KR20250036977A - Composition for preventing or treating obesity and/or metabolic syndrome comprising a mixture of natural compounds - Google Patents

Abstract

The present invention relates to a composition for preventing, improving, and treating obesity and metabolic diseases, comprising a mixture of six compounds as an effective ingredient. The mixture of compounds has excellent safety in the human body as it does not irritate the skin or cause cytotoxicity, and also blocks the process of fat differentiation of immature adipocytes, promotes fat decomposition to suppress excessive lipid accumulation, and induces browning of white adipocytes to promote energy consumption. Thus, the mixture can be usefully used as a pharmaceutical composition, a food composition, an external skin preparation, and a cosmetic composition for preventing, improving, and treating obesity and/or metabolic diseases.

Description

{Composition for preventing or treating obesity and/or metabolic syndrome comprising a mixture of natural compounds}

The present invention relates to a composition for preventing, improving, or treating obesity and/or metabolic diseases, comprising a mixture of six compounds as an effective ingredient. More specifically, the present invention relates to a pharmaceutical, food, cosmetic, or external skin application composition for preventing, improving, or treating obesity and/or metabolic diseases, comprising a mixture of six compounds consisting of ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin as an effective ingredient, which inhibit differentiation of adipocytes to reduce the number of adipocytes, promote lipolysis to release neutral fat into glycerol and fatty acids and release them outside the cells, and induce browning of white adipocytes to promote energy consumption, and which has excellent human safety due to non-irritation of the skin and cytotoxicity.

Obesity refers to the process in which excessive fat accumulates in the body due to an imbalance between energy intake and expenditure (Cell 1996, 87(3), 377; Nature 2000, 404(6778), 635).

Obesity is known to be a cause of chronic diseases such as diabetes, cardiovascular disease, hyperlipidemia, and hypertension (Lancet 2017, 390(10113), 2627). The prevalence of obesity is increasing significantly worldwide, and it is one of the diseases that is easy to develop due to changes in lifestyle and diet in modern society (Lancet, 2017, 390(10113), 2627). Since obesity is accompanied by complications of chronic diseases, prevention and treatment are important.

Currently, various drugs are being used to solve obesity. Naltrexone, an appetite suppressant, and phentermine, a lipolytic enzyme inhibitor, are used for weight control, but they can cause various side effects such as insomnia, nausea, constipation, and depression (Lancet 2010, 376(9741), 595; Lancet 2011, 377(9774), 1341; Am J Clin Nutr. 2012, 95(2), 297). Accordingly, research on obesity solutions that can minimize side effects is actively underway.

Compared to men, women have a higher percentage of body fat, and fat tends to be stored mainly in the buttocks, thighs, and areas close to the skin surface (Br J Nutr. 2008, 99(5), 931). This makes women more prone to accumulating fat, and when excessive fat accumulation occurs, changes occur in the skin, which are called cellulite. Cellulite mainly appears on the upper thighs, abdomen, and buttocks, and is also called "orange peel" because of its uneven skin characteristics. It is known to affect about 90% of women, and for the majority of women, it is considered a cosmetic problem (Int J Cosmet Sci. 2006, 28(3), 175). To solve this problem, materials that promote lipolysis of excessively accumulated fat or prevent excessive fat cell differentiation are being developed.

Adipocytes accumulate fat in the form of triacylglycerol for energy storage, and these adipocytes combine to form adipose tissue (Int J Obes Relat Metab Disord. 2003, 27(8), 875). Adipose tissue can be largely divided into white adipocytes and brown adipocytes based on the functional and morphological characteristics of the adipocytes (Endocrinology 2013, 154(9), 2992).

White fat is a white adipose tissue mainly distributed in the abdomen or visceral fat. Its main function is to absorb fatty acids and store energy in the form of lipids. White fat has unilocular lipid droplets and a small number of mitochondria (Endocrinology 2013, 154(9), 2992).

Brown fat is a tissue composed of adipocytes that generate heat to maintain body temperature. Brown fat has high expression of proteins that regulate thermogenesis, such as Uncoupling protein-1 (UCP-1), and has small, multilocular fat globules. Due to these characteristics, brown fat contributes to thermogenesis and has a large number of mitochondria (Int J Cosmet Sci. 2006, 28(3), 175). Initially, brown fat was found mainly in newborns, but recent studies have shown that adults also have some brown fat (N Engl J Med. 2009, 360(15), 1500; Endocr Rev. 2013, 34(3), 413).

Each fat cell has its own unique function and characteristics, and these fat tissues perform physiological roles such as energy metabolism, body temperature regulation, and hormone secretion, and also play an important role in body fat regulation and metabolism.

The demand for anti-obesity, diet, and cellulite removal products without side effects is increasing, and research on natural products with anti-obesity effects is also actively being conducted.

Accordingly, the inventors of the present invention, while conducting research on natural products with anti-obesity efficacy, manufactured a complex of various natural substances based on the research results that the efficacy of a complex is superior to that of a single component, and confirmed the anti-obesity efficacy. As a result, it was confirmed that a complex of six compounds like the present invention is significantly superior to a single compound in the effect of inhibiting the formation of fat droplets through the inhibition of adipocyte differentiation and the promotion of lipolysis, and is superior in the effect of promoting brown fat related to heat production and energy consumption, and thus found it to be very useful as a natural anti-obesity treatment, and completed the present invention.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity and/or metabolic diseases, comprising a mixture of six compounds as an active ingredient.

Another object of the present invention is to provide a skin external composition for preventing or treating obesity, which comprises a mixture of six compounds as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving obesity and/or target diseases, comprising a mixture of six compounds as an effective ingredient.

Another object of the present invention is to provide a cosmetic composition for preventing or improving obesity, which comprises a mixture of six compounds as an effective ingredient.

Another object of the present invention is to provide a method for preventing, improving, or treating obesity and/or metabolic disease using a composition comprising a mixture of six compounds as an active ingredient.

