Traditional Chinese medicine composition for preventing and treating chronic hepatitis cirrhosis and hepatic fibrosis, traditional Chinese medicine compound preparation and application

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for preventing and treating chronic hepatitis cirrhosis and hepatic fibrosis, a traditional Chinese medicine compound preparation and application. On the basis of combined antiviral treatment, the traditional Chinese medicine compound preparation can remarkably improve symptoms such as hypochondriac discomfort, hypodynamia and poor appetite of a patient, reduce serological indexes (such as HA and LN) of hepatic fibrosis, improve the liver hardness number (LSM) and effectively delay and even partially reverse the hepatic fibrosis process, and the unique advantage of combined treatment of traditional Chinese medicine and western medicine is shown. The traditional Chinese medicine compound preparation is rigorous in formula and clear in principle, and has remarkable clinical applicability and popularization and application value. The traditional Chinese medicine composition is developed into fixed dosage forms such as a mixture, so that standardization and normalization of traditional Chinese medicine treatment of hepatic fibrosis are promoted, and the traditional Chinese medicine composition has good social and economic benefits.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition, a traditional Chinese medicine compound preparation, and its application for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis. Background Technology

[0002] Chronic hepatitis, cirrhosis, and advanced liver fibrosis are key pathological stages in the progression of chronic liver disease and important turning points affecting patient prognosis. Advanced liver fibrosis is considered a "reversible window" for the transition from liver fibrosis to cirrhosis. If timely and effective intervention is not provided at this stage, irreversible structural remodeling of liver tissue will occur, further evolving into cirrhosis, hepatocellular carcinoma, or even end-stage liver disease, seriously threatening the patient's life and health.

[0003] Epidemiological data shows that my country, as a high-incidence area for liver disease, has a large number of patients with chronic hepatitis B virus (HBV) infection and non-alcoholic fatty liver disease (NAFLD). According to a study published in the *Chinese Journal of Hepatology* in 2023, approximately 30%–50% of patients with chronic hepatitis B and NAFLD will gradually develop varying degrees of liver fibrosis, with 10%–20% progressing to cirrhosis within 5–10 years, severely impacting their quality of life. Another multicenter follow-up study indicated that the 5-year survival rate for cirrhosis patients is approximately 55% in the compensated stage, but drops sharply to 14%–35% once decompensated. Furthermore, approximately 85% of primary liver cancers occur on the basis of cirrhosis, highlighting the urgency and importance of intervention for liver fibrosis and early cirrhosis.

[0004] In terms of treatment, modern medicine currently mainly employs etiological treatment (such as antiviral therapy) and symptomatic supportive treatment (such as liver protection and enzyme reduction, portal hypertension management, etc.). Although the application of nucleoside (acid) analogs and interferon can effectively inhibit viral replication and control liver inflammation, their reversal effect on existing fibrotic tissue is limited. Currently, no specific anti-liver fibrosis chemical drugs have been approved for marketing globally, and existing treatments are insufficient to fundamentally block the disease progression chain of "liver fibrosis—cirrhosis—liver cancer." In recent years, some targeted drugs (such as preparations targeting TGF-β, PDGF, and other signaling pathways) have shown some potential in preclinical studies, but they still face challenges such as insufficient targeting, unclear long-term safety, and large individual variability in efficacy.

[0005] Against this backdrop, the advantages of traditional Chinese medicine (TCM) in the overall regulation and multi-target intervention of anti-liver fibrosis treatment are increasingly recognized. Studies have found that TCM, through the principle of "syndrome differentiation and treatment," has a clear mechanism of action in improving liver microcirculation, inhibiting hepatic stellate cell activation, and regulating the balance between extracellular matrix synthesis and degradation. Multiple clinical studies have also confirmed that TCM compound preparations, such as Fuzheng Huayu Pian and Anluo Huaxian Wan, when combined with antiviral therapy, can further improve serological indicators of liver fibrosis and liver stiffness (LSM), with some patients even achieving histological reversal. Therefore, given the current lack of ideal anti-liver fibrosis drugs in modern medicine, further exploring the potential of TCM in reversing liver fibrosis and delaying cirrhosis, and systematically verifying its efficacy and safety using evidence-based medicine methods, has significant clinical value and scientific significance. In this context, based on long-term clinical practice, this invention proposes a TCM compound preparation with the effects of soothing the liver and strengthening the spleen, promoting blood circulation and removing blood stasis, and softening and dispersing masses, aiming to provide an effective and safe TCM treatment option for patients with chronic hepatitis, cirrhosis, and advanced liver fibrosis. Summary of the Invention

[0006] This invention aims to provide a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, and a compound traditional Chinese medicine preparation derived therefrom that composition, which has the effects of soothing the liver and strengthening the spleen, promoting blood circulation and removing blood stasis, softening and dispersing masses. This composition is applied to the preparation of drugs for delaying and treating chronic hepatitis, cirrhosis, and liver fibrosis. It can slow the progression of chronic hepatitis and cirrhosis, reverse progressive liver fibrosis, and is safe and effective. It is suitable for patients with liver stagnation and spleen deficiency, and dampness and blood stasis syndrome, and can improve their clinical symptoms and liver pathological state, providing an effective and safe traditional Chinese medicine treatment option for patients with chronic hepatitis, cirrhosis, and progressive liver fibrosis.

