KR20210151693A - Composition for preventing, improving or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorinas as effective ingredients - Google Patents

Abstract

The present invention relates to a composition for preventing, treating or ameliorating a metabolic syndrome, comprising β-gentiobiosyl paeoniflorin as an active ingredient and, more particularly, to a composition for preventing, treating or ameliorating a metabolic syndrome, comprising as an active ingredient β-gentiobiosyl paeoniflorin, which exhibits the action of increasing glucose uptake into muscle cells and inhibiting the activity of lipase. The composition of the present invention comprising β-gentiobiosyl paeoniflorin as an active ingredient increases glucose uptake into muscle cells and exhibits an activity of inhibiting lipase, and thus can be advantageously used in the development of an agent for preventing, ameliorating or treating metabolic syndrome including diabetes and obesity.

Description

A composition for preventing, treating or improving metabolic syndrome comprising β-gentiobiosyl paeoniflorin as an active ingredient {Composition for preventing, improving or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorinas as effective ingredients}

The present invention relates to a composition for preventing, treating or improving metabolic syndrome comprising β-gentiobiosil paoniflorin as an active ingredient, and more particularly, to a composition for increasing glucose absorption into muscle cells and inhibiting the activity of lipase. It relates to a composition for preventing, treating or improving metabolic syndrome, comprising β-gentiobiosil paoniflorin, which exhibits action, as an active ingredient.

In modern society, the rapid economic development and abundant nutritional intake, while significantly decreasing the amount of exercise, causes two or more complex metabolic diseases such as obesity, diabetes, high blood pressure, hypertriglyceridemia, hypercholesterolemia, and arteriosclerosis. The prevalence of Metabolic Syndrome is increasing, and according to the 2005 National Health and Nutrition Examination Survey data, the overall figure is 32.3% (32.9% for men, 31.8% for women). As a result, heart disease and stroke are increasing enough to occupy the second and third leading causes of death in Koreans. This is a symptom that occurs when the metabolic wastes and toxins that are caused by a poorly balanced metabolism cannot be released, and the accumulated waste products in the body lose their functions. Metabolism also known as insulin resistance syndrome syndrome develops. Metabolic syndrome can cause damage to the coronary arteries, which can cause heart disease or stroke, or decrease the ability of the kidneys to remove salts to cause high blood pressure, increase the proportion of triglycerides that cause cardiovascular disease, and increase blood pressure. It increases the risk of clotting and is also known to result in reduced insulin production with type 2 diabetes, resulting in damage to the eyes, kidneys, and nerves.

An effective drug for the treatment of metabolic syndrome has not yet been developed, and only attempts are made to treat the metabolic syndrome using drugs for diabetes, dyslipidemia and hypertension. Currently available drugs for the treatment of metabolic syndrome include metformin, a thiazolidinediones (TZD) class of drugs used as a treatment for diabetes, a glucosidase inhibitor, and a dipeptidyl peptidase (DDP)-IV inhibitor. In addition, blood pressure drugs and dyslipidemia drugs are attracting attention. However, there is a limit to improving the metabolic syndrome with these drugs.

Looking at the known factors related to the cause and treatment of metabolic syndrome, exercise, diet, body weight, blood sugar, triglyceride, cholesterol, insulin resistance, adiponectin, leptin, AMP-activated protein kinase (AMPK) activity , sex hormones such as estrogen, genetic factors, and the concentration of malonyl-CoA in vivo are directly or indirectly involved.

Therefore, for the effective management or treatment of metabolic syndrome with complex symptoms, it is ideal to develop a material capable of improving obesity, which is a fundamental cause of metabolic syndrome, at the same time as having a hypoglycemic effect for maintaining normal blood sugar. Research and development for therapeutic agents is insufficient.

Accordingly, the present inventors repeated intensive research to develop a new material capable of improving obesity and simultaneously lowering blood sugar for effective improvement of metabolic syndrome. As well as showing the effect, it was discovered that it also exerts an anti-obesity effect at the same time and completed the present invention.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient. provides

In order to achieve another object of the present invention, the present invention provides a food composition for preventing or improving metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the β-gentiobiosyl paoniflorin is a glycoside of paoniflorin having the structure of Formula 1 below, chemically synthesized by a method known in the art, using a commercially available material, or from a natural product. can be separated

[Formula 1]

In one aspect of the present invention, the β- gentiobiosyl paoniflorin is Leuconostoc sp. LN180020 strain (Accession No.: KCTC13719BP) characterized in that it is produced by bioconversion of paoniflorin can do.

