Pharmaceutical composition comprising sleepy primrose extract as active ingredient for preventing or treating metabolic diseases

Abstract

The present invention relates to a pharmaceutical composition, a food composition, and a cosmetic composition, each comprising a sleepy primrose extract as an active ingredient for preventing or alleviating / treating metabolic diseases. The composition of the present invention inhibits adipocyte differentiation and fat accumulation and reduces weight gain, body fat gain, adipocyte size, liver weight, and liver fat accumulation and improves insulin resistance in a high-fat diet-induced obesity animal model. Accordingly, the composition can effectively prevent, ameliorate, or treat metabolic diseases such as obesity, fatty liver, and diabetes, and thus is expected to have broad applications in the medical and healthcare fields.

Description

Pharmaceutical composition for the prevention or treatment of metabolic diseases containing drowsy primrose extract as an active ingredient

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a drowsy primrose extract as an active ingredient.

[0002] Since metabolic diseases were named by Reaven GM in 1988, they have become a common health issue encountered in primary care. Metabolic diseases encompass conditions such as increased body fat, elevated blood pressure, elevated blood sugar, and abnormal blood lipid levels; they are not isolated diseases but rather lifestyle-related conditions resulting from the combination of genetic predisposition and environmental factors, such as dietary habits. It is known that the prevalence of metabolic diseases in primary care reaches approximately 30%, and this rate increases with age and the severity of obesity. The medical significance of these metabolic diseases is evident in the fact that individuals with metabolic diseases have lower life expectancy and higher mortality rates from cardiovascular diseases compared to those without. Recently, in Korea as well, the obese population has been increasing significantly due to the Westernization of dietary habits and the improvement of cultural standards. The obesity rate among Korean adults stood at 32.5% in 2022, an increase of 0.3 percentage points from 32.2% in the previous year (2022 Obesity Rates by Gender and Age Group, Korea Disease Control and Prevention Agency). This rapid increase is noted when compared to the 24.5% rate recorded in 2013. The prevalence of cardiovascular diseases, such as hypertension and hyperlipidemia, is also increasing rapidly. According to a 2023 report by the National Institutes of Health in Korea, cardiovascular disease ranked second in mortality rates for both men and women. Considering that diabetes is a long-standing condition and that prolonged hyperglycemia can lead to chronic complications in various organs—including the kidneys, eyes, nerves, heart, and blood vessels—the importance of managing and treating metabolic diseases has recently been gaining prominence.

[0003] Accordingly, various compositions for the prevention or treatment of metabolic diseases have been researched and developed; however, most conventional treatments for metabolic diseases such as obesity and diabetes consist of synthetic compounds, posing a high risk of side effects due to the nature of long-term use. For example, statins, the most representative treatments for hyperlipidemia, can affect muscles, leading to side effects such as muscle pain or, in severe cases, muscle damage; furthermore, long-term use may cause elevated liver enzyme levels or liver dysfunction. Additionally, some synthetic antidiabetic drugs are known to cause side effects such as weight gain, gastrointestinal disorders, and cardiovascular problems. Therefore, there is a demand for the development of plant-derived natural therapeutic agents that remain safe even with long-term use. Natural products generally have fewer side effects and contain various bioactive components, making them safe for long-term use.

[0004] Accordingly, the present invention has been devised to solve the above-mentioned problem and relates to a composition for the prevention or improvement / treatment of metabolic diseases comprising a sleepy primrose plant extract as an active ingredient. Since the composition of the present invention is a natural product, it has a low risk of side effects even with long-term use and can effectively prevent, improve, or treat metabolic diseases, and is expected to be widely used in the medical and health fields.

[0005] One objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases comprising an extract of sleepy primrose as an active ingredient.

[0006] Another objective of the present invention is to provide a food composition for the prevention or improvement of metabolic diseases comprising an extract of sleepy primrose.

[0007] Another objective of the present invention is to provide a cosmetic composition for the prevention or improvement of metabolic diseases comprising an extract of sleepy primrose.

[0008] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0009] Various embodiments described herein are described with reference to the drawings. In the following description, various specific details, such as specific forms, compositions, and processes, are described for a complete understanding of the invention. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to unnecessarily obscure the invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that the particular features, forms, compositions, or characteristics described in association with the embodiment are included in one or more embodiments of the invention. Accordingly, the context of "in one embodiment" or "an embodiment" expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. Additionally, particular features, forms, compositions, or characteristics may be combined in any suitable way in one or more embodiments.

