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WO2024237777A1 - Compositions et méthodes pour prévenir et/ou traiter un trouble de pigmentation de la peau - Google Patents

Compositions et méthodes pour prévenir et/ou traiter un trouble de pigmentation de la peau Download PDF

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Publication number
WO2024237777A1
WO2024237777A1 PCT/MY2023/000005 MY2023000005W WO2024237777A1 WO 2024237777 A1 WO2024237777 A1 WO 2024237777A1 MY 2023000005 W MY2023000005 W MY 2023000005W WO 2024237777 A1 WO2024237777 A1 WO 2024237777A1
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WIPO (PCT)
Prior art keywords
composition
acetyl
skin
weight
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/MY2023/000005
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English (en)
Inventor
Ursula Rho Wan CHONG
Angela Ching Ling TEOH
Nur Rizi ZAMBERI
Elaine Shu Ching LEE
Yi Peng NG
Wendy Yen Sun HEE
Juin Onn WOO
Ivy Wan Yee HOW
Ka Heng LEE
Mong Sah TOH
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Winnox Cosmeceutics Sdn Bhd
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Winnox Cosmeceutics Sdn Bhd
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Priority to PCT/MY2023/000005 priority Critical patent/WO2024237777A1/fr
Priority to TW113105987A priority patent/TW202446359A/zh
Publication of WO2024237777A1 publication Critical patent/WO2024237777A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • compositions and methods for preventing and/or treating skin pigmentation are provided.
  • the present disclosure relates to compositions for preventing and/or treating a skin pigmentation disorder and for non-therapeutic skin lightening.
  • the present disclosure also relates to methods and uses for treating skin pigmentation disorders, and for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts, and to non-therapeutic methods for lightening skin.
  • Melanogenesis is a process that occurs in melanosomes by melanocytes involving a series of enzymatic and chemical reactions to produce the pigment melanin, which predominantly occurs in the epidermal layer of the skin.
  • Skin hyperpigmentation is a common condition in humans that is primarily caused by excessive melanin synthesis and storage through uncontrolled melanogenesis. Increased melanin production can be triggered by numerous factors including excessive sun exposure, hormonal changes, skin inflammation and age, as well as many other biological processes (Nieuweboer-Krobotova, 2013).
  • Post-inflammatory hyperpigmentation refers to the darkening of skin that occurs due to uncontrolled melanogenic processes resulting from an inflammatory eruption or cutaneous injury.
  • Skin comprises multiple layers, including the epidermal (outer), dermal and hypodermal layers.
  • the structure of these layers relies on the formation and maintenance of complex biological networks that consist of various cell types and macromolecules. Separating the epidermal and dermal skin layers is a basement membrane to which epidermal basal cells are atached.
  • the main protein families that make up the macromolecules found in the extracellular matrices include: collagens, elastins, adhesive glycoproteins and proteoglycans (Latouf et al., 2014), which play a role in the elasticity, firmness and structure of the skin.
  • melanogenesis inhibitors are based on accelerated epidermal turnover which rely on the removal of melanin from the outer layers of the skin.
  • Such treatments include exfoliating agents (e.g. AHA or BHA), antihyperpigmentation agents including kojic acid and hydroquinone, that act to inhibit melanin synthesis, melanosome blockers (e.g. niacinamide) which act to retard melanosome transfer from melanocytes to keratinocytes, and anti-inflammatory agents (e.g. stearyl glycyrrhetinate) which act to retard skin inflammation, as well as combinations of any of above.
  • exfoliating agents e.g. AHA or BHA
  • antihyperpigmentation agents including kojic acid and hydroquinone
  • melanosome blockers e.g. niacinamide
  • anti-inflammatory agents e.g. stearyl glycyrrhetinate
  • topical treatments are effective in lightening skin tone, they are often less effective in treating hyperpigmentation disorders. This is due to their mode of action primarily acting upon epidermal melanosis.
  • many products currently available on the market for treating hyperpigmentation may contain ingredients that have been associated with possible adverse effects, including hydroquinone and kojic acid.
  • facial laser treatments including Q-switched with nano-second pulse-width technology are considered effective methods for lightening or eliminating dermal melanosis, but these treatments are costly and invasive (Watanabe, 2014).
  • DEJs dermal-epidermal junctions
  • N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-lfistidine acetyl tetrapeptide-9
  • N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine acetyl tetrapeptide- 11
  • N-acetyl-L-alanyl-L-leucyl-L-histidyl-L-lysyl-L-valyl-L-lysinamide acetyl sh- hexapeptide-5 amide acetate
  • a composition for preventing and/or treating a skin hyperpigmentation disorder and/or cosmetic skin whitening including: a) N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine (acetyl tetrapeptide- 9) or salt thereof and N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine (acetyl tetrapeptide- 11) or salt thereof; and b) an ascorbic acid derivative, or salt thereof; wherein the weight ratio of N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine or salt thereof to N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine or salt thereof is in the range of from 10:1 to 1
  • the active agents present in component a) are present in a weight ratio of N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine to N-acetyl-L-prolyl-L- prolyl-L-tyrosyl-L -leucine in the range of from 5:1 to 1:5, or optionally in a weight ratio of N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine to N-acetyl-L-prolyl-L-prolyl- L-tyrosyl-L-leucine in the range of from 2:1 to 1 :2.
  • component b) is selected from the group consisting of 3-O-ethyl ascorbic acid, 2-O-ethyl ascorbic acid, ascorbyl glucoside, ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, sodium ascorbic phosphate, caprylyl 2-glyceryl ascorbate, 3-glyceryl ascorbate, bis-glyceryl ascorbate, hexyl 3-glyceryl ascorbate, myristyl 3-glyceryl ascorbate, and lauryl glyceryl ascorbate.
  • component b) is 3-O-ethyl ascorbic acid.
  • component b) is ascorbyl glucoside.
  • the amount of the active agents N-acetyl-L-glutaminyl-L-alpha- aspartyl-L-valyl-L-histidine and N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine that are present in component a) are each independently present in the combination in the range of from 0.0001% to 1% by weight of the composition, optionally from 0.0005% to 0.005% by weight of the composition, optionally from 0.001% to 0.002% by weight of the composition.
  • the amount of component b) is present in the range of from 0.1% to 10% by weight of the composition, optionally from 0.2% to 8% by weight of the composition, optionally from 1% to 2% by weight of the composition.
  • the composition does not contain any anti-hyperpigmentation agent other than components a) and b).
  • the composition is for topical application.
  • the composition comprises one or more pharmaceutically or cosmetically suitable excipients.
  • the composition comprises one or more of the following: an antiinflammatory agent, a sunscreen agent, an antioxidant, a desquamation agent, and an exfoliating agent.
  • the composition is in the form of a cream, lotion, serum, paste, wax, liquid, semisolid composition or a sprayable composition.
  • a method of preventing, treating, and/or reducing a symptom associated with, a skin pigmentation disorder in a subject or a method of inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in the dermal fibroblasts of a subject, or a non-therapeutic method of skin whitening and/or lightening of a subject, comprising administering an effective amount of a composition as defined in the first aspect, to the subject.
  • composition of the first aspect as defined herein for the manufacture of a medicament for the prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • composition of the first aspect as defined herein for use in prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • compositions for preventing and/or treating a skin hyperpigmentation disorder and/or cosmetic skin whitening including: a) N-acetyl-L-alanyl-L-leucyl- L-histidyl-L-lysyl-L-valyl-L-lysinamide
  • the component b) is selected from the group consisting of 3-O-ethyl ascorbic acid, 2-O-ethyl ascorbic acid, L-ascorbic acid, ascorbyl glucoside, ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, sodium ascorbic phosphate, caprylyl 2- glyceryl ascorbate, 3 -glyceryl ascorbate, bis-glyceryl ascorbate, hexyl 3 -glyceryl ascorbate, myristyl 3 -glyceryl ascorbate, and lauryl glyceryl ascorbate.
  • component b) is ascorbyl glucoside.
  • component b) is 3-O-ethyl ascorbic acid.
  • the amount of component a) is present in the range of from 0.0001% to 1% by weight of the composition, optionally from 0.0005% to 0.005% by weight of the composition, optionally from 0.001% to 0.002% by weight of the composition.
