Skin treatment methods

Abstract

The present invention provides compounds for use in the treatment and / or prevention of a target skin condition. [Solution] Formula (I) TIFF2026086753000022.tif59114 The present invention provides a compound of formula (I) or a salt thereof (wherein A, B, C, D, W, X, Y, and Z are each independently selected from H and OH), which is administered topically. Furthermore, the present invention provides a topical composition of the compound of formula (I) and a process for preparing the composition.

Description

Technical Field

[0001] The present disclosure relates to methods for treating and preventing skin conditions and disorders such as melasma, including topical administration of urolithin. The present disclosure also relates to cosmetic uses such as skin lightening. Topical compositions containing urolithin, and processes for making such compositions including the use of, for example, micronized urolithin are also provided.

Background Art

[0002] Skin conditions associated with hyperpigmentation such as melasma are problems that affect many people. Melasma tends to appear as brown, yellowish-brown or gray spots on the face, and most commonly affects women aged 20 to 50, but can also occur in men. Factors that can contribute to the likelihood and severity of melasma include exposure to sunlight / ultraviolet light, pregnancy, and exposure to hormonal drugs including contraceptives. Melasma is also known as chloasma and melasma gravidarum. Treatments include skin lightening agents such as hydroquinone or kojic acid, skin peeling and laser treatment.

[0003] However, products containing hydroquinone and kojic acid can cause irritation, inflammation, and / or contact dermatitis, and in some cases hydroquinone can cause an increase in skin darkening. In order to reduce skin irritation, it may be necessary to combine a steroid active ingredient with a skin lightening agent. Chemical peeling (e.g., glycolic acid-based) can also be used, but in some cases scarring and / or depigmentation may occur. As a result, melasma and other skin conditions associated with hyperpigmentation, such as senile pigmentation The need for effective treatments for plaques / lentiformities remains, as do sunlight and skin Further agents are still needed to protect against the damaging effects of other environmental conditions to which they are exposed. It is said that...

[0004] Many people lighten their skin for cosmetic reasons, such as to even out their skin tone. Alternatively, choose skin bleaching. Improved or alternative approaches for such treatments. Providing support is also desirable.

[0005] Uroritin is a compound of ellagitannins produced, for example, by the colon microbiota of mammals. These are a group of metabolites derived from ellagic acid. Urolithin is a compound useful for promoting longevity. It has been proposed that this is the case. For example, WO201 under the name Amazentis SA See 4 / 004902. A composition for oral administration of urolithin has been proposed. For example, WO2014 / 004092 describes animal experiments in which urolithin A was mixed with food. It is described as follows. [Overview of the project]

[0006] This disclosure relates to methods for preventing and / or treating the skin condition, disease, or disorder in question. Therefore, the formula for the effective quantity is (I).

[0007] [ka]

[0008] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) The present invention provides a method comprising topically administering a compound or a salt thereof.

[0009] This disclosure also relates to a formula for use in the treatment and / or prevention of the skin condition in question. (I)

[0010] [ka]

[0011] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) A compound or salt thereof of formula (I) or a salt thereof that is administered topically. To provide.

[0012] This disclosure also relates to manufacturing pharmaceuticals for the treatment and / or prevention of the skin condition in question. Equation (I)

[0013] [ka]

[0014] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) The use of the compound or salt thereof, wherein the compound of formula (I) or a salt thereof is locally administered Provides the intended use.

[0015] This disclosure also relates to skin bleaching and / or lightening of skin color, and / or skin A method for lightening the skin tone, wherein the effective amount of formula (I)

[0016] [ka]

[0017] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) The present invention provides a method comprising topically administering a compound or a salt thereof.

[0018] The target skin bleaching, and / or lightening of skin color (skin whitening), and / or skin Methods for lightening skin tone include depigmentation.

[0019] This disclosure is, a) Compounds of formula (I) or salts thereof,

[0020] [ka]

[0021] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) Provide a composition for topical administration comprising at least one excipient suitable for topical administration.

[0022] This disclosure also relates to a process for obtaining a topical administration composition, wherein the composition is a) Compounds of formula (I) or salts thereof,

[0023] [ka]

[0024] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) comprising at least one excipient suitable for topical administration, The process is - To provide a finely powdered compound of formula (I) or a salt thereof, - A finely powdered compound of formula (I) or a salt thereof, and at least one suitable for topical administration. This includes mixing in the excipients.

[0025] This disclosure also provides a process for obtaining a composition for topical administration, and the composition is a) Compounds of formula (I) or salts thereof,

[0026] [ka]

[0027] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) comprising at least one excipient suitable for topical administration, The process is -D in the range of -0.5 to 50 μm 50 and D in the range of 5-100 μm 90 He has a slight To provide a powdered compound of formula (I) or a salt thereof, - A finely powdered compound of formula (I) or a salt thereof, and at least one suitable for topical administration. This includes mixing in the excipients.

[0028] Another embodiment of the present invention provides a composition that can be obtained by the process of the present invention. To be served. [Brief explanation of the drawing]

[0029] [Figure 1] This figure shows the results of a skin cell viability assay performed on EpiDerm® tissue after treatment with 25, 50, and 100 μM water (NC), 0.5% DMSO, and urolithin A (UA) for 96 hours. The dashed line represents 90% viability; below this threshold, the compound is considered irritating. [Figure 2] This is a top view of MelanoDerm® tissue after treatment with 50 μM and 100 μM water, 2% kojic acid, 0.2% DMSO, and urolithin A for 14 days. [Figure 3]This figure shows the L values ​​measured from MelanoDerm™ tissue after treatment with 50 μM and 100 μM water, 2% kojic acid, 0.2% DMSO, and urolithin A for 4, 7, 11, and 14 days. Statistics were calculated using a two-way ANOVA test. **P<0.01;***P<0.001 corresponds to the Holm-Sidak post-hoc test for multiple comparisons of each group against the negative control group. [Figure 4] This figure shows the melanin content measured from MelanoDerm® tissue after treatment with 50 μM and 100 μM water, 2% kojic acid, 0.2% DMSO, and uroritin A for 14 days. Statistical significance was performed using one-way ANOVA. ***P<0.001 corresponds to Dunnett's post-hoc test for multiple comparisons of each group against a negative control. Additional Student's t-tests comparing the 2% kojic acid and 100 μM uroritin A groups are also reported. [Modes for carrying out the invention]

[0030] This disclosure relates to the treatment of skin conditions, including topical administration of a compound of formula (I), namely urolithin. and / or provides a method of prevention. Urolithin is administered orally, but in many conditions In this situation, the bioavailability of the compound is limited. Also, urolithin compounds The substance is known to be highly water-insoluble. Despite the above properties, the inventors have found that Urolithin is suitable for topical administration and is used in in vitro assays for melasma, a hyperpigmented skin condition. We discovered that it showed unexpectedly good results in this regard.

[0031] Compound of formula (I) and its salt Uroritin is a substance that acts as a countermeasure against ellagitannins and ellagic acid in the intestinal microorganisms of mammals, including humans. These are metabolites produced by the action of the biological community. Ellagic acid and ellagic acid are produced by Zac It is a compound commonly found in foods such as nuts and berries. Ellagitannin is found in the intestines. Absorption into itself is minimal. Uroritin is a compound having the representative structure (I) shown above. It is a class of urolithin. Some particularly common urolithin structures are shown in structure (I). This is listed in Table 1 below.

[0032] [Table 1]

[0033] In practice, for commercial-scale products, it is convenient to synthesize urolithin. The route is described, for example, in WO2014 / 004902. Any structure (I) The urolithin structure may be used in the methods of this disclosure.

[0034] In one embodiment of the use and methods of this disclosure, a suitable compound is one in which A, C, D and Z are H and the combination of formula (I) in which B, W, X and Y are all H, independently selected from OH It is an object.

[0035] A particularly suitable compound is the naturally occurring urolithin. Therefore, Z is preferably is OH, and W, X, and Y are preferably all H. If H, and both A and B are H, and C, D and Z are all OH, then The compound is urolithin C. W, X, and Y are all H, and A, B, C, and D are all If H is and Z is OH, the compound is urolithin B. W, X and Y are all If H, and A, B, and C are all H, and D and Z are both OH, then The compound is urolithin A. Preferably, the urolithin used in the method of the present disclosure is uro It is lysin A, urolithin B, urolithin C, or urolithin D. Most preferably, The urolithin used is urolithin A.

