阅读说明：本技术 香连丸及其提取物、药物组合物与香连丸产物的新用途 (New application of rhizoma coptidis pill, extract and pharmaceutical composition thereof and rhizoma coptidis pill product ) 是由 李学刚 叶小利 于 2020-05-28 设计创作，主要内容包括：本发明提供一种香连丸及其提取物、药物组合物与香连丸产物的新用途,具有降血糖和预防糖尿病并发症的作用,在糖尿病肾病模型中,本发明香连丸产物能降低血糖和UACR,加快神经传输速度,表明有明显的治疗糖尿病及其并发症的作用；此外,本发明香连丸产物还能降低血脂、体重、肝脏脂肪含量,具有降血脂、减肥以及预防脂肪肝的作用。(The invention provides a xianglian pill and an extract thereof, a pharmaceutical composition and a new application of a xianglian pill product, which have the effects of reducing blood sugar and preventing diabetic complications; in addition, the product of the xianglian pill can reduce the blood fat, the body weight and the fat content of the liver, and has the functions of reducing the blood fat, losing weight and preventing fatty liver.)

1. A rhizoma coptidis pill extract, wherein the rhizoma coptidis pill is composed of 4 parts of golden thread and 1 part of costustoot, and is characterized in that the content of the total alkaloids of the rhizoma coptidis pill extract is 38-38.4%; the rhizoma coptidis total alkaloids comprise 22.3-22.5% of berberine, 6.1-6.2% of palmatine, 6.4-6.5% of coptisine and 3.1-3.2% of epiberberine.

2. The extract of xianglian wan as claimed in claim 1, wherein the extract of xianglian wan is prepared according to a method comprising: weighing 4 parts of golden thread and 1 part of costus root, and mixing; crushing a sample; reflux-extracting with 5 times of 30-80% ethanol for 1-3 times; mixing extractive solutions, recovering solvent to obtain extract, and drying.

3. A pellets of xianglian comprising the extract of xianglian pellets as claimed in claim 1 or 2.

4. A pharmaceutical composition comprising the extract of xianglian wan as claimed in claim 1 or 2.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is a tablet, capsule, pill, granule, or mixture.

6. A new use of XIANGLIAN pill in preventing or treating diabetes or diabetic complication is provided; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is the pharmaceutical composition of the capsule dosage form of claim 5.

7. The novel use according to claim 6, wherein the diabetic complication comprises diabetic nephropathy.

8. A new use of XIANGLIAN pill in preparing medicine for preventing or treating hyperlipemia; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is the pharmaceutical composition of the capsule dosage form of claim 5.

9. A new use of XIANGLIAN pill in preparing medicine for preventing or treating fatty liver; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is the pharmaceutical composition of the capsule dosage form of claim 5.

10. A new use of XIANGLIAN pill in preventing or treating obesity is provided; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is the pharmaceutical composition of the capsule dosage form of claim 5.

Technical Field

The invention relates to the field of application of traditional compound Chinese medicine preparations, in particular to a xianglian pill and a new application of an extract, a pharmaceutical composition and a xianglian pill product thereof.

Background

Xianglian Wan is from Li Jiang Bing Yan Ji Fang (hand-collected prescription for Lijian Bing) from Juan Qi of political and materia Medica, and is composed of Coptidis rhizoma and radix aucklandiae. Through evolution, the xianglian pill collected and carried by the current Chinese pharmacopoeia consists of 4 parts of golden thread and 1 part of costus root. Has effects in clearing away heat, eliminating dampness, promoting qi circulation, and relieving pain, and can be used for treating dysentery due to damp-heat in large intestine, with symptoms of purulent and bloody stool, tenesmus, fever, abdominal pain, enteritis, and bacillary dysentery.

