WO2016110168A1

WO2016110168A1 - Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for relief and/or treatment of diabetes and medicament

Info

Publication number: WO2016110168A1
Application number: PCT/CN2015/096991
Authority: WO
Inventors: 富力; 王凯乾; 王硕; 惠敏; 刘正贤; 鲁岐; 柳洋; 付强; 鲁明明; 冯雪; 盖鑫; 刘国友; 付文斐; 周庆丰; 郭永学
Original assignee: 富力
Priority date: 2015-01-09
Filing date: 2015-12-10
Publication date: 2016-07-14
Also published as: CN105816470A

Abstract

Applications of 20(R)-ginsenosides Rg3 in preparing a medicament or a healthcare product for relief and/or treatment of diabetic disorders. The medicament or the healthcare product for relief and/or treatment of the diabetic disorders, comprising 20(R)-ginsenosides Rg3.

Description

Application of 20(R)-ginsenoside Rg3 in the preparation of a drug or health care product for relieving or/and treating diabetes

Technical field

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

Background technique

Diabetes is a chronic disease that is a serious health hazard and is one of the major health problems facing humanity today. Diabetes can be divided into insulin-dependent diabetes mellitus (IDDM, type I) and non-insulin-dependent diabetes mellitus (NIDDM, type II). With the development of social economy and changes in people's lifestyles, the number of diabetic patients (mainly type 2 diabetes) has increased rapidly. According to statistics, 3 to 5% of diabetic patients are added every year in the world, and more than 90% of them are type 2 diabetes. The incidence of diabetes in China is about 3.21%. At present, the incidence of diabetes is on the rise in the world, especially in developing countries. The mortality rate is second only to cardiovascular and cerebrovascular diseases and cancer, and it is considered to be the third largest killer of human beings. The World Health Organization and the International Diabetes Federation will set the November 14th of each year as World Diabetes Day. Professor PAUL AIMMER, Director of the International Diabetes Institute, said: "The rapid development of diabetes may be more harmful than AIDS." It is estimated that there are about 140 million people with diabetes in the world. It is estimated that by 2025, the number of diabetic patients worldwide will reach 299 million. There are more than 40 million diabetic patients in China, and nearly 2 million are added each year. Therefore, active prevention and treatment of diabetes is imminent. Oral anti-diabetic drugs are classified according to the mechanism of action, mainly in the following categories: 1 insulin and insulin analogs; 2 insulin-promoting drugs; 3 aldose reductase inhibitors; 4 insulin sensitizers; 5 drugs for inhibiting glucose absorption, Such as α-glucosidase inhibitors. At present, the combination of drugs in the treatment of type 2 diabetes has increased the physiological and economic burden of patients. At present, oral hypoglycemic drugs for treating diabetes can temporarily control the blood sugar of patients, but it does not completely prevent the development of the disease and complications. Therefore, the development of new mechanisms of action or new types of high-efficiency and low-toxic anti-diabetic drugs has become the focus of new drug research and development in the world.

The famous medicinal materials of ginseng Chinese medicine, modern medical research shows that the main functions and effects of ginseng are: the role of the central nervous system, anti-cancer anti-tumor effect, immune function regulation, anti-diabetes effect, enhance liver function, cardiovascular and cerebrovascular disorders Improvement, anti-atherosclerosis, blood pressure regulation, and menopausal disorders And anti-osteoporosis, anti-fatigue, anti-oxidation, anti-aging and so on. As the main active ingredient of ginseng, ginsenoside is widely studied and used. Among them, 20(R)-ginsenoside Rg3 is the most attractive. It is the main active ingredient of ginseng and has good safety. It has been made into anti-tumor oral preparation. It has been used clinically and has been intensively studied as an injection.

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

Summary of the invention

The object of the present invention is to provide a 20(R)-ginsenoside Rg3 for alleviating or/and treating the performance and efficacy of a diabetic disease, and providing 20(R) for the technical problems existing in the existing drugs or health care products for treating diabetes diseases. - New medicinal use of ginsenoside Rg3, a new application in medicines or health foods for the treatment, conditioning and alleviation of diabetic conditions.

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 relieving or/and treating a diabetic disease.

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

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

The content of the 20(R)-ginsenoside Rg3 is 1% to 98%; preferably 30 to 80%, and more preferably 60%.

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

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 PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) found in the reference book.

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.

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

Wherein 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 an extract of Astragalus membranaceus, an extract of mulberry leaf, a extract of Radix Rehmanniae, an extract of psoralen, an extract of Cuscuta chinensis, an extract of Polygonum multiflorum, an extract of Polygonatum odoratum, an extract of hawthorn, One or more of Zhimu extract, Angelica extract, Coptidis Rhizoma extract, citrus extract, and pumpkin extract.

