A pharmaceutical composition for treating hepatobiliary diseases and a preparation method thereof

Abstract

The application provides a medicine composition for treating hepatobiliary diseases and a preparation method thereof, and the active ingredients are composed of a compound shown in formula (I) and Astragalus membranaceus and Saussurea involucrata extract, the weight ratio of the compound shown in formula (I) to the Astragalus membranaceus and Saussurea involucrata extract is 1: (1.5-2.0) by weight; compared with the prior art, the medicine composition of the application has a synergistic effect on hepatobiliary diseases, especially gallstones, and the effect is remarkable.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular, to a pharmaceutical composition for treating hepatobiliary system diseases and a preparation method thereof BACKGROUND

[0002] Gallstone, also known as cholelithiasis, is a disease of gallbladder or bile duct with stones; gallbladder infection is a common disease. According to the site of the disease, it is divided into cholecystitis and cholangitis. After the formation of stones in the gallbladder, the gallbladder mucosa can be stimulated, which can not only cause chronic inflammation of the gallbladder, but also cause secondary infection when the stones are embedded in the neck of the gallbladder or the cystic duct, which can cause acute inflammation of the gallbladder; there are many treatment methods for gallstones, and currently there are two main methods for treating gallstones, one is surgical treatment, and the other is non-surgical treatment, that is, symptomatic treatment of traditional Chinese and western medicine, traditional Chinese medicine treatment and other therapies.

[0003] Chuanhuixiang is a plant of the genus Chuanhuixiang of the family Asteraceae; Chuanhuixiang is distributed in western Sichuan and eastern Tibet, and grows in alpine meadows and shrubs at an altitude of 3700-3800 meters. Chuanhuixiang root is used as medicine, with a bitter and bitter taste, and a warm nature; it is returned to the liver, stomach and large intestine, and is used for qi and pain, and is used for treating abdominal distension, vomiting, intestinal rumbling, diarrhea, tenesmus, two sides not comfortable, liver and gallbladder pain and other diseases.

[0004] Radix Astragali is a perennial herb of the genus Astragalus of the Leguminosae family, with a height of 50-100 cm. The main root is thick, woody, often branched, and grayish white. The medicinal use of Astragalus has a history of more than 2000 years, and the root of Astragalus is used as medicine, with a sweet taste, a slightly warm nature, and a function of tonifying qi, astringing the exterior, diuresis, strengthening the heart, lowering blood pressure, antibacterial, supporting toxicity, pus, and enhancing the resistance of capillary blood vessels, antiperspirant and sex hormone-like effects, treating self-hemorrhage, qi deficiency, spleen deficiency, diarrhea, edema and carbuncle.

[0005] Chinese patent CN16549427A discloses hydroxyl citric acid and its derivatives, and the structure of hydroxyl citric acid is shown as formula (I), which can be used for treating gallstones, but no related data of gallstones is given.

[0006] SUMMARY

[0007] The purpose of the present application is to provide a pharmaceutical composition for treating hepatobiliary system diseases, especially gallstones, with good curative effect.

[0008] In a first aspect of the present application, a pharmaceutical composition for treating hepatobiliary diseases is provided, and the active ingredient is composed of a compound of formula (I) and Astragalus Chuanhuixiang extract, and the weight ratio of the compound of formula (I) to Astragalus Chuanhuixiang extract is 1: (1.5-2.0) by weight;

[0009]

[0010] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of compound of formula (I) to extract of Astragalus membranaceus and Aucklandia lappa is 1:(1.5-1.8), preferably 1:(1.65-1.75), and more preferably 1:1.7.

[0011] In the above composition, the Astragalus and Aucklandia extract is composed of Astragalus and Aucklandia ethanol extract and Astragalus and Aucklandia n-hexane extract, preferably in a weight ratio of 1:0.5-0.8, and more preferably in a weight ratio of 1:0.7.

[0012] Furthermore, the preparation method of the Astragalus membranaceus and Aucklandia lappa extract includes the following steps:

[0013] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0014] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3-4 and add 10-15 times the amount of 40-60% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 3-5 hours. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0015] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 7-9 times the amount of n-hexane, extract at 45℃~55℃, stir for 2~4h, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0016] In the above preparation method, in step (2), the preferred weight ratio of Astragalus membranaceus and Aucklandia lappa is 1:3.5.

