Skin decolorizing compositions and uses thereof

Abstract

The present invention relates to a composition comprising cysteamine, azabenzene-4-carboxamide, and glycollic acid. The invention also relates to the cosmetic use thereof for inhibiting, reducing or preventing skin pigmentation, and to the therapeutic use thereof for inhibiting, reducing or preventing diseases or disorders of skin hyperpigmentation.

Description

Technical Field

[0001] The present invention relates to a composition comprising cysteamine, azabenzene-4-carboxamide and glycolic acid. The present invention also relates to its cosmetic use for inhibiting, reducing or preventing skin pigmentation, and its therapeutic use for inhibiting, reducing or preventing diseases or disorders of excessive skin pigmentation. The composition of the present invention reduces irritation to the skin, increases the long-term depigmentation effect after 8 weeks of treatment, provides an immediate depigmentation effect, increases the shelf life and reduces unpleasant odor. Background Art

[0002] Human skin color varies widely throughout the world. Human skin color results from a complex series of cellular processes that take place within melanocytes located in the lower part of the epidermis. These processes result in the synthesis and transfer of a pigment, melanin, which, in addition to being responsible for the color and tone of the skin, is also a key physiological defense against sun-induced damage such as sunburn, photoaging, and photocarcinogenesis.

[0003] Various compositions have been formulated to simply achieve lighter / whiter skin or to address hyperpigmentation disorders such as melasma, freckles, lentigo and dark spots on the skin. The use of such compositions is not limited to the treatment of hyperpigmentation diseases or disorders, but in some cultures / markets, they are also used solely for the purpose of altering or modifying a person's natural healthy skin color.

[0004] A large number of agents and methods for skin depigmentation have been developed and put on the market. Such methods include oral administration of large doses of vitamin C, parenteral administration of glutathione, topical peroxide bleaching agents such as hydrogen peroxide, zinc peroxide, sodium peroxide, etc. for skin depigmentation, and topical application of vitamin C and / or cysteine. However, vitamin C has stability problems, especially in water-based formulations, which can lead to changes in color and odor. Thiol compounds such as glutathione and cysteine ​​have slow and / or generally poor depigmentation properties.

[0005] The most commonly used depigmenting agents are hydroquinone and its derivatives. However, while effective, these compounds have serious harmful side effects. Even at concentrations below 2%, hydroquinone is irritating and cytotoxic to melanocytes. Peroxide depigmenting agents face similar problems. Another known depigmenting agent is tretinoin, which is effective for the treatment of both wrinkles and skin pigmentation, but is also known to cause skin irritation and can lead to darkening of the skin.

[0006] A variety of polyphenols present in plant extracts have also been used for skin depigmentation purposes. Such natural polyphenols are, for example, anthraquinones, arylbenzofurans, chalcones, coumarins and flavonoids. One class of polyphenol compounds that has received widespread attention is based on substituted resorcinol and its derivatives. However, although they have relatively good skin whitening abilities, they often have stability problems, which are also often accompanied by the loss of skin whitening efficacy, making them generally unsuitable for topical use.

[0007] Another agent that exhibits an interesting depigmenting effect is nicotinamide. Nicotinamide is a 3-substituted pyridine that exerts its skin depigmenting effect by inhibiting the transfer of melanosomes from melanocytes to keratinocytes. Although nicotinamide is well tolerated by human skin, it has a poor depigmenting effect on the skin.

[0008] Cysteamine is incorporated as a therapeutic agent into various topical compositions and dermatological compositions, such as pharmaceutical compositions or cosmetic compositions, and is generally used as a drug for managing skin depigmentation. However, the unpleasant odor leads to poor patient compliance, limiting its use.

[0009] Cysteamine has also been combined with citric acid, glycolic acid or lactic acid (Swiss Patent No. CH706226A2). However, the combination involves citric acid, glycolic acid and lactic acid concentrations equal to or less than 1%. The effects of higher concentrations of citric acid, glycolic acid and lactic acid in combination with cysteamine have not been reported in the prior art, possibly due to the inflammatory risks associated with higher concentrations of organic acids.

[0010] Thus, there remains a need for a skin depigmenting composition that provides effective whitening capabilities over a period of weeks and that does not cause significant inflammation, irritation, or photosensitivity to the skin following application.

[0011] An ideal skin depigmenting composition should have a strong, rapid and selective depigmenting effect, be free of short-term or long-term side effects, be well tolerated, be able to act at one or more steps of the pigmentation process, have a sufficiently long shelf life, and its odor should not be considered unpleasant. Summary of the invention

[0012] One aspect of the present invention provides a composition comprising

[0013] 0.2% w / w to 20% w / w of cysteamine or a salt thereof,

[0014] 0.2% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, and

[0015] • 2% w / w to 20% w / w glycolic acid.

[0016] Another aspect of the invention provides a composition of the invention for use in a method of inhibiting, reducing or preventing a skin hyperpigmentation disease or disorder in a subject.

[0017] Yet another aspect of the present invention provides a cosmetic method for inhibiting, reducing or preventing pigmentation of normal healthy skin, comprising topically applying the composition of the present invention to the skin of a subject in need thereof.

[0018] Another aspect of the present invention provides a cosmetic method for inhibiting, reducing or preventing pigmentation of normal healthy skin, comprising the following steps:

[0019] a) topically applying to an area of ​​the skin of a subject in need thereof a first composition comprising:

[0020] 0.2% w / w to 20% w / w of cysteamine or a salt thereof, and

[0021] 2% w / w to 20% w / w glycolic acid,

[0022] b) rinsing off said first composition,

[0023] c) topically applying to said area of ​​skin a second composition comprising 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof,

[0024] d) Repeat steps a), b) and c) to obtain the desired skin depigmentation effect.

[0025] Another aspect of the present invention provides a combination product comprising a first composition and a second composition for separate topical application, wherein

[0026] the first composition comprises 0.2% w / w to 20% w / w of cysteamine or a salt thereof and 2% w / w to 20% w / w of glycolic acid,

[0027] and

[0028] • The second composition comprises 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof.

[0029] Another aspect of the present invention provides a method for reducing the bad smell of cysteamine or its salt, which comprises combining 0.2% w / w to 20% w / w of cysteamine or its salt with 0.2% w / w to 20% w / w of azidine-4-carboxamide or its salt and 2% w / w to 20% w / w of glycolic acid. DETAILED DESCRIPTION

[0030] All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. The publications and applications discussed herein only provide the disclosures prior to the filing date of the present application. Anything herein should not be construed as admitting that the present invention has no right to be earlier than such publications due to prior inventions. In addition, materials, methods and embodiments are illustrative only and are not intended to be limiting.

[0031] In case of conflict, the present specification (including definitions) shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of this article belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0032] The term "comprising" is generally used in an inclusive sense, that is, allowing one or more features or components to be present. Also as used in the specification and claims, the language "comprising" may include similar embodiments described with "consisting of" and / or "consisting essentially of".

[0033] As used in the specification and claims, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0034] As used in the specification and claims, the term "and / or" used in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A", and "B".

[0035] As used herein, the term "at least one" means "one or more" and also encompasses the terms "at least two," "at least three," "at least four," etc.

[0036] As used herein, the term "therapeutically effective amount" is defined as an amount of an agent sufficient to detectably and reproducibly improve, reduce, minimize or limit the extent of a skin disorder, disease or condition, or symptoms thereof.

[0037] As used herein, the term "depigmenting effective amount" means an amount of a compound or composition sufficient to significantly induce a positive benefit on skin depigmentation (preferably reducing the darkening or rate of darkening of the skin) but low enough to avoid serious side effects.

[0038] As used herein, the term "pharmaceutically acceptable excipient" means that the composition so described, or components thereof, are suitable for administration to the subject's (patient's) body without undue toxicity, incompatibility, instability, irritability, allergic response, and the like.