The xianglian pill contains a large amount of coptis root, so the xianglian pill has poor (bitter) taste and large volume and is not beneficial to oral administration. Therefore, enterprises develop the concentrated xianglian pills as the concentrated xianglian pills, and the main processes comprise: pulverizing radix aucklandiae into fine powder; pulverizing Coptidis rhizoma into coarse powder or coarse powder, soaking in 45% ethanol solvent for 24 hr, percolating until percolate is colorless, collecting percolate, recovering ethanol, concentrating to appropriate amount, mixing with above fine powder, adding appropriate amount of starch or microcrystalline cellulose, making into 1000 pills, drying, and polishing to obtain the final product (2015 edition of Chinese pharmacopoeia). The volume of the condensed xianglian pill is reduced by 60 percent compared with that of the xianglian pill. The process directly crushes the costustoot into the medicine, so that the volume of the concentrated xianglian pill is still larger, and the taste of the pill is still poorer.

Later, based on the concentrated xianglian pill, the enterprises developed the xianglian capsule, and the main processes include: extracting volatile oil from radix aucklandiae by steam distillation, and collecting volatile oil; filtering the water solution after extracting volatile oil, concentrating the filtrate to appropriate amount, drying, and pulverizing into fine powder; reflux-extracting Coptidis rhizoma with 70% ethanol at 75-80 deg.C for three times, the first time for 2 hr, and the second and third times for 1 hr, mixing extractive solutions, filtering, recovering ethanol from filtrate, concentrating to appropriate amount, drying, pulverizing into fine powder, adding above fine powder and appropriate amount of adjuvants, mixing, granulating, drying, spraying radix aucklandiae volatile oil, mixing, and making into capsule of 1000 granules. The volume of the xianglian capsule is 25 percent of that of the xianglian pill. The xianglian capsule has obviously reduced volume, improved taste and other advantages. However, the xianglian capsule has complex process, and volatile oil is firstly extracted and then water-soluble extract is extracted; the extract is sticky, is not easy to be encapsulated and is forced to be added with starch; the addition of starch also affects the volume of the encapsulate.

In addition, the xianglian pill is a classic and famous prescription, and the treatment effect of the xianglian pill is always limited to 'treating dysentery caused by damp-heat in large intestine with symptoms of purulent blood in stool, tenesmus, fever and abdominal pain, enteritis and bacillary dysentery with the symptoms', and a new treatment effect is not developed.

Diabetes Mellitus (DM) is a common genetically predisposed disease of abnormal glucose metabolism and endocrine disturbance caused by absolute or relative insulin hyposecretion. In 2015, 4.15 hundred million diabetics exist in the world, and the number of diabetics reaches 6.42 hundred million by 2040 years. Diabetes is one of the major diseases seriously harming human health.

Diabetes is mainly manifested by abnormal carbohydrate metabolism and metabolic disorders of substances such as fat, protein and the like, and long-term hyperglycemia can cause serious diabetic complications including microvascular complications, diabetic nephropathy, diabetic cardiomyopathy, diabetic nervous system lesions, diabetic skin lesions, diabetic complicated infection and the like.

Diabetic Kidney Disease (DKD) is one of the most common microvascular complications of diabetes, and is an important cause of end-stage renal disease, which severely affects the quality of life of patients by the end stage of the disease. Modern medicine mainly reduces blood sugar, controls blood pressure and reduces proteinuria for DKD control, but still does not effectively control disease progress. Diabetic kidney diseases belong to the category of diabetes in the broad sense, and can be classified into diseases such as kidney-yang, stranguria with chyluria, consumptive disease, edema and obstruction according to clinical symptoms. At present, no unified opinion is formed on the pathogenesis of the diabetic nephropathy, most clinical researches of the diabetic nephropathy are clinical tests of various doctors, and self-proposed empirical methods are mostly adopted for intervention, so that the follow-up research on the action mechanism of the medicine and the clinical popularization and application are not facilitated.

Disclosure of Invention

The invention provides a new therapeutic effect which aims at solving the problem that the existing xianglian pill has no development on the new therapeutic effect and is used for treating dysentery caused by damp-heat in large intestine with symptoms of purulent blood in stool, tenesmus, fever and abdominal pain, enteritis and bacillary dysentery with the symptoms.

