A traditional Chinese medicine composition, preparation and application for treating liver-spleen disharmony syndrome of chronic hepatitis B in combination with entecavir

Abstract

The present application relates to the field of traditional Chinese medicine, and more particularly to a traditional Chinese medicine composition, preparation and application for treating liver-spleen disharmony syndrome of chronic hepatitis B in combination with entecavir. The traditional Chinese medicine composition is prepared from the following raw materials by weight parts: fried radix bupleuri 1-10 parts, fried angelica 5-15 parts, fried radix paeoniae alba 8-16 parts, fried radix atractylodis 8-16 parts, poria 10-20 parts, fried radix glycyrrhizae 1-10 parts, radix isatidis 5-15 parts, and fried barley 10-20 parts. The present application proposes the application of the traditional Chinese medicine composition in combination with entecavir in the preparation of a medicine for treating liver-spleen disharmony syndrome of chronic hepatitis B. The combined medicine treatment has good safety, high practicability, and good efficacy in treating liver-spleen disharmony syndrome of chronic hepatitis B.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine, specifically to a traditional Chinese medicine composition, preparation, and application for treating liver-spleen disharmony syndrome in combination with entecavir for chronic hepatitis B. Background Technology

[0002] Chronic hepatitis B (CHB) is a long-term inflammatory liver disease caused by the hepatitis B virus (HBV), clinically characterized by a positive HBsAg (hepatitis B surface antigen) test and a course of illness exceeding six months. This disease is not only related to persistent viral infection but also closely linked to various factors such as the body's immune response, genetic factors, and lifestyle. Clinical studies have shown that long-term HBV infection leads to gradual liver damage, potentially progressing to cirrhosis and even liver cancer. With increasing societal pressures and the prevalence of unhealthy lifestyle habits, the incidence of chronic hepatitis B is on the rise, especially among young people, placing a significant burden on their physical and mental health and exacerbating the pressure on the social healthcare system.

[0003] Traditional Chinese medicine (TCM) theory holds that the occurrence of chronic hepatitis B is closely related to disharmony between the liver and spleen, and stagnation of qi and blood. The liver governs the free flow of qi, while the spleen governs digestion and transformation. The pathological basis of liver-spleen disharmony leads to impaired qi and blood circulation, ultimately affecting liver health. Liver qi stagnation and spleen-stomach weakness are common clinical manifestations in patients with chronic hepatitis B. According to the *Suwen* (Plain Questions) chapter "On the Circulation of Vital Energy," liver qi stagnation often causes symptoms such as hypochondriac pain, loss of appetite, and fatigue, while spleen-stomach weakness leads to symptoms such as poor appetite, loose stools, and abdominal distension. Modern medical research indicates that liver-spleen imbalance is a significant factor in the chronicity of hepatitis B.

[0004] To effectively treat chronic hepatitis B with liver-spleen disharmony, current treatment methods often involve combining antiviral drugs such as entecavir with traditional Chinese medicine (TCM). Entecavir is a classic antiviral drug for hepatitis B, possessing significant antiviral effects, but its efficacy in improving liver function, regulating liver and spleen function, and alleviating symptoms is limited. Therefore, many clinical studies have begun exploring treatment regimens combining TCM with Western medicine, hoping to achieve a dual therapeutic effect through the regulating effects of TCM, such as soothing the liver and relieving stagnation, and strengthening the spleen and stomach.

[0005] In recent years, studies have shown that some traditional Chinese medicine formulas, such as Xiaoyao San, can improve symptoms caused by liver-spleen disharmony, enhance liver function, and slow the progression of liver fibrosis. The main mechanism of action of Xiaoyao San is to soothe the liver and relieve stagnation, harmonize the spleen and stomach, and alleviate liver qi stagnation caused by emotional distress. The herbs in this formula, such as Bupleurum, Angelica sinensis, and Paeonia lactiflora, have shown good efficacy in regulating liver qi, promoting blood circulation, and harmonizing the spleen and stomach. However, existing research mainly focuses on the single application of Xiaoyao San; there is a lack of sufficient research to support its combined use with Western medicine, especially in cases of chronic hepatitis B complicated by liver fibrosis.

[0006] According to existing literature, research on the treatment of chronic hepatitis B with Xiaoyao San combined with entecavir has yielded some results, indicating that this combined treatment can effectively improve liver function, slow the progression of liver fibrosis, and improve TCM syndromes. However, research on specific liver-spleen disharmony syndromes is still relatively scarce, and some clinical studies have failed to comprehensively explore the effects of combined treatment on liver stiffness, serum liver fibrosis markers, and quality of life.

[0007] In existing technologies, research on the treatment of chronic hepatitis B with traditional Chinese medicine for liver-spleen disharmony mainly focuses on regulating the liver and spleen and improving symptoms. However, how to effectively combine the antiviral effects of modern drugs and utilize the holistic conditioning function of traditional Chinese medicine to achieve the best therapeutic effect is still a topic worthy of in-depth exploration. Summary of the Invention

[0008] This application, based on clinical diagnosis and treatment, found that CHB patients are mostly those who have been infected with pathogenic factors for a long time. These pathogenic factors lie dormant in the liver, accumulating over time and becoming difficult to eliminate. Furthermore, the rapid pace of modern society, increased life pressure, and more complex work lead to increased mental stress, excessive thinking and fatigue, resulting in stagnation of liver qi and an imbalance in the ascending and descending of qi. Simultaneously, widespread fatigue, lack of sleep, irregular eating habits, and excessive sexual activity can all deplete the body's vital energy, leading to spleen and stomach weakness, insufficient qi and blood, and exacerbating the progression of the disease.

[0009] Specifically, the causes of this disease are as follows:

[0010] (1) External pathogenic factors: Damp-heat pathogenic factors invade the body, affecting the spleen and stomach, leading to impaired spleen function and difficulty in digestion. If damp-heat stagnates in the liver and gallbladder meridians, liver qi becomes disordered, gallbladder qi fails to flow, liver qi rises against the clear yang, and bile overflows to the skin, resulting in jaundice. Prolonged damp-heat pathogenic factors further damage the liver and spleen, leading to poor circulation of qi and blood, resulting in qi stagnation and blood stasis, and a prolonged and difficult-to-cure condition. In the later stages of the disease, yin fluids may be depleted, leading to liver and kidney yin deficiency. Yin deficiency leads to fire excess, and the combination of deficiency fire and pathogenic factors makes the condition more complex. At the same time, the pathogenic factors remain hidden in the liver meridians for a long time, and phlegm and blood stasis gradually accumulate, which can also prolong the course of the disease.

[0011] (2) Improper Diet: The Suwen (Plain Questions) chapter "On the Circulation of Vital Energy" emphasizes: "Therefore, one should carefully harmonize the five flavors, so that the bones are straight and the tendons are supple, the qi and blood flow smoothly, and the pores are tight." After the five grains are digested by the stomach and transformed by the spleen, their essence is distributed to the five internal organs, six bowels, four limbs and hundreds of bones, nourishing the body's life. Poor eating habits and irregular eating will damage the foundation of acquired constitution. The five grains are the staple food for growth and development; the five fruits are the auxiliary food, providing various trace elements; the five meats are the benefit, supplementing the body and adding nutrition to the staple food of the five grains; the five vegetables are the supplement, increasing appetite, filling the stomach, aiding digestion, and preventing disease. Therefore, when these are combined and consumed, the essence and qi are preserved and will not become weak. The "Dietary Manual of Sui Xi Ju" also records: "There is no mysterious secret to nourishing life; it is simply a matter of regulating one's diet. If one eats without knowing the taste, it is already a vegetarian meal; if one eats excessively, one is close to being a beast." In modern society, due to the increasingly fast pace of work and life, people often neglect the regularity of their diet, leading to overeating, not eating when hungry, eating too quickly, and consuming too much rich, fatty, spicy, and fried food, which damages the spleen and stomach's digestive function, disrupts the balance of ascending and descending of clear and turbid substances, causes stagnation in the liver and spleen, and aggravates diseases.

