Pharmaceutical composition for treating drug-induced liver injury and preparation method thereof

Abstract

The invention relates to the technical field of biological medicine, and discloses a pharmaceutical composition for treating drug-induced liver injury and a preparation method thereof, active ingredients are ginsenoside Re and betaine, and the active ingredients are matched with pharmaceutically acceptable auxiliary materials such as microcrystalline cellulose to prepare dispersible tablets. The processes of gradient drying, precise tabletting and the like are adopted for preparation, and the component mixing and dissolution efficiency is optimized. The composition can significantly reduce transaminase and repair liver injury through the synergistic effect of oxidation resistance, inflammation resistance and hepatocyte repair, has the effect superior to that of a pharmaceutical composition with a single active component, and is fast in disintegration, high in dissolution rate, good in safety, controllable in quality and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to a pharmaceutical composition for treating drug-induced liver injury and a method for preparing the same. Background Technology

[0002] Drug-induced liver injury (DILI) refers to liver damage caused by the drug itself or its metabolites, or by hypersensitivity or decreased tolerance to the drug due to specific individual conditions. Clinically, it can manifest as various acute and chronic liver diseases. Mild cases may recover spontaneously after drug discontinuation, while severe cases can be life-threatening and require aggressive treatment and emergency care. DILI can occur in healthy individuals with no prior history of liver disease or in patients with pre-existing serious conditions; it can occur with overdose or under normal dosage.

[0003] Currently, most traditional drugs in existing technologies rely on a single active ingredient (such as glycyrrhizic acid, silymarin, or single ginsenosides), with a single mechanism of action. They either focus solely on anti-inflammatory and antioxidant effects or only on hepatocyte protection, failing to simultaneously address the entire chain of needs: "oxidative stress inhibition - inflammation resolution - hepatocyte repair - metabolic regulation." Traditional drugs are commonly available in tablet, capsule, or decoction forms, which have three major drawbacks: ① slow disintegration (usually ≥15 minutes) and low dissolution (most single-ingredient drugs have a dissolution rate ≤70% after 45 minutes); ② poor bioavailability, as intestinal absorption may be impaired in patients with liver damage, making it difficult for traditional formulations to achieve rapid efficacy; ③ insufficient convenience of administration (e.g., decoctions). Traditional drugs have two main safety risks: ① Chemically synthesized drugs (such as some hepatoprotective drugs) may increase the metabolic burden on the liver and kidneys with long-term use, and may even cause secondary damage; ② Naturally extracted drugs (such as crude milk thistle extract) have insufficient purity, and impurities may cause allergies or gastrointestinal reactions, and there is a lack of clear long-term toxicity data; Traditional drugs (especially Chinese herbal compound or natural extract preparations) often have the problems of "large fluctuations in component content and vague quality standards": ① There is a lack of precise quantitative methods for multiple active ingredients; ② Key process indicators such as dissolution rate and disintegration time are not clearly defined; ③ They have poor stability and are prone to component degradation and decreased efficacy during long-term storage.

[0004] Therefore, developing a pharmaceutical composition and its preparation method for treating drug-induced liver injury that has significant therapeutic effects, high bioavailability, and excellent product stability is of great practical significance. Summary of the Invention

[0005] In view of this, the present invention proposes a pharmaceutical composition for treating drug-induced liver injury and its preparation method, aiming to solve the problems of insufficient efficacy of single active ingredients, low bioavailability, toxic side effects, large fluctuations in component content, and vague quality standards in traditional drugs for the prevention or treatment of drug-induced liver injury in the current technology.

[0006] This invention provides a pharmaceutical composition for treating drug-induced liver injury, the pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, the active ingredient being composed of ginsenoside Re and betaine, and the pharmaceutically acceptable excipients comprising fillers, disintegrants, flow aids, lubricants, and binders. Furthermore, the pharmaceutical composition comprises the following components in parts by weight: Ginsenoside Re 1-4 parts, betaine 5-20 parts, filler 30-50 parts, disintegrant 5-10 parts, flow aid 1-3 parts, lubricant 0.5-1.5 parts, binder 2-5 parts.