  • the amount of component b) is present in the range of from 0.1% to 10% by weight of the composition, optionally from 0.5% to 8% by weight of the composition, optionally from 1% to 2% by weight of the composition.
  • composition of the fifth aspect is for topical application.
  • composition of the fifth aspect comprises one or more pharmaceutically or cosmetically suitable excipients.
  • the composition of the fifth aspect comprises one or more of the following: an anti-inflammatory agent, a sunscreen agent, an antioxidant, a desquamation agent, and an exfoliating agent.
  • the composition of the fifth aspect is in the form of a cream, lotion, serum, paste, wax, liquid, semisolid composition or a sprayable composition.
  • a method of preventing, treating, and/or reducing a symptom associated with, a skin pigmentation disorder in a subject or a method of inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in the dermal fibroblasts of a subject, or a non-therapeutic method of skin whitening and/or lightening of a subject, comprising administering an effective amount of N-acetyl-L-alanyl- L-leucyl-L-histidyl-L-lysyl-L-valyl-L-lysinamide (acetyl sh-hexapeptide-5 amide acetate) or salt thereof, to the subject.
  • N-acetyl-L-alanyl-L-leucyl-L-histidyl-L-lysyl- L-valyl-L-lysinamide (acetyl sh-hexapeptide-5 amide acetate) or salt thereof, for the manufacture of a medicament for the prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • N-acetyl-L-alanyl-L-leucyl-L-histidyl-L-lysyl-L-valyl- L-lysinamide (acetyl sh-hexapeptide-5 amide acetate) or salt thereof for use in prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • a method of preventing, treating, and/or reducing a symptom associated with, a skin pigmentation disorder in a subject or a method of inhibiting melanin production and/or promoting melanin degradation in the dermal fibroblasts of a subject, or a non-therapeutic method of skin whitening and/or lightening of a subject, comprising administering an effective amount of a composition of the fifth aspect as defined herein, to the subject.
  • composition of the fifth aspect as defined herein for the manufacture of a medicament for the prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • composition of the fifth aspect as defined herein for use in prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder, or for inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in dermal fibroblasts.
  • the method, use or composition for use as defined herein when used to prevent and/or treat a skin hyperpigmentation disorder is selected from the group consisting of skin hyperpigmentation, melasma, solar lentigo, nevus of Ota, nevus of Ito and congenital dermal melanocytosis.
  • first Unless otherwise indicated, terms such as “first,” “second,” etc. are used herein merely as labels, and are not intended to impose ordinal, positional, or hierarchical requirements on the items to which these terms refer. Moreover, reference to a “second” item does not require or preclude the existence of lower-numbered item (e.g., a “first” item) and/or a higher- numbered item (e.g., a “third” item).
  • the phrase “at least one of’, when used with a list of items, means different combinations of one or more of the listed items may be used and only one of the items in the list may be needed.
  • the item may be a particular object, thing, or category.
  • “at least one of’ means any combination of items or number of items may be used from the list, but not all of the items in the list may be required.
  • “at least one of item A, item B, and item C” may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C.
  • “at least one of item A, item B, and item C” may mean, for example and without limitation, two of item A, one of item B, and ten of item C; four of item B and seven of item C; or some other suitable combination.
  • the term “subject” refers to any organism that is susceptible to a disease or condition.
  • the subject can be an animal, a mammal, a primate, a livestock animal (e.g., sheep, cow, horse, pig), a companion animal (e.g., dog, cat), or a laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster).
  • the subject is a mammal.
  • the subject is human.
  • the subject is a non-human animal.
  • treating includes alleviation of symptoms associated with a specific disorder or condition.
  • prevention includes prophylaxis of the specific disorder or condition.
  • anti-hyperpigmentation agent refers to an agent that possesses melanogenic inhibitory activity.
  • the inhibitory activity may, for example, act through inhibition of tyrosinase activity or its protein expression.
  • Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyses the production of melanin and other pigments from tyrosine by oxidation.
  • the disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.
  • compositions useful for preventing and/or treating a skin pigmentation disorder and/or which are useful for non-therapeutic (e.g. cosmetic skin whitening and/or lightening), for example by inhibiting melanin production in epidermal melanocytes and/or promoting melanin degradation in the dermal fibroblasts.
  • non-therapeutic e.g. cosmetic skin whitening and/or lightening
  • the compositions contain a specific peptide or combination of peptides which, when used in combination with ascorbic acid or a derivative and/or salt thereof, provides for unpexcetedly effective reduction of epidermal and dermal melanin.
  • anti-aging agents associated with enhancing skin smoothness and firmness can be effective for reducing skin pigmentation and are particularly effective when used in combination with ascorbic acid derivatives.
  • a correlation between the increased expression of collagens IV and VII, strengthening of dermal- epidermal junctions and reduced skin pigmentation has been identified.
  • anti-melanogenic agents as disclosed herein promote the fibroblasts to produce collagens IV and VII to strengthen dermal-epidermal junctions, thereby inhibiting dermal factor-inducing melanogenesis in the melanocytes and leakage of melanosome from epidermis to dermis.
  • a composition for preventing and/or treating a skin hyperpigmentation disorder and/or cosmetic skin whitening including: a) N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine (acetyl tetrapeptide- 9) or salt thereof and N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine (acetyl tetrapeptide- 11) or salt thereof; and b) an ascorbic acid derivative, or salt thereof; wherein the weight ratio of N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine or salt thereof to N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine or salt thereof is in the range of from 10:1 to 1
  • N-acetyl-L-glutaminyl-L-alpha- aspartyl-L-valyl-L-histidine and N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine and 3-O- ethyl ascorbic acid work synergistically to inhibit melanogenesis activity in the epidermis to diminish melanin content in melanosome internalised fibroblasts and to increase collagen IV and collage VII expression, which strengthens dermal-epidermal junctions, in a skin model of dermal melanosis.
  • composition of the first aspect contains the peptides N-acetyl-L-glutaminyl-L-alpha- aspartyl-L-valyl-L-histidine (acetyl tetrapeptide-9) and N-acetyl-L-prolyl-L-prolyl-L- tyrosyl-L-leucine (acetyl tetrapeptide- 11).
  • acetyl tetrapeptide-9 N-acetyl-L-glutaminyl-L-alpha- aspartyl-L-valyl-L-histidine
  • acetyl tetrapeptide- 11 N-acetyl-L-prolyl-L-prolyl-L- tyrosyl-L-leucine
  • This peptide can be prepared by any suitable means, of obtained from commercial sources.
  • Commercial sources for obtaining this peptide includes, but not limited to BASF (Trade name: Replexium®).
  • acetyl tetrapeptide-9 is used. In some embodiments, a salt form of acetyl tetrapeptide-9 is used.
  • acetyl tetrapeptide- 11 is used.
  • a salt form of acetyl tetrapeptide- 11 is used. Suitable salts include those formed with organic or inorganic acids or bases.
  • Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2 -hydroxy-3 -naphthoate)) salts.
  • pamoate i.e., l,l'
  • Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D- glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl -propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono- , di- or triethanolamine.
  • organic bases for example dicyclohexylamine, N-methyl-D- glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-
  • composition of the first aspect includes an ascorbic acid derivative and/or salt thereof.
  • an ascorbic acid derivative is used.
  • an ascorbic acid salt is used.
  • a salt of an ascorbic acid derivative is used.
  • ascorbic acid derivatives and/or salts thereof include 3-O-ethyl ascorbic acid (3-EAA), 2-O-ethyl ascorbic acid, ascorbyl glucoside, ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, sodium ascorbic phosphate, caprylyl-2-glyceryl ascorbate, 3-glyceryl ascorbate, bis-glyceryl ascorbate, hexyl 3-glyceryl ascorbate, myristyl 3-glyceryl ascorbate and lauryl glyceryl ascorbate.
  • 3-EAA 3-O-ethyl ascorbic acid
  • 2-O-ethyl ascorbic acid 2-O-ethyl ascorbic acid
  • ascorbyl glucoside ascorbyl tetraisopalmitate
  • magnesium ascorbyl phosphate sodium ascorbic phosphate
  • the ascorbic acid derivative and/or salt thereof is 3- O-ethyl ascorbic acid (3-EAA).
  • 3-O-ethyl ascorbic acid is depicted below:
  • 3-O-Ethyl ascorbic acid can be prepared by any suitable means, of obtained from commercial sources.