[0010] In this invention, the term "sleepy primrose" is defined by the scientific name Primula nutans Georgi (PG), a Mongolian plant belonging to the genus Primula of the family Primulaceae. Its native range extends from the subarctic to the Himalayas, and it grows wild in Europe and Asia, including China, Finland, Norway, Nepal, Sweden, Mongolia, Russia, Kazakhstan, and Pakistan. Its original native area is known to be British Columbia, but it is currently extinct in that region. As a perennial plant, its leaves are rose-shaped. The petiole is nearly the same length as the leaf, and sometimes 1 to 3 times longer. The petiole is ovate to oblong or subglobose, with a rounded or wedge-shaped base and a blunt serrated margin. The flower stalk is hairless, and 2 to 6 flowers bloom. The calyx is tubular and bell-shaped, measuring 5–8 mm, and often shows brown dots. The corolla tube is 1–2 times the length of the calyx. The branch width is 12–15 mm, and the leaflets are 4–5.5 x 3–4.5 mm, obovate with concave margins, ring-shaped, and yellow. The style is 7–9 mm long and semi-extended. The capsule is tubular to cylindrical and extends beyond the calyx. The seeds are less than 1 mm in diameter, ovate to hemispherical in outline, and hairless.

[0011] In the present invention, the term "extract" refers to an active ingredient separated from a natural product, such as a plant. For example, it refers to a preparation obtained by squeezing a natural product with a suitable solvent, filtering it, and then evaporating the solvent to concentrate it. Additionally, it may be an extract obtained by an extraction process, a diluted or concentrated extract, a dried product obtained by drying an extract, or a purified product thereof, but is not limited thereto. The extraction method may be obtained by an extraction method selected from the group consisting of solvent extraction, ultrasonic extraction, supercritical extraction, hot water extraction, high-frequency extraction, fermentation, and preparation methods, although it is not limited thereto. In the present invention, it is preferable to use a solvent extraction method or an ultrasonic extraction method, and it is more preferable to use an ultrasonic extraction method. At this time, the ultrasonic extraction may be performed at a frequency of 10 to 100 kHz, 20 to 80 kHz, or 30 to 60 kHz, and is not limited thereto, but is preferably performed at a frequency of 30 to 50 kHz, and more preferably at a frequency of 35 to 45 kHz. Alternatively, the ultrasonic extraction may be performed at a power of 100 to 10000 W, 500 to 5000 W, 1000 to 3000 W, or 1000 to 2000 W. When using the solvent extraction method or the ultrasonic extraction method, the solvent may be selected from the group consisting of water, ethanol, methanol, organic solvents, and mixed solvents thereof. Preferably, ultrasonic extraction may be performed using methanol as the solvent, but is not limited thereto.

[0012] In the present invention, the term "aboveground part" refers to the part of a plant that is exposed above the ground (soil). Generally, elements belonging to the aboveground part include stems, leaves, flowers, bark, and fruits, but are not limited thereto. The sleepy primrose extract of the present invention is preferably an extract of the aboveground part of a sleepy primrose plant, but is not limited thereto.

[0013] In the present invention, the term "underground part" refers to the part of a plant that is below the ground (soil). Generally, elements belonging to the underground part include roots, and the roots include storage roots such as those of radishes, carrots, ginseng, kudzu, and sweet potatoes. In the case of stems or parts existing below the ground, such as bamboo shoots, taro, and lotus roots, they may also be included in the underground part.

[0014] In the present invention, the term "whole plant" refers to the entirety of a plant, including the above-ground and underground parts, among the parts constituting the plant.

[0015] In this invention, the term "metabolism" refers collectively to all material changes occurring within a living organism, such as the decomposition or synthesis of substances. It is classified into anabolism, which synthesizes high-molecular-weight compounds using low-molecular-weight organic or inorganic substances absorbed from the surroundings, and catabolism, which breaks down high-molecular-weight compounds into low-molecular-weight organic or inorganic substances. A state in which the body's energy balance is disrupted due to abnormalities in metabolic processes within the organism is called metabolic disease. More specifically, metabolic disease refers to a collection of abnormal conditions, such as increased body fat, elevated blood pressure, elevated blood sugar, and abnormal blood lipid levels, which increase the risk of cerebrovascular disease and diabetes. In the presence of metabolic disease, the risk of cardiovascular disease increases by more than twofold, and the incidence of diabetes increases by more than tenfold. Metabolic disease is known not as a single disease, but as a comprehensive disease resulting from the combination of genetic predisposition and environmental factors such as diet.

[0016] In this invention, the term "obesity" (or "adipositas") refers to a type of metabolic disease in which a greater-than-normal amount of fat is accumulated in the body. Individuals whose body weight is higher than the normal range but who have high muscle mass and a low body fat percentage are not considered obese. Conversely, even if a person appears thin and has a normal body weight, if their body fat percentage is higher than normal, they are medically diagnosed as obese, or "skinny fat." As such, while body fat percentage is a more important factor than the numerical value of body weight itself, accurately measuring the amount of body fat is difficult; therefore, indirect measurements of the Body Mass Index (BMI) and waist circumference are frequently utilized. In addition to these indirect measurement methods, bioelectrical impedance analysis and computed tomography of abdominal fat are also performed to measure visceral obesity. The aforementioned BMI is an obesity assessment index created by the U.S. insurance industry in 1895, which estimates body fat by dividing body weight (kg) by the square of height (m). Since the World Health Organization (WHO) officially adopted it for the diagnosis of obesity in the 1990s, it is currently widely used in clinical practice. However, concerns were raised regarding the diagnosis of obesity based solely on Body Mass Index (BMI), as the possibility that diagnosing obesity based only on BMI could miss many obese patients was raised at the Endocrine Society's Annual Meeting (ENDO 2023). An analysis of data from the National Health and Nutrition Examination Survey (NHANES) revealed that the obesity diagnosis rate based on total body fat percentage measured by dual-energy x-ray absorptiometry (DEXA) was approximately twice as high as when BMI was used alone. Therefore, considering body fat mass in addition to BMI can be a more accurate method for diagnosing obesity.

