Pharmaceutical compositions containing famesoid x receptor agonists and uses thereof

Abstract

The present application provides a pharmaceutical composition comprising a farnesoid X receptor (FXR) agonist, a folic acid substance and a pharmaceutically acceptable excipient. The present application has the advantage that the pharmaceutical composition provided by the present application has a significant beneficial effect in preventing or assisting in the treatment of fatty liver, and can reduce side effects such as itching, dyslipidemia and the like caused by FXR agonist drugs, so that the pharmaceutical composition provided by the present application has a higher clinical benefit / risk ratio compared with the use of FXR agonists alone. In addition, the compound form of the present product can significantly improve patient compliance.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition containing a farnesol X receptor agonist (FXR agonist) and a folic acid substance and its use, belonging to the field of pharmacy. BACKGROUND

[0002] In recent years, with the improvement of people's living standards, the change of dietary structure (increased intake of high fat and high protein), the incidence of fatty liver has gradually increased, and it shows a trend of younger age. Fatty liver is a common chronic liver disease in clinical practice, the main pathological change is diffuse fatty degeneration of liver cells, including alcoholic and non-alcoholic fatty liver. In addition, long-term and large-dose drug use can also cause drug-induced fatty liver. If no effective intervention measures are taken after the occurrence of fatty liver, it may develop into fatty hepatitis, fatty cirrhosis and even induce liver cancer. The pathogenesis of fatty liver is not clear, and there is no specific treatment drug in clinical practice at present. The main treatment is symptomatic treatment, improvement of liver function and prevention of disease progression.

[0003] Farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver and small intestine, and bile acid is its natural ligand. They jointly regulate lipid metabolism and glucose homeostasis as well as liver inflammation and fibrosis. FXR is an important target for the development of drugs for fatty liver and cholestatic liver disease. FXR agonists have been shown to have significant therapeutic effects on nonalcoholic fatty liver disease (NAFLD), liver fibrosis and cholestatic liver injury. However, clinical trials have found that FXR agonists, while showing therapeutic effects, have also been observed to have dose- and class-related side effects, including itching, elevated total plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, and decreased high-density lipoprotein cholesterol (HDL-C). In addition, it has been found that FXR agonists increase the risk of liver decompensation in patients with cirrhosis PBC, so many promising FXR agonists have been discontinued in preclinical or clinical trials. Therefore, if the side effects of FXR agonists can be overcome, it will help to promote the marketing and application of such drugs and benefit the majority of patients with fatty liver.

[0004] We accidentally discovered in experiments that the combination of a certain proportion of FXR agonists and folic acid substances can not only effectively reduce the liver index of high-fat-induced rats, improve liver function and inflammation indicators, and promote the recovery of fatty liver, but also reduce itching and blood lipid abnormalities caused by FXR agonist drugs. Accordingly, the present application provides a synergistic pharmaceutical composition for preventing or adjuvant treatment of fatty liver, which can improve the benefit / risk ratio of patients and is a significant improvement over existing FXR agonist drug development. SUMMARY

[0005] To overcome the deficiencies of FXR agonist in treating fatty liver, the present application provides a safer and more effective pharmaceutical composition.

[0006] To achieve the above-mentioned object, the present application adopts the following technical solutions:

[0007] A pharmaceutical composition comprises:

[0008] a) a pharmaceutically effective amount of a farnesoid X receptor agonist and one of its pharmaceutically acceptable precursors, active metabolites, or salts; b) a pharmaceutically effective amount of a folic acid substance; and c) a pharmaceutically acceptable excipient.

[0009] In the present application, the pharmaceutically effective amount of the farnesoid X receptor agonist is 0.01-500 mg, and the pharmaceutically effective amount of the folic acid substance is 0.1-5 mg.

[0010] In the present application, the farnesoid X receptor agonist is selected from one of the following: obeticholic acid (OCA), cholic acid (Cholic Acid), Tropifexor (LNJ-452), Cilofexor (GS-9674), Vonafexor (EYP001), Nidufexor (LMB763, Nidofexor), ASC42, TERN-101 (LY2562175), EDP-305, MET-409, Px-104, and HEC96719.