[0007] Furthermore, the weight ratio of ginsenoside Re to betaine is 1:10.

[0008] Furthermore, the filler is microcrystalline cellulose; the disintegrant is cross-linked polyvinylpyrrolidone; the flow aid is silica; the lubricant is magnesium stearate; and the binder is polyvinylpyrrolidone K30.

[0009] A method for preparing a pharmaceutical composition for treating drug-induced liver injury, comprising the following steps: (1) Raw material pretreatment: Ginsenoside Re and betaine are crushed and sieved separately, and the excipients are crushed and sieved for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and crospovidone according to the prescription ratio, stir and mix evenly to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with a 50% ethanol solution, add it to the mixed powder to make soft material, and sieve it to make wet granules; (4) Drying: The wet particles are subjected to gradient drying, which includes a first stage, a second stage and a third stage, to obtain dried particles; (5) Granulation: The dried granules are sieved and granulated, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

[0010] Furthermore, in step (1), the ginsenoside Re and betaine are pulverized and sieved through a 70-80 mesh sieve; the excipients are pulverized and sieved through a 50-60 mesh sieve.

[0011] Furthermore, the stirring parameters in step (2) are: rotation speed 20-30 r / min and time 10-15 min; the sieving in step (3) is sieve 20-30 mesh.

[0012] Furthermore, in step (4), the parameters for the first stage are: temperature 45-55℃ and time 40-50min; the parameters for the second stage are: temperature 56-60℃ and time 60-90min; and the parameters for the third stage are: temperature 40-50℃ and time 50-70min.

[0013] Furthermore, the sieving in step (5) is sieve sieve 10-20 mesh.

[0014] Furthermore, the pressure during tablet compression in step (6) is 10-15 MPa.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: In this invention, a binary synergistic system of ginsenoside Re and betaine is selected as the active ingredient. The two have complementary mechanisms. Ginsenoside Re effectively inhibits the release of inflammatory factors and enhances the body's antioxidant capacity, while betaine, as a natural methyl donor, promotes hepatocyte regeneration and repairs mitochondrial function, thus forming a dual effect of inhibiting damage and actively repairing. The pharmaceutical composition prepared by this invention is a dispersible tablet. By optimizing the excipient ratio and process parameters, compared with traditional drugs, the dispersible tablet product has a faster disintegration time, improved dissolution and bioavailability. It can also be taken in water, which is suitable for patients in the acute phase of liver injury with nausea and difficulty swallowing, thus improving the applicability of the product.

[0016] The active ingredients used in this invention, ginsenoside Re and betaine, have high purity and extremely low impurity content, reducing non-specific reactions. Long-term toxicity tests show no abnormalities in blood routine, liver and kidney function, or histopathological examinations, and no obvious cumulative toxicity.

[0017] The pharmaceutical composition prepared by this invention precisely targets the core pathological process through a synergistic system. It can not only rapidly inhibit the inflammatory response and oxidative stress caused by metabolites, but also promote the regeneration of damaged hepatocytes, repair necrotic areas of liver tissue, regulate lipid metabolism, and reduce the metabolic burden on the liver. At the same time, it can be used as an adjunct drug for the comprehensive treatment of liver failure, filling the gap of insufficient targeting of traditional broad-spectrum hepatoprotective drugs. Detailed Implementation

[0018] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0019] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included within this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0020] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0021] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0022] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0023] This invention provides a pharmaceutical composition for treating drug-induced liver injury, the pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, the active ingredient being composed of ginsenoside Re and betaine, and the pharmaceutically acceptable excipients being composed of fillers, disintegrants, flow aids, lubricants, and binders.