[0012] (3) Emotional Disorder: Emotional instability is closely related to the dysfunction of the internal organs and is also an important risk factor for disease progression. The Ling Shu (Spiritual Pivot) emphasizes: "The will is the means to control the spirit, gather the soul, adapt to cold and heat, and harmonize joy and anger." When the will is in harmony, the spirit is focused and upright, and regret, resentment, anger and righteous indignation are powerless, and the five internal organs can be protected from attack. The Su Wen (Plain Questions) states: "Anger causes qi to rise, joy causes qi to relax, grief causes qi to dissipate, fear causes qi to descend, fright causes qi to become disordered, and thought causes qi to stagnate." Each of the five emotions injures one of the five internal organs, among which anger can injure the liver and thought can injure the spleen. The liver governs emotions. When emotions injure the liver, the liver loses its harmony and the liver qi becomes stagnant. The liver wood and spleen earth are in a generating and restraining relationship. When the liver loses its smooth flow, it can invade the spleen. When the qi of the spleen and stomach is disordered, the transformation and transportation of food essence is inadequate, the acquired foundation is damaged, and the condition is aggravated.

[0013] Specifically, its pathogenesis can be summarized in the following two points.

[0014] (1) The root cause is liver qi stagnation and spleen deficiency with weak blood: In the Five Elements theory, the liver is a wood organ, its body is yin, and its function is yang. The liver governs the free flow of qi, and the smooth flow of liver qi is essential for its circulation. If pathogenic factors such as dampness, heat, and epidemic toxins invade the body and stagnate in the liver, it can lead to liver qi stagnation and qi stagnation. The evolution of qi in the twelve meridians of the internal organs must be stimulated and mobilized by the qi of the liver and gallbladder. When qi is stagnant or the ascending, descending, entering, and exiting of qi are abnormal, the five internal organs will be out of harmony and the qi of the viscera will not flow smoothly. When liver yin is insufficient, the body and function are out of harmony, and the free flow of liver qi is impaired. This can be directly manifested in the body's qi stagnation, and clinically, symptoms such as chest, rib, and lower abdominal distension and pain or migratory pain may appear. The liver thrives on free flow and dislikes stagnation. If the liver's function of regulating qi is impaired, the flow of qi becomes stagnant, easily leading to emotional abnormalities. It is also said that "all diseases originate from qi." Excessive joy disperses heart qi and weakens the spirit; anger and mania cause qi to flow upwards; excessive sadness and sentimentality dissipate qi; fear and shock cause qi to sink; and excessive worry and grief cause qi to stagnate and become obstructed. Emotional imbalances and the liver's function of regulating qi mutually influence each other, clinically manifesting as depression or occasional irritability, poor emotional regulation, and susceptibility to the emotions of others. The liver governs the tendons and ligaments; stagnation of liver qi and insufficient liver blood can lead to malnourishment of the tendons and ligaments, resulting in symptoms such as general weakness and numbness.

[0015] The spleen, belonging to the Earth element in the Five Elements theory, prefers dryness and dislikes dampness. It governs the transformation and transportation of the essence of food and water. The spleen governs the ascending of clear Qi, while the stomach governs the descending of Qi. The spleen and stomach reside in the middle Jiao (middle burner), serving as the pivot of Qi's ascending, descending, entering, and exiting. If the diet is unbalanced, with excessive consumption of rich, fatty, sweet, spicy, and stimulating foods, it easily obstructs the middle Jiao, hindering transformation and transportation, leading to symptoms such as abdominal distension, poor appetite, nausea, acid reflux, and belching. Those with spleen deficiency and weak blood lack the power to transform food and water into essential nutrients for the whole body. This inadequate transformation and transportation easily leads to the accumulation of phlegm and dampness. Excessive dampness can also impair the spleen, exacerbating spleen deficiency, as "dampness likes to return to the spleen because of its affinity with the same Qi." The *Suwen* (Plain Questions) states, "Those with spleen disease, when deficient, experience abdominal distension, intestinal rumbling, diarrhea, and indigestion." When the spleen is damaged by diet, its transformation and transportation become inadequate, causing the small intestine to fail to separate clear and turbid substances, resulting in the simultaneous passage of fluids and waste. Clinically, this often manifests as irregular bowel movements, or even prolonged diarrhea.

[0016] Liver and spleen disorders can also spread to each other. The *Synopsis of Prescriptions of the Golden Chamber* states, "When you see a liver disease, you know it will affect the spleen; you should first strengthen the spleen." When the earth element (spleen and stomach) is weak, the branches and leaves of a tree will wither and decay. Nourishing the earth strengthens the roots and solidifies the body, allowing the fluids in the soil to support the branches and leaves, circulating freely, enabling the tree to flourish. The spleen, being the central damp earth element, is generally calm and often stagnant; therefore, it needs the support of wood element to regulate its flow. The liver belongs to wood, and the spleen to earth; earth nourishes wood, hence "wood relies on earth for nourishment." Excessive liver wood can overpower spleen earth, a condition known as "rebellious attack on the spleen." Therefore, when the spleen and stomach are weak, and the source of qi and blood production is insufficient, the liver wood cannot be nourished, and its smooth flow cannot be achieved, which can also lead to liver qi stagnation and damage to the spleen earth. Thus, liver qi stagnation and spleen deficiency are mutually causal and interactive. Clinically, it is necessary to differentiate the deficiency and excess, strength and weakness of these two elements to adhere to the pathogenesis and achieve effective treatment.

[0017] (2) Mixed with liver meridian disharmony and phlegm-blood stasis: Although CHB initially presents as an invasion of damp-heat epidemic toxins, due to the inherent difficulty in eliminating these toxins and the long course of the disease, the damp-heat epidemic toxins often remain as "latent evils" in the early stages. When the body is weak or is re-infected by external evils, these toxins can trigger the disease or cause it to progress again. The pathogenic qi can enter the five viscera and stagnate internally, or flow into the blood vessels and cause yin-yang disharmony. It enters the collaterals through the meridians and often accumulates and stagnates in the liver meridians. Ye Tianshi believed that the liver, which is associated with wind and wood, harbors ministerial fire, which is strong and dynamic. It needs to be softened by harmonizing the liver meridians to soften its strong nature. The liver meridians not only regulate blood circulation but also regulate the flow of qi. Therefore, when pathogenic toxins stagnate for a long time and accumulate, the collaterals become blocked, affecting both "qi" and "blood". This is consistent with the phenomenon of emotional distress or the progression of liver fibrosis in CHB patients in clinical practice.

[0018] When liver qi is stagnant, spleen qi fails to function properly, body fluids stagnate, blood circulation is impaired, and liver meridians become disharmonious, gradually leading to phlegm and blood stasis. Flowing phlegm, if it accumulates and solidifies in the internal organs, can gradually obstruct qi and cause blood stasis. As early as the Qing Dynasty, Tang Rongchuan, in his *Treatise on Blood Disorders: Blood Stasis*, proposed the pathological mechanism of the mutual binding of blood stasis and phlegm, stating that "blood stasis transforms into water, causing edema; prolonged blood accumulation can also transform into phlegm." The mutual binding of phlegm and blood stasis can obstruct qi and blood, and can also influence each other, leading to a gradual worsening of the other's accumulation. Studies have found that necrotic deposition of epithelial cells in hepatocytes and hepatic sinusoids can cause impaired microcirculation in the liver, leading to blood stasis; other studies have shown that hepatocyte matrix deposition caused by activation of hepatic stellate cells can be caused by phlegm and viscous lipids, thereby altering hemodynamics in the hepatic sinusoids, increasing resistance, and further aggravating blood stasis. Therefore, phlegm and blood stasis obstructing the meridians is one of the important pathological factors in the progression of chronic hepatitis to liver fibrosis and cirrhosis. Phlegm and blood stasis can "rise and fall with the Qi, reaching everywhere." If dead blood is not removed, new blood cannot be generated. Phlegm and blood stasis become entangled and hidden, causing the condition to recur and prolong. In turn, it affects the Qi mechanism of the spleen and stomach in the middle Jiao, aggravating the abnormal transmission and transformation. Clinically, symptoms such as abdominal distension, indigestion, and loose stools are often seen.

