Composition for protecting skin containing thymol ester compound

Abstract

The present specification relates to a composition for skin protection, which comprises, as an active ingredient, thymol 3, 4, 5-trimethoxycinnamate (3, 4, 5-Trimethoxycinnate Thymol Ester), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The composition according to the present disclosure improves the expression of a DNA repair-related gene in skin cells that are photo-aged by ultraviolet light, thereby being capable of inhibiting or preventing skin damage caused by ultraviolet light or external environment or oxidative stress.

Description

Technical Field

[0001] The present specification discloses a skin protection composition comprising 3,4,5-trimethoxycinnamate thymol ester or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient. Background Art

[0002] The skin is the largest tissue in the outermost layer surrounding the human body, and thus is affected by many external environments more than anywhere else. In particular, harmful light such as ultraviolet rays that cause oxidative stress or environmental pollution factors such as dust directly act on skin cells constituting the skin, thereby damaging genes such as DNA. When such damaged DNA cannot be repaired well, cell functions are abnormal or apoptosis is caused, and diseases such as cancer are also caused.

[0003] Among methods for repairing DNA damage, there are various methods depending on the cause and degree of damage, and many genes are involved. When the skin ages, the expression of genes involved in NDA damage decreases, and thus the ability to repair DNA is greatly reduced. Eventually, even short-term exposure to a harmful environment can cause skin damage.

[0004] As the lifespan of humans increases and environmental pollution intensifies, factors causing skin damage are continuously accumulating. Therefore, it is a very necessary technology to improve the biological ability to repair DNA damage. However, a technology for preventing skin damage that can prevent and inhibit skin damage without other side effects has not been developed yet. Summary of the Invention

[0005] Technical Problem to be Solved

[0006] On the one hand, the present disclosure aims to provide a composition comprising 3,4,5-trimethoxycinnamate thymol ester as an active ingredient, thereby having a skin protection effect.

[0007] Means for Solving the Problem

[0008] On the one hand, the present disclosure provides a skin protection composition comprising 3,4,5-trimethoxycinnamate thymol ester or a stereoisomer, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.

[0009] Advantageous Effects of the Invention

[0010] On the one hand, the composition according to the present disclosure can inhibit or prevent skin damage or aging.

[0011] On the one hand, the composition according to the present disclosure can inhibit or prevent skin damage caused by photoaging.

[0012] On the one hand, the composition according to the present disclosure can increase the expression of genes for repairing DNA damage.

[0013] On the one hand, the composition according to the present disclosure can increase the expression of genes for repairing DNA damaged by photoaging.

[0014] On the one hand, the composition according to the present disclosure increases the expression of genes related to DNA repair in skin cells photoaged by ultraviolet rays, thereby being able to inhibit or prevent skin damage caused by ultraviolet rays, external environment, or oxidative stress. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 and Figure 2 are the results of observing the expression of aging genes according to an embodiment of the present disclosure;

[0016] Figures 3 to 5 Each is the result of observing the expression of DNA repair genes according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0017] Hereinafter, the present invention will be further described in detail through the following examples. However, the following examples are provided only for the purpose of assisting in understanding the present invention as examples, and the scope and range of the present invention are not limited thereto.

[0018] In an exemplary implementation of the present invention, there is provided a composition for skin protection, which includes 3,4,5-Trimethoxycinnamate Thymol Ester, its stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates as active ingredients.

[0019] In another exemplary implementation of the present invention, there is provided a method for protecting skin, the method including the step of administering a composition, wherein the composition includes 3,4,5-Trimethoxycinnamate Thymol Ester, its stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates as active ingredients.

[0020] In yet another exemplary embodiment of the present invention, there is provided the use of 3,4,5-trimethoxycinnamate thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates for preparing a composition for skin protection.

[0021] In yet another exemplary embodiment of the present invention, there is provided a non-therapeutic use of 3,4,5-trimethoxycinnamate thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates for protecting the skin.

[0022] In yet another exemplary embodiment of the present invention, there is provided 3,4,5-trimethoxycinnamate thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates for protecting the skin.

[0023] In one embodiment, the skin protection may be inhibiting or preventing skin damage.

[0024] In one embodiment, the skin protection may be improving skin self-renewal ability.

[0025] In one embodiment, the skin protection may be repairing DNA damage.