In another aspect of the present invention, the β- gentiobiosil paoniflorin is leuconostok in powder, extract or extract of peony ( Paeonia lactiflora ) or genus Paeonia ( Paeonia ) containing paoniflorin as an index component. Genus ( Leuconostoc sp.) LN180020 strain (Accession No.: KCTC13719BP) after inoculation can be characterized in that it is produced by fermentation.

As used herein, the term 'peony' refers to the root, stem, leaf, flower, seed, and fruit of a plant having the scientific name Paeonia lactiflora , preferably the root of Paeonia lactiflora used as a medicine. The peony as a medicine is also called Paeoniae Radix or Peony root, and more specifically, it refers to the root of the peony Paeonia lactiflora Pallas or other closely related plants (Peony and Paeoniaceae) used as medicinal parts.

The peony extract may be extracted by a solvent extraction method known in the art. The extraction solvent is not limited thereto, but water, a lower alcohol having 1 (C1) to 6 (C6) carbon atoms, an organic solvent, or a mixture thereof may be used. The lower alcohol having 1 (C1) to 6 (C6) carbon atoms is not limited thereto, but may be methanol, ethanol, alcohol, propanol, isopropanol, butanol, pentanol, hexanol, and the organic solvent is not limited thereto, acetone, ethyl acetate, n-nucleic acid, diethyl ether, acetone, or benzene. Preferably, extraction may be performed with water or an alcohol having 1 to 6 carbon atoms or a mixed solvent thereof, and more preferably water, ethanol or alcohol. A small amount of water (eg, 95% ethanol, 99% ethanol) may be added to alcohol to reflect physicochemical properties such as hygroscopicity.

As used herein, the term “pharmaceutically acceptable salt” refers to a salt in a form that can be used pharmaceutically among salts in which a cation and anion are bonded by electrostatic attraction, usually with a metal salt, an organic base and salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine salts with, etc.; salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; Salts with basic amino acids may be salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, or the like. For the purposes of the present invention, the pharmaceutically acceptable salt may be interpreted as an acid addition salt or a base addition salt of imatinib suitable for the treatment of patients expected to develop vascular permeability-related diseases or have the disease, but in particular, However, the present invention is not limited thereto.

In the present invention, the metabolic syndrome may be one or more selected from the group consisting of diabetes, obesity, fatty liver, dyslipidemia, arteriosclerosis, insulin resistance syndrome, and complications thereof, preferably diabetes and/or obesity, and complications thereof may include.

In the present invention, 'diabetes', which is the subject of treatment or prevention, is a metabolic disorder syndrome characterized by a deficiency of insulin hormone produced in beta cells of the pancreas or abnormal insulin resistance and high blood sugar caused by both of these defects. Such diabetes can be divided into insulin-dependent diabetes mellitus (IDDM, Type 1) and non-insulin-dependent diabetes mellitus (NIDDM, Type 2) caused by insulin resistance and impaired insulin secretion. In both type 1 and type 2 diabetes, various complications such as heart disease, intestinal disease, eye disease, neurological disease, and stroke occur. Short-term hypoglycemia and hyperglycemia will cause acute complications. Diabetes mellitus causes chronic high blood sugar and lipid and protein metabolism as well as carbohydrate metabolism. The conditions are various and are directly caused by hyperglycemia, including diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cataract, keratosis, diabetic arteriosclerosis, etc. in the retina, kidney, nerve, and cardiovascular system.

Accordingly, diabetes in the present invention includes diabetes or diabetes complications caused by diabetes, and more specifically, may be type 1 diabetes, type 2 diabetes, or gestational diabetes. In the case of diabetic complications, it may be a disease caused by the destruction or functional decline of islet cells of Langerhans, or a disease caused by an increase in blood glucose concentration, specifically, but not limited to, diabetic peripheral neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cataract, keratosis, diabetic arteriosclerosis.

Since the composition provided by the present invention exhibits an action of increasing glucose absorption into muscle cells, it can be very usefully utilized for glycemic control in diabetic patients.