[0039] As used herein, the term "dermatologically acceptable" means that the compositions so described, or components thereof, are suitable for use in contact with mammalian, preferably human, skin without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

[0040] As used herein, the term "treatment" refers to therapeutic measures or preventive measures. Treatment can be applied to a subject who has a medical disorder (e.g., a skin disorder or condition) or may eventually develop the disorder or condition to prevent, cure, delay, reduce the severity of the disorder or recurring disorder, or improve one or more symptoms of the disorder or recurring disorder.

[0041] As used herein, the terms "cosmetic," "cosmetic management," or "cosmetic treatment" are non-therapeutic treatments of skin conditions that are not disease or pathological conditions.

[0042] As used herein, the term "topical" or "topically" refers to applying the composition of the present invention to the surface of the skin and / or parts thereof (e.g., facial skin, neck skin, arm skin, hand skin, leg skin and scalp skin, elbow skin, knee skin, male or female genital and anal area) so that it can exhibit local activity. Thus, topical forms include cosmetic, dermatological and / or pharmaceutical dosage forms suitable for external use, so as to result in direct contact with the skin and / or parts thereof.

[0043] As used herein, the term "subject" is recognized in the art and is used herein to refer to mammals, most preferably humans. In some embodiments, the subject is a subject in need of treatment or a subject suffering from a skin pigmentation disease or disorder (e.g., hyperpigmentation). However, in other embodiments, the subject can be a normal subject with normal healthy skin and needs to whiten its skin (whitening). The term does not represent a specific age or gender. Therefore, it is intended to cover adults, young people and newborn subjects, whether male or female.

[0044] As used herein, the term "depigmentation" (or lightening, whitening, whitening, and brightening, which are used interchangeably herein) is the whitening or loss of pigment of the skin. Skin depigmenting agents or compositions are also referred to as "skin whitening agents (lightener)", "skin whitening agents", "skin toning agents" and "skin brightening agents (brightener)". Regardless of the terms used, the general premise is that they all involve the darkening of the skin or a reduction in the rate of darkening, which results in a loss of pigment.

[0045] As used herein, the term "instant depigmentation / depigmenting effect", or "instant skin depigmentation" is a visual effect that results in a whiter skin tone within seconds or minutes after application of a topical product / composition. This effect makes the skin instantly radiant and the skin tone more even, which is perceived by a reduction in the melanin index.

[0046] As used herein, the term "post-inflammatory hyperpigmentation" refers to changes in melanin content in response to an inflammatory event (e.g., acne, scratching, laser treatment, insect stings or bites, sunburn, etc.), particularly in individuals with darker skin tones or colors.

[0047] As used herein, the term "reduction" or "reducing" the bad smell (e.g., sulfur smell) of cysteamine or its salt or ester refers to the attenuation, alleviation and / or reduction of the bad smell, so that the bad smell is no longer perceived or barely perceived by human subjects. It also refers to the elimination and / or disappearance of the bad smell.

[0048] Applicants have surprisingly discovered that the combination of 0.2% w / w to 20% w / w cysteamine or a salt thereof, 0.2% w / w to 20% w / w azabenzene-4-carboxamide or a salt thereof, and 2% w / w to 20% w / w glycolic acid provides unexpected benefits and synergistic effects in the following areas: long-term and immediate skin depigmentation, anti-inflammatory effects, increase in shelf life, and reduction in the unpleasant odor of cysteamine or a salt thereof.

[0049] Firstly, the applicants surprisingly discovered that the combination of 0.2% w / w to 20% w / w cysteamine or a salt thereof, 0.2% w / w to 20% w / w azabenzene-4-carboxamide or a salt thereof, and 2% w / w to 20% w / w glycolic acid provides a less irritating formulation compared to those of the prior art comprising lower concentrations of glycolic acid, whereas glycolic acid itself is considered an irritant in the medical literature.

[0050] Secondly, in contrast to existing cysteamine formulations comprising glycolic acid at a concentration of less than 1%, the compositions of the present invention comprising cysteamine, azabenzene-4-carboxamide and 2% or more glycolic acid exhibit an immediate skin depigmentation effect only seconds after application to human skin, while reducing the unpleasant odor of cysteamine. An immediate depigmentation effect is very rare and adds tremendous value and benefit to the product (composition), especially in terms of patient compliance. Indeed, one of the most common problems with depigmenting topical treatments is their onset of action: it usually takes 2 to 4 weeks to see very preliminary results. Therefore, because no depigmentation effect is seen after the first application, many patients stop treatment prematurely due to lack of motivation. Such an immediate depigmentation effect does not occur with the combination of cysteamine and azabenzene-4-carboxamide in combination with other alpha-hydroxy acids (AHAs) such as lactic acid or tartaric acid.

[0051] Third, Applicants surprisingly discovered that the addition of azabenzene-4-carboxamide, even at low percentages (0.2% to as high as 20%), to a composition comprising cysteamine or a salt thereof and glycolic acid synergistically increased the long-term skin depigmentation effect, which was significantly more visible and perceptible to the treated subjects after 8 weeks of treatment. According to an embodiment, Applicants surprisingly discovered that when azabenzene-4-carboxamide is not administered simultaneously with cysteamine or a salt thereof and glycolic acid, but is administered in a skin depigmentation method (a "2-step" method), the skin depigmentation effect after 8 weeks is even further improved.

[0052] Furthermore, Applicants have surprisingly found that the addition of 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof to a composition already comprising cysteamine or a salt thereof and glycolic acid reduces the unpleasant odor of cysteamine even more substantially, resulting in increased acceptability of the product to the treated subjects.

[0053] Finally, the combination of cysteamine with glycolic acid and azidine-4-carboxamide at concentrations equal to or greater than 2% exhibited a surprising synergistic effect on increasing the shelf life and durability of the product, which was hitherto unknown.

[0054] Therefore, one aspect of the present invention provides a composition comprising

[0055] 0.2% w / w to 20% w / w of cysteamine or a salt thereof,

[0056] 0.2% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, and

[0057] • 2% w / w to 20% w / w glycolic acid.

[0058] In some embodiments, the composition of the present invention comprises 5% w / w to 20% w / w cysteamine or a salt thereof, or 2% w / w to 12% w / w cysteamine or a salt thereof, or 5% w / w to 12% w / w cysteamine or a salt thereof, or 0.2% w / w to 7% w / w cysteamine or a salt thereof, or 2% w / w to 7% w / w cysteamine or a salt thereof, or 3% w / w to 20% w / w cysteamine or a salt thereof, or 1% w / w to 12% w / w cysteamine or a salt thereof, or 3% w / w to 12% w / w cysteamine or a salt thereof, or 0.2% w / w to 7% w / w cysteamine or a salt thereof, or 1% w / w to 7% w / w cysteamine or a salt thereof.

[0059] In other embodiments, the composition of the present invention comprises 3% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof.

[0060] In further embodiments, the compositions of the present invention comprise 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid.

[0061] In an embodiment, the composition of the invention comprises

[0062] 5% w / w to 20% w / w of cysteamine or a salt thereof,

[0063] 3% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, and

[0064] · 3.5% w / w to 20% w / w glycolic acid.

[0065] In a further embodiment, the composition of the invention comprises

[0066] 0.2% w / w to 7% w / w of cysteamine or a salt thereof,

[0067] 0.2% w / w to 10% w / w of azobenzene-4-carboxamide or a salt thereof, and

[0068] 2% w / w to 10% w / w glycolic acid.

[0069] The present invention also provides a combination product comprising or consisting of a first composition and a second composition for separate topical application, wherein

[0070] the first composition comprises 0.2% w / w to 20% w / w of cysteamine or a salt thereof and 2% w / w to 20% w / w of glycolic acid,

[0071] and

[0072] • The second composition comprises 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof.