The present invention relates to a composition for preventing, improving, and treating obesity and metabolic diseases by inhibiting adipocyte differentiation, promoting lipolysis, and inducing brown fat transformation, which comprises a mixture of six compounds as an effective ingredient. More specifically, the present invention relates to a cosmetic composition, a composition for external skin application, a pharmaceutical composition, and a food composition comprising a mixture of six compounds as an effective ingredient. The composition is free of skin irritation and cytotoxicity, and thus has excellent human safety, while inducing brown fat transformation of white adipocytes to promote energy consumption of adipocytes, thereby effectively preventing, improving, and treating obesity and metabolic diseases. In addition, the composition can effectively inhibit lipid accumulation and excessive secretion by inhibiting adipocyte differentiation, reducing the number of adipocytes, and promoting lipolysis, thereby effectively preventing, improving, and treating obesity and metabolic diseases.

In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating obesity or metabolic disease, comprising a mixture of six compounds as an active ingredient.

In the present invention, the six compounds are ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin.

The above six compounds can be obtained by extraction and separation from natural products, chemical synthesis, or biological synthesis using microorganisms or recombinant microorganisms.

The above natural product may be a plant, for example, ursolic acid can be obtained from apple peel, peppermint, rosemary, rivander, etc., and resveratrol can be obtained from grape skin, grape seeds, mulberries, etc. In addition, asiaticoside can be obtained from centella asiatica, etc., and caffeine can be obtained from green tea, black tea, coffee beans, etc. In addition, niacinamide can be obtained from green vegetables or grains, etc., and naringin can be obtained from citrus fruits, especially grapefruit.

In the present invention, the term “mixture” means a homogeneous mixture of six compounds.

The above mixture comprises six compounds, specifically, ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin, in a weight ratio of 0.1 to 2: 1 to 20: 0.05 to 2: 1 to 20: : 50 to 90: 1 to 20, preferably in a weight ratio of 0.1 to 1: 5 to 20: 0.05 to 1.5: 5 to 20: 50 to 80: 5 to 20, more preferably in a weight ratio of 0.2 to 0.8: 7 to 15: 0.05 to 1: 7 to 15: 50 to 70: 7 to 15, even more preferably in a weight ratio of 0.3 to 0.7: 8 to 14: 0.1 to 0.6: 8 to 14: It may be included in a weight ratio of 55~70: 8~14, more preferably in a weight ratio of 0.4~0.6: 9~13: 0.1~0.3: 9~13: 60~70: 9~13, and most preferably in a weight ratio of 0.5: 11: 0.2: 11: 66.3: 11.

In the above weight ratio range, six compounds can be dissolved in a solvent (e.g., butylene glycol, propylene glycol, alcohol, etc.) with optimal solubility while being non-cytotoxic, and can exhibit excellent effects in preventing, treating, and improving obesity and metabolic diseases.

The mixture of six compounds, which are effective ingredients of the composition of the present invention, has the effect of promoting brown adipocyte transformation of white adipocytes, i.e. brown fat transformation, by increasing the expression of UCP-1 (uncoupling protein-1) protein, and thus increasing energy consumption (see Figures 6 and 7).

The above "brown adipogenesis" refers to the process in which white adipocytes are converted into brown adipocytes and have the functional characteristics of brown adipocytes. The structural characteristics of brown adipocytes can be confirmed by an increase in the number of mitochondria and an increase in UCP-1 protein.

The above UCP-1 (uncoupling protein-1) protein is a protein that exists only in the mitochondria of brown adipose tissue, and plays a role in converting excess energy into heat and releasing it. The UCP-1 protein is specifically expressed in brown adipose cells, is located in the inner mitochondrial membrane, and reduces ATP synthesis by oxidative phosphorylation in mitochondria while generating heat.

In one specific example, it was confirmed that a mixture of six compounds of the present invention has the effect of promoting brown fat by increasing the number of mitochondria and UCP-1 protein in adipocytes (see Figures 6 and 7).

In addition, the mixture of six compounds, which is an effective ingredient of the composition of the present invention, has the effect of inhibiting hyperdifferentiation of fat cells, reducing the number of fat cells, and inhibiting accumulation and excessive secretion of lipids.

In one specific embodiment, it was confirmed that the mixture of six compounds of the present invention has the effect of inhibiting the hyperdifferentiation ability of adipocytes, thereby inhibiting an increase in the number of adipocytes, and inhibiting the degree of lipid production by adipocytes, thereby inhibiting lipid accumulation and lipid secretion (see Figures 3 to 5).

In another specific embodiment, it was confirmed that the mixture of six compounds of the present invention has the effect of promoting lipolysis, thereby liberating neutral fat into glycerol and fatty acids and releasing them out of cells (see FIG. 8).

Therefore, the composition containing the mixture of six compounds of the present invention as an active ingredient is useful for the prevention, improvement, and treatment of obesity and metabolic diseases due to the effects of promoting brown fat formation, increasing energy consumption of adipocytes, inhibiting adipocyte differentiation, inhibiting lipid accumulation in adipocytes, and inhibiting excessive lipid secretion by adipocytes.

In addition, a composition containing a mixture of six compounds of the present invention as an active ingredient is useful for preventing and reducing cellulite, which is mainly formed on the abdomen, buttocks, thighs, etc.

The term "obesity" of the present invention refers to a condition in which the number of fat cells is higher than average and lipids are excessively accumulated in the fat cells.

The term "metabolic disease" of the present invention refers to a disease caused by obesity or highly correlated with obesity. Examples thereof may be, but are not necessarily limited to, fatty liver, type 2 diabetes, hypertension, stroke, hyperlipidemia, arteriosclerosis, cardiovascular disease, and lipid-related metabolic syndrome. The lipid-related metabolic syndrome refers to a disease in which several metabolic diseases, such as diabetes and obesity, occur simultaneously in one person.

The term "cellulite" of the present invention refers to a condition in which subcutaneous fat tissue causes circulatory problems due to excessive accumulation of fat and waste, resulting in bumpy skin like an orange peel.