On the other hand, although a person who is generally overweight, but not obese, a person with a lot of muscle can gain a lot of weight, so a state in which there is an excess of adipose tissue in the body is referred to as "obesity". The term "obesity" refers to a state of excessive body fat, and clinically refers to a case in which the body mass index is 25 in Korea and 30 or more according to the World Health Organization (WHO). In general, it refers to a case in which the body weight is higher than the normal value, but even if the body weight is not very high, obesity is diagnosed when the proportion of body fat in the body composition is high, and it refers to a disease that occurs in both adults and children. Such obesity is not only due to weight gain, but also overeating, excessive drinking and bulimia, hypertension, diabetes, increased plasma insulin concentration, insulin resistance, dyslipidemia, metabolic syndrome, insulin resistance syndrome, obesity-related gastroesophageal reflux disease, arteriosclerosis, hypercholesterol Hyperemia, hyperuric acidemia, lower back pain, cardiac hypertrophy and left ventricle hypertrophy, lipodystrophy, nonalcoholic steatohepatitis, cardiovascular disease, or obesity-related complications such as polycystic ovary syndrome can occur.

The composition provided by the present invention exhibits an activity of inhibiting lipase, which aids in absorption by decomposing fat, and thus can be very usefully used to improve obesity.

In the present invention, the 'fatty liver' is a disease caused by the accumulation of excessive fat (mainly, triglycerides) in the liver, and generally means that more than 5% of the weight of the liver is accumulated. In the present invention, the fatty liver includes non-alcoholic fatty liver, alcoholic fatty liver, and non-alcoholic fatty liver disease.

Preferably, in the present invention, the fatty liver includes non-alcoholic fatty liver disease (NAFLD). The non-alcoholic fatty liver disease (NAFLD) is a generic term for diseases caused by the deposition of fat in the liver of a person without a drinking history.

Specifically, the non-alcoholic fatty liver disease (NAFLD), regardless of alcohol, is overweight and obesity, insulin resistance, diabetes (type 1 diabetes (T1D), type 2 diabetes, etc.), dyslipidemia (hyperlipidemia), metabolic syndrome (For example, high blood pressure, high blood sugar, abdominal obesity, metabolic syndrome caused by low HDL cholesterol and high triglycerides) is a common chronic liver disease that is caused by the accumulation of excess fat (mainly, triglycerides) in the liver. This means that more than 5% of the liver's weight is accumulated as fat and diseases caused by it.

The non-alcoholic fatty liver disease (NAFLD) is a non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis (liver fibrosis) in which only fat is simply accumulated in the liver without damage to the liver cells. cirrhosis) may even develop into liver cancer. Specifically, the non-alcoholic fatty liver disease (NAFLD) is a simple fatty liver with only steatosis without hepatocellular damage, steatosis and type 2 steatohepatitis with an inflammatory reaction in the lobules due to severe and prolonged damage to the hepatocytes, steatosis and It can be divided into type 3 with fatty necrosis with balloon-shaped degeneration of hepatocytes and type 4 with mallysosomes or fibrosis with the above-mentioned type 3 findings.

The steatohepatitis is known as steatohepatitis in about 10% of all fatty liver disease patients, and the nonalcoholic steatohepatitis (NASH) is caused by an increase in triglyceride production due to hyperinsulinemia and a decrease in fat metabolism function. If the non-alcoholic fatty liver and non-alcoholic steatohepatitis are left unattended, liver function may deteriorate and liver cirrhosis may occur through liver fibrosis.

The liver fibrosis is a kind of wound healing process that appears in liver tissue. When the liver tissue is damaged by hepatitis virus, nonalcoholic fatty liver, drugs, etc., the vascular structure in the liver lobules in the process of continuously repeating damage and regeneration of the liver cells. is collapsed, and the regenerative nodules that have lost their function take their place, causing a fibrotic reaction in the liver, which can lead to cirrhosis, in which the liver becomes hard.

The damaged hepatocytes secrete reactive oxygen species and inflammatory substances to activate Kupffer cells and inflammatory cells, which leads to activation of hepatic stellate cells. In the normal state, hepatic stellate cells are only the main storage of vitamin A, but when liver damage occurs, they are activated and synthesize and secrete various extracellular matrixes such as collagen, which can cause liver fibrosis. If liver damage is chronically repeated, damaged hepatocytes are no longer regenerated and are gradually replaced by extracellular matrix such as collagen, which can lead to liver fibrosis and cirrhosis.