[0073] In an embodiment, the combination product of the present invention consists of the following first and second compositions:

[0074] The first composition consists of:

[0075] o 0.2% w / w to 20% w / w of cysteamine or a salt thereof, preferably 5% w / w to 20% w / w of cysteamine or a salt thereof, or 2% w / w to 12% w / w of cysteamine or a salt thereof, or 5% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 2% w / w to 7% w / w of cysteamine or a salt thereof, or 3% w / w to 20% w / w of cysteamine or a salt thereof, or 1% w / w to 12% w / w of cysteamine or a salt thereof, or 3% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 1% w / w to 7% w / w of cysteamine or a salt thereof,

[0076] o 2% w / w to 20% w / w glycolic acid, preferably 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid,

[0077] ο 0.01% w / w to 1% w / w retinol, and

[0078] o cosmetically acceptable excipients,

[0079] and

[0080] The second composition consists of:

[0081] 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, preferably 3% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof,

[0082] o Up to 15% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% w / w to 15% w / w or 0.01% w / w to 10% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof; preferably 0.01% w / w to 15% w / w or 0.01% w / w to 10% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol and / or combinations thereof,

[0083] ο0.01% to 1% retinol, and

[0084] o Cosmetically acceptable excipients.

[0085] In the context of the present invention, Tasman pepper is a natural Australian active ingredient extracted from Tasmanian pepper berries.

[0086] In some embodiments, the first composition of the combination product of the present invention comprises 5% w / w to 20% w / w cysteamine or a salt thereof, or 2% w / w to 12% w / w cysteamine or a salt thereof, or 5% w / w to 12% w / w cysteamine or a salt thereof, or 0.2% w / w to 7% w / w cysteamine or a salt thereof, or 2% w / w to 7% w / w cysteamine or a salt thereof, or 3% w / w to 20% w / w cysteamine or a salt thereof, or 1% w / w to 12% w / w cysteamine or a salt thereof, or 3% w / w to 12% w / w cysteamine or a salt thereof, or 0.2% w / w to 7% w / w cysteamine or a salt thereof, or 1% w / w to 7% w / w cysteamine or a salt thereof.

[0087] In other embodiments, the first composition of the combination product of the present invention comprises 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid.

[0088] In a further embodiment, the second composition of the combination product of the present invention comprises 3% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof.

[0089] In the present disclosure, the %w / w of cysteamine or its salt refers to the %w / w of cysteamine (cysteamine free base). Thus, any specific mass referred to as "cysteamine or its salt" refers to the mass equivalent of the free base (cysteamine free base), and any specific mass referred to as a specific salt of cysteamine (e.g., cysteamine hydrochloride) refers to the mass of the specific salt. The above definition can also be applied to the %w / w of azabenzene-4-carboxamide or its salt, for example, any specific mass referred to as "azabenzene-4-carboxamide or its salt" refers to the mass equivalent of the free base (azabenzene-4-carboxamide).

[0090] Here, the term "cysteamine" is intended to encompass any (pharmaceutically or cosmetically or dermatologically) acceptable salt, ester, solvate, hydrate, prodrug or any other compound that is capable of (directly or indirectly) providing cysteamine when administered to a patient. Preferred salts of cysteamine are hydrochloride, bitartrate, phosphate. Any compound that is a prodrug of cysteamine is within the scope and spirit of the present invention. The term "prodrug" is used in its broadest sense and includes derivatives that are converted to cysteamine in vivo. Prodrugs can be hydrolyzed, oxidized or otherwise reacted under biological conditions to provide cysteamine. Examples of prodrugs include, but are not limited to, derivatives and metabolites of cysteamine, including biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Prodrugs can generally be prepared using well-known methods such as those described by Burger in "Medicinal Chemistry and Drug Discovery" 6th edition (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers). In addition, the cysteamine mentioned herein may be in crystalline or amorphous form, as a free compound or as a solvate (e.g., hydrate), and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known in the art.

[0091] The salts of azabenzene-4-carboxamide are pharmaceutically acceptable salts, cosmetically acceptable salts and dermatologically acceptable salts.

[0092] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of azabenzene-4-carboxamide, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of azabenzene-4-carboxamide can be prepared from inorganic or organic acids, or can be prepared in situ during the final separation and purification of azabenzene-4-carboxamide. Examples of such inorganic acids are hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids and sulfonic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acids, arylsulfonic acids. Suitable pharmaceutically acceptable base addition salts of azabenzene-4-carboxamide include metal salts made from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are ammonium salts, quaternary salts such as tetramethylammonium salts, amino acid addition salts such as glycine and arginine salts. Other information about pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case where the agent is solid, it will be appreciated by those skilled in the art that the compounds, agents and salts of the present invention may exist in different crystalline forms or polymorphic forms, all of which are intended to be within the scope of the present invention.

[0093] The combination products and compositions of the present invention can be prepared by any method known in the art for cosmetic compositions, dermatological compositions and / or pharmaceutical compositions. Typically, the method involves simple mixing or blending of the components; however, particularly when insoluble or immiscible components are used, higher agitation or homogenization may be required to prepare suitable compositions, such as emulsions or suspensions, etc. In addition, during the preparation process, it may be necessary to add known pH adjusting agents to maintain the composition for topical application at a suitable pH, particularly if a base ingredient is to be used. Typically, the pH range should be from about 3.5 to about 8.

[0094] In some embodiments, the composition of the present invention is a cosmetic composition further comprising a cosmetically acceptable excipient for topical application.

[0095] In some embodiments, the composition of the present invention is a dermatological composition further comprising a dermatologically acceptable excipient for dermatological administration.

[0096] In some embodiments, the composition of the present invention is a pharmaceutical composition further comprising a pharmaceutically acceptable excipient for oral administration or topical application.

[0097] In some embodiments, the present invention provides a composition consisting of:

[0098] 0.2% w / w to 20% w / w of cysteamine or a salt thereof,

[0099] 0.2% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof,

[0100] 2% w / w to 20% w / w glycolic acid,

[0101] 0.01% w / w% to 1% w / w retinol, and

[0102] - Cosmetically acceptable excipients for topical application, or pharmaceutically acceptable excipients for oral administration or topical application.

[0103] The cosmetic composition, dermatological composition and pharmaceutical composition according to the present invention also contain one or more cosmetically, dermatologically or pharmaceutically acceptable excipients commonly used in such compositions, such as preservatives, antioxidants, chelating agents, bactericides, fragrances, substances that prevent foaming, dyes, pigments with coloring effects, thickeners, propellants, surfactant substances, emulsifiers, softening substances, moisturizing substances and / or moisture-retaining substances, distilled water, fats, oils, waxes, or other conventional ingredients of cosmetic compositions, dermatological compositions or pharmaceutical compositions, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. Based on the desired product, those skilled in the art can easily select the necessary amount of cosmetically, dermatologically or pharmaceutically acceptable excipients.

[0104] Moisturizing substances can be incorporated into the composition of the present invention to maintain hydration or to moisturize the skin. Moisturizers that prevent water from evaporating from the skin by providing a protective coating are called emollients. In addition, emollients provide softening or soothing effects on the skin surface and are generally considered to be safe for topical use. Preferred emollients include mineral oil, lanolin, petrolatum, caprylic / capric triglycerides, cholesterol, silicone oils such as dimethicone, cyclomethicone, almond oil, jojoba oil, avocado oil, castor oil, sesame oil, sunflower oil, coconut oil and grapeseed oil, cocoa butter, olive oil, aloe extract, fatty acids such as oleic acid and stearic acid, fatty alcohols such as cetyl alcohol and hexadecyl alcohol (ENJAY), diisopropyl adipate, hydroxybenzoates, C 9-15 Benzoic acid esters of alcohols, isononyl isononanoate, ethers such as polyoxypropylene butyl ether and polyoxypropylene cetyl ether, and C 12-15Alkyl benzoates and mixtures thereof. Moisturizing substances that bind water and thereby retain it on the surface of the skin are called humectants. Suitable humectants may be incorporated into the skin depigmenting composition of the present invention, such as glycerol, polypropylene glycol, polyethylene glycol, lactic acid, pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin, ceramide, lecithin, sorbitol, PEG-4 and mixtures thereof.