The mixture content of the six compounds included in the above composition is not particularly limited, but may be included in an amount of 0.00001 to 100 wt%, preferably 0.0001 to 15 wt%, more preferably 0.001 to 15 wt%, and even more preferably 0.001 to 10 wt% based on the total weight of the composition.

The term "pharmaceutical composition" of the present invention means a composition manufactured for the purpose of preventing or treating a disease, and may be formulated and used in various forms according to conventional methods. For example, it may be formulated as an oral formulation such as a powder, granule, tablet, capsule, suspension, emulsion, syrup, or aerosol, and may be formulated and used as a parenteral formulation using a diluent or excipient such as a lubricant, a humectant, a flavoring agent, an emulsifier, a suspending agent, a preservative, or a surfactant. In addition, it may be formulated and used in the form of an external preparation, a suppository, an external skin preparation, and a sterile injectable solution. As a specific example, the composition of the present invention may be used in an oral dosage form by oral administration. As another specific example, the composition of the present invention may be used by directly applying or spreading it on an area where a large number of fat cells are distributed, such as the thighs, buttocks, or abdomen. The above application and distribution are not limited to the above area and can be applied to any area where fat cells have developed.

In addition, depending on each formulation, it can be manufactured by additionally including pharmaceutically acceptable carriers, such as buffers, analgesics, solubilizers, isotonic agents, stabilizers, and carriers known in the art.

The term "pharmaceutically acceptable carrier" used in the present invention may mean a carrier or diluent that does not stimulate a living organism and does not inhibit the biological activity and properties of the active ingredient to be injected.

The type of the carrier usable in the present invention is not particularly limited, and any carrier commonly used in the relevant technical field and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, etc. These may be used alone or in combination of two or more. The carrier may be a non-naturally occurring carrier.

The composition of the present invention can be administered in a pharmaceutically effective amount. The pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined according to factors including the patient's health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the administration method, the administration time, the administration route and the excretion rate, the treatment period, the drugs used in combination or simultaneously, and other factors well known in the medical field. Specifically, the dosage is generally 0.01 mg to 5000 mg per 1 kg of the body weight of the administered subject per day, and may be administered once or several times a day at regular intervals depending on the judgment of a doctor or pharmacist, but is not limited thereto.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with or as an appropriate set of other pharmaceutically active compounds exhibiting a preventive or therapeutic effect on obesity and/or metabolic diseases.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without causing side effects by considering all of the above factors, and this can be easily determined by those skilled in the art.

As an example, and not limited thereto, in addition to a pharmaceutical composition containing a mixture of six compounds of the present invention as an active ingredient, the present invention can be used in combination with conventional obesity treatment agents, such as locasein, which acts on the central nervous system to reduce appetite by activating the appetite suppression center, orlistat, which is a fat absorption inhibitor that acts on the non-central nervous system for obesity treatment, and liraglutide, which is an appetite regulating GLP-1 (Glucagon-Like Peptide 1) analogue for obesity treatment.

In the present invention, the term "administration" means introducing the pharmaceutical composition of the present invention into a subject by any appropriate method, and the route of administration of the composition of the present invention may be administered through various routes, such as oral or parenteral, as long as it can reach the target tissue.

The method of administration of the pharmaceutical composition according to the present invention is not particularly limited, and may follow a method commonly used in the relevant technical field. As a non-limiting example of the above-mentioned method of administration, the composition may be administered orally or parenterally. Specifically, the composition of the present invention may be used by a method such as directly applying or spreading to areas where a large number of fat cells are distributed, such as the thighs, buttocks, or abdomen.

The pharmaceutical composition according to the present invention can be prepared in various dosage forms depending on the intended administration method.

The frequency of administration of the composition of the present invention is not particularly limited, but may be administered once a day or administered several times in divided doses.

In another aspect, the present invention provides a method for preventing or treating obesity or a metabolic disease, comprising a step of administering a pharmaceutical composition comprising a mixture of six compounds as an active ingredient.

The mixture of the above six compounds and its effects in preventing and treating obesity and metabolic diseases are as described above.

The term "subject" as used in the present invention may mean any animal, including humans, that has developed or is likely to develop obesity and/or metabolic disease. The animal may be, but is not limited to, mammals such as cows, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for symptoms similar thereto, as well as humans.

The above-described preventive or therapeutic method of the present invention may specifically include a step of administering the composition in a pharmaceutically effective amount to a subject who has developed or is at risk of developing obesity and/or metabolic disease. The method of administration is as described above.

The above prevention may mean any act of inhibiting or delaying the onset of obesity and/or metabolic disease by administering to a subject a composition for preventing or treating obesity and/or metabolic disease according to the present invention.

In addition, the treatment may mean any act of administering the composition of the present invention to a subject suspected of having obesity and/or a metabolic disease to improve or benefit the symptoms of obesity and/or a metabolic disease.

The pharmaceutical composition comprising a mixture of the above six compounds is as described above.

The composition of the present invention may contain, for administration, a pharmaceutically acceptable carrier, excipient or diluent in addition to the effective ingredients described above. The carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The appropriate dosage of the composition of the present invention varies depending on the patient's condition and weight, the degree of the disease, the drug form, and the time, but can be appropriately selected by a person skilled in the art. Specifically, the dosage of the mixture of the six compounds may be 10 to 500 mg/kg.

In another aspect, the present invention provides a skin external composition for preventing or treating obesity, comprising a mixture of six compounds as an active ingredient.

The mixture of the above six compounds and its effect in preventing or treating obesity are as described above.

The skin external composition of the present invention can be used for the purpose of preventing and improving obesity, and the skin external composition can be applied to areas such as the thighs, buttocks, and abdomen where cellulite generated by excessive fat differentiation is excessively distributed, and is not limited to the above areas, but can be applied to any area where fat cells have developed.