[0019] In summary, the applicant believes that this disease is closely related to external pathogenic factors, improper diet, and emotional distress. The disease progression revolves around "liver qi stagnation and spleen deficiency with blood weakness," and in its later stages, it becomes difficult to cure due to the involvement of "liver meridian disharmony and phlegm-blood stasis." Therefore, the applicant proposes that the core of treating liver-spleen disharmony syndrome in CHB lies in "strengthening the spleen and stomach, and soothing the liver and dispersing stagnation," thereby establishing a traditional Chinese medicine composition.

[0020] This invention addresses the shortcomings of existing technologies by providing a traditional Chinese medicine composition for treating liver-spleen disharmony syndrome in chronic hepatitis B in combination with entecavir. This traditional Chinese medicine composition is based on the core principles of "strengthening the spleen and stomach, soothing the liver and dispersing stagnation." When combined with entecavir, it demonstrates good efficacy in treating liver-spleen disharmony syndrome in chronic hepatitis B, significantly improving liver function and TCM symptoms, enhancing patients' quality of life, and delaying liver fibrosis. No adverse reactions have been observed, indicating high safety.

[0021] To achieve the above objectives, the present invention adopts the following technical solution: A traditional Chinese medicine composition for treating liver-spleen disharmony syndrome in chronic hepatitis B in combination with entecavir, wherein the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 1-10 parts of stir-fried Bupleurum chinense, 5-15 parts of stir-fried Angelica sinensis, 8-16 parts of stir-fried Paeonia lactiflora, 8-16 parts of stir-fried Atractylodes macrocephala, 10-20 parts of Poria cocos, 1-10 parts of prepared Glycyrrhiza uralensis, 5-15 parts of Artemisia capillaris, and 10-20 parts of stir-fried Hordeum vulgare.

[0022] As a preferred option, the herbal combination is prepared from the following raw materials in parts by weight: 4-8 parts of stir-fried Bupleurum chinense, 8-12 parts of stir-fried Angelica sinensis, 10-14 parts of stir-fried Paeonia lactiflora, 10-14 parts of stir-fried Atractylodes macrocephala, 13-17 parts of Poria cocos, 4-8 parts of prepared Glycyrrhiza uralensis, 7-11 parts of Artemisia capillaris, and 13-17 parts of stir-fried Hordeum vulgare.

[0023] As a preferred option, the herbal combination is prepared from the following raw materials in parts by weight: 6 parts of stir-fried Bupleurum chinense, 10 parts of stir-fried Angelica sinensis, 12 parts of stir-fried Paeonia lactiflora, 12 parts of stir-fried Atractylodes macrocephala, 15 parts of Poria cocos, 6 parts of prepared Glycyrrhiza uralensis, 9 parts of Artemisia capillaris, and 15 parts of stir-fried Hordeum vulgare.

[0024] Furthermore, the present invention also provides a traditional Chinese medicine composition preparation for the combined treatment of liver-spleen disharmony syndrome in chronic hepatitis B with entecavir, wherein the traditional Chinese medicine composition preparation includes the aforementioned traditional Chinese medicine composition and / or added pharmaceutical excipients.

[0025] Preferably, the traditional Chinese medicine composition preparation is a tablet, granule, pill, powder, ointment, capsule, granule, powder, or liquid preparation.

[0026] Furthermore, the present invention also provides the application of the aforementioned traditional Chinese medicine composition or the aforementioned traditional Chinese medicine composition preparation combined with entecavir in the preparation of a drug for treating liver-spleen disharmony syndrome in chronic hepatitis B.

[0027] As a preferred treatment, the therapeutic effects of treating liver-spleen disharmony syndrome in chronic hepatitis B include: After treatment, the levels of ALT, AST, ALB, and TBiL were all significantly improved compared with before treatment. The HBsAg and HBeAg seroconversion rates were significantly improved after treatment compared with those before treatment; The quantitative levels of HBV-DNA decreased significantly after treatment; The level of liver fibrosis after treatment, including LSM value, serum liver fibrosis markers HA, LN, PCIII, and CIV, was significantly lower than before treatment. The chronic liver disease scores increased significantly after treatment. The chronic liver disease score includes aspects of abdominal symptoms, fatigue, systemic symptoms, activity level, emotional function, and anxiety. The total TCM syndrome scores after treatment were significantly lower than before treatment; After treatment, the patient experienced significant improvement in symptoms such as rib pain, abdominal distension and loose stools, belching and acid reflux, dry mouth and bitter taste, depression or irritability, and insomnia and excessive dreaming compared to before treatment.

[0028] Furthermore, the present invention also provides a drug kit for treating liver-spleen disharmony syndrome in chronic hepatitis B, characterized in that it comprises: First component: the traditional Chinese medicine composition or the traditional Chinese medicine composition preparation described above; Second component: entecavir or a pharmaceutically acceptable salt thereof.

[0029] Preferably, the first and second components are packaged in the same outer packaging and accompanied by instructions to patients to administer the medication according to the following periodic procedure: the Chinese medicine composition is taken orally twice daily, each time corresponding to 150 mL of concentrated decoction or an equal amount of solid preparation, one hour after breakfast and dinner respectively; entecavir is taken continuously at 0.5 mg daily for the entire course of treatment; one course of treatment is three months of continuous use, and one course of treatment is given annually.

[0030] Furthermore, the present invention also provides the application of the aforementioned drug kit in the preparation of a drug for treating liver-spleen disharmony syndrome in chronic hepatitis B. This application is used to treat liver-spleen disharmony syndrome in chronic hepatitis B, and the therapeutic effects include: After treatment, the levels of ALT, AST, ALB, and TBiL were all significantly improved compared with before treatment. The HBsAg and HBeAg seroconversion rates were significantly improved after treatment compared with those before treatment; The quantitative levels of HBV-DNA decreased significantly after treatment; The level of liver fibrosis after treatment, including LSM value, serum liver fibrosis markers HA, LN, PCIII, and CIV, was significantly lower than before treatment. The chronic liver disease scores increased significantly after treatment. The chronic liver disease score includes aspects of abdominal symptoms, fatigue, systemic symptoms, activity level, emotional function, and anxiety. The total TCM syndrome scores after treatment were significantly lower than before treatment; After treatment, the patient experienced significant improvement in symptoms such as rib pain, abdominal distension and loose stools, belching and acid reflux, dry mouth and bitter taste, depression or irritability, and insomnia and excessive dreaming compared to before treatment.

[0031] Furthermore, the present invention also provides the following steps for preparing the traditional Chinese medicine composition: weighing all medicinal materials according to the proportion, decocting and concentrating them, and preparing them into a formulation in an appropriate dosage form.

[0032] Traditional Chinese Medicine Composition: Formulation Analysis of the Traditional Chinese Medicine Composition of the Present Invention: In this formula, stir-fried Bupleurum is the principal herb. Stir-fried Bupleurum harmonizes the exterior and interior, soothes the liver and relieves stagnation, and raises Yang Qi, thus regulating liver Qi and promoting liver Yang. Stir-fried Angelica sinensis and stir-fried Paeonia lactiflora are the assistant herbs. Angelica sinensis invigorates blood and relieves pain, and enters the liver and spleen meridians to replenish blood deficiency in the liver and spleen. Combined with Bupleurum, it can dredge the liver and spleen Qi mechanisms, regulate the blood of the liver and spleen, and relieve stagnation of Qi in the meridians. Stir-fried Paeonia lactiflora can tonify the spleen and soften the liver, tonifying earth and suppressing wood. Bupleurum primarily soothes, while Paeonia lactiflora primarily astringes; together, they achieve the effect of soothing the liver without depleting Yin blood and preserving Yin without stagnation of Qi. Stir-fried Atractylodes macrocephala and Poria cocos are the adjuvant herbs. Together, they can strengthen the spleen, stop diarrhea, resolve dampness and eliminate phlegm, enhancing the spleen-tonifying effect and promoting blood circulation in the waist and navel area. Artemisia capillaris and stir-fried Hordeum vulgare are the adjuvant herbs. They can soothe the liver and spleen, aid digestion, calm the mind, invigorate blood, and reduce swelling. Prepared licorice root is used as the guiding herb to soothe liver tension, strengthen the spleen and stomach, and harmonize the middle jiao. The entire formula works synergistically to soothe the liver and spleen, nourish yin and moisten dryness, disperse stagnation and reduce swelling, thus allowing the liver and spleen qi to flow smoothly, balancing the preservation of yin and blood with the rise of liver yang. It also invigorates blood circulation, reduces swelling, removes blood stasis and promotes new tissue growth, and calms the mind and spirit. Therefore, liver-spleen disharmony is eliminated, digestion and absorption are restored, and emotions are harmonized. The combination of herbs in this application addresses both the root cause and the symptoms, working synergistically to soothe the liver and regulate qi, strengthen the spleen and harmonize the middle jiao, relieve depression and calm the mind, invigorate blood circulation and reduce swelling, soften the liver and relieve pain, and calm the heart. When used, the liver and spleen are soothed, qi stagnation is dispersed, and heart qi stagnation is relieved, thus liver-spleen disharmony is eliminated, and emotions are harmonized.