[0011] In the present application, the folic acid substance is selected from one of the following: 5-methyltetrahydrofolic acid, formyltetrahydrofolic acid, active metabolites of folic acid or folic acid salts, and substances that can release / generate folic acid in vivo. In the present application, the amount of the folic acid substance is calculated based on the molar mass of folic acid, for example, 0.416 mg of 5-methyltetrahydrofolic acid and 0.4 mg of folic acid are equimolar, and at this time, the amount of 5-methyltetrahydrofolic acid (calculated based on the molar mass of folic acid) is 0.4 mg.

[0012] In the present application, the pharmaceutically effective amount of obeticholic acid is 1-50 mg, preferably 5-25 mg; the pharmaceutically effective amount of tropifexor is 0.01-0.5 mg, preferably 0.03-0.2 mg; the pharmaceutically effective amount of cholic acid is 5-30 mg, preferably 10-20 mg; the pharmaceutically effective amount of seladelpar is 10-200 mg, preferably 30-100 mg; the pharmaceutically effective amount of volixibat is 30-500 mg, preferably 100-200 mg; the pharmaceutically effective amount of ASC42 is 1-20 mg, preferably 5-15 mg; the pharmaceutically effective amount of TERN-101 is 1-20 mg, preferably 3-10 mg; the pharmaceutically effective amount of EDP-305 is 1-5 mg, preferably 1-2.5 mg; the pharmaceutically effective amount of MET-409 is 10-100 mg, preferably 50-80 mg; the pharmaceutically effective amount of Px-104 is 1-20 mg, preferably 5-10 mg; the pharmaceutically effective amount of nimezimesor is 5-100 mg, preferably 25-50 mg; the pharmaceutically effective amount of HEC96719 is 0.1-5 mg, preferably 0.25-2 mg.

[0013] In the present application, the pharmaceutically effective amount of folic acid substance is preferably 0.2-1.2 mg.

[0014] In the present application, the farnesoid X receptor agonist is preferably one or more of obeticholic acid, tropifexor, cholic acid, seladelpar, volixibat.

[0015] In the present application, the folic acid substance is preferably one of folic acid or 5-methyltetrahydrofolic acid.

[0016] As a preferred embodiment, the pharmaceutical composition provided by the present application contains 5-25 mg of obeticholic acid and 0.2-1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0017] As a preferred embodiment, the pharmaceutical composition provided by the present application contains 0.03-0.2 mg of tropifexor and 0.2-1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0018] As a preferred embodiment, the pharmaceutical composition provided by the present application contains 10-20 mg of cholic acid and 0.2-1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0019] As a preferred embodiment, the pharmaceutical composition provided by the present application contains 30-100 mg of seladelpar and 0.2-1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0020] As a preferred embodiment, the pharmaceutical composition provided by the present application contains 100-200 mg of volixibat and 0.2-1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0021] As one preferred embodiment, the pharmaceutical composition according to the present application contains 5 to 15 mg of ASC42 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0022] As one preferred embodiment, the pharmaceutical composition according to the present application contains 3 to 10 mg of TERN-101 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0023] As one preferred embodiment, the pharmaceutical composition according to the present application contains 1 to 2.5 mg of EDP-305 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0024] As one preferred embodiment, the pharmaceutical composition according to the present application contains 50 to 80 mg of MET-409 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0025] As one preferred embodiment, the pharmaceutical composition according to the present application contains 5 to 10 mg of Px-104 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0026] As one preferred embodiment, the pharmaceutical composition according to the present application contains 25 to 50 mg of Nidufens and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0027] As one preferred embodiment, the pharmaceutical composition according to the present application contains 0.25 to 2 mg of HEC96719 and 0.2 to 1.2 mg of folic acid or 5-methyltetrahydrofolic acid.

[0028] In the present application, the acceptable excipient or carrier or mixture thereof includes one or more of a pharmaceutically or food grade saccharide or functional sweetener, a filler, a wetting agent, a binder, and a lubricant.

[0029] In the present application, the dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form, including but not limited to a general tablet, a double-layer tablet, a multi-layer tablet, a sustained-release tablet, a single-chamber controlled-release tablet, a double-chamber controlled-release tablet, a microporous type controlled-release tablet, a sublingual tablet, an oral quick-disintegration tablet, a dispersible tablet, a chewable tablet, an enteric tablet, a granule, a pill, an enteric capsule, a delayed-release tablet, a time / position release tablet, a general capsule, a sustained-release capsule, a controlled-release capsule, a capsule containing pellets or small tablets, a pH-dependent capsule containing pellets or small tablets, a liposome, a nano-preparation, a microcapsule, a microemulsion, a porous polymer microsphere, an oral solution, a syrup, a powder, a lyophilized powder, a film, a suspension, an emulsion, a drop, or a patch, etc., among which a tablet, a capsule, a granule, a pill, an oral solution, a powder, a liposome, a nano-preparation, a microcapsule, a microemulsion, and a porous polymer microsphere are preferred.