The composition for external application of the skin according to the present invention can be formulated containing a cosmetically or dermatologically acceptable medium or base. It can be provided in any formulation suitable for topical application, for example, in the form of a solution, a gel, a solid, a pasty anhydrous product, an emulsion obtained by dispersing an oil phase in an aqueous phase, a suspension, a microemulsion, a microcapsule, a microgranule, or a vesicular dispersion of ionic (liposomes) and nonionic types, or in the form of a cream, a skin, a lotion, a powder, an ointment, a spray, a pack or a concealer stick. It can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant. These compositions can be prepared according to conventional methods in the art.

In addition, the skin external composition according to the present invention may contain adjuvants commonly used in the fields of cosmetology or dermatology, such as fatty substances, organic solvents, solubilizers, thickeners, gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, metal ion sequestering agents, chelating agents, preservatives, vitamins, blocking agents, humectants, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or any other ingredients commonly used in cosmetics. The adjuvants are introduced in an amount commonly used in the fields of cosmetology or dermatology.

The mixture content of the six compounds included in the above composition is not particularly limited, but may be included in an amount of 0.00001 to 100 wt%, preferably 0.0001 to 15 wt%, more preferably 0.001 to 15 wt%, and even more preferably 0.001 to 10 wt% based on the total weight of the composition.

In another aspect, the present invention provides a food composition for preventing or improving obesity and/or metabolic disease, comprising a mixture of six compounds as an active ingredient.

The mixture of the above six compounds and its effects in preventing and improving obesity and metabolic diseases are as described above.

In the present invention, “improvement of obesity” means suppressing, alleviating, or eliminating an increase in the number of fat cells and excessive accumulation of lipids in fat cells due to hyperdifferentiation of fat cells in an individual, or promoting brown fat cell transformation of white fat cells, i.e. brown fat transformation, thereby increasing energy consumption of fat cells.

In the present invention, “improvement of metabolic disease” means suppressing, alleviating, or eliminating metabolic disease caused by an increase in the number of adipocytes due to hyperdifferentiation of adipocytes in an individual and excessive accumulation of lipids in adipocytes.

When the composition of the present invention is used as a food additive, the mixture of the above six compounds can be added as it is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The mixing amount of the effective ingredients can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment), and a food-related acceptable food auxiliary additive can be additionally included. Since the composition of the present invention contains components composed of non-cytotoxic contents as effective ingredients, there is no problem in terms of stability, so there is no significant limitation on the mixing amount.

The food composition of the present invention can include all foods in the conventional sense, and can be used interchangeably with terms known in the art, such as functional food and health functional food.

The term "functional food" of the present invention means a food manufactured and processed using raw materials or ingredients having functionality useful to the human body, and "functionality" means consumption for the purpose of obtaining a useful effect for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects.

In addition, the term "health functional food" of the present invention refers to a food manufactured or processed by using a specific ingredient as a raw material or by extracting, concentrating, refining, mixing, etc. a specific ingredient contained in a food raw material for the purpose of health supplementation, and refers to a food designed and processed so that the above-mentioned ingredient can sufficiently exert a bioregulatory function, such as biodefense, regulation of biological rhythm, prevention and recovery of disease, on the body, and the above-mentioned health food composition can perform functions related to disease prevention and disease recovery.

There is no limitation on the type of food in which the composition of the present invention for preventing or improving obesity and/or metabolic disease can be used. In addition, a composition comprising the mixture of the six compounds of the present invention as an active ingredient can be prepared by mixing other appropriate auxiliary ingredients that can be contained in foods and known additives according to the selection of a person skilled in the art. Examples of foods to which the mixture can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and the mixture according to the present invention and its fractions can be prepared by adding them to juice, tea, jelly, and juice, etc., which are prepared using the mixture and its fractions as main ingredients.

In addition, foods applicable to the present invention may include all foods, such as special nutritional foods (e.g., formulated milk, infant/toddler food, etc.), processed meat products, fish products, tofu, starch jelly, noodles (e.g., ramen, noodles, etc.), health supplements, seasoned foods (e.g., soy sauce, soybean paste, red pepper paste, mixed sauce, etc.), sauces, confectionery (e.g., snacks), processed dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi types, pickled vegetables, etc.), beverages (e.g., fruit and vegetable beverages, soy milk, fermented beverages, etc.), natural seasonings (e.g., ramen soup, etc.).

The mixture content of the six compounds included in the above composition is not particularly limited, but may be included in an amount of 0.00001 to 100 wt%, preferably 0.0001 to 15 wt%, more preferably 0.001 to 15 wt%, and even more preferably 0.001 to 10 wt% based on the total weight of the composition.

When the health functional food composition of the present invention is used in the form of a beverage, it may contain various sweeteners, flavoring agents, or natural carbohydrates as additional ingredients, like conventional beverages. In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, it may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.

In another aspect, the present invention provides a cosmetic composition for preventing and improving obesity, comprising a mixture of six compounds as an active ingredient.

The mixture of the above six compounds and its effects on preventing and improving obesity are as described above.

The cosmetic composition of the present invention can be used for the purpose of preventing and improving obesity, and the cosmetic composition can be applied to areas such as thighs and buttocks where cellulite generated by excessive fat differentiation is excessively distributed, and is not limited to the above areas, but can be applied to any area where fat cells have developed.

In the present invention, the component included in the "cosmetic composition" may include, in addition to the effective ingredient, components commonly used in cosmetic compositions, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances, and carriers. The cosmetic composition of the present invention may be manufactured in any formulation commonly manufactured in the art, and may be formulated as, for example, a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, a surfactant-containing cleansing, an oil, a powder foundation, an emulsion foundation, a wax foundation, a pack, a massage cream, and a spray, but is not limited thereto. More specifically, the cosmetic composition may be manufactured in the form of a flexible toner, a nourishing toner, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, cleansing water, a pack, a spray, or a powder.

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide can be used as a carrier component.