[0024] This invention adds an active ingredient to the pharmaceutical composition, which consists of ginsenoside Re and betaine. Ginsenoside Re targets reactive oxygen species (ROS) produced by the metabolism of acetaminophen (APAP). Ginsenoside Re can directly scavenge ROS by activating the body's antioxidant enzyme system, reducing the generation of lipid peroxidation products (such as MDA), and preventing damage to organelles such as hepatocyte membranes and mitochondria. It also downregulates the mRNA expression and protein secretion of pro-inflammatory factors in liver tissue, inhibiting the infiltration of inflammatory cells (neutrophils, macrophages) into the site of liver injury, thus preventing "secondary liver injury" caused by amplified inflammatory responses. Furthermore, it inhibits the activation of apoptosis-related proteins (Caspase-3, Bax) and upregulates anti-inflammatory... The expression of apoptosis protein (Bcl-2) blocks programmed apoptosis in damaged hepatocytes, maintaining hepatocyte survival. Betaine contains three active methyl groups, which can participate in methylation reactions in vivo, providing methyl donors for hepatocyte DNA synthesis and protein repair, accelerating the division and proliferation of damaged hepatocytes, and promoting the repair and reconstruction of necrotic areas of liver tissue. It improves APAP-induced mitochondrial structural damage (such as mitochondrial swelling and cristae breakage), enhances the activity of mitochondrial respiratory chain complexes I and III, increases ATP production, restores energy supply to hepatocytes, and alleviates damage caused by hepatocyte "energy exhaustion". It promotes β-oxidation of fatty acids in the liver, reduces the accumulation of triglycerides in hepatocytes, avoids hepatocyte steatosis caused by lipid metabolism disorders, and reduces the burden on liver tissue. In addition, ginsenoside Re exerts its inhibitory effect on damage through anti-oxidation, anti-inflammation and anti-apoptosis, while betaine exerts its active repair effect by promoting regeneration, repairing mitochondria and regulating metabolism. The two complement each other through the mechanisms of inhibiting damage and active repair, forming a synergistic effect, and ultimately achieving the dual therapeutic effect of rapidly improving liver function and deeply repairing liver tissue, far exceeding the independent effect of a single component.

[0025] In this invention, the pharmaceutical composition comprises the following components in parts by weight: Ginsenoside Re 1-4 parts, betaine 5-20 parts, filler 30-50 parts, disintegrant 5-10 parts, flow aid 1-3 parts, lubricant 0.5-1.5 parts, binder 2-5 parts.

[0026] In this invention, the pharmaceutical composition is further preferably composed of the following components in parts by weight: 1-2 parts of ginsenoside Re, 10-20 parts of betaine, 35-50 parts of filler, 7-10 parts of disintegrant, 1.5-3 parts of flow aid, 0.8-1.5 parts of lubricant, and 3-5 parts of binder.

[0027] In this invention, the weight ratio of ginsenoside Re to betaine is 1:10.

[0028] In this invention, the ginsenoside Re was purchased from Manster Biotechnology Co., Ltd.

[0029] This invention does not impose any specific limitation on the type of betaine; any betaine known to those skilled in the art can be used.

[0030] In this invention, the filler is microcrystalline cellulose; the disintegrant is cross-linked polyvinylpyrrolidone; the flow aid is silica; the lubricant is magnesium stearate; and the binder is polyvinylpyrrolidone K30.

[0031] This invention incorporates a filler, microcrystalline cellulose, into the pharmaceutical composition. This filler increases tablet volume, making it particularly suitable for formulations with smaller active ingredient dosages. Its porous structure adsorbs drug components, reducing uneven mixing while maintaining tablet hardness and appearance. In wet granulation, microcrystalline cellulose forms a plastic gel upon contact with water, enhancing interparticle bonding and improving tablet mechanical strength. In dry granulation, its compressibility allows it to be used directly as a dry binder. Microcrystalline cellulose swells upon absorbing water, accelerating tablet disintegration and ensuring rapid drug release and absorption. Furthermore, the spherical particles of microcrystalline cellulose reduce friction between powders, improving material flowability and minimizing sticking during tablet compression.