In order to solve the technical problems, the invention provides a Chinese goldthread pill extract, wherein the Chinese goldthread pill is composed of 4 parts of golden thread and 1 part of costustoot, and the content of the total alkaloids of the golden thread of the Chinese goldthread pill extract is 38-38.4%; the coptis total alkaloid contains 22.3-22.5% of berberine, 6.1-6.2% of palmatine, 6.4-6.5% of coptisine and 3.1-3.2% of epiberberine.

The xianglian pill extract is prepared according to the method: weighing 4 parts of golden thread and 1 part of costus root, and mixing; crushing a sample; reflux-extracting with 5 times of 30-80% ethanol for 1-3 times; mixing extractive solutions, recovering solvent to obtain extract, and drying.

The invention also provides a xianglian pill which comprises the xianglian pill extract.

The invention also provides a pharmaceutical composition comprising the xianglian pill extract as described in any one of the above.

Further, the pharmaceutical composition is a tablet, a capsule, a pill, a granule or a mixture.

The invention also provides a new application of the xianglian pill product in medicaments for preventing or treating diabetes or diabetic complications; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule, an extract of the xianglian pill, a xianglian pill pharmaceutical composition and a new xianglian capsule; the Xinxianglian capsule is a medicinal composition of the capsule dosage form.

Further wherein the diabetic complication comprises diabetic nephropathy.

The invention also provides a new application of the xianglian pill product in preparing a medicament for preventing or treating hyperlipidemia; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is a pharmaceutical composition of the capsule dosage form.

The invention also provides a new application of the xianglian pill product in medicaments for preventing or treating fatty liver; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is a pharmaceutical composition of the capsule dosage form.

The invention also provides a new application of the xianglian pill product in medicaments for preventing or treating obesity; the product of the xianglian pill comprises at least one of a xianglian pill, a concentrated xianglian pill, a xianglian capsule and a new xianglian capsule; the Xinxianglian capsule is a pharmaceutical composition of the capsule dosage form.

Except for special description, the parts are parts by weight, and the percentages are mass percentages.

The invention has the beneficial effects that:

the invention discloses a Chinese medicinal composition and a preparation method thereof, and the Chinese medicinal composition has the effects of reducing blood sugar and preventing diabetic complications (such as diabetic nephropathy); in addition, the extract of the xianglian pill can reduce the blood fat, the body weight and the fat content of the liver, and has the effects of reducing the blood fat, losing weight and preventing fatty liver.

Moreover, according to the preparation method of the xianglian pill extract, the prepared medicinal composition has smaller volume, is easier to granulate and is more convenient to take orally;

finally, the medicinal active ingredients (the extract of the xianglian pill) of the xianglian pill product are prepared into tablets, capsules, pills, granules and other medicinal preparations suitable for clinical use, so that the clinical adaptability is effectively improved.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail by the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the present invention can be commercially available or prepared by existing methods.

Example 1:

weighing 80g of coptis tablet and 20g of fructus evodiae, performing reflux extraction for 3 times by using 30% ethanol in an amount which is 5 times that of the coptis tablet and 20g of fructus evodiae, combining extraction liquids, filtering and recovering a solvent, concentrating the mixture into thick paste, drying, crushing, and encapsulating to obtain the Xinxianglian capsule. HPLC (High Performance Liquid Chromatography) content analysis shows that the Xinxianglian capsule contains 22.5% of berberine, 6.2% of palmatine, 6.5% of coptisine and 3.2% of epiberberine.

Example 2:

weighing 80g of coptis tablet and 20g of fructus evodiae, performing reflux extraction for 1 time by using 80% ethanol in an amount which is 5 times that of the coptis tablet and 20g of fructus evodiae, combining extraction liquids, filtering and recovering a solvent, concentrating into thick paste, drying, crushing, and encapsulating to obtain the Xinxianglian capsule. HPLC content analysis shows that the Xinxianglian capsule contains 22.3% of berberine, 6.1% of palmatine, 6.5% of coptisine and 3.1% of epiberberine.