[0026] In one embodiment, the 3,4,5-trimethoxycinnamate thymol ester is (5-methyl-2-propan-2-ylphenyl) (E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoate which can be represented by the following Chemical Formula 1.

[0027]

Chemical Formula 1

[0028]

[0029] In this specification, "isomers" include, in particular, not only optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, or mixtures thereof), but also conformational isomers (i.e., isomers that differ only in the angle of more than one chemical bond), positional isomers (in particular, tautomers or geometric isomers) (e.g., cis-trans isomers).

[0030] In this specification, "essentially pure" means that, for example, when used with respect to enantiomers or diastereomers, there are about 90% or more, preferably about 95% or more, more preferably about 97% or more or about 98% or more, further preferably about 99% or more, and even more preferably about 99.5% or more (w / w) of the specific compounds of the enantiomers or diastereomers that can be cited.

[0031] In this specification, "pharmaceutically acceptable" means that when used at a normal medicinal dosage, it avoids significant toxic effects and thus can obtain or has obtained approval from a government or equivalent regulatory agency for use in animals, more specifically in humans, or is listed in a pharmacopoeia or is recognized as part of other general pharmacopoeias.

[0032] In the present specification, "pharmaceutically acceptable salt" refers to a salt according to an aspect of the present invention that is pharmaceutically acceptable and has the preferred pharmacological activity of the parent compound. The salt may include (1) formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, hexadienedioic acid, i.e., acid addition salts; or (2) salts formed when the acidic protons present in the parent compound are replaced.

[0033] In the present specification, "hydrate" refers to a compound combined with water, and is a broad concept including inclusion compounds in which there is no chemical binding force between water and the compound.

[0034] In the present specification, "solvate" refers to a higher-order compound formed between the molecules or ions of a solute and the molecules or ions of a solvent.

[0035] In one implementation example, the composition may be for inhibiting or preventing skin damage.

[0036] In one implementation example, the composition may be for improving skin self-renewal ability.

[0037] In one implementation example, the composition may be for repairing DNA damage.

[0038] In one implementation example, the damage may be caused by one or more selected from the group consisting of oxidative stress, alkali, drugs, aging, and ultraviolet rays.

[0039] In one implementation example, the ultraviolet ray may be one or more of UVA and UVB.

[0040] In one implementation example, the composition may increase the expression of DNA repair genes.

[0041] In one implementation example, the DNA repair genes may include one or more selected from the group consisting of APEX1, XPA, and RPA1.

[0042] The APEX1 is a gene involved in base excision repair, the XPA is a gene involved in nucleotide excision repair, and the RPA1 is a gene involved in mismatch repair. Primarily, base excision repair is involved in DNA damage caused by oxidative stress or alkali, and nucleotide excision repair is involved in DNA damage caused by ultraviolet rays or anticancer agents. Finally, mismatch repair is involved in repairing DNA damage that may occur during cell replication.

[0043] In one implementation example, the composition can inhibit the expression of aging genes.

[0044] In one implementation example, the aging genes may include one or more of P21 and P16.

[0045] In one implementation example, the concentration of the active ingredient, based on the total volume of the composition, can be 0.1 to 100 g / L.

[0046] For example, the concentration of the active ingredient, based on the total volume of the composition, can be 0.1 g / L or more, 0.5 g / L or more, 1 g / L or more, 5 g / L or more, 10 g / L or more, 20 g / L or more, 30 g / L or more, 40 g / L or more, 50 g / L or more, 60 g / L or more, 70 g / L or more, 80 g / L or more, or 90 g / L or more, and can be 100 g / L or less, 90 g / L or less, 80 g / L or less, 70 g / L or less, 60 g / L or less, 50 g / L or less, 40 g / L or less, 30 g / L or less, 20 g / L or less, 10 g / L or less, 5 g / L or less, 1 g / L or less, or 0.5 g / L or less.

[0047] In one implementation example, the composition can be a skin external preparation composition.

[0048] In one implementation example, the composition can be a non-therapeutic transdermal composition.

[0049] The skin external preparation or transdermal composition is a general term for any type that can be applied externally to the skin, and various dosage forms of cosmetics, pharmaceuticals, etc. are included herein.

[0050] In one implementation example, the composition can be a cosmetic composition.