[0017] In the above preparation method, step (2) preferably uses a 50% ethanol solution.

[0018] The "times" mentioned in steps (2) and (3) are based on the weight of Astragalus membranaceus and Aucklandia lappa. For example, in step (2), the weight of Astragalus membranaceus and Aucklandia lappa is 1 kg. In step (2), "adding 10-15 times the amount of 40-60% ethanol solution" means "adding 10-15 kg of 40-60% ethanol solution". In step (3), "adding 7-9 times the amount of n-hexane" means "adding 7-9 kg of n-hexane".

[0019] Furthermore, the pharmaceutical composition also includes pharmaceutically acceptable excipients.

[0020] Furthermore, the pharmaceutical composition is an oral pharmaceutical composition, which may be an oral lyophilized powder, granules, oral liquid, tablets, etc.

[0021] Another object of the present invention is to provide the use of the above composition in the preparation of a medicament for treating hepatobiliary diseases.

[0022] Furthermore, the aforementioned liver and gallbladder disease is gallstones.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The pharmaceutical composition of the present invention comprises an active ingredient consisting of an extract of Astragalus membranaceus obtained by a specific preparation method and a compound of formula (I) in a specific weight ratio. The two work synergistically to treat liver and gallbladder diseases, especially gallstones, with significant effects. Detailed Implementation

[0025] This invention discloses a pharmaceutical composition for treating hepatobiliary diseases and its preparation method. Those skilled in the art can refer to the content of this invention and, in conjunction with the principles of drug extraction and pharmaceutical formulation, appropriately modify the process parameters to achieve the desired result. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention. The application of this invention has been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0026] To better understand the invention and not to limit its scope, all figures indicating amounts, percentages, and other numerical values ​​used in this application should, in all cases, be understood to be modified by the word "approximately." Each numerical parameter should at least be considered as obtained based on reported significant figures and through conventional rounding methods.

[0027] The present invention will be further illustrated by the following examples, but the examples do not limit the present invention in any way.

[0028] Preparation Example 1: Astragalus and Aucklandia Extract

[0029] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0030] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 and add 12 times the amount of 50% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 4h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0031] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 8 times the amount of n-hexane, extract at a temperature of 48℃~52℃, stir for 3 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0032] Preparation Example 2: Astragalus and Aucklandia Extract

[0033] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0034] Step (2): Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 were added to 13 times the amount of 50% ethanol solution and the extraction temperature was 75-80℃. The extraction time was 3.5h. After the extraction was completed, the solid and liquid were separated and the extract was dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue was Astragalus membranaceus and Aucklandia lappa extract powder.

[0035] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 7 times the amount of n-hexane, extract at a temperature of 48℃~52℃, stir for 3.2h, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0036] Preparation Example 3: Astragalus and Aucklandia Extract

[0037] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0038] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3 and add 10 times the amount of 60% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 3h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0039] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 7 times the amount of n-hexane, extract at 45℃~50℃, stir for 2 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0040] Preparation Example 4: Astragalus and Aucklandia Extract

[0041] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0042] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:4 and add 15 times the amount of 40% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 5h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0043] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 9 times the amount of n-hexane, extract at a temperature of 50℃~55℃, stir for 4 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0044] Preparation Example 5: Astragalus and Aucklandia Extract

[0045] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0046] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 and add 12 times the amount of 50% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 4 hours. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract.

[0047] Preparation Example 6: Astragalus and Aucklandia Extract

[0048] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0049] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 and add 8 times the amount of n-hexane. The extraction temperature is 48℃~52℃ and the stirring extraction time is 3h. After the extraction is completed, the solid and liquid are separated and the extract is dried to obtain Astragalus membranaceus and Aucklandia lappa n-hexane extract.

[0050] Preparation Example 7: Astragalus and Aucklandia Extract

[0051] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0052] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 and add 12 times the amount of 10% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 4h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0053] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 8 times the amount of n-hexane, extract at a temperature of 48℃~52℃, stir for 3 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0054] Preparation Example 8: Astragalus and Aucklandia Extract

[0055] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0056] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3.5 and add 12 times the amount of anhydrous ethanol solution. The extraction temperature is 75-80℃. The extraction time is 4h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0057] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 8 times the amount of n-hexane, extract at a temperature of 48℃~52℃, stir for 3 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0058] Preparation Example 9: Astragalus and Aucklandia Extract

[0059] Step (1): Wash the astragalus and costus root thoroughly and let them air dry;

[0060] Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:1 and add 12 times the amount of 50% ethanol solution. The extraction temperature is 75-80℃. The extraction time is 4h. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder.