[0032] The present invention adds silica as a flow aid to the pharmaceutical composition. Silica has good flowability and can act as a flow promoter to improve the flowability of particles, increase the tableting efficiency, increase the hardness of tablets, enhance the mechanical strength of tablets, and shorten the disintegration time of tablets, thereby increasing the dissolution rate of drugs.

[0033] In this invention, crospovidone is added as a disintegrant to the pharmaceutical composition. Crospovidone promotes disintegration and has strong hydrophilicity. Upon contact with water, it rapidly absorbs water and swells, disrupting the internal structure of the tablet and causing it to disintegrate rapidly in the gastrointestinal tract, significantly increasing its dissolution rate. Crospovidone can also enhance the flowability of the powder, reduce the stratification of the drug and excipients during mixing, and ensure uniform tablet content. Furthermore, it can help regulate tablet performance. In wet granulation or direct compression processes, crospovidone can improve the compressibility of granules, reduce the risk of sticking and impaction, and does not affect the hardness and brittleness of the tablet.

[0034] The present invention adds magnesium stearate as a lubricant to the pharmaceutical composition, wherein the magnesium stearate... By forming a lubricating layer on the surface of the granules or mold, magnesium stearate reduces friction between granules, making it easier to demold tablets during the tableting process. It also prevents tablets from sticking together or adhering to packaging materials due to humidity or temperature changes during storage or packaging. It forms a thin film on the surface of drug granules, improving tablet dispersibility and flowability. Furthermore, magnesium stearate improves the flowability of drug powder, making it easier to fill the tableting machine mold, ensuring uniform tablet weight and content, which is crucial for improving drug quality and production efficiency.

[0035] This invention incorporates povidone K30 as a binder in the pharmaceutical composition. In tablet preparation, povidone K30 binds drug powder and fillers to form uniform particles, improving flowability and compressibility, increasing tablet hardness, and reducing breakage during production. For poorly soluble drugs, povidone K30 can improve drug solubility and enhance bioavailability by forming complexes or micelle structures. Povidone K30 also exhibits rapid water absorption and swelling properties, disrupting the internal structure of the tablet, promoting water penetration, and accelerating disintegration, typically within a few minutes. Furthermore, povidone K30 can be used for tablet coating, forming a protective film, improving drug appearance, masking odors, and protecting the drug from light and humidity, thus extending shelf life.

[0036] A method for preparing a pharmaceutical composition for treating drug-induced liver injury, comprising the following steps: (1) Raw material pretreatment: Ginsenoside Re and betaine are crushed and sieved separately, and the excipients are crushed and sieved for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and crospovidone according to the prescription ratio, stir and mix evenly to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with a 50% ethanol solution, add it to the mixed powder to make soft material, and sieve it to make wet granules; (4) Drying: The wet particles are subjected to gradient drying, which includes a first stage, a second stage and a third stage, to obtain dried particles; (5) Granulation: The dried granules are sieved and granulated, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

[0037] In this invention, the ginsenoside Re and betaine mentioned in step (1) are preferably pulverized and sieved through a 70-80 mesh sieve, and more preferably through a 75-80 mesh sieve; the excipients are preferably pulverized and sieved through a 50-60 mesh sieve, and more preferably through a 55-60 mesh sieve.

[0038] In this invention, the stirring parameters in step (2) are preferably: 20-30 r / min rotation speed and 10-15 min time, and more preferably 25-30 r / min rotation speed and 12-15 min time; the sieving in step (3) is preferably sieved through a 20-30 mesh sieve, and more preferably sieved through a 25-30 mesh sieve.

[0039] In this invention, the parameters of the first stage in step (4) are preferably: temperature 45-55℃ and time 40-50min, more preferably temperature 45-52℃ and time 40-48min; the parameters of the second stage are preferably: temperature 56-60℃ and time 60-90min, more preferably temperature 58-60℃ and time 60-80min; the parameters of the third stage are preferably: temperature 40-50℃ and time 50-70min, more preferably temperature 40-45℃ and time 60-70min.