[0017] In this invention, the term "diabetes" refers to a type of metabolic disease characterized by insufficient insulin secretion or a failure to perform normal functions. It is characterized by hyperglycemia, which is an elevated concentration of glucose in the blood, and causes various symptoms and signs, as well as the excretion of glucose in the urine. Diagnosis is made through blood tests; in the absence of symptoms, diabetes is defined as a blood glucose level of 126 mg / dL or higher measured after fasting for at least 8 hours, or a blood glucose level of 200 mg / dL or higher 2 hours after an oral glucose tolerance test. Diabetes is also diagnosed when there is excessive water intake, frequent urination, and weight loss, while blood glucose measured regardless of meals is 200 mg / dL or higher. Diabetes is classified into Type 1 and Type 2; Type 1 diabetes, also known as "juvenile diabetes," is a disease caused by the inability to produce any insulin. Type 2 diabetes, characterized by a relative deficiency of insulin, is marked by insulin resistance (a condition in which the function of insulin to lower blood sugar is impaired, preventing cells from effectively burning glucose). While environmental factors such as high-calorie, high-fat, and high-protein diets resulting from the Westernization of eating habits, lack of exercise, and stress appear to play a significant role in Type 2 diabetes, an increasing number of studies suggest it can also be caused by defects in specific genes, as well as pancreatic surgery, infections, and medications.

[0018] In this invention, the term "liver disease" refers to liver disease as a type of metabolic disease, encompassing metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and steatotic liver disease (SLD). Metabolic dysfunction-associated steatotic liver disease (MAFLD) is a new definition that emerged as the view that nonalcoholic fatty liver disease (NAFLD) is a disease in which the effects of systemic metabolic disorders manifest in the liver became dominant. It is diagnosed based on whether it meets criteria related to metabolic abnormalities, departing from the existing approach of excluding secondary causes of fatty liver such as excessive alcohol intake or underlying liver disease. Conventional diagnostic criteria for NAFLD lacked metabolic risk factors closely related to the patient's clinical prognosis, which made it difficult to identify patients at high risk of developing cardiovascular disease or advanced fibrosis.Accordingly, in 2020, an international expert panel consisting of the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Latin American Association for the Study of the Liver (ALEH) presented new criteria for liver diseases, including MAFLD, as shown in Table 1 below. This is evaluated as helpful in diagnosing liver steatosis that occurs due to metabolic abnormalities in underlying chronic liver diseases, including alcoholic liver disease (ALD), while excluding patients with simple liver steatosis who have a lower risk of cardiovascular disease compared to NAFLD.

[0019] Metabolic risk factorsAlcohol (g / week)OthersMASLDLargeMale <210, Female <140MetALDLargeMale 210-420, Female 140-350MAFLDLargeAnyNAFLDMediumMale <210, Female <140ALDSmallMale >420, Female >350Specific etiology SLDSmallMale <210, Female <140DILI, Viral.Cryptogenic SLDSmallMale <210, Female <140Cryptogenic* MASLD: metabolic dysfunction-associated steatotic liver disease* MetALD: MASLD with increased alcohol intake* MAFLD: metabolic dysfunction associated fatty liver disease* NAFLD: Nonalcohlic fatty liver disease* ALD: alcohol-associated liver disease* SLD: steatotic liver disease

[0020] Specifically, MAFLD is defined as a condition in which one or more of the following are met along with fatty liver: 1) overweight or obesity, 2) type 2 diabetes, or 3) metabolic imbalance. Metabolic imbalance refers to a condition in which two or more of the following are present: hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance. Since MAFLD has a high potential to progress to liver-related complications such as cirrhosis, liver failure, hepatocellular carcinoma, and death, strict management is necessary before the onset of the disease or in the early stages of its development.