[0036] [ka]

[0037] The present invention also includes the use of a suitable salt of the compound of formula (I), for example, a pharmaceutically acceptable salt. Includes. Suitable salts according to the present invention include those formed using organic or inorganic bases. Pharmacologically acceptable base salts include ammonium salts, alkali metal salts, such as potassium and Salts of sodium, alkaline earth metal salts, such as salts of calcium and magnesium, Furthermore, salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucomine, Morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-low Alkylamines, such as ethyl-, tert-butyl-, diethyl-, and diisopropyl -, triethyl-, tributyl- or dimethyl-propylamine, or mono-, di -or trihydroxy lower alkylamines, e.g., mono-, di-, or triethanolamines. It contains ylamine.

[0038] Those skilled in organic chemistry will know that many organic compounds react with each other or from each other. It will be understood that these can form complexes with solvents that precipitate or crystallize. The complex is known as the "solvate". The present invention also provides the solvate of the compound of formula (I), Those skilled in the art will understand that this also includes the solvates of its salts. This includes compounds whose associated solvents are pharmaceutically acceptable. Hydrates (when the associated solvent is water) (ru) is an example of a solvate.

[0039] composition The method disclosed herein involves topical administration of a compound of formula (I) or a salt thereof. The indication also, a) Compounds of formula (I) or salts thereof,

[0040] [ka]

[0041] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) The present invention relates to a composition for topical administration comprising at least one excipient suitable for topical administration.

[0042] In some preferred embodiments, the compound of formula (I) used in the composition is uro It is lithin A.

[0043] In some preferred embodiments, the formula used to generate compositions of the present disclosure is The compound (I) or its salt (e.g., urolithin A) is micronized. Powdering results in good activity and a topical composition that can be easily applied to the skin.

[0044] When a finely powdered compound of formula (I) or a salt thereof is used, preferably the compound Or salts (e.g., urolithin A) have a diameter of less than 100 μm. 50 Having size, that is, quality In terms of quantity, 50% of the compound or salt has a particle size of less than 100 μm. More preferably, the compound Alternatively, salts (e.g., urolithin A) should be less than 75 μm, e.g., less than 50 μm, e.g., 25 μm D less than m, for example less than 20 μm, for example less than 10 μm 50It has a size. More preferably or, the compound or salt (e.g., urolithin A) has a D within the range of 0.5 to 50 μm, such as 0.5 to 2 0 μm, such as 0.5 to 10 μm, such as 1.0 to 10 μm, such as 1.5 to 7.5 μm , such as 2 to 7 μm, such as 2.8 to 5.5 μm 50 It has. In some embodiments, the compound or salt (e.g., urolithin A) has a D of about 3.9 μm 50 and has. In some embodiments, the compound or salt (e.g., urolithin A) has a D of about 7 .1 μm 50 It has. Preferably, the compound or salt (e.g., urolithin A) has a D size of less than 100 μm 90 It has a size. More preferably, the compound or its salt (e.g., u rolithin A) has a D size of less than 75 μm, such as less than 50 μm, such as less than 25 μm, such as less than 20 μm, such as less than 15 μm 90 It has a size. The compound or salt (e.g., urolithin A) preferably has a D within the range of 5 to 100 μm, such as 5 to 50 μm, such as 5 to 20 μm, such as 7.5 to 15 μm, such as 8 to 20 μm, such as 8.2 to 16.0 μm and has a D 90 In some embodiments, the compound or salt (e.g., urolithin A) has a D of about 11.5 μm 90 and has. In some embodiments, the compound or salt ([[]] e.g., urolithin A) has a D of about 13.5 μm 90 It has. Preferably, the compound or salt (e.g., urolithin A) has a D within the range of 0.5 to 2 μm, or within the range of 0.5 to 1.0 μm and has a D 10 It has. Preferably, the compound or salt (e.g., urolithin A) has a D size of less than 50 μm 10It has a size. More preferably, a compound or a salt thereof (e.g., urocide). A) is less than 25 μm, for example less than 20 μm, for example less than 15 μm, for example less than 10 μm. D is full, for example, less than 5 μm, for example less than 2 μm. 10 It has size. Compound or salt (e.g.) For example, urolithin A) is preferably 0.1 to 25 μm, for example 0.1 to 10 μm, for example D in the range of 0.5 to 5 μm, for example 0.5 to 2 μm, for example 0.5 to 1.0 μm 10 It has. In some embodiments, the compound or salt (e.g., urolithin A) is about 1.2 μm D 10 It has a compound or salt (e.g., Rolitin A) is a D of approximately 0.7 μm 10 It has formula (I The compound of ) or its salt (e.g., urolithin A) is in the range of 0.5 to 50 μm. 50 and D in the range of 5-100 μm 90 It has formula (I The compound or salt of (e.g., urolithin A) is in the range of 8-20 μm. 90 , 2 D within the range of ~7μm 50 and D in the range of 0.5 to 2 μm 10 It has several. In the embodiment, the compound of formula (I) or its salt (e.g., urolithin A) is 8.2~ D within the range of 16.0 μm 90 , D in the range of 2.8~5.5μm 50 and 0.5~1 D within the range of 0.0 μm 10 It has. Micronization is achieved by methods established in this art. It can be done, for example, compression milling, hammer milling, universal or pin milling. Jet milling, or (for example, spiral jet milling or fluidized bed jet milling) Jet milling can be used. Jet milling is particularly suitable. Particle size Methods for determining the size are known in the art, for example, Beckman Co. under L3 13 320 or Malvern Mastersizer 200 Equipment such as 0 can be used. In some embodiments, particle size (e.g., D 10 , D 50 , and / or D 90 The value is Malvern Mastersize This can be determined using r2000.

[0045] In an alternative embodiment, the compound or salt (e.g., urolithin A) is 75 μm or less. For example, 50 μm or less, for example, 25 μm or less, for example, 20 μm or less, for example, 10 μm or less D 50 It has a size.

[0046] In an alternative embodiment, the compound or salt (e.g., urolithin A) is 75 μm or less. For example, 50 μm or less, for example, 30 μm or less, for example, 25 μm or less, for example, 20 μm or less, For example, D 15 μm or less 90 It has a size.

[0047] In an alternative embodiment, the compound or salt (e.g., urolithin A) is 25 μm or less. For example, 20 μm or less, for example, 15 μm or less, for example, 10 μm or less, for example, 5 μm or less, example For example, D2 is less than 2 μm. 10 It has a size.

[0048] Therefore, in some embodiments, the composition is -For example, D in the range of 0.5 to 50 μm 50, and D in the range of 5-100 μm 90 of The present invention provides a finely powdered compound of formula (I) or a salt thereof (e.g., urolithin A). The matter, and - A finely powdered compound of formula (I) or a salt thereof, and at least one suitable for topical administration. It can be obtained by a process that includes mixing in the excipients.

[0049] Therefore, a process for obtaining a composition for topical administration is also provided, and the composition is a) Compounds of formula (I) or salts thereof,

[0050] [ka]

[0051] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) comprising at least one excipient suitable for topical administration, The process is The process involves pulverizing the compound of formula (I) or its salt, - A finely powdered compound of formula (I) or a salt thereof, and at least one suitable for topical administration. This includes mixing in the excipient. In some preferred embodiments, the compound is This is Lolitin A.

[0052] Therefore, a process for obtaining a composition for topical administration is also provided, and the composition is a) Compounds of formula (I) or salts thereof,

[0053] [ka]

[0054] (In the formula, A, B, C, D, W, X, Y, and Z are each independently H and OH) (Selected from) Furthermore b) comprising at least one excipient suitable for topical administration, The process is - The compound of formula (I) or a salt thereof is pulverized, thereby creating a D in the range of 0.5 to 50 μm. 50 , and D in the range of 5-100 μm 90 A finely powdered compound of formula (I) having And the production of that salt, - A finely powdered compound of formula (I) or a salt thereof, and at least one suitable for topical administration. This includes mixing in the excipient. In some preferred embodiments, the compound is uro It is lithin A.

