Use of a pharmaceutical composition in the treatment of moderate fatty liver

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to the application of a pharmaceutical composition in the treatment of moderate fatty liver. This invention provides a combination of levocarnitine and trimetazidine, which, through the synergistic effect of levocarnitine and trimetazidine, treats moderate non-alcoholic fatty liver from the perspective of fat and glucose metabolism, thereby achieving its application in the treatment of moderate fatty liver.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of a pharmaceutical composition in the treatment of moderate fatty liver. Background Technology

[0002] Fatty liver disease is classified into mild, moderate, and severe based on fat content, and into alcoholic fatty liver disease, non-alcoholic fatty liver disease, and fatty liver caused by other reasons (such as drug-induced fatty liver). With improved living standards and more diverse diets, the prevalence of fatty liver disease, especially non-alcoholic fatty liver disease, is increasing year by year. Approximately 2 billion people worldwide are affected, making it the leading cause of chronic liver disease globally.

[0003] Mild fatty liver can be managed by lifestyle interventions to reduce body fat percentage and improve histopathological features. However, for non-alcoholic fatty liver disease patients who fail to achieve effective weight loss and control of metabolic risk factors after 3-6 months of lifestyle interventions, drug treatment is necessary.

[0004] The pathogenesis of non-alcoholic fatty liver disease (NAFLD) has been confirmed by research to involve a decrease or decline in the mitochondrial β-fatty acid oxidation function in hepatocytes. This prevents the metabolism of fat in the liver through oxidation, leading to the accumulation of large amounts of fat within hepatocytes. Currently, there are no universally accepted drugs specifically approved for the treatment of NAFLD. Drug treatment for NAFLD primarily focuses on treating comorbidities and improving related symptoms. Hypoglycemic agents (such as metformin tablets) are suitable for patients with type 2 diabetes, while statins (such as rosuvastatin calcium tablets) are suitable for patients with hyperlipidemia.

[0005] For the treatment of non-alcoholic fatty liver disease, most drugs currently focus on treating complications of fatty liver and improving related symptoms. There are no drugs specifically for moderate non-alcoholic fatty liver disease. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a drug combination of levocarnitine and trimetazidine. Through the synergistic effect of levocarnitine and trimetazidine, moderate non-alcoholic fatty liver disease is treated from the perspective of fat and glucose metabolism, thereby achieving its application in the treatment of moderate fatty liver disease.

[0007] Specifically, the first aspect of the present invention is to provide an application of a pharmaceutical composition in the treatment of moderate fatty liver, wherein the pharmaceutical composition is levocarnitine and trimetazidine, and the mass ratio of levocarnitine to trimetazidine is 100:1 to 200:1.

[0008] In some embodiments, the trimetazidine is trimetazidine hydrochloride.

[0009] In some embodiments, the dosage form of the pharmaceutical composition is one of tablets, capsules, soft capsules, granules, pills, suspensions, drops, or oral liquid preparations.

[0010] In some embodiments, the dosage form of the pharmaceutical composition is a tablet.

[0011] In some embodiments, the moderate fatty liver is moderate non-alcoholic fatty liver disease.

[0012] Levocarnitine trimetazidine bilayer tablets are taken orally, making them convenient to take and easy to carry due to their reasonable packaging. Beneficial effects

[0013] The L-carnitine and trimetazidine composition of this invention utilizes L-carnitine as a carrier to transport long-chain fatty acids into liver cells, thereby promoting β-oxidation. L-carnitine is a substance naturally present in the human body; however, the body cannot synthesize L-carnitine and must obtain it from food. However, the amount of L-carnitine obtained from food is very limited. Therefore, when the body lacks L-carnitine and cannot break down large amounts of fat in a timely manner, it must be supplemented through medication. The promotion of long-chain fatty acid transport and fatty acid oxidation by L-carnitine is an oxygen-consuming process, requiring far more oxygen molecules than glucose oxidation. Trimetazidine selectively blocks long-chain 3-ketoacyl-CoA thiolytic enzymes, inhibiting fatty acid β-oxidation and thus promoting glucose oxidation. This optimizes cellular energy supply, maintains appropriate energy metabolism during ischemia, prevents the decline in intracellular ATP levels, and ensures the normal function of ion pumps and the normal operation of transmembrane sodium-potassium flow, maintaining the stability of the intracellular environment. The combination of L-carnitine and trimetazidine can balance the oxidation of fat and glucose in the liver, providing reasonable energy to liver cells and thus protecting the normal functioning of the liver. Detailed Implementation

[0014] Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any discrepancy, the definitions in this specification shall prevail.