[0021] In the present invention, the term "pharmacological composition" refers to a composition administered for a specific purpose. For the purposes of the present invention, the pharmacological composition of the present invention is intended to prevent or treat metabolic diseases and may additionally include an acceptable carrier, excipient, or diluent in addition to the active ingredient of the present invention involved therein. Furthermore, the pharmacological composition according to the present invention comprises 0.1 to 50 weight percent of the active ingredient of the present invention based on the total weight of the composition. Carriers, excipients, and diluents that may be included in the composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0022] Specifically, the pharmaceutical composition for the prevention and treatment of metabolic diseases according to the present invention preferably comprises a drowsy primrose extract, and the prevention may include, without limitation, any act of blocking, suppressing, or delaying symptoms caused by metabolic diseases using the pharmaceutical composition of the present invention, and the treatment may include, without limitation, any act of improving or benefiting symptoms caused by metabolic diseases using the pharmaceutical composition of the present invention.

[0023] In addition, in the present invention, administration means introducing the composition of the present invention to a patient by any appropriate method, and the route of administration of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. Specifically, it may be in the form of oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, rectal administration, intraluminal administration, intraperitoneal administration, intrathecal administration, or ocular administration, but is not limited thereto. In the present invention, the effective dose may be adjusted according to various factors including the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation, the patient's age, weight, general health condition, gender and diet, the time of administration, the route of administration and the secretion rate of the composition, the duration of treatment, and concurrently used drugs.

[0024] In the present invention, the pharmaceutical composition may be characterized in that it is in the form of a capsule, tablet, granule, injection, ointment, powder, gel, or beverage, and the pharmaceutical composition may be characterized in that it is preferably intended for animals, more preferably for mammals, and most preferably for humans.

[0025] In the present invention, the term "food composition" means a composition administered for a specific purpose. For the purposes of the present invention, the food composition of the present invention is to prevent or improve metabolic diseases and comprises primrose extract as an active ingredient.

[0026] The food composition containing the active ingredient of the present invention can be manufactured in the form of various food products, such as beverages, chewing gum, tea, vitamin complexes, powders, granules, tablets, capsules, jellies, gels, confectionery, rice cakes, bread, etc. Since the food composition of the present invention is composed of improved natural foods with almost no toxicity or side effects, it can be used with confidence even when taken for a long period for preventive purposes. When the composition of the present invention is included in a food composition, the amount may be added in a ratio of 0.1 to 100% of the total weight. Here, when the food composition is manufactured in the form of a beverage, there are no special limitations other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in ordinary beverages. That is, as natural carbohydrates, it may include monosaccharides such as glucose, disaccharides and polysaccharides such as fructose and sucrose, conventional polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. Examples of the above-mentioned flavoring agents include natural flavoring agents (taumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.). In addition, the food composition of the present invention may contain various nutritional agents, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination. The proportion of such additives is generally selected in the range of 0.1 to 100 parts by weight per 100 parts by weight of the composition of the present invention, but is not limited thereto.

[0027] In the present invention, the term "cosmetic composition" means a composition administered for a specific purpose. For the purposes of the present invention, the cosmetic composition of the present invention is to prevent or improve metabolic diseases and comprises primrose extract as an active ingredient.

[0028] A cosmetic composition containing the active ingredient of the present invention may be manufactured in the form of a lotion, a nourishing lotion, a nourishing essence, a massage cream, a beauty bath additive, a body lotion, a body milk, a bath oil, a baby oil, a baby powder, a shower gel, a shower cream, a sunscreen lotion, a sunscreen cream, a tanning cream, a skin lotion, a skin cream, a cosmetic for UV protection, a cleansing milk, a hair removal agent (for cosmetic use), a face and body lotion, a face and body cream, a skin whitening cream, a hand lotion, a hair lotion, a cosmetic cream, jasmine oil, a bath soap, a liquid soap, a beauty soap, a shampoo, a hand cleanser (hand cleaner), a medicinal soap (for non-medical use), a cream soap, a facial wash, a hair rinse, a cosmetic soap, a teeth whitening gel, a toothpaste, etc. To this end, the composition of the present invention may further include a suitable carrier, excipient, or diluent that is conventionally used in the manufacture of cosmetic compositions. Carriers, excipients, or diluents that may be further added to the cosmetic composition of the present invention include, but are not limited to, purified water, oil, wax, fatty acid, fatty acid alcohol, fatty acid ester, surfactant, humectant, thickener, antioxidant, viscosity stabilizer, chelating agent, buffer, lower alcohol, etc. Additionally, whitening agents, moisturizers, vitamins, sunscreens, perfumes, dyes, antibiotics, antibacterial agents, and antifungal agents may be included as needed. As the oil, hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm oil, jojoba oil, and avocado oil may be used, and as the wax, beeswax, spermaceti, carnauba, candelilla, montan, ceresin, liquid paraffin, and lanolin may be used. As fatty acids, stearic acid, linoleic acid, linolenic acid, and oleic acid may be used; as fatty acid alcohols, cetyl alcohol, octyldodecanol, oleyl alcohol, pantenol, lanolin alcohol, stearyl alcohol, and hexadecanol may be used; and as fatty acid esters, isopropyl myristate, isopropyl palmitate, and butyl stearate may be used.Cationic surfactants, anionic surfactants, and nonionic surfactants known in the art can be used as surfactants, and surfactants derived from natural products are preferred as much as possible. In addition, hygroscopic agents, thickeners, antioxidants, etc., widely known in the cosmetics field may be included, and the types and amounts thereof are as known in the art.

