal lipidation, ie, the addition of a saturated or unsaturated C 12 -C 18 Fatty acids, such as myristic acid or palmitic acid; and / or can be amidated (-NH2) at the C-terminus. In one embodiment, the N-terminus of SEQ ID NO:51 includes a palmitoyl group and the C-terminus includes an amide group (-NH2).

[0112] As in Example 3 (and Figure 4 ), in an in vitro assay using reconstructed human pigmented epidermis, the combination of the MIA inhibitor peptide of SEQ ID NO: 40 and the peptide of SEQ ID NO: 51 resulted in a significant increase in melanin production, which was significantly higher than the expected effect of adding only a single peptide.

[0113] The peptide Pro-Pro is a pro-pigmenting peptide disclosed, for example, in the international patent application WO-A-2014 / 080376.

[0114] Within the meaning of the present invention, the peptide Pro-Pro may include an N-terminal lipidation, ie the addition of a saturated or unsaturated C 12 -C 18Fatty acids, such as myristic acid or palmitic acid; and / or an amide group (-NH2) is added at the C-terminus. In one embodiment, the N-terminus of the peptide Pro-Pro includes a palmitoyl group, and it can be represented as CH3-(CH2) 14 CO-Pro-Pro (palmitoyl-prolyl-proline).

[0115] As in Example 4 (and Figure 5 ), in in vitro experiments with reconstructed human pigmented epidermis, the combination of the MIA inhibitor peptide of SEQ ID NO: 40 and the peptide Pro-Pro resulted in a significant increase in melanin production, which was significantly higher than expected from the addition of only a single peptide.

[0116] In one embodiment, the MIA inhibitor peptide is combined with the peptide of SEQ ID NO:50.

[0117] In one embodiment, the MIA inhibitor peptide is combined with the peptide of SEQ ID NO:51.

[0118] In one embodiment, the MIA inhibitor peptide is combined with the peptide Pro-Pro.

[0119] In one embodiment, the MIA inhibitor 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 peptide Pro-Pro.

[0120] In one embodiment, the MIA inhibitor peptide is combined with the peptide of SEQ ID NO: 50, the peptide of SEQ ID NO: 51 and the peptide Pro-Pro.

[0121] The weight ratio of the MIA inhibitor peptide (a) of SEQ ID NO: 40 to the additional peptide (b) in the composition of the present invention is 1:1 to 100:1, preferably 2:1 to 50:1, wherein the additional peptide (b) is the peptide of SEQ ID NO: 50 or the peptide of SEQ ID NO: 51 or the peptide Pro-Pro.

[0122] When more than one additional peptide of SEQ ID NO:50, SEQ ID NO:51 or Pro-Pro is added to the composition, the weight ratio is related to the individual weight ratios of the MIA inhibitor peptide of SEQ ID NO:40 to each additional peptide.

[0123] When the composition of the present invention comprises the peptide of SEQ ID NO: 50, the weight ratio of the MIA inhibitor peptide to the peptide of SEQ ID NO: 50 is preferably 2:1 to 50:1, more preferably 5:1 to 25:1.

[0124] When the composition of the present invention comprises the peptide of SEQ ID NO: 51, the weight ratio of the MIA inhibitor peptide to the peptide of SEQ ID NO: 51 is preferably 2:1 to 60:1, more preferably 10:1 to 50:1, and even more preferably 20:1 to 40:1.

[0125] When the composition of the present invention comprises the peptide Pro-Pro, the weight ratio of the MIA inhibitor peptide to the peptide Pro-Pro is preferably from 1:1 to 10:1, more preferably from 2:1 to 5:1.

[0126] Optional additional ingredients

[0127] Optionally, the compositions of the present invention may contain snail secretions as an additional active ingredient.

[0128] Snail secretion, also known as snail mucus, is a mucus or body secretion produced by snails (gastropods) through glands in the foot of the gastropod. This mucus is composed of water and a complex mixture of substances, including proteoglycans, glycosaminoglycans, glycoproteins, hyaluronic acid, copper peptides, antimicrobial peptides and metal ions; the main components are allantoin, collagen, elastin and glycolic acid (Cillia et al., Antimicrobial properties of terrestrial snail and slugmucus, J. Complement. Integr. Med., 2018, 15(3)).

