WO2016124080A1

WO2016124080A1 - Use of 20(r)-ginsenoside rg3 in preparation of drug for preventing or/and treating obesity and drug

Info

Publication number: WO2016124080A1
Application number: PCT/CN2016/071569
Authority: WO
Inventors: 富力; 惠敏; 王凯乾; 刘正贤; 鲁明明; 盖鑫; 柳洋; 鲁岐; 刘国友; 王硕; 樊宏宇
Original assignee: 富力
Priority date: 2015-02-06
Filing date: 2016-01-21
Publication date: 2016-08-11
Also published as: CN105982905A

Abstract

Provided is a use of 20(R)-ginsenoside Rg3 in the preparation of a drug or health food for preventing or/and treating obesity. Experiments have proven that 20(R)-ginsenoside Rg3 has the advantages of having a remarkable effect on treating obesity and has few side effects, and can be used as the single active ingredient or in combination with other active ingredients.

Description

Application of 20(R)-ginsenoside Rg3 in preparing medicine for preventing or/and treating obesity

Technical field

The invention belongs to the field of medicine, relates to a medicine for treating obesity or health food, and particularly relates to the application of a traditional Chinese medicine ginseng extract component in preventing or/and treating obesity medicine or health food.

Background technique

Obesity is commonly known as rich disease. As people's living standards continue to improve, obesity has become more and more concerned. It can be predicted that obesity will become one of the main reasons for affecting physical health in the 21st century. Obesity is the result of a combination of genetic and environmental factors that cause excessive accumulation and/or abnormal distribution of body fat and weight gain. The World Health Organization believes that obesity is an epidemic in most developed and developing countries. At present, there are 1 billion people in the world who are overweight. Nearly 15% of adults in China are overweight and obese. It is roughly estimated that there are at least 200-300 million overweight people in the country, and at least 30-40 million people with obesity. The data shows that it is 70 million people. Obesity not only affects posture and activity, but also causes a series of changes in physiological functions. At the same time, obesity also increases the incidence of some diseases, such as coronary artery disease, cardiac arrest, arterial hypertension, peripheral vascular disease, hyperlipidemia, diabetes, gout, pulmonary insufficiency, sleep and respiratory arrest, Osteoarthritis, cholecystitis and low-resistance infection, cholelithiasis, chronic venous stasis ulcer, gastroesophageal reflux, sexual dysfunction caused by dysmenorrhea, hirsutism, infertility and urgency, frequent urination. In addition, the incidence of endometrial cancer, colon cancer, prostate cancer and breast cancer may increase in obese patients, obesity after amenorrhea can increase the risk of uterine cancer and breast cancer in obese patients. Obesity patients have excessive accumulation of liver fat, increased fatty acid synthesis in the liver, oxidative disorders, reduced decomposition, and reduced output, all of which can cause accumulation of various forms of fatty acids, mainly triglycerides in the liver. The oxidation products of these fatty acids and fatty acids can destroy the hepatocyte biofilm, resulting in cytotoxicity. Excessive triglyceride is deposited in the liver and aggregates into fat droplets, which gradually increase and can cause hepatocytes to swell; fat accumulates in the liver for a long time, affecting the liver's oxygen supply and blood supply, and its metabolism is continuously affected. These can cause inflammatory cell infiltration, degeneration and necrosis, resulting in steatohepatitis. Once the liver has fibrosis and pseudolobule formation, fatty liver is formed. Body mass index (BMI), ie weight/height (m) ² and waist circumference, are generally used clinically to determine the extent of obesity. In China, the ideal BMI value is 21kg/m ² , and the BMI value greater than 24 is obese. Excessive BMI is a major risk factor for the onset of type 2 diabetes. As the BMI increases, the likelihood of developing diabetes increases exponentially. Excluding age, the risk of diabetes in women with BMI greater than 35 increased by 93-fold and 42-fold, respectively, compared with those of the same sex with a BMI of less than 21. In addition, it is worth noting that the distribution of adipose tissue is also an important risk factor for the onset of diabetes. Even if the BMI is controlled within the normal range, if the waist circumference is greater than 102 cm, the risk of diabetes will increase by 3.5 times. Especially in elderly and obese diabetics, due to obesity, fat cell infiltration, the number of insulin receptors on the cell membrane is reduced, endogenous and exogenous insulin sensitivity is reduced, resulting in elevated blood sugar. A survey of cadres with an average age of 62 years showed that the prevalence of type 2 diabetes and fasting hyperglycemia in more than half of overweight and abdominal obesity was significantly higher than that of non-overweight and non-obese, and the rate of triglyceride increased. Also increased significantly. Most obese patients have increased oxygen consumption and increased cardiac output. The increase in blood volume in obese patients is proportional to body weight. An increase in blood volume leads to an increase in ventricular filling, and an increase in ventricular filling and cardiac output can cause changes in cardiac structure, causing eccentric hypertrophy. Studies have shown that the weight of the left ventricle is directly proportional to BMI. An increase in cardiac output combined with an increase in peripheral vascular resistance leads to the development of hypertension, which in turn leads to thickening of the ventricular wall and the development of centripetal hypertrophy. In a heart disease study called Framingham, the size of the body was directly related to congestive heart failure. In addition, due to hypertrophy of the left ventricle, the incidence of coronary heart disease and arrhythmia can be increased. Obese women with age increase after menopause, increased intra-abdominal fat content, increased risk factors for cardiovascular disease. Therefore, obesity is also associated with coronary heart disease and arrhythmias. Obesity can also cause sleep-disordered breathing. The accumulation of fat in the chest wall and abdomen affects the movement of the thoracic and diaphragm muscles. The general obesity has no obvious clinical manifestations, and for a few extremely obese people can cause ventilatory function disorders, which can Decreased arterial oxygen saturation and increased carbon dioxide saturation, as well as apnea, etc., eventually lead to persistent hypoxia and hypercapnia. Clinically known as obesity–hypoventilation syndrome, also known as piekwiekian Syndrome. In addition, obesity can also cause a series of psychological and social adaptation problems, such as inferiority, forgetfulness, mental retardation, and decreased social adaptability.