[0033] The herbal composition of this invention differs from that of Xiaoyao San in that it is based on Xiaoyao San, but with the removal of ginger and mint, and the addition of "Liu Ji Nu" and "fried malt". However, its efficacy and indications focus more on dispersing stagnation and resolving masses, aiming to halt the progression of liver fibrosis in chronic hepatitis B, resulting in a significantly different therapeutic goal. Clinically, these patients often present with liver qi stagnation and spleen and stomach weakness; therefore, the addition of fried malt, which can soothe the liver and harmonize the spleen and stomach, enhances the overall effect of the formula on the liver, stomach, and spleen. Furthermore, it was observed that these patients often experience emotional distress, depression, or irritability, and often have liver meridian disharmony; therefore, Liu Ji Nu, which can calm the nerves, resolve blood stasis, and unblock meridians, is added. Fried malt also has the effect of reducing swelling and dispersing masses; together, they enhance the overall effect of the formula on emotions and liver meridians. By adding and subtracting these two ingredients, the formula remains concise while strengthening its effects of "strengthening the spleen and stomach, soothing the liver, and dispersing masses". It is evident that the Chinese herbal composition is designed to address the characteristics of chronic hepatitis caused by phlegm and blood stasis, which leads to prolonged illness and gradual progression towards liver fibrosis and cirrhosis. Its purpose is fundamentally different from that of Xiaoyao San.

[0034] This invention relates to the application of a traditional Chinese medicine composition combined with entecavir in the preparation of a drug for treating liver-spleen disharmony syndrome in chronic hepatitis B. This combined drug therapy exhibits good safety, high practicality, and good efficacy in treating liver-spleen disharmony syndrome in chronic hepatitis B. 1) This invention effectively improves liver function, enhances patients' quality of life, and delays liver fibrosis. It incorporates considerations of the "hepatitis-liver fibrosis" transformation, approaching the issue from two angles: serological changes and transient liver elastography. The results show that the herbal composition of this invention not only improves liver stiffness but also reduces four serological indicators of liver fibrosis. This indicates that both the herbal composition of this invention combined with entecavir and the original Xiaoyao San formula combined with entecavir can improve the clinical symptoms of chronic hepatitis B, reduce inflammation, and delay the progression of liver fibrosis. Furthermore, in the study of the herbal composition of this invention combined with entecavir for the treatment of chronic hepatitis B, the preliminary experimental results, obtained by measuring liver stiffness and serum indicators of liver fibrosis, comprehensively reflect the clinical efficacy of the combined treatment in delaying and preventing liver fibrosis. The formula includes roasted malt, which regulates and tonifies the middle jiao and is good at restoring stomach qi, to counteract the downward-draining properties of Liu Ji Nu, thus achieving the effect of supporting the body's resistance and eliminating pathogenic factors. Secondly, roasted malt and Artemisia annua have a synergistic effect in promoting qi circulation, aiding digestion, and eliminating stagnation. Malt is the germinating caryopsis of barley, a plant of the Poaceae family. The "Treatise on the Nature of Medicinal Herbs" states that it can "digest undigested food, dispel cold qi, and relieve abdominal distension." When used together, the two herbs can cure chronic diseases and eliminate long-standing accumulations, and are especially suitable for chronic liver diseases that have not healed for a long time and where pathogenic toxins have accumulated.

[0035] 2) It can effectively improve the TCM syndrome of patients with liver-spleen disharmony in chronic hepatitis B, especially in regulating emotions and improving sleep. This is related to the enhanced sedative and calming effects of Liu Ji Nu and the enhanced liver-soothing and spleen-stomach-regulating effects of roasted malt. With a stronger calming and yin-yang harmonizing effect than the original Xiaoyao San formula, the herbal composition also shows better efficacy in treating insomnia and excessive dreaming. This indicates that the herbal composition of this invention, through innovative additions, can more comprehensively treat TCM clinical syndromes induced by liver-spleen disharmony.

[0036] Compared with existing technologies, the present invention has the following technical effects: 1. The literature [Zhao Xiaodan. Clinical study on the treatment of chronic hepatitis B with liver stagnation and spleen deficiency syndrome by Xiaoyao San combined with entecavir [D]. Chengdu University of Traditional Chinese Medicine, 2018.] found that the improvement in liver function indicators and TCM syndrome scores in patients with chronic hepatitis B with liver stagnation and spleen deficiency syndrome by Xiaoyao San combined with entecavir was better than that by entecavir alone. In this invention, the combination of TCM composition and entecavir also has better TCM and Western medicine efficacy than the control group. In terms of TCM syndrome, compared with the former, the TCM composition can better improve emotional function, such as depression or irritability, and can improve the overall quality of life of patients with liver disease. This is related to the sedative and calming effects of Liu Ji Nu and the liver-soothing and spleen-stomach-regulating effects of roasted malt. Through stronger calming and yin-yang harmonizing effects than the original Xiaoyao San, the TCM composition also has better efficacy in treating insomnia and dreaminess. This shows that the TCM composition can more comprehensively treat TCM clinical syndromes induced by liver and spleen disharmony through innovative addition of ingredients.

[0037] 2. The literature [Study on the efficacy of Xiaoyao San combined with entecavir in the treatment of chronic hepatitis B with liver stagnation and spleen deficiency [J]. Shaanxi Journal of Traditional Chinese Medicine, 2020, 41(06):754-757.] found that Xiaoyao San not only has the above-mentioned effects, but also has a better therapeutic effect on liver stiffness than entecavir alone. This invention incorporates the consideration of the "hepatitis-liver fibrosis" transformation, and approaches the problem from two angles: serological changes and transient elastography of the liver. It found that the Chinese medicine composition can not only improve liver stiffness, but also reduce the four indicators of liver fibrosis in serology. This shows that both the Chinese medicine composition combined with entecavir and the original Xiaoyao San combined with entecavir can improve the clinical symptoms of chronic hepatitis B, reduce inflammation, and delay the progression of liver fibrosis. Moreover, in the study of the Chinese medicine composition combined with entecavir in the treatment of chronic hepatitis B, by measuring liver stiffness and serum liver fibrosis indicators, the preliminary test results comprehensively reflect the clinical efficacy of the combined treatment in delaying and preventing liver fibrosis. It is evident that the traditional Chinese medicine composition, by more effectively exerting its effects of "strengthening the spleen and stomach, soothing the liver and dispersing stagnation," demonstrates certain clinical advantages in improving liver function, enhancing patients' quality of life, and delaying the progression of liver fibrosis.

