KR20230112764A - Composition comprising N-trans-caffeoyltyramine for skin whitening and enhancing skin barrier - Google Patents

Abstract

The present invention provides a composition containing N-trans-caffeoyltyramine, in particular, a cosmetic composition, a pharmaceutical composition, and a food composition for skin whitening and skin barrier enhancement.
The composition containing N-trans-caffeoyltyramine of the present invention exhibits skin protection functions such as skin whitening, moisturizing, and reduction of inflammatory response in a complex manner, so that it can be used in cosmetics, pharmaceuticals, and food fields, such as functional cosmetics, external medicines, and functional foods. It can be usefully used as a multifunctional material.

Description

Composition comprising N-trans-caffeoyltyramine for skin whitening and enhancing skin barrier

The present invention relates to a composition for skin whitening and skin barrier strengthening, and more particularly, to a composition for skin whitening and skin barrier strengthening containing N-trans-caffeoyltyramine.

Recently, as we enter an aging society, interest in skin is increasing, and accordingly, interest in functional cosmetics is increasing. Existing functional cosmetics have been developed in the form of independent functions such as skin whitening, wrinkle improvement, and itching relief, but the recent cosmetic consumption trend is increasing the preference for products containing various functionalities in one product.

Accordingly, there are cases in which cosmetics are manufactured by combining a plurality of materials each having functionality, but in this case, there is a possibility that unexpected side effects may occur due to the plurality of materials mixed, and the efficacy of functional ingredients may offset each other. cannot be ruled out

Therefore, in order to solve these problems, the need for a single material that exhibits various functions and an approach are emerging.

Kuo et al. BMC Complementary and Alternative Medicine (2017) 17:71

The problem to be solved by the present invention is to provide a substance that can be used as a new material for multi-functional cosmetics when manufacturing functional cosmetics by complexly exhibiting skin protection functions such as skin whitening, moisturizing, and reducing inflammatory response.

The problem to be solved by the present invention is not limited to the above-mentioned problem, and other technical problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

In order to solve the above problems, according to one aspect of the present invention, a composition for skin whitening and skin barrier strengthening containing N-trans-caffeoyltyramine is provided.

In one embodiment, the skin whitening may be by α-MSH-mediated inhibition of melanin production or α-MSH-mediated inhibition of tyrosinase activity.

In one embodiment, the strengthening of the skin barrier may be due to moisturizing or reduction of inflammatory response, and in this case, the moisturizing is HAS-2, CerS3, AQP3, filaggrin, involucrin and loricrin. (loricrin) may be due to the expression of one or more selected from the group consisting of, the inflammation may be allergic inflammation or atopic inflammation.

According to another aspect of the present invention, a method for skin whitening and skin barrier strengthening is provided by a method of administering N-trans-caffeoyltyramine to a subject in need thereof.

According to another aspect of the present invention, a cosmetic composition for skin whitening and skin barrier enhancement containing N-trans-caffeoyltyramine is provided.

According to another aspect of the present invention, a pharmaceutical composition for skin whitening and skin barrier enhancement containing N-trans-caffeoyltyramine is provided.

According to another aspect of the present invention, there is provided a food composition for skin whitening and skin barrier strengthening containing N-trans-caffeoyltyramine.

According to the present invention, N-trans-caffeoyltyramine complexly exhibits skin protection functions such as skin whitening, moisturizing, and reduction of inflammatory response, so that a composition containing N-trans-caffeoyltyramine is used for skin whitening and skin barrier strengthening. It can be used as a cosmetic composition, a pharmaceutical composition and a food composition, and in particular, it has been found to be helpful in relieving itching caused by atopy, which is increasing in infants and young children, and thus can be applied to functional cosmetics as well as pharmaceuticals.

Therefore, the composition containing N-trans-caffeoyltyramine of the present invention can be usefully used as a material for multi-functional products in the fields of cosmetics, drugs, and food, as well as functional cosmetics, pharmaceutical preparations, and functional foods.

The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the description of the present invention or the configuration of the invention described in the claims.

1 is a ¹ H NMR spectrum of synthesized N-trans-caffeoyltyramine.
Figure 2 is a ¹³ C NMR spectrum of synthesized N-trans-caffeoyltyramine.
Figure 3 shows the effect of N-trans-caffeoyltyramine on the proliferation of melanoma cells (A), the effect on α-MSH-mediated melanin synthesis (B), and the effect on α-MSH-mediated tyrosinase activity (C). it's a graph
4 is a result of measuring the effect of N-trans-caffeoyltyramine on mRNA levels of HAS-2, CerS3, AQP3, filaggrin, involucrin, and loricrin.
Figure 5 is the result of measuring the effect of N-trans-caffeoyltyramine on the mRNA levels of COX-2, TNF-α, and iNOS and on the production of nitric oxide.

