阅读说明：本技术 一种治疗非酒精性脂肪肝的组合物及用途 (Composition for treating non-alcoholic fatty liver disease and application ) 是由 袁中文 冯森玲 严鹏科 于 2020-05-22 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及一种治疗非酒精性脂肪肝的组合物及用途。本发明提供的治疗非酒精性脂肪肝的组合物,包括以下组分及其重量百分数：50-80％的青钱柳总黄酮、20-50％的川陈皮素。本发明提供的治疗非酒精性脂肪肝的组合物,首创性的将青钱柳总黄酮与川陈皮素结合使用,具有降低转氨酶,降血脂,降血糖,降低脂质过氧化,调节胰岛素抵抗等作用,提高单独使用青钱柳黄酮时治疗非酒精性脂肪肝的效果,可以有效用于制备防治非酒精性脂肪肝药物,为实现健康中国提供了极大的助力。(The invention belongs to the technical field of medicines, and particularly relates to a composition for treating non-alcoholic fatty liver disease and application thereof. The composition for treating the non-alcoholic fatty liver disease comprises the following components in percentage by weight: 50-80% of cyclocarya paliurus total flavone, and 20-50% of nobiletin. The composition for treating the non-alcoholic fatty liver disease provided by the invention is used by combining cyclocarya paliurus total flavonoids with nobiletin for the first time, has the effects of reducing transaminase, reducing blood fat, reducing blood sugar, reducing lipid peroxidation, regulating insulin resistance and the like, improves the effect of treating the non-alcoholic fatty liver disease when the cyclocarya paliurus flavonoids are used alone, can be effectively used for preparing a medicine for preventing and treating the non-alcoholic fatty liver disease, and provides great assistance for realizing healthy China.)

1. The composition for treating the non-alcoholic fatty liver disease is characterized by comprising the following components in percentage by weight: 50-80% of cyclocarya paliurus total flavone, and 20-50% of nobiletin.

2. The composition for treating non-alcoholic fatty liver disease according to claim 1, which comprises the following components in percentage by weight: 75% of cyclocarya paliurus total flavonoids and 25% of nobiletin.

3. The composition for treating non-alcoholic fatty liver disease as set forth in claim 1 or 2, wherein the preparation method of total flavonoids of cyclocarya paliurus comprises the steps of:

a. taking dried leaves of cyclocarya paliurus, crushing, sieving with a 40-50-mesh sieve to obtain cyclocarya paliurus coarse powder, soaking the cyclocarya paliurus coarse powder in 90% ethanol water solution for 0.5h, heating and refluxing for 2h, extracting for 2 times, combining extracting solutions, filtering, concentrating under reduced pressure until no alcohol smell exists, extracting for 3 times with petroleum ether, removing the petroleum ether layer, extracting water phase with ethyl acetate for 3 times, combining ethyl acetate extracting solutions, concentrating under reduced pressure and drying to obtain extract dry paste;

b. b, preparing the extract dry paste obtained in the step a into suspension with the mass concentration of 1mg/mL by using ultrapure water, adding the suspension into a D101 macroporous resin column, eluting by using ultrapure water to remove impurities, eluting by using 80% ethanol water solution to obtain cyclocarya paliurus total flavone eluent, and further concentrating the cyclocarya paliurus total flavone eluent under reduced pressure and freeze-drying to obtain the cyclocarya paliurus total flavone eluent.

4. Use of the composition for treating non-alcoholic fatty liver disease according to any one of claims 1 to 3 in the preparation of a medicament for treating non-alcoholic fatty liver disease.

5. A pharmaceutical preparation for treating non-alcoholic fatty liver disease, comprising the composition for treating non-alcoholic fatty liver disease according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

6. The pharmaceutical preparation for treating non-alcoholic fatty liver disease according to claim 5, wherein the dosage form of the pharmaceutical preparation comprises granules, tablets, pellets and capsules.

7. The pharmaceutical preparation for treating non-alcoholic fatty liver disease according to claim 5, wherein the pharmaceutically acceptable excipients are one or more of starch, dextrin, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, magnesium stearate and aerosil.

8. The pharmaceutical preparation for treating non-alcoholic fatty liver disease according to claim 5, wherein the composition for treating non-alcoholic fatty liver disease is added in an amount of 30 to 80 parts by weight based on 100 parts by weight of the pharmaceutical preparation.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a composition for treating non-alcoholic fatty liver disease and application thereof.

Background

The WHO recent data showed that 39% of adults 18 years old and older (19 billion people) were overweight and 13% were obese (6.5 billion people) and that over 3.4 billion children 5-19 years old and adolescents were overweight or obese worldwide in 2016. The statistical data in China shows that in 2015, the overweight rate of adults aged 18 years and older in the country is 30.1%, the obesity rate is 11.9%, the overweight rate of teenagers aged 6-17 years is 9.6%, and the obesity rate is 6.4%. An increase in body mass index is a major risk factor for the development of non-infectious diseases such as cardiovascular diseases, diabetes, tumors, etc., and weight management is becoming a major concern of society.