That is, the nonalcoholic fatty liver disease (NAFLD) is a continuous disease that progresses from simple nonalcoholic fatty liver to steatohepatitis and liver fibrosis to cirrhosis.

The pharmaceutical composition according to the present invention can be effectively used for the treatment of nonalcoholic fatty liver disease (NAFLD), not only nonalcoholic fatty liver, but also nonalcoholic steatohepatitis (NASH) and liver fibrosis.

In the present invention, 'dyslipidemia' refers to a state in which total cholesterol, LDL cholesterol, and triglycerides in the blood are increased or HDL cholesterol is decreased, and in the group consisting of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia It may be any one or more selected. The hyperlipidemia refers to a state in which lipids including cholesterol and triglycerides are increased in blood. Hyperlipidemia, although asymptomatic, may increase the risk of coronary artery disease, such as atherosclerosis or myocardial infarction. The hypercholesterolemia is a state in which cholesterol in the blood is increased, and total cholesterol and LDL cholesterol are high. The hypertriglyceridemia refers to a state in which triglycerides are increased in blood. If dyslipidemia persists, excess cholesterol in the blood may be deposited on the walls of blood vessels. After a lot of cholesterol is deposited on the walls of blood vessels, inflammatory and oxidative reactions progress, reducing the elasticity of blood vessels, thickening blood vessel walls, and blocking smooth blood flow, complications such as arteriosclerosis, angina, and stroke may occur.

In the present invention, 'insulin resistance syndrome' is a concept that collectively refers to diseases induced by insulin resistance. Cell resistance to insulin action, hyperinsulinemia, increase in very low density lipoprotein (VLDL) and triglycerides, It refers to a disease characterized by a decrease in high density lipoprotein (HDL) and hypertension, and is a concept recognized as a risk factor for cardiovascular disease and type 2 diabetes (Reaven GM., Role of insulin resistance in human). disease, Diabetes, 37:1595-607 (1988)). It is also known that insulin resistance increases intracellular oxidative stress along with risk factors such as high blood pressure, diabetes, and smoking, and induces an inflammatory response by changing the signaling system to advance atherosclerosis.

In an example of the present invention, whether β-gentiobiosyl paoniflorin exhibits an activity of inhibiting lipase decomposing lipids, and the extent thereof was compared with paoniflorin. As a result, β-gentiobiosyl paoniflorin exhibited very excellent lipase inhibitory activity, and it was confirmed that this activity was significantly superior to paoniflorin. That is, it indicates that β-gentiobiosyl paoniflorin has very excellent anti-obesity activity.

In another embodiment of the present invention, as a result of comparing the effects of administration of β-gentiobiosil paoniflorin or paoniflorin to an animal model induced by administration of a high-fat diet, body weight, total cholesterol in blood , triglycerides and LDL levels, AST, ALT levels, fasting blood glucose and insulin resistance were significantly decreased in the β-gentiobiosil paoniflorin group compared to the paoniflorin group, and even in the case of β- It was confirmed that a significant increase was observed in the gentiobiosil paoniflorin-administered group. That is, it indicates that β-gentiobiosyl paoniflorin has significantly higher effects on diabetes, obesity, fatty liver and dyslipidemia compared to paoniflorin.

As used herein, 'treatment' or 'improvement' refers to inhibiting the occurrence or recurrence of a disease, alleviating symptoms, reducing direct or indirect pathological consequences of a disease, reducing the rate of disease progression, ameliorating, ameliorating, alleviating or ameliorating a disease state. means the prognosis. As used herein, the term 'prevention' refers to any action that suppresses the onset or delays the progression of a disease.

The pharmaceutical composition according to the present invention can be variously formulated according to the route of administration by methods known in the art together with a pharmaceutically acceptable carrier for the treatment of metabolic syndrome. The carrier includes all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.

The pharmaceutical composition according to the present invention may be administered to a patient in a pharmaceutically effective amount, that is, in an amount sufficient to prevent or alleviate symptoms and treat metabolic syndrome. For example, a typical daily dose may be administered in the range of about 0.01 to 1000 mg/kg, preferably, it may be administered in the range of about 1 to 100 mg/kg. The pharmaceutical composition of the present invention may be administered once or divided into several doses within a preferred dosage range. In addition, the dosage of the pharmaceutical composition according to the present invention may be appropriately selected by those skilled in the art according to the route of administration, administration, age, sex, body weight, individual differences, and disease state.