[0129] Such secretions can be collected and recovered from live snails, for example as disclosed in US Pat. No. 5,538,740 or US Patent Application No. US-A-2018 / 0064635. Generally, after subjecting the gastropod to certain stress conditions, the secretions are collected and filtered.

[0130] Snail secretions are usually in liquid form, with a pH value usually in the range of 5-8, a density usually in the range of about 1.0 to about 1.1 mg / ml, a dry residue usually in the range of 0.1% to 3%, preferably 0.2% to 2%, more preferably 0.25% to 1%, and even more preferably 0.3% to 0.7%. The protein content is usually in the range of 0.1-3 mg / ml.

[0131] Snail secretions are commercially available from various sources, for example, Cobiosa (Spain) (sold as the product Poly Helixan PF) or CENTISIALaboratorio di Fitocosmesi di Bruno Dott.ssa Laura Francesca & C.sas (Italy) (sold as Prodotto 580038).

[0132] The secretion can be obtained from different species of gastropods, including Achatinafulica, Cornu aspersum (also Helix aspersa, Cryptomphalusaspersa or Cantareus aspersus), Helix pomatia, Helix hortensis, Helix nemoralis, Helix cardidula, Helix tchthyomma, Helix fructicicola, Helix strigella, Helix fruticum, Helix bidens, Helix arbostorum, Helix rotundata, Helix aculeata, Helix pulchella, Helix personata, Helix holoserica, Helix aperta, Helix parnassia, Helix alonensis, Helix candidissima, Helix pisana or Helix gualteviana. In a specific embodiment, the snail secretion is obtained from Cornu aspersum, also known as Helix aspersa, Cryptomphalus aspersa, or Cantareus aspersus.

[0133] Medicinal and cosmetic uses of snail secretions have been disclosed in the prior art, for example as an antimicrobial agent, for wound repair, for skin protection or as an anti-aging agent.

[0134] The combined use of MIA inhibitor peptides and snail secretions is disclosed in International Patent Application WO-A-2022 / 008251.

[0135] The amount of snail secretions (if present) in the compositions of the present invention is generally from 0.5% to 15%, preferably from 1% to 10%, more preferably from 2% to 8%, still more preferably about 5%, wherein the percentages are expressed as the weight of the snail secretions relative to the total weight of the composition.

[0136] Composition

[0137] The compositions of the present invention comprise at least one pharmaceutically acceptable excipient.

[0138] The term "pharmaceutically acceptable excipient" refers to an ingredient in a pharmaceutical or cosmetic composition that is not an active ingredient, is useful in preparing the composition, and is generally safe and non-toxic for human pharmaceutical or cosmetic use. In particular, the compositions of the present invention are generally intended for external use, applied topically to the affected area of ​​skin, and thus a pharmaceutically acceptable excipient is "dermatologically acceptable," meaning that it is suitable for use in contact with human skin tissue and is non-toxic.

[0139] In one embodiment, the composition of the present invention is for topical application, i.e., it is spread on the skin in the area to be treated, i.e., in an area showing depigmentation, typically vitiligo depigmentation, or prone to showing depigmentation. Topical, skin or skin application are used interchangeably herein.

[0140] Any type of formulation suitable for topical administration can be used. Typically, the compositions of the present invention are in the form of creams, gels, jelly emulsions, lotions, pastes, foams, solutions, suspensions, emulsions, milks, or stick formulations, for example, as are well known in the art. For example, jelly emulsions are a formulation between creams and gels: unlike creams, jelly emulsions are aqueous gel solutions or oily gel solutions, but they appear opaque like creams and are typically white.