[0055] As described above, the compound of formula (I) is a mammalian compound that is equivalent to ellagitannin and ellagic acid. These are metabolites produced by the action of the gut microbiota, such as pomegranates, nuts, and berries. These are polyphenol compounds commonly found in food. Typically, the compositions of this disclosure, The compound of formula (I) or its salt used in the method and use is in a purified form. It is most commonly obtained by chemical synthesis and purification. Therefore, in some embodiments... In this, the compound of formula (I) or a salt thereof used to produce the composition is at least Also 90% by weight purity, at least 95% by weight purity, at least 97% by weight purity, less At least 98% by weight purity, at least 99% by weight purity, or at least 99.5% Yes. In some embodiments, 10% by weight of the polyphenols present in the composition is not If the amount is less than 5% by weight, less than 3% by weight, less than 2% by weight, or less than 1% by weight, then the formula (I) is applied. It is not a compound or a salt thereof. In some embodiments, the composition is a compound of formula (I) It substantially contains no polyphenols other than the substance or its salts.

[0056] The compositions disclosed herein are for topical application and are suitable for topical application, for example, the action portion of an active compound. It facilitates delivery to the site, ensures compatibility with active compounds, and provides good chemical and physical stability. It also contains safe, non-irritating, or low-irritating excipients. Most commonly, the composition It is a semi-solid or liquid composition. In some embodiments, the composition is liquid. In other embodiments, the composition is semi-solid. In some embodiments, the composition is The product is available in the form of a solution, suspension, emulsion, gel, solid, or liposome formulation.

[0057] Typically, the composition (e.g., cream) is, for example, 50% to 99.9% of the composition's weight. 995%, or 60% to 99.9995%, or 70% to 99.9995%, or 80% to 99.9995%, or 90% to 99.9995%, or 95% to 99%. 9995%, 50%~99.995%, or 60%~99.995%, or 70%~ 99.995%, or 80% to 99.995%, or 90% to 99.995%, also 95%~99.995%, or 70%~99.99%, or 80%~99.99% , or 90%~99.99%, or 95%~99.99%, or 70%~99.9% , or 80%~99.9%, or 90%~99.9%, or 95%~99.9%, Or 98%~99.9%, or 80%~99%, or 90%~99%, or 95% Locally acceptable carriers or vehicles that can constitute %~99% or 98%~99% It contains. In some embodiments, the compound of formula (I) or a salt thereof is 0.00 05wt%~50wt%, 0.0005wt%~40wt%, 0.0005wt%~30 Weight%, 0.0005wt%~20wt%, 0.0005wt%~10wt%, 0.00 05wt%~1wt%, 0.005wt%~50wt%, 0.005wt%~40wt% , 0.005wt%~30wt%, 0.005wt%~20wt%, 0.005wt%~ 10wt%, 0.005wt%~1wt%, 0.01wt%~30wt%, 0.01wt% %~20wt%, 0.01wt%~10wt%, 0.01wt%~5wt%, 0.1wt% %~30wt%, 0.1wt%~20wt%, 0.1wt%~10wt%, 0.1wt% ~5wt%, 0.1wt%~2wt%, 1wt%~20wt%, 1wt%~10wt%, It is present in the composition in an amount ranging from 1% to 5% by weight, or from 1% to 2% by weight. In several embodiments, the compound of formula (I) or its salt is expressed in concentrations of 1 μM to 2.5 M, 1 μ M~1M, 1μM~100mM, 1μM~10mM, 1μM~100μM, 10μM~2 .5M, 10μM~1M, 10μM~100mM, 10μM~10mM, 10μM~5m M, 10μM~1mM, 10μM~500μM, 10μM~250μM, 25μM~2. 5M, 25μM~1M, 25μM~100mM, 25μM~10mM, 25μM~5mM , 25μM~1mM, 25μM~500μM, 25μM~250μM, 100μM~2. 5M, 100μM~1M, 100μM~100mM, 100μM~10mM, 100μM ~1mM, 500μM~2.5M, 500μM~1M, 500μM~100mM, 500 It is present in the composition at concentrations ranging from μM to 10 mM, or from 500 μM to 1 mM. For example A composition containing the compound of formula (I) or a salt thereof at different concentrations may be used. For example, compositions for cosmetic use, or commercially available compositions for patients with less severe symptoms, are lower Compositions that may contain concentrations of active agents and require a prescription, for example, intended for the treatment of severe symptoms. These may contain higher concentrations of activators.

[0058] In further embodiments, the compound of formula (I) or a salt thereof is 0.01 μM to 100 mM, 0.01μM~10mM, 0.01μM~1mM, 0.01μM~100μM, 0 Concentrations within the range of 0.1 μM to 500 μM, 0.1 μM to 100 μM, or 1 μM to 50 μM. It is present in the composition at a certain degree.

[0059] In one embodiment, the topical composition (cream, etc.) of the present invention is 0.0001% to 5%, For example, 0.0001% to 1%, for example, 0.0001% to 0.1%, for example, 0.0001% It contains ~0.01% of the compound of formula (I) or a salt thereof. In further embodiments, this The topical composition (cream, etc.) contains 0.001% to 0.5%, for example, 0.001% to 0. It contains 1%, for example, 0.01% to 0.1% of the compound or salt of formula (I). Further experimentation In terms of application, the topical composition (cream, etc.) of the present invention is used in a concentration of 0.005% to 0.05%, for example. For example, it contains 0.001% to 0.01% of the compound of formula (I) or a salt thereof. Examples of components include oils, glycerides (including triglycerides, diglycerides, and / or monoglycerides), and Mechanical solvent (alcohol, etc.), water, wax, grease, surfactant, emollient, moisturizer, Skin conditioning agent, thickener, emulsifier, gelling agent, foaming agent, antioxidant, buffering agent , chelating agents, emulsions, flavoring agents, coloring agents, fragrances or perfumes, additional therapeutic agents, and Additional cosmetic activators may be used. The above mixture may be used.

[0060] In some embodiments, the composition includes oil and / or lipid components. Topical application. Examples of oils that can be used in formulations for this purpose are well known in the art, including cottonseed oil, peanut oil, and corn oil. Contains koji oil, wheat germ oil, olive oil, castor oil, soybean oil, mineral oil, sesame oil, and evening primrose oil. In some embodiments, the composition is up to 90% by weight, up to 80% by weight, Up to 70% by weight, Up to 60% by weight, Up to 50% by weight, Up to 40% by weight, Up to 30% by weight, Up to 20% by weight, Up to 10% by weight, Up to 5% by weight, 1% to 50% by weight, 1% to 4% by weight 0wt%, 1wt%~30wt%, 1wt%~20wt%, 1wt%~10wt%, 5wt Amount%~50wt%, 5wt%~40wt%, 5wt%~30wt%, 5wt%~20wt %, 5wt%~10wt%, 10wt%~50wt%, 10wt%~40wt%, 10wt Contains oil in an amount of % to 30% by weight.

[0061] In some embodiments, the composition contains an organic solvent. Examples of organic solvents include A Glycol solvents (e.g., ethanol, isopropanol, ethylene glycol, propylene) Examples include glycols, pyrrolidones (e.g., N-methylpyrrolidinone), and DMSO. In some embodiments, the composition is up to 90% by weight of the composition, up to 80% by weight. , up to 70% by weight, up to 60% by weight, up to 50% by weight, up to 40% by weight, up to 30% by weight , up to 20% by weight, up to 10% by weight, up to 5% by weight, up to 3% by weight, up to 2% by weight, up to 1wt%, 0.1wt%~20wt%, 0.1wt%~15wt%, 0.1wt%~10 Weight%, 0.1% to 5% by weight, 0.1% to 3% by weight, 0.1% to 2% by weight, 0.1wt%~1wt%, 1wt%~50wt%, 1wt%~40wt%, 1wt%~3 0wt%, 1wt%~20wt%, 1wt%~10wt%, 5wt%~50wt%, 5wt Amount%~40wt%, 5wt%~30wt%, 5wt%~20wt%, 5wt%~10wt %, 10wt%~50wt%, 10wt%~40wt%, 10wt%~30wt%, 10 It contains an amount of organic solvent ranging from % to 20% by weight.