[0105] The composition of the present invention may also contain conventional alcohols, in particular lower alcohols, preferably ethanol and / or isopropanol, lower diols or polyols and their ethers, preferably propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether or ethylene glycol monobutyl ether, propylene glycol monomethyl ether or propylene glycol monoethyl ether or propylene glycol monobutyl ether, diethylene glycol monomethyl ether or diethylene glycol monoethyl ether and similar products, polymers, foam stabilizers, electrolytes, especially one or more thickeners. Thickeners that can be used in the composition of the present invention to help make the consistency of the product suitable include carbomer, silicon dioxide, magnesium silicate and / or aluminum silicate, beeswax, stearic acid, stearyl alcohol, polysaccharides and their derivatives, such as xanthan gum, hydroxypropylcellulose, polyacrylamide, acrylate cross-linked polymers, preferably carbomer, such as 980, 981, 1382, 2984, 5984 types alone or a mixture thereof.

[0106] Suitable stabilizers that may be included in the compositions of the present invention to stabilize components such as, for example, emulsifiers or foam builders / stabilizers include, but are not limited to, alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; organic bases, such as diethanolamine (DEA), triethanolamine (TEA), aminomethyl propanol, and mixtures thereof; amino acids, such as arginine and lysine, and any combination of any of the foregoing.

[0107] The composition of the invention may also contain a filter substance or sunscreen that absorbs UV radiation, wherein the total weight of the filter substance is, for example, 0.001% to 30%, preferably 0.5% to 10%, based on the total weight of the preparation. The composition may also be used as a sunscreen for the skin. Such UV filters include, for example, the following: avobenzene, cinoxate, dioxybenzone, homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, phenylbenzimidazole sulfonic acid, sulfisobenzone, titanium dioxide, triethanolamine salicylate and zinc oxide.

[0108] The compositions of the present invention may also include one or more skin permeation agents. These are additives that have a direct effect on the permeability of the skin barrier when applied to the skin: increasing the rate and / or amount at which certain other compounds are able to penetrate into the skin layers. Exemplary organic permeation enhancers include dimethyl sulfoxide, isopropyl myristate, decyl alcohol, undecanol or dodecanol, propylene glycol, polyethylene glycol, C 9-11 or C 12-15 Fatty alcohols, azone, alkyl pyrrolidones, diethoxy glycol (Transcutol), lecithin, etc. Surfactants can also be used as penetration enhancers.

[0109] According to an embodiment, the composition of the present invention may further comprise at least one skin benefit agent selected from the group consisting of kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, heparan sulfate and its analogs, dermatan sulfate and its analogs, chondroitin sulfate and its analogs, emblica extract, daisy extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, tert-butylhydroquinone, retinol, panthenol, vitamin E selected from tocopherol and tocopheryl acetate, vitamin C selected from ascorbyl palmitate, sodium ascorbyl phosphate and ascorbic acid, vitamin B or its derivatives, moisturizing sugars selected from xylitol glucoside, anhydroxylitol and xylitol, diacids, corticosteroids, 4-substituted resorcinol derivatives and mixtures thereof. In a further embodiment, at least one skin benefit agent is selected from the group consisting of: vitamin C selected from ascorbyl palmitate, sodium ascorbyl phosphate and ascorbic acid, vitamin E selected from tocopherol and tocopheryl acetate, panthenol, retinol, a natural extract selected from Tasmannia Lanceolata fruit / leaf extract and barley (Hordeum Vulgare) seed powder, and a moisturizing sugar selected from xylitol glucoside, anhydroxylitol and xylitol. In a further embodiment, at least one skin benefit agent is selected from the group consisting of kojic acid, arbutin, deoxyarbutin, soy extract, licorice extract, heparan sulfate, dermatan sulfate, chondroitin sulfate, emblica extract, daisy extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, tertiary butylhydroquinone, retinol, panthenol, vitamin E selected from tocopherol and tocopheryl acetate, vitamin C selected from ascorbyl palmitate, sodium ascorbyl phosphate and ascorbic acid, vitamin B, moisturizing sugars selected from xylitol glucoside, anhydroxylitol and xylitol, diacids, corticosteroids and mixtures thereof.

[0110] According to another embodiment, the composition of the present invention may also include liposomes (unilamellar liposomes and / or multilamellar liposomes of any size), nanoliposomes (niosomes) or any encapsulation system (e.g., microcapsules, nanocapsules, cubic liquid crystal nanoparticles (cubosomes)) to deliver any component of the composition to its site of action. The optimal type and size of liposomes, nanoliposomes and / or encapsulation systems and the nature of the medium in which they are dispersed can be easily selected by a person skilled in the art.

[0111] The composition of the present invention may be a cosmetic composition, a dermatological composition or a pharmaceutical composition and may be present in a variety of forms, such as emulsions, suspensions, solutions, etc. In certain embodiments, the composition of the present invention is in the form of a lotion, cream, gel, solution, spray, cleanser, powder, ointment, wax, lipstick, soap, shampoo, hydroalcoholic solution, suspension, scrub, impregnated pad, skin conditioner and other types of cosmetic compositions. In further embodiments, the composition of the present invention may be, for example, an anhydrous formulation, an oil-free formulation, an emulsion or microemulsion of the water-in-oil (W / O) type or the oil-in-water (O / W) type, a multiple emulsion such as the water-in-oil-in-water (W / O / W) type, a solid stick or even an aerosol.

[0112] Preferred forms of the composition of the present invention are gel, lotion, cream, powder.

[0113] In some embodiments, the present invention is directed to a topical composition that promotes immediate skin depigmentation through the concerted action of the active ingredients cysteamine or a salt thereof, azabenzene-4-carboxamide or a salt thereof, and glycolic acid.

[0114] In some embodiments, the present invention relates to a topical composition that promotes anti-inflammatory effects through the synergistic action of the active ingredients cysteamine or a salt thereof, azabenzene-4-carboxamide or a salt thereof, and glycolic acid.

[0115] In some embodiments, the present invention is directed to a topical composition that promotes increased shelf life through the synergistic effect of the active ingredients cysteamine or a salt thereof, azabenzene-4-carboxamide or a salt thereof, and glycolic acid.

[0116] The compositions of the present invention significantly reduce or eliminate bad odor and enhance the organoleptic properties, which are more acceptable and suitable for topical pharmaceutical and cosmetic applications.

[0117] According to one aspect of the invention, the composition of the invention is used for depigmentation (whitening or whitening) of human skin. According to a further aspect, the invention provides a method for inhibiting, reducing or preventing skin pigmentation. The human skin is preferably at least one of facial skin, neck skin, arm skin, hand skin, leg skin, elbow skin, knee skin, skin of the axillary region, scalp skin, and skin of the male or female genital region.

[0118] In some embodiments, the composition of the present invention is used for the cosmetic depigmentation of human natural healthy skin, i.e. non-therapeutic use, which is unrelated to the disease or pathological state of the treatment skin. In some embodiments, cosmetic depigmentation (cosmetic inhibition, reduction or prevention of skin pigmentation) relates to skin whitening, skin luminescence, skin lightening, skin uniformity, skin depigmentation, anti-brown spots and / or plaques. In other embodiments, the skin pigmentation to be reduced or prevented according to the method of the present invention can be the pigmentation of a normal amount. For example, if a subject wishes to reduce or prevent the pigmentation of at least one skin area for cosmetic reasons, the method can be used.