[0141] Suitable carriers can be, for example, anhydrous, such as fats, waxes, animal and vegetable oils and mixtures of solid and liquid hydrocarbons. Or carriers can be the aqueous solution of water or hydrophilic substances. Suitably, carriers can be in the form of emulsions. Emulsions can generally be oil-in-water emulsions, water-in-oil emulsions, water-in-oil-in-water emulsions, oil-in-water-in-oil emulsions or water-in-silicone oil emulsions. Emulsions can generally be described as having continuous aqueous phase (oil-in-water and water-in-oil-in-water) or continuous oil phase (water-in-oil and oil-in-water-in-oil). The oil phase can include silicone oil, non-silicone oil, such as paraffin hydrocarbons, fatty alcohols (such as stearyl alcohol, cetyl alcohol or cetearyl alcohol), fatty acids (such as stearic acid, oleic acid), fatty acid esters (such as isopropyl myristate, isopropyl palmitate), waxes or vegetable oils (such as castor oil, rapeseed oil, cottonseed oil, jojoba oil or peanut oil), or its mixture. The aqueous phase may include water or an aqueous solution of a hydrophilic substance, such as an alcohol (eg ethanol, isopropanol), a polyol (eg glycerol, sorbitol), an α-hydroxy acid, an amino acid, a protein hydrolyzate, a monosaccharide or a polysaccharide.

[0142] Emulsifier is a surface-active agent (surfactant), is a common component of emulsion, including nonionic surfactants, anionic surfactants, cationic surfactants and amphoteric surfactants. Nonionic surfactants include ethoxylated fatty alcohols, ethoxylated fatty acid esters, alkyl glycosides or alkyl oligodextrose, ethoxylated sorbitol fatty acid esters, monoglycerol / polyglycerol fatty acid esters, ethoxylated monoglycerides, ethoxylated polyglycerol esters, alkyl dimethylamine oxide or poloxamer etc. Anionic surfactants include alkaline soaps, alkyl sulfates, alkyl ether sulfates, alkyl sulfosuccinates, alkyl phosphates, acyl sarcosinates or acyl isethionates etc. Cationic surfactants include quaternary ammonium salts or pyridinium salts etc. Amphoteric surfactants include imidazoline derivatives, betaines, amidobetaines and sulfobetaines.

[0143] Other common ingredients in formulations include, for example, emollients, humectants, preservatives, viscosity control agents, antioxidants, pH adjusters, UV filters, chelating agents, fragrances, and colorants. Common emollients include paraffins, silicones, fatty alcohols, fatty acids, fatty acid-alcohol esters, triglycerides, ceramides, phospholipids, and waxes. Humectants 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 control the viscosity of the formulation, such as xanthan gum, gellan gum, gum arabic, carrageenan, chitosan, collagen, tragacanth gum, pectin, starch derivatives, carbomer, cellulose derivatives (such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose or carboxymethyl cellulose), polyamide, glutamine, colloidal silicon dioxide or wax (such as beeswax or vegetable wax) and the like.

[0144] Some components of the composition can act as penetration enhancers to promote the penetration of the active ingredient throughout the stratum corneum. Common penetration enhancers are, for example, short-chain alcohols such as ethanol or isopropanol; 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, phthalates, ethyl oleate, glyceryl monooleate, monocaprylin, tricaprylin, isopropyl myristate, isopropyl palmitate, propylene glycol monolaurate or propylene glycol monocaprylate; ether alcohols such as 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-butanediol or 1,3-butanediol; pyrrolidone, such as N-methyl-2-pyrrolidone or 2-pyrrolidone; sulfoxides, such as decylmethylsulfoxide or dimethylsulfoxide; anionic surfactants; cationic surfactants; nonionic surfactants; terpenes, such as eugenol D-limonene, menthol, menthone, farnesol or nerol (for example, as disclosed in Lane ME, Skin penetration enhancers, Int. J. Pharm., 2013, 447, 12-21 or Haque et al., Chemical enhancer: a simplified way to modulate barrier function of the stratum corneum, Adv. Pharm. Bull., 2018, 8(2), 169-179).

[0145] The compositions of the present invention typically have a slightly acidic pH close to the physiological pH of the skin. Common acidity regulators are organic acids, including hydroxy acids and fatty acids. Some of the most common pH regulators in cosmetic emulsions are hydroxy acids, such as lactic acid or citric acid.