  • Commercial sources for obtaining 3-O-ethyl ascorbic acid include, but are not limited to, Nippon Fine Chemical Co. Ltd. (Trade name: Ethyl ascorbic acid), Corum Inc. (Trade name: Et-VCTM), Kimika, LLC (Trade name: Neosome OL EAA), Sigma- Aldrich and Naturalis SRL (Trade name: Nio-VCS).
  • the ascorbic acid derivative and/or salt thereof is ascorbyl glucoside.
  • the chemical structure of ascorbyl glucoside is provided below:
  • Ascorbyl glucoside can be prepared by any suitable means, of obtained from commercial sources.
  • Commercial sources for obtaining ascorbyl glucoside include, but are not limited to Sigma-Aldrich, DKSH (Trade name: AA2G), SpecChem (Trade name: SpecWhite 02), Macrocare (Trade name: V2G), Kimika, LLC (Trade name: iVit Glucoside C), etc.
  • the weight range of acetyl tetrapeptide-9 to acetyl tetrapeptide- 11 is in the range of from 10:1 to 1:10, or from 9:1 to 1:9, or from 8:1 to 1:8, or from 7:1 to 1 :7, or from 6:1 to 1:6, or from 5:1 to 1:5, or from 4:1 to 1 :4, or from 3:1 to 1:3, or from 2:1 to 1 :2, or about 1:1.
  • the weight ratio of acetyl tetrapeptide-9 to acetyl tetrapeptide- 11 is in the range of from 1 :1 to 1 :1.5, or from 1:1.1 to 1:1.3, or about 1 :1.2.
  • acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.00001% to 1% by weight of the composition, or from 0.00001% to 0.01% by weight of the composition, or from 0.00035% to 0.0013% by weight of the composition, or from 0.0009% to 0.0011% by weight of the composition, or about 0,001% by weight of the composition.
  • acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.00001% to 1% by weight of the composition, or from 0.00001% to 0.01% by weight of the composition, or from 0.000525% to 0.00165% by weight of the composition, or from 0.0009% to 0.0014% by weight of the composition, or about 0,0012% by weight of the composition.
  • acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.00001% to 1% by weight of the composition, and acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.00001% to 1% by weight of the composition. In some embodiments, acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.00001% to 0.01% by weight of the composition, and acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.00001% to 0.01% by weight of the composition.
  • acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.00035% to 0.0013% by weight of the composition, and acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.000525% to 0.00165% by weight of the composition. In some embodiments, acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.0009% to 0.0011% by weight of the composition, and acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.0009% to 0.0014% by weight of the composition.
  • acetyl tetrapeptide-9 is present in the composition in an amount of about 0.001% by weight of the composition
  • acetyl tetrapeptide- 11 is present in the composition in an amount of about 0.0012% by weight of the composition.
  • the composition comprises an ascorbic acid derivative and/or a salt thereof in a range of from 0.01 to 20% by weight of the composition, or from 0.1% to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%, or about 0.5%, or about 1%.
  • the composition of the present disclosure comprises 3-O-ethyl ascorbic acid in an amount within the range of from 0.1% to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%.
  • the composition of the present disclosure comprises an amount of ascorbyl glucoside in the range of from 0.1 % to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%.
  • acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.0009% to 0.0011% by weight of the composition
  • acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.0009% to 0.0014% by weight of the composition
  • 3-O-ethyl ascorbic acid is present in an amount in the range of from 0.5% to 2% by weight.
  • acetyl tetrapeptide-9 is present in the composition in an amount of about 0.001% by weight of the composition
  • acetyl tetrapeptide- 11 is present in the composition in an amount of about 0.0012% by weight of the composition
  • 3-O-ethyl ascorbic acid is present in an amount of about 0.5% by weight, or about 1% by weight.
  • acetyl tetrapeptide-9 is present in the composition in an amount in the range of from 0.0009% to 0.0011% by weight of the composition
  • acetyl tetrapeptide- 11 is present in the composition in an amount in the range of from 0.0009% to 0.0014% by weight of the composition
  • ascorbyl glucoside is present in an amount in the range of from 0.5% to 2% by weight.
  • acetyl tetrapeptide-9 is present in the composition in an amount of about 0.001% by weight of the composition
  • acetyl tetrapeptide- 11 is present in the composition in an amount of about 0.0012% by weight of the composition
  • ascorbyl glucoside is present in an amount of about 0.5% by weight, or about 1% by weight.
  • the composition comprises independently from 0.0005 % to 0.005% by weight of each of the active agents N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L- histidine (acetyl tetrapeptide-9) and N-acetyl-L-prolyl-L-prolyl-L-tyrosyl-L-leucine (acetyl tetrapeptide-11) as component a) and comprises from 0.2% to 8% of 3-O-ethyl ascorbic acid as component b) and optionally wherein the weight ratio of component a) to component b) is in the range of from 1 : 16,000 to 1 :40, or from 1 : 1 ,600 to 1 :400, or about 1 : 1 ,000.
  • compositions for preventing and/or treating a skin hyperpigmentation disorder and/or cosmetic skin whitening including: a) N -acetyl-L-alany 1-L-leucy 1- L-histidy 1-L-ly sy 1-L-valy 1-L-ly sinamide
  • N-acetyl-L-alanyl-L-leucyl- L- histidyl-L-lysyl-L-valyl-L-lysinamide acetyl sh-hexapeptide-5 amide acetate
  • ascorbyl glucoside work synergistically to inhibit melanogenesis activity in the epidermis, concomitantly to diminish melanin content in melanosome internalised fibroblasts in dermis, and increase collagen IV and collagen VII expression, which strengthens dermal-epidermal junctions, in a skin model of dermal melanosis.
  • acetyl sh-hexapeptide-5 amide acetate is used. In some embodiments, a salt form of acetyl sh-hexapeptide-5 amide acetate is used.
  • This peptide can be prepared by any suitable route, and is known from, for example, (US2022/0062145A1).
  • This peptide can be prepared by any suitable means, of obtained from commercial sources.
  • Commercial sources for obtaining this peptide includes, but not limited to Lipotrue (Trade name: VersillinTM).
  • acetyl sh-hexapeptide-5 amide acetate is present in the composition in an amount in the range of from 0.00001% to 1% by weight of the composition, or from 0.00001% to 0.01% by weight of the composition, or from 0.0004% to 0.0015% by weight of the composition, or from 0.00035% to 0.0013% by weight of the composition, or from 0.0009% to 0.0011% by weight of the composition, or about 0,001% by weight of the composition.
  • the composition includes an ascorbic acid derivative and/or salt thereof.
  • an ascorbic acid derivative is used.
  • an ascorbic acid salt is used.
  • a salt of an ascorbic acid derivative is used.
  • ascorbic acid derivatives and/or salts thereof include 3-O-ethyl ascorbic acid (3-EAA), 2-O-ethyl ascorbic acid, ascorbyl glucoside, ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, sodium ascorbic phosphate, caprylyl-2-glyceiyl ascorbate, 3-glyceryl ascorbate, bis-glyceryl ascorbate, hexyl 3-glyceryl ascorbate, myristyl 3-glyceryl ascorbate and lauryl glyceryl ascorbate.
  • 3-EAA 3-O-ethyl ascorbic acid
  • 2-O-ethyl ascorbic acid 2-O-ethyl ascorbic acid
  • ascorbyl glucoside ascorbyl tetraisopalmitate
  • magnesium ascorbyl phosphate sodium ascorbic phosphate
  • the ascorbic acid derivative and/or salt thereof is 3-O-ethyl ascorbic acid (3-EAA).
  • the ascorbic acid derivative and/or salt thereof is ascorbyl glucoside.
  • the composition comprises an ascorbic acid derivative and/or a salt thereof in a range of from 0.01 to 20% by weight of the composition, or from 0.1% to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%, or about 0.5%, or about 1%.
  • the composition of the present disclosure comprises 3-O-ethyl ascorbic acid in an amount within the range of from 0.1% to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%.
  • the composition of the present disclosure comprises an amount of ascorbyl glucoside in the range of from 0.1% to 10% by weight of the composition, or from 0.1% to 9%, or from 0.1% to 8%, or from 0.1% to 7%, or from 0.1% to 6%, or from 0.1% to 5%, or from 0.2% to 10%, or from 0.2% to 9%, or from 0.2% to 8%, or from 0.5% to 8%, or from 0.5% to 5%, or from 0.5% to 3%, or from 0.5% to 2.5%, or from 0.5% to 2%, or from 1% to 2%.