[0029] Hereinafter, in one embodiment of the present invention, a pharmaceutical composition for the prevention or treatment of metabolic diseases is provided, comprising an extract of sleepy primrose as an active ingredient, wherein the sleepy primrose has the scientific name Primula nutans Georgi, the pharmaceutical composition for the prevention or treatment of metabolic diseases is provided, wherein the extract is prepared by ultrasonic extraction, wherein the ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W, the pharmaceutical composition for the prevention or treatment of metabolic diseases is provided, wherein the extract is a whole plant extract of sleepy primrose, and wherein the metabolic diseases include obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, and thyroid disease. The present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein one or more are selected from the group consisting of hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout, and wherein the fatty liver is metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), and nonalcoholic fatty liver disease;The present invention provides a pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein one or more are selected from the group consisting of NAFLD, alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

[0030] In another aspect of the present invention, a method for preparing a pharmaceutical composition for the prevention or treatment of metabolic diseases is provided, comprising the step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W.

[0031] In another aspect of the present invention, a food composition for the prevention or improvement of metabolic diseases is provided, comprising an extract of sleepy primrose, wherein the sleepy primrose has the scientific name Primula nutans Georgi, wherein the extract is prepared by ultrasonic extraction, wherein the ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W, wherein the extract is a whole plant extract of sleepy primrose, wherein the metabolic diseases include obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, The present invention provides a food composition for the prevention or improvement of metabolic diseases, wherein one or more are selected from the group consisting of hypertension, hypotension, hyperglycemia, hypoglycemia, and gout, and the fatty liver is metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), and nonalcoholic fatty liver disease.The present invention provides a food composition for the prevention or improvement of metabolic diseases, wherein one or more are selected from the group consisting of NAFLD, alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

[0032] In another aspect of the present invention, a method for preparing a food composition for the prevention or improvement of metabolic diseases is provided, comprising the step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W.

[0033] In another aspect of the present invention, a cosmetic composition for the prevention or improvement of metabolic diseases is provided, comprising an extract of sleepy primrose, wherein the sleepy primrose has the scientific name Primula nutans Georgi, wherein the extract is prepared by ultrasonic extraction, wherein the ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W, wherein the extract is a whole plant extract of sleepy primrose, wherein the metabolic diseases include obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, The present invention provides a cosmetic composition for the prevention or improvement of metabolic diseases, wherein the fatty liver is one or more selected from the group consisting of hypertension, hypotension, hyperglycemia, hypoglycemia, and gout, wherein the fatty liver is metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), and nonalcoholic fatty liver disease.The present invention provides a cosmetic composition for the prevention or improvement of metabolic diseases, wherein one or more are selected from the group consisting of NAFLD, alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

[0034] In another aspect of the present invention, a method for preparing a cosmetic composition for the prevention or improvement of metabolic diseases is provided, comprising the step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W.

[0035] In another aspect of the present invention, a method for preventing or treating a metabolic disease is provided, comprising the step of administering a sleepy primrose extract within a pharmaceutically acceptable range to an individual requiring treatment; wherein the sleepy primrose has the scientific name Primula nutans Georgi; wherein the extract is prepared by ultrasonic extraction; wherein the ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W; wherein the extract is a whole plant extract of sleepy primrose; and wherein the metabolic disease is obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, The present invention provides a method for the prevention or treatment of a metabolic disease, wherein the metabolic disease is one or more selected from the group consisting of hypotension, hyperglycemia, hypoglycemia, and gout, and the fatty liver is metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), and nonalcoholic fatty liver disease.The present invention provides a method for the prevention or treatment of a metabolic disease, which is one or more selected from the group consisting of NAFLD, alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

[0036] In another aspect of the present invention, a use for preventing or treating metabolic diseases is provided for a sleepy primrose extract, wherein the sleepy primrose has the scientific name Primula nutans Georgi, the use for preventing or treating metabolic diseases is provided for a use for preventing or treating metabolic diseases is provided for a use for preventing or treating metabolic diseases is provided for a use for preparing the extract by ultrasonic extraction, wherein the ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W, the use for preventing or treating metabolic diseases is provided for a use for preventing or treating metabolic diseases is provided for a use for preventing or treating metabolic diseases is provided for a use for a use for preventing preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is provided for preventing metabolic diseases is Provides a use for the prevention or treatment of metabolic diseases, wherein one or more selected from the group consisting of hyperglycemia, hypoglycemia, and gout, and said fatty liver is metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic fatty liver disease (NAFLD), and alcohol-associated liver disease;Provides a use for the prevention or treatment of metabolic diseases, wherein one or more are selected from the group consisting of ALD, and steatotic liver disease (SLD).