[0146] A single excipient can perform multiple functions. The above ingredients, as well as many other suitable excipients for dermatological preparations, are well known to the skilled formulator of topical compositions. These ingredients are commercially available from companies such as Comercial Química Massó, SA, Evonik, DuPont, or Dow Corning.

[0147] Preparation of the topical compositions is carried out according to procedures well known to those skilled in the art of formulating dermatological compositions and generally involves the simple steps of mixing and optionally heating the component ingredients.

[0148] For example, a cream can generally be prepared by heating an oil phase and an aqueous phase separately to a temperature of about 60 to 80° C., and then mixing under stirring to prepare an emulsion.

[0149] For example, Cosmetic Formulation. Principles and Practice, edited by Benson HAE, Roberts MS, Rodrigues Leite-Silva V., and Walters KA, CRC Press, 2019, or other similar reference books, which describe the main components of the composition and their preparation methods. In addition, the European Commission database "CosIng" discloses regulated cosmetic substances and ingredients (https: / / ec.europa.eu / growth / tools-databases / cosing).

[0150] 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 inhibitor peptide, additional peptide and snail secretion (if present) are added and mixed thoroughly, and finally the pH of the composition is adjusted.

[0151] Use of the composition

[0152] As shown in the in vitro repigmentation assays of the Examples, the combination of the MIA inhibitor peptide and the additional peptide described above is very effective in repigmenting the skin.

[0153] Therefore, another aspect of the present invention is a composition of the present invention for use in preventing and / or treating vitiligo.

[0154] Another aspect of the present invention is a method for preventing and / or treating vitiligo in a patient in need thereof, comprising the step of administering a therapeutically effective amount of a composition of the present invention.

[0155] The compositions of the present invention may also be used for cosmetic, non-therapeutic re-pigmentation of small areas of depigmented, whitened skin that may not be specifically defined as having vitiligo.

[0156] Therefore, another aspect of the present invention is the cosmetic, non-therapeutic use of the compositions according to the invention for skin repigmentation.

[0157] Another aspect of the present invention is a method of repigmenting skin in a subject in need thereof, comprising the step of applying an effective amount of a composition of the present invention.

[0158] The cosmetic use of skin repigmentation is understood as a process aimed at partially or completely restoring the normal pigmentation of depigmented or hypopigmented skin patches in human subjects.

[0159] Similarly, treatment of vitiligo is understood as a process aimed at ameliorating the symptoms of vitiligo, i.e., partially or completely restoring normal pigmentation to depigmented or hypopigmented skin patches in human subjects.

[0160] In one embodiment, the prevention and / or treatment of vitiligo relates to the prevention or treatment of non-segmental vitiligo.

[0161] Vitiligo prevention aims to prevent the onset of vitiligo symptoms in subjects known to be susceptible to vitiligo who have either been diagnosed early, before symptoms develop, for example by testing for the presence of MIA protein in melanocytes, or who have a known genetic predisposition to the disease. Vitiligo prevention also includes treating patients who have previously recovered from vitiligo, i.e., those who have achieved re-pigmentation of the skin depigmented by vitiligo, to prevent the recurrence of vitiligo symptoms.

[0162] Typically, the composition of the invention is applied topically, ie, it is spread over the vitiligo or depigmented skin patches.

[0163] In one embodiment, the compositions of the present invention can be delivered transdermally, for example by iontophoresis, ultrasound, or using microneedles (Escobar-Chávez et al. Microneedles: a valuable physical enhancer to increase transdermal drug delivery, J. Clin. Pharmacol., 2011, 51(7), 964-977).

[0164] The amount of the composition that is considered "effective" for treating or preventing vitiligo or for cosmetic, non-therapeutic skin repigmentation may vary depending on many factors, such as the severity and stage of progression of the depigmentation condition, or the specific formulation used. The skilled artisan can readily adjust the amount in each case. Typically, the amount of topical composition applied to the affected skin may be about 1 mg / cm2 of skin surface area. 2 ) from about 0.1 mg of the composition to about 100 mg, preferably about 5 mg / cm 2 to about 10 mg / cm 2 .