Non-alcoholic fatty liver disease (NAFLD) refers to a type of chronic hepatitis with pathological changes of liver tissues similar to alcoholic hepatitis but without clear drinking history, is derived from excessive accumulation of liver fat related to Insulin Resistance (IR), has the characteristics of hepatocyte degeneration, necrosis, inflammation infiltration and the like, and can further develop into non-alcoholic fatty hepatitis, liver cirrhosis and liver cancer. Epidemiological survey shows that the incidence rate of NAFLD in China is about 15%, the incidence rate of NAFLD in Europe and America is more than 20%, and obesity (especially central obesity) is an important risk factor for the occurrence of NAFLD. The prevalence of NAFLD was found to be 16.4% when the body mass index BMI < 25; when BMI is more than 30, the prevalence rate of NAFLD is 75.8%; while the prevalence of NAFLD in morbid obesity (BMI > 40) is as high as 96%. Screening of effective drugs based on the pathogenesis of obesity and NAFLD is the focus of current research, focusing on insulin sensitizers, antioxidants, lipid lowering drugs, etc.

Cyclocarya paliurus (Batal) Iljinskaja is a folium arbor of cyclocarya of Juglandaceae, and has sweet leaf taste, and has effects of promoting fluid production, clearing heat, lowering blood pressure, lowering blood sugar, reducing blood lipid, and prolonging life. The cyclocarya paliurus leaves and barks recorded in the Chinese traditional medicine resource Zhi Yao have the functions of clearing heat, reducing swelling and relieving pain. Cyclocarya paliurus leaves mainly contain chemical components such as polysaccharide, flavone and triterpenes. The research on the pharmacological activity shows that: the polysaccharide in the cyclocarya paliurus has pharmacological activities of reducing blood sugar, reducing blood fat, resisting lipid peroxidation and the like; the flavone can inhibit the activity of alpha-glucosidase and has strong ability of scavenging free radicals. However, the oral bioavailability of flavonoids in cyclocarya paliurus is low due to the low solubility of the flavonoids, which is usually a substrate of a transport protein and other factors, and the key problem of restricting the clinical application of flavonoids is solved. Therefore, the research on the treatment of the non-alcoholic fatty liver disease by the total flavonoids of cyclocarya paliurus is not sufficient at present, and the total flavonoids of cyclocarya paliurus are not developed in the fields of medicine and health care.

Therefore, the development of a composition for treating non-alcoholic fatty liver disease by using total flavonoids of cyclocarya paliurus as main raw materials is urgently needed, which can effectively promote the absorption of flavonoids in vivo to improve the bioavailability of the flavonoids, and improve the activity of the total flavonoids of cyclocarya paliurus for treating non-alcoholic fatty liver disease.

Disclosure of Invention

In order to solve the problems in the prior art, the invention aims to provide a composition prepared by compounding cyclocarya paliurus total flavonoids serving as main raw materials with nobiletin, so as to improve the activity of the cyclocarya paliurus flavonoids in treating non-alcoholic fatty liver.

The technical scheme of the invention is as follows:

a composition for treating non-alcoholic fatty liver disease comprises the following components by weight percent: 50-80% of cyclocarya paliurus total flavone, and 20-50% of nobiletin.

Further, the composition for treating the non-alcoholic fatty liver disease comprises the following components in percentage by weight: 75% of cyclocarya paliurus total flavonoids and 25% of nobiletin.

Furthermore, the preparation method of the total flavonoids of cyclocarya paliurus comprises the following steps:

a. taking dried leaves of cyclocarya paliurus, crushing, sieving with a 40-50-mesh sieve to obtain cyclocarya paliurus coarse powder, soaking the cyclocarya paliurus coarse powder in 90% ethanol water solution for 0.5h, heating and refluxing for 2h, extracting for 2 times, combining extracting solutions, filtering, concentrating under reduced pressure until no alcohol smell exists, extracting for 3 times with petroleum ether, removing the petroleum ether layer, extracting water phase with ethyl acetate for 3 times, combining ethyl acetate extracting solutions, concentrating under reduced pressure and drying to obtain extract dry paste;

b. b, preparing the extract dry paste obtained in the step a into suspension with the mass concentration of 1mg/mL by using ultrapure water, adding the suspension into a D101 macroporous resin column, eluting by using ultrapure water to remove impurities, eluting by using 80% ethanol water solution to obtain cyclocarya paliurus total flavone eluent, and further concentrating the cyclocarya paliurus total flavone eluent under reduced pressure and freeze-drying to obtain the cyclocarya paliurus total flavone eluent.

Furthermore, the total flavone of cyclocarya paliurus contains one or more of quercetin, kaempferol-3-O-rhamnoside, quercetin-7-O-glucoside, quercetin-3-O-rhamnoside, kaempferol-4' -O-glucoside, kaempferol-7-O-glucoside, quercetin-3-O-glucoside and quercetin-3-O-glucuronide through LC-MS analysis.