[0015] Unless otherwise stated, all percentages, portions, proportions, etc. are by weight.

[0016] The terms “comprising,” “including,” “having,” “containing,” “or any other variation thereof” as used herein are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements, but may also include elements not expressly listed or other elements inherent to such composition, process, method, article, or apparatus.

[0017] When quantities, parts by weight, or other numerical values ​​or parameters are given as ranges, preferred ranges, or a series of upper and lower preferred values, it should be understood that they specifically disclose all ranges formed by any pair of values ​​of any larger or preferred range limit and any smaller or preferred range limit, regardless of whether the ranges are disclosed separately. For example, when describing a range of "1 to 5", the described range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. Unless otherwise stated, where numerical ranges are described herein, the range is intended to include the range endpoints as well as all integers, fractions, decimals, etc., within that range.

[0018] Furthermore, the indefinite articles “a” and “an” preceding the elements or components of this disclosure are intended to indicate that there is no limitation on the number of times the said element or component appears (i.e., occurs). Therefore, “a” or “an” should be understood to include one or at least one, and unless the quantity is explicitly stated to be singular, the singular form of the said element or component also includes the plural case.

[0019] Unless otherwise specified, the materials, methods, and examples described herein are exemplary and not limiting. While similar or equivalent methods and materials may be used in implementing or testing this disclosure, suitable methods and materials are also described herein.

[0020] This disclosure is described in detail below.

[0021] Experiments have demonstrated the therapeutic effect of levocarnitine trimetazidine bilayer tablets on moderate non-alcoholic fatty liver disease.

[0022] 1. Experimental Methods 1.1 Preparation of animal models The model group rats were administered 10 ml / kg of fat emulsion by gavage daily. The fat emulsion composition was as follows: per 100 ml, it contained 10 g cholesterol, 30 g lard, 3 g choline, 10 ml Tween-80, 20 ml propylene glycol, and purified water to a final volume of 100 ml. This was continued for 8 weeks.

[0023] 1.2 Animal Grouping Healthy Wistar rats, half male and half female, weighing 200±20g, were randomly divided into 5 groups of 15 rats each.

[0024] Normal group and model control group: purified water was administered by gavage at a dose of 10 ml / kg / day.

[0025] Metformin tablet group (hereinafter referred to as "metformin group"): 9 g / kg / day by gavage, continuously for 1 month.

[0026] Rosuvastatin calcium tablet group (hereinafter referred to as "statin group"): 9g / kg / day by gavage, continuously for 1 month.

[0027] Levocarnitine trimetazidine bilayer tablet group (referred to as "Levocarnitine group"): 9 g / kg / day by gavage, continuously administered for 1 month.

[0028] After the last administration, the patient was kept fasting for 12 hours and weighed. Anesthetized intraperitoneally with 10% chloral hydrate solution, blood was drawn from the orbital cavity, the patient was euthanized, serum was separated, and the liver was quickly harvested.

[0029] 1.3 Index Measurement 1.3.1 Liver index measurement The removed liver was rinsed thoroughly with saline solution and weighed. The liver weight as a percentage of body weight was used as the liver index.

[0030] 1.3.2 Blood lipid and blood glucose measurement Following the kit instructions, measure triglycerides (TG), total cholesterol (TC), and fasting blood glucose (FBS) on an automated biochemical analyzer.

[0031] 1.3.3 Liver function tests Following the kit's operating instructions, measure alanine aminotransferase (ALT) and aspartate aminotransferase (AST) on an automated biochemical analyzer. 1.3.4 Determination of Energy Metabolism Indicators 1.3.4.1 Pyruvate dehydrogenase (PDH) monitoring: Liver tissue was collected, and mitochondria were extracted according to the Stephan method (JBC, 1991, 266(31): 20998-21003.). Pyruvate dehydrogenase (PDH) was measured according to the method of Hinman et al. (CML S, 2004, (61): 220-229). The method is briefly described as follows: an appropriate amount of mitochondria was added to the assay solution (NAD+ 2.5 mmol / L, coenzyme A 0.1 mmol / L, TPP 0.2 mmol / L, DTT 0.3 mmol / L, MgCl2 1 mmol / L, BSA 1 mg / ml, pH 7.8 phosphate buffer 0.05 mol / L, INT 0.6 mmol / L, lipoamide dehydrogenase 0.1 mg / ml), and the reaction was started with 5 mmol / L pyruvate. The sample was scanned at 500 nm for 5 min.