[0051] The external form of the cosmetic composition may contain a cosmetically or dermatologically acceptable medium or matrix. As all dosage forms suitable for topical use, it can be provided, for example, in the form of a solution, gel, solid, anhydrous paste, emulsion obtained by dispersing an oil phase in an aqueous phase, suspension, microemulsion, microcapsule, microsphere, or ionic (liposome) and non-ionic vesicle dispersant, or in the form of a cream, lotion, milk, powder, ointment, spray, or concealer stick. The composition can be prepared by conventional methods in the art. The composition according to the present disclosure can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

[0052] The dosage form of the cosmetic composition according to an embodiment of the present disclosure is not particularly limited. For example, it can be formulated into cosmetics such as a flexible lotion, astringent lotion, nutritive lotion, nutritive cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, makeup remover, mask, powder, body milk, emollient cream, emollient oil, and emollient essence.

[0053] When the dosage form of the cosmetic composition according to the present disclosure is a paste, cream, or gel, as the carrier component, animal fibers, plant fibers, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide can be used.

[0054] When the dosage form of the cosmetic composition according to the present disclosure is a powder or spray, as the carrier component, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used. Especially in the case where the dosage form is a spray, a propellant such as chlorofluorocarbon, propane / butane, or dimethyl ether can be further contained.

[0055] When the dosage form of the cosmetic composition according to the present disclosure is a solution or emulsion, as the carrier component, a solvent, solubilizer, or emulsifier is used, such as water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol oil, glycerol fatty acid esters, polyethylene glycol, or sorbitan fatty acid esters.

[0056] When the dosage form of the cosmetic composition according to the present disclosure is a suspension, as the carrier component, a liquid diluent such as water, ethanol, or propylene glycol; a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitan ester, and polyoxyethylene sorbitan anhydride ester; microcrystalline cellulose; aluminum metahydroxide; bentonite, agar, or tragacanth can be used.

[0057] When the dosage form of the cosmetic composition of the present disclosure is a surfactant-containing cleanser, as the carrier component, fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, hydroxyethyl sulfonates, imidazoline derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkylamide betaines, fatty alcohols, fatty acid glycerol esters, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters, etc. can be used.

[0058] In addition to the active ingredient, the cosmetic composition of the present disclosure may further contain functional additives and components included in general cosmetic compositions. As the functional additives, components selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, sphingolipids, and seaweed juice can be included.

[0059] Furthermore, in the cosmetic composition of the present disclosure, together with the functional additives, components included in general cosmetic compositions are formulated as needed. As the additional formulated components, examples can include oil components, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, ethanol, pigments, fragrances, blood circulation promoters, cooling agents, antiperspirants, pure water, etc.

[0060] In one implementation example, the composition can be an oral composition.

[0061] In one implementation example, the composition can be an oral composition for antioxidation.

[0062] The oral composition according to the present disclosure can be in a liquid or solid dosage form, and can be tablets, capsules, soft capsules, pills, granules, beverages (drink preparations), fat-reducing bars, chocolates, caramel dosage forms, or cookie-like dosage forms, and its dosage form is not particularly limited.

[0063] In addition to the active ingredient, the oral composition according to the present disclosure may, as needed, further contain excipients, sugars, fragrances, pigments, oils, proteins, etc.

[0064] In one implementation example, the 3,4,5-trimethoxycinnamoyl thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates can be applied or ingested at an application or intake amount of 0.01 to 10 mg / kg / day.

[0065] For example, the coating amount or intake amount may be 0.01 mg / kg / day or more, 0.1 mg / kg / day or more, 0.5 mg / kg / day or more, 1 mg / kg / day or more, 3 mg / kg / day or more, 5 mg / kg / day or more, 7 mg / kg / day or more, or 9 mg / kg / day or more, and may be 10 mg / kg / day or less, 8 mg / kg / day or less, 6 mg / kg / day or less, 4 mg / kg / day or less, 2 mg / kg / day or less, 1 mg / kg / day or less, 0.5 mg / kg / day or less, 0.1 mg / kg / day or less, or 0.05 mg / kg / day or less.

[0066] In one implementation example, the composition may be a pharmaceutical composition.

