Skin depigmenting compositions and uses thereof

Abstract

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 skin hyperpigmentation diseases or disorders. One aspect of the present invention provides a composition comprising 0.2% to 20% w / w of cysteamine or a salt thereof, 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, and 2% to 20% w / w of glycolic acid.

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 skin hyperpigmentation diseases or disorders. The composition of the present invention provides immediate depigmenting effects after 8 weeks of treatment, resulting in reduced skin irritation, increased long-term depigmenting efficacy, increased shelf life, and reduced unpleasant odor. [Background technology]

[0002] Human skin color varies considerably throughout the world. Human skin tone results from a complex series of cellular processes that take place in melanocytes, located in the lower epidermis. These processes result in the synthesis and transfer of the pigment melanin, which is not only responsible for skin color and tone but also an important physiological defense against sun-induced damage, such as sunburn, photoaging, and photocarcinogenesis.

[0003] Various compositions have been formulated in an attempt to simply obtain brighter / lighter skin or to address hyperpigmentation disorders such as melasma, freckles, lentigines, and dark spots on the skin. The use of such compositions is not limited to use in the treatment of pigmentation diseases or disorders, but may also be used in some cultures / markets simply to change or modify the natural, healthy skin color of a person.

[0004] Numerous agents and methods for skin depigmentation have been developed and are commercially available. Such methods include oral administration of large amounts of vitamin C, parenteral administration of glutathione, topical administration of peroxide bleaching agents such as hydrogen peroxide, zinc peroxide, and sodium peroxide for skin depigmentation, and topical application of vitamin C and / or cysteine. However, vitamin C has stability issues and changes in color and odor, especially in aqueous formulations. Thiol compounds such as glutathione and cysteine ​​have slow and / or generally inadequate depigmenting performance characteristics.

[0005] The most commonly used depigmenting agents are hydroquinone and its derivatives. However, although these compounds are effective, they have serious and harmful side effects. Even at concentrations below 2%, hydroquinone is irritating to melanocytes and is also cytotoxic. Similar problems have been experienced with peroxide depigmenting agents. Another known depigmenting agent is tretinoin, which is an effective treatment for both wrinkles and skin pigmentation, but is also known to cause dermatitis, which can lead to skin darkening.

[0006] A wide range of polyphenols present in plant extracts have also been used for the purpose of skin depigmentation.Such natural polyphenols are, for example, anthraquinones, arylbenzofurans, chalcones, coumarins, and flavonoids.One class of polyphenolic compounds that has attracted much attention is based on substituted resorcinol and its derivatives.However, despite their relatively excellent skin whitening ability, they tend to suffer from stability problems, which often result in a loss of skin whitening efficacy, and are generally not suitable for topical application.

[0007] Another drug that has shown interesting depigmenting effects is nicotinamide. Nicotinamide is a 3-substituted pyridine that exerts its skin depigmenting effect by inhibiting melanosome transfer from melanocytes to keratinocytes. Despite being well tolerated by human skin, nicotinamide has poor skin depigmenting effects.

[0008] Cysteamine has been formulated as a therapeutic agent in a variety of topical and dermatological compositions, such as pharmaceutical or cosmetic compositions, and is commonly used as a drug to manage skin depigmentation, however, its use is limited by poor patient compliance due to its unpleasant odor.

[0009] Cysteamine has also been used in combination with citric acid, glycolic acid, or lactic acid (Patent Document 1). However, this combination was associated with concentrations of citric acid, glycolic acid, and lactic acid of 1% or less. 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, probably due to the risk of inflammation associated with higher concentrations of organic acids.

[0010] Therefore, there remains a need for skin depigmenting compositions that provide effective whitening capabilities in just a few weeks and do not cause significant inflammation, irritation, or photosensitivity to the skin after application.

[0011] An ideal skin depigmenting composition should have a strong, rapid and selective depigmenting effect, be well tolerated, have no short- or long-term side effects, act at one or more stages of the pigmentation process, have a sufficiently long shelf life, and, in that regard, should not have an odor that is perceived as unpleasant. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] Swiss Patent No. 706 226 A2 Summary of the Invention

[0013] One aspect of the present invention is 0.2% to 20% w / w of cysteamine or its salts, 0.2% to 20% w / w of azabenzene-4-carboxamide or its salts, and 2% to 20% w / w glycolic acid A composition comprising:

[0014] Another aspect of the present invention provides a composition of the present invention for use in a method for inhibiting, reducing or preventing a skin hyperpigmentation disease or disorder in a subject.

[0015] A further aspect of the present invention provides a cosmetic method for inhibiting, reducing or preventing pigmentation in normal, healthy skin, comprising topically applying a composition of the present invention to the skin of a subject in need thereof.

[0016] A further aspect of the present invention is a cosmetic method for inhibiting, reducing or preventing pigmentation in normal healthy skin, comprising: a) 0.2% to 20% w / w of cysteamine or a salt thereof, and 2% to 20% w / w glycolic acid topically applying to an area of ​​skin of a subject in need thereof a first composition comprising: b) rinsing the first composition; c) topically applying to said area of ​​skin a second composition comprising 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof; d) repeating steps a), b) and c) to achieve the desired skin depigmentation effect. The present invention provides a method comprising:

[0017] Another aspect of the present invention is a combination product comprising a first composition and a second composition for separate topical application, the first composition comprises 0.2% to 20% w / w of cysteamine or a salt thereof and 2% to 20% w / w of glycolic acid; A combination product is provided, wherein the second composition comprises 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof.

[0018] Another aspect of the present invention provides a method for reducing the unpleasant odor of cysteamine or a salt thereof, comprising combining 0.2% to 20% w / w of cysteamine or a salt thereof with 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof and 2% to 20% w / w of glycolic acid. DETAILED DESCRIPTION OF THE INVENTION

[0019] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0020] In case of conflict, the present specification, including definitions, will control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0021] The term "comprise" is generally used in the sense of include, i.e., permitting the presence of one or more features or components. Also, as used in the specification and claims, the term "comprising" can include similar embodiments described with the terms "consisting of" and / or "consisting essentially of."

[0022] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0023] As used in this specification and claims, the term "and / or" when used in phrases such as "A and / or B" is intended to include "A and B," "A or B," or "A" and "B."

[0024] As used herein, the term "at least one" means "one or more," and is inclusive of terms such as "at least two," "at least three," "at least four," etc.

[0025] As used herein, the term "therapeutically effective amount" is defined as an amount of an agent sufficient to detectably and repeatedly improve, reduce, minimize or limit the extent of a skin disorder, disease or condition or its symptoms.

[0026] As used herein, the term "hypigmenting-effective amount" means an amount of a compound or composition that is sufficient to significantly induce a beneficial benefit to skin depigmentation, preferably a reduction in melanization or melanization rate of the skin, but low enough to avoid serious side effects.