[0038] 3. Literature [Clinical study of 30 cases of compensated cirrhosis after hepatitis B with Xiaoyao San combined with entecavir for the treatment of liver stagnation and spleen deficiency type [J]. Jiangsu Journal of Traditional Chinese Medicine, 2020, 52(11):28-31.DOI:10.19844 / j.cnki.1672-397X.2020.11.010.] Ge Bingjing et al. found that the combination of Xiaoyao San and entecavir for the treatment of patients with compensated cirrhosis after hepatitis B with liver stagnation and spleen deficiency type was superior to entecavir alone in terms of TCM syndrome efficacy, especially in terms of irritability, excessive thinking, and frequent sighing. However, no significant advantage was found in terms of liver function and virological response rate. In the literature "Effects of Xiaoyao San combined with entecavir on fibrosis and iron metabolism in patients with compensated hepatitis B cirrhosis of liver qi stagnation and spleen deficiency type [J]. Journal of Hunan University of Traditional Chinese Medicine, 2021, 41(02):296-302.", Ge Bingjing et al. further found in their subsequent study on the treatment of this disease with Xiaoyao San that the original Xiaoyao San formula was superior to the control group in improving liver fibrosis scores (APRI, FIB-4, GPR) and iron metabolism regulation. However, this study did not show a significant advantage in the efficacy of liver ultrasound parameters (portal vein diameter, spleen thickness, spleen length). The above studies represent beneficial attempts by the original Xiaoyao San formula in the prevention and treatment of cirrhosis and in delaying or reversing liver fibrosis. They indicate that the original Xiaoyao San formula can play a role in liver fibrosis to a certain extent. However, the overall evidence is still insufficient based solely on the improvement of TCM syndromes and liver fibrosis scores. For example, the 2022 Guidelines for the Prevention and Treatment of Chronic Hepatitis B [Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition) [J]. Practical Hepatology Journal, 2023, 26(03):457-478.] clearly points out that the dynamic changes in APRI and FIB-4 results cannot accurately reflect the reversal of liver fibrosis and clinical outcomes. In the study of TCM combination combined with entecavir for the treatment of chronic hepatitis B, the liver stiffness value was measured in conjunction with four serum liver fibrosis indicators, and the combination showed a good effect in reducing liver stiffness value, demonstrating the clinical advantages of TCM combination combined with entecavir in delaying and preventing liver fibrosis.

[0039] In summary, the traditional Chinese medicine composition of this invention demonstrates certain clinical advantages in improving liver function, enhancing patients' quality of life, and delaying the progression of liver fibrosis by more effectively exerting its effects of "strengthening the spleen and stomach, soothing the liver and dispersing nodules." This invention focuses on the intervention of liver fibrosis in patients with chronic hepatitis B, aiming to leverage the role of traditional Chinese medicine in disease prevention and treatment—"protecting the unaffected areas before disease develops"—by enhancing the dispersing and swelling-reducing effects of the original Xiaoyao San formula, achieving early treatment and intervention in the "hepatitis-liver fibrosis" transformation, thereby reducing the development of cirrhosis and alleviating the social burden of liver disease healthcare. Attached Figure Description

[0040] Figure 1 To compare the aspartate aminotransferase (AST) levels between the two groups of patients before and after treatment.

[0041] Figure 2 To compare alanine aminotransferase (ALT) levels between the two patient groups before and after treatment.

[0042] Figure 3 To compare albumin (ALB) levels between the two patient groups before and after treatment.

[0043] Figure 4 To compare the total bilirubin (TBiL) levels between the two groups of patients before and after treatment.

[0044] Figure 5 This study compares the aspartate aminotransferase (AST) levels in two groups of patients before and after treatment.

[0045] Figure 6 This study compares the alanine aminotransferase (ALT) levels in two groups of patients before and after treatment.

[0046] Figure 7 The study compared albumin (ALB) levels in the two groups of patients before and after treatment.

[0047] Figure 8 The total bilirubin (TBiL) levels in the two groups of patients were compared before and after treatment.

[0048] Figure 9 To compare liver stiffness (LSM) values ​​between the two groups of patients before and after treatment.

[0049] Figure 10 The liver stiffness (LSM) values ​​of the two groups of patients were compared before and after treatment.

[0050] Figure 11 To compare the four indicators of liver fibrosis in the two groups before treatment, the four indicators of liver fibrosis include hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and type IV collagen (CIV).

[0051] Figure 12 To compare the four indicators of liver fibrosis in the two groups after treatment, the four indicators of liver fibrosis include hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and type IV collagen (CIV).

[0052] Figure 13 This study compared four indicators of liver fibrosis before and after treatment in the control group. The four indicators of liver fibrosis include hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and type IV collagen (CIV).

[0053] Figure 14The study compared four indicators of liver fibrosis before and after treatment in the experimental group. These four indicators included hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and type IV collagen (CIV).

[0054] Figure 15 This study compares the total scores of the Chronic Liver Disease Questionnaire between the two groups of patients before and after treatment.

[0055] Figure 16 This study compares the total scores of the chronic liver disease questionnaire within the two patient groups before and after treatment.

[0056] Figure 17 This study compares the questionnaire items of the two groups of chronic liver disease before treatment.

[0057] Figure 18 This study compares the various questionnaire items of the two groups of chronic liver disease after treatment.

[0058] Figure 19 This is a comparison of various items in the chronic liver disease questionnaire before and after treatment in the control group.

[0059] Figure 20 This study compares various items in the chronic liver disease questionnaire before and after treatment in the experimental group.

[0060] Figure 21 This study compares the overall efficacy of TCM syndromes in two groups of patients.

[0061] Figure 22 To compare the total scores of TCM syndromes between the two groups of patients before and after treatment.

[0062] Figure 23 The total scores of TCM syndromes within the two groups of patients were compared before and after treatment.

[0063] Figure 24 This study compares the scores of various TCM syndromes in the two groups before treatment.

[0064] Figure 25 To compare the scores of various TCM syndromes in the two groups after treatment.

[0065] Figure 26 This study compares the scores of various TCM syndromes before and after treatment in the control group.

[0066] Figure 27 This study compares the scores of various TCM syndromes before and after treatment in the experimental group. Detailed Implementation

[0067] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the protection scope of the present invention.

[0068] Study on the beneficial effects of this invention: I. Research Materials and Methods (a) Research data 1. Research Subjects This invention selected patients admitted to the outpatient and inpatient departments of the Department of Gastroenterology and Infectious Diseases of Zhejiang Tongde Hospital (a provincial-level tertiary public hospital) from September 2023 to December 2024 as research subjects. All enrolled cases were clinically diagnosed with chronic hepatitis B and met the TCM diagnostic criteria for liver-spleen disharmony.

[0069] 2. Diagnostic criteria and syndrome differentiation criteria (1) Western medicine diagnostic criteria Referring to the clinical diagnosis of HBeAg-positive CHB in the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition)," this invention incorporates the following Western medicine diagnostic criteria for patients: ①HBV-DNA and / or HBsAg positive for more than 6 months; ②serum HBeAg positive; ③accompanied by persistent or recurrent ALT abnormalities, or liver histology showing obvious inflammation and necrosis, or liver histology / non-invasive indicators showing significant fibrosis (≥F2).

[0070] (2) Traditional Chinese Medicine diagnostic criteria for liver-spleen disharmony: Based on the relevant diagnostic criteria in the "Technical Guidelines for Clinical Research of New Traditional Chinese Medicine Drugs" and the "Guidelines for the Diagnosis and Treatment of Chronic Hepatitis B with Traditional Chinese Medicine (2018 Edition)," and according to clinical practice, the diagnostic criteria for liver-spleen disharmony syndrome in chronic hepatitis B in this invention are as follows: Main symptoms: ① Distending pain in the hypochondrium; ② Abdominal distension and loose stools; Secondary symptoms: ① Poor appetite; ② Fatigue and weakness; ③ Belching and acid reflux; ④ Depression or irritability; ⑤ Dry mouth and bitter taste; ⑥ Insomnia and excessive dreaming; Tongue and pulse: ① Tongue is pale red or has teeth marks, with a thin white coating; ② Pulse: Deep and wiry; Diagnostic criteria: The main symptoms ① and ② are necessary symptoms, and 1 to 2 secondary symptoms are met. With reference to the tongue and pulse, this syndrome type can be identified.

[0071] 3. Inclusion criteria (1) Age 18-80 years old, gender not limited; (2) Meets both Western medicine diagnostic criteria and traditional Chinese medicine syndrome differentiation criteria; (3) No contraindications for use in the study; (4) Possess the ability to act independently and be able to strictly follow medical advice for standardized treatment.