[0067] The pharmaceutical composition according to an embodiment of the present invention may further contain pharmaceutical adjuvants such as preservatives, stabilizers, wettable powders or emulsification promoters, salts and / or buffering agents for adjusting osmotic pressure, and other therapeutically useful substances, and can be formulated into various oral dosage forms or parenteral dosage forms according to conventional methods.

[0068] As the oral dosage form, for example, there are tablets, pills, hard capsules and soft capsules, liquids, suspensions, emulsions, syrups, powders, powders, fine granules, granules, pellets, etc. In addition to the active ingredient, these dosage forms may contain surfactants, diluents (such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts, and polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone, and may optionally contain pharmaceutical additives such as disintegrants, absorbents, colorants, flavoring agents, and sweetening agents such as starch, agar, alginic acid or its sodium salt. The tablets can be prepared by conventional mixing, granulation or coating methods.

[0069] In addition, as the parenteral dosage form, it may be a transdermal dosage form. For example, it may be dosage forms such as injections, drip infusions, ointments, emulsions, gels, creams, sprays, suspensions, oils, suppositories, patches, etc., but is not limited thereto.

[0070] In one implementation example, the 3,4,5-trimethoxycinnamoyl thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates may be administered at a dosage of 0.01 to 30 mg / kg / day.

[0071] For example, the dosage can be 0.01 mg / kg / day or more, 0.1 mg / kg / day or more, 1 mg / kg / day or more, or 5 mg / kg / day or more, and can be 10 mg / kg / day or less, 5 mg / kg / day or less, 1 mg / kg / day or less, 0.1 mg / kg / day or less, or 0.05 mg / kg / day or less.

[0072] Hereinafter, the present invention will be further described in detail by the following examples. However, the following examples are provided only for the purpose of assisting in understanding the present invention as examples, and the scope and range of the present invention are not limited thereto.

[0073] Example

[0074] Preparation of 3,4,5-Trimethoxycinnamate Thymol Ester

[0075] Purchase Melasolv (CAS No. 504394-57-4) of trimethoxycinnamate thymol ester from COSMANN Co., Ltd. (located in Hwaseong City, Gyeonggi-do).

[0076] Experimental Example

[0077] Experimental Example 1 - Inhibitory Damage Experiment Using Human Normal Melanogenesis Cells

[0078] Melanogenesis cells (Normal human epidermal melanocyte) isolated from normal human skin were treated with ultraviolet B (312 nm) at 20 mJ once a day for 2 days, and then cultured for 1 month. Melasolv was dissolved in DMSO at 1000X, and after irradiation with ultraviolet light, it was immediately placed in the culture medium and treated at 1 ppm and 5 ppm. The culture medium containing the test substance was replaced every two days, and the cells were cultured in an incubator at 37 °C and 5% CO2. After the experiment, the cells were lysed in TRIzol, and total RNA (total RNA) was isolated, and then cDNA was synthesized here, and real-time fluorescence quantitative PCR (real-time PCR) was performed to compare the relative expression levels of each gene. The RNA was quantified, the same amount of RNA was placed between the experimental groups, and the expression of each gene was corrected using the expression of GAPDH as a house-keeping gene, so as to relatively compare the expression levels.

[0079] The gene primers used were as described below and were purchased from APPLIED BIOSYSTEMS.

[0080] APEX1 (Hs00172396_m1), XPA (Hs00902270_m1), RPA1 (Hs00161419_m1), GAPDH (Hs02786624_g1), p21 (Hs00355782_m1), p16 (Hs00923894_m1)

[0081] First, as Figure 1 and 2 shown, it can be confirmed that in skin cells (melanocytes) treated with ultraviolet rays and cultured for 1 month, p16 and p21, which are senescence genes, increase and senescence occurs.

[0082] Then, as Figures 3 - 5 shown, the expression of three representative genes involved in DNA repair was confirmed. At this time, it was confirmed that the expression of all types of DNA repair genes was significantly reduced statistically due to photoaging.

[0083] However, it can be confirmed that when ultraviolet rays are irradiated to cells and Melasolv is treated at 1 ppm and 5 ppm, the expression of senescence genes is inhibited in a concentration-dependent manner (see Figure 1 , 2 ), and the expression of DNA repair genes reduced due to photoaging is increased (see Figures 3 - 5 ).