[0007] To achieve the above-mentioned objectives, the present invention is implemented through the following technical solution: A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis includes the following raw materials: Astragalus, vinegar-processed turtle shell, Bupleurum chinense, Poria cocos, Angelica sinensis, Paeonia lactiflora, Polygonum hydropiper, vinegar-processed Curcuma zedoaria, and Campsis grandiflora.

[0008] As a preferred embodiment, a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis comprises, by weight, the following active pharmaceutical ingredients: Astragalus membranaceus 100-250 parts, vinegar-processed turtle shell 80-250 parts, Bupleurum chinense 60-190 parts, Poria cocos 70-240 parts, Angelica sinensis 50-180 parts, Paeonia lactiflora 60-230 parts, Polygonum hydropiper 40-100 parts, Curcuma zedoaria 50-160 parts, Campsis grandiflora 50-170 parts.

[0009] As a preferred embodiment, a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis comprises, by weight, the following active pharmaceutical ingredients: Astragalus membranaceus 100-200 parts, vinegar-processed turtle shell 100-200 parts, Bupleurum chinense 80-160 parts, Poria cocos 100-200 parts, Angelica sinensis 70-140 parts, Paeonia lactiflora 100-200 parts, Polygonum hydropiper 50-80 parts, Curcuma zedoaria 70-140 parts, Campsis grandiflora 60-150 parts.

[0010] As a preferred embodiment, a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis comprises, by weight, the following active pharmaceutical ingredients: Astragalus membranaceus 130-180 parts, vinegar-processed turtle shell 130-180 parts, Bupleurum chinense 90-140 parts, Poria cocos 130-180 parts, Angelica sinensis 90-120 parts, Paeonia lactiflora 130-180 parts, Polygonum hydropiper 55-70 parts, vinegar-processed Curcuma zedoaria 85-110 parts, and Campsis grandiflora 80-100 parts.

[0011] As a preferred embodiment, a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis comprises, by weight, the following active pharmaceutical ingredients: Astragalus membranaceus 150 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 120 parts, Poria cocos 150 parts, Angelica sinensis 100 parts, Paeonia lactiflora 150 parts, Polygonum hydropiper 60 parts, vinegar-processed Curcuma zedoaria 100 parts, and Campsis grandiflora 90 parts.

[0012] A traditional Chinese medicine compound preparation includes a traditional Chinese medicine composition as described above for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis, wherein the traditional Chinese medicine compound preparation is a decoction, tablet, capsule, granule, pill or mixture.

[0013] The traditional Chinese medicine compound preparation of this invention is derived from the clinical experience formula of Hangzhou Xixi Hospital. It strictly follows the principles of syndrome differentiation and treatment in traditional Chinese medicine. Its drug composition and dosage ratio are based on the treatment concept of "regulating the liver and spleen, treating qi and blood, and combining attack and tonification". Each drug complements the other and plays a synergistic role.

[0014] Liver inflammation is the core pathological link throughout the entire course of chronic liver disease, with liver fibrosis, cirrhosis, and even liver cancer being common progression pathways. Cirrhosis, as the end stage of many chronic liver diseases, is characterized by diffuse liver fibrosis and the formation of regenerative nodules, accompanied by distortion of liver lobules and microvascular structures. In Asia, hepatitis B virus (HBV) infection is the main cause of cirrhosis. HBV belongs to the hepatotropic DNA virus family, with a partially double-stranded circular DNA genome. It has a persistent infection and a high tendency to become chronic. If the virus is not completely cleared after infection, it easily prolongs into chronic hepatitis and gradually evolves into liver fibrosis and cirrhosis. Early liver fibrosis often presents with atypical clinical symptoms and is easily overlooked. As the disease progresses, patients may experience symptoms such as hypochondriac pain, abdominal distension, jaundice, and lower extremity edema. In severe cases, it progresses to the decompensated stage, complicated by esophageal and gastric variceal bleeding, hepatic encephalopathy, and other complications, significantly increasing the mortality rate. my country is a country with a high incidence of hepatitis B. According to epidemiological statistics, there are approximately 120 million hepatitis B virus carriers, of whom about 70 million develop liver fibrosis. Although current antiviral therapy (such as nucleoside analogues) can increase the HBV-DNA seroconversion rate to over 90%, due to factors such as viral mutation, poor treatment adherence, and immune tolerance, some patients still have low-level viral replication, which continues to drive the progression of liver fibrosis. In addition, early liver fibrosis lacks sensitive symptoms and signs, and screening and intervention are generally lagging behind, becoming a significant bottleneck in the prevention and control of cirrhosis.