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 for treating a diabetic disease comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of 20(R)-ginsenoside Rg3, wherein the therapeutically effective amount is 0.06 to 12 mg/kg.d, preferably It is 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 the amount of the agent in need of an effective effect; the "therapeutically effective amount" is adjustable and variable, and is ultimately determined by the medical personnel, the factors considered including the route of administration. And the general nature of the formulation, the recipient's weight, age, etc., and the nature and severity of the condition being treated.

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, and uses it for mitigation. It can solve and treat diabetic diseases, and can be prepared into medicines or health foods for relieving or/and treating diabetes, thereby opening up a new field for the application of ginseng medicines.

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

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

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 relieving and treating diabetes 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, with astragalus extracting) Extract, mulberry leaf extract, Radix Rehmanniae extract, psoralen extract, Cuscuta chinensis extract, Polygonum multiflorum extract, Polygonatum extract, Hawthorn extract, Zhimu extract, Angelica extract, Coptis extract, Fructus striata extract And one or more of the pumpkin extracts are combined to prepare a compound medicine for treating diabetes.

detailed description

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 astragalus 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

Mulberry leaf extract 200g

Starch 1000g

The ginsenoside Rg3, the mulberry leaf 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:

Ginsenoside Rg3, Zhimu extract, Radix Rehmanniae extract and pumpkin powder were mixed and granulated, and then bagged to prepare 10,000 bags.

Test Example 1 Experimental study on the effect of 20(R)-ginsenoside Rg3 on blood glucose in diabetic rats

1 experimental material

1.1 drugs and reagents

Ginsenoside Rg3 (content >98%), produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 2012303; 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: metformin hydrochloride tablets, Sino-US Shanghai Squibb Pharmaceutical Co., Ltd., batch number: 2011-0412;

Streptozotocin: sigma company, batch number: 2010-0201.

1.2 animals

Wistar rats, weighing 180±20g, were purchased from Experimental Animal Center of Dalian Medical University, and the quality certificate number was SCXK(13)2012-0002.

2 experimental methods

2.1 grouping high blood sugar model

Twenty qualified rats were selected and divided into 4 groups (normal control group, streptozotocin model group, Rg3 group, positive drug control group). Among them, streptozotocin model group, Rg3 group and positive drug control group were large. The rats were injected with streptozotocin 65 mg/kg 3 days before the start of the experiment.

Group 1 was the normal control group, and group 2, 3, and 4 were the streptozotocin treatment model group, and the same amount of pure water was forcibly administered orally.

2.2 administration

The rats in the normal control group were orally administered with the same amount of purified water; the rats in the model group treated with streptozotocin were given orally with the same amount of purified water; 0.5 mL/time, 8:00 am, 12:00, and 16:00, a total of 3 times. Rats in Rg3 group were orally administered with ginsenoside Rg3 (10 mg/mL), 0.5 mL/time, 3 times in the morning, in the middle and in the evening for 14 consecutive days. The rats in the positive drug control group were orally administered with the positive control drug metformin hydrochloride. Tablets (10 mg/mL), 0.5 mL/time, 3 times in the morning, in the middle and the evening, for 14 consecutive days.

Feed and water were freely ingested during the experiment. Blood glucose was measured in each group of animals at 0 days (before administration), 7 days, and 14 days after administration. At 10:00 am each time, blood was collected from the tail vein of the rat under anesthesia without anesthesia, and the blood glucose concentration in the blood was measured.

3 test results

With SPSS11.0 processing, all data were tested for normality and homogeneity of variance. The results of blood glucose concentration determination in each group were compared by one-way analysis of variance. The SNK-q test was used to compare the two groups. The test level was α=0.05. The results are shown in Table 1.

Table 1 Effect of ginsenoside Rg3 on blood glucose in rats (mg/dL) (x±s, n=5)

Note: Compare #P<0.05 with the model group.

After 3 days of injection of streptozotocin in the tail vein of rats, the blood glucose concentration was significantly higher than that of the normal control group. From the test results in Table 1, it can be seen that after 7 days of continuous administration, the increase of blood glucose concentration in the ginsenoside Rg3 group is lower than that in the model group, the difference in blood glucose concentration before and after administration, the ginsenoside Rg3 group is smaller than the model group, and the ginsenoside Rg3 The difference in blood glucose between the group and the model group was increased, and this phenomenon was more pronounced after 14 days of continuous administration. With the increase in the number of days of ginsenoside Rg3 administration, the difference in blood glucose between the ginsenoside Rg3 group and the model group was more significant. The ginsenoside Rg3 dosage is stronger than the hypoglycemic effect of the commonly used hypoglycemic agent metformin. The experimental results show that ginsenoside Rg3 has a hypoglycemic effect on streptozotocin hyperglycemic rats.