[0119] Therefore, according to an embodiment, the present invention provides a cosmetic use of the composition of the present invention for inhibiting, reducing or preventing skin pigmentation of normal healthy skin. The skin is preferably at least one of facial skin, neck skin, arm skin, hand skin, leg skin, elbow skin, knee skin, skin of the axillary region, scalp skin, and skin of the male or female genital region. The term "normal skin" refers to healthy skin without pigmentation disorders or diseases.

[0120] The present invention also provides a cosmetic method for inhibiting, reducing or preventing skin pigmentation of normal healthy skin, which comprises topically applying the composition of the present invention to the skin of a subject in need thereof.

[0121] According to another embodiment, the present invention also provides a kind of pigmentation of the normal healthy skin for reducing the patient with generalized vitiligo to reduce the cosmetic method of the difference between sick skin and normal healthy skin, which comprises that the composition of the present invention is locally applied to skin.In the present embodiment, the subject may suffer from the disease of insufficient pigmentation in one or more areas causing skin, or suffer from local melanin deficiency such as vitiligo.The pigmentation of the affected skin area is reduced or lacks, and these areas may be significantly different from adjacent unaffected pigmentation normal and sufficient skin area.By reducing the pigmentation degree of unaffected (normal health) skin or preventing the pigmentation of the normal degree of unaffected (normal health) skin, the difference in the pigmentation between affected skin and unaffected skin area can be reduced.

[0122] The cosmetic method of the present invention is repeated several times sufficient to inhibit, reduce or prevent skin pigmentation of normal healthy skin, for example until the desired depigmentation effect (end point) is achieved, and / or after the desired depigmentation effect is achieved, the method of the present invention does not need to be repeated every day, every day in a row, or one to six times a week to maintain the depigmentation result or effect.

[0123] In a further embodiment of the cosmetic method of the present invention, when the desired depigmentation effect has been achieved, it is not necessary to continue using the cosmetic method of the present invention for inhibiting, reducing or preventing skin pigmentation in normal healthy skin every day, every consecutive day, or one to six times a week to maintain the depigmentation result or effect.

[0124] Another aspect of the present invention provides a cosmetic method for inhibiting, reducing or preventing pigmentation of normal healthy skin, comprising the following steps:

[0125] a) topically applying to an area of ​​the skin of a subject in need thereof a first composition comprising:

[0126] 0.2% w / w to 20% w / w of cysteamine or a salt thereof, preferably 5% w / w to 20% w / w of cysteamine or a salt thereof, or 2% w / w to 12% w / w of cysteamine or a salt thereof, or 5% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 2% w / w to 7% w / w of cysteamine or a salt thereof, or 3% w / w to 20% w / w of cysteamine or a salt thereof, or 1% w / w to 12% w / w of cysteamine or a salt thereof, or 3% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 1% w / w to 7% w / w of cysteamine or a salt thereof, and

[0127] 2% w / w to 20% w / w glycolic acid, preferably 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid,

[0128] b) rinsing off the first composition,

[0129] c) topically applying to said area of ​​skin a second composition comprising: 0.2% w / w to 20% w / w azabenzene-4-carboxamide or a salt thereof, preferably 3% w / w to 20% w / w azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w azabenzene-4-carboxamide or a salt thereof, or 0.5% w / w to 10% w / w azabenzene-4-carboxamide or a salt thereof,

[0130] d) Repeat steps a), b) and c) to obtain the desired skin depigmentation effect (end point).

[0131] In some embodiments of the cosmetic method, in step a), the first composition is topically applied to an area of ​​the skin of a subject in need thereof for a period of time, e.g., 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, or 2 hours, or for 15 to 30 minutes, 15 to 45 minutes, 15 minutes to 1 hour, 15 minutes to 2 hours.

[0132] In other embodiments of the cosmetic method, prior to topical application of the second composition, rinsing off the first composition in step b) is generally performed by any suitable method. In some embodiments, the suitable method is selected from:

[0133] Rinse with water with or without a suitable detergent.

[0134] Remove with any suitable solvent or cleaner,

[0135] Remove with a dry or wet pad, and / or

[0136] Its combination.

[0137] The cosmetic method of the present invention is repeated for a time period or number of times sufficient to obtain the desired skin depigmentation effect (end point), such as one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, 2 months, three months, one year, two years, three years or more; or such as one to four weeks, one to eight weeks, one week to one year, one week to two years, one week to five years. In another embodiment, after achieving the desired depigmentation effect, it is not necessary to repeat the cosmetic method of the present invention every day, continuously every day or one to four times a week to maintain the depigmentation result or effect.

[0138] In further embodiments of the cosmetic method, when the desired depigmentation effect (end point) has been achieved, continued use of the cosmetic method may not be required every day, not required every consecutive day, or one to four times per week to maintain the depigmentation result or effect.

[0139] In a further embodiment of the cosmetic method, the first composition consists of:

[0140] 0.2% w / w to 20% w / w of cysteamine or a salt thereof, preferably 5% w / w to 20% w / w of cysteamine or a salt thereof, or 2% w / w to 12% w / w of cysteamine or a salt thereof, or 5% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 2% w / w to 7% w / w of cysteamine or a salt thereof, or 3% w / w to 20% w / w of cysteamine or a salt thereof, or 1% w / w to 12% w / w of cysteamine or a salt thereof, or 3% w / w to 12% w / w of cysteamine or a salt thereof, or 0.2% w / w to 7% w / w of cysteamine or a salt thereof, or 1% w / w to 7% w / w of cysteamine or a salt thereof,

[0141] o 2% w / w to 20% w / w glycolic acid, preferably 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid,

[0142] ο 0.01% w / w to 1% w / w retinol, and

[0143] o Cosmetically acceptable excipients.

[0144] In a further embodiment of the cosmetic method, the second composition consists of:

[0145] 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, preferably 3% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof,

[0146] o Up to 15% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% w / w to 15% w / w, or 0.01% w / w to 10% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof; preferably 0.01% w / w to 15% w / w, or 0.01% w / w to 10% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol and / or combinations thereof,

[0147] ο 0.01% w / w to 1% w / w retinol, and

[0148] o Cosmetically acceptable excipients.

[0149] In some other embodiments, the compositions of the present invention are used for the medical / therapeutic treatment of a skin hyperpigmentation disorder or disease selected from the group consisting of melasma, phytophotodermatitis, lentigine (solar lentigo and senile lentigo), freckles, café au lait spots (possibly associated with neurofibromatosis or Albright syndrome), acanthosis nigricans, facial skin discoloration, Addison's disease, biliary cirrhosis, ectopic ACTH syndrome, eosinophilia-myalgia Syndrome, folate deficiency, hemochromatosis, junctional and mixed nevus, melanosis secondary to metastatic melanoma, Nelson syndrome, pellagra, pigmented actinic keratosis, pigmented keratinocyte tumors, POEMS syndrome, porphyria cutanea tarda, seborrheic keratosis, vitamin B12 deficiency, Whipple's disease and / or post-inflammatory hyperpigmentation; preferably, the skin hyperpigmentation disorder or disease is selected from melasma, lentigo, post-inflammatory hyperpigmentation and / or facial skin discoloration. Post-inflammatory hyperpigmentation may be due to skin injury, burns, bites, various inflammatory reactions such as acne or lupus inflammation.

[0150] Skin hyperpigmentation disorders or diseases are usually due to increased production and accumulation of melanin, increased number of melanocytes, and / or increased activity of melanogenic enzymes. Ultraviolet light, chronic inflammation, skin damage, and abnormal release of alpha-melanocyte stimulating hormone (α-MSH) are triggering factors for skin hyperpigmentation disorders or diseases.

[0151] Skin hyperpigmentation can also be drug-induced hyperpigmentation, light-induced hyperpigmentation, and chemically-induced hyperpigmentation.