[0015] Modern medicine has made significant progress in antiviral treatment and inflammation control, but it still lacks specific drugs to reverse existing liver fibrosis. Therefore, combining the advantages of traditional Chinese medicine (TCM) in multi-target regulation and overall conditioning to intervene in liver fibrosis has become a current research hotspot. According to TCM theory, liver fibrosis and cirrhosis can be categorized under "hypochondriac pain," "accumulation," and "abdominal masses," with the key pathogenesis being "liver stagnation and spleen deficiency, with dampness and blood stasis mutually binding." For example, the *Medical Essentials: Accumulation* states, "The formation of accumulations is due to insufficient vital energy, which then allows pathogenic factors to take hold," indicating that deficiency of vital energy is the basis of the disease. The *Treatise on Blood Disorders* also emphasizes, "Without removing blood stasis, new blood cannot be generated," clearly indicating that internal obstruction of blood stasis is a crucial link in the formation of fibrosis. Therefore, treatment should be based on the principle of "strengthening the body's resistance and eliminating pathogenic factors," employing methods such as "soothing the liver and strengthening the spleen, promoting blood circulation and removing blood stasis, softening and dispersing masses."

[0016] This formula consists of nine herbs: Astragalus membranaceus, vinegar-processed turtle shell, Bupleurum chinense, Poria cocos, Angelica sinensis, Paeonia lactiflora, Polygonum hydropiper, Curcuma zedoaria, and Campsis grandiflora. Astragalus membranaceus tonifies the middle energizer and replenishes qi; vinegar-processed turtle shell nourishes yin, subdues yang, softens hardness, and dissipates nodules—these are the principal herbs. Bupleurum chinense soothes the liver and relieves stagnation, guiding the other herbs into the liver meridian; Angelica sinensis and Paeonia lactiflora nourish blood and soften the liver; Poria cocos strengthens the spleen and eliminates dampness—these are the assistant herbs. Polygonum hydropiper, Curcuma zedoaria, and Campsis grandiflora invigorate blood, eliminate masses, break up accumulations, and dissipate nodules—these are the adjuvant herbs. The entire formula embodies the academic thought of "treating both the liver and spleen, and regulating qi and blood," aligning with the core pathogenesis of this disease: deficiency in the root and excess in the branch, and the mutual binding of blood stasis and dampness.

[0017] Clinical practice has shown that the traditional Chinese medicine compound preparation of this invention, when combined with antiviral therapy, can significantly improve symptoms such as hypochondriac discomfort, fatigue, and poor appetite in patients, reduce serological indicators of liver fibrosis (such as HA and LN), improve liver stiffness (LSM), and effectively delay or even partially reverse the process of liver fibrosis, demonstrating the unique advantages of integrated traditional Chinese and Western medicine treatment.

[0018] In summary, the traditional Chinese medicine compound preparation of this invention has a rigorous formulation and clear theoretical basis, possessing significant clinical applicability and value for widespread application. Developing it into a fixed dosage form such as a compound preparation will help promote the standardization and normalization of traditional Chinese medicine treatment for liver fibrosis, yielding good social and economic benefits.

[0019] Preferably, when the traditional Chinese medicine compound preparation is a decoction or mixture, its preparation method includes the following steps: Weigh the raw material and soak it in 5-10 times its weight of cold water. Boil for 1.5-2.5 hours, filter, combine the filtrates, concentrate at 60 °C, add ethylparaben while hot, stir well, let stand, and take the supernatant to obtain the decoction or mixture.

[0020] As a further preferred embodiment, when the traditional Chinese medicine compound preparation is a decoction or mixture, its preparation method includes the following steps: soaking the raw material in 5-10 times its weight of cold water, decocting twice, the first decoction for 1.5 h and the second decoction for 1 h, filtering, combining the filtrates, concentrating to a relative density of 1.10±0.05 at 60 ℃, adding ethylparaben while hot, stirring well, letting stand, taking the supernatant to obtain the decoction or mixture.

[0021] Preferably, when the traditional Chinese medicine compound preparation is in the form of tablets, capsules, granules, or pills, its preparation method includes the following steps: Weigh the active pharmaceutical ingredient and grind it into powder. Add an ethanol aqueous solution and heat under reflux for 1.5 to 4.5 hours. Combine the extracts, recover the ethanol, and mix the resulting extract with pharmaceutical excipients to make tablets, capsules, granules, or pills.