  • acetyl sh-hexapeptide-5 amide acetate is present in the composition in an amount in the range of from 0.0009% to 0.0011% by weight of the composition, and 3-O-ethyl ascorbic acid is present in an amount in the range of from 0.5% to 2% by weight.
  • acetyl sh-hexapeptide-5 amide acetate is present in the composition in an amount of about 0.001% by weight of the composition, and 3-O-ethyl ascorbic acid is present in an amount of about 0.5% by weight, or about 1% by weight.
  • acetyl sh-hexapeptide-5 amide acetate is present in the composition in an amount in the range of from 0.0009% to 0.0011% by weight of the composition, and ascorbyl glucoside is present in an amount in the range of from 0.5% to 2% by weight.
  • acetyl sh-hexapeptide-5 amide acetate is present in the composition in an amount of about 0.001% by weight of the composition, and ascorbyl glucoside is present in an amount of about 0.5% by weight, or about 1% by weight.
  • the composition comprises independently from 0.0005 % to 0.005% by weight of each of the active agents N-acetyl-L-alanyl-L-leucyl- L-histidyl-L-lysyl-L- valyl-L-lysinamide (acetyl sh-hexapeptide-5 amide acetate) as component a) and comprises from 0.2% to 8% of ascorbyl glucoside as component b) and optionally wherein the weight ratio of component a) to component b) is in the range of from 1 :16,000 to 1 :40, or from 1 : 1 ,600 to 1 :400, or about 1 : 1 ,000.
  • the compositions may include other components that strengthen integrity of the dermal-epidermal junction.
  • examples include palmitoyl tripeptide-38, palmitoyl tripeptide-5, camosie, palmitoyl tripeptide-1, palmitoyl tetrapeptide-7, cyclotetrapeptide-24 aminocyclohexane carboxylate, tripeptide- 10 citrulline and palmitoyl pentapeptide-4.
  • the composition may include a retinoid and/or derivative thereof (e.g. triretinoin, retinol, retinaldehydes, retinyl esters, hydroxypinacolone retinoate).
  • the composition may include niacinamide and/or a derivative thereof.
  • the composition may include adenosine and/or a derivative thereof.
  • the composition may include a Centella asiatica extract.
  • the composition does not contain any anti-hyperpigmentation agent other than a) and b).
  • the composition does not contain any skin lightening agent other than a) and b).
  • the composition consists of or consists essentially of components a) and b), and one or more carriers and/or excipients.
  • compositions of the present disclosure may be formulated as appropriate for any desired method of administration.
  • the composition of the present disclosure may be formulated as a topical composition, suitable to be applied topically to the skin.
  • compositions of the present disclosure additionally may also contain other additives.
  • the compositions of the present disclosure may include known additional cosmetic or pharmaceutical agents.
  • the composition consists of or consists essentially of components a) and b), one or more carriers and/or excipients, and optionally one or more additional cosmetic or pharmaceutical agents which are not antihyperpigmentation agents or skin lightening agents.
  • CTFA Cosmetic Ingredient Handbook Second Edition, 1992 describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which may be suitable for use in the compositions of the present disclosure.
  • suitable formulation ingredients include: antioxidants, binders, biological additives, buffering agents, colorants, thickeners, pearlescent agents, polymers, astringents, silicones, odor absorbers, gelling agents (e.g. hydrophilic or lipophilic gelling agents), fragrance, humectants, fillers, solvents, opacifying agents, skin-lightening agents, skin tanning agents, perfumes, conditioners, exfoliating agents, solubilisers (e.g.
  • methylpropanediol sunscreens
  • vitamins colouring agents
  • pH adjusters e.g. sodium hydroxide
  • preservatives e.g. ethyhexylglycerin, phenoxyethanol, or hydroxyacetophenone
  • rheological modifiers foaming agents, surfactants, emollients, natural extracts, essential oils, skin sensates, scalp soothing agents, and scalp healing agents.
  • composition of the present disclosure may also comprise other skin conditioning agents, including, but not limited to, vitamins or vitamin derivatives and macro or micro capsules containing vitamins or their derivatives, cosmetic peptides, plant extracts, polyphenol compounds, sunscreen additives, sunscreen agents, sensorial additives or texturisers, natural extracts and essential oils.
  • skin conditioning agents including, but not limited to, vitamins or vitamin derivatives and macro or micro capsules containing vitamins or their derivatives, cosmetic peptides, plant extracts, polyphenol compounds, sunscreen additives, sunscreen agents, sensorial additives or texturisers, natural extracts and essential oils.
  • the composition of the present disclosure comprises one or more of the following: an anti-inflammatory agent, a sunscreen agent, an antioxidant, a desquamation agent, and an exfoliating agent.
  • the compositions may be formulated with one or more other components that are advantageous for treatment of skin conditions, for example, hyaluronic acid and/or aloe vera gel.
  • the composition comprises a pharmaceutically or cosmetically acceptable carrier or vehicle, and/or comprises one or more excipients.
  • the pharmaceutically or cosmetically acceptable vehicle may be any pharmaceutically or cosmetically acceptable vehicle, including pharmaceutically and/or dermatologically acceptable carriers, including surfactants.
  • Pharmaceutically and/or dermatologically acceptable carriers are preferably compatible with skin, nails, mucous membranes, tissues and/or hair, and may include any conventionally used pharmaceutical or dermatological carriers meeting these requirements.
  • the carriers and/or vehicles may aid in formulating the ascorbic acid or a derivative and/or a salt thereof, or anti-hyperpigmentation agent, into suitable pharmaceutical or cosmetic formulations.
  • Carriers include, but are not limited to, emollients, emulsifiers, and rheological modifiers.
  • Emollients suitable for use in the vehicle or carrier for the compositions of the disclosure include, for example, Cl 2- 15 alkyl benzoates, PPG-3 myristyl ether, paraffinum liquidum and dimethicone.
  • Emulsifiers suitable for use in the vehicle or carrier for the compositions of the disclosure include, for example, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, Ceteareth-20 (cetostearyl alcohol, which is polyethylene glycol ether of cetearyl alcohol).
  • Rheological modifiers suitable for use in the vehicle or carrier for the compositions of the disclosure include, for example, carbomer, glyceryl polyacrylate, and acrylates/C 10-30 alkyl acrylate crosspolymer.
  • Other suitable carriers include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene and/or polyoxypropylene compounds, emulsifying wax, sorbitan monostearate, polysorbate 60 (polyoxyethylene(20) sorbitan monostearate), cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, sodium hyaluronate, hyaluronic acid, and water.
  • compositions of the present disclosure may be provided in any suitable form, for example the compositions may be formulated as ointments, liquids, lotions, pastes, foams, sprays, serums, masks, gels, hydrogels or transdermal patches, leave- on and rinse-off lotions or toners, skin ampoules, skin cleansers, facial and eye make-up removers, leave on hair conditioners or hair vitamins, hair styling aids, shower gels/creams, toilet bars, antiperspirants, deodorants, depilatories, all colour cosmetics including, but not limited to, lipsticks and foundations, sunless tanners or sunscreen lotions, shampoos, conditioners, hair tonics, mousses, gels, liposomes, or other topically suitable forms.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, emulsifying and/or gelling agents (e.g. emulsion of oil in water, emulsion of water in oil or emulsion of water in silicone).
  • Lotions may be formulated with an aqueous or oily base and generally also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, colouring agents or preservatives (e.g., methyl paraben, propyl paraben, phenoxyethanol).
  • Ointments, creams, lotions and the like may also be formulated to comprise Cl-3-alkoxylated oils and waxes (e.g., ethoxylated vegetable oils, ethoxylated jojoba oil/wax, ethoxylated lanolin oil, ethoxylated coconut oil, ethoxylated cocoa butter).
  • oils and waxes e.g., ethoxylated vegetable oils, ethoxylated jojoba oil/wax, ethoxylated lanolin oil, ethoxylated coconut oil, ethoxylated cocoa butter.
  • Any cosmetic product that contains water i.e., creams, gels, lotions, etc
  • a preservative for the compositions of the present disclosure include ethylhexylglycerine, phenoxyethanol, chlorphensin and sodium metabisulfite.
