Detailed Description
Hereinafter, embodiments of the present invention are described in detail to enable persons having ordinary skill in the art to which the present invention pertains to easily practice the present invention. However, the present invention may be embodied in various forms and is not limited to the embodiments described herein.
In the present specification, the improvement of the skin whitening function means a case where the color of the stratum corneum located on the outer layer of the skin becomes bright and white. The stratum corneum, which is the primary protective membrane of the skin, can be easily damaged by the external environment. In order to impart whitening power to such skin, a temporary problem is generally solved by applying a prescription of an external preparation for skin, but a fundamental problem is difficult to solve, and further, most of the external preparation for skin is not used for solving the problem, but only shows an effect of simply shielding the degree of black marks in skin, so that the problem of hyperpigmentation of skin cannot be fundamentally improved by simply applying a prescription of an external preparation for skin. For this reason, the present inventors confirmed that a compound represented by a specific chemical formula constituting a composition according to an embodiment can solve the fundamental problems described above, and thus can fundamentally improve the skin whitening efficacy, thereby completing the present invention.
More specifically, the composition according to an embodiment can expect skin whitening effect by blocking synthesis of melanin by normal melanocytes of human beings.
In this regard, it is known that the increase in melanin production occurs when the intracellular concentration of c-AMP increases, and the decrease in melanin production occurs when the extracellular signal-regulated kinase (extracellular signal regulated kinase, ERK) pathway is activated. However, as a method for activating the extracellular signal-regulated kinase pathway, a method for stimulating a signal transduction pathway that phosphorylates extracellular signal-regulated kinase is known, and when protein phosphatase 2A (protein phosphatase a, pp 2A) which is an enzyme that dephosphorylates extracellular signal-regulated kinase is inhibited, extracellular signal-regulated kinase is activated, and thus, although a skin whitening effect can be expected by the decomposition of microphthalmia-associated transcription factor (Microphthalmia-associated transcription factor, MITF) eventually, an effective method for inhibiting the protein phosphatase 2A has not recently appeared.
In view of this, the present inventors have confirmed that when a composition containing a specific compound as an active ingredient (more specifically, a composition containing the specific compound as an active ingredient in a specific concentration range) is treated to normal human melanogenic cells, melanin synthesis blocking effects are exhibited, and have completed the present invention.
On the other hand, as in the above method, substances that directly inhibit melanin-producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)) need to be used in high concentrations, and therefore, not only side effects such as skin irritation can occur, but also kojic acid (kojic acid) has a possibility of causing skin cancer, and is therefore prohibited from being used. However, the composition according to an embodiment is not a substance directly inhibiting melanin producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)), and thus can exhibit a safer and stronger whitening effect by inhibiting melanin production while not irritating the skin with little side effects.
In the present specification, when there is no additional definition, "combination" means mixing or copolymerization. The "copolymerization" means block copolymerization or random copolymerization, and the "copolymer" means block copolymer or random copolymer.
Hereinafter, a skin whitening composition according to an embodiment will be described.
The composition for skin whitening according to an embodiment contains a compound represented by the following chemical formula 1 as an active ingredient:
[ chemical formula 1]
In the chemical formula 1 described above, a compound having the formula,
X is CRR '(R and R' are each independently a hydrogen atom or a substituted or unsubstituted C1 to C10 alkyl group), an oxygen atom or a sulfur atom,
L1 is a substituted or unsubstituted C1 to C20 alkylene group,
R1 is hydroxy, substituted or unsubstituted C1 to C20 alkyl, or substituted or unsubstituted C1 to C20 alkoxy.
For example, the compound represented by the chemical formula 1 may be a substance derived from lactobacillus fermentum. Recently, as the interest in health has increased, the demand for skin-immune cosmetics has been attracting attention, and efforts have been made to develop microbiome materials that improve skin defense functions and have various skin effects, however, there has been no material capable of expecting skin whitening effects. The inventors of the present invention have conceived whether a material capable of achieving a skin whitening effect can be obtained from a microbiome material, and have thus conducted years of research and experiments on various microbiome materials, and have finally confirmed that a skin whitening effect can be achieved when the compound represented by the chemical formula 1 from lactobacillus ferments (lactobacillus ferment) is used, thereby completing the present invention.