[0022] As a further preferred embodiment, when the traditional Chinese medicine compound preparation is in the form of tablets, capsules, granules, or pills, its preparation method includes the following steps: Weigh the active pharmaceutical ingredient and grind it into powder. Add 35 times the mass of 80% ethanol aqueous solution and heat under reflux for extraction 3 times, 1.5 h each time. Combine the extracts, recover the ethanol, and mix the obtained extract with pharmaceutical excipients to make tablets, capsules, granules or pills.

[0023] The above-mentioned traditional Chinese medicine composition is used in the preparation of drugs for delaying and treating chronic hepatitis, cirrhosis and liver fibrosis.

[0024] The above-mentioned traditional Chinese medicine composition is used in the preparation of drugs for the prevention and treatment of chronic hepatitis, cirrhosis and progressive liver fibrosis mainly caused by hepatitis B virus infection.

[0025] Therefore, the present invention has the following beneficial effects: (1) The traditional Chinese medicine compound preparation of the present invention can significantly improve symptoms such as hypochondriac discomfort, fatigue, and poor appetite in patients on the basis of combined antiviral treatment, reduce serological indicators of liver fibrosis (such as HA, LN, etc.), improve liver stiffness value (LSM), effectively delay or even partially reverse the process of liver fibrosis, and show the unique advantages of the combination of traditional Chinese and Western medicine treatment. (2) The traditional Chinese medicine compound preparation of the present invention has a rigorous formulation and clear theoretical basis, and has significant clinical applicability and promotional application value. Developing it into a fixed dosage form such as a compound preparation will help promote the standardization and normalization of traditional Chinese medicine treatment for liver fibrosis, and has good social and economic benefits. Detailed Implementation

[0026] The present invention will be further described below with reference to specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0027] Example 1 This embodiment provides a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis, a traditional Chinese medicine compound preparation including the traditional Chinese medicine composition, its preparation method and application.

[0028] A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 150 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 120 parts, Poria cocos 150 parts, Angelica sinensis 100 parts, Paeonia lactiflora 150 parts, Polygonum hydropiper 60 parts, vinegar-processed Curcuma zedoaria 100 parts, and Campsis grandiflora 90 parts.

[0029] A method for preparing a traditional Chinese medicine compound preparation includes the following steps: Weigh the above nine raw materials, mix them, and grind them into powder. Add 35 times their mass (i.e., ethanol aqueous solution: raw material = 35:1, m / m) of 80% ethanol aqueous solution, and extract by reflux three times, each time for 1.5 h. Combine the extracts, recover the ethanol, and obtain the extract. Take 600 g of the extract, add 350 g of dextrin, and mix well to obtain a mixture. Use 35% of the total mass of the mixture (80% ethanol aqueous solution) and 3.5% povidone as a binder to prepare a soft mass, dry it at 55 ℃, pulverize it through a 10-mesh sieve, and make it into granules, thus obtaining the traditional Chinese medicine compound preparation. It is denoted as Qi Jia San Jie Granules.

[0030] The above-mentioned traditional Chinese medicine composition is used in the preparation of drugs for delaying and treating chronic hepatitis, cirrhosis and liver fibrosis.

[0031] The above-mentioned traditional Chinese medicine composition is used in the preparation of drugs for the prevention and treatment of chronic hepatitis, cirrhosis and progressive liver fibrosis mainly caused by hepatitis B virus infection.

[0032] Example 2 The difference between this embodiment and Embodiment 1 is that: A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 100 parts, vinegar-processed turtle shell 180 parts, Bupleurum chinense 70 parts, Poria cocos 190 parts, Angelica sinensis 70 parts, Paeonia lactiflora 190 parts, Polygonum hydropiper 50 parts, vinegar-processed Curcuma zedoaria 140 parts, and Campsis grandiflora 60 parts.

[0033] A method for preparing a traditional Chinese medicine compound preparation, wherein 620 g of extract and 360 g of dextrin are added instead of 600 g of extract and 350 g of dextrin. All other steps are the same as in Example 1.

[0034] Example 3 This embodiment provides a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis, a traditional Chinese medicine compound preparation including the traditional Chinese medicine composition and its preparation method.

[0035] A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 200 parts, vinegar-processed turtle shell 100 parts, Bupleurum chinense 150 parts, Poria cocos 110 parts, Angelica sinensis 120 parts, Paeonia lactiflora 130 parts, Polygonum hydropiper 90 parts, vinegar-processed Curcuma zedoaria 55 parts, and Campsis grandiflora 145 parts.

[0036] A method for preparing a traditional Chinese medicine compound preparation includes the following steps: Weigh the above nine raw materials, mix them, grind them into powder, add 35 times their weight (i.e., ethanol aqueous solution: raw material = 35:1, m / m) of 80% ethanol aqueous solution, heat and reflux to extract three times, each time for 1.5 h, combine the extracts, recover the ethanol, and obtain the extract. Take 610 g of the extract, add 250 g of starch and 15 g of magnesium stearate, mix thoroughly, granulate with 90% ethanol aqueous solution as a wetting agent, pass through a 16-mesh sieve, compress into tablets, coat with ethyl cellulose, and make into tablets to obtain the traditional Chinese medicine compound preparation.

