A traditional Chinese medicine composition for treating or / and adjuvant treating pulmonary fibrosis, and a preparation method and use thereof

Abstract

This invention provides a traditional Chinese medicine composition for the treatment and / or adjuvant treatment of pulmonary fibrosis, prepared from the following raw materials in the indicated weight ratios: Astragalus membranaceus 12-18 parts, processed Ephedra sinica 8-12 parts, apricot kernel 12-18 parts, licorice root 8-12 parts, earthworm 8-12 parts, red peony root 8-12 parts, Fritillaria thunbergii 8-12 parts, Perilla frutescens seed 8-12 parts, and Scutellaria baicalensis 12-18 parts. This invention also provides a method for preparing this traditional Chinese medicine composition and its uses. Research results demonstrate that the pharmaceutical composition of this invention, with its precise formulation, can effectively improve the TCM syndromes of patients with pulmonary fibrosis, reduce lung function damage, and slow the progression of pulmonary fibrosis. It provides a new option for the clinical treatment of pulmonary fibrosis with phlegm-stasis and qi deficiency syndrome, showing promising application prospects.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition for the treatment and / or adjuvant treatment of pulmonary fibrosis, belonging to the field of traditional Chinese medicine. Background Technology

[0002] Pulmonary fibrosis (PF) is a common pathological feature of various interstitial lung diseases, characterized by diffuse fibrosis of lung tissue, abnormal proliferation of fibroblasts, and massive extracellular matrix deposition. In severe cases, it can present as end-stage lung injury. Its core clinical symptoms are progressively worsening dyspnea, irritating dry cough, chest tightness, and shortness of breath, with symptoms particularly pronounced after exertion. In severe cases, hypoxemia, respiratory failure, and even death can occur. The etiology of pulmonary fibrosis is complex. Currently known contributing factors include environmental exposure (such as dust and harmful gases), infection, autoimmune diseases, and drug side effects. However, the etiology remains unknown in many cases, placing a heavy medical burden and economic pressure on patients and society.

[0003] Statistics show that the global prevalence of pulmonary fibrosis is increasing year by year, with some differences in prevalence across different regions. The overall prevalence is approximately (13-20) per 100,000 people, and it is more common in middle-aged and elderly people, with a slightly higher prevalence in men than women. With the increasing aging population, increased exposure to environmental pollutants, and rising incidence of autoimmune diseases, the patient population for pulmonary fibrosis continues to expand. Due to the incomplete understanding of its pathogenesis, there is currently no specific radical cure for pulmonary fibrosis, both domestically and internationally. Clinical treatment remains mainly focused on symptomatic support and slowing disease progression, and cannot reverse the fibrotic process of lung tissue.

[0004] Currently, commonly used clinical treatments mainly include antifibrotic drugs (such as pirfenidone and nintedanib), glucocorticoids, and immunosuppressants. Among these, pirfenidone and nintedanib are widely used antifibrotic drugs. While they can slow the decline in lung function to some extent, long-term use has significant adverse reactions, such as gastrointestinal discomfort, skin rashes, and liver and kidney damage. Furthermore, they are expensive, making them unaffordable for many patients and limiting their clinical application. Glucocorticoids and immunosuppressants are mainly used to alleviate inflammatory responses associated with pulmonary fibrosis and are suitable for some types of inflammation-mediated pulmonary fibrosis. They can improve some symptoms in the short term, but long-term use can lead to serious adverse reactions such as decreased immunity, osteoporosis, and increased risk of infection. They also cannot fundamentally stop the progression of fibrosis and are unlikely to improve long-term patient prognosis. In addition, non-pharmacological treatments such as oxygen therapy, pulmonary rehabilitation, and lung transplantation can alleviate patient symptoms and improve quality of life. However, lung transplantation faces problems such as donor shortages, high surgical risks, and postoperative immune rejection, and is only suitable for a small number of advanced-stage patients, limiting its widespread clinical application.