Test Example 2 Experimental study on the effect of 20(R)-ginsenoside Rg3 on insulin secretion in diabetic rats

1 experimental material

1.1 drugs and reagents

Positive control drug: pioglitazone hydrochloride tablets (Austin): purchased from Beijing Taiyang Pharmaceutical Co., Ltd., specification: 15mg × 7 tablets (batch number: H20130520), remove the tablets into fine powder during the experiment, and prepare with distilled water. The solution at a concentration of 0.15 mg/ml was stored at 4 ° C and the shelf life was three days. Remove the liquid before the gavage and place it at room temperature for use.

Streptozotocin (STZ): sigma, batch number: 2010-0201.

1.2 animals

Sixty healthy male SD rats, 6 weeks old, weighing 180-200 g, were purchased from Experimental Animal Center of Dalian Medical University, and the quality certificate number was SCXK (13) 2012-0002.

2 experimental methods

2.1 Model establishment

Sixty male Sprague-Dawley rats weighing 180-200 g, one week after adaptive feeding, were randomly divided into normal control group (15 rats) and 45 model rats by random weight (computer random number method). The normal control group was given basic feed, and the model was given high-fat and high-calorie feed for 8 weeks. After 8 weeks, fasting and water-free for 12 hours, the model was given a one-time intraperitoneal injection of 2% streptozotocin (STZ) solution 25mg/Kg to establish a type 2 diabetes model with peripheral IR; the normal control group was intraperitoneally injected with the same dose. Citric acid-sodium citrate buffer. On the third day after modeling, blood samples were taken to detect fasting blood glucose and fasting blood insulin levels, and insulin sensitivity index was calculated. Animals with fasting blood glucose ≥16.7mmol/L and fasting insulin 20mu/L-40mu/L were randomly divided into pathological models. Group, RG3 treatment group and pioglitazone treatment group.

STZ solution preparation method: Weigh a certain amount of STZ, prepare a 2% concentration with 0.1 mol/L citric acid-sodium citrate buffer solution, adjust the pH value to 4.21, and operate in an ice bath. 0.1mol/L citric acid-sodium citrate buffer preparation method: 1.05 g of citric acid was weighed and dissolved in 50 ml of ionic sterile water to prepare 0.1 mol/L citric acid solution A. 1.47 g of sodium citrate was weighed and dissolved in 50 ml of ionic sterile water to prepare a 0.1 mol/L sodium citrate solution B. 36.9 ml of A solution and 23.1 ml of B solution were mixed and formulated into 60 ml of a buffer solution. The pH meter was adjusted to pH 4.21, sterilized by high temperature and high pressure (121 ° C) for 15 min, and stored at 4 ° C for use.

2.2 Feed formula

Ordinary feed (ie basic feed): (meet the general quality requirements of Chinese experimental animal compound feed (GB 14924.1), laboratory animal feed standard (GB 14924.2-2001).) The specific nutrients are:

Crude protein ≥ 18%, crude fat ≥ 5%, crude fiber ≤ 5%, coarse ash ≤ 8%; amino acid (% of feed): arginine ≥ 0.90%, lysine ≥ 0.85%, methionine ≥ 0.35%, Cystine ≥ 0.25%, tryptophan ≥ 0.20%, glycine ≥ 0.95%, histidine ≥ 0.38%, leucine ≥ 1.40%, isoleucine ≥ 0.95%, phenylalanine ≥ 0.85%, cheese Amino acid ≥ 0.60%, threonine ≥ 0.65%, valine ≥ 0.90%, mineral content: calcium ≥ 1.00%, phosphorus ≥ 0.85%, potassium ≥ 0.55%, sodium ≥ 0.25%, magnesium ≥ 0.15%, iron ≥300ppm, zinc≥40ppm, ≥140ppm, copper≥12ppm, cobalt≥0.7ppm, iodine≥1.8ppm, vitamin content: vitamin A≥17IU/g, vitamin D≥4IU/g, vitamin E≥45ppm, vitamin K≥ 2.0ppm, thiamine, B1 ≥ 15ppm, riboflavin ≥ 9ppm, niacin ≥ 70ppm, pantothenic acid ≥ 30ppm, choline ≥ 1900ppm, pyridoxine ≥ 10ppm, folic acid ≥ 2.0ppm, biotin ≥ 0.20ppm, vitamin B12 ≥0.08ppm.

High-sugar and high-fat diet formula: 2% cholesterol, 0.25% sodium citrate, 10% lard, 5% sucrose, 82.75% basic feed.