When the formulation of the present invention is a solution or emulsion, a solvent, a solubilizer or an emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

When the formulation of the present invention is a suspension, liquid diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth, etc. can be used as carrier components.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and particularly in the case of a spray, a propellant such as chlorofluorohydrocarbon, propane/butane or dimethyl ether may be additionally included.

When the formulation of the present invention is a surfactant-containing cleansing agent, the carrier component may include fatty alcohol sulfate, fatty alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkyl amidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester.

When the cosmetic composition of the present invention is soap, a cleansing formulation containing a surfactant, or a cleansing formulation not containing a surfactant, it can be applied to the skin and then wiped off, removed, or washed off with water. As specific examples, the soap is liquid soap, powder soap, solid soap, and oil soap, the cleansing formulation containing a surfactant is cleansing foam, cleansing water, cleansing towel, and cleansing pack, and the cleansing formulation not containing a surfactant is cleansing cream, cleansing lotion, cleansing water, and cleansing gel, but is not limited thereto.

The mixture content of the six compounds included in the above composition is not particularly limited, but may be included in an amount of 0.00001 to 100 wt%, preferably 0.0001 to 15 wt%, more preferably 0.001 to 15 wt%, and even more preferably 0.001 to 10 wt% based on the total weight of the composition.

The mixture of six compounds of the present invention is free of skin irritation and cytotoxicity, and thus has excellent human safety, while inhibiting differentiation of adipocytes, reducing the number of adipocytes, promoting lipolysis and releasing it externally, and inducing brown fat transformation of fat, and thus can be usefully used as a pharmaceutical composition, a food composition, a skin external application composition, and a cosmetic composition for preventing, improving, and treating obesity and/or lipid metabolism disorders. In addition, the mixture of six compounds of the present invention can be effectively applied to body parts where adipocytes are developed, such as the thighs, buttocks, and abdomen, where cellulite generated by hyperdifferentiation of fat is excessively distributed, for the purpose of inhibiting accumulation and excessive secretion of lipids.

Figure 1 shows the results of measuring the effect of each of the six compounds and their mixtures on the inhibition of adipocyte differentiation in 3T3-L1 preadipocytes.
Figure 2 shows the results of confirming the degree of cytotoxicity according to the concentration of six compounds.
Figure 3 shows the results of measuring the effect of inhibiting adipocyte differentiation of 3T3-L1 preadipocytes by a mixture of six compounds that exhibit optimal solubility without cytotoxicity.
Figure 4 shows the results of measuring the inhibitory effect of a mixture of six compounds on triglyceride accumulation in 3T3-L1 preadipocytes.
Figure 5 shows the results of measuring GPDH activity by a mixture of six compounds.
Figure 6 shows the results of measuring the effect of a mixture of six compounds on promoting UCP-1 and mtTFA expression.
Figure 7 shows the results of confirming the brown fat effect of 3T3-L1 adipocytes induced into white fat by a mixture of six compounds using immunofluorescence.
Figure 8 shows the results of measuring the lipolysis promotion effect of 3T3-L1 adipocytes induced into white fat by a mixture of six compounds.

Hereinafter, in order to help understand the present invention, examples and the like will be described in detail. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the art.

Example 1: Selection of compounds and confirmation of their mixture's effects on inhibiting adipocyte differentiation and intracellular lipid accumulation

Based on previous studies on the selection and combination of various compounds, the inventors of the present invention selected ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin from among natural compounds, and attempted to confirm whether a mixture of these selected compounds is more effective in the prevention, improvement, and treatment of obesity and metabolic diseases than each compound individually.

Specifically, a mixture was prepared by mixing ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin in a weight ratio of 1: 1: 1: 1: 1, and the effects of inhibiting adipocyte differentiation and thereby intracellular lipid accumulation were confirmed.

Specifically, adipocytes (3T3-L1) were purchased and prepared from ATCC (American Tissue Culture Collection, USA) and cultured in DMEM medium supplemented with 10% BCS (Bovine Calf Serum). To differentiate into adipocytes, 1 × 10 ⁵ cells were seeded per well in a 6-well plate with DMEM medium containing 10% BCS, and cultured in an incubator under 5% CO ₂ and 37°C conditions until the cells reached 100% confluency. After additional culture for 2 days after replacing the medium, differentiation was induced by treating MDI cocktail (0.5 mM methylisobutylxanthine, 0.25 μM dexamethason, 1 μg/mL insulin) in DMEM containing 10% FBS (fetal bovine serum). After 3 days, the medium was replaced with DMEM (containing 10% FBS) containing insulin (1 μg/mL), and again 3 days later, the medium was replaced with DMEM (containing 10% FBS) and cultured for 3 days. The samples were treated together from the time of inducing differentiation by treating with MDI cocktail and were re-treated at the same concentration every time the culture medium was replaced thereafter. The amount of lipid accumulated in the differentiated cells was stained using Oil Red O staining, dissolved with isopropyl alcohol, and measured for optical density at 540 nm.

As shown in Fig. 1, when immature adipocytes 3T3-L1 were treated with MDI, differentiation into adipocytes was induced and intracellular lipids were accumulated. When this was stained with Oil Red O and absorbance was measured, the group treated with the mixture of the six compounds showed significantly superior inhibition of adipocyte differentiation and inhibition of intracellular lipid accumulation compared to the group treated with the six compounds alone.

Example 2: Selection of the optimal mixing ratio of a mixture of six compounds and confirmation of the mixture's effect on suppressing intracellular lipid accumulation

According to Example 1, the cytotoxicity of the six compounds whose efficacy was confirmed according to adipocyte treatment was confirmed. Specifically, adipocytes (3T3-L1) were purchased from ATCC (American Tissue Culture Collection, USA) and prepared, and cultured in DMEM medium supplemented with 10% BCS (Bovine Calf Serum). The cultured adipocytes were seeded at 1 × 10 ⁴ per well in a 24-well plate, and then treated with each of the six compounds at different concentrations and cultured in an incubator under 5% CO ₂ and 37°C conditions for 15 days. The cell culture time for the toxicity test reflected the time required for both the adipocyte differentiation inhibition test and the white fat conversion experiment, and the degree of cytotoxicity was determined through the MTT assay after culture for up to 15 days. The six compounds were treated at concentrations ranging from a minimum of 1 μg/mL to a maximum of 60 μg/mL to confirm cytotoxicity, and it was determined that cytotoxicity was present starting from the concentration that showed cell viability of 80% or less.