[0032] 1.3.4.2 Detection of Free Fatty Acid Concentration (FFA): Take an appropriate amount of liver tissue, wash it with physiological saline, prepare a 10% homogenate with physiological saline to prepare a sample, and determine the FFA content according to the instructions of the free fatty acid (FFA) assay kit.

[0033] 1.3.4.3 ATP content detection: An appropriate amount of liver tissue was collected and cryopreserved in liquid nitrogen. Samples were then prepared, and the ATP content of the tissue was determined using an ATP assay kit: the ATP assay reagent was dissolved in an ice-water bath. The liver sample was removed from the liquid nitrogen and a 10% liver homogenate was prepared on ice. The concentration of ATP in the liver homogenate was detected using the luciferase method.

[0034] 2. Experimental Results 2.1 Effects on liver index in fatty liver of rats Table 1 Comparison of liver index among animals in different treatment groups

[0035] # P < 0.05 ## P < 0.01 vs. normal group; * P < 0.05 ** P < 0.01, VS model group.

[0036] Table 1 shows that the liver index of the model group rats was significantly higher than that of the normal rats, indicating hepatomegaly, a clear symptom of moderate fatty liver. The liver index of all drug-treated groups decreased significantly, with the most significant decrease observed in the levofloxacin group, suggesting that the drug formulation can effectively alleviate moderate fatty liver.

[0037] 2.2 Effects on blood lipids and blood glucose Table 2. Changes in blood lipids in each treatment group

[0038] # P < 0.05 ## P < 0.01 vs. normal group; *P < 0.05, **P < 0.01 vs. model group As shown in Table 2, the biguanide group showed a significant reduction in FBS, while the reduction in TG and TC was not significant; the statin group showed a significant reduction in TG and TC, while the reduction in FBS was not significant; the levofloxacin group showed a significant reduction in both FBS and TG and TC.

[0039] 2.3 Effects on liver function Table 3 Changes in liver function indicators in animals of each treatment group

[0040] # P < 0.05 ## P < 0.01 vs. normal group; *P < 0.05, **P < 0.01 vs. model group As shown in Table 3, the left flexure group showed a more significant improvement in liver function and an increase in ATP.

[0041] 3. Conclusion The use of L-carnitine-trimetazidine bilayer tablets to treat moderate non-alcoholic fatty liver disease reduced blood glucose and lipids, improved PDH activity, reduced FFA concentration, and optimized ATP production, indicating that L-carnitine-trimetazidine bilayer tablets have a therapeutic effect on glucose and lipid metabolism imbalance in moderate non-alcoholic fatty liver disease and can play a role in prevention and effective treatment.

[0042] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. The use of a pharmaceutical composition in the treatment of moderate fatty liver, characterized in that, The pharmaceutical composition is levocarnitine and trimetazidine, wherein the mass ratio of levocarnitine to trimetazidine is 100:1 to 200:

1.

2. The application of the pharmaceutical composition according to claim 1 in the treatment of moderate fatty liver, characterized in that, The trimetazidine is trimetazidine hydrochloride.

3. The application of the pharmaceutical composition according to claim 2 in the treatment of moderate fatty liver, characterized in that, The dosage form of the pharmaceutical composition is one of the following: tablets, capsules, soft capsules, granules, pills, suspensions, drop pills, or oral liquid preparations.

4. The use of the pharmaceutical composition according to claim 3 in the treatment of moderate fatty liver, characterized in that, The dosage form of the pharmaceutical composition is tablets.

5. The use of the pharmaceutical composition according to claim 1 in the treatment of moderate fatty liver, characterized in that, The moderate fatty liver mentioned refers to moderate non-alcoholic fatty liver disease.

Images