[0061] Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 8 times the amount of n-hexane, extract at a temperature of 48℃~52℃, stir for 3 hours, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract.

[0062] Examples 1-11: Pharmaceutical Compositions

[0063] (1) Composition

[0064]

[0065] (2) Preparation method

[0066] S1. Add the compound of formula (I) and Astragalus membranaceus extract to water for injection, add 54g of sodium sulfobutyl-β-cyclodextrin, stir for 2-3 hours, and filter through 1.0μm, 0.45μm and 0.22μm filters into a freeze dryer.

[0067] S2, freeze-drying.

[0068] Comparative Examples 1-2: Pharmaceutical Compositions

[0069] (1) Composition

[0070]

[0071] (2) Preparation method:

[0072]

[0073] Comparative Examples 3-4: Pharmaceutical Compositions

[0074] (1) Composition

[0075]

[0076] (2) Preparation method: Same as in Example 1.

[0077] Example 12: Pharmacodynamic Test

[0078] 1. Materials and Methods

[0079] 1.1 Animals

[0080] Male healthy guinea pigs (weighing 220-280g) should be acclimatized for one week at a room temperature of approximately 25±2℃ and a relative humidity of 50%~70%.

[0081] 1.2 Test Drugs

[0082] The pharmaceutical compositions prepared in Examples 1-10 and Comparative Examples 1-4 of this invention.

[0083] 1.3 Grouping and Modeling

[0084] Mice were randomly divided into a control group, a model group, Example 1-11 groups, and Comparative Example 1-4 groups, with 20 mice in each group. Except for the control group, all mice underwent modeling.

[0085] Model establishment: Mice were fed a litholytic diet (containing 15% fat, 1.5% cholesterol, and 0.5% bile acids) to establish a mouse gallstone model for 10 weeks. After 10 weeks, 10 model mice were sacrificed, and the gallbladders were dissected and bile was collected in glass test tubes. The color was observed, and a portion of the bile sample was extracted, placed on a glass slide, and observed under a polarized light microscope. The presence of numerous cholesterol crystal particles filling the field of view indicated successful model establishment.

[0086] 1.4 Administration method

[0087] The gallstone model group and the control group were fed normal feed for 4 weeks.

[0088] The experimental groups (Examples 1-11 and Comparative Examples 1-2) were fed normal feed and then given the corresponding drug composition at 25 mg / kg for 4 weeks.

[0089] Bile and liver collection: After 4 weeks of feeding, mice were anesthetized with ether and fixed on a dissection table. The gallbladder was fully exposed during surgery, and its color, size, and gallstone formation were observed visually. Bile was collected in PCR tubes, stored at -20°C, and labeled for testing.

[0090] Take one drop of bile from the gallbladder of each mouse and prepare a smear. The method for preparing the smear is as follows: place one drop of bile on one end of a glass slide, allowing the bile to be evenly dispersed on the slide, leaving a thin bile film on the slide; observe the cholesterol crystallization in the mouse bile under a polarized light microscope.

[0091] Combining visual and microscopic observation, a six-level judgment standard was used to assess and score the gallstone formation in the gallbladder of mice. The specific six-level judgment standard is as follows:

[0092] Grade 0: The gallbladder is filled with clear bile, with no cholesterol crystals, and is scored as 0 points;

[0093] Level 1: 1 to 10 crystals exist, counted as 1 point;

[0094] Level 2: 11 to 20 crystals exist, counted as 2 points;

[0095] Level 3: 21-50 crystals exist, scored as 3 points;

[0096] Level 4: 50 or more crystals are present, scored as 4 points;

[0097] Level 5: A round gallstone is found in the gallbladder with the naked eye, which is scored as 5 points.

[0098] 2. Experimental Results

[0099]

[0100] From the table above, we can draw the following conclusions:

[0101] (1) The pharmaceutical compositions prepared in Examples 1-4 can treat gallstones.

[0102] Compared with the model control group, the drug compositions prepared in Examples 1-4 can significantly reduce the number of cholesterol crystals in the gallbladder. Specifically, the average score of Examples 1-4 is less than 1 point, which is significantly different from the average score of 4.7 points of the model group, indicating that the drug compositions prepared in Examples 1-4 can treat gallstones.