[0152] The disease related to skin hyperpigmentation is characterized at least in part by the presence of endogenous skin pigmentation greater than the desired amount affecting at least one skin area of ​​the subject. In one embodiment, the disease related to hyperpigmentation is characterized at least in part by the presence of endogenous skin pigmentation greater than the normal amount affecting at least one skin area of ​​the subject. Endogenous skin pigmentation greater than the normal amount refers to objectively greater than the amount of pigmentation present in another skin area of ​​(a) the subject, including but not limited to the average amount of pigmentation of the subject's skin, or (b) at an earlier time (e.g., before developing into hyperpigmentation), the amount of pigmentation in the same skin area of ​​the subject. In different embodiments, hyperpigmentation may be accompanied by or show malignant or non-malignant (i.e., benign) disease. Endogenous skin pigmentation refers to skin pigmentation produced by cells in the skin, which should be distinguished from, for example, skin pigmentation produced by injecting dyes such as tattoos into the skin or other forms of exogenous skin pigmentation.

[0153] The present invention also provides use of the composition of the present invention as a medicine.

[0154] The present invention also provides use of a composition of the present invention in a method for inhibiting, reducing or preventing a skin hyperpigmentation disorder or disease in a subject.

[0155] The present invention also provides a method for inhibiting, reducing or preventing a skin hyperpigmentation disorder or disease, comprising topically applying the composition of the present invention to the skin of a subject in need thereof.

[0156] In a further embodiment of the method of the present invention, when the desired depigmentation effect has been achieved, the method of the present invention for inhibiting, reducing or preventing skin hyperpigmentation disorders or diseases may not need to be continued every day, every consecutive day, or one to four times a week to maintain the depigmentation results or effects.

[0157] The methods of the present invention are repeated several times sufficient to inhibit, reduce or prevent skin hyperpigmentation disorders or diseases, for example until the desired depigmentation effect (end point) is achieved, and / or after the desired depigmentation effect is achieved, the methods of the present invention do not need to be repeated every day, not continuously every day, or one to four times a week to maintain the depigmentation results or effects.

[0158] In the method of the present invention for inhibiting, reducing or preventing skin pigmentation disorders or diseases and / or skin pigmentation of normal healthy skin, it will be understood by those of ordinary skill in the art that the endpoint selected in a particular case will vary according to the disease, condition or disorder being treated, the desired skin appearance, the desired result of the patient, subject or treating physician, and other factors. If the composition or combination product is used for whitening skin color, such as, for example, for cosmetic treatment, or for reversing hyperpigmentation caused by, for example, inflammation or diseases such as melasma, any one or more endpoints may be selected. For example, the endpoint may be defined subjectively, such as, for example, when the subject is only "satisfied" with the treatment results. For pharmacological compositions, the endpoint may be determined by the patient or treating physician's satisfaction with the treatment results. Alternatively, the endpoint may be objectively defined. For example, the skin of the treatment area of ​​the patient or subject may be compared to a color chart. When the skin color in the treatment area is similar in appearance to the color on the chart, the treatment terminates. Alternatively, the reflectance of the treated skin may be measured, and when the treated skin reaches a specified reflectance, the treatment (cosmetic or therapeutic) may be terminated. In another method, the amount of melanin in the skin may be measured.

[0159] Hyperpigmented skin areas or areas of skin to be depigmented can involve and be as small as about 1 mm 2 Skin area (portion) up to and including the entire skin surface. In certain common embodiments, the hyperpigmented skin area or skin area to be depigmented may involve and refer to about 1 cm 2 To tens of cm 2 In a given subject, there may be a single hyperpigmented area / area to be depigmented, or there may be more than one hyperpigmented area / area to be depigmented. When a subject has more than one hyperpigmented area / area to be depigmented, the multiple hyperpigmented areas / areas to be depigmented may be similar or different in size, shape and / or pigmentation.

[0160] Thus, the uses and methods of the present invention for inhibiting, reducing or preventing skin hyperpigmentation disorders or diseases and / or skin pigmentation of normal healthy skin comprise the step of applying a composition of the present invention or a combination product of the present invention locally (topically) to the pigmented skin to reduce skin pigmentation. In one embodiment, the topical application is a topical application.

[0161] In the method for inhibiting, reducing or preventing skin pigmentation disorders or diseases and / or skin pigmentation of normal healthy skin according to the present invention, a composition or a combination product is applied to the skin, preferably human skin. The amount of the composition applied to the skin depends on the form of the composition and its mode of application. For example, a spray formulation can be applied to provide a thin and uniform coating on the skin. Similarly, emulsions, creams, gels, shampoos, etc. are usually applied in an amount that provides a thin coating to the treatment area: consistent with the application of topical topical ointments, creams, emulsions, etc. Usually, for the whole body, that is, for the exposed skin of an "ordinary person" wearing a swimsuit, 1.65m tall, 68kg in weight, and 0.81m in waist circumference, the standard of application (especially all or substantially all of the skin surface (including hairy or hairless skin) is to be treated) is about 20mL to 60mL. This translates into an application standard of about 2mg / cm 2 Skin surface (including hairy or hairless skin surface). On the face, a typical application standard is 0.5 mL to 1.0 mL. At this application level, the amount of composition applied ranges from about 0.1 mg / cm 2 Skin: about 10 mg / cm 2 Skin, preferably about 1 mg / cm 2 Skin: about 3 mg / cm 2 skin.

[0162] The composition of the present invention or the combination product of the present invention can be applied once or multiple times a day according to the activities that the specific subject participates in. For example, the subject participating in the normal working day activities may wish to apply the composition or combination product twice a day, once in the morning and once in the evening, together with normal grooming. On the other hand, if the subject plans outdoor activities, such as sunbathing and sports, the composition or combination product can be applied before and during such activities, just like the sunscreen composition is regularly applied during the day. The composition or combination product can be used for the hyperpigmentation of the face and neck, or by applying a suitable composition to the scalp, face and neck area, to change the normal dark color of the scalp or body to a whiter color. However, the composition or combination product of the present invention can also be applied to the whole body, particularly to areas not covered by clothes, such as arms, neck and calves.

[0163] For application, the cosmetic, dermatological and pharmaceutical compositions of the present invention can be applied to the skin (to the body surface) in a conventional manner for cosmetics and medicines and in a sufficient depigmenting effective amount to have a local external effect (i.e., a local effect as opposed to a systemic effect).

[0164] Another aspect of the present invention provides a method for reducing the bad smell of cysteamine or its salt, which comprises combining 0.2% w / w to 20% w / w of cysteamine or its salt with 0.2% w / w to 20% w / w of azidine-4-carboxamide or its salt and 2% w / w to 20% w / w of glycolic acid.

[0165] In some embodiments of the method for reducing bad odor, the content of cysteamine or its salt is 5% w / w to 20% w / w, or 2% w / w to 12% w / w, or 5% w / w to 12% w / w, or 0.2% w / w to 7% w / w, or 2% w / w to 7% w / w, or 3% w / w to 20% w / w of cysteamine or its salt, or 1% w / w to 12% w / w of cysteamine or its salt, or 3% w / w to 12% w / w of cysteamine or its salt, or 0.2% w / w to 7% w / w of cysteamine or its salt, or 1% w / w to 7% w / w of cysteamine or its salt.

[0166] In other embodiments of the method for reducing bad odor, the content of azabenzene-4-carboxamide or its salt is 3% w / w to 20% w / w, or 2% w / w to 10% w / w, or 3% w / w to 10% w / w, or 0.2% w / w to 10% w / w.

[0167] In further embodiments of the method of reducing bad odour, the glycolic acid is present in an amount of 3.5% w / w to 20% w / w, or 3.5% w / w to 15% w / w, or 2% w / w to 10% w / w, or 2% w / w to 15% w / w.

[0168] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It will be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all steps, features, compositions and compounds mentioned or indicated in this specification, either individually or collectively, and any and all combinations of any two or more of the steps or features. Therefore, the present disclosure should be considered to be illustrative and not restrictive in all respects, and the scope of the invention is indicated by the appended claims, and all changes falling within the meaning and scope of equivalents are intended to be included therein.