As shown in Fig. 2, ursolic acid exhibited cytotoxicity at concentrations of 1 μg/mL, resveratrol at 20 μg/mL, asiaticoside at 1 μg/mL, caffeine at 20 μg/mL, and naringin at concentrations higher than 20 μg/mL, and niacinamide exhibited a cell viability rate of over 80% at all concentrations treated. Therefore, the six compounds were prepared as mixtures by combining each compound at a concentration at which each compound exhibited optimal solubility within a concentration that did not exhibit cytotoxicity. Specifically, six compounds were weighed and mixed at a weight ratio of 0.5: 11: 0.2: 11: 66.3: 11 (ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin, with respect to a total weight of 100 wt%), and then a mixer or grinder was used to manufacture a powder of homogeneous particles.

In order to confirm the inhibition of adipocyte differentiation and the resulting inhibition of intracellular lipid accumulation for the optimal mixture of the above-mentioned six compounds, the same method as in Example 1 was performed. As a result, as can be seen in Fig. 3, the optimal mixture of the above-mentioned six compounds exhibited excellent inhibition of adipocyte differentiation and the resulting inhibition of intracellular lipid accumulation without cytotoxicity.

Example 3: Neutral fat triglyceride suppression effect of mixture of 6 compounds

In order to measure the degree of inhibition of triglyceride production, which is a neutral fat, according to fat differentiation by the mixture of six compounds manufactured in the above Example 2, the following experiment was conducted. As in Example 1, immature adipocytes 3T3-L1 were treated with MDI to induce differentiation into adipocytes, and then the samples were treated together and cultured, and the degree of triglyceride finally produced was measured using a triglyceride determination kit (Sigma, USA). In addition, the activity of GPDH (glycerol-3-phosphate dehydrogenase), an enzyme that plays a role in synthesizing neutral fat in adipocytes, was measured using a GDPH assay kit (Takara, Japan).

As shown in Figures 4 and 5, it was confirmed that the amount of triglyceride decreased in a concentration-dependent manner under conditions in which a mixture of six compounds was treated, and the activity of GPDH also decreased in a concentration-dependent manner.

Example 4: Brown fat induction effect of a mixture of six compounds

In order to confirm whether the mixture of six compounds has the effect of inducing the conversion of white fat into brown fat, the expression levels of UCP-1 and mtTFA (mitochondrial transcription factor A), a key activator of mitochondrial transcription, according to the treatment with the mixture of six compounds were confirmed by western blot. Specifically, as in Example 1, immature adipocytes 3T3-L1 were treated with MDI to induce differentiation into adipocytes, and then the DMEM medium containing 10% FBS was replaced every 3 days from the 9th day to the 15th day with the mixture of six compounds of Example 2 at a concentration of 50 μg/mL. The cells were harvested on the 15th day after the induction of differentiation, and the harvested cells were disrupted by sonication and then centrifuged to collect the lysate. Western blot was performed using the collected cell lysate to compare the expression levels of UCP-1 and mtTFA for each condition. To confirm the level of expression, the bands of the Western blot were quantified using ImageJ, and the values corrected using GAPDH*Glyceraldehyde 3-phosphate dehydrogenase were displayed in a graph.

As shown in Figure 6, under conditions where a mixture of six compounds was treated, the expression of UCP-1 was confirmed to increase by more than 465% and the expression of mtTFA was confirmed to increase by more than 825% compared to the untreated group.

Example 5: Brown fat induction effect of a mixture of six compounds

In addition to the above Example 4, in order to confirm the effect of the mixture of six compounds inducing the conversion of white fat into brown fat, the increase in mitochondrial and UCP-1 proteins according to the treatment with the mixture of six compounds was confirmed by immunofluorescence. Specifically, as in Example 1, immature adipocytes 3T3-L1 were treated with MDI to induce differentiation into adipocytes, and then the DMEM medium (10% FBS) treated with the mixture of six compounds of Example 2 was replaced every 3 days from the 9th to the 15th day. On the 15th day after the induction of differentiation, the cells were fixed by treating them with 4% (v/v) parafomaldehyde, and then treated with 0.1% Triton X-100 to increase the permeability of the cell membrane. After blocking with 10% goat serum for 30 minutes at room temperature, the sections were incubated with UCP-1 antibody (anti-UCP-1, 1:100) at 4°C for 12 hours, followed by incubation with Cyanine 5 (Cy5) fluorescence-labeled secondary antibody (anti-mouse IgG Cy5, 1:500) at room temperature for 2 hours. For mitochondrial staining, Mito-Tracker Green (Cell Signaling, USA) was used for 1 hour, and nuclear staining was performed for 10 minutes using Hoechst 33342 (Invitrogen, USA). The results were confirmed using a fluorescence microscope.

As shown in Figure 7, the test group treated with the mixture of six compounds showed a concentration-dependent UCP-1 expression induction effect compared to the untreated group.

Example 6: Effect of promoting lipolysis of mixture of 6 compounds

The lipolytic efficacy of a mixture of six compounds was confirmed. Specifically, as in Example 1, immature adipocytes 3T3-L1 were treated with MDI to induce differentiation into adipocytes, and then the DMEM medium (10% FBS) treated with the mixture of six compounds of Example 2 was replaced every three days from the 9th to the 15th day. On the 15th day after differentiation induction, the degree of lipolysis was observed under a microscope using the Oil Red O staining method. In addition, the degree of lipolysis was confirmed by measuring the fatty acids and glycerol released as neutral fat is decomposed.