  • exemplary emollients include Cl 2- 15 alkyl benzoate, PPG-3 myristyl ether, isopropyl lauroyl sarcosinate, glycerin and bis-PEG-18 methyl ether dimethyl silane.
  • An humectant is 1,2-hexane diol or betaine.
  • An exemplary rheological modifier includes hydroxyethyl acrylate, sodium acryloyldimethyl taurate copolymer, or mixtures thereof.
  • compositions of the present disclosure comprise one or more of the following: water, an alkyl benzoate, PPG-3 myristyl ether, hydroxy aery late/sodium acryloyldimethyl taurate copolymer, ethylhexylglycerin, phenoxythanol, methylpropanediol, betaine, sclerotium gum, sodium polyacryloyldimethyl taurate, disodium EDTA, sodium hyaluronate, bis-PEG-18 methyl ether dimethyl silane, PEG- 12 dimethicone, glycerin, chlorphenesin, sodium metabisulfite, lactic acid, dicaprylyl carbonate, and polyacrylate crosspolymer-6.
  • compositions of the present disclosure may be compositions suitable for topical use.
  • the composition is for topical application.
  • the topical use could for example be by way of incorporating components a) and b) in a leave-on or in a rinse off product that is applied to the human body primarily for improving skin appearance and general aesthetic benefit.
  • skin as used herein, is meant to include the external surface of mammals, especially humans and includes skin, scalp and hair.
  • the use of the compositions of the present disclosure may for example be by way of incorporation in a leave-on composition.
  • compositions can be in the form of a liquid, lotion, cream, foam, scrub, gel, soap bar, toner, or applied with an implement or via a face mask, pad or patch in any form of materials.
  • Non-limiting examples of such compositions include leave-on skin lotions and creams in the forms of oil/silicone in water emulsion, water in oil/silicone emulsion and multiple emulsions, serums, shampoos, conditioners, shower gels, toilet bars, antiperspirants, deodorants, depilatories, lipsticks, foundations, mascara, sunscreen lotions, ointments, sprays, pastes, mousses, foams, gels, liposomes, or other topically suitable forms.
  • compositions of the present disclosure are in the form of a cream, lotion, paste, wax, liquid, semisolid composition or a sprayable composition
  • compositions are in the form of a spray
  • the carri ⁇ r ⁇ isvstfitably water and the compositions may further comprise preservative such as benzyl alcohol (for example, in an amount of from 0.1 - 5 wt%), co-solvents such as propylene glycol (for example, in an amount of from 1 - 20 wt%), and surfactants such as PEG-40 hydrogenated castor oil (for example, in an amount of from 1 - 20 wt%).
  • preservative such as benzyl alcohol (for example, in an amount of from 0.1 - 5 wt%)
  • co-solvents such as propylene glycol (for example, in an amount of from 1 - 20 wt%)
  • surfactants such as PEG-40 hydrogenated castor oil (for example, in an amount of from 1 - 20 wt%).
  • compositions are in the form of a lotion, they may for example further comprise water in the presence of a suitable emulsifying agent.
  • suitable emulsifying agents are ceteareth-20, PEG- 100 stearate, glyceryl stearate, sodium cetearyl sulfate.
  • compositions may further comprise emollients in the form of esters and/or hydrocarbons and/or silicones and/or plant oils and fragrances, preservatives (such as benzyl alcohol at levels of, for instance, 0.1 10%) and humectant and/or excipients (such as glycerol, for instance at levels of 0.5 - 10% and cyclomethicone at levels of between 0.1 - 20%).
  • emollients in the form of esters and/or hydrocarbons and/or silicones and/or plant oils and fragrances
  • preservatives such as benzyl alcohol at levels of, for instance, 0.1 10%
  • humectant and/or excipients such as glycerol, for instance at levels of 0.5 - 10% and cyclomethicone at levels of between 0.1 - 20%.
  • compositions When the compositions are in the form of an ointment, they may for example further comprise a conventional ointment base to which the active ingredient is added.
  • the ointment base may be a paraffin, such as soft paraffin, or a combination of soft and liquid paraffin.
  • Other ointment bases may also be used such as polyalkylene glycol (such as polyethylene or polypropylene glycol) base.
  • Other possible components of an ointment composition include emulsifying wax (for example, in an amount of between 1 - 40%, preferably 5 - 40%), and optionally one or more preservatives.
  • compositions are in the form of a liquid soap
  • any known liquid soap may be used.
  • the pH of the liquid soap base may be adjusted to that which is suitable for topical use.
  • compositions are an anhydrous cream
  • any suitable cream base may be used.
  • a preferred cream base is petrolatum cream and/or natural plant oils and waxes with introduction of consistency factors.
  • compositions are a shampoo or conditioner
  • they may for example further comprise one or more of a surfactant, a thickening agent, a pH adjuster/buffer, an aesthetic additive, water, a conditioner, a preservative and moisturisers/vitamins in addition to the active ingredients.
  • Shampoos may also include other active components known to those skilled in the art as having some advantage when included in a shampoo formula or in a medicinal combination for treating a hyperpigmentation disorder.
  • a shampoo may comprise a primary surfactant to provide flash foam for cleaning the hair by removing dirt and other impurities.
  • a secondary surfactant may be included to provide stable foam and to reduce the harshness of the primary surfactant.
  • a surfactant may be used that includes a charged, hydrophilic head group and a long, hydrophobic alkyl chain tail.
  • Surfactants are configured to reduce surface tension of an interphase between dirt and hair and allowing the dirt to be transported into an aqueous medium to be rinsed free from the hair and scalp.
  • Examples of surfactants that may be contained in a shampoo in accordance with certain embodiments include sodium laureth sulphate, ammonium laureth sulfate, and sodium cocoyl isethionate.
  • co-surfactants include cocamide MEA and cocoamidopropyl betaine.
  • Suitable thickening or suspending agents include carbomer and PEG 150 distearate.
  • the thickening agent may be included to stabilise the shampoo during storage and/or to prevent the settling or dumping of pigments and silicone.
  • Suitable pH adjusters or buffers include citric acid, tartaric and sodium hydroxide.
  • the pH adjuster or buffer is configured to cause the shampoo to be gentle to the skin. A lower pH may cause hair to be compact and to shine and to protect the surfactant from hydrolysis, and as such, the pH
  • components a) and b) can be prepared in stabilised topical composition and applied on the skin.
  • components a) and/or b) may for example be provided in an encapsulated format within the compositions.
  • the encapsulation technology may be used to protect and enhance transdermal delivery.
  • Suitable encapsulation technologies may be selected from the group consisting of liposomes, niosomes, nano-emulsions, and cyclodextrin inclusion technologies.
  • Suitable encapsulation technologies may be produced by any means known in the art and are not limited to the present disclosure.
  • An encapsulation material may for example comprise an emulsifier and a co-emulsifier.
  • the emulsifier may be selected from glyceryl esters of different fatty chains, including, but not limited to, glyceryl citrate, glyceryl lactate, glyceryl myristate, glyceryl laurate, glyceryl linoleate, glyceryl oleate or any combination thereof or any mixed glyceryl esters of fatty acids including citrate, lactate, myristate, laurate, linoleate and/or oleate.
  • the emulsifier is glyceryl citrate/lactate/linoleate/oleate (a mixed ester of citric acid, lactic acid, linoleic acid and oleic acid with glycerol).
  • the co-emulsifier is a di or polyglyceryl ester selected from, but not limited to, diglyceryl monooleate, polyglyceryl monooleate, polyglyceryl monolinoleate, or any combination thereof. In particular embodiments, the co-emulsifier is diglyceryl monooleate.
  • the stabiliser can for example be selected from organic substances of any kind that may solubilise the emulsifiers. Suitable examples include alcohols or glycols, including, but not limited to, ethanol, isopropanol, propylene glycol, pentylene glycol, caprylyl glycol, especially pentylene glycol.
  • the present disclosure further relates to methods and uses for treating skin pigmentation disorders, and for reducing melanin in dermal fibroblasts, using the compositions and agents described herein.
  • the compositions may be used to treat, control, prevent and ameliorate skin hyperpigmentation in a safe and non-invasive way.
  • fibroblast cells in the dermal layer of skin are involved in uptake of melanosomes, and that melanin can be retained in fibroblast cells and may be degraded at a slower rate, thus contributing to a persistently darker skin tone.