[0037] The composition of the present invention has the effect of inhibiting adipocyte differentiation and fat accumulation, reducing body weight gain, body fat gain, adipocyte size, liver weight, and liver fat accumulation in a high-fat diet-induced obese animal model, and improving insulin resistance.

[0038] Figure 1 is a figure showing the cytotoxicity of a PG extract (PGE) at different concentrations according to one embodiment of the present invention.

[0039] Figure 2 is a figure showing the inhibitory effect of PG extract (PGE) on intracellular fat accumulation according to concentration, according to one embodiment of the present invention.

[0040] Figure 3 is a figure showing the inhibition of PPARγ mRNA expression, a transcription factor that promotes adipocyte differentiation, according to the concentration of a PG extract (PGE) in one embodiment of the present invention.

[0041] Figure 4 is a figure showing the inhibition of FABP4 mRNA expression, an adipocyte marker gene, according to the concentration of a PG extract (PGE) according to one embodiment of the present invention.

[0042] Figure 5 is a figure showing the inhibition of FAS mRNA expression, a fatty acid synthesis gene, according to the concentration of PG extract (PGE) in one embodiment of the present invention.

[0043] Figure 6 is a figure showing the inhibition of SCD1 mRNA expression, a key enzyme in the lipid synthesis metabolic process, according to an embodiment of the present invention, by concentration of PG extract (PGE).

[0044] FIG. 7 is a figure showing the inhibitory effect of a PG extract (PGE) on high-fat diet-induced body weight gain according to one embodiment of the present invention.

[0045] FIG. 8 is a figure showing the inhibitory effect of a PG extract (PGE) on an increase in body fat induced by a high-fat diet according to one embodiment of the present invention.

[0046] FIG. 9 is a figure showing the inhibitory effect of a PG extract (PGE) on the increase in liver tissue weight induced by a high-fat diet according to one embodiment of the present invention.

[0047] FIG. 10 is a figure showing the inhibitory effect of PG extract (PGE) on the increase in adipocyte size in adipose tissue and the increase in triglycerides in liver tissue induced by a high-fat diet according to an embodiment of the present invention.

[0048] FIG. 11 is a figure showing the improvement effect of a PG extract (PGE) on high-fat diet-induced insulin resistance as a result of a glucose tolerance test (GTT) according to one embodiment of the present invention.

[0049] FIG. 12 is a figure showing the improvement effect of a PG extract (PGE) on high-fat diet-induced insulin resistance as a result of an insulin tolerance test (ITT) according to one embodiment of the present invention.

[0050] When the body weight, body fat, and liver tissue weight of mice fed a high-fat diet with PGE 0, 10, or 30 mg / kg were measured, mice fed only a high-fat diet without PGE showed a significant increase in body weight compared to the control group fed a normal diet (NCD). In particular, body fat increased by approximately 6 times compared to the NCD group. On the other hand, mice fed a high-fat diet with PGE 10 or 30 mg / kg showed a significant decrease in body weight, body fat, and liver tissue weight compared to mice fed only a high-fat diet without PGE.

[0051] The present invention will be described in more detail below through examples. These examples are intended solely to explain the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the invention.

[0052] Examples

[0053] 1. Preparation of sleepy primrose extract

[0054] The whole plant (72 g) of Primula nutans Georgi (PG), dried in the shade, was powdered, and 1 L of 99.9% methanol (v / v) was added. Extraction was performed using an ultrasonic extractor (SDN-900H, SD-ULTRASONIC CO., LTD) at room temperature for 30 cycles (40KHz, 1500W, ultrasonic treatment for 15 minutes - 120 minutes per cycle). Subsequently, the extract was filtered (Qualitative Filter No.100, HYUNDAI MICRO CO., LTD) and dried under reduced pressure to obtain Primula nutans Georgi extract (6.76 g).

[0055] 2. Cell culture

[0056] 3T3-L1 preadipocytes obtained from the American Type Culture Collection (ATCC) were cultured in DMEM medium containing 10% FBS, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37°C and 10% CO2.

[0057] During the differentiation of 3T3-L1 preadipocytes into adipocytes, place 5.0 × 10⁶ cells in a 12-well culture plate. 4Adipocyte differentiation was initiated by dispensing into / wells and culturing for 48 hours in differentiation medium containing 10% FBS, hormone cocktail (1×MDI), 0.5 mM IBMX (3-isobutyl-1-methylxanthine), 1 μM dexamethasone, and 1 μg / ml insulin. Subsequently, starting from day 2, the cells were cultured in DMEM adipocyte maintenance medium containing 10% FBS and 1 μg / ml insulin.