As shown in Figure 8, it was confirmed that the fat globules were reduced, the amount of intracellular fatty acids was confirmed to decrease in a concentration-dependent manner, and the amount of glycerol in the medium was confirmed to increase in a concentration-dependent manner.

Example 7: Safety test for human skin of a mixture of six compounds.

7-1. Manufacturing of external skin preparation containing a mixture of six compounds

In order to verify whether the mixture of six compounds, which was proven to have anti-obesity and brown fat-blocking effects in the experiments of Examples 2 to 6 above, is safe for human skin, a skin topical preparation containing the mixture of six compounds prepared in Example 2 above was prepared with the ingredient contents shown in Table 1 below, and a skin safety verification experiment was performed.

To manufacture a skin external preparation, purified water, glycerin, and butylene glycol were mixed and dissolved at 70°C (aqueous phase part), and the remaining ingredients except for the above three ingredients and trimethanolamine were dissolved at 70°C (oil phase part). The oil phase was added to the aqueous phase and stirred with a homogenizer (Tokushu Kika, Japan) to perform primary emulsification, and trimethanolamine was finally added thereto. After removing the air bubbles formed in the mixture, it was cooled to room temperature to manufacture a skin external preparation.

ingredient Content (%) Control group Test group Purified water 72 71 glycerin 8.0 8.0 Butylene glycol 4.0 4.0 Mixture of six compounds of Example 2 0 1.0 Caprylic Capri Triglyceride 8.0 8.0 Squalane 5.0 5.0 Cetearyl Glucuronide 1.5 1.5 Sorbitan stearate 0.4 0.4 Cetearyl alcohol 1.0 1.0 Trimethanolamine 0.1 0.1 Total weight 100 100

7-2. Skin cumulative irritation test

Each skin external preparation manufactured in Example 7-1 was applied to the upper arm area of 30 healthy adults every other day for a total of nine 24-hour cumulative patches to determine whether the mixture of six compounds irritated the skin.

The patch application method used a Finn chamber (Epitest Ltd, Finland). 15 ul of each skin topical agent was dropped into the chamber, and then the patch application was performed. The degree of reaction shown on the skin each time was scored using the following experimental formula 1, and the results are shown in Table 2 below.

[Experimental Formula 1]

Average Response Rate = [[Response Index × Response Rate / Total Number of Examiners × Highest Score (4 points)] × 100] ÷ Number of Examinations (9 times)

At this time, ± in the reactivity was given a score of 1 point, + was given 2 points, and ++ was given 4 points, and when the average reactivity was less than 3, it was judged to be a safe composition.

Test substance Number of subjects who responded average
Reaction rate 1 week 2 weeks 3 weeks 1st 2nd 3rd 4th 5th 6th 7th 8th 9th ± + ++ ± + ++ ± + ++ ± + ++ ± + ++ ± + ++ ± + ++ ± + ++ ± + ++ Control group - - - - - - - - - - - - - - - - - - - - - - - - - - - 0.00 Test group 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - - 0.19 Number of arrested persons
(number of people) 30 30 30 30 30 30 30 30 30

In the test group in Table 2 above, the number of people corresponding to ±, +, and ++ was 1, 0, and 0, respectively, and the rest showed no reaction. According to the equation described above, the average reaction rate is 0.19, which is 3 or less, so it was determined to be a safe composition.

As described in Table 2 above, the skin external preparation including the mixture of six compounds (test group) did not show a distinct cumulative irritation pattern like the control group, and was determined to be a safe substance for human skin.

Formulation Example 1: Cosmetic Formulation

Preparation Example 1-1: Softening Toner

As shown in Table 3 below, a flexible toner containing a mixture of six compounds of the present invention as an effective ingredient was manufactured according to a conventional method.

ingredient weight% Mixture of 6 compounds 0.01 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 Ethanol 10.0 Triethanolamine 0.1 Preservatives, trace colors, trace flavors and trace purified water 82.79 aggregate 100.0

Preparation Example 1-2: Nourishing Toner

As shown in Table 4 below, a nutritional toner containing the mixture of six compounds of the present invention as an effective ingredient was manufactured according to a conventional method.

ingredient weight% Mixture of 6 compounds 0.01 beeswax 4.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 Liquid paraffin 5.0 Squalane 5.0 Caprylic/Capric Triglyceride 5.0 glycerin 3.0 Butylene glycol 3.0 Propylene glycol 3.0 Carboxyvinyl polymer 0.1 Triethanolamine 0.2 Preservatives, trace colors, trace flavors and trace purified water 69.69 aggregate 100.0

Preparation Example 1-3: Nourishing Cream

A nutritional cream containing a mixture of six compounds of the present invention as an effective ingredient, as shown in Table 5 below, was manufactured according to a conventional method.

ingredient weight% Mixture of 6 compounds 0.01 beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 Liquid paraffin 10.0 Squalane 5.0 Caprylic/Capric Triglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservatives, trace colors, trace flavors and trace purified water 56.79 aggregate 100.0

Preparation Example 1-4: Massage Cream

A nutritional cream containing the mixture of six compounds of the present invention as an effective ingredient, as shown in Table 6 below, was manufactured according to a conventional method.

ingredient weight% Mixture of 6 compounds 0.01 beeswax 10.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprylic/Capric Triglyceride 4.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservatives, trace colors, trace flavors and trace purified water 27.49 aggregate 100.0

Preparation Example 1-5: Pack

A pack containing a mixture of six compounds of the present invention as an active ingredient, as shown in Table 7 below, was manufactured according to a conventional method.

ingredient weight% Mixture of 6 compounds 0.01 polyvinyl alcohol 13.0 Sodium carboxymethyl cellulose 0.2 Allantoin 0.1 Ethanol 5.0 Nonylphenyl ether 0.3 Preservatives, trace colors, trace flavors and trace purified water 81.39 aggregate 100.0

Preparation Example 2: Pharmaceutical preparation

Preparation Example 2-1: Preparation of a Sanje

ingredient Content (g) Mixture of 6 compounds 2.0 Lactose 1.0

The above ingredients were mixed and filled into a sealed bag to prepare a powdered preparation.