  • the novel findings by the present inventors have emerged as a strategy for treating hyperpigmentation by inhibiting dermal factor inducing melanogenesis in the melanocytes through strengthening dermal-epidermal junctions. Accordingly, it has been identified that ascorbic acid derivatives such as 3-O-ethyl ascorbic acid and ascorbyl glucoside, in combination with certain peptides, provides superior anti-hyperpigmentation properties, providing superior results in diminishing melanin content in fibroblast cells.
  • ascorbic acid derivatives such as 3-O-ethyl ascorbic acid and ascorbyl glucoside
  • 3-O-ethyl ascorbic acid and N-acetyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidine and N-acetyl-L- prolyl-L-prolyl-L-tyrosyl-L-leucine have been shown to synergistically inhibit melanogenesis activity in the epidermis and reduced melanin content in melanosome internalised fibroblasts in a human skin model of dermal melanosis.
  • compositions comprising ascorbic acid derivatives and/or salts thereof and peptides, may also act to promote depigmentation via alternative mechanisms, including, but not limited to, autophagic activity, which accelerates melanin clearance at both epidermal and dermal skin layers, and phagocytic activity by melanophages, which aid in melanosome clearance at both epidermal and dermal skin layers.
  • autophagic activity which accelerates melanin clearance at both epidermal and dermal skin layers
  • phagocytic activity by melanophages which aid in melanosome clearance at both epidermal and dermal skin layers.
  • composition of the present disclosure in a method as defined herein demonstrates minimal negative effects on tissue viability of reconstituted skin and cell viability of the fibroblasts, which indicates that the inhibitory activity to achieve melanin reduction mediated by the compositions of the present disclosure are not due to cytotoxic effects.
  • a method of preventing, treating, and/or reducing a symptom associated with, a skin pigmentation disorder in a subject comprising administering an effective amount of a composition as defined herein to the subject.
  • compositions as defined herein for the manufacture of a medicament for the prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder in a subject.
  • compositions as defined herein for the manufacture of a medicament for reducing melanin in dermal fibroblasts of a subject.
  • compositions as defined herein for use in the prevention, treatment, and/or reduction of a symptom associated with, a skin pigmentation disorder.
  • composition as defined herein for use in reducing melanin in dermal fibroblasts.
  • the composition is for promoting skin lightening. In some embodiments, the composition is for treating skin hyperpigmentation. In some embodiments, the composition enhances the dermal-epidermal junction through promoting protein expression of collagen IV and/or collagen VII.
  • composition of the present disclosure can be used to treat skin pigmentation disorders including, but not limited to, skin hyperpigmentation, melasma, solar lentigo, nevus of Ota, nevus of Ito and congenital dermal melanocytosis, post-inflammatory hyper- or hyperpigmentation, progressive pigmentary purpura, a canthosis nigricans, and incontinentia pigmenti.
  • the skin pigmentation disorder is selected from the group consisting of skin hyperpigmentation, melasma, solar lentigo, nevus of Ota, nevus of Ito, and congenital dermal melanocytosis.
  • the composition is applied topically, to the skin of a subject.
  • the subject is a human subject. In some embodiments the subject is an adult subject. In some embodiments the subject is a human subject of at least 30 years age, at least 35 years age, at least 40 years age, at least 45 years age, at least 50 years age, at least 55 years age, or at least 60 years age. In some embodiments, the subject is male. In some embodiments, the subject is female.
  • the present disclosure also relates to non-therapeutic methods for lightening skin, for example, the composition of the present disclosure may be applied in cosmetic uses to lighten skin colour.
  • a non-therapeutic method of skin lightening of a subject comprising administering an effective amount of a composition as defined herein to the subject.
  • the composition is applied topically to the skin of the subject.
  • compositions of the present disclosure may for example be a topical composition that is to be applied on an external surface of a subject.
  • the external surface may be one or more of the scalp, face, arms, legs or torso of a subject.
  • the compositions of the present disclosure demonstrate effective skin bioavailability which allows skin penetration to lighten skin tone, which has been demonstrated in human skin penetration and efficacy studies and the biomimetic skin model of dermal melanosis.
  • the composition of the present disclosure is administered once daily, or twice daily, or three times daily, or four times daily, for example for a period of time sufficient to bring about a desired level of improvement in hyperpigmentation.
  • the compositions may be used less frequently if that will provide the required effects. For example, it may be applied once every other day or once, twice, three or four times a week, or on an ad hoc or as needed basis.
  • a user may topically administer a composition of the present disclosure directly to the skin where decreased pigmentation is desired by gently massaging the composition of the present disclosure into the desired area.
  • the composition of the present disclosure is left on the skin or other area where decreased pigmentation is desired between applications.
  • Topical application of the compositions of the present disclosure may continue for any suitable period of time. For example, within a few days to a few weeks, a user may notice a reduction in pigmentation.
  • topical treatment with the composition of the present disclosure may demonstrate anti-hyperpigmentation effects by significantly reducing the skin tone of identified hyperpigmentation in, for example, as short as 4- weeks of product application.
  • compositions of the present diclosure should be applied will vary depending on the desired effect.
  • degree of therapeutic and/or cosmetic enhancement will vary and may be directly proportional with the total amount of compositions used.
  • Topical application of the compositions may be administered in any amount and at any frequency sufficient to bring about the desired level of improvement in the hyperpigmentation.
  • compositions may be applied in amounts ranging from about 1 ppm to about 10,000 ppm of peptides, or from about 2 ppm to about 2,000 ppm, or from about 3 ppm to about 1,000 ppm, or from about 4 ppm to about 500 ppm, or from about 5 ppm to about 100 ppm, or from about 5 ppm to about 50 ppm, or from about 10 ppm to about 25 ppm, or from about 10 ppm to about 20 ppm.
  • compositions of the present disclosure may be applied to the area to be treated, for example, the face, by spraying, dabbing, swabbing, rubbing or massaging.
  • a composition of the present disclosure may be provided in a liquid, lotion, cream, foam, serum, ointment, foundation, scrub, gel, soap bar, toner, or applied with an implement or via a face mask, pad or patch in any form of materials or other leave-on product formulation, which preferably may be applied on at least a daily basis.
  • compositions of the present disclosure may be prepared by any suitable method known to a person skilled in the art.
  • compositions are prepared as compositions suitable for topical use.
  • compositions are prepared as emulsions.
  • the compositions of the present disclosure may be prepared by combining an aqueous phase and a lipid phase, followed by homogenisation.
  • compositions may comprise suitable solvents or agents which act to enhance the absorption of other ingredients into the skin, humectants and anti-irritants, gums for producing a gel base that may have skin smoothing and soothing properties, emulsion stabilising and viscosity controlling agents, agents which act to prevent deterioration of the formulation, moisture attracting agents, emollients, hair/skin-conditioning agents, agents which help improve the overall texture and finish of skin care formulae, gelling agents, preservatives, agents which reduce the appearance of large pores, age spots and hyperpigmentation, including lactic acids, and subjecting this mixture to homogenisation.
  • suitable solvents or agents which act to enhance the absorption of other ingredients into the skin humectants and anti-irritants, gums for producing a gel base that may have skin smoothing and soothing properties
  • emulsion stabilising and viscosity controlling agents agents which act to prevent deterioration of the formulation
  • moisture attracting agents emollients
  • compositions are prepared as compositions suitable for topical use, by combining suitable solvents which may enhance the absorption of other ingredients into skin, such as methylpropanediol, humectants and anti-irritants, such as betaine, natural gums such as sclerotium gum, emulsion stabilizing and viscosity agents such as sodium polyacryloyldimethyl taurate, anti-deterioration, agents such as disodium EDTA, moisture attractants, such as sodium hyaluronate, water-dispersible silicones, such as bis-PEG-18 methyl ether dimethyl silane, which may act as emollients and with added foam-boosting properties, hair/skin conditioning agents, such as PEG- 12 dimethicone, other suitable emollients selected from Cl 2- 15 alkyl benzoate, PPG-3 myristyl ether and glycerin, gelling agents selected from hydroxy ethyl acrylate/sodium acryl
  • suitable solvents
  • Example 1 Investigation of dermal-epidermal junction integrity, its role in skin hyperpigmentation and identification of relevant biomarkers.
  • DEJ dermal-epidermal junction
  • Ex vivo skin explants from two young donors were obtained from Genoskin® for this study.