Example 3:

weighing 80g of coptis tablet and 20g of fructus evodiae, performing reflux extraction for 2 times by using 50% ethanol in an amount which is 5 times that of the coptis tablet and 20g of fructus evodiae, combining extraction liquids, filtering and recovering a solvent, concentrating into thick paste, drying, crushing, and encapsulating to obtain the Xinxianglian capsule. HPLC content analysis shows that the Xinxianglian capsule contains 22.4% of berberine, 6.2% of palmatine, 6.4% of coptisine and 3.1% of epiberberine.

Example 4 Effect test for treating diabetes and complications thereof

Control drug 1 (berberine): weighing 1kg of berberine monomer, adding starch, and making into capsule with berberine content of 38%.

Control drug 2 (total alkaloids of coptis): weighing Coptidis rhizoma total alkaloids, adding starch, and making into capsule, wherein the Coptidis rhizoma total alkaloids are controlled to be 38% (berberine 22.4%, palmatine 6.0%, berberine 6.4%, and epiberberine 3.2%).

Control drug 3 (xianglian pill): 4 parts of golden thread and 1 part of costus root. Pulverizing, mixing, and making into watered pill (2015 edition of Chinese pharmacopoeia). HPLC analysis shows that the content of total alkaloids is 7.52% (berberine 4.4%, palmatine 1.2%, coptisine 1.28%, epiberberine 0.64%).

Control drug 4 (concentrated xianglian pill): 4 parts of golden thread and 1 part of costus root. The concentrated xianglian pills are produced according to the process of processing the concentrated xianglian pills in the 'Chinese pharmacopoeia' 2015 edition. HPLC analysis shows that the content of total alkaloids is 14.04% (berberine 8.8%, palmatine 2.4%, coptisine 1.56%, epiberberine 1.28%).

Control 5 (xianglian capsule): 4 parts of golden thread and 1 part of costus root. Processing "xianglian capsule" according to the ministerial standard (WS3-146(Z-136) -2004 (Z)): extracting volatile oil from radix aucklandiae by steam distillation, and collecting volatile oil; filtering the water solution after extracting volatile oil, concentrating the filtrate to appropriate amount, drying, and pulverizing into fine powder; reflux-extracting Coptidis rhizoma with 70% ethanol at 75-80 deg.C for three times, the first time for 2 hr, and the second and third times for 1 hr, mixing extractive solutions, filtering, recovering ethanol from filtrate, concentrating to appropriate amount, drying, pulverizing into fine powder, adding above fine powder and appropriate amount of adjuvants, mixing, granulating, drying, spraying radix aucklandiae volatile oil, mixing, and making into capsule of 1000 granules. HPLC analysis shows that the content of total alkaloids is 28.08% (berberine 17.6%, palmatine 4.8%, berberine 3.12%, epiberberine 2.56%).

Control drug 6: pulverizing radix aucklandiae, and directly administering to stomach.

New xianglian capsule: prepared according to example 3. HPLC analysis shows that the content of total alkaloids is 38.1% (berberine 22.4%, palmatine 6.2%, berberine 6.4%, epiberberine 3.1%).

The experimental method for treating diabetes and complications is carried out according to the research guiding principle of natural medicines (traditional Chinese medicines) new medicines: male db/m mice were set as normal groups, and male db/db mice (diabetic nephropathy model) were divided into model groups and drug control groups, each group containing 10 mice. The total alkaloid (berberine, palmatine, coptisine and epiberberine) dosage of each medicine group is 100mg/kg, and radix aucklandiae group dosage is 1329 mg/kg; the concentration of the medicine is 10mg/mL (the concentration refers to the concentration of total alkaloids), normal group and model group are respectively administered with physiological saline with the same volume, the administration is continuously carried out for 8 weeks, after the experiment is finished, the 24h urine volume is collected by a metabolism cage, and the content of urine microalbumin urine (diabetic nephropathy detection index) is measured by an ELISA kit; killing the mouse, taking down the nerve transmission speed (diabetic neuropathy detection index) of the sciatic nerve detector; finally, the serum creatinine and the like were measured, and the ratio UACR (urinary microalbumin divided by creatinine) of urinary creatinine was calculated for 24 hours. Specific results are shown in table 1.