[0072] 4. Exclusion Criteria (1) Liver cirrhosis or malignant liver tumor has developed; (2) Patients with serious primary diseases of the cardiovascular, renal and hematopoietic systems, as well as mental illnesses; (3) Pregnant or breastfeeding women; persons with disabilities as defined by law; (4) Those who are unwilling to accept research measures or have other reasons for not being able to cooperate; (5) Those with a known or suspected history of allergy to or severe adverse reactions to traditional Chinese medicine; (6) Individuals who participated in other clinical trials within 3 months prior to enrollment; (7) History of malignant tumors; (8) Patients with diseases that may interfere with the results of tongue diagnosis and pulse diagnosis, such as hemangioma, varicose veins of the lower extremities, tongue lesions, etc.; (9) Other situations in which the researchers believe that it is not appropriate for them to participate in this trial, including those who have received traditional Chinese medicine treatment within the past 2 weeks.

[0073] 5. Rejection criteria and dropout criteria (1) Anyone who is wrongly included because he does not meet the inclusion criteria, is unable to cooperate in completing the study protocol, violates the medication guidelines and trial protocol, or participates in other drug clinical trials during the study period will be excluded from the study.

[0074] (2) Any subject who is lost to follow-up or voluntarily withdraws from the study due to missing data that prevents effective statistical evaluation, serious adverse events or abnormal physiological reactions that lead to termination of treatment, or loss to follow-up or voluntary withdrawal from the study, shall be considered a dropout case.

[0075] 6. Ethical requirements This invention has been approved by the Ethics Committee of Zhejiang Provincial Tongde Hospital (Approval No.: Zhe Tongde Lun Shen 2023 Yan No. 029).

[0076] (II) Research Methods 1. Sample size estimation The sample size was calculated according to the principles of randomization and control, and the calculation formula is as follows: ; Based on the principles of statistical sample size calculation, let α = 0.05 and the power be 90%, then Z α =1.96, Z β =1.28. Based on a literature review of the disease related to this invention, the expected effective rate is 90% in the experimental group and 60% in the control group, i.e., P1=0.9, P2=0.6. The calculated n=44 cases. According to the requirements of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines" and based on the patients' consultation status, the expected dropout rate is 10%, therefore, the final calculated n1=n2=48 cases, requiring a total of 96 subjects to be included in the study.

[0077] 2. Grouping method This invention employs a randomized controlled design, selecting 96 patients enrolled between September 2023 and December 2024 as research subjects. The random number table method using SPSS 26.0 software was used for grouping. The experimental group and the control group each included 48 patients. The grouping process strictly followed the randomization principle to ensure the comparability of baseline characteristics between the two groups.

[0078] 3. Treatment Plan (1) Experimental group This invention relates to a traditional Chinese medicine composition combined with entecavir for treatment. The traditional Chinese medicine composition consists of the following: 6g of stir-fried Bupleurum chinense, 10g of stir-fried Angelica sinensis, 12g of stir-fried Paeonia lactiflora, 12g of stir-fried Atractylodes macrocephala, 15g of Poria cocos, 6g of prepared Glycyrrhiza uralensis, 9g of Artemisia capillaris, and 15g of stir-fried Hordeum vulgare. This prescription is prepared and delivered by the Traditional Chinese Medicine Pharmacy of Zhejiang Provincial Tongde Hospital. Each dose consists of 150mL x 2 packets, to be taken warm one hour after breakfast and dinner. Entecavir (0.5mg x 21 tablets, Suzhou Dongrui Pharmaceutical Co., Ltd., National Drug Approval Number: H20100129) 0.5mg is taken orally, one tablet daily. A course of treatment consists of 3 consecutive months, with one course of treatment per year.

[0079] (2) Control group Treatment with entecavir. Entecavir (0.5mg x 21 tablets, Suzhou Dongrui Pharmaceutical Co., Ltd., National Drug Approval Number: H20100129) 0.5mg orally, one tablet daily. One course of treatment is three consecutive months, with one course per year.

[0080] 4. Observation Indicators (1) General situation Before treatment, general information such as name, gender, and age of the enrolled patients was collected. Statistical analysis was then performed to determine whether there were any differences in the general characteristics of the patients between the two groups that might affect the subsequent conduct of the trial.

[0081] (2) Serological markers ① Liver function tests: including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBiL), and albumin (ALB); ②HBsAg and HBeAg seroconversion rate: This is the percentage of patients who have achieved HBsAg and HBeAg seroconversion after treatment out of the total number of patients in this group; ③ HBV-DNA quantitative index: HBV-DNA < 30 IU / L is negative.

[0082] (3) Chronic Liver Disease Questionnaire (CLDQ) Indicators The Chronic Liver Disease Questionnaire (CLDQ) compiled by Younossi ZM et al. was used, which includes six dimensions: abdominal symptoms, fatigue, systemic symptoms, emotional function, anxiety, and activity level. The CLDQ has a total of 29 items. The scores of each item are added together to form the total score. The higher the score, the higher the quality of life of the patient with chronic liver disease.

[0083] (4) Liver fibrosis markers ① Liver stiffness measurement (LSM): The LSM value was measured by transient elastography based on ultrasound technology before and after treatment, and the unit is kPa.

[0084] ② Serum four markers for liver fibrosis: These include hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), and type IV collagen (CIV). This test has auxiliary diagnostic value for liver fibrosis.

[0085] (5) Indicators of TCM syndrome efficacy A TCM syndrome scale was developed based on the 2002 edition of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs (Trial Implementation)". Each symptom was scored using a four-level grading system according to its severity (Level 0: None; Level I: Mild symptoms, not affecting daily life; Level II: Obvious symptoms, partially affecting daily life; Level III: Severe symptoms, significantly affecting daily life). Primary symptoms were scored at 0, 2, 4, or 6 points, and secondary symptoms at 0, 1, 2, or 3 points.

[0086] (6) Safety observation Safety monitoring indicators include basic vital signs, routine blood, urine, and stool tests, cardiopulmonary function, and renal function. Cardiopulmonary function is monitored through electrocardiograms and chest X-rays before and after treatment. Throughout the treatment course, the patient is kept in constant contact, and any adverse reactions or events are recorded promptly.

[0087] 5. Evaluation Criteria (1) Evaluation criteria for TCM syndrome differentiation and treatment efficacy The nimodipine method was used: Efficacy index = (Pre-treatment score - Post-treatment score) / Pre-treatment score × 100%. ① Clinical cure: Main symptoms and signs disappeared or basically disappeared, efficacy index ≥ 95%; ② Significant improvement: Main symptoms and signs significantly improved, 70% ≤ efficacy index < 95%; ③ Effective: Main symptoms and signs significantly improved, 30% ≤ efficacy index < 70%; ④ Ineffective: Main symptoms and signs showed no significant improvement, or even worsened, efficacy index < 30%. Total effective rate = (Number of cured cases + Number of significantly effective cases + Number of effective cases) / Total number of cases × 100%.

[0088] (2) Safety evaluation standards The safety evaluation criteria were formulated with reference to the 2002 edition of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines (Trial)": ① Grade I: Safe, no adverse reactions occurred during treatment; ② Grade II: Relatively safe, if adverse reactions occur, no special treatment is required and the trial can continue; ③ Grade III: Safety issues exist, adverse reactions occur during the trial, the trial can continue after treatment; ④ Grade IV: Serious adverse reactions occur, the trial must be terminated immediately.

[0089] (III) Statistical Methods SPSS 26.0 software was used to analyze the data results. Quantitative data were analyzed using the mean. ± standard deviation s () indicates that the data conforms to a normal distribution. t The statistical significance level was determined using the chi-square test for count data and the rank-sum test for non-normally distributed measurement and ordinal data. The statistical significance level was set at α = 0.05. P <0.05 indicates a statistically significant difference in the test results; P >0.05, indicating no statistically significant difference in the test results.

