Application of grizoprevir in preparation of medicine for preventing, relieving and / or treating obesity and fatty liver disease and medicine composition of grizoprevir

Abstract

The invention belongs to the technical field of medicines, and discloses application of grizoprevir in preparation of medicines for preventing, relieving and / or treating obesity and fatty liver diseases and a pharmaceutical composition of the grizoprevir. The research of the inventor proves that the grazoprevir has an inhibiting effect on liver lipid deposition generated by high-fat and high-cholesterol diet induction, the ratio of liver weight to body weight is obviously reduced, and fibrosis in the liver is obviously improved, so that a new indication is provided for clinical application of the grazoprevir, and the grazoprevir has a good clinical application prospect. And potential and good application prospects are opened for the field of treating obesity and fatty liver diseases by using the grizoprevir.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of gzopivir in the preparation of drugs for the prevention, relief and / or treatment of obesity and fatty liver disease, and pharmaceutical compositions thereof. Background Technology

[0002] Fatty liver disease (FAD) is a common liver pathology characterized by excessive fat accumulation in hepatocytes due to various causes. Based on different etiologies, FAD is generally divided into two main categories: alcoholic fatty liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinicopathological syndrome characterized by excessive fat deposition in hepatocytes, excluding alcohol and other clearly defined liver-damaging factors. Its incidence has increased significantly, with a global prevalence of approximately 24%. Clinical findings show that the incidence of NAFLD in obese individuals is about three times the average prevalence, suggesting a close link between obesity and NAFLD. Currently, there are no approved drugs for the treatment of NAFLD, therefore, there is an urgent need to explore effective treatments.

[0003] In the current biopharmaceutical industry, generic drugs face significantly reduced profit margins due to centralized procurement policies; imitation innovation targeting established targets struggles to gain a market advantage; and while original innovation holds great promise, it involves high R&D costs, long cycles, and significant risks. Against this backdrop, the "drug repurposing" strategy is an effective approach to drug development. Existing drugs, having undergone clinical trials and extensive observation of numerous cases over extended periods, demonstrate a more effective guarantee of safety, a more comprehensive understanding of potential adverse reactions, and relatively lower costs associated with clinical trials. Therefore, researching known clinical drugs and expanding their new functions and indications can greatly promote the development of clinical treatments, conserve healthcare resources, and enhance the market value of drugs.

[0004] Grazoprevir hydrate is an antiviral agent that acts on non-protein 3 / 4A protease inhibitors. Multiple clinical studies have shown that the combination of grazoprevir and elbasvir can treat hepatitis C to some extent, with mild side effects and low toxicity. However, there are currently no reports on the application of grazoprevir in the preparation of drugs for the prevention, relief, and / or treatment of NAFLD. Fatty liver disease is seriously threatening the health of Chinese people, having become the most prevalent liver disease, with an increasing incidence rate and a trend towards younger age of onset. Therefore, researching new applications of grazoprevir and its use in the preparation of drugs for the prevention, relief, and / or treatment of obesity and fatty liver disease, thereby overcoming the lack of effective treatments in existing technologies, is a research trend for those skilled in the art. Summary of the Invention

[0005] The purpose of this invention is to provide the use of gzopivir in the preparation of medicaments for the prevention, relief and / or treatment of obesity and fatty liver disease, and pharmaceutical compositions thereof.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides the use of gzopivir in the preparation of medicaments for the prevention, relief and / or treatment of obesity and fatty liver disease.

[0007] Preferably, the obesity is obesity induced by a high-fat diet.

[0008] Preferably, the fatty liver disease is non-alcoholic fatty liver disease (NAFLD).

[0009] More preferably, the NAFLD is diet-induced non-alcoholic fatty liver disease.

[0010] More preferably, the NAFLD is selected from non-alcoholic simple fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis.

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising gzopivir and pharmaceutically acceptable excipients.

[0012] Preferably, the dosage form of the pharmaceutical composition is tablets, granules, capsules, sprays, injections, oral solutions, or any combination thereof.

[0013] Preferably, the dosage of gzopivir is 40-80 mg / time, taken 1-2 times daily.

[0014] Preferably, the pharmaceutical composition is used to prepare a drug for improving liver inflammation and / or fibrosis in patients with fatty liver.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention is the first to discover, through pharmacological experiments, that glizopivir has a good therapeutic effect on fatty liver disease, especially NAFLD induced by a high-fat diet. Systematic experimental studies have shown that glizopivir significantly inhibits lipid deposition induced by a high-fat diet, resulting in a significant decrease in both liver weight and body weight, demonstrating its potential for treating obesity. It also significantly improves hepatic steatosis and effectively inhibits hepatic fibrosis. Compared to existing technologies, this invention is the first to discover that glizopivir can be used to prevent and / or treat obesity and fatty liver disease, especially obesity induced by a high-fat diet and non-alcoholic fatty liver disease, with significant effects. Attached Figure Description

[0016] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0017] Figure 1 The graph shows the statistical results of liver weight, body weight, and liver weight / body weight of mice in the NC group, HFHC group, and gzopivir group in Example 1. Figure 2 The images show the HE and PSR staining results of liver tissues from mice in the NC, HFHC, and gzopivir groups in Example 1. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of the present invention will be described in detail below. The provided embodiments are merely illustrative of the method of the present invention and do not limit the remaining content disclosed in the present invention in any way.