For example, in the chemical formula 1, X is an oxygen atom, and R1 is a hydroxyl group.
For example, the chemical formula 1 may be represented by the following chemical formula 1-1, but is not limited thereto.
[ Chemical formulas 1-1]
For example, the compound represented by the chemical formula 1 may be contained at a concentration of 0.01 μm to 10mM with respect to the total amount of the composition. When the compound represented by the chemical formula 1 is contained in the concentration range, melanin production of melanin producing cells of normal human skin can be effectively inhibited without cytotoxicity, thereby further increasing the whitening efficacy.
Specifically, the compound represented by the chemical formula 1 in the composition may contain a concentration of 0.01 μm to 10mM, for example, a concentration of 0.1 μm to 10mM, for example, a concentration of 1 μm to 10mM, for example, a concentration of 0.01mM to 10mM, for example, a concentration of 0.1mM to 10mM, with respect to the total amount of the composition. For example, the compound represented by the chemical formula 1 in the composition may be contained at a concentration of 0.01 μm or more, for example, 0.1 μm or more, for example, 1 μm or more, for example, 10 μm or more, for example, 100 μm or more, and may be contained at a concentration of 10mM or less, for example, 1mM or less, with respect to the total amount of the composition. When the compound represented by the chemical formula 1 is used at a concentration of less than 0.01 μm, the degree of inhibiting the new generation of melanin in the melanin producing cells (melanocytes) is weak, and thus the skin whitening function improving effect cannot be provided. In addition, when the compound represented by the chemical formula 1 is used at a concentration exceeding 10mM, cytotoxicity is exhibited to be harmful to human body, and thus may not be preferable. Still further, when the compound represented by the chemical formula 1 is a compound derived from lactobacillus fermentum (lactobacillus ferment), the compound represented by the chemical formula 1 (derived from lactobacillus fermentum (lactobacillus ferment)) in the composition may contain a concentration of 10 μm to 10mM, for example, a concentration of 100 μm to 5 mM. The case of using the compound represented by the chemical formula 1 in the form of a lactobacillus fermentation belongs to the case of using a natural substance, compared with the case of using the compound represented by the chemical formula 1 by synthesizing it in addition, and thus there is a possibility that a concentration range in which there is no cytotoxicity may be different while actually suppressing the new generation of melanin in melanin producing cells (melanocytes). This is considered to be the case of natural substances, unlike the case of chemically synthesized substances, capable of limiting or altering the desired functional expression by the interaction between the various components included in the composition.
The hyperpigmentation in the skin can be caused by various factors such as in vivo hormonal abnormalities, genetic diseases, ultraviolet irradiation and the like after the skin inflammatory reaction, and for this reason, melanin synthesis abnormality, distribution abnormality and the like can be given as main factors.
The main function of melanin is to remove oxygen radicals and protect the skin from damage caused by oxygen radicals. Melanin is therefore often indicative of an effective countermeasure system to protect skin from physical and chemical toxic substances. In melanocytes, after Tyrosine (Tyrosine) is converted into dopaquinone (Dapaquinone) by melanin-producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)), melanin production as described above is completed by the action of the enzymes and spontaneous oxidation reactions.
The known methods for inhibiting melanin formation are generally as follows.
First, there is a method of blocking ultraviolet rays to remove a main cause of melanin generation. This method is to make the cosmetic composition contain a light scattering agent or a light blocking agent, and thus can expect good results.
Next, the synthesis of a core carbohydrate required for activating melanin producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)) such as Glucosamine (Glucosamine) is inhibited, whereby the production of melanin can be suppressed.
In addition, the function of melanin producing enzyme (TRP 1), which is an enzyme involved in melanin production, can be blocked by kojic acid (Kojic acid) or arbutin.
Further, it is also possible to inhibit the division of melanocytes by using substances such as hydroquinone (hydroquinone) which are specific toxic to melanocytes which produce melanin.
In addition, a method of reducing and decoloring the produced melanin has been described.
Currently, most of studies for finding whitening compositions have focused on substances that directly inhibit melanin-producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)) involved in melanin production. However, in addition to the direct inhibition of melanin-producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)), studies have been proposed in which whitening effects can be expected by regulating signal transduction (signal transduction) involved in the expression of melanin-producing enzymes (TRP 1, TRP2, tyrosinase (tyrosinase)) (Briganti S, camera E, picardo m.pigment Cell Res, 2003, 16 (2): 101-10).