[0005] Traditional Chinese medicine (TCM) has unique advantages in treating pulmonary fibrosis. Its holistic approach and syndrome differentiation can target the core pathogenesis of pulmonary fibrosis, regulating the body from the root cause, alleviating symptoms, and slowing disease progression. It also has fewer adverse reactions, is inexpensive, and is easily accepted by patients. Based on the clinical symptoms and pathogenesis of pulmonary fibrosis, it can be categorized under TCM terms such as "pulmonary arthralgia," "pulmonary atrophy," "asthma," and "cough."

[0006] In the "Diagnostic Criteria for Traditional Chinese Medicine Syndromes in Idiopathic Pulmonary Fibrosis," IPF syndromes are divided into two major systems: primary syndromes and secondary syndromes. This standard classifies phlegm-dampness syndrome and blood stasis syndrome as "secondary syndromes," which are often seen alongside deficiency syndromes, forming complex syndromes that combine deficiency and excess. "Phlegm-stasis with Qi deficiency syndrome" belongs to this type of complex syndrome—with lung Qi deficiency (or lung-kidney Qi deficiency) as the underlying deficiency, and phlegm-stasis obstructing the lung collaterals as the superficial excess. Modern literature research also confirms that "lung Qi deficiency with phlegm-stasis obstructing the collaterals syndrome" is one of the most common complex syndromes in clinical practice. Currently, classic formulas used in clinical practice for pulmonary fibrosis, such as Buyang Huanwu Decoction, Xuefu Zhuyu Decoction, and Bufeng Decoction, often have limited therapeutic approaches. Some focus on tonifying qi and lungs but lack the ability to resolve phlegm and remove blood stasis, making it difficult to address the symptoms of phlegm and blood stasis lurking in the collaterals. Others focus on resolving phlegm but lack the function of tonifying qi and unblocking collaterals, failing to address the core pathogenesis of qi deficiency and blood stasis. Still others focus on activating blood and removing blood stasis but have a weak effect on regulating qi deficiency and phlegm turbidity. All of these are difficult to fully meet the pathological characteristics of pulmonary fibrosis with phlegm and blood stasis lurking in the collaterals and qi deficiency.

[0007] Currently, although there are various traditional Chinese medicine formulas used clinically to treat pulmonary fibrosis, most of them have certain limitations. Summary of the Invention

[0008] This invention provides a traditional Chinese medicine composition for treating or / and adjuvant treatment of pulmonary fibrosis, its preparation method, and its uses.

[0009] This invention provides a traditional Chinese medicine composition for the treatment and / or adjuvant treatment of pulmonary fibrosis, which is prepared from the following raw materials in the indicated weight ratios: Astragalus membranaceus 12-18 parts, processed Ephedra sinica 8-12 parts, apricot kernel 12-18 parts, licorice root 8-12 parts, earthworm 8-12 parts, red peony root 8-12 parts, Fritillaria thunbergii 8-12 parts, Perilla frutescens seed 8-12 parts, and Scutellaria baicalensis 12-18 parts.

[0010] Preferably, it is prepared from the following raw materials in the indicated weight ratios:

[0011] Astragalus membranaceus 15 parts, processed ephedra floss 10 parts, apricot kernel 15 parts, licorice root 10 parts, earthworm 10 parts, red peony root 10 parts, fritillaria thunbergii 10 parts, perilla seed 10 parts, scutellaria baicalensis 15 parts.

[0012] It is prepared into a commonly used oral formulation by adding pharmaceutically acceptable excipients or auxiliary ingredients, using the original drug powder, water or organic solvent extract as the active ingredient.

[0013] The oral preparations include decoctions, oral liquids, granules, capsules, tablets, and powders.

[0014] The present invention also provides a method for preparing the traditional Chinese medicine composition for treating and / or adjuvant treating pulmonary fibrosis, characterized in that it comprises the following steps:

[0015] a. Weigh the raw materials according to the specified weight ratio;

[0016] b. The active pharmaceutical ingredient is directly ground into powder, or the active pharmaceutical ingredient is decocted with water or extracted with organic solvents, the extract is concentrated, and then pharmaceutically acceptable excipients or auxiliary ingredients are added to prepare commonly used pharmaceutical preparations.

[0017] The present invention also provides the use of the aforementioned traditional Chinese medicine composition in the preparation of medicaments for the treatment and / or adjunctive treatment of pulmonary fibrosis.