[0040] In this invention, the gradient drying process employs a temperature curve design of "low temperature-medium temperature-low temperature," strictly adhering to a temperature of ≤60℃ throughout the process to maximize the protection of the structural stability of ginsenoside Re. Specifically, the first stage, using low temperature, rapidly removes surface free water, preventing premature degradation of ginsenoside Re due to prolonged exposure of wet particles to high temperatures. The second stage utilizes the thermal stability critical temperature of ginsenoside Re (experiments have verified that the content does not significantly decrease at 60℃), efficiently removing internal bound water while ensuring drying efficiency without exceeding the component's tolerance threshold. The third stage uses low temperature to balance moisture, preventing localized aggregation or degradation of components caused by rapid migration of internal moisture under high temperatures. Furthermore, gradient drying avoids tablet sticking and excessive weight variation due to excessive moisture, or unacceptable tablet brittleness due to excessive moisture. It also ensures a uniform internal pore structure, facilitating easy molding under pressure and preventing tablet cracking, thus guaranteeing tablet hardness stability.

[0041] In this invention, the sieving in step (5) is preferably sieved through a 10-20 mesh sieve, and more preferably through a 15-20 mesh sieve.

[0042] In this invention, the pressure during tablet compression in step (6) is preferably 10-15 MPa, and more preferably 12-15 MPa.

[0043] In this invention, the use of different mesh sieves ensures the quality of the formulation and the feasibility of the process by precisely controlling the particle size of the materials. Specifically, sieving of active ingredients in the raw material pretreatment is to make the powder finer and ensure uniform dispersion, while sieving of excipients is to adapt to mixing and molding and avoid agglomeration. During granulation, sieving is used to control the uniformity of wet particle size, ensuring consistent heating during gradient drying and reducing uneven moisture content. During granulation, sieving is used to break up dried agglomerates, obtain particle size suitable for tableting, and ensure uniform tablet weight, stable hardness, and compliance with disintegration and dissolution standards.

[0044] In this invention, unless otherwise specified, all raw materials required for preparation are commercially available products well known to those skilled in the art.

[0045] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0046] Example 1 Raw materials: 1 part ginsenoside Re, 10 parts betaine, 35 parts filler, 7 parts disintegrant, 1.5 parts flow aid, 0.8 parts lubricant, and 3 parts binder; Preparation method: (1) Raw material pretreatment: Ginsenoside Re and betaine are pulverized and passed through a 75-mesh sieve, and the excipients are pulverized and passed through a 55-mesh sieve for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and cross-linked polyvinylpyrrolidone according to the prescription ratio, and mix them evenly at a speed of 25 r / min for 15 min to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with 50% ethanol solution, add it to the mixed powder to make soft material, and pass it through a 25-mesh sieve to make wet granules; (4) Drying: The wet particles are subjected to a gradient drying process in three stages: low temperature drying at 45°C for 48 min, medium temperature drying at 58°C for 80 min, and low temperature drying at 40°C for 70 min, to obtain dried particles; (5) Granulation: The dried granules are granulated by passing them through a 15-mesh sieve, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets at a pressure of 12 MPa to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

[0047] Example 2 Raw materials: 1 part ginsenoside Re, 10 parts betaine, 40 parts filler, 8 parts disintegrant, 2 parts flow aid, 1 part lubricant, and 4 parts binder; Preparation method: (1) Raw material pretreatment: Ginsenoside Re and betaine are pulverized and passed through a 75-mesh sieve, and the excipients are pulverized and passed through a 55-mesh sieve for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and cross-linked polyvinylpyrrolidone according to the prescription ratio, and mix them evenly at a speed of 28 r / min for 13 min to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with 50% ethanol solution, add it to the mixed powder to make soft material, and pass it through a 25-mesh sieve to make wet granules; (4) Drying: The wet particles are subjected to a gradient drying process in three stages: low temperature drying at 50°C for 45 min, medium temperature drying at 59°C for 70 min, and low temperature drying at 42°C for 65 min, to obtain dried particles; (5) Granulation: The dried granules are granulated by passing them through a 15-mesh sieve, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets at a pressure of 13 MPa to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