[0027] As used herein, the term "pharmaceutically acceptable excipient" means that the composition so described or its components are suitable for administration to the subject's (patient's) body without undue toxicity, incompatibility, instability, hypersensitivity, allergic reaction, etc.

[0028] As used herein, the term "dermatologically acceptable" means that the composition so described or its components are suitable for use in contact with the skin of mammals, preferably humans, without undue toxicity, incompatibility, instability, irritation, allergic response, or the like.

[0029] As used herein, the term "treatment" refers to a therapeutic or preventative measure. A treatment can be administered to a subject who has a medical disorder, such as a skin disorder or condition, or who may ultimately acquire the disorder or condition, to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disorder or a recurring disorder.

[0030] 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.

[0031] As used herein, the term "topical" or "topically" refers to the application of the compositions of the present invention to the surface of the skin and / or a part thereof, such as the skin of the face, neck, arms, hands, legs and scalp, elbows, knees, male or female genital and anal areas, etc., so as to exhibit local activity. Thus, topical forms encompass cosmetic, dermatological and / or pharmaceutical dosage forms suitable for external application, such that direct contact with the skin and / or a part thereof occurs.

[0032] As used herein, the term "subject" is well-recognized in the art and is used herein to refer to a mammal, most preferably a human. In some embodiments, the subject is a subject in need of treatment or a subject with a skin pigmentation disease or disorder, such as hyperpigmentation. However, in other embodiments, the subject may be a normal subject with normal, healthy skin and in need of skin lightening (whitening). The term does not denote a particular age or sex. Thus, it is intended to include adult, juvenile, and newborn subjects, regardless of whether they are male or female.

[0033] As used herein, "depigmentation" (or lightening, bleaching, whitening, and brightening, as used interchangeably herein) is the lightening or loss of pigment in the skin. Skin depigmenting agents or compositions are also referred to as "skin lighteners," "skin whiteners," "skin even-toners," and "skin brighteners." Whatever term is used, the general premise is that they all involve a reduction in the melanization or rate of melanization of the skin, resulting in a loss of pigment.

[0034] As used herein, the terms "instant depigmenting effect," "instant bleaching effect," or "instant skin depigmentation" refer to the visual effect of lightening skin tone within seconds or minutes after application of a topical product / composition. This effect results in immediate skin radiance and a more even skin tone, perceived by a decrease in the melanin index.

[0035] As used herein, the term "post-inflammatory hyperpigmentation" refers to changes in melanin content as a response to an inflammatory event (e.g., acne, scratch, laser treatment, insect bite or sting, sunburn, etc.), particularly in individuals with darker skin tones or pigmentation.

[0036] As used herein, the term "reduction" or "reducing" of an unpleasant odor, such as the sulfur odor of cysteamine or a salt or ester thereof, refers to the attenuation, mitigation, and / or reduction of the unpleasant odor such that the unpleasant odor is not perceived or is barely perceived by a human subject. The term also refers to the elimination and / or elimination of the unpleasant odor.

[0037] The Applicant has surprisingly found that a combination of 0.2% to 20% w / w of cysteamine or a salt thereof, 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, and 2% to 20% w / w of glycolic acid provides unexpected benefits and synergistic effects in the following areas: long-term and immediate skin depigmentation, anti-inflammatory effect, increased shelf life, and reduction of the unpleasant odor of cysteamine or a salt thereof.

[0038] First, the Applicant has surprisingly found that a combination of 0.2% to 20% w / w cysteamine or a salt thereof, 0.2% to 20% w / w azabenzene-4-carboxamide or a salt thereof, and 2% to 20% w / w glycolic acid provides a less irritating formulation compared to prior art formulations having lower concentrations of glycolic acid, even though glycolic acid itself is regarded in the medical literature as an irritant.

[0039] Second, in contrast to existing cysteamine formulations containing glycolic acid at concentrations less than 1%, the compositions of the present invention, containing cysteamine, azabenzene-4-carboxamide, and 2% or more glycolic acid, exhibit immediate skin depigmentation effects just seconds after application to human skin, while reducing the unpleasant odor of cysteamine. Instant depigmentation effects are extremely rare, providing significant value and advantages to the product (composition), particularly in terms of patient compliance. Indeed, one of the most frequent problems with topical depigmentation treatments is their onset of action, which typically takes 2 to 4 weeks for initial results to appear. Therefore, many patients discontinue treatment early due to lack of motivation after not seeing depigmentation effects after the first application. Combining cysteamine and azabenzene-4-carboxamide with other alpha-hydroxy acids (AHAs), such as lactic acid or tartaric acid, does not produce such immediate depigmentation effects.

[0040] Third, the applicant has surprisingly found that the addition of azabenzene-4-carboxamide to a composition comprising cysteamine or a salt thereof and glycolic acid, even at low percentages starting from 0.2% up to 20%, synergistically increases the long-term skin depigmenting effect, making it significantly more visible and perceptible by the treated subject after 8 weeks of treatment. According to one embodiment, the applicant has surprisingly found that when azabenzene-4-carboxamide is applied in a skin depigmenting method (a "two-step" method) rather than simultaneously with cysteamine or a salt thereof and glycolic acid, the skin depigmenting effect after 8 weeks is even further improved.

[0041] Furthermore, the Applicant has surprisingly found that the addition of 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof to a composition already containing cysteamine or a salt thereof and glycolic acid results in an even greater reduction in the unpleasant odor of cysteamine, leading to increased acceptability of the product by the treated subjects.

[0042] Finally, the combination of cysteamine and glycolic acid at concentrations of 2% or higher together with azabenzene-4-carboxamide exhibits a surprising synergistic effect that has not been previously known to improve the shelf life and durability of the product.

[0043] Thus, one aspect of the present invention is 0.2% to 20% w / w of cysteamine or its salts, 0.2% to 20% w / w of azabenzene-4-carboxamide or its salts, and 2% to 20% w / w glycolic acid A composition comprising:

[0044] In some embodiments, the compositions of the present invention comprise 5% to 20% w / w cysteamine or a salt thereof, or 2% to 12% w / w cysteamine or a salt thereof, or 5% to 12% w / w cysteamine or a salt thereof, or 0.2% to 7% w / w cysteamine or a salt thereof, or 2% to 7% w / w cysteamine or a salt thereof, or 3% to 20% w / w cysteamine or a salt thereof, or 1% to 12% w / w cysteamine or a salt thereof, or 3% to 12% w / w cysteamine or a salt thereof, or 0.2% to 7% w / w cysteamine or a salt thereof, or 1% to 7% w / w cysteamine or a salt thereof.

[0045] In other embodiments, the composition of the present invention comprises 3% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% to 10% w / w of azabenzene-4-carboxamide or a salt thereof.