At present, the treatment of obesity mainly includes diet behavior therapy, exercise therapy, drug therapy and surgery. For most obese patients, reducing heat intake and increasing physical activity is not enough. It is often stopped after losing weight, and the weight rises rapidly, even exceeding the weight before weight loss. Select surgery (usually vertical ligature stomach) Angioplasty and gastric bypass surgery are also considered too risky to accept. Early application of drug treatment can prevent the occurrence of complications and enhance patient confidence. In view of the fact that the effectiveness of current diet pills and the safety of long-term use have not been ideal, individual treatment options should be selected according to different situations, and at the same time, weight-loss drugs must be adhered to on the basis of controlling diet and exercise. There are two main types of diet pills that have been developed and marketed: one is an appetite suppressant, which mainly reduces the intake of food by regulating the feeding center of the hypothalamus to reduce the intake of food, such as fenfluramine ( Fenfluramine) and sibutramine. Because the food contains a lot The essential nutrients of other organisms, long-term fasting will have very serious consequences for the body, plus the damage of heart valves caused by fenfluramine and dexfenfluramine, the drug has been banned by the FDA in 1997. Sibutramine is also very limited in its application due to adverse reactions such as dry mouth, headache, palpitations, and elevated blood pressure. Second, lipid absorption inhibitors, such as Orlistat, reduce the absorption of lipids in the intestine by inhibiting the intestinal lipase. Long-term use can cause the lack of fat-soluble vitamins in the body, and Colon cancer is dangerous, and American consumer organizations are asking Orlistat to withdraw from the market.

As a main active ingredient of ginseng, ginseng saponin is widely used and used as ginseng. Among them, 20(R)-ginsenoside Rg3 is the most attractive ingredient. It is the main active ingredient of ginseng and has good safety. The anti-tumor oral preparation is prepared for clinical use and is intensively studied as an injection.

The inventors used advanced separation and purification technology to extract 20(R)-ginsenoside Rg3, an active ingredient for treating obesity, from ginseng herbs, and can provide a highly effective and low-toxic drug for obesity patients.

Summary of the invention

The primary object of the present invention is to provide a new application of 20(R)-ginsenoside Rg3 for preventing or/and treating obesity diseases, and to provide 20(R)-ginsenoside Rg3, in view of the technical problems existing in the treatment and treatment of obesity. Therapeutic properties and efficacy of obesity, a new application in the treatment, conditioning and alleviation of obesity disorders or health foods.

In order to achieve the above object, an aspect of the present invention provides an application of 20(R)-ginsenoside Rg3 in the preparation of a medicament or a health care product for preventing or/and treating obesity.

In the process of screening natural active ingredients having an effect of preventing or/and treating obesity, the inventors have found that 20(R)-ginsenoside Rg3 in the chemical composition of ginseng has a strong inhibitory effect on obesity.

Wherein the drug consists of 20(R)-ginsenoside Rg3 and a pharmaceutically acceptable carrier.