[0165] The composition of the present invention can be topically applied once or multiple times per day, for example twice, three times or four times per day. The composition is usually applied by spreading it on the skin, usually only to the affected skin area. The duration of treatment can be adjusted according to the evolution of pigmentation. Usually, treatment can last for several weeks, for example 1, 2, 3 or 4 weeks, or several months, for example 1 to 12 months, or even longer, depending on the severity of the depigmentation symptoms and the development of the disease. A skilled person can easily adjust the duration of treatment.

[0166] Advantageously, treatment with the composition of the invention may be combined with phototherapy, for example by simple sun exposure or the use of a tanning bed, to stimulate the formation and migration of melanocytes and thus promote re-pigmentation.

[0167] Therefore, another aspect of the present invention is a method for preventing and / or treating vitiligo in a patient in need thereof, comprising the steps of administering a therapeutically effective amount of a composition of the present invention and exposing the treated skin area to phototherapy.

[0168] As used herein, the term "light therapy" or "phototherapy" includes exposure to sunlight or radiation of specific wavelengths, such as ultraviolet radiation, including UVA and UVB radiation. Thus, "light therapy" can be performed by simply exposing yourself to sunlight, or using a tanning bed, or using a radiation-emitting device, particularly an ultraviolet-emitting device.

[0169] The duration of phototherapy is not critical and can vary, for example, from about 2 minutes to about 2 hours per day, or every other day, or two or three times per week, among other suitable options.

[0170] Vitiligo, or general skin depigmentation, can affect any part of the skin, so the composition can be applied to any area of ​​affected (depigmented) skin. The skin areas most commonly affected, and therefore more in need of treatment, are the hands and face, around body openings (eyes, nostrils, mouth, navel, and genital area), and in body folds such as the underarms and groin.

[0171] In one embodiment, the use of the compositions of the present invention for the treatment of skin depigmentation, in particular vitiligo, may be combined with the use of antioxidants, in particular when this therapy is combined with phototherapy, to reduce possible negative effects of radiation exposure.

[0172] Antioxidants are generally taken orally. Suitable antioxidants include vitamin E, vitamin C, carotenoids (such as lycopene), beta-carotene, alpha-carotene, green tea extract, zinc, selenium, leukocyte polysaccharide extract, etc., or a combination thereof.

[0173] They can be formulated as dietary oral supplements, typically as tablets, powders or capsules, for example, using standard excipients and manufacturing techniques known in the art.

[0174] Another aspect of the present invention is also a method for preventing and / or treating vitiligo in a patient in need thereof, comprising the steps of administering a therapeutically effective amount of a composition of the present invention, exposing the treated skin area to phototherapy, and administering an antioxidant to the patient.

[0175] The present invention can be defined according to the following embodiments:

[0176] 1. A composition comprising:

[0177] (a) an MIA inhibitor peptide of SEQ ID NO: 40;

[0178] (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 peptide Pro-Pro; and

[0179] (c) at least one pharmaceutically acceptable excipient.

[0180] 2. The composition according to embodiment 1, characterized in that the MIA inhibitor 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.

[0181] 3. The composition according to embodiment 2, characterized in that the C-terminal amide group is selected from -CONH2, -CONHR and -CONR2, wherein R is C1-C4 alkyl, preferably -CO-NH2.

[0182] 4. The composition according to embodiment 1, characterized in that the MIA inhibitor peptide of SEQ ID NO: 40 is neither acetylated nor amidated.

[0183] 5. The composition according to any one of embodiments 1 to 4, characterized in that the MIA inhibitor peptide is encapsulated or bound to carrier nanoparticles.

[0184] 6. A composition according to any one of embodiments 1 to 5, characterized in that the amount of MIA inhibitor peptide in the composition is 0.0001% to 1%, preferably 0.0005% to 0.1%, more preferably 0.001% to 0.05%, wherein the percentages are expressed as the weight of the MIA inhibitor polypeptide relative to the total weight of the composition.