[0062] In some embodiments, the composition contains medium-chain triglycerides. D is the formula CH2(OR 1 )-CH(OR 2 )-CH2(OR 3 It is a compound of ) and in the formula, R 2 and R 3 This is generally expressed by the formula -C(=O)(CH2) n CH3 is a medium-chain fatty acid group, and formula In the medium chain, n is in the range of 4 to 10, for example, 6 to 8. Medium-chain fatty acids have 6 to 12 carbon atoms. These are fatty acids with aliphatic ends. The aliphatic ends are mainly saturated. Certain medium-chain fatty acids... Fatty acids include caproic acid (hexanoic acid, C6:0), caprylic acid (octanoic acid, C8:0), Contains capric acid (decanoic acid, C10:0) and lauric acid (dodecanoic acid, C12:0). Hmm. Myristic acid (tetradecanoic acid, C14:0) may also be present in small amounts. Most commonly The medium-chain triglycerides used are generally caprylic and capric triglycerides. The composition of the present invention contains a mixture of medium-chain triglycerides and contains 95% or more saturated fatty acids. The ceride component may consist of a homogeneous single medium-chain triglyceride compound, more generally. The medium-chain triglyceride component in the composition of the present invention is two or more different medium-chain triglycerides. It is a mixture of compounds.

[0063] The European Pharmacopoeia defines medium-chain triglycerides as Cocos nucifera L. (coconut). The hard, dried fraction of the endosperm of Elaeis guineenis Jacq. It is described as a fixed oil extracted from the dried endosperm of the (African oil palm). In both the Japanese Pharmacopoeia and USPNF, medium-chain triglycerides require the presence of certain fatty acids. The following specifications apply to riserid: Caproic acid (C6) ≤ 2.0%; Caprylic acid (C8) ) 50.0~80.0%; Capric acid (C10) 20.0~50.0%; Lauric acid (C 12) ≤ 3.0%; and myristic acid (C14) ≤ 1%.

[0064] In particular, the medium-chain triglycerides used in the composition of the present invention are present in the following proportions. Contains a mixture of triglycerides and fatty acid chains: C6 ≤ 5%; C8 50-70%; C10 30-50%; and C12 ≤ 12%, e.g., C6 ≤ 0.5%; C8 55-65%; C10 35-45%; and C12 ≤ 1.5%.

[0065] Medium-chain triglycerides for use in the compositions of the present invention can be obtained from any suitable source. It is possible. In some embodiments, the composition is up to 90% by weight of the composition, up to 80wt%, 70wt% max, 60wt% max, 50wt% max, 40wt% max, max 30% by weight, maximum 20% by weight, maximum 10% by weight, maximum 5% by weight, 1% to 50% by weight, 1wt%~40wt%, 1wt%~30wt%, 1wt%~20wt%, 1wt%~10 Weight%, 5wt%~50wt%, 5wt%~40wt%, 5wt%~30wt%, 5wt %~20wt%, 5wt%~10wt%, 10wt%~50wt%, 10wt%~40wt Contains medium-chain triglycerides in amounts of %, 10% to 30% by weight, and 10% to 30% by weight. nothing.

[0066] In some embodiments, the composition comprises a skin emollient, the skin emollient being a pre-drying agent. These are materials used for prevention and / or easing. Examples of emollients include vegetable oils and mineral oils. Examples include silicone oils, fatty acid esters, and alcohols such as 1-hexadecanol. It can be done.

[0067] In some embodiments, the composition includes an emulsifier. Examples of emulsifiers include PPG-1 -PEG-9 Lauryl Glycol Ether (Trade Name: Eumulgin L), PEG- 60 Hydrogenated castor oil (product name: Cremophor CO60), cetyl alcohol and Glyceryl stearate and PEG-75 stearate and ceteth-20 and ste Ares-20 (product name: Emulium Delta), Cetearyl alcohol (product name) :Nafoi1618), Hydroxyethyl acrylate / Sodium acryloyl dimethyl Chiltaurate copolymer and water and squalane and polysorbate 60 and sorbate Contains rubitan isostearate (product name: Simulgel NS).

[0068] In some embodiments, the composition includes a thickening agent. Examples of thickening agents include cross-linked acrylic. Rate (e.g., Carbopol982), hydrophobic modified acrylate (e.g., Carbo pol1382), cellulose derivatives (sodium carboxymethylcellulose, hydro Hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose (e.g., methylcellulose) and natural rubber (e.g., guar, xanthan gum, sclerotium) It contains (m, carrageenan, pectin). When used, the thickener is typically a combination of It is used in amounts of up to 5% by weight or up to 1% by weight of the product.

[0069] An example of a metal chelating agent or metal ion sequestering agent is EDTA (ethylenediaminetetraacetic acid). This is salt.

[0070] When surfactants are used, typically they make up to 40% by weight of the composition, or up to 30% by weight. It is used in amounts of % by weight, or up to 20% by weight, or up to 10% by weight.

[0071] In some embodiments, the composition includes a compound of formula (I) or a salt thereof, in addition to It contains various activators. For example, the composition treats or prevents skin conditions such as melisma. It may also contain additional activators useful for this purpose, such as hydroquinone or kojic acid.

[0072] Examples of suitable types of compositions include creams, pastes, ointments, solutions, lotions, and formulas. This includes mousses, gels, sticks, and sprays. Further examples of suitable compositions include: Creams, dispersions, emulsions, gels, ointments, lotions, milks, mousses, sprays , or it contains tonic.

[0073] In some embodiments, the composition is a cream or lotion, for example, a skin cream. It is in the form of a cream. Creams are usually oil-in-water (o / w) or water-in-oil (w / o) formulas. It takes the form of an oil and water emulsion, which is classified as an emulsion. In terms of application, the composition is a cream, which is an oil-in-water emulsion. In application, the composition consists of 5% to 50% oil (e.g., emollient) and 45% to 8% It is a cream containing 5% water. Topical creams usually contain emulsifiers and / or thickeners. It contains these.

[0074] Lotions are typically liquid products containing active ingredients suspended or dissolved in a liquid carrier. This refers to a preparation. A lotion is, for example, water-based and / or organic solvent (e.g., alcohol) It may also be a formulation of -.

[0075] In some embodiments, the composition is in the form of an ointment. Ointments are usually hydrocarbons ( It is a semi-solid preparation of petrolatum, mineral oil, paraffin, synthetic hydrocarbons, etc., and in many cases, viscosity It is watery and / or greasy. Often, ointments contain little to no water. It may not be necessary to include it. In some embodiments, the ointment is a hydrocarbon / oil base, skin softening Thickening agent (e.g., about 2% to 10% by weight) and thickener (e.g., about 1% to 2% by weight) It includes. In some embodiments, the composition is in the form of a gel. The gel is typically This includes gelling agents (natural rubber, acrylate polymer / copolymer, or cellulose derivatives, etc.) ) and a suitable liquid component (e.g., an organic solvent such as alcohol). In terms of application form, the composition is in the form of a paste. The paste is typically a powder and A mixture of liquid or semi-solid carriers, such as an ointment.

[0076] This disclosure relates, for example, to the protection of skin from damage caused by the environment, such as sunlight. Formula (I) as a nutrient to protect against damage caused by UV radiation. This relates to the use of compounds. Therefore, in some embodiments, the compound of formula (I) is included. The topical composition is a sunscreen composition, such as a cream, lotion, or spray. Such compositions typically include a compound of formula (I) or a salt thereof, in addition to UV blocking. It contains physical and / or chemical sunscreens such as agents. In some embodiments, The sunscreen composition includes, for example, a physical sunscreen such as titanium dioxide or zinc oxide. In some embodiments, the sunscreen composition is, for example, oxybenzone, avobene. Gluzon, octisaleate, octocrylene, homosaleate and / or octinoxer Includes chemical sunscreens such as [mention specific types of sunscreens].

[0077] UV blocking agents are effective in the UV region at one or more wavelengths between 290 nanometers (nm) and 400 nm. It may also be an organic compound that absorbs light. For example, a UV blocker may be an organic compound that absorbs light from 290 nm to 400 nm. At least 10,000 mol for at least one wavelength within the nm range -1 L cm -1 (For example, at least 25,000 mol) -1 Lcm -1 , at least 50, 000mol -1 Lcm -1 at least 75,000 mol -1 Lcm -1 ,Also at least 100,000 mol -1 Lcm -1 The molar extinction coefficient may also be shown.