Wherein the 20(R)-ginsenoside Rg3 content is ≥1%, preferably ≥30%, further preferably ≥60%, still more preferably ≥80%, still more preferably ≥98%.

In particular, the 20(R)-ginsenoside Rg3 content is from 1% to 98%; preferably from 30% to 80%, more preferably 60%.

In particular, pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent. A compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and P. J. Weller. Edited by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994).

In particular, the carrier comprises an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; and a binder, Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavoring agents, spices, etc.;

Wherein the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, a gel, a cream, a cataplasm, a rubber plaster. Or in the form of a plaster.

In particular, the 20(R)-ginsenoside Rg3 content is ≥1%, preferably ≥30%, further preferably ≥60%, still more preferably ≥80%, still more preferably ≥98%.

Another aspect of the present invention provides a medicament or health care product comprising 20(R)-ginsenoside Rg3 for preventing or/and treating an obesity disease.

In particular, the 20(R)-ginsenoside Rg3 content is ≥1%, preferably 1% to 98%; preferably 30% to 80%, and still more preferably 60%.

In particular, the ratio of the weight of the 20(R)-ginsenoside Rg3 to the total weight of the drug or health care product is from 0.01 to 10:100, preferably from 0.1 to 10:100, further preferably from 1 to 10:100. .

In particular, the medicine or health care product further includes raw rhubarb extract, glutinous rice extract, Polygonum cuspidatum extract, Atractylodes lancea extract, Alisma orientalis extract, Cassia extract, Senna leaf extract, Coix seed extract One or more of the substance, the raw hawthorn extract, the Ligustrum lucidum extract, the hawthorn extract, the hazelnut extract, the chrysanthemum extract soy protein powder, and the soybean phospholipid.

The medicament can be prepared into various dosage forms by methods well known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, injections, sprays, aerosols, gels. , cream, cataplasm, rubber plaster or plaster.

The present invention also provides a method of treating an obesity disease comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of 20(R)-ginsenoside Rg3, the therapeutically effective amount of which is 0.06 to 12 mg/kg.d, It is preferably 1 to 6 mg/kg.d, and more preferably 1.5 to 3 mg/kg.d.

The term "therapeutically effective amount" as used herein, unless otherwise indicated, is intended to mean a medicament which is required to produce an effective effect. "Therapeutically effective amount" is adjustable and variable, and is ultimately determined by the medical staff. The factors considered include the route of administration and the nature of the formulation, the recipient's weight, age, etc., and the nature of the disease being treated and severity.

Compared with the prior art, the present invention has the following distinct advantages:

1. The present invention excavates a new medicinal value for the known compound 20(R)-ginsenoside Rg3, which is used for alleviating and treating obesity, and can be prepared into a medicament for preventing or/and treating obesity or Health foods have opened up a new field for the application of ginseng herbs.

2. A series of experimental studies of the present invention demonstrate that 20(R)-ginsenoside Rg3 has significant efficacy in preventing and treating obesity.

3. The 20(R)-ginsenoside Rg3 of the invention has strong pharmacological action, has remarkable effects for preventing, regulating and treating obesity, has quick effect, small toxic and side effects, good safety, can be taken for a long time, and has good medicinal use. prospect.

4. The raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.

5. The present invention can prepare a medicament for preventing and treating obesity by using a single component of 20(R)-ginsenoside Rg3 active ingredient, and can also use 20(R)-ginsenoside Rg3 and other active ingredients (for example, Rhubarb extract, glutinous rice extract, Polygonum cuspidatum extract, Atractylodes lancea extract, Alisma orientalis extract, Cassia extract, Senna leaf extract, Coix seed extract, Raw hawthorn extract, Ligustrum lucidum extract, A compound medicine for treating obesity is prepared by co-preparing a combination of hawthorn extract, hazelnut extract, chrysanthemum extract soy protein powder, and soybean phospholipid.

Detailed ways

The beneficial effects of the formulations of the present invention are further described below by way of specific examples, which are merely exemplary and not limiting as to the scope of the invention. It should be understood that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the invention, and such modifications and substitutions fall within the scope of the present invention.

Example 1 Rg3 tablet

Rg3 tablets were prepared according to the following ratios:

After ginsenoside Rg3 and starch were uniformly mixed, granules were prepared, and talc powder and magnesium stearate were added and uniformly mixed, and then pressed into 10,000 tablets.

Example 2 Rg3 granules

Rg3 granules were prepared according to the following ratio:

Ginsenoside Rg3 (content 63%) 200g

Microcrystalline cellulose 1000g

The ginsenoside Rg3 and the microcrystalline cellulose were uniformly mixed, and then granulated into bags to prepare 10,000 bags.