[0185] 7. The composition according to any one of embodiments 1 to 6, characterized in that it comprises the peptide of SEQ ID NO: 50.

[0186] 8. A composition according to embodiment 7, characterized in that the peptide of SEQ 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).

[0187] 9. The composition according to any one of embodiments 1 to 8, characterized in that it comprises the peptide of SEQ ID NO: 51.

[0188] 10. The composition according to embodiment 9, characterized in that the N-terminus of the peptide of SEQ ID NO: 51 includes a palmitoyl group and the C-terminus includes an amide group (-NH2).

[0189] 11. Composition according to any one of embodiments 1 to 10, characterized in that it comprises the peptide Pro-Pro.

[0190] 12. The composition according to embodiment 11, characterized in that the N-terminus of the peptide Pro-Pro comprises a palmitoyl group (palmitoyl-prolyl-proline).

[0191] 13. The composition according to any one of embodiments 1 to 12, characterized in that the weight ratio of the MIA inhibitor peptide (a) to the additional peptide (b) is 1:1 to 100:1, preferably 2:1 to 50:1.

[0192] 14. The composition according to embodiment 7 or 8, characterized in that the weight ratio of the MIA inhibitor peptide (a) to the peptide of SEQ ID NO: 50 is 2:1 to 50:1, preferably 5:1 to 25:1.

[0193] 15. The composition according to embodiment 9 or 10, characterized in that the weight ratio of the MIA inhibitor peptide (a) to the peptide of SEQ ID NO: 51 is 2:1 to 60:1, preferably 10:1 to 50:1, more preferably 20:1 to 40:1.

[0194] 16. The composition according to embodiment 11 or 12, characterized in that the weight ratio of the MIA inhibitor peptide (a) to the peptide Pro-Pro is 1:1 to 10:1, preferably 2:1 to 5:1.

[0195] 17. The composition according to any one of embodiments 1 to 16, characterized in that the composition comprises snail secretions.

[0196] 18. The composition according to embodiment 17, characterized in that the amount of snail secretions in the composition is 0.5% to 15%, preferably 1% to 10%, more preferably 2% to 8%, and even more preferably about 5%, wherein the percentages are expressed as the weight of snail secretions relative to the total weight of the composition.

[0197] 19. The composition according to any one of embodiments 1 to 18, characterized in that it is for topical administration.

[0198] 20. The composition according to embodiment 19, characterized in that it is selected from creams, gels, jelly emulsions, lotions, pastes, foams, solutions, suspensions, emulsions, milks or stick preparations, preferably selected from creams, gels and jelly emulsions, more preferably selected from creams and gels.

[0199] 21. The composition according to any one of embodiments 1 to 20, for use in preventing and / or treating vitiligo.

[0200] 22. The composition for use according to embodiment 21, wherein the vitiligo is non-segmental vitiligo.

[0201] 23. Cosmetic non-therapeutic use of the composition according to any one of embodiments 1 to 20 for skin repigmentation.

[0202] 24. A method for preventing and / or treating vitiligo in a patient in need thereof, comprising the step of administering a therapeutically effective amount of the composition of any one of embodiments 1 to 20.

[0203] 25. A method for preventing and / or treating vitiligo in a patient in need thereof, comprising the steps of administering a therapeutically effective amount of the composition of any one of embodiments 1 to 20 and exposing the treated skin area to phototherapy.

[0204] 26. The method of embodiment 25, wherein the light therapy comprises exposure to sunlight or radiation of a specific wavelength, such as UV radiation, including UVA and UVB radiation.

[0205] 27. The method of embodiment 25 or 26, wherein the method comprises the additional step of administering an antioxidant to the patient.

[0206] 28. The method of any one of embodiments 24 to 25, wherein the vitiligo is non-segmental vitiligo.