[0090] II. Research Results (a) Case completion status From July 2023 to December 2024, this invention recruited 96 eligible participants who were randomly assigned to either an experimental group or a control group, with 48 participants in each group. During the study, one participant in the experimental group failed to complete the scale assessment, and one patient in the control group was lost to follow-up and excluded. Ultimately, 47 participants in each group completed the entire study, with an overall dropout rate of 2.1%. See Table 1 for details. Table 1 Completion status of the two groups of patients

[0091] (II) Comparison of general data 1. Gender comparison This invention included 94 subjects, comprising 60 males (63.83%) and 34 females (36.17%). The experimental group consisted of 31 males (65.96%) and 16 females (34.04%), with a sex ratio of 1.94:1; the control group consisted of 29 males (61.70%) and 18 females (38.30%), with a sex ratio of 1.611:1. Statistical analysis showed no significant difference in sex distribution between the two groups. P A value >0.05 indicates that baseline characteristics are comparable between groups. See Table 2 for details: Table 2 Comparison of gender between the two groups of patients

[0092] Note: The chi-square test was used to compare the sex ratios between the two patient groups. 2. Age comparison The subjects in this invention ranged in age from 18 to 74 years. The experimental group ranged in age from 18 to 71 years, with a mean age of (41.98 ± 12.84) years; the control group ranged in age from 23 to 74 years, with a mean age of (43.70 ± 13.45) years. Statistical analysis showed no significant differences in mean age or age distribution between the two groups. P A value >0.05 indicates that the baseline data between groups are comparable. See Table 3 for details: Table 3 Comparison of ages between the two groups of patients

[0093] Note: The chi-square test was used to compare the age distribution of the two groups of patients; the independent samples test was used to compare the mean age of the two groups of patients. t test.

[0094] (III) Comparison of efficacy and safety 1. Comparison of treatment efficacy based on serological markers (1) Comparison of liver function indicators All liver function indicators before and after treatment conformed to normal distribution and homogeneity of variance. Before treatment, there were no statistically significant differences in AST, ALT, ALB, and TBiL levels between the two groups. P >0.05). After 12 weeks of treatment, there were statistically significant differences in AST, ALT, ALB, and TBiL levels between the two patient groups. P <0.05). See Table 4 for details. Figures 1-4 : Table 4 Comparison of AST, ALT, ALB, and TBiL levels between the two groups before and after treatment.

[0095] Note: Comparisons of AST, ALT, ALB, and TBiL levels between the two groups before and after treatment all used independent samples. t test After 12 weeks of treatment, the levels of AST, ALT, ALB, and TBiL in both groups were significantly improved compared with those before treatment, with statistically significant differences. P <0.05). See Table 5 for details. Figures 5-8 : Table 5 Comparison of AST, ALT, ALB, and TBiL levels before and after treatment in the two groups of patients.

[0096] Note: Comparisons of AST, ALT, ALB, and TBiL levels within both groups before and after treatment were performed using paired samples. t test.

[0097] (2) Comparison of HBsAg and HBeAg seroconversion rates The changes in HBsAg and HBeAg seroconversion rates were compared between the two groups after 12 weeks of treatment with different regimens. The HBsAg seroconversion rate was 0 in both the experimental and control groups, while the HBeAg seroconversion rates were 27.66% and 17.02%, respectively. The seroconversion rate in the experimental group was slightly higher than that in the control group, but the difference was not statistically significant. P >0.05). See Table 6 for details: Table 6 Comparison of HBsAg and HBeAg seroconversion rates between the two groups of patients

[0098] Note: The HBeAg seroconversion rate after treatment was compared between the two groups using the chi-square test.* P >0.05.

[0099] (3) Comparison of HBV-DNA quantitative indicators Before and after treatment, the HBV-DNA quantitative indicators in both groups conformed to normal distribution and homogeneity of variance. Before treatment, there was no significant difference in HBV-DNA quantitative test results between the two groups. P >0.05). After 12 weeks of intervention, the HBV-DNA quantitative levels in both groups were significantly lower than baseline. P <0.05), but there was no statistically significant difference between the two groups ( P >0.05). See Table 7 for details: Table 7 Comparison of HBV-DNA quantitative indicators between the two groups of patients

[0100] Note: Comparisons of HBV-DNA quantitative indicators between the two patient groups before and after treatment used independent samples. t Tests; comparisons of HBV-DNA quantitative indicators before and after treatment within the group, all using paired samples. t test.

[0101] 2. Comparison of treatment efficacy for liver fibrosis markers (1) LSM value Both groups showed normal distribution and homogeneity of variance in LSM values ​​before and after treatment. At baseline, there was no statistically significant difference in LSM values ​​between the two groups. P >0.05). After 12 weeks of intervention, the LSM values ​​of both groups were significantly lower than before treatment, and the difference was statistically significant. P <0.05). Intergroup comparisons showed a statistically significant difference after treatment ( P <0.05). See Table 8 for details. Figures 9-10 : Table 8 Comparison of LSM between the two groups of patients

[0102] Note: Comparisons of LSM values ​​between the two groups before and after treatment used independent samples. t Test; for comparison of LSM values ​​within the two groups before and after treatment, paired samples were used. t test.

[0103] (2) Four indicators of serum liver fibrosis Both groups showed normal distribution and homogeneity of variance in all liver fibrosis indicators before and after treatment. Before treatment, a comparison of the four serum liver fibrosis indicators between the experimental and control groups revealed no statistically significant differences between them. P >0.05). After 12 weeks of treatment with different regimens, the serum liver fibrosis markers in both groups showed significant improvement compared to before treatment, with statistically significant differences. P <0.05). After treatment, there were statistically significant differences between the experimental group and the control group in all four serum liver fibrosis indicators. P <0.05). See Table 9 for details. Figures 11-14 : Table 9 Comparison of four serum liver fibrosis markers between the two groups of patients

[0104] Note: Independent samples were used to compare the four serum liver fibrosis markers between the two groups before and after treatment. t Tests; Comparison of serum liver fibrosis markers before and after treatment in both groups, using paired samples. t test.

[0105] 3. Comparison of Chronic Liver Disease Questionnaire Scores Before treatment, there was no statistically significant difference in the total CLDQ scores between the two groups. P >0.05). After 12 weeks of treatment intervention, there was a statistically significant difference in the total CLDQ score between the two groups ( P <0.05). Compared with baseline values, the total CLDQ score of both groups improved significantly after treatment, and the difference was statistically significant. P <0.05). See Table 10 for details. Figures 15-16 : Table 10 Comparison of total scores on the Chronic Liver Disease Questionnaire

[0106] Note: The comparison of the total scores of the Chronic Liver Disease Questionnaire between the two groups before and after treatment used an independent sample. t Test; Comparison of total scores on the Chronic Liver Disease Questionnaire between the two groups before and after treatment, using paired samples. t test.

[0107] Before treatment, the CLDQ scores of the experimental group and the control group were compared, and there were no statistically significant differences between the groups. P >0.05). After 12 weeks of treatment with different regimens, the CLDQ scores of the experimental group and the control group showed that both groups of patients had significant improvements in abdominal symptoms, fatigue, systemic symptoms, and activity level compared to before treatment. P <0.05), and there was a statistically significant difference between the groups after treatment ( P <0.05). Regarding emotional function and anxiety, the control group showed no significant improvement compared to before treatment ( P >0.05), the experimental group showed significant improvement compared to before treatment ( P <0.05). See Table 11 for details. Figures 17-20 : Table 11 Comparison of scores from the chronic liver disease questionnaire before and after treatment in the two groups.

[0108] Note: The scores of each item in the chronic liver disease questionnaire were compared using the rank-sum test.

[0109] 4. Comparison of TCM syndrome differentiation and treatment efficacy (1) Comparison of overall efficacy of TCM syndromes After 12 weeks of intervention treatment, the TCM syndrome efficacy assessment of the experimental group showed a total effective rate of 85.11%, significantly higher than the 65.96% of the control group, and the difference between the two groups was statistically significant. P <0.05). See Table 12 for details. Figure 21 : Table 12 Comparison of overall efficacy of TCM syndromes in the two groups of patients

[0110] Note: The overall effective rate of TCM syndromes in the two groups of patients was compared using the rank-sum test.

[0111] (2) Comparison of total TCM syndrome scores between the two groups of patients before and after treatment Both groups of patients had total TCM syndrome scores that conformed to a normal distribution and homogeneity of variance before and after treatment. At baseline, there was no significant difference in TCM syndrome scores between the two groups. P >0.05). After 12 weeks of treatment intervention, there was a statistically significant difference in the total TCM syndrome scores between the two groups ( P <0.05). See Table 13 for details. Figure 22 : Table 13 Comparison of total TCM syndrome scores between the two groups of patients before and after treatment.