[0046] In further embodiments, the compositions of the invention comprise between 3.5% and 20% w / w glycolic acid, or between 3.5% and 15% w / w glycolic acid, or between 2% and 10% w / w glycolic acid, or between 2% and 15% w / w glycolic acid.

[0047] In one embodiment, the composition of the present invention comprises: 5% to 20% w / w of cysteamine or its salts, 3% to 20% w / w of azabenzene-4-carboxamide or its salts, and 3.5% to 20% w / w glycolic acid Includes:

[0048] In a further embodiment, the composition of the present invention comprises: 0.2% to 7% w / w of cysteamine or its salts, 0.2% to 10% w / w of azabenzene-4-carboxamide or its salts, and 2% to 10% w / w glycolic acid Includes:

[0049] The present invention also provides a combination product comprising or consisting of a first composition and a second composition for separate topical application, the first composition comprises 0.2% to 20% w / w of cysteamine or a salt thereof, and 2% to 20% w / w of glycolic acid; The second composition contains 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof.

[0050] In one embodiment, the combination product of the present invention comprises: a first composition, 0.2% to 20% w / w of cysteamine or a salt thereof, preferably 5% to 20% w / w of cysteamine or a salt thereof, or 2% to 12% w / w of cysteamine or a salt thereof, or 5% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 2% to 7% w / w of cysteamine or a salt thereof, or 3% to 20% w / w of cysteamine or a salt thereof, or 1% to 12% w / w of cysteamine or a salt thereof, or 3% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 1% to 7% w / w of cysteamine or a salt thereof, 2% to 20% w / w glycolic acid, preferably 3.5% to 20% w / w glycolic acid, or 3.5% to 15% w / w glycolic acid, or 2% to 10% w / w glycolic acid, or 2% to 15% w / w glycolic acid, 0.01% to 1% w / w retinol, and Cosmetically acceptable excipients a first composition consisting of and a second composition, 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, preferably 3% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, up to 15% w / w of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% to 15% w / w or 0.01% to 10% of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% to 15% w / w or 0.01% to 10% of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol and / or combinations thereof, 0.01% to 1% retinol, and Cosmetically acceptable excipients A second composition consisting of It consists of:

[0051] In the context of the present invention, Tasman pepper is a natural active ingredient of Australian origin extracted from Tasmanian pepper berries.

[0052] In some embodiments, the first composition of the combination product of the invention comprises 5% to 20% w / w cysteamine or a salt thereof, or 2% to 12% w / w cysteamine or a salt thereof, or 5% to 12% w / w cysteamine or a salt thereof, or 0.2% to 7% w / w cysteamine or a salt thereof, or 2% to 7% w / w cysteamine or a salt thereof, or 3% to 20% w / w cysteamine or a salt thereof, or 1% to 12% w / w cysteamine or a salt thereof, or 3% to 12% w / w cysteamine or a salt thereof, or 0.2% to 7% w / w cysteamine or a salt thereof, or 1% to 7% w / w cysteamine or a salt thereof.

[0053] In other embodiments, the first composition of the combination product of the invention comprises between 3.5% and 20% w / w glycolic acid, or between 3.5% and 15% w / w glycolic acid, or between 2% and 10% w / w glycolic acid, or between 2% and 15% w / w glycolic acid.

[0054] In a further embodiment, the second composition of the combination product of the invention comprises 3% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% to 10% w / w of azabenzene-4-carboxamide or a salt thereof.

[0055] In this disclosure, % w / w of cysteamine or a salt thereof refers to % w / w of cysteamine (cysteamine free base). Thus, any reference to a specific mass of "cysteamine or a salt thereof" refers to the mass equivalent to the free base (cysteamine free base), and any reference to a specific mass of a specific salt of cysteamine, such as cysteamine hydrochloride, refers to the mass of the specific salt. The above definition also applies to % w / w of azabenzene-4-carboxamide or a salt thereof, for example, any reference to a specific mass of "azabenzene-4-carboxamide or a salt thereof" refers to the mass equivalent to the free base (azabenzene-4-carboxamide).

[0056] As used herein, the term "cysteamine" is intended to include any (pharmaceutically, cosmetically, or dermatologically) acceptable salt, ester, solvate, hydrate, prodrug, or any other compound that can provide cysteamine (directly or indirectly) upon administration to a patient. Preferred salts of cysteamine are hydrochloride, tartrate, and 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 hydrolyze, oxidize, or otherwise react under biological conditions to provide cysteamine. Examples of prodrugs include, but are not limited to, derivatives and metabolites of cysteamine that contain biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's "Medicinal Chemistry and Drug Discovery" 6th ed. (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers). In addition, the cysteamine referred to herein may be in crystalline or amorphous form, either as a free compound or as a solvate (e.g., hydrate), and all forms are intended to be within the scope of the present invention. Solvation methods are generally known in the art.

[0057] Salts of azabenzene-4-carboxamide are pharmaceutically acceptable salts, cosmetically acceptable salts and dermatologically acceptable salts.

[0058] 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 isolation 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 the aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes, including 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, and 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, as well as organic salts made from organic bases such as choline, diethanolamine, and morpholine. Other examples of organic salts are quaternary salts such as ammonium salts and tetramethylammonium salts; and amino acid addition salts such as salts with glycine and arginine. Further information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. For solid pharmaceutical agents, those skilled in the art will understand that the compounds, agents, and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention.

[0059] The combination products and compositions of the present invention can be prepared by any method known in the art for cosmetic, dermatological, and / or pharmaceutical compositions. Generally, this method involves simple mixing or blending of the ingredients, although more intensive stirring or homogenization may be required to prepare a suitable composition, such as an emulsion or suspension, particularly when insoluble or immiscible ingredients are used. Additionally, during preparation, it may be desirable to add known pH adjusters to maintain the appropriate pH of the composition for topical application, particularly when basic ingredients are used. Generally, the pH should be in the range of about 3.5 to about 8.

[0060] In some embodiments, the compositions of the present invention are cosmetic compositions further comprising cosmetically acceptable excipients for topical administration.

[0061] In some embodiments, the compositions of the present invention are dermatological compositions further comprising a dermatologically acceptable excipient for dermatological administration.

[0062] In some embodiments, the compositions of the present invention are pharmaceutical compositions further comprising a pharmaceutically acceptable excipient for oral or topical administration.

[0063] In some embodiments, the present invention provides 0.2% to 20% w / w of cysteamine or its salts, 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, 2% to 20% w / w glycolic acid, 0.01% to 1% w / w retinol, and Cosmetically acceptable excipients for topical administration or pharmaceutically acceptable excipients for oral or topical administration A composition comprising:

[0064] The cosmetic, dermatological and pharmaceutical compositions according to the present invention may further comprise one or more cosmetically, dermatologically or pharmaceutically acceptable excipients conventionally used in such compositions, such as preservatives, antioxidants, chelating agents, bactericides, fragrances, substances for preventing foaming, dyes, pigments with coloring effects, thickeners, propellants, surfactants, emulsifiers, emollients, moisturizing and / or moisture-retaining substances, distilled water, fats, oils, waxes or other conventional components of cosmetic, dermatological or pharmaceutical compositions, such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives. The required amount of cosmetically, dermatologically or pharmaceutically acceptable excipients can be easily selected by those skilled in the art based on the desired product.