Example 3 Rg3 capsule

Rg3 capsules were prepared according to the following ratios:

Ginsenoside Rg3 (content 98%) 10g

Starch 1000g

The ginsenoside Rg3 and the starch were uniformly mixed and then encapsulated to prepare 10,000 tablets.

Example 4 Rg3 tablets

Rg3 tablets were prepared according to the following ratios:

The ginsenoside Rg3, the rhubarb extract, the raw hawthorn extract and the starch were uniformly mixed and granulated, and talc powder and magnesium stearate were added and mixed, and then pressed into 10,000 tablets.

Example 5 Rg3 capsule

Rg3 capsules were prepared according to the following ratios:

Ginsenoside Rg3 (content 63%) 30g

Atractylodes Rhizome Extract 30g

Starch 1000g

The ginsenoside Rg3, the Atractylodes macrocephala extract and the starch were uniformly mixed and then encapsulated to prepare 10,000 tablets.

Example 6 Rg3 granules

Rg3 granules were prepared according to the following ratio:

The ginsenoside Rg3, the hazelnut extract, the scorpion scorpion extract, the soybean phospholipid and the soy protein powder were mixed and granulated, and then bagged to prepare 10,000 bags.

Experimental Study on the Treatment of Obesity in Rats by Test Example 120(R)-Ginsenoside Rg3

1 experimental material

1.1 drugs and reagents

Ginsenoside Rg3 (content >98%), Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20120303; ginsenoside Rg3 standard provided by China National Institute for the Control of Pharmaceutical and Biological Products, and HPLC calibration, the content is 98.2%;

Positive control drug:

Orlistat Capsule, Chongqing Huasen Pharmaceutical Co., Ltd., batch number: 2011-1002;

Sodium pentobarbital, Shanghai Chemical Reagent Purchasing and Supply Station, sub-package, imported batch, batch number: 120112; used in 0.4% aqueous solution.

1.2 animals

Wistar rats, weighing 200±20g, both male and female, were purchased from the Experimental Animal Center of Dalian Medical University, and the quality certificate number was SCXK(13)2002-0002.

1.3 Animal feed

The common feed was purchased from the Experimental Animal Center of Dalian Medical University. The common feeds were as follows: flour 19% corn flour 23% sorghum flour 6% bran 10% soybean meal 15% vegetable oil 2% cod liver oil 1% fish meal 10% bone meal 1% beer yeast 1% salt 1% starch 6.6% glycine 3.4% methionine 0.5% calcium carbonate 0.5%.

High-fat and high-salt feed, such as: ordinary feed 100g, cooked lard 10g, whole milk powder 10g, 1 egg, 10 drops of cod liver oil, fresh soybean sprouts 250g, salt 2.5%. The fresh soybean sprouts are dried, crushed and mixed with the common feed in proportion. The mixed feed is weighed daily and added to the eggs, milk powder, cod liver oil, salt and water to mix and knead the strips for use.

1.4 Instrument

2 experimental methods

2.1 grouping and administration

The rats were weighed and randomly divided into 6 groups, 10 in each group, which were blank control group, model control group, positive drug control group, ginsenoside Rg3 high, medium and low dose groups. The blank control group was given pure water by intragastric administration at 0.lml/10g after the start of the experiment; the model control group was given the same volume of purified water by intragastric administration of 0.1 ml/g; the positive drug control group was given orlistat 10 mg/kg by gavage. Ginsenoside Rg3 was administered intragastrically at a high, medium and low dose group of ginsenoside Rg3 at 6 mg/kg, 3 mg/kg, 1.5 mg/kg, once a day.

2.2 Modeling method

Except for the blank control group, the other groups were given self-made high-fat and high-salt feed, and the feeding and drinking water were not restricted. The experiment was 6 weeks.

2.3 Observation indicators

(1) general conditions; food intake, water consumption, activity, feces, etc.;

(2) body weight (g), body length (cm), Lee index = [W/H ² ] (where W is rat body weight; H is rat body length), abdominal circumference (cm);

(3) Heart wet weight (g), liver wet weight (g).

2.4 Observation method

The food intake, the amount of water consumed, and the general state of the rats were observed every day. Rats were weighed weekly with electronic weight (w), and the rat abdominal circumference was measured with a soft ruler around the upper edge of the rat femur. After fasting for 12 hours at the end of the sixth week, pentobarbital was used. Sodium 0.lml/10g intraperitoneal injection anesthesia, bound to the homemade wooden board, with a soft ruler to measure the length of the nose to the anus, measured body length (H); then open the abdominal cavity, dial away from the abdominal aorta, blood collection of abdominal aorta, The serum was centrifuged at 2,500 rpm for 10 minutes, and the serum was pipetted into a cannonball tube and stored in a -20 ° C refrigerator for storage; then the rat heart and liver were picked and the wet weight was weighed with a tissue balance. .