The composition according to an embodiment is excellent in the effect of inhibiting the new generation of melanin in melanin producing cells (melanocytes) in particular, and thus is excellent in the skin whitening effect when used in skin where hyperpigmentation is caused by skin pigmentation inducing factors.
An embodiment provides a composition for skin whitening comprising the compound represented by the chemical formula 1 as an active ingredient, which may contain the compound represented by the chemical formula 1 alone in a pharmaceutically effective amount or include one or more pharmaceutically acceptable carriers, excipients or diluents.
The "pharmaceutically effective amount" in the above is an amount sufficient to exhibit the intended physiological or pharmacological activity by administering the physiologically active ingredient to an animal or human. However, the pharmaceutically effective amount may be appropriately changed according to the degree of symptoms, age, body weight, health state, sex, administration route, and treatment time of the patient, and the like.
In addition, "pharmaceutically acceptable" in the above description means that the physiologically acceptable and human administration does not generally cause allergic reactions such as gastrointestinal disorders, dizziness, or the like. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginic acid, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be contained.
For example, the composition may be a cosmetic composition.
In the present specification, "cosmetic" may refer to all substances having not only a cosmetic function but also a medical function in addition to the cosmetic function.
The formulation of the cosmetic composition is not particularly limited and may be appropriately selected depending on the purpose.
For example, the cosmetic composition may be formulated as a solution, suspension, emulsion, paste, gel, cream, emulsion, powder, soap, surfactant-containing cleanser, oil, powder foundation, milky foundation, waxy foundation, spray, etc., but is not limited thereto. In more detail, the cosmetic composition may be formulated as a cleansing agent, a nutritional liquid (tonic), a hair styling agent, a nutritional lotion, an essence emulsion, a hair treatment agent, a hair cream, a shampoo, an emulsion, a hair tonic, a hair dye, or the like; base cosmetics of oil-in-water (O/W), water-in-oil (W/O) and the like. For example, the composition may have a dosage form selected from the group consisting of a skin lotion, an astringent, an emulsion, a milk emulsion, a moisturizing emulsion, a nourishing emulsion, a massage cream, a nourishing cream, a moisturizing cream, a hand cream, an ointment, a foundation, an essence, a nourishing essence, a mask, a soap, a cleansing foam, a cleansing emulsion, a cleansing cream, a body lotion, a bath emulsion, an ointment, a gel, a cream, a patch, and a spray. In addition, in each dosage form, other components than the essential components may be appropriately selected and formulated according to the kind of other external preparations, the purpose of use, and the like, by those skilled in the art. For example, uv blockers, hair conditioning agents, fragrances, and the like may also be included.
The cosmetic composition may contain a cosmetically acceptable medium or substrate. As all formulations suitable for topical use, it may be provided, for example, as solutions, gels, solid or pasty anhydrous products, emulsions, suspensions, microemulsions, microcapsules, microbead spheres or as ionic (liposomal) and/or nonionic vesicle dispersions, or as creams, lotions, emulsions, powders, ointments, sprays or concealers, obtained by dispersing the oil phase in the aqueous phase. The composition may be prepared according to conventional methods in the art.
When the dosage form of the present invention is a solution or emulsion, as a carrier component, a solvent, a solubilizing agent or a demulsifier is used, for example, water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butanediol oil, glycerol fatty ester, polyethylene glycol or fatty acid ester of sorbitol.
When the dosage form of the present invention is a suspension, as a carrier ingredient, a liquid diluent such as water, ethanol or propylene glycol may be used; suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters, and polyoxyethylene sorbitan esters; microcrystalline cellulose; aluminum metahydroxide; bentonite, agar or tragacanth, and the like.
When the dosage form of the present invention is a paste, cream or gel, as a carrier component, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, or the like can be used.
When the dosage form of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, especially when a spray is used, a propellant such as chlorofluorocarbon, propane/butane or dimethyl ether may be contained.
In one aspect of the present invention, the cosmetic composition may further contain a tackifier. Examples of the thickener included in the cosmetic composition of the present invention include methylcellulose, carboxymethylcellulose, carboxymethyl hydroxyguanine, hydroxymethyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, polyquaternium, cetostearyl alcohol, stearic acid, carrageenan, etc., and more than one of carboxymethyl cellulose, carboxyvinyl polymer and polyquaternium may be preferably used, and carboxyvinyl polymer may be most preferably used.