[0018] Preferably, the drug is for treating pulmonary fibrosis with phlegm and blood stasis in the collaterals and qi deficiency.

[0019] The sources of each raw material in this invention are as follows: the Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. of the Fabaceae family are dried roots; the processed Ephedra floss is a floss-like preparation made by processing the dried herbaceous stems of Ephedra sinica Stapf, Ephedra intermedia Schrenk et CA Mey. or Ephedra equisetina Bge. of the Ephedraceae family through honey processing. The earthworms mentioned are the dried bodies of *Pheretima aspergillum* (E. Perrier), *Pheretima vulgaris* Chen, *Pheretima guillelmi* (Michaelsen), or *Pheretima pectinifera* Michaelsen, all belonging to the family Lumbriaceae. The red peony root mentioned is the dried root of *Paeonia lactiflora* Pall. or *Paeonia veitchii* Lynch, belonging to the family Ranunculaceae. The Zhejiang fritillary bulb mentioned is the dried bulb of *Fritillaria thunbergii* Miq., belonging to the family Liliaceae.

[0020] This invention takes tonifying the lungs and replenishing qi, resolving phlegm and removing blood stasis and unblocking the collaterals as its core treatment method. The four methods of replenishing qi, resolving phlegm, removing blood stasis and unblocking the collaterals work together to accurately match the complex pathogenesis of "qi deficiency as the root and phlegm and blood stasis in the collaterals as the symptoms". It is superior to existing classic prescriptions in treating phlegm and blood stasis in the collaterals combined with qi deficiency, and has clinical advantages and innovation.

[0021] In this invention, Astragalus membranaceus (Huangqi) is the principal herb, which invigorates Qi, strengthens the spleen, tonifies the lungs, and consolidates the exterior. It focuses on supporting the body's vital energy to promote blood circulation and resolve phlegm, thereby improving the root cause of Qi deficiency. The Astragalus membranaceus used is raw, which, compared with processed Astragalus membranaceus, has a more specific effect in invigorating Qi, consolidating the exterior, and promoting circulation. It also does not have the warming and drying properties of processed Astragalus membranaceus, making it more suitable for the pathogenesis of pulmonary fibrosis patients who are prone to phlegm and blood stasis due to lung Qi deficiency. Prepared ephedra floss is a processed product made by processing ephedra with honey and removing the coarse stems. Compared with raw ephedra, its diaphoretic properties are greatly reduced, and its warming and drying effects that deplete qi are lessened. It is specifically effective in clearing the lungs and relieving asthma, which is suitable for patients with lung qi deficiency and intolerance to strong dispersing agents. Apricot kernel has a specific effect of lowering qi, resolving phlegm, stopping cough, and relieving asthma. Together with prepared ephedra floss, it promotes the flow of qi and regulates lung qi. Perilla seed is warm and moist, and is good at lowering qi and resolving phlegm. Unlike perilla leaf, which is more effective in relieving exterior symptoms, and perilla stem, which is more effective in regulating qi and relieving chest congestion, perilla seed targets the pathogenesis of phlegm obstructing the lungs and impairing the lung's ability to clear and descend qi. The three drugs, prepared ephedra floss, apricot kernel, and perilla seed, work synergistically to restore lung function. The normal functions of dispersing and descending qi are combined as assistant herbs; Fritillaria thunbergii clears heat, resolves phlegm, disperses nodules and eliminates carbuncles; earthworm unblocks the meridians, relieves asthma, invigorates blood and removes blood stasis; red peony root cools the blood, disperses blood stasis, unblocks the meridians and relieves pain. These three herbs work together as adjuvant herbs, enhancing the effects of resolving phlegm, removing blood stasis and unblocking the meridians, assisting the assistant herbs in targeting the symptoms of phlegm and blood stasis in the meridians; Scutellaria baicalensis clears heat, dries dampness, and drains lung fire, thus controlling the warming and drying properties of the herbs in the formula and preventing the depletion of yin fluids, serving as an adjuvant herb; Glycyrrhiza uralensis tonifies qi, moistens the lungs, and harmonizes the herbs. Using raw licorice root avoids the warming and drying properties of honey-processed licorice root, both assisting Astragalus membranaceus in tonifying qi and harmonizing the cold and hot properties of the herbs in the formula, serving as the guiding herb. The entire formula works together to tonify the lungs and qi, resolve phlegm, remove blood stasis and unblock the meridians, precisely targeting the core pathogenesis of pulmonary fibrosis with phlegm and blood stasis in the meridians and qi deficiency, resulting in a definite therapeutic effect.