[0058] 3. Confirmation of the fat-inhibiting effect of sleepy primrose extract in adipocytes

[0059] 3T3-L1 adipocytes were treated with primrose extract (PGE) at concentrations of 0, 25, 50, 100, or 200 μg / ml, and cell viability was measured after 24 hours using the WST-8 Cell Viability Assay Kit. The test results confirmed that PGE is very safe in terms of toxicity, as there was no significant difference in cell viability compared to untreated cells (0 μg / ml) even at high concentrations (200 μg / ml) (Fig. 1). In addition, Oil Red O staining was performed to confirm the fat reduction effect. The results showed that treatment with 25 μg / ml resulted in approximately 50% reduction in fat drop compared to untreated cells (0 μg / ml), while treatment with 50 μg / ml or higher resulted in almost no intracellular fat drop (Fig. 2). This suggests that PGE can be used to effectively inhibit fat accumulation without the risk of toxicity.

[0060] Additionally, after lysis of PGE-treated cells, mRNA was purified using an RNA extraction kit and cDNA was synthesized. Quantitative real-time PCR (qRT-PCR) was performed to compare the mRNA expression levels of PPARγ (Peroxisome Proliferator-Activated Receptor gamma), a transcription factor promoting adipocyte differentiation; FABP4 (Fatty Acid Binding Protein 4), an adipocyte marker gene; FAS (Fatty Acid Synthase), a fatty acid synthesis gene; and SCD1 (Stearoyl-CoA 9-desaturase), a key enzyme in lipid synthesis metabolism. Cell 36B4 was used as an internal control for calculating gene expression levels. As a result of the test, mRNA expression for PPARγ (Fig. 3), FABP4 (Fig. 4), FAS (Fig. 5), and SCD1 (Fig. 6) all similarly decreased sharply in the PGE-treated group. In particular, when treated with PGE 50 μg / ml or higher, the expression of all genes related to fatty acid synthesis decreased to less than 20% compared to untreated PGE (0 μg / ml), indicating a very significant inhibitory effect on lipid synthesis. This is also consistent with the Oil Red O staining results (Fig. 2).

[0061] 4. Preparation of animal models for metabolic diseases

[0062] Male 6-week-old BALB / c mice were purchased from Orient Bio (Seongnam, Korea) and were reared at an indoor temperature of 22±2℃ with sufficient water and feed until use in the experiment. Mice were randomly separated into groups of 7, and obesity and fatty liver were induced by feeding a high-fat diet containing 60% fat for 16 weeks following a 1-week acclimatization diet. PGE was administered intraperitoneally three times a week while feeding the mice the high-fat diet.

[0063] 5. Confirmation of the therapeutic effects of sleepy primrose extract on obesity and liver disease in animal models

[0064] As a result of measuring body weight (Fig. 7), body fat (Fig. 8), and liver tissue weight (Fig. 9) of mice fed a high-fat diet with PGE 0, 10, or 30 mg / kg, mice fed only a high-fat diet without PGE showed a significant increase in body weight compared to the control group fed a normal diet (NCD). In particular, body fat increased by approximately 6 times compared to the NCD group. On the other hand, mice fed a high-fat diet with PGE 10 or 30 mg / kg showed a significant reduction in body weight, body fat, and liver tissue weight compared to mice fed only a high-fat diet without PGE.

[0065] The results of eosin staining of sectioned adipose tissue or liver tissue clearly demonstrate the effect of PGE on reducing adipocyte size and triglycerides in liver tissue (Fig. 10). The staining results of white adipose tissue (WAT) and brown adipose tissue (BAT) indicate that the adipocyte size, which had significantly increased due to a high-fat diet, was reduced by the administration of PGE, and the liver tissue staining results indicate that the large amount of triglycerides deposited in liver tissue due to a high-fat diet was effectively reduced by the administration of PGE.

[0066] 6. Confirmation of the therapeutic effect of sleepy primrose extract on diabetes in an animal model

[0067] To test glucose tolerance in mice fed a normal diet or a high-fat diet with PGE 0, 10, or 30 mg / kg, the mice were fasted for 12 hours prior to the test, and tail veins were collected to measure blood glucose levels while in a fasted state. Subsequently, a glucose solution (1.5 g / kg glucose) was orally administered to the mice, and blood glucose levels were re-measured at 0, 15, 30, 45, 60, 90, and 120 minutes. The test results showed that the basal blood glucose levels of all mice were approximately 150–180 mg / dL -1 Despite being in a similar range, after 30 minutes, mice fed only a high-fat diet without PGE had a peak blood glucose of approximately 600 mg / dL -1 ...showed significantly higher values ​​compared to other groups. Mice fed a high-fat diet with PGE 10 or 30 mg / kg exhibited peak blood glucose levels similar to those of mice fed a normal diet. The difference in the magnitude of blood glucose decline after peak was even more pronounced, with mice fed only a high-fat diet showing approximately 500 mg / dL even at 120 minutes. -1 Although the blood glucose levels were high, mice fed a high-fat diet with PGE 10 or 30 mg / kg maintained a similar level of blood glucose reduction as mice fed a normal diet (Fig. 11).