The present invention provides a composition for skin whitening and skin barrier strengthening comprising N-trans-caffeoyltyramine.

The present invention relates to the skin whitening function of the N-trans-caffeoyltyramine compound and the skin barrier strengthening function such as moisturizing and reducing inflammatory response, alpha melanocyte stimulating hormone, α-MSH) by confirming the effect of inhibiting melanin production and the effect of reducing the expression of various biomarkers involved in allergic inflammation and moisturizing, the effectiveness of N-trans-caffeoyltyramine for skin whitening and skin barrier strengthening was confirmed, and the mechanism of action of N-trans-caffeoyltyramine was confirmed through analysis of intracellular molecular mechanisms.

Accordingly, in one embodiment of the present invention, the skin whitening may be by inhibiting α-MSH-mediated melanin production or inhibiting α-MSH-mediated tyrosinase activity. Specifically, N-trans-caffeoyltyramine was found to inhibit α-MSH-mediated melanin synthesis in a concentration-dependent manner. In addition, N-trans-caffeoyltyramine was found to inhibit α-MSH-mediated tyrosinase activity in a concentration-dependent manner.

In addition, in one embodiment of the present invention, the strengthening of the skin barrier may be due to moisturizing or reduction of inflammatory response, and in this case, the moisturizing is HAS-2, CerS3, AQP3, filaggrin, involucrin ( It may be caused by the expression of one or more selected from the group consisting of involucrin and loricrin, and the inflammation may be allergic inflammation or atopic inflammation.

In other words, how does N-trans-caffeoyltyramine affect the mRNA levels of HAS-2, CerS3, AQP3, filaggrin, involucrin, and loricrin, known as biomarkers related to moisturizing? As a result of confirmation, it was confirmed that the expression level of the biomarkers increased as the concentration of N-trans-caffeoyltyramine increased, and in particular, it was confirmed that a significant value was exhibited at 10 μM.

By confirming the efficacy of N-trans-caffeoyltyramine as described above, N-trans-caffeoyltyramine complexly exhibited skin protection functions such as skin whitening, moisturizing, and reduction of inflammatory response, and thus multi-functional cosmetics for future functional cosmetics manufacturing. It was confirmed that it can be used as a material for

Accordingly, the present invention provides a method for skin whitening and skin barrier strengthening by administering N-trans-caffeoyltyramine to a subject in need thereof.

The present invention also provides skin whitening and skin barrier strengthening uses of N-trans-caffeoyltyramine.

In addition, the present invention provides a cosmetic composition for skin whitening and skin barrier enhancement comprising N-trans-caffeoyltyramine.

When the composition containing N-trans-caffeoyltyramine of the present invention is used as a cosmetic composition, it can be prepared in any formulation commonly prepared in the art as a functional cosmetic and hair care cosmetic, for example, an emulsion. , creams, lotions, packs, foundations, lotions, serums, hair cosmetics, and the like.

Ingredients included in the cosmetic composition of the present invention may include ingredients commonly used in cosmetic compositions other than the N-trans-caffeoyltyramine, for example, stabilizers, solubilizers, vitamins, pigments, and fragrances. including conventional adjuvants and carriers. When the formulation of the present invention is a paste, cream or gel, animal fiber, vegetable fiber, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component. can

The present invention also provides a pharmaceutical composition for skin whitening and skin barrier enhancement comprising N-trans-caffeoyltyramine.

The pharmaceutical composition of the present invention includes the N-trans-caffeoyltyramine as an active ingredient, and may further include pharmaceutically acceptable additives.

The pharmaceutical composition may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively, and the additives are A pharmaceutically acceptable carrier or diluent is included. The pharmaceutically acceptable carrier includes lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil; and the like. In addition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants are included. Solid preparations for oral use include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, and gelatin. and the like, and may include lubricants such as magnesium stearate and talc. Oral liquid preparations include suspensions, internal solutions, emulsions, syrups, and the like, and may include diluents such as water and liquid paraffin, wetting agents, sweeteners, aromatics, and preservatives. Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations, and suppositories, and non-aqueous solvents and suspensions include vegetable oils, injectable esters such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween based base, cacao paper, laurin paper, glycerogelatin, etc. may be used.

Preferably, the pharmaceutical composition of the present invention may be an external preparation for the skin, more preferably a cream formulation. The external skin preparation may be, for example, ointment, patch, gel, cream or spray formulation. When the composition is an external preparation for skin, it may additionally contain a fatty substance, an organic solvent, a solubilizing agent, a thickening agent and a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, and an ionic type. Emulsifiers, non-ionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic activators, lipophilic activators or lipid vesicles commonly used in external skin preparations It may contain adjuvants commonly used in the field of dermatology, such as any other ingredients. In addition, the components may be introduced in an amount generally used in the field of skin science.