TABLE 1 comparison of the effects of the drugs on diabetes and its complications

Group of	Fasting blood glucose (mmol/L)	UACR(μg/mg)	Speed of nerve Transmission (m/s)
				Blank group	4.32±1.68	58.29±5.83	71.2±4.5
Model set	29.78±2.72##	528.35±68.65##	32.1±2.5
				Control drug 1 group (100mg/kg)	20.54±2.35**	310.45±30.14**	52.9±3.2*
Control drug 2 group (100mg/kg)	18.45±2.47**	302.84±31.93**	55.6±3.6**
				Control drug 3 group (100mg/kg)	14.31±2.45**Δ	238.33±27.93**Δ	63.7±4.1**Δ
Control drug 4 groups (100mg/kg)	14.11±2.46**Δ	235.66±22.41**Δ	64.3±3.7**Δ
				Control drug 5 group (100mg/kg)	13.91±2.42**Δ	233.05±31.33**Δ	64.8±4.1**Δ
6 group of control drugs (1329mg/kg)	29.56±2.98	525.45±33.43	32.4±4.6
				New xianglian capsule group (100mg/kg)	13.11±2.18**Δ	228.05±21.35**Δ	66.8±4.3**Δ

Note: compared to the normal group:^#P<0.05，^##P<0.01; compared to the model set:^*P<0.05，^**P<0.01; compared with the total alkali group:^ΔP<0.05。

as can be seen from Table 1, the blood glucose, UACR and nerve transmission rate of the model group were significantly increased and decreased compared with those of the normal group, indicating that the model was successfully made (^#P<0.05). Compared with the model group, the blood sugar of each drug group is obviously reduced, and the UACR is obviously reducedThe nerve transmission speed is obviously accelerated, which shows that the medicine has obvious function of treating diabetes and complications thereof: (^*P<0.05); the effect of the total alkaloids is superior to berberine; the effect of the xianglian pill series is superior to that of the coptis total alkaloid (rhizoma Coptidis)^ΔP<0.05). Compared with total alkaloids, the XIANGLIAN pill has reduced blood sugar, reduced UACR, and increased nerve transmission rate; and all reach a significant change level (P)<0.05), indicating that the hypoglycemic and diabetic complication preventing effects of the xianglian pill, the concentrated xianglian pill, the xianglian capsule and the Xinxianglian capsule are obviously better than those of the coptis total alkaloids. Experiments also find that the costus root has no effects of reducing blood sugar and preventing diabetes (contrast medicament 6), but the blood sugar reducing effect of the coptis root can be obviously improved after the costus root and the coptis root are compounded, which shows that the coptis root and the costus root have the synergistic effect of reducing blood sugar and treating diabetic complications.

Example 5 experiments on reducing blood lipid, reducing weight and preventing fatty liver

Control drug 1 (berberine): weighing 1kg of berberine monomer, adding starch, and making into capsule with berberine content of 38%.

Control drug 2 (total alkaloids of coptis): weighing Coptidis rhizoma total alkaloids, adding starch, and making into capsule, wherein the Coptidis rhizoma total alkaloids are controlled to be 38% (berberine 22.4%, palmatine 6.0%, berberine 6.4%, and epiberberine 3.2%).

Control drug 3 (xianglian pill): 4 parts of golden thread and 1 part of costus root. Pulverizing, mixing, and making into watered pill (2015 edition of Chinese pharmacopoeia). HPLC analysis shows that the content of total alkaloids is 7.52% (berberine 4.4%, palmatine 1.2%, coptisine 1.28%, epiberberine 0.64%).

Control drug 4 (concentrated xianglian pill): 4 parts of golden thread and 1 part of costus root. The concentrated xianglian pills are produced according to the process of processing the concentrated xianglian pills in the 'Chinese pharmacopoeia' 2015 edition. HPLC analysis shows that the content of total alkaloids is 14.04% (berberine 8.8%, palmatine 2.4%, coptisine 1.56%, epiberberine 1.28%).