In one embodiment of the present invention, the cosmetic composition may appropriately contain various bases and additives as needed, and the kinds and amounts of these components may be easily selected by the inventors. May contain acceptable additives as needed, for example, and may also contain ingredients such as preservatives, pigments, additives and the like which are conventional in the art.
The preservative may be phenoxyethanol (Phenoxyethanol) or 1,2-hexanediol (1, 2-Hexanediol), and the perfume may be artificial perfume.
In addition, in one embodiment of the present invention, the cosmetic composition may contain a water-soluble vitamin, an oil-soluble vitamin, a high molecular peptide, a high molecular polysaccharide, a sphingolipid, and a composition of the group consisting of seaweed juice. Examples of the formulation components that may be added in addition to these components include a grease component, a humectant, a lubricant (emollients), a surfactant, organic and inorganic pigments, an organic powder, an ultraviolet absorber, a preservative, a bactericide, an antioxidant, a plant extract, a pH adjuster, ethanol, a pigment, a perfume, a blood circulation promoter, a cooling agent, an antiperspirant, purified water, and the like.
The blending components that can be added are not limited to this, and any of the above components may be blended within a range that does not impair the object and effect of the present invention.
Further, the cosmetic composition according to an embodiment, as described above, can be used not only as a pharmaceutical composition but also as a health food. For example, the food can be easily used as a main material, a sub-material, a food additive, a functional food or a beverage for food.
The term "food" means a natural substance or processed product containing one or more nutrients, preferably means a state that can be directly eaten after a certain degree of processing steps, and means that the food, food additives, functional foods, and beverages are all contained in the usual meaning.
Examples of foods to which the food composition may be added include various foods, beverages, chewing gums, teas, vitamin complexes, functional foods, and the like. Further, including special nutritional foods (e.g., formula milk powder, infant, baby food, etc.), processed meat products, fish products, tofu, bean jelly, flour (e.g., stretched flour, noodles, etc.), bread, health aids, seasonings (e.g., soy sauce, chili sauce, mixed sauce, etc.), sauces, biscuits (e.g., snack foods), candies, chocolates, chewing gum, ice cream, dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, cured foods (various kimchi, pickles), beverages (e.g., fruit beverages, vegetable beverages, soy milk, fermented beverages, etc.), natural seasonings (e.g., stretched noodle seasoning packets, etc.), but are not limited thereto. The food, beverage or food additive may be prepared by conventional preparation methods.
The "functional food" or "health food" refers to a food group in which a food is processed by giving added value to the food by physical, biochemical, or bioengineering methods so that the function of the food is exerted for a specific purpose, or a food in which the food component has an in vivo regulatory function related to regulation of a biological defense rhythm, prevention of diseases, recovery of diseases, or the like, is designed so that the organism is sufficiently expressed, and the food may be a health food. The functional food may include a food auxiliary additive which is acceptable in terms of food, and may further include suitable carriers, excipients and diluents which are generally used in the preparation of functional foods.
The kind of the health food is not limited thereto, and may be in the form of powder, granule, lozenge, capsule or beverage.
Another embodiment provides a method of skin lightening in an individual, the method comprising the step of administering the composition to the individual. The description of the composition is as described above.
The administration may be by methods well known in the art. The administration may be, for example, intravenous, intramuscular, oral, transdermal (transdermal), mucosal, intranasal (intranasal), intratracheal (INTRATRACHEAL), or subcutaneous administration, and the administration may be directly to the individual by any means. The administration may be systemic or local. The administration may be topical to the site where skin aging is present. The administration may be, for example, by coating. By coating is meant all methods by which the composition is brought into contact with the skin of an individual by a suitable method by which the composition can be absorbed into the skin.
The individual may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat or cat. The individual may be an individual in need of improvement, delay or inhibition of skin hyperpigmentation. The individual may be an individual in need of inhibiting apoptosis, inhibiting protein expression of a melanogenesis enzyme (Tyrosinase), or increasing antioxidant activity.