[0030] In the present application, the pharmaceutical composition is used in the preparation of a product for the treatment of fatty liver disease.

[0031] In the present application, the fatty liver disease includes obesity fatty liver, alcoholic fatty liver, non-alcoholic fatty liver, diabetic fatty liver, hyperlipidemic fatty liver, rapid weight loss fatty liver, starvation fatty liver, nutritional fatty liver, pregnancy fatty liver, drug-induced fatty liver or fatty hepatitis.

[0032] In the present application, the use of the pharmaceutical composition in the preparation of a product for assisting in the prevention and / or treatment of non-alcoholic steatohepatitis.

[0033] In the present application, the use of the pharmaceutical composition in the preparation of a product for reducing the risk of pruritus and dyslipidemia caused by farnesol X receptor agonist drugs.

[0034] The beneficial effects of the present application are: the present application provides a pharmaceutical composition containing a pharmaceutically effective amount of farnesol X receptor agonist and folic acid substance, which can be used for the treatment of fatty liver disease, and can reduce the pruritus and dyslipidemia caused by farnesol X receptor agonist, and the pharmaceutical composition produces an unexpected synergistic effect, which is stronger than the single application of farnesol X receptor agonist or folic acid substance, which provides a new solution for the treatment of fatty liver disease. DETAILED DESCRIPTION

[0035] The present application will be further described below in conjunction with the specific embodiments, which are not limitations of the present application, and any equivalent replacement in the art according to the content of the present application shall fall within the scope of the present application.

[0036] To prove the scientificity of the pharmaceutical composition provided by the present application, it is proved that the combination of the two components of the pharmaceutical composition is reasonable, and the combination can produce a synergistic effect, rather than a simple pharmacological effect superposition, and the Q value method of Jin Zhengjun is introduced for analysis. Jin Zhengjun Q value method, also known as probability addition method, according to the pharmacological effect of two drugs combined and the pharmacological effect of two drugs used in the dose-effect curve area, the following calculation formula is used: Q = E A+B / (E A +E B -E A *E B ), in which the numerator represents the "measured combined effect", and the denominator represents the "expected combined effect", (in order to meet the analysis of the pharmacological effect relationship of components and composition, the pharmacological effect is converted into an effect that can directly reflect the strength of the pharmacological effect, the calculation formula is: E i = 1-P i / P 模型组 , P i is the pharmacological index of each component, and P 模型组Q is the ratio of the two: Q is less than 0.85, the two drugs are considered to be antagonistic; less than 1.15 greater than 0.85, it is considered to be additive; greater than 1.15 is considered to be synergistic.

[0037] Example 1: Preventive effect of the composition of the present application on high-fat diet-induced fatty liver rats

[0038] High-fat diet can induce an increase in plasma free fatty acids and plasma lipoprotein metabolism disorders, forming abnormal blood lipid metabolism, leading to excessive deposition of liver lipids. We used high-fat diet to induce fatty liver rat model, to detect the preventive effect of the composition on rat liver steatosis.

[0039] I. Method

[0040] Experimental animals and grouping: SPF healthy SD rats, half male and half female, weighing 200±20g, purchased from Guangdong Medical Laboratory Animal Center. Raising in an environment with room temperature 18-28℃ and relative humidity 40%-70%, free access to water. Adapted to ordinary feed for 1 week, randomly divided into the following Table 1 groups, 10 rats in each group.