The route of administration may be oral or parenteral administration. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, rectal, or pancreatic administration. It may be administered internally, but is not limited thereto, and most preferably, it may be administered orally.

When the pharmaceutical composition of the present invention is orally administered, powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers according to methods known in the art together with a suitable oral administration carrier It can be formulated in the form of, etc. Examples of suitable carriers include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, cellulose, Cellulose, including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant if necessary. Furthermore, the pharmaceutical composition may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and a preservative.

In addition, when administered parenterally, the pharmaceutical composition of the present invention may be formulated according to methods known in the art in the form of injections, transdermal administration agents, nasal inhalants, etc. together with suitable parenteral carriers.

In addition, the pharmaceutical composition may be administered by any device capable of transporting the active agent to a target cell. Preferred administration methods and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, or drip injections. Injections include aqueous solvents such as physiological saline or Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol or glycerin). It can be prepared using, stabilizers for preventing deterioration (eg, ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, to inhibit the growth of microorganisms and a pharmaceutical carrier such as a preservative (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

In the case of the injection, it must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. For injection, examples of suitable carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof, and/or a solvent or dispersion medium containing vegetable oil. can More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, it may further include various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, in most cases, the injection may further contain an isotonic agent such as sugar or sodium chloride.

As other pharmaceutically acceptable carriers, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition according to the present invention may contain one or more buffers (eg saline or PBS), carbohydrates (eg glucose, mannose, sucrose or dextran), antioxidants, bacteriostats, chelating agents (eg EDTA or glutathione), adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents and/or preservatives.

In addition, the pharmaceutical compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

In addition, the pharmaceutical composition of the present invention may be administered alone or in combination with a known compound having an effect on the treatment of metabolic syndrome.

Meanwhile, the present invention provides a food composition for preventing or improving metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.

The food composition of the present invention includes all types of functional foods, nutritional supplements, health foods, and food additives.

Food compositions of this type can be prepared in various forms according to conventional methods known in the art. Although not limited thereto, for example, as a health food, β-gentiobiosil paoniflorin can be prepared in the form of tea, juice, and drink and ingested by liquefying, granulating, encapsulating, and powdering so that it can be consumed. . In addition, it can be prepared in the form of a composition by mixing with a known active ingredient known to be effective for metabolic syndrome. In addition, functional foods include, but are not limited to, beverages (including alcoholic beverages), fruits and processed foods thereof (eg, canned fruit, bottled, jam, marmalade, etc.), fish, meat, and processed foods (eg, ham, sausages) corn beef, etc.), breads and noodles (eg udon noodles, soba noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, syrup, dairy products (eg butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable It can be prepared by adding β-gentiobiosil paoniflorin to proteins, retort foods, frozen foods, and various seasonings (eg, soybean paste, soy sauce, sauce, etc.). In addition, in order to use β-gentiobiosil paoniflorin in the form of an additive, it may be prepared and used in the form of a powder or a concentrate.

The preferred content of β-gentiobiosyl paoniflorin in the food composition of the present invention is not limited thereto, but is preferably 0.1 to 90% by weight of the final prepared food. More preferably, the food composition containing β-gentiobiosil paoniflorin of the present invention as an active ingredient is mixed with an active ingredient known to be effective on metabolic syndrome in the form of a health functional food or dietary supplement. can be manufactured with

The health functional food composition for preventing or improving metabolic syndrome of the present invention contains β-gentiobiosil paoniflorin, which promotes glucose absorption into muscle cells and inhibits lipase activity, as an active ingredient, It is characterized in that it is effective in preventing or improving metabolic syndrome including obesity.

The composition of the present invention comprising β-gentiobiosil paoniflorin as an active ingredient increases glucose absorption into muscle cells and exhibits an activity of inhibiting lipase, thereby preventing, ameliorating or treating metabolic syndrome including diabetes and obesity. It can be very usefully used in the development of therapeutic agents.