[0169] The above description will be more fully understood with reference to the following examples. However, these examples are exemplary methods of implementing the present invention and are not intended to limit the application and scope of the present invention.

[0170] Example

[0171] Examples of the compositions of the present invention:

[0172] Composition A (Emulsion E / WQSP)

[0173] - Cysteamine 8%

[0174] -Sodium Ascorbyl Phosphate 1%

[0175] -Ascorbyl palmitate 1.5%

[0176] -Azobenzene-4-carboxamide 5%

[0177] - Glycolic acid 5%

[0178] - Aromatherapy 0.1%

[0179] Example 1

[0180] Topical compositions containing high percentages of cysteamine or its salts and azidine-4-carboxamide may be considered irritating to the skin. The addition of glycolic acid reduced the irritation and produced a soothing effect, which was surprising since glycolic acid is generally irritating to the skin. When glycolic acid was replaced with other alpha-hydroxy acids (AHAs) such as lactic acid or tartaric acid or when glycolic acid was reduced to 1%, the irritation reduction and soothing effects were not present.

[0181] Compositions tested:

[0182] o Cysteamine hydrochloride: 5% w / w to 20% w / w

[0183] o Azobenzene-4-carboxamide: 3% w / w to 20% w / w

[0184] ο Glycolic acid: 3.5% w / w to 20% w / w

[0185] Test 1: Irritation potential scores were measured on 20 volunteers after a 48-hour patch test under occlusive conditions. The results are shown below.

[0186]

[0187]

[0188] Test 2: Hemoglobin levels were measured to assess the reduction in inflammation after 24 h of SLS exposure.

[0189] 20 volunteers were tested. On the back of each volunteer, 15 skin squares were determined. The SLS patch of closure was applied for 24 hours, resulting in an increase in hemoglobin content (inflammatory symptoms, such as redness). For 3 consecutive days, a small amount of cream (about 50 mg) was applied to the corresponding squares by external uninformed and trained personnel with disposable latex finger pads every day, and the finger pads were changed between each square. The position of each cream on each square was randomly determined by an external person, and the volunteers and researchers were all uninformed. Hemoglobin content was measured after 72 hours, and the results are as follows.

[0190] The composition comprises: Hemoglobin levels decreased compared to untreated areas 5% Cysteamine hydrochloride + 3% Azobenzene-4-carboxamide <![CDATA[+0.5% # ]]> 12% Cysteamine hydrochloride + 10% Azobenzene-4-carboxamide <![CDATA[+1% # ]]> 20% Cysteamine hydrochloride + 20% Azobenzene-4-carboxamide <![CDATA[+5% # ]]> 1% glycolic acid <![CDATA[+2.1% # ]]> 3.5% glycolic acid <![CDATA[+2.3% # ]]> 20% Glycolic Acid <![CDATA[+3% # ]]> 5% cysteamine hydrochloride + 3% azobenzene-4-carboxamide + 1% glycolic acid <![CDATA[+4.6% # ]]> 5% Cysteamine hydrochloride + 3% Azobenzene-4-carboxamide + 3.5% glycolic acid -24％* 12% cysteamine hydrochloride + 10% azobenzene-4-carboxamide + 3.5% glycolic acid -26％* 20% cysteamine hydrochloride + 20% azobenzene-4-carboxamide + 20% glycolic acid -29％* 12% cysteamine hydrochloride + 10% azobenzene-4-carboxamide + 3.5% lactic acid <![CDATA[+4.9% # ]]> 12% cysteamine hydrochloride + 10% azobenzene-4-carboxamide + 20% lactic acid <![CDATA[+8.0% # ]]> 12% cysteamine hydrochloride + 10% azobenzene-4-carboxamide + 3.5% tartaric acid <![CDATA[+3.7% # ]]> 12% cysteamine hydrochloride + 10% azobenzene-4-carboxamide + 20% tartaric acid <![CDATA[+4.3% # ]]> 20% cysteamine hydrochloride + 25% azobenzene-4-carboxamide + 20% glycolic acid <![CDATA[+8.2% # ]]>

[0191] # Significant damage to the skin barrier / induction of inflammation compared to untreated areas

[0192] * Significantly improved skin barrier / reduced inflammation compared to untreated areas

[0193] Embodiment 2:

[0194] Cysteamine and glycolic acid had limited depigmentation effects after 8 weeks of treatment. The addition of azabenzene-4-carboxamide synergistically increased the depigmentation effect, which was significantly more visible and perceived by the treated subjects, even at low percentages (%). When azabenzene-4-carboxamide was replaced with other azabenzene-4-carboxamide isomers, such as azabenzene-2-carboxamide and azabenzene-3-carboxamide, there was no synergistic effect and the perceived depigmentation effect was low. Surprisingly, it has been observed that the skin depigmentation effect is improved when azabenzene-4-carboxamide is applied in a two-step method, which consists of applying a first composition comprising cysteamine or a salt thereof and glycolic acid for a certain time (e.g., 15 minutes), then rinsing off the first composition, and finally applying a separate second composition comprising azabenzene-4-carboxamide. However, when azabenzene-4-carboxamide is replaced with other azabenzene-4-carboxamide isomers, such as azabenzene-3-carboxamide, the two-step application method does not improve the skin depigmentation effect.

[0195] Compositions tested:

[0196] o Cysteamine hydrochloride: 0.2% w / w to 7% w / w

[0197] ο Glycolic acid: 2% w / w to 10% w / w

[0198] o Azobenzene-4-carboxamide: 0.2% w / w to 10% w / w

[0199] Test 3: Measurement of the skin color index (Dermacatch) after 8 weeks of treatment. 6 volunteers were tested. On both arms of each volunteer, 20 skin squares were determined using UV radiation. Over 8 weeks, the volunteers were asked to apply a small amount of cream (about 50 mg) on ​​the corresponding squares with a disposable latex finger pad, changing the finger pad between each square. The position of each cream on each square was randomly determined by an external person, and neither the volunteers nor the researchers knew about it. After 8 weeks of daily application, the external researcher measured the melanin index with Dermacatch, measuring 6 times on each square. The following results are the averages of all values ​​obtained by the formula (6 volunteers, 6 measurements). In addition, the volunteers were asked to evaluate the effect of the depigmentation treatment on a scale of 0-5 (0 = no effect; 5 = very high effect).

[0200]

[0201]

[0202]

[0203] *Significant compared with baseline

[0204] **Combination synergy

[0205] ***Significantly more effective than taking all 3 ingredients simultaneously

[0206] Embodiment 3:

[0207] The combination of cysteamine, azabenzene-4-carboxamide and glycolic acid has a synergistic immediate depigmentation effect. In addition, when the three compounds are combined together, the shelf life of the composition is synergistically increased.

[0208] Compositions tested:

[0209] o Cysteamine hydrochloride: 0.2% w / w to 20% w / w

[0210] o Azobenzene-4-carboxamide: 0.2% w / w to 20% w / w

[0211] ο Glycolic acid: 2% w / w to 20% w / w

[0212] Test 4: Measurement of the skin color index (Dermacatch) 15 seconds after application of the topical composition. 6 volunteers were tested. On both arms of each volunteer, 21 skin squares were determined. The position of each cream on each square was randomly determined by an external person, and the volunteers and researchers were not aware of it. An external, uninformed and trained person applied a small amount of cream (about 50 mg) to the corresponding square with a disposable latex finger pad, replaced the finger pad between each square, and measured the skin color index by Dermacatch, measuring 6 times on each square. The following results are the averages of all values ​​obtained by the formula (6 volunteers, 6 measurements). In addition, the volunteers were asked to evaluate the effect of the immediate depigmentation treatment on a scale of 0-5 (0 = none; 5 = very high) by comparing with the normal skin around the determined skin square.