[0041] Modeling and biochemical index detection: the normal diet group was continued to be fed with ordinary feed, and the rest of the groups were fed with high-fat feed (calorie ratio: carbohydrate 35%, fat 51%, protein 14%). The rats in each group were free to eat and drink. The modeling was started at the same time as the administration. The normal diet group and the high-fat diet group were given 0.5% carboxymethylcellulose sodium solution by gavage, and the rest of the groups were given the corresponding drugs, once a day. The rats were weighed before administration every day, and the administration dose was adjusted accordingly. After 14 weeks of continuous feeding, the rats were anesthetized with chloral hydrate, the liver tissue was dissected and observed for its morphology and color, rinsed with normal saline and dried with filter paper, and the liver wet weight (mg) was measured and the liver index was calculated. Liver index = liver wet weight (mg) / body weight (g). Take 0.1 g of liver tissue from the same part of the rat liver, cut it into pieces, add normal saline, homogenize, centrifuge at 2000 r / min for 15 min, separate the supernatant, and store at -20℃ for testing. The expression levels of alanine aminotransferase (ALT) and liver aspartate aminotransferase (AST) were detected by automatic biochemical analyzer.

[0042] II. Results

[0043] Serum ALT and AST are indicators related to liver fat accumulation, hepatocyte injury and liver fibrosis progression. As shown in Table 1, compared with the normal diet group, the liver index, ALT and AST of the high-fat diet group rats were significantly increased after 14 weeks of feeding (P<0.01), and it was observed that the liver of the normal diet group rats was red, soft, and no nodules appeared, and the surface was smooth, while the liver of the high-fat diet group rats was enlarged, the capsule was tight, and the surface was yellow, oily and blunt, indicating that the model was successfully constructed. Compared with the high-fat diet group, the liver index, ALT and AST of the partial single drug group (obeticholic acid group, cholic acid group, tropifexor group, selonsertib group, and velocimab group) and the two-drug combination group were significantly reduced (P<0.05 or P<0.01). Therefore, it is indicated that the drugs in the above groups have a significant effect on improving fatty liver disease in model rats.

[0044] At the same time, compared with the corresponding single drug group, the rats in the obeticholic acid+FA group, tropifexor+FA group, selonsertib+FA group, and velocimab+FA group were more obvious in reducing ALT and AST, while the ALT and AST indicators of the cholic acid+FA group were slightly lower than those of the corresponding cholic acid single drug group, but there was no significant difference. This indicates that after the combination of FXR agonists and folic acid, the effect of improving the fatty liver indicators of model rats is obvious. The Q values of the effect of obeticholic acid+FA group in reducing liver index, ALT and AST are 1.54, 1.85 and 2.04 respectively. Similarly, the Q values of tropifexor+FA group and selonsertib+FA group are all greater than 1.15, and the related indicators are not much different from the normal diet group, indicating that the combination of obeticholic acid or tropifexor or selonsertib and folic acid has a synergistic effect in improving fatty liver and can effectively prevent fatty liver. The Q value of cholic acid+FA group in reducing ATL and AST is less than 1.15 and greater than 0.85, which is an additive effect. Although the Q value of velocimab+FA group in reducing liver index, ALT and AST is greater than 1.15, the effect of this combination is not as good as that of obeticholic acid+FA group, tropifexor+FA group and selonsertib+FA group.

[0045] Based on the experimental data, it can be known that obeticholic acid+FA, tropifexor+FA and selonsertib+FA are preferred combinations that can significantly improve the liver pathological indicators of model rats, that is, obeticholic acid, tropifexor and selonsertib are preferred types of FXR agonists, which can be combined with folic acid to play a synergistic role in preventing fatty liver disease.

[0046] Table 1 Comparison of liver index, ALT and AST of rats in each group after 14 weeks of feeding n=9-10

[0047]

[0048]

[0049] Note: compared with normal diet group, aa P < 0.01; compared with high-fat diet group, b P < 0.05, bb P < 0.01.

[0050] Example 2: Therapeutic effect of the composition of the present application on CCl4 compound high-fat diet-induced fatty liver in rats and adverse reaction reduction effect

[0051] Carbon tetrachloride (CCl4) is a typical liver lipid peroxidation damage substance, which is activated by cytochrome oxidase P450 in the liver to form CCl3 - and Cl - , leading to lipid peroxidation of liver microsomes, and also damaging the structure and function of mitochondria to reduce their ability to oxidize and decompose fat, and damaging the endoplasmic reticulum to reduce the synthesis and secretion of lipoprotein. The present application uses subcutaneous injection of CCl4 and high-fat diet to induce a rat fatty liver model, detects liver function, blood lipid indicators and tumor necrosis factor alpha content in each group of rats, to study the effect of the composition on treating fatty liver disease and reducing the incidence of adverse reactions of FXR agonist drugs.