[0037] Example 4 This embodiment provides a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis, a traditional Chinese medicine compound preparation including the traditional Chinese medicine composition and its preparation method.

[0038] A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 130 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 160 parts, Poria cocos 100 parts, Angelica sinensis 140 parts, Paeonia lactiflora 100 parts, Polygonum hydropiper 40 parts, vinegar-processed Curcuma zedoaria 155 parts, and Campsis grandiflora 60 parts.

[0039] A method for preparing a traditional Chinese medicine compound preparation includes the following steps: Weigh the above nine raw materials, mix them, and grind them into powder. Add 35 times the mass (i.e., ethanol aqueous solution: raw material = 35:1, m / m) of 80% ethanol aqueous solution, and extract by heating and reflux three times, each time for 1.5 hours. Combine the extracts to obtain the extract. Recover the ethanol and concentrate it into a thick paste. Take 640 g of the extract, add an appropriate amount of polyethylene glycol 6000, heat to melt, add the above thick paste, mix well, and drop it into cooled liquid paraffin at a dropping rate of 90-100 drops / min to make drop pills, thus obtaining the traditional Chinese medicine compound preparation.

[0040] Example 5 The formulation of the traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis in this embodiment is the same as that in Example 1.

[0041] The difference between this embodiment and Embodiment 1 is that: A method for preparing a traditional Chinese medicine compound preparation, wherein the extract is concentrated and dried under reduced pressure at 0.09 MPa, dried in a vacuum drying oven, pulverized into a fine powder, sieved, and encapsulated to obtain the traditional Chinese medicine compound preparation. Alternatively, 600 g of the extract is replaced with 350 g of dextrin, mixed thoroughly to obtain a mixture. A soft material is prepared using an 80% ethanol aqueous solution (35% by mass of the mixture) and 3.5% povidone as a binder, dried at 55 °C, pulverized through a 10-mesh sieve, and made into granules to obtain the traditional Chinese medicine compound preparation. All other steps are the same as in Example 1.

[0042] Example 6 The formulation of the traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis in this embodiment is the same as that in Example 1.

[0043] The difference between this embodiment and Embodiment 1 is that: A method for preparing a traditional Chinese medicine compound preparation includes the following steps: Weigh the above nine raw materials, soak them in 5-10 times their weight of cold water, decoct twice (1.5 h for the first decoction and 1 h for the second decoction), filter, combine the filtrates, and concentrate until the relative density of the concentrate at 60 ℃ is 1.10±0.05. While hot, add 0.5 g of ethylparaben, stir well, let stand, take the supernatant, add water to 1000 mL, stir well, dispense, sterilize, and prepare the compound preparation of traditional Chinese medicine.

[0044] Example 7 The formulation of the traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis in this embodiment is the same as that in Example 1.

[0045] The difference between this embodiment and Embodiment 1 is that: A method for preparing a traditional Chinese medicine compound preparation includes the following steps: Weigh the above nine raw materials, soak them in 5-10 times their weight of cold water, decoct twice (1.5 h for the first decoction and 1 h for the second decoction), filter, combine the filtrates, and concentrate until the relative density of the concentrate at 60 ℃ is 1.10±0.05. While hot, add 0.8 g of ethylparaben, stir well, let stand, take the supernatant, add water to 1900 mL, stir well, dispense, sterilize, and prepare the compound preparation of traditional Chinese medicine.

[0046] Example 8 The difference between this embodiment and Embodiment 1 is that: A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 150 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 0 parts, Poria cocos 150 parts, Angelica sinensis 100 parts, Paeonia lactiflora 150 parts, Polygonum hydropiper 60 parts, vinegar-processed Curcuma zedoaria 100 parts, and Campsis grandiflora 90 parts. That is, Bupleurum chinense is not added.

[0047] A method for preparing a traditional Chinese medicine compound preparation, wherein the above eight raw materials are used instead of the above nine raw materials; and 580 g of extract is used instead of 600 g of extract. All other steps are the same as in Example 1.

[0048] Example 9 The difference between this embodiment and Embodiment 1 is that: A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, comprising the following active pharmaceutical ingredients by weight: Astragalus membranaceus 150 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 120 parts, Poria cocos 150 parts, Angelica sinensis 100 parts, Paeonia lactiflora 150 parts, Polygonum hydropiper 0 parts, vinegar-processed Curcuma zedoaria 100 parts, and Campsis grandiflora 90 parts. That is, without adding Polygonum hydropiper.

[0049] A method for preparing a traditional Chinese medicine compound preparation, wherein the above eight raw materials are used instead of the above nine raw materials; and 590 g of extract is used instead of 600 g of extract. All other steps are the same as in Example 1.