[0065] Moisturizing agents can be incorporated into the compositions of the present invention to maintain skin hydration or replenish moisture to the skin.Moisturizing agents that prevent moisture evaporation from the skin by providing a protective film are called emollients.In addition, emollients provide a softening or soothing effect on the skin surface and are generally considered safe for topical use.Preferred emollients include mineral oil, lanolin, petrolatum, capric / caprylic triglyceride, cholesterol, silicones such as dimethicone and 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 and hexadecyl (ENJAY), diisopropyl adipate, hydroxybenzoic acid esters, C 9~15 Benzoic acid esters of alcohols, isononyl isononanoate, ethers such as polyoxypropylene butyl ether and polyoxypropylene cetyl ether, and C 12~15-alkyl benzoates, and mixtures thereof. Moisturizing substances that bind water and thereby retain it on the skin surface are called humectants. Suitable humectants, such as glycerin, polypropylene glycol, polyethylene glycol, lactic acid, pyrrolidone carboxylic acid, urea, phospholipids, collagen, elastin, ceramide, lecithin, sorbitol, PEG-4, and mixtures thereof, can be incorporated into the skin depigmenting composition of the present invention.

[0066] The compositions of the present invention may also contain conventional alcohols, especially lower alcohols, preferably ethanol and / or isopropanol, lower diols or polyols and their ethers, preferably propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl or monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether, and similar products, polymers, foam stabilizers, electrolytes, and in particular one or more thickeners. Thickeners that can be used in the compositions of the present invention to help achieve a suitable product consistency include carbomer, silicon dioxide, magnesium and / or aluminum silicate, beeswax, stearic acid, stearyl alcohol polysaccharides and their derivatives, such as xanthan gum, hydroxypropyl cellulose, polyacrylamide, acrylate crosspolymers, preferably carbomer, such as Carbopol® types 980, 981, 1382, 2984, and 5984, alone or in mixtures thereof.

[0067] Suitable stabilizers that may be included in the compositions of the present invention to stabilize ingredients such as emulsifiers or foam builders / stabilizers include, but are not limited to, alkali hydroxides such as sodium hydroxide and potassium hydroxide; organic bases such as diethanolamine (DEA), triethanolamine (TEA), aminomethylpropanol, and mixtures thereof; amino acids such as arginine and lysine, and any combination of any of the foregoing.

[0068] The compositions of the present invention may also contain UV radiation-absorbing filters or sunscreens, the total amount of which is, for example, 0.001 to 30%, preferably 0.5 to 10%, based on the total weight of the formulation. The compositions may also function as sunscreens for the skin. Examples of such UV filters include avenobenzene, cinoxate, dioxybenzone, homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, phenylbenzimidazole sulfonic acid, sulisobenzone, titanium dioxide, trolamine salicylate, and zinc oxide.

[0069] The compositions of the present invention may also contain one or more skin penetration agents. These are additives that, when applied to the skin, directly affect the permeability of the skin barrier. They increase the rate and / or amount at which certain other compounds can penetrate the skin layers. Exemplary organic penetration enhancers include dimethyl sulfoxide; isopropyl myristate; decyl, undecyl, or dodecyl alcohol; propylene glycol; polyethylene glycol; C 9~11 or C 12~15 Examples include fatty alcohols; azone; alkylpyrrolidone; diethoxyglycol (Transcutol); lecithin, etc. Surfactants can also be used as penetration enhancers.

[0070] According to one embodiment, the composition of the present invention may further comprise at least one skin benefit agent selected from the group comprising kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, heparan sulfate and analogs thereof, dermatan sulfate and analogs thereof, chondroitin sulfate and analogs thereof, Phyllanthus emblica extract, Bellis perennis extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, t-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 and derivatives thereof, moisturizing sugars selected from xylitylglucoside, anhydrous xylitol, and xylitol, dioic acid, corticosteroids, 4-substituted resorcinol derivatives, and mixtures thereof. In further embodiments, the 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, natural extracts selected from Tasmannia Lanceolata Fruit / Leaf Extract and Hordeum Vulgare Seed Flour, and moisturizing sugars selected from xylitylglucoside, anhydrous xylitol, and xylitol.In further embodiments, the at least one skin benefit agent is selected from the group consisting of kojic acid, arbutin, deoxyarbutin, soybean extract, licorice extract, heparan sulfate, dermatan sulfate, chondroitin sulfate, Emblica officinalis extract, Daisy extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, t-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 xylitylglucoside, anhydrous xylitol, and xylitol, dioic acid, corticosteroids, and mixtures thereof.

[0071] According to another embodiment, the composition of the present invention may also further comprise liposomes (unilamellar and / or multilamellar liposomes of any size), niosomes, or any encapsulation system (microencapsulation, nanoencapsulation, cubosomes, etc.) to facilitate the delivery of any component of the composition to the site of action. The optimal type and size of the liposomes, niosomes and / or encapsulation system, as well as the nature of the medium in which they are dispersed, can be easily selected by a person skilled in the art.

[0072] The compositions of the present invention may be cosmetic, dermatological, or pharmaceutical compositions and may exist in a wide variety of forms, such as emulsions, suspensions, solutions, etc. In certain embodiments, the compositions of the present invention are in the form of lotions, creams, gels, solutions, sprays, cleansers, powders, ointments, waxes, lipsticks, soaps, shampoos, hydroalcoholic solutions, suspensions, scrubs, saturated pads, skin conditioners, and other types of cosmetic compositions. In further embodiments, the compositions of the present invention may be, for example, anhydrous preparations, oil-free preparations, water-in-oil (W / O) or oil-in-water (O / W) emulsions or microemulsions, such as water-in-oil-in-water (W / O / W) multiple emulsions, solid sticks, or even aerosols.

[0073] The preferred forms of the composition of the present invention are gel, lotion, emulsion and powder forms.

[0074] In some embodiments, the present invention relates to topical compositions that promote immediate skin depigmentation through the synergistic action of the active ingredients cysteamine or a salt thereof, azabenzene-4-carboxamide or a salt thereof, and glycolic acid.

[0075] In some embodiments, the present invention relates to topical compositions that promote 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.

[0076] In some embodiments, the present invention relates to topical compositions that promote increased shelf life through the synergistic action of the active ingredients cysteamine or a salt thereof, azabenzene-4-carboxamide or a salt thereof, and glycolic acid.