  • the explants were equilibrated in the provided proprietary tissue culture medium for one hour prior to commencing the experiment. After equilibration, culture medium was replaced with fresh culture medium.
  • a concentration of 500 ng/mL of neuregulin and 500 ng/ml of matrix metalloproteinase-3 (MMP-3) (R&D Systems, Abingdon, UK) were then added to the explant cultures and incubated overnight. The process was repeated three times before the skin explants were harvested for melanin quantification using Fontana-Masson histological staining. Collagen IV and collagen VII proteins were also stained using an immunofluorescent staining method and target protein expression levels were quantified using NIS-Elements imaging software (Nikon, Japan).
  • MMP-3 stromelysin- 1
  • MMP-3 can degrade a broad range of substrates including extracellular matrix components, collagen IV and collagen VII in the DEJ.
  • MMP-3 was used in this study to induce DEJ impairment in young skin to facilitate an investigation of potential biomarkers.
  • Table 1.2 indicates that the test skin sample treated with MMP-3 and induced by neuregulin show an increase in melanin levels. It was also discovered that collagen IV and VII expression was significantly reduced by MMP-3. This observation validated that these two proteins can be used as biomarkers to assess DEJ integrity.
  • DEJ integrity plays a significant role in neuregulin-induced skin hyperpigmentation and collagen IV and collagen VII are useful biomarkers to assess DEJ integrity.
  • Example 2 Investigation of the combination of acetyl tetrapeptide-11 and acetyl tetrapeptide-9, or acetyl SH-hexapeptide-5 amide acetate in reducing melanin levels in skin with impaired DEJ
  • test and control formulations were prepared by premixing the ingredients of each Phases A and B (Table 2.1), then combining the Phase A and Phase B solutions and homogenising at 2500 rpm for 5 minutes. Then, the premixed ingredients of Phase C was added into the solution containing both Phases A and B and stirred at 100-200 rpm for 30 minutes.
  • Ex vivo skin explants from two young donors were obtained from Genoskin® for this study.
  • the skins were equilibrated in the provided tissue culture medium for one hour prior to commencing the experiment. After equilibration, the culture medium was replaced with fresh culture medium. Then, 500 ng/ml of neuregulin (dermal melanogenic factor) and 150 ng/ml of metalloproteinase-3 (MMP-3, to degrade DEJ) were added to the culture medium and the explants incubated overnight.
  • the culture medium was replaced with fresh culture medium supplemented with 500 ng/ml of neuregulin and 500 ng/ml of MMP-3.
  • Topical treatments listed in Table 2.1 were applied to the skin and left for four hours at 37°C under 5% CO2. After four hours, the treatment product was washed off with phosphate buffered saline (PBS) and the skin explants were incubated overnight at 37°C under 5% CO2. The product treatment and wash step were repeated without MMP-3 in the next day before the skin explants were harvested for melanin quantification using Fontana-Masson staining.
  • PBS phosphate buffered saline
  • Collagen IV and Collagen VII were also stained using an immunofluorescent staining method and protein expression was quantified using NIS-Elements imaging software (Nikon, Japan).
  • acetyl tetrapeptide- 11 and acetyl tetrapeptide-9, or acetyl sh-hexapeptide-5 amide acetate are useful active ingredients in reducing skin melanin levels and to promote significant collagen VII expression in human skin explants obtained from young donors with MMP-3 induced DEJ impairment.
  • Example 3 Evaluation of the efficacy a topically administered aqueous composition comprising of active agents 3-EAA, acetyl tetrapeptide-11 and acetyl tetrapeptide-9 for the treatment of hyperpigmentation in clinical and ex vivo samples 3.1 Objective
  • test and control formulations were prepared by premixing the Phase A ingredients (Table 3.1) by adding each ingredient sequentially into the aqueous solution and stirring at 100-200 rpm for 15 minutes until fully dissolved. All ingredients in Phase B were mixed until fully dissolved, then added into the Phase A solution and stirred at 100-200 rpm for 5 minutes. Lastly, the preservatives (aminomethyl propanol and chlorphenesin, glycerin, phenoxyethanol) were added to the Phase A/B solution and stirred at 100-200 rpm for 5 minutes.
  • topical treatment with Formula 5 significantly reduced the melanin levels of neuregulin-induced skin hyperpigmentation in skin explants with MMP-3 -induced DEJ impairment when compared to an untreated control.
  • a significant increase of collagen IV and VII expression was observed in skin explants treated with Formula 5 as compared to untreated skin explants.
  • An inverse correlation of melanin levels compared to collagen IV and VII levels after treatment was observed.
  • results illustrated in Table 3.2 showed that topical treatment of Formula 5 reduced the skin tone difference between the established pigmented skin test zone as compared to a clear control skin region. Skin tone was measured immediately prior to topical administration and 4 weeks post administration of Formula 5.
  • Topical administration of Formula 5, comprising of 3-EAA, AT-11 and AT-9 was efficacious in reducing melanin levels in human skin explants with neuregulin-induced skin hyperpigmentation in DEJ impairment as compared to an untreated control.
  • This combination of active agents is a useful treatment for skin hyperpigmentation and has been shown to lighten skin tone in human clinical trial participants after 4 weeks.
  • Example 4 Evaluation of the efficacy and reproducibility of a topically administered aqueous composition comprising of active agents 3-EAA, acetyl tetrapeptide- 11 and acetyl tetrapeptide-9 for the treatment of hyperpigmentation in skin explants
  • test and control formulations were prepared by premixing the Phase A ingredients (Table 4.1) by adding each ingredient sequentially into the aqueous solution and stirring at 100-200 rpm for 15 minutes until fully dissolved. All ingredients in Phase B were mixed until fully dissolved, then added into the Phase A solution and stirred at 100-200 rpm for 5 minutes. Lastly, the preservatives (chlorphenesin, and phenoxyethanol) were added to the Phase A/B solution and stirred at 100-200 rpm for a further 5 minutes.
  • topical treatment of Formula 7 significantly reduced the melanin levels in skin explants with neuregulin-induced DEJ impairment when compared to control Formula 6 (without active agents).
  • significant elevation of Collagen IV and VII expression was observed in skin explants treated with Formula 7 as compared to skin explants treated with Formula 6.
  • Formula 7, comprising the combination of active agents 3- EAA, AT-11 and AT-9, demonstrated significant efficacy in melanin reduction in skin with DEJ impairment and enhanced expression of proteins crucial for function and stability of the extracellular matrix, namely, collagen IV and collagen VII.
  • Topical administration of Formula 7, comprising of 3-EAA, AT-11 and AT-9 was reproducibly efficacious in reducing melanin levels in human skin explants with neuregulin- induced skin hyperpigmentation and DE J impairment as compared to an untreated control.
  • the efficacy of Formula 7 for lightening skin was confirmed in a repeat experiment.
  • This composition of active agents when administered topically in the concentration tested is a useful treatment for skin hyperpigmentation.
  • Example 5 Evaluation of the efficacy of a topically administered emulsion composition comprising of active agents ascorbyl glucoside (AA2G) and acetyl sh- hexapeptide-5 amide acetate (ASH5AA) for the treatment of skin hyperpigmentation
  • active agents ascorbyl glucoside (AA2G) and acetyl sh- hexapeptide-5 amide acetate (ASH5AA) for the treatment of skin hyperpigmentation
  • test and control formulations were prepared by premixing Phase A and Phase B ingredients (Table 5.1) independently in separate containers until dispersed homogeneously at 70°C to 75°C. Then, Phase B was added into Phase A and stirred at 3500 rpm for 15 minutes. Phase C was mixed until fully dissolved and added into the Phase A/B solution at 60°C and stirred at 3500 rpm for 5 minutes. Then, Phase D was mixed until fully dissolved and add into the Phase A/B/C solution at 45°C and stirred at 100-200 rpm for 5 minutes. Lastly, ingredients in Phase E were added sequentially into Phase A/B/C/D solution and stirred at 100-200 rpm for 30 minutes.
  • Formula 9 As shown in Table 5.2, topical administration of Formula 8 or Formula 9 significantly reduced the melanin levels in neuregulin-induced skin hyperpigmentation in skin explants with MMP-3-induced DEJ impairment when compared to an untreated control.
  • Formula 9 (comprising active agents AA2G and ASH5AA) showed a greater reduction of melanin than observed with Formula 8 (formula without active agents, that is ‘base formula’) treated samples.