[0050] Example 10 The traditional Chinese medicine compound preparation of this invention underwent clinical efficacy observation at the outpatient department of Hangzhou Xixi Hospital from January 2020 to December 2024, aiming to evaluate its therapeutic effects on chronic hepatitis cirrhosis (compensated stage) and progressive liver fibrosis (traditional Chinese medicine syndrome of liver stagnation and spleen deficiency with dampness and blood stasis). The clinical usage is summarized as follows: I. Materials and Methods 1.1 Research Design A self-controlled pre- and post-test protocol was adopted.

[0051] 1.2 Case Selection A total of 120 patients were included, all of whom met the relevant diagnostic criteria in the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition)" and the "Consensus on the Diagnosis and Treatment of Liver Fibrosis (2019 Edition)".

[0052] Age range: 28-76 years, mean age (51.8±10.7) years; Gender distribution: 78 males (65%) and 44 females (35%).

[0053] 1.3 Inclusion Criteria (1) Meets the diagnostic criteria for chronic hepatitis cirrhosis (compensated stage) or progressive liver fibrosis; (2) According to traditional Chinese medicine diagnosis, it belongs to the syndrome of liver stagnation and spleen deficiency with dampness and blood stasis; (3) The patient signs the informed consent form.

[0054] 1.4 Exclusion Criteria (1) Decompensated stage of cirrhosis (with complications such as ascites and hepatic encephalopathy). (2) Comorbid hepatocellular carcinoma or other serious heart or kidney diseases; (3) Known allergy to any component of this preparation.

[0055] 1.5 Dosing regimen (1) Experimental group: In addition to routine treatment with entecavir (ETV), the experimental group was treated with the Qijia Sanjie Granules (a traditional Chinese medicine compound preparation) prepared in Example 1, 50 mg twice a day.

[0056] (2) Control group 1: Same as the experimental group, except for routine treatment with entecavir (ETV), no traditional Chinese medicine compound preparations were used for treatment.

[0057] (3) Control group 2: In addition to routine treatment with entecavir (ETV), control group 2 was treated with Astragalus membranaceus granules prepared in Example 9 (the difference from Example 1 is that only the Chinese medicinal material of Polygonum hydropiper was removed), 50 mg twice a day.

[0058] (4) Control group 3: In addition to routine treatment with entecavir (ETV), control group 3 was treated with Astragalus membranaceus granules prepared in Example 8 (the difference from Example 1 is that only the Chinese herbal medicine Bupleurum chinense was removed), 50 mg twice a day.

[0059] 1.6 Evaluation of therapeutic effect (1) Evaluation of the efficacy of treatment for the degree of liver fibrosis While liver histopathological examination is the gold standard for evaluating the degree of liver fibrosis, its clinical application is limited due to its invasive nature. Therefore, this study used liver stiffness measurement and serum markers of liver fibrosis—hyaluronic acid, laminin, type IV collagen, and type III procollagen—as the main indicators for evaluating treatment efficacy.

[0060] The criteria for judging the efficacy are as follows: (1.1) Effective: After treatment, the liver stiffness measurement value decreased by ≥10% compared with the baseline level before treatment, or two or more of the above four serological markers decreased by ≥25% compared with the baseline level; (1.2) Invalid: Those that do not meet the above "valid" criteria.

[0061] (2) Evaluation of the efficacy of TCM syndromes The efficacy of TCM symptom assessment was calculated using the nimodipine method, with the efficacy index calculated as follows: [(Total symptom score before treatment - Total symptom score after treatment) / Total symptom score before treatment] × 100%. The efficacy level was determined as follows: Clinical cure: The main symptoms and signs have disappeared or basically disappeared, and the efficacy index is ≥90%; Significant improvement: Major symptoms and signs show marked improvement, with 70% ≤ efficacy index < 90%; Effective: Major symptoms and signs improved, with 30% ≤ efficacy index < 70%; Ineffective: The main symptoms and signs show no significant improvement or even worsen, and the efficacy index is <30%.

[0062] 1.7 Therapeutic efficacy observation indicators Evaluation indicators for both groups of patients before and 24 weeks after medication included: (1) Serum liver fibrosis markers: hyaluronic acid, laminin, type IV collagen, and type III procollagen N-terminal peptide; (2) Biochemical indicators: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total bilirubin; (3) Complete blood count and renal function indicators: red blood cell count, white blood cell count, hemoglobin, creatinine, serum urea nitrogen; (4) Imaging observation: Observe the changes in liver stiffness measurement (LSM) before and after treatment; (5) Symptoms in Traditional Chinese Medicine: Main symptoms: Discomfort in the liver area, pain in the hypochondrium; fatigue and weakness; heaviness in the limbs; Secondary symptoms: poor appetite, abdominal distension after meals; nausea and vomiting; dry mouth and bitter taste; sallow complexion; red moles and streaks; varicose veins under the tongue; loose or sticky stools; Tongue and pulse: enlarged tongue, dark purple tongue body or with petechiae and ecchymosis, thick white and greasy tongue coating, and choppy or wiry pulse.