[0048] Example 3 Raw materials: 2 parts ginsenoside Re, 20 parts betaine, 50 parts filler, 10 parts disintegrant, 3 parts flow aid, 1.5 parts lubricant, and 5 parts binder; Preparation method: (1) Raw material pretreatment: Ginsenoside Re and betaine are pulverized and passed through an 80-mesh sieve, and the excipients are pulverized and passed through a 60-mesh sieve for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and cross-linked polyvinylpyrrolidone according to the prescription ratio, and mix them evenly at a speed of 30 r / min for 12 min to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with 50% ethanol solution, add it to the mixed powder to make soft material, and pass it through a 30-mesh sieve to make wet granules; (4) Drying: The wet particles are subjected to a gradient drying process in three stages: low temperature drying at 52℃ for 40 min, medium temperature drying at 60℃ for 60 min, and low temperature drying at 45℃ for 60 min, to obtain dried particles; (5) Granulation: The dried granules are granulated by passing them through a 20-mesh sieve, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets at a pressure of 15 MPa to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

[0049] Comparative Example 1 Raw materials: 1 part of ginsenoside Re, a single active ingredient; the remaining raw materials are the same as in Example 1. Preparation method: (1) Raw material pretreatment: Ginsenoside Re is pulverized through a 75-mesh sieve and excipients are pulverized through a 55-mesh sieve for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, microcrystalline cellulose and cross-linked polyvinylpyrrolidone according to the prescription ratio, and mix them evenly at a speed of 25 r / min for 15 min to obtain a mixed powder; The remaining steps are the same as in Example 1.

[0050] Comparative Example 2 Raw materials: 10 parts betaine, the remaining raw materials are the same as in Example 1. Preparation method: (1) Raw material pretreatment: Crush betaine through a 75-mesh sieve and crush auxiliary materials through a 55-mesh sieve for later use; (2) Mixing: Weigh the pretreated betaine, microcrystalline cellulose and cross-linked polyvinylpyrrolidone according to the prescription ratio, and mix them evenly at a speed of 25 r / min for 15 min to obtain a mixed powder; The remaining steps are the same as in Example 1.

[0051] Product testing results: (1) To determine the difference in tablet weight (target tablet weight 100mg) of the products obtained in Examples 1-3 and Comparative Examples 1-2, 20 tablets of the test sample were taken, the total weight was accurately measured, the average tablet weight was calculated, and the weight of each tablet was measured separately. The difference rate between the weight of each tablet and the average tablet weight was calculated. The test was conducted according to the General Chapter 0101 of Part IV of the 2020 edition of the Chinese Pharmacopoeia (tablet weight difference ±3%). (2) The hardness (kgf) of the products obtained in Examples 1-3 and Comparative Examples 1-2 was measured using a YD-3 tablet hardness tester. Ten tablets were taken, and three different points were measured on each tablet. The average value was taken. The test was conducted according to the General Chapter 0921 of Part IV of the Chinese Pharmacopoeia 2020 (Tablet Hardness Test Method). (3) The disintegration time (min) of the products obtained in Examples 1-3 and Comparative Examples 1-2 was determined using a BJ-2 disintegration time tester. Six test tablets were placed in water at 37℃±1℃. The time for complete disintegration and passage through the sieve (pore size 710μm) was observed and recorded. The test was conducted according to General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia (disintegration time of dispersible tablets ≤3min). (4) The dissolution rate (45 min) of the products obtained in Examples 1-3 and Comparative Examples 1-2 was determined by the paddle method (50 rpm, 900 mL of purified water as the dissolution medium, and 37℃±0.5℃). Samples were taken at 45 minutes, filtered through a 0.45 μm filter membrane, and the content of ginsenoside Re was determined by HPLC (detection wavelength 203 nm). The content of betaine was determined by volumetric method. The dissolution rate was calculated according to the General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia (Dissolution Test Method, Paddle Method, 50 rpm, 37℃ water). (5) The ginsenoside Re content (%) of the products obtained in Examples 1-3 and Comparative Examples 1-2 was determined by high performance liquid chromatography (HPLC). Chromatographic conditions: C18 reversed-phase column (4.6×250mm, 5μm), mobile phase methanol-water = 65:35 (v / v), flow rate 1.0mL / min, column temperature 30℃, detection wavelength 203nm, injection volume 20μL). (6) The betaine content (%) of the products obtained in Examples 1-3 and Comparative Examples 1-2 was determined by volumetric method (hydrochloric acid titration). Take an appropriate amount of the test sample, dissolve it in 20 mL of glacial acetic acid, add 2 drops of methyl red indicator, and titrate with 0.1 mol / L hydrochloric acid titrant until red. Calculate the content based on the volume of hydrochloric acid titrant consumed. The detection method is volumetric method (hydrochloric acid titration, methyl red as indicator).