[0084] In particular, in the Figure 4 XPA gene, the increase in gene expression by 5 ppm of Melasolv is higher than that of the control group, and thus it can be confirmed that the DNA repair ability is significantly improved. This result indicates that Melasolv improves the ability of cells to repair all types of DNA damage caused by oxidative stress, bases, drugs, ultraviolet rays, and aging, and thus can prevent and inhibit skin damage (*P < 0.05, **P < 0.01).

[0085] Specific example

[0086] Specific example 1: Use of 3,4,5-trimethoxycinnamate thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates for preparing a composition for skin protection.

[0087] Specific example 2: A use, according to specific example 1, wherein the composition is used to inhibit or prevent skin damage.

[0088] Specific example 3: A use, according to specific example 1 or 2, wherein the composition is used to improve skin self-renewal ability.

[0089] Specific Example 4: A use, according to any one of Specific Examples 1 to 3, wherein the composition is used for repairing DNA damage.

[0090] Specific Example 5: A use, according to any one of Specific Examples 1 to 4, wherein the damage is damage caused by one or more selected from the group consisting of oxidative stress, alkali, drug, aging, and ultraviolet light.

[0091] Specific Example 6: A use, according to any one of Specific Examples 1 to 5, wherein the ultraviolet light is one or more of UVA and UVB.

[0092] Specific Example 7: A use, according to any one of Specific Examples 1 to 6, wherein the composition increases the expression of DNA repair genes.

[0093] Specific Example 8: A use, according to any one of Specific Examples 1 to 7, wherein the DNA repair genes include one or more selected from the group consisting of APEX1, XPA, and RPA1.

[0094] Specific Example 9: A use, according to any one of Specific Examples 1 to 8, wherein the composition inhibits the expression of aging genes.

[0095] Specific Example 10: A use, according to any one of Specific Examples 1 to 9, wherein the aging genes include one or more of P21 and P16.

[0096] Specific Example 11: A use, according to any one of Specific Examples 1 to 10, wherein the concentration of the active ingredient is 0.1 to 100 g / L based on the total volume of the composition.

[0097] Specific Example 12: A use, according to any one of Specific Examples 1 to 11, wherein the composition is a topical skin agent.

[0098] Specific Example 13: A use, according to any one of Specific Examples 1 to 12, wherein the composition is a cosmetic composition.

[0099] Specific Example 14: A use, according to any one of Specific Examples 1 to 13, wherein the composition is an oral composition.

[0100] Specific Example 15: A use, according to any one of Specific Examples 1 to 14, wherein the composition is a pharmaceutical composition.

[0101] Specific Example 16: A use, according to any one of Specific Examples 1 to 15, wherein the 3,4,5-trimethoxycinnamate thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates are administered at a dosage of 0.01 to 30 mg / kg / day.

Claims

1. Use of 3,4,5-trimethoxycinnamoyl thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates for preparing a composition for skin protection.

2. The use according to claim 1, wherein: The composition is used for inhibiting or preventing skin damage.

3. The use according to claim 1, wherein: The composition is used for improving skin self-renewal ability.

4. The use according to claim 1, wherein: The composition is used for repairing DNA damage.

5. The use according to claim 2 or 4, wherein: The damage is damage caused by one or more selected from the group consisting of oxidative stress, alkali, drugs, aging and ultraviolet rays.

6. The use according to claim 5, wherein: The ultraviolet ray is one or more of UVA and UVB.

7. The use according to claim 1, wherein: The composition increases the expression of DNA repair genes.

8. The use according to claim 7, wherein: The DNA repair genes include one or more selected from the group consisting of APEX1, XPA and RPA1.

9. The use according to claim 1, wherein: The composition inhibits the expression of aging genes.

10. The use according to claim 9, wherein: The aging genes include one or more of P21 and P16.

11. The use according to claim 1, wherein: The concentration of 3,4,5-trimethoxycinnamoyl thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates is 0.1 to 100 g / L based on the total volume of the composition.

12. The use according to claim 1, wherein: The composition is a topical skin agent.

13. The use according to claim 1, wherein: The composition is a cosmetic composition.

14. The use according to claim 1, wherein: The composition is a pharmaceutical composition.

15. The use according to claim 1, wherein: The 3,4,5-trimethoxycinnamoyl thymol ester, its stereoisomers, pharmaceutically acceptable salts, hydrates or solvates are administered at a dosage of 0.01 to 30 mg / kg / day.

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