[0078] In some embodiments, the UV blocking agent is one or more waves in the range of 290 nm to 320 nm. It may also be an organic compound that absorbs light in the UV-B region (i.e., a UV-B blocker). For example, UV blocking agents have at least one wavelength in the range of 290nm to 320nm. In contrast, at least 10,000 mol -1 Lcm -1 (For example, at least 25,0 00mol -1 Lcm -1 at least 50,000 mol -1 Lcm -1 , less 75,000 mol each -1 Lcm -1 , or at least 100,000 mol -1 Lcm -1 The molar extinction coefficient may be 290. In some cases, the UV blocker may be 290 At least 10,000 mol at all wavelengths in the range of nm to 320 nm -1 Lcm -1 The molar extinction coefficient may also be shown.

[0079] In some embodiments, the UV blocking agent is one or more waves in the range of 320 nm to 400 nm. It may also be an organic compound that absorbs light in the UV-A region (i.e., a UV-A blocker). For example, UV blocking agents have at least one wavelength in the range of 320nm to 400nm. In contrast, at least 10,000 mol -1 Lcm -1 (For example, at least 25,0 00mol -1 Lcm -1 at least 50,000 mol -1 Lcm -1 , less 75,000 mol each -1 Lcm -1 , or at least 100,000 mol -1 Lcm -1The molar extinction coefficient may be 320. In some cases, the UV blocker may be 320 At least 10,000 mol at all wavelengths in the range of nm to 400 nm -1 Lcm -1 The molar extinction coefficient may also be shown.

[0080] Examples of suitable UV blocking agents include, for example, p-aminobenzoic acid, benzoate O, and phenylbe. Nzuimidazole sulfonic acid, cinoxate, dixoibenzone, oxybenzone, homo Salate, Menthyl anthranilate, Octocrylene, Octyl methoxycinnamate, Salate Octyl cylate, surisobenzone, trolamine salicylate, ecamsul, 4-methylben Zyliden camphor, bisoctrizole, bemotoridinol, bisdisrizole dinatol Lium, tris-biphenyltriazine, drometrizole, trisiloxane, benzof Enon-9, ethylhexyl triazone, diethylamino hydroxybenzoylhexyl Benzoate, iscotridinol, polysilicone-15, amyloxate, and so These combinations are included. In some embodiments, the UV blocker is p-amino Benzoic acid, benzoate O, phenylbenzimidazole sulfonic acid, cinoxate, dixyl Soybenzone, oxybenzone, homosalate, menthyl anthranilate, octocri Len, Octyl 15-methoxycinnamate, Octyl salicylate, Sulisobenzone, Sa It may be thoramine lycylate, ecumsul, or a combination thereof. In application, the UV blocking agent is avobenzone, oxybenzone, or a combination thereof. It's fine to do so.

[0081] The sunscreen is added to the composition in an amount of 0.5% to 10% by weight, based on the total weight of the composition. It may be present inside. The composition is measured using the international standard ISO 24444:2010(E). If so, it can be formulated to show an SPF of at least 15 (for example, at least 30). .

[0082] This disclosure also relates, for example, to cosmetic skin bleaching and / or skin lightening. Therefore, in some embodiments, topical compositions comprising the compound of formula (I) make Up-compositions include, for example, foundation compositions.

[0083] Surprisingly, urolithin A is lipophilic excipient, such as oil and / or medium-chain triglycerides. It was found to be particularly soluble in topical cream compositions containing riserids. The resulting product, after mixing, has a homogeneous appearance with no solid urolithin A present, and is smooth on the skin. It has a certain texture. When finely powdered urolithin A is mixed with skin cream, the color becomes darker. A smooth mixture was formed, which means that urolithin dissolved in the cream's ingredients, or This indicates that it is suspended in the cream matrix.

[0084] Therefore, in some embodiments, the topical composition is an organic solvent suitable for topical administration. It includes. In some embodiments, the composition includes oil and / or lipid components.

[0085] In some embodiments, the topical composition is monoglycerides, diglycerides, and / or containing triglycerides. In some embodiments, the composition contains medium-chain triglycerides. Contains cerides.

[0086] In some embodiments, the water content of the composition is low, for example, the composition is 20% by weight. Contains less than, less than 10% by weight, less than 5% by weight, less than 2% by weight, or less than 1% by weight of water. It may be. In some embodiments, the composition is substantially water-free. However, In some other embodiments, for example, the composition is mixed with water and oil, for example, an emulsifier. Or, if it contains a mixture of water and an organic solvent, the composition contains a considerable proportion of water. That's good too.

[0087] This disclosure relates to compositions for topical administration. Compounds of formula (I) were previously administered orally. Here it is. Some excipients suitable for topical formulations of active substances are unsuitable for oral administration, and this disclosure It should be understood that this includes formulations containing one or more excipients unsuitable for oral administration.

[0088] In some embodiments, the composition is active on and / or through the skin. To assist in the delivery of the ingredients, it contains skin penetration enhancers. Examples of skin penetration enhancers include sulfo Hoxides (DMSO, etc.), pyrrolidone, terpenes, fatty acids, alcohols, glycols, glycans It contains coal ether and glycerides.

[0089] In some embodiments, the composition (e.g., cream) is a composition (e.g., oil and 1 ml of a topical cream composition containing / or lipophilic components such as medium-chain triglycerides The compound of formula (I) is present at a maximum level of 100 mg, and therefore at a maximum level of 100 mg per ml. or its salts. Therefore, the composition is, for example, a compound of formula (I) or its salts (e.g. For example, uroritin A) at 0.001-100 mg / ml, 0.01-100 mg / ml, 0.05~100mg / ml, 0.1~100mg / ml, 5~100mg / ml, 10 ~100mg / ml, 0.01~50mg / ml, 0.05~50mg / ml, 0.1~ 50mg / ml, 0.5~50mg / ml, 1~50mg / ml, 5~50mg / ml, 0.001~0.1mg / ml, 0.01~10mg / ml, 0.05~10mg / ml , 0.1~10mg / ml, 0.5~10mg / ml, 1~10mg / ml, 0.01~ 5mg / ml, 0.05~5mg / ml, 0.1~5mg / ml, 0.5~5mg / ml , 1~5mg / ml, 0.01~1mg / ml, 0.05~1mg / ml, 0.1~1m g / ml, 0.5-1 mg / ml, 0.01-0.5 mg / ml, or 0.05-0. It may be contained in an amount within the range of 5 mg / ml (composition).

[0090] Examples of topical compositions of the present invention include the following:

[0091] [Table 2]

[0092] use The compound of formula (I) is a treatment agent for various conditions associated with insufficient mitochondrial function. It has been proposed that mitochondria produce energy for the survival of cells, i.e., in the respiratory chain. A central drive that can initiate both creation and death, i.e., apoptosis. It is a cellular organelle. More recently, dysfunctional mitochondria have been shown to be unable to autophagy, that is, mitochondria It has been shown that it can be specifically targeted for elimination by a process called tophagy. Increased mitophagy (removal of dysfunctional mitochondria) leads to mitochondrial rejuvenation. It is understood that this leads to an improvement in mitochondrial function. Uroritin A is... It has been found to induce mitophagy in teeth and extend their lifespan. (Ryu et al.) See Nature Medicine, 2016, 22, pp. 879-888.

[0093] Unlike previous approaches that focused on oral administration, when the pigment comes into contact with a skin sample, In an in vitro assay of melasma, a skin condition characterized by excessive deposition, urolithin A showed unexpectedly good results. It has been found that the following results are observed. At higher concentrations than those tested, for example 100 μM, Urolithin provides a faster skin brightening effect, and is used for therapeutic and cosmetic skin brightening. This method shows a significant reduction in melanin content compared to the currently used 2% kojic acid. This brought about...

[0094] Therefore, this disclosure relates to the effective amount of a compound of formula (I) or a salt thereof (e.g., urolithin A This includes topical administration to the target skin condition, disease or disorder, and / or provide a treatment method. This disclosure also provides a preventive measure for the skin condition, disease or disorder of the subject. A method of treatment, a) a compound of formula (I) or a salt thereof (e.g., urolith A) and b) compositions containing at least one excipient suitable for topical administration This includes methods that involve administering the substance.

[0095] In some embodiments, the method is more effective than administration using current therapies such as kojic acid. It provides a faster effect on skin pigmentation.