[0207] Example

[0208] Example 1 : Reconstructed human pigmented epidermis treated with a combination of an MIA inhibitor peptide and the peptide of SEQ ID NO: 50 In vitro re-pigmentation assay in (RHPE)

[0209] To evaluate the recolorization effect, a reconstructed epidermal model was used, i.e., a polycarbonate filter ( Melanocytes and keratinocytes were added to RHPE (purchased from Episkin).

[0210] Sample tissues were treated with the test product for 6 days (from day 1 to day 6). After each application, the samples were incubated at 37°C, and melanin extraction was performed 6 days after treatment (i.e., day 7). Untreated samples were also analyzed as controls. Cell viability was also assessed.

[0211] After treatment, each sample filter was immersed in 800 μl of Melanin was extracted by heating the cells overnight at 63°C in a 4% celite column (Perkin Elmer). The optical density of the supernatant was measured at 405 nm on 300 μl of the extract using synthetic melanin as a reference. Six samples were used for each treatment and the average was calculated.

[0212] The test is handled as follows:

[0213]

[0214] The peptide of SEQ ID NO: 50 used in this experiment was acetylated at the N-terminus.

[0215] Another similar test was performed using the same treatment method, but the samples were irradiated at the same time. In the second test, the samples were irradiated at 300 W / m 2 The strength of the product is 150J / m 2 of radiation three times.

[0216] For each treatment, the increase in melanin production compared to the control group (0) was calculated. To analyze possible synergistic effects, the experimental increase in melanin in the combined treatment (A+B) was compared with the theoretical increase that would be expected if a simple additive effect were obtained.

[0217] The results are as follows (median of 6 samples used, SE represents standard error):

[0218]

[0219] The results in the above table are as follows Figure 1 As shown, the grey bars represent the experimental results of the combination, and the black bars represent the theoretical results of the combination.

[0220] The results of the sample radiation measurement are shown in the following table (median value of the 6 samples used):

[0221]

[0222] The results in the above table are as follows Figure 2 As shown, the grey bars represent the experimental results of the combination, and the black bars represent the theoretical results of the combination.

[0223] In both assays, a synergistic effect in increasing melanin production was observed due to the combination of the two peptides, both with and without irradiation, as the increase obtained by the combination was significantly higher than would be expected from either peptide acting alone.

[0224] Example 2: Reconstructed human pigment treated with a combination of MIA inhibitor peptide and SEQ ID: 50 peptide at different ratios In vitro repigmentation assay in the epidermis (RHPE)

[0225] Another in vitro repigmentation assay was performed using the same reconstructed epidermal model and the same methods as disclosed in Example 1. In this case, the assay was performed in the absence of irradiation.

[0226] The treatments tested were the same peptide combinations as in Example 1, but with different weight ratios between them, as shown in the following table:

[0227]

[0228] The results are as follows (median of the 6 samples used):

[0229]

[0230] The results in the above table are as follows Figure 3 shown.

[0231] Example 3 : Reconstructed human pigmented epidermis (RHPE) treated with a combination of MIA inhibitor peptide and SEQ ID: 51 peptide In vitro re-pigmentation assay

[0232] In this example, the same reconstructed skin model was used, namely based on a polycarbonate filter ( Melanocytes and keratinocytes were added to RHPE (purchased from Episkin) using the same protocol as disclosed in Example 1.

[0233] The treatments tested were as follows:

[0234]

[0235] For each treatment, the increase in melanin production compared to the control group (0) was calculated. To analyze possible synergistic effects, the experimental increase in melanin in the combined treatment (A+C) was compared with the theoretical increase that would be expected if a simple additive effect were obtained.

[0236] The results are as follows (median of 6 samples used):

[0237]

[0238] The results in the above table are as follows Figure 4 As shown, the grey bars represent the experimental results and the black bars represent the expected theoretical values ​​for simple additive effects.

[0239] Again, a synergistic effect in increasing melanin production was observed due to the combination of the two peptides, as the increase in the combination was significantly higher than would be expected due to the additive effects of the two peptides.

[0240] Similar irradiation tests were also conducted with similar results.