3 test results

3.1 General condition observation of test rats and changes in diet and drinking water

During the experiment, the mental state of the rats was not abnormal. The model control group was lazy, the hair was fluffy, not active, sometimes loose, and the rats in the other administration groups were active. No hair removal, dullness, runny, feces. Abnormal reactions such as morphological changes. There was no difference in the food intake and drinking water between the treatment groups and the model control group during the experiment, which was not statistically significant (P>0.05), but the food intake and water consumption of the high-fat diet groups were slightly higher than those of the normal diet group.

3.2 Effects of ginsenoside Rg3 on body weight, body length and Lee index in rats

Table 1 shows the effect of 20(R)-ginsenoside Rg3 on the growth state of rats. The results of measuring body weight, body length and Lee index of rats are shown in Table 1.

Table 1 Changes in rat growth status (

n=10)

Note: Compared with the model group, *P<0.05**P<0.01***P<0.00, and the blank control group △P<0.01△△P<0.001.

It can be seen from Table 1 that the body weight of the model group is different from that of the normal group (P<0.01). The Lee index of the model group and the Lee index of the normal group are different (P<0.001), suggesting that the rats The obesity model was successful; the weight of rats in the high dose group of ginsenoside Rg3 was different from that in the model group (P<0.001); the high dose group There was a difference in the Lee index between the Rat Lee index and the model group (P<0.001). The Lee index of the ginsenoside Rg3 middle dose group and the model group were different (P<0.01); the ginsenoside Rg3 was low. The Lee index of the rats in the dose group and the Lee index in the model group were different (P<0.05), suggesting that the high, medium and low doses of 20(R)-ginsenoside Rg3 can significantly reduce the body weight of the rats, reduce the Lee index, and have weight loss. Role, because there is no difference in body length of each group, suggesting that 20(R)-ginsenoside Rg3 does not affect the growth of animals.

3.3 Effects of ginsenoside Rg3 on visceral wet weight of rats

The effect of 20(R)-ginsenoside Rg3 on the visceral wet weight of rats is shown in Table 2.

Table 2 Changes in visceral wet weight of rats

Note: Compared with the model group *P<0.05**P<0.01 compared with the blank control group △P<0.05

As can be seen from Table 2, the heart, liver and normal groups of the model group were different (P<0.05), suggesting that high-fat diet increased the risk of visceral disease in obese rats; ginsenoside Rg3 high-dose group had large liver and model group There was a difference in rat liver (P<0.01), suggesting that 20(R)-ginsenoside Rg3 can reduce liver wet weight, improve visceral fat metabolism disorder, and has the effect of losing weight. It can be used to treat obesity.

Claims

20(R)-Ginsenoside Rg3 is used in the preparation of a medicament or a health care product for preventing or/and treating obesity.
The use according to claim 1, wherein the drug consists of 20(R)-ginsenoside Rg3 and a pharmaceutically acceptable carrier.
The use according to claim 1 or 2, wherein the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, or a gel. In the form of a lotion, cream, cataplasm, rubber plaster or plaster.
The use according to claim 1 or 2, characterized in that the content of the 20(R)-ginsenoside Rg3 is ≥1%.
The use according to Claim 4, characterized in that the content of 20(R)-ginsenoside Rg3 is from 1% to 98%.
A medicament or health care product for preventing or/and treating obesity characterized by containing 20(R)-ginsenoside Rg3.
The pharmaceutical or nutraceutical according to claim 6, wherein the ratio of the weight of the 20(R)-ginsenoside Rg3 to the total weight of the drug or health care product is from 0.01 to 10:100.
The pharmaceutical or nutraceutical according to claim 6, wherein the content of 20(R)-ginsenoside Rg3 is ≥1%.
The pharmaceutical or nutraceutical according to claim 8, wherein the 20(R)-ginsenoside Rg3 is contained in an amount of from 1% to 98%.
The medicine or health care product according to claim 6, which further comprises raw rhubarb extract, glutinous rice extract Extract, Polygonum cuspidatum extract, Atractylodes lancea extract, Alisma orientalis extract, Cassia extract, Senna leaf extract, Coix seed extract, Raw hawthorn extract, Ligustrum lucidum extract, Hawthorn extract, Gardenia One or more of an extract, a chrysanthemum extract, a soy protein powder, and a soybean phospholipid.