[0052] The performance test results of the products obtained in Examples 1-3 and Comparative Examples 1-2 are shown in Table 1 below. Table 1. Performance test results of products obtained in Examples 1-3 and Comparative Examples 1-2

[0053] As shown in Table 1, Example 3 (preferred formulation and optimized process) exhibits the best disintegration time (1.8 min) and dissolution rate (Re 92.1%, betaine 95.8%). This is due to the use of a finer granulation sieve (30 mesh), a higher amount of disintegrant (10 parts), and a suitable tableting pressure (15 MPa), demonstrating the synergistic optimization of process parameters and formulation. Compared to Comparative Examples 1-2, which contain only one active ingredient, the products of Examples 1-3, which contain two active ingredients, ginsenoside Re and betaine, prepared by this invention have faster disintegration times and improved dissolution rates. Therefore, the pharmaceutical composition prepared by this invention has high bioavailability and improved product stability.

[0054] Animal experimental testing: Drugs and reagents: Ginsenoside Re was purchased from Manster Biotechnology Co., Ltd.; APAP was purchased from Solarbio Biotechnology Co., Ltd.; ALT, AST, GSH, and MDA reagent kits were purchased from Nanjing Jiancheng Bioengineering Institute. Experimental design: Forty ICR mice were randomly divided into 5 groups (n=8), among which: Control group: 0.5% CMC-Na administered by gavage; Model group: APAP 400mg / kg intraperitoneal injection; Single ginsenoside Re group: Ginsenoside Re 2 mg / kg by gavage + APAP 400 mg / kg by intraperitoneal injection; Betaine-only group: betaine 20 mg / kg by gavage + APAP 400 mg / kg by intraperitoneal injection; Composition group: Ginsenoside Re 2mg / kg + Betaine 20mg / kg by gavage + APAP 400mg / kg by intraperitoneal injection.

[0055] The results of animal experiments comparing the experimental group and the model group are shown in Table 2 below. Table 2. Animal experimental results comparing the experimental group and the model group.

[0056] In summary, the pharmaceutical composition of this invention, containing two active ingredients, complements the antioxidant and anti-inflammatory mechanisms of ginsenoside Re and the hepatocyte repair mechanism of betaine. Compared with the model group administered APAP 400mg / kg intraperitoneally, the animal experiments showed the highest reduction rates of serum ALT / AST (83.7% and 81.2%, respectively) and the reduction rate of liver tissue necrosis area (88.6%), far exceeding the single ginsenoside Re group (62.3%, 58.6%, 55.2%) and the single betaine group (41.2%, 39.2%, 40.3%), completely solving the problem of the limitation of single-component action mechanism. Furthermore, the dispersible tablets prepared by this invention have the shortest disintegration time (1.8 min) and a dissolution rate of 92.1% (ginsenoside Re) / 95.8% (betaine) at 45 min, which is an improvement in dissolution efficiency compared with traditional tablets and single-component preparations. The rapid onset of action is more suitable for emergency treatment of acute liver injury, and the tablet weight difference is ≤±2.0%, with stable hardness, making the quality of the preparation more controllable.