1 is a result of evaluating the lipase inhibitory activity of each of the specified test substances such as β-gentiobiosil paoniflorin.
2 is an HPLC chromatogram showing the contents of indicator substances and new useful substances in non-fermented peony extract (non-fermented, (a)) and lactic acid bacteria fermented product (fermented, (b)) of peony extract.
Figure 3 is a non-fermented peony extract (non-fermented) and lactic acid bacteria fermented (fermented) of the peony extract, respectively, the peony indicator material before bioconversion (paeoniflorin, paeoniflorin) and the material after bioconversion to separate and purify the LC-MS is the result of performing
4 is a result showing H, C, HMBC NMR spectral data of substances before and after bioconversion in peony extract.
5 is a result of measuring body weight, HbA1c, fasting blood glucose and HOMA-IR after administration of paoniflorin or β-gentiobiosil paoniflorin to a high-fat diet animal model.
6 is a result showing the results of measuring the indicated indicators by collecting blood after administering paoniflorin or β-gentiobiosil paoniflorin to a high-fat diet animal model.

Hereinafter, the present invention will be described in detail by way of Examples.

However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

Example 1: Lipase inhibitory activity of β-gentiobiosyl paoniflorin

Lipase inhibitory activity was measured as follows. After dissolving 5mg/ml of lipase in 150ul of reaction solution (100mM Tris-Hcl, pH 8.2), mix each test sample with 100uM solution, and react at 37°C for 5 minutes. After that, 30ul of a solution in which the substrate p-nitrophenyl palmitate (PNPP) or 4-nitrophenyl dodecanoate (PNPD) was dissolved at 0.1% (W/V) in 5 mM sodium acetate (pH 5.0) solution was added, followed by reaction at 37°C for 12 hours. . The results were measured with a spectrophotometer at a wavelength of 409 nm. Orlistat was used as a control, and as experimental samples, paeoniflorin, β-gentiobiosyl paeoniflorin, albiflorin and benzoic acid were used.

As shown in FIG. 1, as a result of the lipase inhibitory activity, Orlistat used as a positive control showed inhibitory activity of 61.7% and 50.4%, respectively, on PNPP and PNPD substrates, and β-gentiobiosil paoniflorin was 19.0%, It exhibited 31.6% inhibitory activity. On the other hand, paoniflorin showed an inhibitory activity of 3.5% and 17.6%, and no significant inhibitory activity was observed with albiflorin and benzoic acid.

Example 2: Bioconversion of Paoniflorin in Peony Extract

A peony extract was prepared by adding 10 times (w/v) water to 1 g of peony dry weight and extracting at 121 degrees for 15 minutes, and Leuconostoc sp. LN180020 (group μ number: KCTC 13719BP) 2 It was inoculated at a concentration of x 10 ⁹ CFU/ml and cultured for 48 hours in a culture room at 28°C. After that, the same amount of ethanol was added to the culture (supernatant) for extraction, followed by HPLC (with TSK-GEL ODS-100V 5 μm column (4.6 mm×15 cm), 25°C, UV 230 nm, 15-100% methanol gradient conditions). High-performance liquid chromatography) was performed to analyze the presence or absence of bioconversion. Liquid chromatography mass spectrometry (LC-MS) analysis for identifying the bioconverted material was performed by dissolving the supernatant in methanol and using the QTrap 3200 connected with Turbolon Spray source (AB SCIEX, Singapore) (Luna C18 (2), 100 ×2.0 mm, 3 μm; guard cartridge system, security guard #KJ 0-4282; Phenomenex, USA). The column was maintained at 25°C with 100% methanol (A) and HPLC water (B) containing 0.04% trifluoroacetic acid at a flow rate of 1.0 mL/min, and the sample was sampled at 15% for the first 5 minutes. After flowing methanol, the methanol concentration was sequentially increased from 15% to 100% from 5 minutes to 20 minutes, maintained at 100% methanol for 20 minutes to 25 minutes, and from 100% to 15% from 25 minutes to 35 minutes The methanol concentration was decreased until , and after that, it was measured while maintaining 15% methanol for 5 minutes (Table 1).

As a result of performing HPLC to analyze the component converted by LN180020 in the leuconostok genus, the indicator substance decreased near the retention time of the fermented peony extract at about 15 minutes ( FIG. 2 ), and corresponds to a new useful component at about 14.2 minutes It was confirmed that the peak to be increased. In addition, in order to confirm the reduced indicator substances and new useful components, each corresponding peak was analyzed by thin layer chromatography using silica gel 60G F254 glass plate in the developing solvent methanol:chloroform (1.5:5). As a result of separation and purification and LC-MS analysis, it was found that the indicator material at about 15 minutes was paeoniflorin with a molecular weight of 480.3, and after conversion at about 14.2 minutes, the new useful component material had a molecular weight of 642.3. was confirmed (FIG. 3).