[0063] 1.8 Statistical Methods Data analysis was performed using SPSS 27.0 statistical software. Quantitative data, after normality testing, were expressed as mean ± standard deviation for those conforming to a normal distribution, and paired t-tests were used for comparisons before and after treatment within each group. Data not conforming to a normal distribution were expressed as median (interquartile range), and paired rank-sum tests were used for comparisons before and after treatment within each group. Categorical data were expressed as percentages and analyzed using chi-square tests or Fisher's exact tests. Ordinal data were analyzed using rank-sum tests. All tests were two-tailed, and a p-value < 0.05 was considered statistically significant.

[0064] II. Results 1. Baseline characteristics analysis of cases This study included 120 cases. The patients ranged in age from 28 to 76 years, with a mean age of (51.8 ± 10.7) years. There were 76 males and 36 females.

[0065] 2. Evaluation of therapeutic effect 2.1 Symptoms in Traditional Chinese Medicine: Before treatment, patients presented with symptoms such as hypochondriac pain, hepatosplenomegaly, fatigue, and weakness. A few patients also experienced symptoms such as decreased appetite, pale complexion, and insomnia. After treatment, the clinical symptoms of the patients were significantly reduced compared with those before treatment (P<0.05 or P<0.01), as shown in Table 1 below.

[0066] Table 1: Changes in TCM syndrome scores before and after treatment

[0067] 2.2 Results of four liver fibrosis marker tests: Serum liver fibrosis markers before and after treatment: hyaluronic acid and laminin were significantly lower than before treatment, with statistically significant differences (P<0.05). Type IV collagen and type III procollagen N-terminal peptide were lower before and after treatment, but the differences were not statistically significant. Results are shown in Table 2 below.

[0068] Table 2: Changes in the four liver fibrosis parameters before and after treatment

[0069] 2.3 APRI and FIB-4 test results: The levels of APRI and FIB-4 in patients before and after treatment were significantly lower than before treatment, and the difference was statistically significant (P<0.05). The results are shown in Table 3 below.

[0070] Table 3: Changes in APRI and FIB-4 results before and after treatment

[0071] 2.4 Biochemical indicator test results: The levels of ALT, AST, GGT, ALP, and TBIL remained stable before and after treatment, with no significant changes (P>0.05). The results are shown in Table 4 below.

[0072] Table 4: Changes in various biochemical indicators before and after treatment

[0073] 2.5 Comparison of blood routine and renal function indicators: There were no significant changes in red blood cell count, white blood cell count, hemoglobin, creatinine, and serum urea nitrogen levels before and after treatment (P>0.05), as shown in Table 5 below.

[0074] Table 5: Comparison of blood routine and renal function before and after treatment in patients.

[0075] 2.6 Comparison of Liver Stiffness Measurement (LSM) values: After 24 weeks of treatment, LSM values ​​decreased in all groups compared with before treatment (P<0.05), and there was a significant difference between the groups before and after treatment (P<0.05), as shown in Table 6 below.

[0076] Table 6: Changes in LSM results before and after treatment

[0077] 3. Analysis of safety indicators No adverse clinical symptoms were observed in the 120 patients included, and no clinically significant abnormalities were found in safety indicators such as blood routine tests and liver function tests.

[0078] III. Conclusion Qi Jia San Jie Fang (i.e., the traditional Chinese medicine composition formula of this invention for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis) is an effective empirical formula developed by renowned traditional Chinese medicine doctors in our hospital for chronic hepatitis B cirrhosis and progressive liver fibrosis. This formula emphasizes simultaneous treatment of the liver and spleen, qi and blood, and a combination of tonifying and purging methods, possessing the effects of tonifying qi, promoting blood circulation, removing blood stasis, softening and dispersing masses. As a long-term in-house preparation, clinical trials have shown that: Analysis of the efficacy of liver fibrosis markers: After treatment, the levels of hyaluronic acid, laminin, and type IV collagen in patients decreased significantly compared with before treatment, indicating that the treatment with Qijia Sanjie Decoction can improve liver fibrosis markers and delay the progression of liver fibrosis. The observation of LSM showed that the LSM level decreased after treatment compared with that before treatment, which was statistically significant (P<0.05), indicating that the treatment of Qijia Sanjie Decoction can improve the pathological process of liver fibrosis. Comparison of TCM syndrome scores: Patients with chronic hepatitis B cirrhosis and advanced liver fibrosis often present with hypochondriac pain, fatigue, dry mouth, bitter taste, and gastrointestinal symptoms. This study focused on the statistical analysis of symptoms such as hypochondriac pain, fatigue, abdominal distension and pain, nausea and vomiting, dry mouth, bitter taste, poor appetite, sallow complexion, and lethargy. The analysis showed that treatment significantly improved these symptoms. Combined with the TCM syndrome score results, this demonstrates that the Qi Jia San Jie Fang formula has a good therapeutic effect in improving patients' clinical symptoms.