[0096] In some embodiments, skin conditions, diseases, or disorders are associated with hyperpigmentation. A skin condition, disease, or disorder. In some embodiments, a skin condition, disease Or a disorder is a skin condition, disease, or disorder related to insufficient mitochondrial activity. ru.

[0097] In some embodiments, skin diseases, disorders, or conditions include melasma, freckles, and melanosis during pregnancy. skin disease, hyperpigmentation, skin aging, senile pigment spots, lentigo, skin inflammation, skin irritation, skin infection, Warts, psoriasis, and skin damage caused by environmental and / or treatments It is selected from a group consisting of protection. Skin diseases, disorders, or conditions are also melanosis. Selected from dermatitis, melanosis, and endocrine disorders such as Addison and Cushing's syndrome. ru.

[0098] In some embodiments, the skin disease, disorder, or condition is melasma. Melasma is Also known as melasma and pregnancy melanosis, melasma is a condition that affects adults, especially women, between the ages of 20 and 50. This is a common skin condition, primarily affecting the face with brown, yellowish-brown, or gray pigmentation. The spots often become more noticeable in summer and less noticeable in winter. Possible melasma. There are several factors that contribute to its severity, including exposure to sunlight and / or ultraviolet light, Stress, pregnancy, hypothyroidism, and certain active ingredients, especially oral contraceptives, can all contribute to thyroid problems. This includes the administration of luminescent active ingredients. Other contributing factors include certain cosmetics. Therefore, in some embodiments, skin conditions, diseases, or disorders are stress-related. Melasma, pregnancy-related melasma, hypothyroidism-related melasma, melasma associated with the administration of active ingredients, sunlight and / or melasma associated with exposure to ultraviolet light, as well as hepatic plaque associated with exposure to chemicals. This is melasma selected from a group consisting of patches.

[0099] Tests for determining the identification of skin brightening agents and skin darkening agents are known in the art, and reference is made to, for example, US2008 / 0249029 and US2012 / 0128613. For example, as described in US2012 / 0128613, one epidermal equivalent system useful for conducting these types of studies is the MelanoDerm™ system commercially available from MatTek (Ashland, MA). This system contains normal human melanocytes along with normal human epidermal keratinocytes, and these are cultured to form a highly differentiated multilayer model of human epidermis. The compounds and compositions of the present disclosure also find use in the treatment and / or prevention of hyperpigmentation, such as age-related hyperpigmentation of the skin, or other conditions, diseases or disorders associated with post-inflammatory hyperpigmentation. Thus, in some embodiments, the skin disease, disorder or condition is skin aging, senile lentigines or dark spots. In some embodiments, the method is for protecting the skin from damage caused by the environment, such as damage caused by sunlight / ultraviolet light. In some embodiments, the method is for protecting the skin from damage caused by radiation, such as UV, beta or gamma radiation, including during medical treatment of conditions such as cancer. The compounds of the present disclosure also find use in the treatment and / or prevention of skin conditions where enhancing mitophagy and / or autophagy provides a beneficial effect. In some embodiments,

[0100]

[0101] The method is selected from the group consisting of skin inflammation, skin irritation, skin infection, warts, and psoriasis. It is intended to treat and / or prevent a disease, disorder, or condition.

[0102] In some embodiments, the methods disclosed herein are used to treat and / or prevent medical conditions. It is for the purpose of, that is, the subject is an individual with a disease, medical condition, or disability. Yes. Subjects having a skin disease, condition or disorder, as referred to herein, , subjects who have symptoms diagnosed by a physician as having a skin disease, disorder, or condition, If examined by a doctor, this person would be diagnosed with a skin disease, disorder, or condition. It is the target.

[0103] However, in other embodiments, the compound of formula (I) or a salt thereof is used to treat certain diseases. Alternatively, it is intended to be administered to subjects who are not suffering from a disability. For example, the subject is healthy. A healthy individual, that is, an individual without skin disorders, diseases, or conditions, for example, a smoother individual. For cosmetic reasons such as providing a more even skin tone or color. , the compound of formula (I) or a salt thereof is administered topically to bleach the skin or change the skin color and / or individuals whose hue is to be lightened. Therefore, several implementations In terms of form, the subject is healthy and / or the compound of formula (I) or a salt thereof is applied topically. The method of administration is cosmetic. As referred to herein, healthy subjects If examined by a doctor, they would be diagnosed with a skin disease, disorder, or condition. This refers to subjects who do not exhibit symptoms.

[0104] Effective amount of compound (I) or a salt thereof, or a composition containing the compound, to be taken. This varies depending on the administration method, age, weight, and general health condition of the patient. Factors such as condition, age, and weight may be important, and a dosage scale may be used to provide the optimal response. The image can be adjusted.

[0105] The target organism is any organism that benefits from the topical administration of the compound of formula (I) according to the present invention. In some embodiments, the subject is a mammal, for example, a mammal other than a human, for example, a neutron. The subjects are children, dogs, goats, horses, and cows, but more preferably, humans. In one embodiment, the subject is male. In some embodiments, the subject is female. Yes. In certain embodiments, the subject may be a child, but other more preferred embodiments In the application method, the subject is an adult. In some embodiments, the subject is at least 20 years old, at least 25 years old, at least 30 years old, at least 35 years old, at least 40 years old, At least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, They may be 65 years old, at least 70 years old, or at least 75 years old. The target age range is, for example, 18-50 years old, 18-40 years old, or 18-30 years old. That's fine.

[0106] Typically, a composition containing the compound is applied to the affected area of ​​the skin, for example, on the surface. It can be spread and / or rubbed in. The treatment is preferably by a series of doses. For example, topical administration of the compound may be once, twice, or three times a day over a period of time, It can be performed in the required number of doses. The effective dose of the compound increases during the course of a particular treatment. It will also be understood that it may decrease. As described above, when urolic in A at a concentration of 100 μM is administered, the skin brightening effect determined by optical spectrophotometry is accelerated, and the melanin content is significantly reduced compared to 2% kojic acid. Therefore, in some embodiments, the method includes dosing at a lower frequency than current treatments such as kojic acid. For example, in some embodiments, application may be once every 2, 3, or 4 days, or for example only once a week as may be required.

[0107] For example, when daily administration of a compound of formula (I) or a salt thereof (such as urolicin A) to a subject is carried out, the amount may be, for example, 0.1 mg to 5 g per day, for example 1 mg to 5 g per day, for example 10 mg to 5 g per day, for example 20 mg to 2500 mg per day, for example 50 mg to 1500 mg per day, for example 100 mg to 1,500 mg per day, for example 150 mg to 1,500 mg per day, for example 200 mg to 1,5 00 mg per day, for example 250 mg to 1500 mg per day, for example 50 mg to 1 000 mg per day, for example 250 mg to 1000 mg per day, for example 10 mg to 1000 mg per day, for example 10 mg to 750 mg per day, for example 20 mg to 5 00 mg per day, for example 50 mg to 500 mg per day, for example 50 mg to 250 mg per day. In some embodiments, the dosage is 250 mg / day, in another embodiment, the dosage is 500 mg / day, and in a further embodiment, the dosage is 750 mg / day, and in a further embodiment, the dosage is 1000 mg / day. In some embodiments, a compound of formula (I) or a salt thereof (such as urolicin A The dosage may be, for example, within the range of 0.01 to 100 mg / kg / day. The dosage of uroritin is 0.1-100, 0.2-100, 0.2-50, 0.2-40 , 0.2~25, 0.2~10, 0.2~7.5, 0.2~5, 0.25~100, 0. 25~25, 0.25~25, 0.25~10, 0.25~7.5, 0.25~5, 0. 5-50, 0.5-40, 0.5-30, 0.5-25, 0.5-20, 0.5-15, 0.5~10, 0.5~7.5, 0.5~5, 0.75~50, 0.75~25, 0.7 5-20, 0.75-15, 0.75-10, 0.75-7.5, 0.75-5, 1.0 ~50, 1~40, 1~25, 1~20, 1~15, 1~10, 1~7.5, 1~5, 2 ~50, 2~25, 2~20, 2~15, 2~10, 2~7.5, or 2~5 mg / kJ It may be within the range of g / day.