[0052] I. Method

[0053] Experimental animals and grouping: SPF grade SD rats, half male and half female, weighing 200±20g, purchased from Guangdong Medical Laboratory Animal Center. Raising in an environment with room temperature of 18-28℃ and relative humidity of 40%-70%, with free access to water. Adapted to ordinary feed for 1 week, and then randomly divided into the following Table 2 groups, 10 rats in each group.

[0054] Modeling: the normal diet group was continued to be fed with ordinary feed, and the other groups were fed with high-fat feed (calorie ratio: carbohydrate 35%, fat 51%, protein 14%), while intraperitoneal injection of carbon tetrachloride (CCl4) and olive oil preparation oil (50:50) 2mL / kg twice a week, the normal diet group was intraperitoneally injected with olive oil 2mL / kg, for a total of 8 weeks. After 8 weeks, the rats were administered by gavage according to the doses in Table 2, the normal diet group and the model control group were given gavage of normal saline once a day, for 6 weeks. The pruritus phenomenon of the rats was observed and counted throughout the experiment.

[0055] Detection index: At the end of modeling, 2% sodium pentobarbital 3 ml / kg was injected intraperitoneally for anesthesia, and the abdominal cavity was opened. Blood was collected through inferior vena cava, and serum was obtained after centrifugation and stored at -70°C. Small pieces of tissue were cut from the same liver lobe and position and placed in 10% neutral formalin buffer for fixation. The following indexes were detected: (1) high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected by automatic biochemical analyzer; (2) liver tissue free fatty acid (FFA) was detected by biochemical kit; (3) serum TNF-α content was analyzed by ELISA method.

[0056] II. Results

[0057] As a potential hepatotoxin, FFA can damage cell membranes, mitochondrial membranes and lysosomal membranes, thereby causing damage to intracellular micro-organs, and can also significantly enhance the toxicity of TNF-α, IL-2, IL-6, etc., leading to changes such as liver parenchyma degeneration, inflammatory cell infiltration and fibrosis. TNF-α is secreted by activated Kupffer cells and adipocytes, and as a hepatotoxic cytokine, its expression increases during the occurrence of fatty liver, becoming the preferred factor leading to the occurrence of fatty hepatitis.

[0058] As shown in Table 2, compared with the normal diet group, the skin of the model control group and other groups of rats was loose, the fur was dull, and the LDL-C was significantly increased and the HDL-C was significantly decreased (P<0.01), indicating that the modeling was successful. Compared with the model control group, some rats in the low (high) dose obeticholic acid group, low (high) dose tropifexor group, low (high) dose elafibranor group, and dual-drug combination group had back and / or face scratching and eating caused alopecia, and no rats in the low-dose folic acid group and high-dose 5-MTHF group had alopecia. Among them, the pruritus rate of rats in the low-dose FXR agonist group was 40-50%, that in the high-dose FXR agonist group was 60-80%, and that in the low-dose dual-drug combination group was 10-20%, and that in the high-dose dual-drug combination group was 30-40%. At the same time, compared with the model control group, there was no significant difference in LDL-C and HDL-C in the low (high) dose obeticholic acid group, low (high) dose t ropifexor group, and low (high) dose elafibranor group, and the LDL-C (HDL-C) of some rats was slightly higher (lower) than that in the low-dose folic acid group and high-dose 5-MTHF group, and even the LDL-C of a small number of rats was slightly higher than that in the model control group, which was consistent with the specific side effects of pruritus and lipid parameter changes (increased LDL-C content and decreased HDL-C content) caused by FXR agonists. The LDL-C of rats in the dual-drug combination group was significantly decreased (P<0.05 or P<0.01), and the HDL-C was significantly increased (P<0.01), and the improvement effect of pruritus rate, LDL-C and HDL-C indicators in the low-dose FXR agonist combined with low-dose folic acid group was better than that in the high-dose FXR agonist combined with high-dose folic acid group. Therefore, it is indicated that the combination of FXR agonists and folic acid substances can significantly reduce pruritus and improve dyslipidemia, and the side effects are proportional to the dose, and the use of FXR agonists can reduce pruritus and dyslipidemia.