Control 5 (xianglian capsule): 4 parts of golden thread and 1 part of costus root. Processing "xianglian capsule" according to the ministerial standard (WS3-146(Z-136) -2004 (Z)): extracting volatile oil from radix aucklandiae by steam distillation, and collecting volatile oil; filtering the water solution after extracting volatile oil, concentrating the filtrate to appropriate amount, drying, and pulverizing into fine powder; reflux-extracting Coptidis rhizoma with 70% ethanol at 75-80 deg.C for three times, the first time for 2 hr, and the second and third times for 1 hr, mixing extractive solutions, filtering, recovering ethanol from filtrate, concentrating to appropriate amount, drying, pulverizing into fine powder, adding above fine powder and appropriate amount of adjuvants, mixing, granulating, drying, spraying radix aucklandiae volatile oil, mixing, and making into capsule of 1000 granules. HPLC analysis shows that the content of total alkaloids is 28.08% (berberine 17.6%, palmatine 4.8%, berberine 3.12%, epiberberine 2.56%).

Control drug 6: pulverizing radix aucklandiae, and directly administering to stomach.

New xianglian capsule: prepared according to example 3. HPLC analysis shows that the content of total alkaloids is 38.1% (berberine 22.4%, palmatine 6.2%, berberine 6.4%, epiberberine 3.1%).

The blood fat reducing experimental method is carried out according to the research guiding principle of natural medicines (traditional Chinese medicines) new medicines: dividing golden yellow land mice into 7 groups, and administering normal feed to blank group (10 mice) and high-fat feed to high-fat group (60 mice); after 4 weeks, detecting blood lipid indexes, and dividing the golden yellow hamster successfully molded in the high-fat group into 6 groups (8-10 mice in each group); continuously feeding high-fat feed to each high-fat group; the dose of berberine group is 100mg/kg, the dose of total alkaloids (the sum of berberine, palmatine, berberine and epiberberine) of the other drug groups is 100mg/kg, and the dose of radix aucklandiae group is 1329 mg/kg; normal group (blank group) and model group were given the same volume of physiological saline, respectively; continuously feeding for 4 weeks. Then, fasting blood was collected to measure blood lipid levels, Total Cholesterol (TC), Triglyceride (TG), body weight and liver fat, and the specific results are shown in table 2.

TABLE 2 comparison of the hypolipidemic and weight-loss effects

Note: compared to the normal group:^#P<0.05，^##P<0.01; compared to the model set:^*P<0.05，^**P<0.01; compared with the total alkali group:^ΔP<0.05。

as can be seen from Table 2, the blood lipid, body weight and liver fat content of the model group were significantly increased compared to the normal group, indicating that the molding was successful (^#P<0.05). Compared with the model group, the blood fat, the body weight and the liver fat content of each medicine group are obviously reduced and reach obvious levels, which shows that the effects of reducing blood fat, losing weight and preventing fatty liver are obvious (^*P<0.05); the total alkaloids have better effects of reducing blood fat, losing weight and controlling fatty liver than berberine; compared with the total alkaloids group, the effect of reducing blood fat, losing weight and preventing fatty liver of the common corydalis herb pill series products is superior to that of the total alkaloids of the golden thread, and reaches a significant level, which shows that the effect of reducing blood fat, losing weight and preventing fatty liver of the common corydalis herb pill, the concentrated common corydalis herb pill, the common corydalis herb capsule and the Xinxianglian capsule is obvious (delta p)<0.05). Experiments also find that the costus root has almost no effects of reducing blood fat, losing weight and preventing fatty liver (contrast medicament 6), but after the costus root and the coptis root are compounded, the effects of reducing blood fat, losing weight and preventing fatty liver of the coptis root can be obviously improved, which indicates that the coptis root and the costus root have synergistic effects of reducing blood fat, losing weight and preventing fatty liver.