The structure of the new useful ingredient in which the paoniflorin was converted was identified by Proton, Carbon, TOCSY, HSQC, and HMBC NMR, and the results are shown in FIG. 8 . As a result of structural identification, the material produced by bioconversion of paoniflorin was identified as β-gentiobiosyl paeoniflorin ( FIG. 4 ).

Example 3: Confirmation of efficacy in improving obesity, diabetes, dyslipidemia and fatty liver of β-gentiobiosyl paoniflorin in an animal model administered with a high-fat diet

C57BL/6, 8-week-old, male mice were divided into 10 mice in each group as follows to form an experimental group, and a diet and each test substance were administered for a total of 6 weeks:

1) Normal diet

2) High-fat diet

3) High fat diet + metformin (Met) 100mg/kg/day administration group

4) High-fat diet + Paoniflorin (PF) 100mg/kg/day administration group

5) High-fat diet + β-gentiobiosil paoniflorin (βGPF) 100mg/kg/day administration group

After the end of the experiment, blood was collected from each experimental group, and body weight, HbA1c, fasting blood sugar, HOMA-IR, total blood cholesterol (TC), triglyceride (TG), LDL, HDL, NEFA (non-esterified fatty acids), AST and ALT was measured.

The results for this are shown in FIGS. 5 and 6 .

As can be seen in FIGS. 5 and 6 , body weight, HbA1c, fasting blood glucose, HOMA-IR, TC, TG, LDL, AST and ALT levels were higher in the β-gentiobiosil paoniflorin administration group than in the high fat diet administration group. It was significantly decreased compared to that, and it was confirmed that the HDL level was significantly increased. It was confirmed that the effect of the β-gentiobiosil paoniflorin administration group was significantly higher than that of paoniflorin.

Formulation Example 1: Preparation of a pharmaceutical formulation

1. Preparation of powder

2 g of β-gentiobiosyl paoniflorin

1 g lactose

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

2. Preparation of tablets

β-gentiobiosyl paoniflorin 100 mg

Corn Starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above ingredients, tablets were prepared by tableting according to a conventional manufacturing method of tablets.

3. Preparation of capsules

β-gentiobiosyl paoniflorin 100 mg

Corn Starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above ingredients, the capsules were prepared by filling in gelatin capsules according to a conventional manufacturing method of capsules.

4. Preparation of pills

1 g of β-gentiobiosyl paoniflorin

1.5 g lactose

1 g of glycerin

0.5 g of xylitol

After mixing the above components, it was prepared so as to be 4 g per ring according to a conventional method.

5. Preparation of granules

β-gentiobiosyl paoniflorin 150 mg

Soybean extract 50 mg

glucose 200 mg

Starch 600 mg

After mixing the above components, 100 mg of 30% ethanol was added and dried at 60° C. to form granules, and then filled in a bag.

The composition of the present invention comprising β-gentiobiosyl paoniflorin as an active ingredient increases glucose absorption into muscle cells and exhibits an activity of inhibiting lipase, preventing, ameliorating or treating metabolic syndrome including diabetes and obesity. It can be very usefully used in the development of therapeutic agents, so it has very high industrial applicability.

Korea Institute of Biotechnology and Biotechnology KCTC13719BP 20181120

Claims (7)

A pharmaceutical composition for preventing or treating metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 1, wherein the metabolic syndrome is at least one selected from the group consisting of diabetes, obesity, fatty liver, dyslipidemia, arteriosclerosis, insulin resistance syndrome, and complications thereof.
The pharmaceutical composition according to claim 2, wherein the fatty liver is at least one selected from the group consisting of non-alcoholic fatty liver, alcoholic fatty liver, and non-alcoholic steatohepatitis.
The pharmaceutical composition according to claim 1, wherein the composition increases glucose uptake into muscle cells.
The pharmaceutical composition according to claim 1, wherein the composition inhibits the activity of lipase.
According to claim 1, wherein the β- gentiobiosyl paoniflorin is Leuconostoc sp. LN180020 strain (Accession No.: KCTC13719BP) characterized in that produced by bioconversion of paoniflorin pharmaceutical composition.
A food composition for preventing or improving metabolic syndrome comprising β-gentiobiosyl paeoniflorin or a pharmaceutically acceptable salt thereof as an active ingredient.

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