[0077] The compositions of the present invention have significantly reduced or eliminated unpleasant odors and improved organoleptic properties, making them more acceptable and more suitable for topical pharmaceutical and cosmetic applications.

[0078] According to one aspect of the present invention, the composition of the present invention is used for depigmenting (whitening or lightening) human skin. According to a further aspect, the present 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, armpit skin, scalp skin, and skin of the male or female genital area.

[0079] In some embodiments, the compositions of the present invention are used for cosmetic depigmentation of natural, healthy human skin, i.e., for non-therapeutic uses not related to the treatment of skin diseases or pathological conditions. In some embodiments, cosmetic depigmentation (cosmetics that inhibit, reduce, or prevent skin pigmentation) relates to skin whitening, skin radiance, skin brightness, skin evenness, skin depigmentation, and prevention of age spots and / or blemishes. In other embodiments, the skin pigmentation reduced or prevented according to the methods of the present invention can be a normal amount of pigmentation. For example, the methods can be used when a subject desires to reduce or prevent pigmentation in at least some areas of the skin for cosmetic reasons.

[0080] Therefore, according to one embodiment, the present invention provides a cosmetic use of the composition of the present invention for inhibiting, reducing or preventing skin pigmentation in normal, healthy skin. The skin is preferably at least one of the following: facial skin, neck skin, arm skin, hand skin, leg skin, elbow skin, knee skin, axillary region skin, scalp skin, and male or female genital region skin. The term "normal skin" refers to healthy skin without pigmentation disorders or diseases.

[0081] The present invention also provides a cosmetic method for inhibiting, reducing or preventing skin pigmentation in normal, healthy skin, comprising topically applying a composition of the present invention to the skin of a subject in need thereof.

[0082] In another embodiment, the present invention also provides a cosmetic method for reducing the pigmentation of normal, healthy skin in patients with generalized vitiligo to reduce the difference between affected skin and normal, healthy skin, comprising topically applying a composition of the present invention to the skin. In this embodiment, the subject may have a condition that results in hypopigmentation or localized hypomelanosis in one or more areas of the skin, such as vitiligo. Diseased areas of the skin have reduced or absent pigmentation, and these areas may differ significantly from adjacent unaffected areas of the skin that have normal, full pigmentation. The difference in pigmentation between affected and unaffected areas of skin can be reduced by reducing the level of pigmentation in unaffected (normal, healthy) skin or by preventing the normal level of pigmentation.

[0083] The cosmetic method of the present invention is repeated a number of times sufficient to inhibit, reduce or prevent skin pigmentation in normal, healthy skin, for example, until the desired depigmenting effect (endpoint) is achieved and / or after the desired depigmenting effect is achieved, in order to maintain the depigmenting results or effects, the method of the present invention is repeated not daily, not on consecutive days, or 1 to 6 times per week.

[0084] In a further embodiment of the cosmetic method of the present invention, once the desired depigmenting effect has been achieved, the cosmetic method of the present invention for inhibiting, reducing or preventing skin pigmentation in normal healthy skin can continue to be applied not daily, not every day, or 1 to 6 times a week to maintain the depigmenting results or effect.

[0085] Another aspect of the present invention is a cosmetic method for inhibiting, reducing or preventing pigmentation in normal healthy skin, comprising: a) 0.2% to 20% w / w of cysteamine or a salt thereof, preferably 5% to 20% w / w of cysteamine or a salt thereof, or 2% to 12% w / w of cysteamine or a salt thereof, or 5% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 2% to 7% w / w of cysteamine or a salt thereof, or 3% to 20% w / w of cysteamine or a salt thereof, or 1% to 12% w / w of cysteamine or a salt thereof, or 3% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 1% to 7% w / w of cysteamine or a salt thereof, and 2% to 20% w / w glycolic acid, preferably 3.5% to 20% w / w glycolic acid, or 3.5% to 15% w / w glycolic acid, or 2% to 10% w / w glycolic acid, or 2% to 15% w / w glycolic acid topically applying to an area of ​​skin of a subject in need thereof a first composition comprising: b) rinsing the first composition; c) topically applying to said area of ​​skin a second composition comprising 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, preferably 3% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, d) repeating steps a), b) and c) to achieve the desired skin depigmentation effect (endpoint). The present invention provides a beauty method including:

[0086] In some embodiments of the cosmetic method, the first composition in step a) is topically applied to an area of ​​the subject's skin in need thereof for a specific period of time, such as 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, or 2 hours, or for 15 to 30 minutes, 15 to 45 minutes, 15 to 1 hour, or 15 to 2 hours.

[0087] In other embodiments of the cosmetic method, the step of rinsing off the first composition in step b) is typically carried out by any suitable method before topically applying the second composition. In some embodiments, a suitable method includes: Rinse with water, with or without suitable cleaning agents; Removal with any suitable solvent or cleanser; Removal with a dry or wet pad; and / or combinations of these is selected from.

[0088] The cosmetic method of the present invention is repeated for a period or number of times sufficient to achieve the desired skin depigmentation effect (endpoint), such as 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 3 months, 1 year, 2 years, 3 years, or more, or 1 to 4 weeks, 1 to 8 weeks, 1 week to 1 year, 1 week to 2 years, 1 week to 5 years, etc. In another embodiment, after the desired depigmentation effect is achieved, the cosmetic method of the present invention is repeated not every day, not every day, or 1 to 4 times per week to maintain the depigmentation result or effect.

[0089] In further embodiments of the cosmetic method, once the desired depigmenting effect (endpoint) has been achieved, the cosmetic method can continue to be applied less than daily, less than consecutive days, or 1 to 4 times per week to maintain the depigmenting results or effect.

[0090] In a further embodiment of the cosmetic method, the first composition comprises: 0.2% to 20% w / w of cysteamine or a salt thereof, preferably 5% to 20% w / w of cysteamine or a salt thereof, or 2% to 12% w / w of cysteamine or a salt thereof, or 5% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 2% to 7% w / w of cysteamine or a salt thereof, or 3% to 20% w / w of cysteamine or a salt thereof, or 1% to 12% w / w of cysteamine or a salt thereof, or 3% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 1% to 7% w / w of cysteamine or a salt thereof, 2% to 20% w / w glycolic acid, preferably 3.5% to 20% w / w glycolic acid, or 3.5% to 15% w / w glycolic acid, or 2% to 10% w / w glycolic acid, or 2% to 15% w / w glycolic acid, 0.01% to 1% w / w retinol, and Cosmetically acceptable excipients It consists of:

[0091] In a further embodiment of the cosmetic method, the second composition comprises: 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, preferably 3% to 20% w / w of azabenzene-4-carboxamide or a salt thereof, or 2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 3% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.2% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, or 0.5% to 10% w / w of azabenzene-4-carboxamide or a salt thereof, up to 15% w / w of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% to 15% w / w or 0.01% to 10% of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof, preferably 0.01% to 15% w / w or 0.01% to 10% of a skin conditioning agent selected from xylitylglucoside, anhydrous xylitol, xylitol, panthenol and / or combinations thereof, 0.01% to 1% retinol, and Cosmetically acceptable excipients It consists of:

[0092] 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 melasma, phytophotodermatitis, lentigines (solar and senile lentigines), freckles, cafe au lait spots (which may be associated with neurofibromatosis or Albright syndrome), acanthosis nigricans, dyschromatosis facialis, Addison's disease, biliary cirrhosis, ectopic ACTH syndrome, eosinophilia-myalgia syndrome, folate deficiency, hemochromatosis, junctional and compound nevi, melanosis secondary to metastatic melanoma, Nelson's syndrome, pellagra, pigmented actinic keratosis, pigmented keratinocyte tumor, POEMS syndrome, porphyria cutanea tarda, seborrheic keratosis, vitamin B12 deficiency, and Whipple's disease and / or post-inflammatory hyperpigmentation, preferably the skin hyperpigmentation disorder or disease is selected from melasma, lentigines, post-inflammatory hyperpigmentation, and / or dyschromatosis facialis. Post-inflammatory hyperpigmentation can result from a variety of inflammatory responses, such as skin injury, burns, bites, acne or lupus inflammation.

[0093] Skin hyperpigmentation disorders or diseases are typically caused by increased production and accumulation of melanin, increased numbers of melanocytes, and / or increased activity of melanin-producing enzymes. Ultraviolet light, chronic inflammation, skin damage, and abnormal α-melanocyte-stimulating hormone (α-MSH) release are precipitating factors for skin hyperpigmentation disorders or diseases.

[0094] Skin hyperpigmentation can also be drug-induced hyperpigmentation, light-induced hyperpigmentation and chemical-induced hyperpigmentation.

[0095] A condition associated with skin hyperpigmentation is a condition characterized at least in part by the presence of a greater-than-desired amount of endogenous skin pigmentation affecting at least some area of ​​a subject's skin. In one embodiment, a condition associated with hyperpigmentation is a condition characterized at least in part by the presence of a greater-than-normal amount of endogenous skin pigmentation affecting at least some area of ​​a subject's skin. A greater-than-normal amount of endogenous skin pigmentation refers to an amount of pigmentation that is objectively greater than the amount of pigmentation present in either (a) another area of ​​the subject's skin, including, but not limited to, the average amount of pigmentation in the subject's skin, or (b) the same area of ​​the subject's skin at an earlier time, e.g., before the onset of hyperpigmentation. In different embodiments, hyperpigmentation can accompany or be a symptom of either a malignant or non-malignant (i.e., benign) condition. Endogenous skin pigmentation refers to skin pigmentation produced by cells within the skin, which is distinguished from skin pigmentation resulting from, for example, pigment injected into the skin, e.g., tattooing, or other forms of exogenous skin pigmentation.

[0096] The present invention also provides a composition of the invention for use as a pharmaceutical.

[0097] The present invention also provides a composition of the present invention for use in a method for inhibiting, reducing or preventing a skin hyperpigmentation disorder or disease in a subject.

[0098] The present invention further provides a method for inhibiting, reducing or preventing a skin hyperpigmentation disorder or disease, comprising topically applying a composition of the present invention to the skin of a subject in need thereof.

[0099] In a further embodiment of the method of the present invention, once the desired depigmentation effect has been achieved, the method of the present invention for inhibiting, reducing or preventing skin hyperpigmentation disorders or diseases can continue to be applied on a non-daily basis, on non-consecutive days, or 1 to 4 times per week to maintain the depigmentation results or effect.

[0100] The methods of the present invention are repeated a number of times sufficient to inhibit, reduce, or prevent a skin hyperpigmentation disorder or disease, for example, the methods of the present invention are repeated not daily, not on consecutive days, or 1 to 4 times per week until the desired depigmenting effect (endpoint) is achieved and / or to maintain the depigmenting results or effect after the desired depigmenting effect is achieved.

[0101] Those skilled in the art will understand that the endpoint selected in a particular case in the methods of the present invention for inhibiting, reducing, or preventing skin hyperpigmentation disorders or diseases and / or normal, healthy skin will vary depending on the disease, condition, or disorder being treated, the desired skin appearance, the outcome desired by the patient, subject, or treating physician, and other factors. When a composition or combination product is used to lighten skin color, such as for cosmetic treatments, or to reverse hyperpigmentation caused by diseases such as inflammation or melasma, any one or more endpoints can be selected. For example, an endpoint may be defined subjectively, such as when a subject is simply "satisfied" with the treatment results. In the case of pharmacological compositions, an endpoint can be determined by the patient's or treating physician's satisfaction with the results of the treatment. Alternatively, an endpoint may be defined objectively. For example, the patient's or subject's skin in the treated area may be compared to a color chart. When the skin color in the treated area appears similar to the color on the chart, treatment is terminated. Alternatively, the reflectance of the treated skin may be measured, and the treatment (cosmetic or therapeutic) may be terminated when the treated skin reaches a predetermined reflectance. In another method, the amount of melanin in the skin may be measured.

[0102] The hyperpigmented area of ​​skin or the area of ​​skin to be depigmented is approximately 1 mm 2 The term can include and refer to an area (portion) of skin as small as 1 cm up to including the entire surface of the skin. In certain general embodiments, the hyperpigmented area of ​​skin or the area of ​​skin to be depigmented is about 1 cm 2 ~Several tens of cm 2 The term "hyperpigmented area" can include and refer to portions (areas) of skin up to about 1000 nm in size, shape, and / or pigmentation. There may be one hyperpigmented area / area to be depigmented, or there may be more than one hyperpigmented area / area to be depigmented in a given subject. When there is more than one hyperpigmented area / area to be depigmented in a subject, the various hyperpigmented areas / areas to be depigmented may be similar or dissimilar to one another in size, shape, and / or pigmentation.

[0103] Thus, the uses and methods of the present invention for inhibiting, reducing or preventing skin pigmentation in skin hyperpigmentation disorders or diseases and / or normal healthy skin comprise the step of topically (topically) administering a composition of the present invention or a combination product of the present invention to pigmented skin to reduce skin pigmentation. In one embodiment, topically administering is topical administering.