[0103] (2) The pharmaceutical composition prepared in Example 1 is significantly superior to the single active ingredient compound (I) or Astragalus membranaceus extract; compound (I) and Astragalus membranaceus extract have a synergistic effect.

[0104] ① Compared with the model group, the compound of formula (I) in the comparative example group can significantly reduce the number of cholesterol crystals in the gallbladder. Specifically, the average score of the comparative example group was 2.4 points, which was significantly different from the average score of 4.7 points in the model group, indicating that the single active ingredient compound of formula (I) can treat gallstones.

[0105] ② Compared with Comparative Example 1, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly lower than the average score of 2.4 in Comparative Example 1. This indicates that the pharmaceutical composition prepared in Example 1 is significantly superior to the single active ingredient compound (I) in the treatment of gallstones.

[0106] ③ Compared with the model group, the Astragalus and Aucklandia extract in Comparative Example 2 could not significantly reduce the number of cholesterol crystals in the gallbladder. Specifically, the average score of Comparative Example 2 was 4.25, which was not significantly different from the average score of 4.7 in the model group. This indicates that the single active ingredient Astragalus and Aucklandia extract cannot treat gallstones.

[0107] ④ Compared with Comparative Example 2, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly lower than the average score of 4.25 in Comparative Example 2. This indicates that the pharmaceutical composition prepared in Example 1 is significantly superior to Astragalus and Aucklandia extract in the treatment of gallstones.

[0108] Comparative analysis of Example 1 and Comparative Examples 1-2 showed that the compound of formula (I) and Astragalus membranaceus extract had a synergistic effect in the treatment of gallstones, with a significantly enhanced effect.

[0109] (3) The extracts obtained from Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3-4 have a better synergistic effect with the compound of formula (I).

[0110] ① The only difference between the composition of Example 1 and the composition of Example 9 is that the weight ratio of Astragalus membranaceus and Aucklandia lappa is different when preparing the Astragalus membranaceus and Aucklandia lappa extract. In Example 1, it is 1:3.5; in Example 9, it is 1:1.

[0111] ② Compared with Example 9, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly different from the average score of Comparative Example 9 (1.05). This indicates that in the treatment of gallstones, The extract of Astragalus membranaceus and Wood of Bupleurum obtained from a weight ratio of 1:3-4 has synergistic effect with the compound of formula (I) The effect is better than that of the extract of Astragalus membranaceus and Wood of Bupleurum obtained from a weight ratio of 1:1.

[0112] (4) The synergistic effect of Astragalus membranaceus extract composed of Astragalus membranaceus ethanol extract and Astragalus membranaceus n-hexane extract with compound (I) is better than that of Astragalus membranaceus ethanol extract or Astragalus membranaceus n-hexane extract.

[0113] ① The only difference between the composition of Example 1 and the compositions of Examples 5-6 is the composition of the Astragalus and Aucklandia extract. In Example 1, the Astragalus and Aucklandia extract is composed of Astragalus and Aucklandia ethanol extract and Astragalus and Aucklandia n-hexane extract; in Example 5, the Astragalus and Aucklandia extract is Astragalus and Aucklandia ethanol extract; and in Example 6, the Astragalus and Aucklandia extract is Astragalus and Aucklandia n-hexane extract.

[0114] ② Compared with Examples 5 or 6, the pharmaceutical composition prepared in Example 1 significantly reduced the number of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly different from the average score of 1.4 in Example 5 or 1.6 in Example 6. This indicates that in the treatment of gallstones, the synergistic effect of Astragalus membranaceus extract (composed of Astragalus membranaceus ethanol extract and Astragalus membranaceus zedoaria n-hexane extract) with the compound of formula (I) is superior to that of Astragalus membranaceus ethanol extract or Astragalus membranaceus zedoaria n-hexane extract.

[0115] (5) The synergistic effect of Astragalus membranaceus ethanol extract obtained by ethanol extraction at a specific concentration and compound of formula (I) is better than that of Astragalus membranaceus ethanol extract obtained by ethanol extraction at other concentrations.

[0116] ① The only difference between the composition of Example 1 and the compositions of Example 7 or Example 8 is the concentration of the ethanol solution used in preparing the Astragalus membranaceus ethanol extract. Example 1 uses a 50% ethanol solution, Example 7 uses a 10% ethanol solution, and Example 8 uses an anhydrous ethanol solution.