The dose of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of active ingredient, the route and period of administration, and may be appropriately adjusted according to the patient. For example, the active ingredient may be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.001 to 100 mg/kg, and the administration may be administered once or several times a day. In addition, the pharmaceutical composition of the present invention may include 0.001 to 90% by weight of the active ingredient based on the total weight of the composition.

The pharmaceutical composition of the present invention is administered through various routes, for example, oral, dermal, abdominal, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebroventricular injection to animals, including mammals such as livestock and humans. can be administered by

The present invention also provides a food composition for skin whitening and skin barrier strengthening containing N-trans-caffeoyltyramine.

The food composition of the present invention can be used as a health functional food. The term “health functional food” refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body in accordance with the Health Functional Food Act, and “functional” refers to food that is not related to the structure and function of the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients or physiological functions.

The food composition of the present invention may include conventional food additives, and the suitability as the "food additive" is determined according to the general rules of the food additive code approved by the Ministry of Food and Drug Safety and general test methods, etc., unless otherwise specified. It is judged according to the specifications and standards for the item.

Items listed in the "Food Additive Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, goyang pigment, guar gum, and mixed preparations such as sodium L-glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.

The food composition of the present invention is for the purpose of skin whitening and skin barrier strengthening, in particular skin barrier strengthening, moisturizing and reducing and/or improving inflammatory reactions, the composition containing N-trans-caffeoyltyramine in an amount of 0.01 to 95% based on the total weight of the composition. % by weight, preferably 1 to 80% by weight. In addition, for the purpose of skin whitening and skin barrier strengthening, it can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc.

For example, the health functional food in the form of a tablet is obtained by granulating a mixture of the N-trans-caffeoyltyramine-containing composition, an excipient, a binder, a disintegrant, and other additives in a conventional manner, and then adding a lubricant, etc. It may be put into compression molding, or the mixture may be directly compression molded. In addition, the health functional food in the form of a tablet may contain a corrigent, etc., if necessary, and may be coated with an appropriate coating agent, if necessary.

Hard capsules among health functional foods in the form of capsules can be prepared by filling a mixture of the N-trans-caffeoyltyramine-containing composition and additives such as excipients, granular material thereof, or coated granular material in a conventional hard capsule, Soft capsules can be prepared by filling a mixture of the N-trans-caffeoyltyramine-containing composition and additives such as excipients into a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, and a preservative, if necessary.

A health functional food in granular form can be prepared in a granular form from a mixture of the N-trans-caffeoyltyramine-containing composition, excipients, binders, disintegrants, etc. by an appropriate method, and, if necessary, may contain flavoring agents, flavoring agents, etc. can

Definitions of terms for the excipients, binders, disintegrants, lubricants, corrigents, flavoring agents, etc. of the present invention are described in literature known in the art, and include those having the same or similar functions.

Hereinafter, the present invention will be described in more detail through examples. However, the following examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Example 1. Synthesis of N-trans-caffeoyltyramine

<Scheme 1>

N-trans-caffeoyltyramine was synthesized as shown in Scheme 1 above. First, caffeic acid (2.5 mmol, 450 mg) was dissolved in N,N-dimethylformamide (DMF, 0.15 M, 16 mL), and then 1-ethyl-3-(3'-dimethylaminopropyl) Carbodiimide HCl [1-Ethyl-3-(3′ HCl] (EDC-HCl, 1.1 eq, 910 mg) and hydroxybenzotriazole (HOBt, 1.1 eq, 675 mg) were added and stirred at room temperature for 30 tyramine (1.85 eq, 644 mg) and N,N-diisopropylethylamine (DIPEA, 3.5 eq, 1.5 mL) were added to the mixture and the reaction was stirred at room temperature Stirred overnight.Pure water was added and the organic layer was extracted with ethyl acetate (3x10 mL) and dried with MgSO _4. Then the mixture was filtered and concentrated in vacuo.The product was purified by column chromatography (silica gel, methanol/dichloromethane = 1:15, v/v) to give the corresponding product (white powder, 225 mg, 35% yield).

1 and 2 are ¹ H NMR spectrum and ¹³ C NMR spectrum of N-trans-caffeoyltyramine, respectively.