[0104] In the method according to the present invention for inhibiting, reducing, or preventing skin hyperpigmentation disorders or diseases and / or skin pigmentation in normal, healthy skin, a composition or combination product is applied to the skin, preferably human skin. The amount of 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 light, uniform coating on the skin. Similarly, lotions, creams, gels, shampoos, and the like are typically applied in an amount to provide a light coating on the treatment area, consistent with the application of topical medicinal ointments, creams, lotions, and the like. Generally, when treating all or substantially all of the skin surface, particularly including hairy or hairless skin, the application volume is about 20-60 ml for the entire body, i.e., for the exposed skin of an "average individual" wearing a swimsuit, 1.65 m tall, 68 kg in weight, and 0.81 m waist. This corresponds to about 2 mg / cm of skin surface, including hairy or hairless skin surfaces. 2 On the face, a typical application amount is 0.5 to 1.0 ml. At such application levels, the amount of composition applied is about 0.1 to about 10 mg / cm of skin. 2 , preferably about 1 to about 3 mg / cm 2 is in the range.

[0105] The composition of the present invention or the combination product of the present invention can be applied once or multiple times a day depending on the activity that a specific subject is engaged in.For example, a subject who is engaged in normal weekday activities may want to apply the composition or combination product twice a day, once in the morning and once in the afternoon, along with normal grooming.On the other hand, if a subject plans to do outdoor activities such as sunbathing and athletics, the composition or combination product can be applied before and during such activities, just as sunscreen compositions are applied regularly during the day.The composition or combination product can be used for hyperpigmentation of the face and neck, or by applying appropriate composition to the scalp, face and neck area, it can be used to change the dark normal color of the scalp or body to a lighter color.However, the composition or combination product of the present invention can also be applied to the whole body, especially to areas not covered by clothing, such as arms, neck and lower legs.

[0106] For administration, the cosmetic, dermatological, and pharmaceutical compositions of the present invention can be applied to the skin (body surface) in a suitable depigmenting-effective amount by conventional methods for cosmetics and pharmaceuticals and have a topical, localized, as opposed to systemic, effect.

[0107] Another aspect of the present invention provides a method for reducing the unpleasant odor of cysteamine or a salt thereof, comprising combining 0.2% to 20% w / w of cysteamine or a salt thereof with 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof and 2% to 20% w / w of glycolic acid.

[0108] In some embodiments of the method for reducing unpleasant odors, the content of cysteamine or a salt thereof is 5% to 20% w / w, or 2% to 12% w / w, or 5% to 12% w / w, or 0.2% to 7% w / w, or 2% to 7% w / w, or 3% to 20% w / w of cysteamine or a salt thereof, or 1% to 12% w / w of cysteamine or a salt thereof, or 3% to 12% w / w of cysteamine or a salt thereof, or 0.2% to 7% w / w of cysteamine or a salt thereof, or 1% to 7% w / w of cysteamine or a salt thereof.

[0109] In other embodiments of the method for reducing unpleasant odors, the content of azabenzene-4-carboxamide or a salt thereof is 3% to 20% w / w, or 2% to 10% w / w, or 3% to 10% w / w, or 0.2% to 10% w / w.

[0110] In further embodiments of the method for reducing unpleasant odors, the content of glycolic acid is 3.5% to 20% w / w, or 3.5% to 15% w / w, or 2% to 10% w / w, or 2% to 15% w / w.

[0111] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all steps, features, compositions, and compounds referred to or illustrated herein, individually or collectively, as well as any and all combinations of any two or more of said steps or features. The present disclosure, therefore, should be considered in all illustrative and not limiting terms, the scope of the invention being indicated by the appended claims, and all changes that come within the meaning and range of equivalency thereof are intended to be embraced within the scope of the invention.

[0112] The foregoing description will be more fully understood with reference to the following examples, which are merely illustrative of methods of practicing the invention and are not intended to limit the application and scope of the invention. [Example]

[0113] Examples of compositions of the present invention: Composition A (Emulsion E / W QSP) -Cysteamine 8% -Sodium ascorbyl phosphate 1% -Ascorbyl palmitate 1.5% -Azabenzene-4-carboxamide 5% -Glycolic acid 5% -Fragrance 0.1%

[0114] Example 1 Topical compositions containing a high proportion of cysteamine or its salt and azabenzene-4-carboxamide may be considered irritating to the skin.The addition of glycolic acid reduces irritation and provides a soothing effect, which is surprising because glycolic acid is usually irritating to the skin.When glycolic acid is replaced with other alpha-hydroxy acids (AHAs), such as lactic acid or tartaric acid, or when glycolic acid is reduced to 1%, the irritation reduction and soothing effect are not observed.

[0115] Test composition: о Cysteamine hydrochloride: 5%~20% w / w Azabenzene-4-carboxamide: 3% to 20% w / w Glycolic acid: 3.5%~20% w / w

[0116] Study 1: Irritation potential scoring after 48 hours of patch testing under occlusive conditions performed on 20 volunteers. The results are shown below. [Table 1(1)] [Table 1(2)]

[0117] Test 2: Measurement of hemoglobin content to assess reduction in inflammation after 24 hours of exposure to SLS.

[0118] The study was conducted on 20 volunteers. 15 skin compartments were identified on each volunteer's back. After 24 hours of application of the occlusive SLS patch, hemoglobin content increased (signals of inflammatory symptoms such as redness). Each day for three days, a blinded and trained external person applied a small amount of cream (approximately 50 mg) to the corresponding compartment using a disposable latex finger pad, which was replaced between compartments. The location of each cream on each compartment was randomized by an external person, blinded to the volunteers and the investigator. After 72 hours, hemoglobin content was measured, and the results are shown below. [Table 2]

[0119] Example 2: Cysteamine with glycolic acid has limited depigmenting effects after 8 weeks of treatment. The addition of azabenzene-4-carboxamide synergistically increases the depigmenting effect, making it more visible and perceptible by the treated subject, even at a low percentage. When azabenzene-4-carboxamide is replaced with other azabenzene-4-carboxamide isomers, such as azabenzene-2-carboxamide and azabenzene-3-carboxamide, there is no synergistic effect and the depigmenting efficacy is perceived to be low. Surprisingly, it has been observed that applying azabenzene-4-carboxamide in a two-step method, which involves applying a first composition containing cysteamine or its salt and glycolic acid for a certain period of time (e.g., 15 minutes), then rinsing off the first composition, and finally applying a separate second composition containing azabenzene-4-carboxamide, improves the skin depigmenting effect. Again, when azabenzene-4-carboxamide is replaced with other azabenzene-4-carboxamide isomers, such as azabenzene-3-carboxamide, the two-step method of application does not improve skin depigmenting efficacy.