  • Formula 9 significantly increased expression of the Collagen IV and VII when compared the base formula (Formula 8). Taken together, the inverse correlation of melanin levels to collagen IV and VII levels was strongest in samples treated with Formula 9.
  • a topically administered formulation comprising of ascorbyl glucoside and acetyl sh- hexapeptide-5 amide acetate was useful in reducing melanin levels in human skin explants with neuregulin-induced skin hyperpigmentation and DEJ impairment as compared to an untreated control.
  • Example 6 Synergistic anti-hyperpigmentation effect of 3-EAA with Acetyl tetrapeptide-11 and Acetyl tetrapeptide-9 in skin explant ex-vivo
  • Test and control formulations were prepared by premixing the Phase A ingredients (Table 6.1) by adding each ingredient sequentially into the aqueous solution and stirring at 100-200 rpm for 15 minutes until folly dissolved. All ingredients in Phase B were mixed until folly dissolved, then added into the Phase A solution and stirred at 100-200 rpm for 5 minutes. Lastly, the preservatives (Aminomethyl Propanol and Chlorphenesin, Glycerin, Phenoxyethanol) were added to the Phase A/B solution and stirred at 100-200 rpm for a further 5 minutes.
  • the active agent 3-o-ethyl ascorbic acid (3-EAA) works synergistically when combined with Acetyl tetrapeptide- 11 and Acetyl tetrapeptide-9 when reducing melanin levels in human skin explants with neuregulin-induced skin hyperpigmentation and DEJ impairment as compared to an untreated control.
  • Example 7 Comparison of aqueous and emulsion formulations with ascorbic acid derivatives for reducing dermal melanin in vitro as a holistic anti-hyperpigmentation approach
  • test and control formulations were prepared by premixing the Phase A ingredients (Table 7.1) by adding each ingredient sequentially into the aqueous solution and stirring at 100-200 rpm for 15 minutes until fully dissolved. All ingredients in Phase B were mixed until fully dissolved, then added into the Phase A solution and stirred at 100-200 rpm for 5 minutes. Lastly, the preservatives (Aminomethyl Propanol and Chlorphenesin, Glycerin, Phenoxyethanol) were added to the Phase A/B solution and stirred at 100-200 rpm for a further 5 minutes.
  • test and control formulations were prepared by premixing Phase A and Phase B ingredients (Table 7.2) independently in separate containers until dispersed homogeneously at 70°C to 75°C. Then, Phase B was added into Phase A and stirred at 3500 rpm for 15 minutes. Phase C was mixed until fully dissolved and added into the Phase A/B solution at 60°C and stirred at 3500 rpm for 5 minutes. Then, Phase D was mixed until fully dissolved and add into the Phase A/B/C solution at 45°C and stirred at 100-200 rpm for 5 minutes. Lastly, ingredients in Phase E were added sequentially into Phase A/B/C/D solution and stirred at 100-200 rpm for 30 minutes.
  • mice melanoma cells B16-F10 (ATCC, USA) were seeded at a concentration of 5 x 10 5 cells in a T75 tissue culture flask and maintained in complete Dulbecco’s Modified Eagle’s Media (DMEM; Nacalai, Japan) supplemented with 10% foetal bovine serum (FBS), sodium pyruvate (1 mM), L-glutamine (2mM), streptomycin (50 pg/ml) and penicillin (50 U/ml) at 37°C in an atmosphere of 5% CO2 for 5 days. Then, the culture media were centrifuged at 300 xg to sediment the cells debris and the melanosomes where harvested in the supernatant, and referred to as: melanosome conditioned media.
  • DMEM Modified Eagle’s Media
  • human skin fibroblast HS-68 cells (ATCC, USA) were seeded 7 x 10 5 in a T25 tissue culture flask and maintained in DMEM media supplemented with 10% FBS, sodium pyruvate (1 mM), L-glutamine (2mM), streptomycin (50 pg/ml) and penicillin (50 U/ml) at 37°C in an atmosphere of 5% CO2 for 24 hours. Then, the culture media were replaced with melanosome conditioned media and cultured for a further 24 hours. Lastly, the cell viability of treated fibroblast cells was determined by using a MTT assay (Nacalai Tesque, Japan).
  • the fibroblast cells treated with melanosome conditioned media were treated with trypsin and harvested by centrifugation at 10,000 xg for lOmin. The supernatant was removed, and the cell pellets collected. The harvested cells were lysed by re-suspending with IM NaOH (Merck, Germany) and incubated at 80°C for 1 hour. Lastly, the lysed samples were centrifuged at 3000 xg for 5 min, the supernatant were collected for melanin and protein quantification.
  • Human skin fibroblast HS-68 cells were seeded in a 12- well hanging top plate at cell concentration of lx 10 5 cells/well and cultured for 24h under 5% CO2 and 37 °C. Then, the culture media were replaced with melanosome conditioned media and cultured for another 24h. On the same day, reconstituted skin with melanocytes (Melanoderm; Mattek, USA) were maintained with long life maintenance media (LLMM from Mattek, USA) and cultured at 37°C and 5% CO2 overnight. On the next day, the melanosome conditioned media were discarded and rinsed with PBS.
  • melanocytes Melanoderm; Mattek, USA
  • the Melanoderm reconstituted skin was then added to the 12-well hanging top plate containing melanosome conditioned media treated fibroblast cells for co-culturing.
  • the co-culture system was maintained in LLMM media and topical application of each test and control formulation were administered to the skin and incubated for two hours.
  • the formulation was then washed off with PBS.
  • the media was refreshed, and the topical treatments applied every 2 days for total duration of 7 days.
  • fibroblast cells were treated with trypsin and harvested for melanin quantification. Cell viability of treated skin and fibroblast cells were determined by using MTT assay.
  • the total protein was quantified by Bradford assay and CBB solution (Nacalai Tesque, Japan) according to the manufacturer’s instructions.
  • the melanin content was normalised against the total protein content and expressed as total melanin (pg) in one mg of protein.
  • Formula 15 comprising of acetyl tetrapeptide- 11 and acetyl tetrapeptide-9 only, showed insignificant reduction of melanin content in the fibroblast cells.
  • Formula 14 which comprised both the ascorbic acid derivative (3-EAA) and the active agents acetyl tetrapeptide- 11 and acetyl tetrapeptide- 9, demonstrated significant reduction of melanin content in fibroblast cells.
  • the emulsion formula demonstrated the same trend as the aqueous formulation as shown in Table 7.4. That is, Formula 17, which comprised of acetyl sh-hexapeptide-5 amide acetate only showed insignificant reduction of melanin content in fibroblast cells. Again, in contrast, Formula 16, which comprised of the ascorbic acid derivative (ascorbyl glucoside) and acetyl sh-hexapeptide-5 amide acetate, showed a significant reduction of melanin content in fibroblast cells.
  • Hexapeptide-5 fibroblast viability (% viability (% of glucoside
  • Peptides (acetyl tetrapeptide- 11 and acetyl tetrapeptide-9 or acetyl sh-hexapeptide-5 amide acetate) show a reduction in dermal melanin, but the reduced melanin level is not significant when compared to an untreated control in a skin dermal melanosis model in vitro.
  • an ascorbic acid derivative (3-EAA or Ascorbyl glucoside)
  • the reduction in melanin levels was significant in the skin dermal melanosis model in vitro. This demonstrates that these formulations a useful and are promising treatments for skin lightening or skin hyperpigmentation disorders.

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Abstract

L'invention concerne des compositions pour éclaircir la peau et pour prévenir et/ou traiter un trouble de pigmentation de la peau. L'invention concerne également des méthodes et des utilisations pour prévenir et/ou traiter des troubles de pigmentation de la peau, et pour inhiber la production de mélanine dans des mélanocytes épidermiques et/ou favoriser la dégradation de la mélanine dans des fibroblastes dermiques, ainsi que des procédés non thérapeutiques d'éclaircissement de la couleur de la peau.
PCT/MY2023/000005 2023-05-18 2023-05-18 Compositions et méthodes pour prévenir et/ou traiter un trouble de pigmentation de la peau Pending WO2024237777A1 (fr)

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TW113105987A TW202446359A (zh) 2023-05-18 2024-02-20 用於預防及/或治療皮膚色素沉著之組成物和方法

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