[0068] To test insulin resistance, mice were fasted using the same method as described above, and blood glucose levels were measured by collecting tail veins while in a fasting state. Subsequently, an insulin solution (1 unit / kg insulin) was administered intraperitoneally to the mice, and blood glucose levels were re-measured at 0, 15, 30, 45, 60, 90, and 120 minutes. As a result of the experiment, mice fed only a high-fat diet without PGE exhibited a trough blood glucose at 45 minutes, with a blood glucose level of approximately 150 mg / dL -1 Although the level was considerably high, mice fed a high-fat diet along with PGE 10 or 30 mg / kg showed a steady decrease in blood glucose up to 60 minutes, similar to mice on a normal diet, and the blood glucose level also reached 100 mg / dL -1 It was found to be as follows (Fig. 12).

[0069] The results of the glucose tolerance test and insulin tolerance test above suggest that primrose extract (PEG) can be very effectively used as a composition for the prevention or treatment of diabetes.

[0070] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

[0071] The present invention relates to a composition for the prevention or improvement / treatment of metabolic diseases comprising a sleepy primrose plant extract as an active ingredient. Since the composition of the present invention is a natural product with a low risk of side effects even with long-term use and can effectively prevent, improve, or treat metabolic diseases, it is expected to be widely used in the medical and health fields.

Claims

1. A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising an extract of sleepy primrose as an active ingredient.

2. In Paragraph 1, The above-mentioned sleepy primrose is a pharmaceutical composition with the scientific name Primula nutans Georgi.

3. In Paragraph 1, The above extract is a pharmaceutical composition prepared by ultrasonic extraction.

4. In Paragraph 3, A pharmaceutical composition in which the above ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W.

5. In Paragraph 1, The above extract is a pharmaceutical composition in which the extract is an extract of the whole plant of the sleepy primrose.

6. In Paragraph 1, A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout.

7. In Paragraph 6, A pharmaceutical composition in which the above fatty liver is one or more selected from the group consisting of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcohlic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

8. A step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W; comprising a method for preparing a pharmaceutical composition for the prevention or treatment of metabolic diseases.

9. A food composition for the prevention or improvement of metabolic diseases comprising an extract of sleepy primrose.

10. In Paragraph 9, The above sleepy primrose is a food composition with the scientific name Primula nutans Georgi.

11. In Paragraph 9, The above extract is a food composition prepared by ultrasonic extraction.

12. In Paragraph 11, A food composition in which the above ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10000 W.

13. In Paragraph 9, The above extract is a food composition in which the whole plant extract of the sleepy primrose is extracted.

14. In Paragraph 9, A food composition in which the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout.

15. In Paragraph 14, A food composition in which the above fatty liver is one or more selected from the group consisting of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcohlic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

16. A method for preparing a food composition for the prevention or improvement of metabolic diseases, comprising the step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W.

17. A cosmetic composition for the prevention or improvement of metabolic diseases comprising an extract of sleepy primrose.

18. In Paragraph 17, A cosmetic composition in which the above-mentioned sleepy primrose is of the scientific name Primula nutans Georgi.

19. In Paragraph 17, A cosmetic composition in which the above extract is prepared by ultrasonic extraction.

20. In Paragraph 19, A cosmetic composition in which the above ultrasonic extraction is performed at a power of 10 to 100 kHz or 100 to 10,000 W.

21. In Paragraph 17, A cosmetic composition wherein the above extract is an extract of the whole plant of the sleepy primrose.

22. In Paragraph 17, A cosmetic composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout.

23. In Paragraph 22, A cosmetic composition wherein the fatty liver is one or more selected from the group consisting of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatotic liver disease occurring with increased alcohol intake (MASLD with increased alcohol intake; MetALD), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcohlic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and steatotic liver disease (SLD).

24. A method for preparing a cosmetic composition for the prevention or improvement of metabolic diseases, comprising the step of ultrasonically extracting sleepy primrose at a power of 10 to 100 kHz or 100 to 10000 W.

25. A method for preventing or treating a metabolic disease, comprising the step of administering a sleepy primrose extract within a pharmaceutically acceptable range to an individual requiring treatment.

26. In Paragraph 25, A method for the prevention or treatment of metabolic diseases, wherein the above-mentioned sleepy primrose is of the scientific name Primula nutans Georgi.

27. In Paragraph 25, A method for the prevention or treatment of a metabolic disease, wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout.

28. Use of sleepy primrose extract for the prevention or treatment of metabolic diseases.

29. In Paragraph 28, The above sleepy primrose, scientifically known as Primula nutans Georgi, is used for the prevention or treatment of metabolic diseases.

30. In Paragraph 28, The above metabolic disease is one or more selected from the group consisting of obesity, diabetes, fatty liver, hyperlipidemia, cardiovascular disease, phenylketonuria, hyperthyroidism, hypothyroidism, hypertension, hypotension, hyperglycemia, hypoglycemia, and gout, for the purpose of preventing or treating metabolic diseases.

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