Preparation Example 2-2: Preparation of tablets

ingredient Content (mg) Mixture of 6 compounds 100 Corn starch 100 Lactose 100 Magnesium stearate 2

After mixing the above ingredients, tablets were manufactured by pressing them according to the usual method for manufacturing tablets.

Preparation Example 2-3: Preparation of capsules

ingredient Content (mg) Mixture of 6 compounds 100 Corn starch 100 Lactose 100 Magnesium stearate 2

After mixing the above ingredients, the mixture was filled into a gelatin capsule according to a conventional capsule manufacturing method to produce a capsule.

Preparation Example 2-4: Preparation of gel

ingredient weight(%) Mixture of 6 compounds 1.00 Butylene glycol 2.00 glycerin 1.00 Disodium EDTA 0.02 PEG-60 Hydrogenated Castor Oil 1.00 Cocamidopropyl Betaine 4.00 Lauryl Glucoside 6.00 Polysorbate 20 1.00 Sodium benzoate 0.40 Caprylic Glycol 0.20 Sodium lactate 0.50 Hydroxyethyl cellulose 0.70 Purified water 82.18 aggregate 100.0

After mixing the above ingredients, a gel containing a mixture of six compounds as an active ingredient was prepared according to a conventional method.

Preparation Example 2-5: Preparation of ointment

ingredient weight(%) Mixture of 6 compounds 1.0 diethanolamine 1.5 Polyvinyl photolidone 5.0 Propylene glycol 30.0 Purified water 62.5 aggregate 100.0

Manufacturing Example 3: Manufacturing of food

Manufacturing Example 3-1: Manufacturing of wheat flour food

0.5 to 5.0 parts by weight of a mixture of six compounds of the present invention was added to wheat flour, and bread, cake, cookies, crackers, and noodles were manufactured using the mixture.

Manufacturing Example 3-2: Manufacturing of soups and gravies

A mixture of 6 compounds of the present invention in an amount of 0.1 to 5.0 parts by weight was added to soup and broth to prepare a meat product for health promotion, and soup and broth for noodles.

Manufacturing Example 3-3: Manufacturing of ground beef

Ground beef for health promotion was prepared by adding 10 parts by weight of a mixture of six compounds of the present invention to ground beef.

Manufacturing Example 3-4: Manufacturing of dairy products

5 to 10 parts by weight of a mixture of six compounds of the present invention were added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

Manufacturing Example 3-5: Manufacturing of sausages

A sausage food composition including a mixture of six compounds of the present invention was prepared as follows. 65.18 wt% of pork, 25 wt% of chicken, 3.5 wt% of starch, 1.7 wt% of soy protein, 1.62 wt% of salt, 1.4 wt% of glucose, and 1.5 wt% of glycerin, and 0.1 wt% of a mixture of six compounds were blended to prepare a sausage by a conventional method.

Manufacturing Example 3-6: Manufacturing of health drinks

A mixture of 5 g of six compounds of the present invention and auxiliary materials such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%), and water (75%) was homogeneously mixed, sterilized for a moment, and then packaged in small containers such as glass bottles and PET bottles to manufacture the product.

Manufacturing Example 3-7: Manufacturing of vegetable juice

Vegetable juice was prepared by adding 5 g of a mixture of six compounds of the present invention to 1,000 ml of tomato or carrot juice.

Manufacturing Example 3-8: Manufacturing of fruit juice

1 g of a mixture of six compounds of the present invention was added to 1,000 ml of apple or grape juice to prepare fruit juice.

Claims (12)

A pharmaceutical composition for preventing and treating obesity or metabolic disease, comprising ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin as active ingredients. A pharmaceutical composition for preventing and treating obesity or metabolic disease, characterized in that in claim 1, ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin are mixed in a weight ratio of 0.1 to 2: 1 to 20: 0.05 to 2: 1 to 20: : 50 to 90: 1 to 20. A pharmaceutical composition for preventing or treating obesity or metabolic disease, characterized in that in claim 1, the metabolic disease is at least one disease selected from the group consisting of fatty liver, type 2 diabetes, hypertension, stroke, hyperlipidemia, arteriosclerosis, and cardiovascular disease. A composition for external application to the skin for preventing or improving obesity, comprising ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin as active ingredients. A skin external application composition for preventing or improving obesity, characterized in that in claim 4, ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin are mixed in a weight ratio of 0.1 to 2: 1 to 20: 0.05 to 2: 1 to 20: : 50 to 90: 1 to 20. In claim 4, the composition is a composition for external skin application characterized in that it is applied to an area within an individual where cellulite has been formed due to hyperdifferentiation of fat cells and accumulation of lipids within fat cells. A cosmetic composition for preventing or improving obesity, comprising ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin as active ingredients. A cosmetic composition for preventing or improving obesity, characterized in that in claim 7, ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin are mixed in a weight ratio of 0.1 to 2: 1 to 20: 0.05 to 2: 1 to 20: : 50 to 90: 1 to 20. A cosmetic composition according to claim 7, characterized in that the composition is applied to an area within an individual where cellulite is formed due to hyperdifferentiation of fat cells and accumulation of lipids within fat cells. A food composition for preventing or improving obesity or metabolic disease, comprising ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin as active ingredients. A food composition for preventing or improving obesity or metabolic disease, characterized in that in claim 10, ursolic acid, resveratrol, asiaticoside, caffeine, niacinamide, and naringin are mixed in a weight ratio of 0.1 to 2: 1 to 20: 0.05 to 2: 1 to 20: : 50 to 90: 1 to 20. A food composition according to claim 10, wherein the metabolic disease is at least one disease selected from the group consisting of fatty liver, type 2 diabetes, hypertension, stroke, hyperlipidemia, arteriosclerosis, and cardiovascular disease.