[0120] Test composition: о Cysteamine hydrochloride: 0.2%~7% w / w Glycolic acid: 2% to 10% w / w Azabenzene-4-carboxamide: 0.2% to 10% w / w

[0121] Study 3: Measurement of Skin Color Index (Dermacatch) After 8 Weeks of Treatment. This study was conducted on six volunteers. Twenty skin zones were identified on each volunteer's arm using UV irradiation. For eight weeks, volunteers were asked to apply a small amount of cream (approximately 50 mg) to the corresponding zone using a disposable latex finger pad, which was replaced between zones. The location of each cream on each zone was randomized by an external investigator and blinded to the volunteers and investigators. After eight weeks of daily application, an external investigator measured the melanin index using Dermacatch, taking six measurements for each zone. The results below are the average of all values ​​obtained by the formula (six volunteers, six measurements). In addition, volunteers were asked to rate the effectiveness of the depigmentation treatment on a scale of 0 to 5 (0 = no effectiveness, 5 = very high effectiveness). [Table 3(1)] [Table 3(2)]

[0122] Example 3: The combination of cysteamine, azabenzene-4-carboxamide, and glycolic acid has a synergistic immediate depigmenting effect. In addition, combining the three compounds together synergistically increases the shelf life of the composition.

[0123] Test composition: о Cysteamine hydrochloride: 0.2%~20% w / w Azabenzene-4-carboxamide: 0.2% to 20% w / w Glycolic acid: 2% to 20% w / w

[0124] Test 4: Measurement of Skin Color Index (Dermacatch) 15 seconds after application of the topical composition. This test was conducted on six volunteers. 21 skin patches were identified on both arms of each volunteer. The location of each cream on each patch was randomized by an external person, blinded to the volunteer and the investigator. A blinded and trained external person applied a small amount of cream (approximately 50 mg) to the corresponding patch using a disposable latex finger pad, which was replaced between patches, and measured the skin color index using Dermacatch. Six measurements were taken for each patch. The results below are the average of all values ​​obtained by the formula (six volunteers, six measurements). In addition, volunteers were asked to rate the effectiveness of the immediate depigmenting treatment by comparing the identified skin patch with the normal skin surrounding it on a scale of 0 to 5 (0 = none, 5 = very high). [Table 4(1)] [Table 4(2)]

[0125] Test 5: Shelf-life estimation after accelerated stability studies The following compositions were stored at room temperature (20°C-25°C). Every two months, the pH and viscosity of the formulations were measured and compared to baseline. The content of each component of the composition was also measured by analytical method and compared to baseline. The shelf life was determined when one of the parameters, including pH, viscosity, or analytical dose, was measured outside the range [90%-110%] of the baseline value. [Table 5]

[0126] Example 4 The addition of 0.2% to 15% w / w of azabenzene-4-carboxamide or a salt thereof to a composition already containing cysteamine or a salt thereof and glycolic acid further significantly reduces the unpleasant odor of cysteamine, resulting in improved acceptability of the product by treated subjects.

[0127] Test composition: о Cysteamine hydrochloride: 1%~20% w / w Azabenzene-4-carboxamide: 0.2% to 15% w / w Glycolic acid: 2% to 20% w / w

[0128] Test 6: An external operator prepared the compositions in a 50 ml container. Then, a perfumed paper test piece was impregnated with 0.3 ml of the reference composition or the test composition, and then left to dry for 15 minutes. Six volunteers were then asked to first smell the perfumed paper test piece impregnated with the test composition, and then to smell the reference perfumed paper test piece impregnated with the reference composition (containing the same proportion of cysteamine hydrochloride as the test composition), and were assigned the following evaluations: - 1- Unpleasant odors (such as sulfur odor) do not decrease - 2- Slight reduction in unpleasant odors (such as sulfur odor) - 3- Reduced unpleasant odors (such as sulfur odor) - 4- Unpleasant odors (such as sulfur odor) are greatly reduced - 5- Completely eliminates unpleasant odors (such as sulfur odor) For each preparation (baseline and test composition), six volunteers were asked to respond to the question "Is the product cosmetically acceptable?" by rating it on a scale of 1 to 5 (1 = unacceptable, 5 = perfect). [Table 6]

Claims

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

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

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

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

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

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

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

8. 8. The composition of any one of claims 1 to 7, further comprising at least one skin benefit agent selected from the group comprising kojic acid, arbutin, deoxyarbutin, depigmenting oligopeptides, soybean extract, licorice extract, heparan sulfate and analogs thereof, dermatan sulfate and analogs thereof, chondroitin sulfate and analogs thereof, Emblica officinalis extract, Daisy extract, glabridin, polyphenol antioxidants, thiol antioxidants, hydroquinone, methimazole, t-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 a derivative thereof, moisturizing sugar selected from xylitylglucoside, anhydrous xylitol, and xylitol, dioic acid, corticosteroids, 4-substituted resorcinol derivatives, and mixtures thereof.

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

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

11. The hyperpigmentation disease or disorder is selected from the group consisting of melasma, phytophotodermatitis, lentigines (solar and senile lentigines), freckles, cafe au lait spots (which may be associated with neurofibromatosis or Albright syndrome), acanthosis nigricans, dyschromatosis facialis, Addison's disease, biliary cirrhosis, ectopic ACTH syndrome, eosinophilia-myalgia syndrome, folate deficiency, hemochromatosis, junctional and compound nevi, melanosis secondary to metastatic melanoma, Nelson's syndrome, pellagra, and pigmented actinic keratosis. , pigmented keratinocyte neoplasia, POEMS syndrome, porphyria cutanea tarda, seborrheic keratosis, vitamin B12 deficiency, and Whipple's disease and / or post-inflammatory hyperpigmentation, preferably said skin hyperpigmentation disorder or disease is selected from the group comprising melasma, lentigo, post-inflammatory hyperpigmentation, and / or dyschromic facial syndrome.

12. 10. A cosmetic method for inhibiting, reducing or preventing pigmentation in 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. 1. A cosmetic method for inhibiting, reducing or preventing pigmentation in normal healthy skin, comprising: a) 0.2% to 20% w / w of cysteamine or a salt thereof, and 2% to 20% w / w glycolic acid topically applying to an area of ​​skin of a subject in need thereof a first composition comprising: b) rinsing off the first composition; c) topically applying to said area of ​​said skin a second composition comprising 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof; d) repeating steps a), b) and c) to achieve the desired skin depigmentation effect. Beauty methods, including:

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

15. The first composition, o 0.2% to 20% w / w of cysteamine or a salt thereof; o 2% to 20% w / w glycolic acid; o 0.01% to 1% w / w retinol, and Cosmetically acceptable excipients The first composition consists of and The second composition, 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof; up to 15% w / w of a skin conditioning agent selected from xylityl glucoside, anhydrous xylitol, xylitol, panthenol, Tasman pepper natural extract and / or combinations thereof; 0.01% to 1% retinol, and Cosmetically acceptable excipients The second composition consists of 15. The combination product of claim 14, consisting of:

16. A method for reducing the unpleasant odor of cysteamine or a salt thereof, comprising combining 0.2% to 20% w / w of cysteamine or a salt thereof with 0.2% to 20% w / w of azabenzene-4-carboxamide or a salt thereof and 2% to 20% w / w of glycolic acid.

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