[0059] As shown in Table 3, compared with the normal diet group, the serum TNF-α content and liver tissue FFA of the model control group were significantly increased (P<0.01), indicating that the modeling was successful. Compared with the model control group, the serum TNF-α and liver tissue FFA of rats in the low (high) dose obeticholic acid group, low (high) dose t ropifexor group, low (high) dose elafibranor group, and dual-drug combination group were significantly decreased (P<0.05 or P<0.01). Therefore, it is indicated that the above-mentioned drugs have a significant effect of reducing liver cell lipid deposition, inhibiting inflammatory mediator TNF-α, reducing liver inflammation damage, and improving lipid metabolism in CCl4 combined with high-fat diet induced rats. At the same time, compared with the single-drug group, the dual-drug combination group is more obvious in reducing serum TNF-α and liver tissue FFA. This indicates that the combination of FXR agonists and folic acid substances has a more obvious anti-liver injury effect on CCl4 combined with high-fat rats.

[0060] The Q values of the low-dose obeticholic acid + low-dose folic acid group in reducing LDL-C, increasing HDL-C, reducing FFA and TNF-a are 2.66, 3.01, 1.93 and 2.43, respectively. Similarly, the Q values of the other two-drug combination groups are all greater than 1.15. It can be seen that the low-dose and high-dose groups both play a synergistic role in reducing liver cell damage and FFA toxicity, reducing inflammatory damage and liver steatosis, and achieving the purpose of synergistic treatment of fatty liver and inflammation.

[0061] According to the experimental data, the low-dose FXR agonist and low-dose folic acid group are stronger than the high-dose group in reducing the rate of pruritus, LDL-C, TNF-a, liver tissue FFA and increasing HDL-C, and the synergistic effect of each drug is stronger (the Q value is larger). At the same time of reducing side effects, it has stronger liver histology improvement and clinical efficacy, and is a better dose combination.

[0062] Table 2 Comparison of pruritus rate, LDL-C and HDL-C of rats in each group n = 10

[0063]

[0064]

[0065] Note: Compared with the normal diet group, a P < 0.05, aa P < 0.01; compared with the model control group, b P < 0.05, bb P < 0.01.

[0066] Table 3 Comparison of liver tissue FFA and serum TNF-a of rats in each group n = 10

[0067]

[0068]

[0069] Note: Compared with the normal diet group, a P < 0.05, aa P < 0.01; compared with the model control group, b P < 0.05, bb P < 0.01.

Claims

1. A pharmaceutical composition for adjunctive prevention and / or treatment of fatty liver disease induced by a high-fat diet, comprising: a) a) 0.01–500 mg of a farnesoid X receptor agonist or its salt; b) 0.1–5 mg of a folic acid derivative; c) a pharmaceutically acceptable excipient, wherein the farnesoid X receptor agonist is selected from obeticholic acid, zopifexo, or ciclofaxo, and the folic acid derivative is 5-methyltetrahydrofolate or folic acid.

2. The pharmaceutical composition according to claim 1, characterized in that, The effective pharmaceutical dose of the obeticholic acid is 1-50 mg; the effective pharmaceutical dose of the zopiclone is 0.01-0.5 mg; and the effective pharmaceutical dose of the ciclofaxol is 10-200 mg.

3. The pharmaceutical composition according to claim 2, characterized in that, The effective pharmaceutical dose of the obeticholic acid is 5-25 mg; the effective pharmaceutical dose of the zopiclone is 0.03-0.2 mg; and the effective pharmaceutical dose of the ciclofaxol is 30-100 mg.

4. The pharmaceutical composition according to claim 1, characterized in that, The effective medicinal dose of the folic acid-like substances is 0.2–1.2 mg.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The pharmaceutical dosage form of the pharmaceutical composition is an oral preparation, including tablets, capsules, granules, pills, oral liquids, powders, liposomes, nanoformulations, microcapsules, microemulsions, porous polymer microspheres, or other pharmaceutically acceptable dosage forms.

6. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a product for adjuvant prevention and / or treatment of fatty liver disease induced by a high-fat diet.

7. The use according to claim 6, characterized in that, The fatty liver disease induced by the high-fat diet includes fatty liver due to obesity, fatty liver due to diabetes, fatty liver due to hyperlipidemia, fatty liver due to rapid weight loss, fatty liver due to starvation, fatty liver due to nutrition, fatty liver due to pregnancy, or steatohepatitis.

8. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a product for relieving the side effects of pruritus and dyslipidemia caused by farnesoid X receptor agonist drugs.

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