[0117] ② Compared with Examples 7 or 8, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly different from the average score of 1.10 in Example 7 or 1.15 in Example 8. This indicates that in the treatment of gallstones, the synergistic effect of Astragalus membranaceus ethanol extract obtained from a specific concentration (59%) of ethanol and the compound of formula (I) is superior to that obtained from other concentrations (10% or 100%) of ethanol.

[0118] (6) The synergistic effect of a specific ratio of compound (I) and extracts of Astragalus membranaceus and Aucklandia lappa is better than that of other ratios.

[0119] ① The only difference between the composition of Example 1 and the composition of Example 10 is the weight ratio of the compound of formula (I) to the extract of Astragalus membranaceus and Aucklandia lappa. The weight ratio of Example 1 is 1:1.7, while that of Example 10 is 1:1.

[0120] ② Compared with Example 10, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly different from the average score of 1.3 in Example 10. This indicates that in the treatment of gallstones, the combination of compound (I) in a weight ratio of 1:1.7 with Astragalus membranaceus and Aucklandia lappa extract has a synergistic effect superior to other compositions (weight ratio of 1:1).

[0121] (7) The synergistic effect of the combination of compound (I) and Astragalus membranaceus extract is better than that of the combination of derivative of compound (I) and Astragalus membranaceus extract.

[0122] ① The only difference between the composition of Example 1 and the compositions of Comparative Examples 3-4 is that the compounds of Formula (I) are slightly different. In Example 1, the compound is hydroxycitric acid, the compound of Formula (I) is hydroxycitric acid, in Comparative Example 3, the compound of Formula (I) is hydroxycitric acid lactone, and in Comparative Example 4, the compound of Formula (I) is potassium hydroxycitric acid.

[0123] ② Compared with Comparative Examples 3-4, the pharmaceutical composition prepared in Example 1 significantly reduced the amount of cholesterol crystals in the gallbladder. The average score of Example 1 was 0.65, which was significantly different from the average score of 2.0 in Comparative Example 3 and 1.85 in Comparative Example 4. This indicates that in the treatment of gallstones, the synergistic effect of the combination of compound (I) and Astragalus membranaceus extract is superior to that of the combination of derivatives of compound (I) (e.g., hydroxycitrolactone or potassium hydroxycitrate) and Astragalus membranaceus extract.

Claims

1. A pharmaceutical composition for treating hepatobiliary diseases, wherein the active ingredients are composed of a compound of formula (I) and an extract of Astragalus membranaceus and Aucklandia lappa, wherein the weight ratio of the compound of formula (I) to the extract of Astragalus membranaceus and Aucklandia lappa is 1:(1.5-1.8). The Astragalus and Aucklandia extract is composed of Astragalus and Aucklandia ethanol extract and Astragalus and Aucklandia n-hexane extract in a weight ratio of 1:0.5-0.

8. The preparation method of the Astragalus membranaceus and Aucklandia lappa extract includes the following steps: Step (1): Wash the astragalus and costus root thoroughly and let them air dry; Step (2): Take Astragalus membranaceus and Aucklandia lappa in a weight ratio of 1:3-4 and add 10-15 times the amount of 40-60% ethanol solution. The extraction temperature is 75-80℃. The stirring extraction time is 3-5 hours. After the extraction is completed, the solid and liquid are separated. The extract is dried to obtain Astragalus membranaceus and Aucklandia lappa ethanol extract. The filter residue is Astragalus membranaceus and Aucklandia lappa extract powder. Step (3): Take the Astragalus membranaceus extract powder obtained in step (2), add 7-9 times the amount of n-hexane, extract at 45℃~55℃, stir for 2~4h, separate solid and liquid after extraction, and dry the extract to obtain Astragalus membranaceus n-hexane extract. The liver and gallbladder disease mentioned is gallstones.

2. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of compound (I) to Astragalus membranaceus extract is 1:1.

7.

3. The pharmaceutical composition according to claim 1, characterized in that, The Astragalus and Aucklandia extract consists of an ethanol extract and a hexane extract of Astragalus and Aucklandia in a weight ratio of 1:0.

7.

4. The pharmaceutical composition according to claim 1, characterized in that, It also includes pharmaceutically acceptable excipients.

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