[0019] Example 1: Animal Experiment Experimental animals: Male C57BL / 6 mice aged 8-10 weeks and weighing 21.0-25.0g were selected as experimental subjects; Experimental materials: SPF grade feed was purchased from Beijing Huafukang Biotechnology Co., Ltd.; High-fat high-cholesterol diet (HFHC) was purchased from Nantong Trofi Feeding Technology Co., Ltd.; Gzopivir was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd. Experimental conditions: The experiment was conducted in an SPF-grade laboratory animal center with a room temperature of 22–24°C, humidity of 40–70%, and alternating light and dark lighting for 12 hours. Animals had free access to water and food. Eighteen male C57BL / 6 mice were randomly divided into three groups of six after one week of acclimatization: the NC group, the HFHC group, and the glizopeptide group. The HFHC and glizopeptide groups were fed a high-fat, high-cholesterol diet for four weeks, while the NC group was fed an SPF-grade diet for four weeks. After four weeks of feeding, all three groups were simultaneously administered medication. The glizopeptide group was administered glizopeptide (60 mg / kg / time) by gavage, while the NC and HFHC groups were administered an equal amount of 1% CMC-Na by gavage, once daily. During this period, the HFHC and glizopeptide groups continued to be fed a high-fat, high-cholesterol diet, while the NC group continued to be fed an SPF-grade diet. After 12 weeks of medication, tissue samples were collected, and the body weight and liver weight of the mice in each group were measured. The liver weight / body weight ratio was calculated, and the liver tissue was subjected to pathological examination. The experimental results are as follows: Figures 1-2 As shown; The specific steps for pathological testing are as follows: 1) Preparation of paraffin specimen sections: Trim liver → embedding frame treatment → rinsing with running water → dehydration → clearing → embedding → sectioning → spreading → air drying or baking for later use; 2) The main steps of hematoxylin-eosin (HE) staining are: take paraffin specimens, dewax them to water → stain cell nuclei with hematoxylin → stain cytoplasm with eosin → dehydrate and mount the slides → examine under a microscope, and collect and analyze images; 3) The main steps of Sirius Red (PSR) staining are: take paraffin specimen sections, dewax them to water → drop Sirius Red staining solution on the sections → rinse slightly with running water to remove the staining solution from the surface of the sections → stain the cell nuclei with Mayer hematoxylin staining solution → rinse with running water → dehydrate and mount the sections.

[0020] Depend on Figure 1 The statistical results of liver weight, body weight, and liver weight / body weight ratio in mice in the NC group, HFHC group, and gzopivir group after administration of glizopivir showed that, compared with the NC group, the body weight, liver weight / body weight ratio (P<0.01), and liver weight (P<0.001) of mice in the HFHC group were significantly increased, indicating that the model was successfully established. Compared with the HFHC group, the liver weight (P<0.05), liver weight / body weight ratio (P<0.001), and body weight (P<0.001) of mice in the gzopivir group were significantly decreased, indicating that gzopivir can significantly inhibit fat accumulation and weight gain induced by the HFHC diet and has a weight loss effect.

[0021] Combination Figure 2 Pathological staining results of liver tissues from mice in the NC, HFHC, and gzopivir groups after administration of glizopivir showed that, compared with the NC group, HE staining in the HFHC group revealed more dispersed cytoplasm, while PSR staining showed red collagen fiber deposition, indicating experimental success. In contrast, HE staining in the gzopivir group showed improved hepatocyte morphology, denser cytoplasm, and more regular cell arrangement, effectively improving hepatic steatosis. PSR staining showed that administration effectively inhibited hepatic fibrosis. These findings indicate that gzopivir can improve hepatocyte damage, promote hepatocyte repair, reduce hepatic steatosis, and inhibit and reverse hepatic fibrosis, making it effective in treating liver diseases related to hepatocyte damage, fatty liver, and hepatic fibrosis, such as non-alcoholic steatohepatitis and drug-induced liver injury.

[0022] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. Use of gzopivir in the preparation of drugs for the prevention, relief and / or treatment of obesity and fatty liver disease.

2. The application according to claim 1, characterized in that, The obesity mentioned refers to obesity induced by a high-fat diet.

3. The application according to claim 1, characterized in that, The fatty liver disease mentioned is non-alcoholic fatty liver disease (NAFLD).

4. The application according to claim 3, characterized in that, The aforementioned NAFLD refers to diet-induced non-alcoholic fatty liver disease.

5. The application according to claim 3, characterized in that, The NAFLD is selected from non-alcoholic simple fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes gzopivir and pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that, The dosage form of the pharmaceutical composition is tablets, granules, capsules, sprays, injections, oral solutions, or any combination thereof.

8. The pharmaceutical composition according to claim 6, characterized in that, The dosage of gzopivir is 40-80 mg per dose, taken 1-2 times daily.

9. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is used to prepare a drug for improving liver inflammation and / or fibrosis in patients with fatty liver.

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