[0112] Note: The comparison of the total TCM syndrome scores between the two groups of patients before and after treatment used an independent sample. ttest.

[0113] (3) Comparison of total TCM syndrome scores within the two groups before and after treatment After 12 weeks of treatment with different protocols, the total TCM syndrome scores of both groups showed significant differences compared with those before treatment. P <0.05). See Table 14 for details. Figure 23 : Table 14 Comparison of total TCM syndrome scores within the two groups before and after treatment.

[0114] Note: Paired sampling was used to compare the total scores of TCM syndromes within the two groups before and after treatment. t test.

[0115] (4) Comparison of scores for various syndromes in Traditional Chinese Medicine Before treatment, there were no statistically significant differences in the scores of various TCM syndromes between the experimental group and the control group. P >0.05), after treatment, the scores of all TCM syndromes in the experimental group were significantly different from those before treatment ( P <0.05); In the control group, there were statistically significant differences in hypochondriac pain, abdominal distension and loose stools, poor appetite and fatigue compared to before treatment ( P <0.05), while there was no statistically significant difference in belching, acid reflux, dry mouth, bitter taste, depression or irritability, and insomnia compared to before treatment ( P >0.05). After treatment, the scores of various TCM syndromes in the two groups showed statistically significant differences among all syndromes. P <0.05). See Table 15 for details. Figures 24-27 : Table 15 Comparison of TCM syndrome scores before and after treatment in the two groups

[0116] Note: The rank-sum test was used to compare the scores of various syndromes in Traditional Chinese Medicine.

[0117] 5. Comparison of safety and adverse reactions During the study, a systematic safety assessment was conducted on the participants. Through regular monitoring of patients' basic vital signs, routine blood, urine, and stool tests, cardiac and renal function indicators, as well as electrocardiograms and chest imaging, the results showed that all observed indicators fluctuated within the normal range, and no abnormal clinical manifestations or adverse events related to the intervention were observed.

Claims

1. The application of a traditional Chinese medicine composition combined with entecavir in the preparation of a drug for treating liver-spleen disharmony syndrome in chronic hepatitis B, wherein the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 1-10 parts of stir-fried Bupleurum chinense, 5-15 parts of stir-fried Angelica sinensis, 8-16 parts of stir-fried Paeonia lactiflora, 8-16 parts of stir-fried Atractylodes macrocephala, 10-20 parts of Poria cocos, 1-10 parts of prepared Glycyrrhiza uralensis, 5-15 parts of Artemisia capillaris, and 10-20 parts of stir-fried Hordeum vulgare; characterized in that... The therapeutic effects of treating liver-spleen disharmony syndrome in chronic hepatitis B include: After treatment, the levels of ALT, AST, ALB, and TBiL were all significantly improved compared with before treatment. The HBsAg and HBeAg seroconversion rates were significantly improved after treatment compared with those before treatment; The quantitative levels of HBV-DNA decreased significantly after treatment; The level of liver fibrosis after treatment, including LSM value, serum liver fibrosis markers HA, LN, PCIII, and CIV, was significantly lower than before treatment. The chronic liver disease scores increased significantly after treatment. The chronic liver disease score includes aspects of abdominal symptoms, fatigue, systemic symptoms, activity level, emotional function, and anxiety. The total TCM syndrome scores after treatment were significantly lower than before treatment; After treatment, the patient experienced significant improvement in symptoms such as rib pain, abdominal distension and loose stools, belching and acid reflux, dry mouth and bitter taste, depression or irritability, and insomnia and excessive dreaming compared to before treatment.

2. The application according to claim 1, characterized in that, The herbal combination is prepared from the following raw materials in parts by weight: 4-8 parts of stir-fried Bupleurum chinense, 8-12 parts of stir-fried Angelica sinensis, 10-14 parts of stir-fried Paeonia lactiflora, 10-14 parts of stir-fried Atractylodes macrocephala, 13-17 parts of Poria cocos, 4-8 parts of prepared Glycyrrhiza uralensis, 7-11 parts of Artemisia capillaris, and 13-17 parts of stir-fried Hordeum vulgare.

3. The application according to claim 1, characterized in that, The herbal combination is prepared from the following raw materials in parts by weight: 6 parts of stir-fried Bupleurum chinense, 10 parts of stir-fried Angelica sinensis, 12 parts of stir-fried Paeonia lactiflora, 12 parts of stir-fried Atractylodes macrocephala, 15 parts of Poria cocos, 6 parts of prepared Glycyrrhiza uralensis, 9 parts of Artemisia capillaris, and 15 parts of stir-fried Hordeum vulgare.

4. The application of a traditional Chinese medicine composition combined with entecavir in the preparation of a drug for treating liver-spleen disharmony syndrome in chronic hepatitis B, characterized in that... The traditional Chinese medicine composition preparation includes the traditional Chinese medicine composition and / or added pharmaceutical excipients as described in any one of claims 1-3; The therapeutic effects of treating liver-spleen disharmony syndrome in chronic hepatitis B include: After treatment, the levels of ALT, AST, ALB, and TBiL were all significantly improved compared with before treatment. The HBsAg and HBeAg seroconversion rates were significantly improved after treatment compared with those before treatment; The quantitative levels of HBV-DNA decreased significantly after treatment; The level of liver fibrosis after treatment, including LSM value, serum liver fibrosis markers HA, LN, PCIII, and CIV, was significantly lower than before treatment. The chronic liver disease scores increased significantly after treatment. The chronic liver disease score includes aspects of abdominal symptoms, fatigue, systemic symptoms, activity level, emotional function, and anxiety. The total TCM syndrome scores after treatment were significantly lower than before treatment; After treatment, the patient experienced significant improvement in symptoms such as rib pain, abdominal distension and loose stools, belching and acid reflux, dry mouth and bitter taste, depression or irritability, and insomnia and excessive dreaming compared to before treatment.

5. The application according to claim 4, characterized in that, The traditional Chinese medicine composition preparation is in the form of tablets, granules, pills, powders, ointments, capsules, granules, powders, or liquids.

6. A drug kit for treating liver-spleen disharmony syndrome in chronic hepatitis B, characterized in that, include: First component: the traditional Chinese medicine composition used in any one of claims 1-3 or the traditional Chinese medicine composition preparation used in any one of claims 4-5; Second component: entecavir or a pharmaceutically acceptable salt thereof.

7. The drug kit according to claim 6, characterized in that, The first and second components are packaged in the same outer packaging and accompanied by instructions to patients to administer the medication according to the following periodic schedule: the Chinese medicine composition is taken orally twice daily, each time corresponding to 150 mL of concentrated decoction or an equal amount of solid preparation, one hour after breakfast and dinner respectively; entecavir is taken continuously at 0.5 mg daily for the entire course of treatment; one course of treatment is three months of continuous use, and one course of treatment is given annually.

8. The use of the pharmaceutical kit according to any one of claims 6-7 in the preparation of a medicament for treating hepatosplenic disharmony in chronic hepatitis B, wherein the use is for treating hepatosplenic disharmony in chronic hepatitis B, and the therapeutic effects include: After treatment, the levels of ALT, AST, ALB, and TBiL were all significantly improved compared with before treatment. The HBsAg and HBeAg seroconversion rates were significantly improved after treatment compared with those before treatment; The quantitative levels of HBV-DNA decreased significantly after treatment; The level of liver fibrosis after treatment, including LSM value, serum liver fibrosis markers HA, LN, PCIII, and CIV, was significantly lower than before treatment. The chronic liver disease scores increased significantly after treatment. The chronic liver disease score includes aspects of abdominal symptoms, fatigue, systemic symptoms, activity level, emotional function, and anxiety. The total TCM syndrome scores after treatment were significantly lower than before treatment; After treatment, the patient experienced significant improvement in symptoms such as rib pain, abdominal distension and loose stools, belching and acid reflux, dry mouth and bitter taste, depression or irritability, and insomnia and excessive dreaming compared to before treatment.

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