2.3 group administration

Among the 45 animals in the model group, 15 were randomly divided into RG3 treatment group, 15 positive drug control group (pioglitazone treatment group) and 15 pathological model groups according to fasting blood glucose level. Drug treatment was given for 4 weeks after grouping. Normal control group: water was administered by tap water and fed with common feed; pathological model group: gavage with tap water and high-fat and high-fat diet; RG3 treatment group: RG3 6mg/kg·d, and high glucose High-fat diet; pioglitazone treatment group: pioglitazone hydrochloride 0.3mg/kg·d was administered intragastrically, and high-sugar and high-fat diet was given at the same time.

2.4 specimen production

2.4.1 Preparation of blood samples

Blood was collected three times after feeding for 4 weeks in high-sugar and high-fat diet, 72% after intraperitoneal injection of 2% STZ, and 4 weeks after drug treatment. Fasting and water-free for 12 hours, the rats were anesthetized by intraperitoneal injection of 3.5% chloral hydrate. The blood was taken from the iliac veins. The blood was stored in a vacuum blood collection tube, and blood samples were collected as much as possible. After standing for a while, the serum and plasma were separated, and serum and plasma were separated by centrifugation at 3500 r/min for 10 minutes at 4 ° C, and serum and plasma samples were taken. The product was placed in a 1.5 ml cryotube and stored at -70 °C for testing to check blood glucose and blood insulin levels (insulin test specimens were stored within 35 days of frozen storage); statistical analysis.

2.5 detection method

2.5.1 Determination of blood glucose concentration (FBG): Detected by oxidase method and automatic biochemical analyzer.

2.5.2 Determination of blood insulin concentration (FINS): The measurement was carried out by radioimmunoassay, and the serum sample was directly determined by sequential saturation method in the competition inhibition reaction. The INS of the serum sample to be tested is assayed for pre-reaction with the antibody for a period of time, and then I ¹²⁵ -INS is added to compete for the remaining antibody binding sites. When the content of the INS in the test object is high, the remaining antibody binding sites are small, so that the I ¹²⁵ -INS bound to the antibody is less, and vice versa. The antigen-antibody complex is isolated using an immunosuppressant and the radioactivity count in the complex is determined. The binding amount of I ¹²⁵ -INS is a function of the content of INS in the sample, and the content of the sample INS can be obtained by data processing.

3 test results

3.1 Effects of RG3 on blood glucose in experimental type 2 diabetic IR rats

The results of measurement of fasting blood glucose in rats are shown in Table 2.

Table 2: Fasting blood glucose (FBG) in experimental type 2 diabetic IR rats (unit: mmol/L)

Note: Compared with the normal control group at the same time, ※※P<0.01. Compared with the pathological model group at the same time, **P<0.01. Compared with before treatment in this group, ●●P<0.01.

From the measurement results in Table 2, it was found that there was no significant difference in the FBG of each group before modeling. After modeling, the pathological model group, RG3 group, pioglitazone group and the normal control group were significantly different (P<0.01), but there was no significant difference between the three groups. After treatment, there was significant difference between the RG3 group and the pioglitazone group before treatment (P<0.01). There was no significant difference between the pathological model group and the pre-treatment group. There was no significant difference between the RG3 group and the pioglitazone group. There were significant differences between the two groups and the pathological model group (P<0.01).

3.2 Effect of RG3 on blood insulin content in experimental type 2 diabetic IR rats

The results of determination of fasting blood insulin in rats are shown in Table 3:

Table 3 Experimental type 2 diabetes IR rats fasting insulin (FINS) situation unit: IU / L

Note: Compared with the normal control group at the same time, ※※P<0.01. Compared with the pathological model group at the same time, *P<0.05, **P<0.01.

Compared with before treatment in this group, ●P<0.05, ●●P<0.01.

From the measurement results in Table 3, it can be seen that there is no significant difference in FINS between the groups before modeling. After modeling, there were significant differences between the pathological model group, RG3 group and pioglitazone group before the model establishment (P<0.01). There was no significant difference between the three groups. After treatment, there was significant difference between the RG3 group and the pioglitazone group before treatment (P<0.01). There was also significant difference between the pathological model group and the pre-treatment group (P<0.05). There was no difference between the RG3 group and the pioglitazone group. Significantly, the difference between the two groups was significantly higher than that of the pathological model group (P<0.01).

Claims

Use of 20(R)-ginsenoside Rg3 for the preparation of a medicament or nutraceutical for the alleviation and/or treatment of a diabetic condition.
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 alleviating and/or treating diabetes diseases, characterized by comprising 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, further comprising astragalus extract, mulberry leaf extract, rehmannia root extract, psoralen extract, dodder extract, Polygonum multiflorum extract, extract of Rhizoma Polygonati, and hawthorn One or more of the extract, the mother-in-law extract, the angelica extract, the coptis extract, the citrus extract, and the pumpkin extract.