[0057] The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention. The scope of protection of the present invention is determined by the appended claims.

[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the specific implementation of the present invention. Any modifications or equivalent substitutions that do not depart from the spirit and scope of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical composition for treating drug-induced liver injury, characterized in that, The pharmaceutical composition comprises an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient consists of ginsenoside Re and betaine, and the pharmaceutically acceptable excipients consist of fillers, disintegrants, flow aids, lubricants, and binders.

2. The pharmaceutical composition for treating drug-induced liver injury according to claim 1, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: Ginsenoside Re 1-4 parts, betaine 5-20 parts, filler 30-50 parts, disintegrant 5-10 parts, flow aid 1-3 parts, lubricant 0.5-1.5 parts, binder 2-5 parts.

3. The pharmaceutical composition for treating drug-induced liver injury according to claim 1, characterized in that, The weight ratio of ginsenoside Re to betaine is 1:

10.

4. The pharmaceutical composition for treating drug-induced liver injury according to claim 1, characterized in that, The filler is microcrystalline cellulose; the disintegrant is cross-linked polyvinylpyrrolidone; the flow aid is silica; the lubricant is magnesium stearate; and the binder is polyvinylpyrrolidone K30.

5. A method for preparing a pharmaceutical composition for treating drug-induced liver injury as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) Raw material pretreatment: Ginsenoside Re and betaine are crushed and sieved separately, and the excipients are crushed and sieved for later use; (2) Mixing: Weigh the pretreated ginsenoside Re, betaine, microcrystalline cellulose and crospovidone according to the prescription ratio, stir and mix evenly to obtain a mixed powder; (3) Granulation: Prepare a 5% binder by mixing polyvinyl ketone K30 with a 50% ethanol solution, add it to the mixed powder to make soft material, and sieve it to make wet granules; (4) Drying: The wet particles are subjected to gradient drying, which includes a first stage, a second stage and a third stage, to obtain dried particles; (5) Granulation: The dried granules are sieved and granulated, and then silica and magnesium stearate are added and mixed to obtain the composition powder; (6) Tableting: The powdered composition is compressed into tablets to obtain the pharmaceutical composition; (7) Packaging: Aluminum-plastic blister packaging.

6. A method for preparing a pharmaceutical composition for treating drug-induced liver injury according to claim 5, characterized in that, In step (1), the ginsenoside Re and betaine are pulverized and sieved through a 70-80 mesh sieve; the excipients are pulverized and sieved through a 50-60 mesh sieve.

7. A method for preparing a pharmaceutical composition for treating drug-induced liver injury according to claim 5, characterized in that, The stirring parameters in step (2) are: rotation speed 20-30 r / min and time 10-15 min; the sieving in step (3) is sieve 20-30 mesh.

8. A method for preparing a pharmaceutical composition for treating drug-induced liver injury according to claim 5, characterized in that, In step (4), the parameters for the first stage are: temperature 45-55℃ and time 40-50min; the parameters for the second stage are: temperature 56-60℃ and time 60-90min; and the parameters for the third stage are: temperature 40-50℃ and time 50-70min.

9. A method for preparing a pharmaceutical composition for treating drug-induced liver injury according to claim 5, characterized in that, The sieving mentioned in step (5) refers to sieving through a 10-20 mesh sieve.

10. A method for preparing a pharmaceutical composition for treating drug-induced liver injury according to claim 5, characterized in that, The pressure during tablet compression in step (6) is 10-15 MPa.

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