[0241] Example 4 : Reconstructed human pigmented epidermis (RHPE) treated with a combination of MIA inhibitor peptide and peptide Pro-Pro In vitro re-pigmentation assay

[0242] In this example, the same reconstructed epidermal model was used, namely based on a polycarbonate filter ( Melanocytes and keratinocytes were added to RHPE (purchased from Episkin) using the same protocol as disclosed in Example 1.

[0243] The treatments tested were as follows:

[0244]

[0245]

[0246] In particular, the peptide Pro-Pro used in this experiment carries a palmitoyl group at the N-terminus, ie, palmitoyl-prolyl-proline.

[0247] For each treatment, the increase in melanin production compared to the control group (0) was calculated. To analyze possible synergistic effects, the experimental increase in melanin in the combined treatment (A+D) was compared with the theoretical increase that would be expected if a simple additive effect were obtained.

[0248] The results are as follows (median of 6 samples used):

[0249]

[0250] The results in the above table are as follows Figure 5 As shown, the grey bars represent the experimental results and the black bars represent the expected theoretical values ​​for simple additive effects.

[0251] Again, it was observed that the increase in melanin production due to the combination of the two peptides was synergistic, as the combination provided a significantly higher increase in melanin production than would be expected due to the added effects of the two peptides.

[0252] Example 5 Preparation of the composition of the present invention

[0253] Four compositions of the present invention (A, B, C and D) were prepared using the components listed in the following table:

[0254]

[0255]

[0256] The peptide components of the composition (D2, D3a, D3b and D3c) are added as aqueous solutions or water / glycerol solutions containing about 0.1 wt%, about 0.02 wt%, about 0.002 wt% and about 0.6 wt% of the peptide, respectively.

[0257] To prepare the composition, first components A1-A6 are heated to about 70°C to 75°C and mixed thoroughly to obtain a first liquid phase ("Phase A"). Components B1-B8 are mixed separately to form a solution, which is heated to about 70°C to 75°C. Phase A is added to this solution and emulsified in a high shear Ultra-Turrax mixer at 8000 rpm for about 3 minutes, followed by stirring the emulsion in a blade mixer at 300 rpm for about 15 minutes. Components C1-C3 are added at 60°C, the mixture is allowed to cool to room temperature, and finally components D1, D2, D3a / D3b / D3c, and D4 are added. The composition is checked for a final pH in the range of 5.5-6.5 (or adjusted with 10% citric acid or 10% NaOH).

Claims

1. A composition comprising: (a) MIA inhibitor 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 peptide Pro-Pro; and (c) at least one pharmaceutically acceptable excipient.

2. The composition according to claim 1, characterized in that The amount of the MIA inhibitor peptide in the composition is 0.0001% to 1%, preferably 0.0005% to 0.1%, more preferably 0.001% to 0.05%, wherein the percentages are expressed as the weight of the MIA inhibitor polypeptide relative to the total weight of the composition.

3. The composition according to claim 1 or 2, characterized in that It comprises the peptide of SEQ ID NO:

50.

4. The composition according to any one of claims 1 to 3, characterized in that It comprises the peptide of SEQ ID NO:

51.

5. The composition according to any one of claims 1 to 4, characterized in that It contains the peptide Pro-Pro.

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

1.

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

1.

8. The composition according to any one of claims 1 to 7, characterized in that The composition comprises snail secretion.

9. The composition according to claim 8, characterized in that The content of snail secretion in the composition is 0.5% to 15%, preferably 1% to 10%, more preferably 2% to 8%, and even more preferably about 5%, wherein the percentages are expressed as the weight of 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 intended for topical application.

11. The composition according to claim 10, characterized in that The composition is selected from a cream, a gel, a colloid emulsion, a lotion, a paste, a foam, a solution, a suspension, an emulsion, an emulsion or a stick formulation.

12. The composition according to claim 11, characterized in that It is selected from creams, gels and jelly emulsions, more preferably selected from creams and gels.

13. The composition according to any one of claims 1 to 12, for use in preventing and / or treating vitiligo.

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

15. Cosmetic non-therapeutic use of a composition according to any one of claims 1 to 12 for repigmenting the skin.

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