Compound 1 (yield, 2.1±0.1 mg/50 mg EtOAc fraction) was obtained as a white powder. ^1H NMR (400 MHz, MeOD- d4 ) δ 7.37 (d, J = 15.68 Hz, 1H), 7.05 (dd, J = 6.52, 2.0 Hz, 2H), 6.99 (d, J = 2.02 Hz, 1H), 6.71 (dd, J = 8.24, 2.00 Hz, 1H), 6.75 (d, J = 8.15 Hz, 1H), 6.71 (dd, J = 6.52, 2.08 Hz, 2H), 6.33 (d, J = 15.067 Hz, 1H) ), 3.45 (t, J = 7.41 Hz, 2H), 2.74 (t, J = 7.40 Hz, 2H); ¹³ C NMR (100 MHz, MeOD- d4 ) δ (169.3, 156.9, 148.7, 146.7, 142.2, 131.3, 130.7, 128.3, 122.1, 118.4, 116.5, 116.3, 115.1, 42.6, 35 .8). Compound 1 was identified as N-trans-caffeoyltyramine [ N-trans -caffeoyltyramine] by NMR analysis and comparison with previous literature.

Example 2. Verification of melanin production inhibitory effect of N-trans-caffeoyltyramine

In order to confirm the inhibitory effect of N-trans-caffeoyltyramine on melanin production, whether the N-trans-caffeoyltyramine compound synthesized above exhibits an inhibitory effect on melanin synthesis mediated by α-MSH is described below. confirmed together. When melanoma cells were treated with N-trans-caffeoyltyramine in a concentration range of 2-100 μM, there was no significant effect on melanoma cell proliferation (FIG. 3(A)). In contrast, N-trans-caffeoyltyramine inhibited α-MSH-mediated melanin synthesis in a concentration-dependent manner, and was shown to be maximally inhibited at 50 and 100 μM (FIG. 3(B)). In addition, N-trans-caffeoyltyramine inhibited α-MSH-mediated tyrosinase activity in a concentration-dependent manner, and showed maximum inhibition at 50 and 100 μM (FIG. 3(C)). From these results, it can be seen that N-trans-caffeoyltyramine inhibits α-MSH-mediated melanin synthesis through inhibition of tyrosinase activity.

Example 3. Verification of the effect of suppressing the expression of biomarkers related to moisturizing of N-trans-caffeoyltyramine

By checking the effect of N-trans-caffeoyltyramine on the mRNA levels of HAS-2, CerS3, AQP3, filaggrin, involucrin, and loricrin, which are known as biomarkers related to moisturizing, The results are shown in FIG. 4 . As shown in Figure 4, it was confirmed that the expression level of the biomarkers increased as the concentration of N-trans-caffeoyltyramine increased, and in particular, a significant value was shown at 10 μM.

Example 4. Verification of the inhibitory effect of anti-inflammatory biomarkers of N-trans-caffeoyltyramine

The effect of N-trans-caffeoyltyramine on the mRNA levels of COX-2, TNF-α, and iNOS known as biomarkers related to inflammation and the effect on nitric oxide production was confirmed, and the results are shown in FIG. was As shown in Figure 5, the mRNA levels of COX-2 and iNOS, which are inflammatory biomarkers increased by LPS, and nitric oxide production are restored to normal levels as the concentration of N-trans-caffeoyltyramine increases. It was confirmed that it was, and in particular, a significant value was shown at a concentration of 10 μM or more.

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims (12)

A composition for skin whitening and skin barrier strengthening comprising N-trans-caffeoyltyramine. The composition for skin whitening and skin barrier strengthening according to claim 1, wherein the skin whitening is performed by inhibiting α-MSH-mediated melanin production. The composition for skin whitening and skin barrier strengthening according to claim 1, wherein the skin whitening is performed by inhibiting α-MSH-mediated tyrosinase activity. The composition for skin whitening and skin barrier strengthening according to claim 1, wherein the strengthening of the skin barrier is performed by moisturizing. The method of claim 4, characterized in that the moisturizing is by expression of one or more selected from the group consisting of HAS-2, CerS3, AQP3, filaggrin, involucrin and loricrin. , Composition for skin whitening and skin barrier strengthening. The composition for skin whitening and skin barrier strengthening according to claim 1, wherein the strengthening of the skin barrier is caused by reducing the inflammatory response. The composition for skin whitening and skin barrier strengthening according to claim 6, wherein the inflammation is allergic inflammation. The composition for skin whitening and skin barrier strengthening according to claim 6, wherein the inflammation is atopic inflammation. A method of skin whitening and skin barrier strengthening by a method of administering N-trans-caffeoyltyramine to a subject in need thereof. A cosmetic composition for skin whitening and skin barrier enhancement comprising N-trans-caffeoyltyramine. A pharmaceutical composition for skin whitening and skin barrier enhancement comprising N-trans-caffeoyltyramine. A food composition for skin whitening and skin barrier enhancement comprising N-trans-caffeoyltyramine.