The administration may be to each individual daily in an amount of 0.01mg to 10000mg, 0.1mg to 1000mg, for example 0.1mg to 500mg, 0.1mg to 100mg, 0.1mg to 50mg, 0.1mg to 25mg, 1mg to 1000mg, 1mg to 500mg, 1mg to 100mg, 1mg to 50mg, 1mg to 25mg, 5mg to 1000mg, 5mg to 500mg, 5mg to 100mg, 5mg to 50mg, 5mg to 25mg, 10mg to 1000mg, 10mg to 500mg, 10mg to 100mg, 10mg to 50mg or 10mg to 25mg of the composition according to an embodiment. Or the administration may be in a manner such that the composition according to an embodiment is administered at a concentration (working concentration) of 0.01 to 25 μm, 0.05 to 5 μm, 0.075 to 3.75 μm, 0.1 to 2.5 μm, 0.15 to 2 μm, 0.25 to 1.5 μm, 0.4 to 1.25 μm, 0.5 to 1.2 μm, or 0.75 to 1.15 μm.
Form for practicing the invention
The advantages, features and methods of achieving the application herein will be apparent by reference to the detailed embodiments that are described below. The present application will be described in detail with reference to examples. However, the examples are provided for the purpose of specifically explaining the present application, and the scope of the present application is not limited by the examples.
Example (example)
Test example 1:
DMSO was added to the culture medium in such a manner that the final concentration was 0 μm (control group), 0.1 μm, 1 μm, 10 μm by dissolving the compound (CHRISTIAN HANSEN) represented by the following chemical formula 1-1 at 1000X, and melanocytes isolated from normal skin of human being were treated (Normal human epidermal melanocyte). The culture medium containing the test substances was replaced every 2 days and the cells were cultured in a thermostat at 37℃with 5% CO2 for up to 8 days. After the end of the experiment, cells were lysed in 1N NaOH and photographs taken, absorbance was measured at 475nm, whereby the relative melanin amounts were compared, the results being shown in fig. 1 and 2 (statistically significant difference P-value (value) vs control < 0.01).
[ Chemical formulas 1-1]
From FIGS. 1 and 2, it was confirmed that when the compound represented by the chemical formula 1-1 was contained, melanin production in normal melanin producing cells of human beings was effectively inhibited. In particular, it was confirmed that the compound represented by the chemical formula 1-1 inhibited melanin production in a concentration-dependent manner.
Test example 2:
DMSO was added to the culture medium in such a manner that the compound (CHRISTIAN HANSEN) represented by the chemical formula 1-1 was dissolved at 1000X so that the final concentration became 0 μm (control group), 0.1 μm, 1 μm, 10 μm, and melanogenic cells (Normal human epidermal melanocyte) isolated from normal skin of human being were treated. The culture medium containing the test substances was replaced every 2 days and the cells were cultured in a thermostat at 37℃with 5% CO2 for up to 8 days. After the end of the experiment, the medium was washed off and new medium containing CCK8 (Cell counting kit, product of sigma) was added to the cells and further cultured for 1 hour. After further culturing was completed, the medium was collected, absorbance was measured at 450nm and 650nm, and after subtracting 650nm from 450nm, it was compared with the control group, thereby comparing the relative cell viability (cell viability), and the result is shown in fig. 3.
From FIG. 3, it can be confirmed that when the compound represented by the chemical formula 1-1 is contained, there is no cytotoxicity as compared with the control group.
From fig. 1 to 3, it was confirmed that when the concentrations of the compound (CHRISTIAN HANSEN) represented by the chemical formula 1-1 were 0.1 μm, 1 μm, and 10 μm, respectively, all were not cytotoxic and had an inhibitory effect on melanogenesis. In general, when the concentration of the active ingredient is confirmed in a cell experiment, it is generally considered that the concentration of the active ingredient which is about 100 to 1000 times the concentration of the active ingredient used in the cell experiment is the concentration of the active ingredient in the composition actually used, and it can be presumed that the compound represented by the chemical formula 1 as the active ingredient in the whitening composition according to an embodiment is contained at a concentration of 10 μm to 10mM relative to the total amount of the composition, and is optimal in terms of no cytotoxicity and melanogenesis inhibitory effect.
While the preferred embodiments of the present invention have been described in detail above, the scope of the claims of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concepts of the present invention as defined in the claims are also within the scope of the claims of the present invention.