[0213]

[0214]

[0215] **Combination synergy

[0216] Test 5: Shelf Life Estimation after Accelerated Stability Studies

[0217] The following compositions are stored at room temperature (20°C to 25°C). The pH and viscosity of the formulations are measured every 2 months and compared with the baseline. The content of each ingredient of the composition is also measured by analytical methods and compared with the baseline. The shelf life is determined when one of the parameters including pH, viscosity or analytical dose is determined to be beyond the range of the baseline value [90% to 110%].

[0218]

[0219]

[0220] **Combination synergy

[0221] Example 4

[0222] The addition of 0.2% w / w to 15% w / w of azabenzene-4-carboxamide or its salt to a composition already comprising cysteamine or its salt and glycolic acid provides an even greater reduction in the unpleasant smell of cysteamine, resulting in increased acceptability of the product to the treated subjects.

[0223] Compositions tested:

[0224] o Cysteamine hydrochloride: 1% w / w to 20% w / w

[0225] o Azobenzene-4-carboxamide: 0.2% w / w to 15% w / w

[0226] ο Glycolic acid: 2% w / w to 20% w / w

[0227] Test 6: An external operator prepared a composition in a 50 mL container. Then, a fragrance test strip was impregnated with 0.3 mL of the reference composition or the test composition, and then dried for 15 min. Then, 6 volunteers were asked to first smell the fragrance test strip impregnated with the composition to be tested, and then smell the reference fragrance test strip impregnated with the reference composition (containing the same percentage of cysteamine hydrochloride as the composition to be tested), and the following evaluations were performed:

[0228] -1- Unpleasant odor (such as sulfur odor) has not been reduced

[0229] -2-Unpleasant odors (such as sulfur odor) are slightly reduced

[0230] -3-Reduction of unpleasant odors (such as sulfur odor)

[0231] -4-Unpleasant odors (such as sulfur odor) are greatly reduced

[0232] -5- Unpleasant odors (such as sulfur odor) are completely reduced

[0233] For each formulation (baseline composition and test composition), 6 volunteers were asked to answer the question "Is this product acceptable as a cosmetic product?", rating it on a scale of 1 to 5 (1 = unacceptable; 5 = perfect).

[0234]

[0235] **Combination synergy

Claims

1. A composition comprising 0.2% w / w to 20% w / w of cysteamine or a salt thereof, 0.2% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, and • 2% w / w to 20% w / w glycolic acid.

2. The composition of claim 1, comprising 5% w / w to 20% w / w cysteamine or a salt thereof, or 2% w / w to 12% w / w cysteamine or a salt thereof, or 5% w / w to 12% w / w cysteamine or a salt thereof, or 0.2% w / w to 7% w / w cysteamine or a salt thereof, or 2% w / w to 7% w / w cysteamine or a salt thereof.

3. The composition of any one of claims 1 to 2, comprising 3% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% w / w to 10% w / w of azabenzene-4-carboxamide or a salt thereof.

4. The composition of any one of claims 1 to 3, comprising 3.5% w / w to 20% w / w glycolic acid, or 3.5% w / w to 15% w / w glycolic acid, or 2% w / w to 10% w / w glycolic acid, or 2% w / w to 15% w / w glycolic acid.

5. The composition of claim 1, comprising 5% w / w to 20% w / w of cysteamine or a salt thereof, 3% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, and · 3.5% w / w to 20% w / w glycolic acid.

6. The composition of claim 1, comprising 0.2% w / w to 7% w / w of cysteamine or a salt thereof, 0.2% w / w to 10% w / w of azobenzene-4-carboxamide or a salt thereof, and 2% w / w to 10% w / w glycolic acid.

7. The composition of any one of claims 1 to 6, further comprising at least one cosmetically acceptable excipient, dermatologically acceptable excipient or pharmaceutically acceptable excipient.

8. The composition of any one of claims 1 to 7, further comprising at least one skin benefit agent selected from the group consisting of kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, heparan sulfate and its analogs, dermatan sulfate and its analogs, chondroitin sulfate and its analogs, emblica extract, daisy extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, tertiary butylhydroquinone, retinol, panthenol, vitamin E selected from tocopherol and tocopheryl acetate, vitamin C selected from ascorbyl palmitate, sodium ascorbyl phosphate and ascorbic acid, vitamin B or its derivatives, moisturizing sugars selected from xylitol glucoside, anhydroxylitol and xylitol, diacids, corticosteroids, 4-substituted resorcinol derivatives and mixtures thereof.

9. The composition of any one of claims 1 to 8, wherein the composition is in the form of an emulsion, cream, gel, solution, spray, cleanser, powder, ointment, wax, lipstick, soap, shampoo, hydroalcoholic solution, suspension, scrub, impregnated pad or skin conditioner.

10. The composition of any one of claims 1 to 9 for use in a method of inhibiting, reducing or preventing a skin hyperpigmentation disease or disorder in a subject.

11. The composition for use in a method of inhibiting, reducing or preventing a skin pigmentation disease or disorder as claimed in claim 10, wherein the hyperpigmentation disease or disorder is selected from the group consisting of melasma, phytophotodermatitis, lentigo (solar lentigo and senile lentigo), freckles, café au lait spots (possibly associated with neurofibromatosis or Albright syndrome), acanthosis nigricans, facial skin discoloration, Addison's disease, biliary cirrhosis, ectopic ACTH syndrome, eosinophilia-myalgia syndrome, folate deficiency, hemochromatosis, junctional and compound nevi, melanosis secondary to metastatic melanoma, Nelson syndrome, pellagra, pigmented actinic keratosis, pigmented keratinocyte tumors, POEMS syndrome, porphyria cutanea tarda, seborrheic keratosis, vitamin B12 deficiency, Whipple's disease and / or post-inflammatory hyperpigmentation; preferably, the skin hyperpigmentation disorder or disease is selected from the group comprising melasma, lentigo, post-inflammatory hyperpigmentation and / or facial skin discoloration.

12. A cosmetic method for inhibiting, reducing or preventing pigmentation of normal healthy skin, comprising topically applying the composition of any one of claims 1 to 9 to the skin of a subject in need thereof.

13. A cosmetic method for inhibiting, reducing or preventing pigmentation of normal healthy skin, comprising the following steps: a) topically applying to an area of ​​the skin of a subject in need thereof a first composition comprising: 0.2% w / w to 20% w / w of cysteamine or a salt thereof, and 2% w / w to 20% w / w glycolic acid, b) rinsing off said first composition, c) topically applying to said area of ​​skin a second composition comprising 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof, d) Repeat steps a), b) and c) to obtain the desired skin depigmentation effect.

14. A combination product comprising a first composition and a second composition for separate topical application, wherein the first composition comprises 0.2% w / w to 20% w / w of cysteamine or a salt thereof and 2% w / w to 20% w / w of glycolic acid, and • The second composition comprises 0.2% w / w to 20% w / w of azabenzene-4-carboxamide or a salt thereof.

15. The combination product of claim 14, consisting of the following first composition and second composition: The first composition consists of: o 0.2% w / w to 20% w / w of cysteamine or a salt thereof, o2% w / w to 20% w / w glycolic acid, o 0.01% w / w to 1% w / w retinol, and o cosmetically acceptable excipients, and The second composition consists of: o 0.2% w / w to 20% w / w of azobenzene-4-carboxamide or a salt thereof, o Up to 15% w / w of a skin conditioning agent selected from the group consisting of xylitol glucoside, anhydroxylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, o 0.01% w / w to 1% w / w retinol, and o Cosmetically acceptable excipients.

16. A method of reducing the bad smell of cysteamine or a salt thereof, comprising combining 0.2% w / w to 20% w / w cysteamine or a salt thereof, with 0.2% w / w to 20% w / w azabenzene-4-carboxamide or a salt thereof and 0.2% w / w to 20% w / w glycolic acid.

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