The composition for treating the non-alcoholic fatty liver disease can be used for preparing a medicine for treating the non-alcoholic fatty liver disease.

In addition, the invention also provides a pharmaceutical preparation for treating the non-alcoholic fatty liver disease, which comprises the composition for treating the non-alcoholic fatty liver disease and pharmaceutically acceptable auxiliary materials.

Furthermore, the dosage form of the pharmaceutical preparation comprises granules, tablets, micro-pills and capsules.

Further, the dosage form of the pharmaceutical preparation is a capsule.

Further, the pharmaceutically acceptable auxiliary materials are one or more of starch, dextrin, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, magnesium stearate and aerosil.

Further, the pharmaceutical preparation for treating the non-alcoholic fatty liver disease is characterized in that the composition for treating the non-alcoholic fatty liver disease is added in an amount of 30-80 parts by weight based on 100 parts by weight of the pharmaceutical preparation.

In addition, the invention also provides a preparation method of the capsule for treating the non-alcoholic fatty liver disease, which comprises the following steps:

30-80 parts by weight of the composition for treating the non-alcoholic fatty liver disease, 10-20 parts by weight of microcrystalline cellulose, 2-10 parts by weight of sodium carboxymethyl starch and 0.2-2 parts by weight of superfine silica gel powder are uniformly mixed and filled into capsules, and each capsule weighs 0.3-0.8 g.

In the composition for treating the non-alcoholic fatty liver disease, the cyclocarya paliurus total flavonoids are extracts of cyclocarya paliurus. Cyclocarya paliurus (Batal) Iljinskaja is tree of cyclocarya of Juglandaceae, and has effects of promoting fluid production, clearing heat, lowering blood pressure, reducing blood sugar, reducing blood lipid, and prolonging life. Cyclocarya paliurus leaves mainly contain chemical components such as polysaccharide, flavone and triterpenes. The research on the pharmacological activity shows that: the polysaccharide in the cyclocarya paliurus has pharmacological activities of reducing blood sugar, reducing blood fat, resisting lipid peroxidation and the like; the flavone can inhibit the activity of alpha-glucosidase and has strong ability of scavenging free radicals. However, in the prior art, the oral bioavailability of the flavonoids in cyclocarya paliurus is low due to the low solubility of the flavonoids, which is usually a substrate of a transport protein and other factors, which is a key problem for restricting the clinical application of the flavonoids.

Nobiletin (Nobiletin) is mainly extracted from traditional Chinese medicine dried orange peel, belongs to polymethoxylated flavonoids, has the effects of resisting inflammation, resisting oxidation, nourishing nerves, protecting liver and the like, and has research findings that Nobiletin realizes the protective effect of liver cells mainly by inhibiting the up-regulation of lncLSTR in liver, further inhibiting the down-regulation of liver Apoc2 and increasing the clearance rate of liver triglyceride. The nobiletin is an inhibitor of P-glycoprotein, multidrug resistance protein and the like, and can remarkably improve the transmembrane transport rate of related transport protein substrates, thereby improving the oral bioavailability of the substances. The inventor of the application finds that the cooperation of the nobiletin and the total flavonoids of the cyclocarya paliurus can better promote the in-vivo absorption of the effective components of the flavonoids and improve the bioavailability to a greater extent. Therefore, the cyclocarya paliurus total flavonoids are matched with the nobiletin, so that the effects of reducing fat, reducing weight and treating non-alcoholic steatohepatitis can be better exerted, and the cyclocarya paliurus total flavonoids have good application value and development prospect.

Compared with the prior art, the composition for treating the non-alcoholic fatty liver disease provided by the invention has the following advantages:

the inventive composition for treating non-alcoholic fatty liver disease combines the original cyclocarya paliurus total flavonoids with nobiletin, has the effects of reducing transaminase, reducing blood fat, reducing blood sugar, reducing lipid peroxidation, regulating insulin resistance and the like, improves the effect of treating non-alcoholic fatty liver disease when cyclocarya paliurus flavonoids are used alone, can be effectively used for preparing medicines for preventing and treating non-alcoholic fatty liver disease, and provides great assistance for realizing healthy China.

Drawings

FIG. 1 shows the effect of total flavones of cyclocarya paliurus and nobiletin on glucose consumption of insulin resistant HepG2 cells;

FIG. 2 shows the effect of total flavones and nobiletin on DPPH clearance;

FIG. 3 shows the effect of compounding total flavones of cyclocarya paliurus with nobiletin on the body weight, organ index and fat content of a NAFLD model mouse;

FIG. 4 shows the effect of cyclocarya paliurus total flavonoids compounded with nobiletin on the biochemical indexes of a NAFLD model mouse;

FIG. 5 shows the effect of cyclocarya paliurus total flavonoids compounded with nobiletin on liver pathological changes of NAFLD model mice.

Detailed Description

The present invention is further illustrated by the following description of specific embodiments, which are not intended to limit the invention, and various modifications and improvements can be made by those skilled in the art based on the basic idea of the invention, but the invention is within the protection scope of the invention.