[0079] During the treatment, no significant abnormalities were observed in the patient's blood routine and renal function indicators, and no adverse reactions occurred. Currently, there are no clinically effective anti-liver fibrosis drugs or targeted drugs for cirrhosis. This formula has clear clinical efficacy, is safe and reliable, and has clinical application value.

[0080] The above description is merely a detailed explanation of preferred embodiments and principles of the present invention. For those skilled in the art, there may be changes in specific implementation methods based on the ideas provided by the present invention, and these changes should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, characterized in that, Including the following active pharmaceutical ingredients: Astragalus, vinegar-processed turtle shell, Bupleurum chinense, Poria cocos, Angelica sinensis, Paeonia lactiflora, Polygonum hydropiper, vinegar-processed Curcuma zedoaria, and Campsis grandiflora.

2. A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis, characterized in that, By weight, it includes the following active pharmaceutical ingredients: Astragalus membranaceus 100-250 parts, vinegar-processed turtle shell 80-250 parts, Bupleurum chinense 60-190 parts, Poria cocos 70-240 parts, Angelica sinensis 50-180 parts, Paeonia lactiflora 60-230 parts, Polygonum hydropiper 40-100 parts, Curcuma zedoaria 50-160 parts, Campsis grandiflora 50-170 parts.

3. The traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis according to claim 1, characterized in that, By weight, it includes the following active pharmaceutical ingredients: Astragalus membranaceus 100-200 parts, vinegar-processed turtle shell 100-200 parts, Bupleurum chinense 80-160 parts, Poria cocos 100-200 parts, Angelica sinensis 70-140 parts, Paeonia lactiflora 100-200 parts, Polygonum hydropiper 50-80 parts, Curcuma zedoaria 70-140 parts, Campsis grandiflora 60-150 parts.

4. The traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis according to claim 1, characterized in that, By weight, it includes the following active pharmaceutical ingredients: Astragalus membranaceus 130-180 parts, vinegar-processed turtle shell 130-180 parts, Bupleurum chinense 90-140 parts, Poria cocos 130-180 parts, Angelica sinensis 90-120 parts, Paeonia lactiflora 130-180 parts, Polygonum hydropiper 55-70 parts, vinegar-processed Curcuma zedoaria 85-110 parts, and Campsis grandiflora 80-100 parts.

5. A traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis, and liver fibrosis according to claim 1, characterized in that, By weight, it includes the following active pharmaceutical ingredients: Astragalus membranaceus 150 parts, vinegar-processed turtle shell 150 parts, Bupleurum chinense 120 parts, Poria cocos 150 parts, Angelica sinensis 100 parts, Paeonia lactiflora 150 parts, Polygonum hydropiper 60 parts, vinegar-processed Curcuma zedoaria 100 parts, and Campsis grandiflora 90 parts.

6. A traditional Chinese medicine compound preparation, characterized in that, The invention includes a traditional Chinese medicine composition for the prevention and treatment of chronic hepatitis, cirrhosis and liver fibrosis according to any one of claims 1-5, wherein the traditional Chinese medicine compound preparation is a decoction, tablet, capsule, granule, pill or mixture.

7. A traditional Chinese medicine compound preparation according to claim 6, characterized in that, When the traditional Chinese medicine compound preparation is a decoction or mixture, its preparation method includes the following steps: Weigh the raw material and soak it in 5-10 times its weight of cold water. Boil for 1.5-2.5 hours, filter, combine the filtrates, concentrate at 60 °C, add ethylparaben while hot, stir well, let stand, and take the supernatant to obtain the decoction or mixture.

8. A traditional Chinese medicine compound preparation according to claim 6, characterized in that, When the traditional Chinese medicine compound preparation is in the form of tablets, capsules, granules, or pills, its preparation method includes the following steps: Weigh the active pharmaceutical ingredient and grind it into powder. Add an ethanol aqueous solution and heat under reflux for 1.5 to 4.5 hours. Combine the extracts, recover the ethanol, and mix the resulting extract with pharmaceutical excipients to make tablets, capsules, granules, or pills.

9. The use of the traditional Chinese medicine composition according to any one of claims 1-5 in the preparation of a medicament for delaying and treating chronic hepatitis, cirrhosis and liver fibrosis.

10. The use of the traditional Chinese medicine composition according to any one of claims 1-5 in the preparation of a drug for the prevention and treatment of chronic hepatitis, cirrhosis and progressive liver fibrosis mainly caused by hepatitis B virus infection.

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