[0108] A composition containing the compound of formula (I) or a salt thereof is typically administered to a site on the skin. Therefore, in some embodiments, in each application (for example, daily), the chemical The substance is administered at a concentration of 0.001-100 mg / cm³ of the treated skin. 2 For example, the skin surface being treated 0.005~100, 0.01~100, 0.05~100, 0.1~100, 0.5~ 100, 1-100, 5-100, 10-100, 0.001-50, 0.005-50 , 0.01~50, 0.05~50, 0.1~50, 0.5~50, 1~50, 5~50 , 10~50, 0.001~10, 0.005~10, 0.01~10, 0.05~10 , 0.1~10, 0.5~10, 1~10, 0.001~5, 0.005~5, 0.01 ~5, 0.05~5, 0.1~5, 0.5~5, 1~5, 0.001~1, 0.005~ 1, 0.01-1, 0.05-1, or 0.1-1 mg / cm³ 2 Local application in amounts within the specified range To be given.

[0109] This disclosure relates to a method comprising administering a compound of formula (I) or a salt thereof, for use as a pharmaceutical. A compound of formula (I) or a salt thereof, for treating a skin condition, disease or disorder of the subject The use of the compound of formula (I) or a salt thereof for the manufacture of pharmaceuticals, and the compound of formula (I) The present invention provides a composition containing the salt. The above discussion and the embodiments described therein ( For example, regarding the properties, dosage regimen, uses, and compositions of the compound of formula (I), this is mainly based on the following: This discussion was made in the context of discussing the method of disclosure and composition. This discussion is for use as a pharmaceutical product. Compounds of formula (I) or their salts, and for treating a target condition, disease, or disorder. This disclosure includes embodiments relating to the use of a compound of formula (I) or a salt thereof for the manufacture of pharmaceuticals. This applies equally to all aspects of it. [Examples]

[0110] The following embodiments illustrate the present invention. Example 1: Preparation of Uroritin A Uroritin A(4) contains 2-bromo-5-methoxybenzoic acid 1 and resorcinol 2 It was prepared in two steps, starting from [the first step]. The pure compound was obtained as a pale yellow powder.

[0111] [ka]

[0112] Step 1: 2-Bromo-5-methoxybenzoic acid 1 (27.6g; 119mg) in water (120mL) (ol; 1.0 equivalent), Resorcinol 2 (26.3g; 239 mmol; 2.0 equivalents) A mixture of sodium hydroxide (10.5g; 263 mmol; 2.2 equivalents) was left for 1 hour. The solution was heated under reflux. Then, a 5% aqueous solution of copper sulfate (3.88 g of CuSO4 in 50 mL of water) was added. (5H2O; 15.5 mmol; 0.1 equivalent) was added, and the mixture was refluxed for a further 30 minutes. The mixture was cooled to room temperature, and the solid was filtered through a Buchner filter. The residue was washed with cold water. A pale red solid was obtained, which was ground with hot MeOH. The suspension was left overnight at 4°C. The precipitate was filtered and washed with cold MeOH to obtain title compound 3 as a light brown solid.

[0113] Step 2: A suspension of 3 in anhydrous dichloromethane (100 mL) (10.0 g, 41 mmol; 1. (0 equivalents) Add a 1M solution of boron tribromide in anhydrous dichloromethane (110 mL of anhydrous dichloromethane) Add 11.93 mL of pure BBr3 (124 mmol; 3.0 equivalents) to lomethane dropwise at 0°C. The mixture was added by [method]. The mixture was left at 0°C for 1 hour, and then warmed to room temperature. The solution was then heated to [temperature]. It was stirred for 17 hours. Then, plenty of ice was added to the mixture. The yellow precipitate was filtered and cooled with cold water. Washed with [a specific method] to obtain a yellow solid, which was heated under reflux in acetic acid for 3 hours. The hot solution was quickly filtered. The precipitate was then washed with acetic acid, and then with diethyl ether to obtain the title compound 4, which was yellow. It was obtained as a solid. 1 H and 13 The 13C NMR spectrum matched structure 4.

[0114] Example 2: Micronization of Uroritin A MC50 Spiral 20 Jetmill(Valortecs SAS, Bl Using Odelsheim (France), filtered nitrogen was used, supplying 240g / hour. Urolithin A is pulverized using a feeding speed, a venturi pressure of 12 bar, and a mill pressure of 12 bar. D 90 =9μm~15μm and D 50 =Urolith with a particle size distribution of 2~9μm Uroritin A was pulverized to obtain n A. The actual particle size distribution is Malvern Ma Measured using stersizer2000 and D 90 =11.5μm, D 50 =3.9 μm, D 10 The value was 0.7 μm.

[0115] Example 3: Uroritin A Skin Cream Composition 150 mg of finely powdered uroritin A, one spoonful (approximately 5 ml) of commercially available skin cream It was mixed with [unclear]. The skin cream used is available from Pierre Fabre SA. It is sold under the name Avene XeraCalm AD (trademark). According to the manufacturer, the cream contains Avene thermal spring water (avene aqua), glycerin. Phosphorus, mineral oil (liquid paraffin), cetearyl alcohol, evening primrose oil (Evening Primrose Oil), Caprylic / Capric Triglyceride, Cetearyl Glucoside, A Quaphyllum dolomie extract, arginine, carbomer, evening primrose oil / palm oil amino acid pro Pandiol ester, glycine, sodium hydroxide, tocopherol and water (aqua ) contains.

[0116] After mixing, a homogeneous mixture was obtained. The composition was slightly different from the skin cream starting product. It had a dark color. The composition was smooth and had a uniform color. The presence of urolithin was It did not have any noticeable effect on the texture of the skin cream product.

[0117] Example 4: Ingredients of urolithin A related to skin viability in EpiDerm® culture In vitro testing Pre-screening treatment conditions: Excellent skin brightening agents inhibit melanin synthesis, but combination It should not cause cytotoxicity to tissue. Urolithin on skin cell viability. The effects of A were measured using EpiDerm tissue (EPI-200). Reconstructed H Skin model EpiDerm (trademark) (EPI-200, MatTek, Ashland) (USA) cultured normal human-derived cells were used to form a multilayer, highly differentiated model of human epidermis. It consists of epidermal keratinocytes.

[0118] Tissue maintenance medium (EP1-10 available from MatTek Corporation) The cells were grown in 0-LLMM. The treatment was performed at the base of the cell, i.e., by dissolving the test compound in the maintenance medium. This continued for a total of 96 hours. Two EpiDerm (trademark) organizations (n=2) were tested for each condition. The conditions used were: 1) water, 2) DMSO 0.5%, 3) urolithin A 25 μM, 4) The concentrations were 50 μM for urolithin A and 100 μM for urolithin A. Maintenance media, with or without DMSO, were replaced every 48 hours.

[0119] Cell viability is quantitatively measured after extraction from tissue, based on the amount of cells in the mitochondria. Existing MTT\[(3-4,5-dimethylthiazole-2-yl)2,5-diphenyl Measured by dehydrogenase conversion of tetrazolium bromide to the blue formazan salt. The MTT assay involves placing tissue samples in a 24-well plate containing MTT medium (1 mg / ml). This was done by transferring the mitochondria of the cells. After 3 hours of MTT incubation, the mitochondria of the cells were transferred. The blue formazan salt formed by this process was mixed with 2.0 ml of tissue isopropanol (extract solution). Extraction was performed using product code MTT-100-EXT, and the optical density of the extracted formazan was measured using spectral light. The determination was made using a thermometer at 570 nm. The relative detail of each tissue was expressed as a percentage of the mean of the negative control tissue. The cell survival rate was calculated.

[0120] Figure 1 shows the results of a survival assay performed on EpiDerm® tissue. Survival rate It showed that it was more than 90% under all conditions and had no cytotoxicity. This means that A does not impair the survival rate of skin cells at the test concentration.

[0121] Example 5: Uroritin in MelanoDerm® culture for melanin formation In vitro trial A MatTek Corporation (Ashland, Massachusetts) MelanoDerm™ culture medium (USA) is used for pigmented 3D bio-skin equivalent models. MEL-300 tissue is obtained by seeding melanocytes into keratinocytes. MEL-300-B culture medium contains melanin cells derived from Black donor tissue. It is used to evaluate the possibility of skin lightening. MEL-300-B is used in the long-life maintenance medium ( Available from MatTek Corporation (EP1-100-LLMM) The tissue replicates were prepared and cultured for a total of 14 days. A total of four tissue replicates (n=4) were used in each group.