Example 6: safety test of drugs

The experimental method comprises the following steps: and (3) balancing 70 Km mice with the age of 4 weeks for 3-5 days by using a barrier isolation system, wherein sterile feed and water are sufficient. Mice were randomly divided into 7 groups of 10 mice each; the Xinxianglian capsule and each drug control group are respectively prepared into 20 percent solution, except a blank control group, each drug experimental group is respectively gavaged with 0.6mL, and is gavaged once in 8 hours and is continuously gavaged with stomach for three times (the total dose is 18 g/kg). Then, the mice were allowed to feed freely, the body weight was measured 3 days later, and after 15 days, the mortality of each group was counted, and the results are shown in Table 3.

Control drug 1 (berberine): weighing 1kg of berberine monomer, adding starch, and making into capsule with berberine content of 38%.

Control drug 2 (total alkaloids of coptis): weighing Coptidis rhizoma total alkaloids, adding starch, and making into capsule, wherein the Coptidis rhizoma total alkaloids are controlled to be 38% (berberine 22.4%, palmatine 6.0%, berberine 6.4%, and epiberberine 3.2%).

Control drug 3 (xianglian pill): 4 parts of golden thread and 1 part of costus root. Pulverizing, mixing, and making into watered pill (2015 edition of Chinese pharmacopoeia). HPLC analysis shows that the content of total alkaloids is 7.52% (berberine 4.4%, palmatine 1.2%, coptisine 1.28%, epiberberine 0.64%).

Control drug 4 (concentrated xianglian pill): 4 parts of golden thread and 1 part of costus root. The concentrated xianglian pills are produced according to the process of processing the concentrated xianglian pills in the 'Chinese pharmacopoeia' 2015 edition. HPLC analysis shows that the content of total alkaloids is 14.04% (berberine 8.8%, palmatine 2.4%, coptisine 1.56%, epiberberine 1.28%).

Control 5 (xianglian capsule): 4 parts of golden thread and 1 part of costus root. Processing "xianglian capsule" according to the ministerial standard (WS3-146(Z-136) -2004 (Z)): extracting volatile oil from radix aucklandiae by steam distillation, and collecting volatile oil; filtering the water solution after extracting volatile oil, concentrating the filtrate to appropriate amount, drying, and pulverizing into fine powder; reflux-extracting Coptidis rhizoma with 70% ethanol at 75-80 deg.C for three times, the first time for 2 hr, and the second and third times for 1 hr, mixing extractive solutions, filtering, recovering ethanol from filtrate, concentrating to appropriate amount, drying, pulverizing into fine powder, adding above fine powder and appropriate amount of adjuvants, mixing, granulating, drying, spraying radix aucklandiae volatile oil, mixing, and making into capsule of 1000 granules. HPLC analysis shows that the content of total alkaloids is 28.08% (berberine 17.6%, palmatine 4.8%, berberine 3.12%, epiberberine 2.56%).

New xianglian capsule: prepared according to example 3. HPLC analysis shows that the content of total alkaloids is 38.1% (berberine 22.4%, palmatine 6.2%, berberine 6.4%, epiberberine 3.1%).

The test method comprises the following steps: the drug was formulated as a 20% solution, 1mL of the solution was gavaged per mouse, and then the mice were observed for weight change and counted for death within 15 days. The results are given in Table 3 below.

TABLE 3 evaluation of safety test results

As can be seen from Table 3, the administration of a large dose of the drug directly to the mice resulted in some weight loss in the mice; the xianglian pill group also had one mouse dead. The observation of the change of body weight for 3 days revealed that the weight loss of mice was more severe when the "Xianglian Wan" (control drug 3) was orally administered directly to the mice (see below)^*P<0.05), the weight of the mice is increased along with the increase of the concentration degree of the medicine, which indicates that the safety of the medicine is increased; this may be related to the fact that the bulk drug contains more impurities and the safety is reduced.

The above description is further intended to describe the present invention in detail with reference to specific embodiments, and it should not be construed that the present invention is limited to the description. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.