[0122] Untreated tissue was used as a negative control. Maintenance media was replaced every two days.

[0123] Maintenance media with final concentrations of 50 and 100 μM, prepared from a stock solution of 50 mM DMSO, are added. By adding this, urolithin A was applied to the sample. The vehicle control was 0.2 in the maintenance medium. Prepared using % DMSO. Maintenance medium to which urolithin A or DMSO is added is It was replaced every two days. Kojic acid, 2% ammonium in 50:50 butylene glycol:water. Used as a sex control, locally (i.e., on the epidermis of the MelanoDerm® sample) It was applied to the outermost layer, the stratum corneum. Kojic acid is used to treat melanoma and melanocytes. It is a well-known inhibitor of tyrosinase, an important enzyme involved in pigment formation, and is used in cosmetics. Used to treat hyperpigmentation, melasma, and wrinkles. Every two days, rinse the tissue with sterile PBS. After removing the kojic acid, add 2% kojic acid to a 50:50 butylene glycol:water solution. A fresh preparation was added. The maintenance medium was also replaced at the same time.

[0124] a. Macroscopic view of pigmentation using a Nikon Eclipse Ti microscope on day 14. For precise analysis, all tissues were photographed from above. Figure 2 shows the resulting photographs. Macroscopic view. From a tactical perspective, tissues treated with 50 μM and 100 μM urolithin A were negative controls. It is clear that the brightness is consistently higher than that of the DMSO 0.2% group. Also, 50 μM Tissue treated with 100 μM urolithin A was compared to a positive control applied topically at 2%. It can also be observed that the tissue is as bright as tissue treated with ujic acid.

[0125] b. The lightness of the sample was measured using Konica Minolta color spectrometers on days 0, 4, 7, 11, and 14. The L value was evaluated by measuring it using a hygrometer (CM-700d). The L value indicates how much the color is This indicates brightness or darkness, with black corresponding to L=0 and white corresponding to L=100. Figure 3 This represents the L value measured in different samples. The L value is the negative pair from day 4 to day 14. The levels were significantly higher in tissues treated with 50 μM and 100 μM uroritin A than in the untreated group. Unexpectedly, 50 μM or 100 μM urolithin A reacted faster than 0.2% kojic acid. It had the effect of brightening the tissue. This was particularly noticeable on days 4 and 7, and urolithin Tissue treated with A has a higher L value than tissue treated with kojic acid. Furthermore, the L values ​​of tissues treated with urolithin A and kojic acid were equivalent, as shown in Figure 2. This confirms that the effect was observed. Significant effects were observed at 50 μM and 100 μM concentrations. Extrapolating from these results, in another embodiment of the present invention, the range is 1 μM to 50 μM. This demonstrates that lower concentrations of urolithin A can be used in the methods and compositions of the present invention. Yes, they are.

[0126] c. Three tissue samples were used for melanin quantification in each group. The tissue samples were first infused in PBS. The tissue was incubated, and any remaining phenol red was removed from the maintenance medium. 500 μl of Solvable (trademark) (Tissue and Gel Solubi lizer 0.5 M-Packard BioScience Co. Catalog Number Place the sample in a 1.7 ml microcentrifuge tube containing 6NE9100, and combine it with a melanin standard at 95°C. Incubated overnight at °C. Melanin standard: Melanin (Sigma catalog number M8) By dissolving 631) in 1 mg / ml of Solvable (trademark), the stock solution is prepared. The solution was prepared. The dilution ratios of the standard curve using the undiluted solution are shown in Table 1.

[0127] [Table 3]

[0128] After incubation overnight, the sample was centrifuged at 13,000 rpm for 5 minutes to remove the insoluble material. The samples were pelletized. 200 μl of each sample was transferred to a 96-well plate and read at 490 nm. The results were obtained. Figure 4 shows the melanin content expressed in μg. Statistical significance was determined using a one-way ANOVA. This was performed using ANOVA, followed by multiple comparisons of each group against the negative control using Dunn's method. A post-hoc test (ett) was performed. Both 50 and 100 μM urolithin A were negative controls. In comparison, it significantly reduces melanin content by 65% ​​and 67%, respectively. 2% Kou Diacid also significantly reduces melanin content by 62%. Furthermore, a follow-up study comparing these two groups... According to the Canadian Student's t-test, melanin after treatment with 100 μM urolithin A The kojic acid content is significantly lower than when 2% kojic acid is used. These results are different. This is consistent with the visual evaluation of brightness and L value shown in Figures 2 and 3.

Claims

1. A topical composition for treating a target skin condition, comprising urolithin A or a salt thereof, The aforementioned skin condition is selected to protect the skin from skin inflammation, skin irritation, damage caused by sunlight / ultraviolet light, or damage caused by radiation therapy. A composition in which the urolithin A or a salt thereof is present in an amount ranging from 0.1 to 5% by weight.

2. The composition according to claim 1, wherein the skin condition is skin inflammation.

3. The composition according to claim 1, wherein the skin condition is skin irritation.

4. The composition according to claim 1, wherein the condition is damage caused by sunlight / ultraviolet light.

5. The composition according to claim 1 for protecting the skin from damage caused by radiation therapy.

6. The composition according to claim 5, wherein the radiation is beta or gamma rays.

7. The composition according to any one of claims 1 to 6, further comprising at least one excipient suitable for topical application.

8. The composition according to any one of claims 1 to 7, wherein the composition comprises 0.1 to 2% urolithin A or a salt thereof.

9. The composition according to any one of claims 1 to 8, wherein the composition comprises one or more of the following: (a) The composition is substantially free of polyphenols other than urolithin A or its salts; (b) Micronized urolithin A or a salt thereof; (c) Organic solvents; (d) Skin penetration enhancers; (e) Lipids, such as triglycerides including mono, di, and / or medium-chain triglycerides; (f) less than 5% by weight of water; (g) The composition is semi-solid; (h) The composition is a cream, paste, or ointment; (i) The composition is a skin cream; (j) The composition is a sunscreen composition; (k) substances that are physical and / or chemical sunscreens; and (l) Uroritin A or a salt thereof is present in the composition in an amount ranging from 1 to 2% by weight.

10. The composition according to any one of claims 1 to 9, wherein the urolithin A or a salt thereof is a finely powdered urolithin A or a salt thereof.

11. The urolithin A or its salt is a finely ground urolithin A or its salt having the following particle size distribution: (a) D in the range of 0.5 to 50 μm ５０ and D in the range of 5 to 100 μm ９０ Having, or (b) D 20 μm or smaller ５０ and D 30 μm or smaller ９０ Having, The composition according to any one of claims 1 to 10.

12. Micronized urolithin A or its salt, A topical composition comprising at least one excipient suitable for topical administration, The particle size distribution of the finely powdered urolithin A or its salt is (a) D in the range of 0.5 to 50 μm ５０ and D in the range of 5 to 100 μm ９０ Having, or (b) D 20 μm or smaller ５０ and D 30 μm or smaller ９０ A composition having the following characteristics.

13. The topical application composition according to claim 12, wherein the composition further comprises one or more of the following: (a) Organic solvents; (b) Skin penetration enhancers; (c) Lipids, such as triglycerides including mono, di, and / or medium-chain triglycerides; (d) Water at less than 5% by weight.

14. a) Semi-solid; b) Cream, paste or ointment; or c) It is a skin cream. The composition according to claim 12 or 13.

15. A sunscreen composition according to any one of claims 12 to 14.

16. The composition according to claim 15, comprising a physical and / or chemical sunscreen substance.

17. The composition according to any one of claims 12 to 16, wherein the urolithin A or a salt thereof is present in the composition in an amount within the range of 0.1 to 5% by weight.

18. A method for preparing the composition according to claim 12, - Micronizing urolithin A or its salt, and - Mixing finely powdered urolithin A or a salt thereof with at least one excipient suitable for topical administration. Methods that include...

19. The method according to claim 18, wherein the pulverized urolithin A or a salt thereof has a particle size distribution selected from any of the following. (a) D in the range of 0.5 to 50 μm ５０ and D in the range of 5 to 100 μm ９０ or (b) D 20 μm or smaller ５０ and D 30 μm or smaller ９０ .

Images