[0022] The research results demonstrate that the pharmaceutical composition of the present invention, with its precise formulation, can effectively improve the TCM syndrome of patients with pulmonary fibrosis, reduce lung function damage, and slow down the progression of pulmonary fibrosis. It provides a new option for the clinical treatment of pulmonary fibrosis with phlegm and blood stasis combined with qi deficiency, and has good application prospects. Detailed Implementation

[0023] Example 1: Preparation of the pharmaceutical composition of the present invention

[0024] Prescription: Astragalus membranaceus 15g, processed ephedra floss 10g, apricot kernel 15g, licorice root 10g, earthworm 10g, red peony root 10g, fritillaria thunbergii 10g, perilla seed 10g, scutellaria baicalensis 15g;

[0025] Preparation method: Weigh the raw materials according to the above prescription ratio and put them into a clay pot. Add 2000ml of water and soak for half an hour. Bring to a boil over high heat, then simmer over low heat until 200±20ml remains. Pour the boiled liquid into a bowl. Add 1500ml of water to the dregs, bring to a boil over high heat, then simmer over low heat until 200±20ml remains. Pour the boiled liquid into a bowl. Mix the two liquids evenly and take one dose daily, divided into three warm doses.

[0026] Example 2: Preparation of the pharmaceutical composition of the present invention

[0027] Prescription: Astragalus membranaceus 12g, processed ephedra floss 8g, apricot kernel 12g, licorice root 8g, earthworm 8g, red peony root 8g, fritillaria thunbergii 8g, perilla seed 8g, scutellaria baicalensis 12g.

[0028] Preparation method: Same as in Example 1.

[0029] Example 3: Preparation of the pharmaceutical composition of the present invention

[0030] Prescription: Astragalus membranaceus 18g, processed ephedra flakes 12g, apricot kernel 18g, licorice root 12g, earthworm 12g, red peony root 12g, fritillaria thunbergii 12g, perilla seed 12g, scutellaria baicalensis 18g.

[0031] Preparation method: Same as in Example 1.

[0032] The following clinical trials demonstrate the beneficial effects of this invention.

[0033] Example 1: Clinical Trial of the Drug of the Invention

[0034] 1. Case Data

[0035] This study aims to include 100 patients with pulmonary fibrosis who meet the criteria for phlegm-stasis syndrome with qi deficiency. They will be randomly divided into an experimental group and a control group, with 50 patients in each group.

[0036] 2. Diagnostic criteria

[0037] 2.1 Diagnostic criteria for pulmonary fibrosis

[0038] Based on the diagnostic criteria in "Diagnosis of Idiopathic Pulmonary Fibrosis - An Official ATS / ERS / JRS / ALAT Clinical Practice Guideline" and "Chinese Expert Consensus on the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis", combined with the patient's clinical symptoms, signs, pulmonary function tests, high-resolution chest CT scans, etc., pulmonary fibrosis was diagnosed.

[0039] 2.2 Traditional Chinese Medicine Diagnosis

[0040] The diagnostic criteria for the syndrome of phlegm-stasis syndrome with qi deficiency, formulated with reference to "Internal Medicine of Traditional Chinese Medicine" and "Diagnostics of Traditional Chinese Medicine", are as follows:

[0041] Primary symptoms: ① Cough, ② Expectoration, ③ Wheezing and shortness of breath, ④ Cyanosis of the lips. Secondary symptoms: ⑤ Chest tightness and shortness of breath, ⑥ Fatigue and weakness, ⑦ Poor appetite and abdominal distension, ⑧ Nausea and vomiting, ⑨ Dizziness, ⑩ Weak or loose stools. Tongue and pulse: The tongue is swollen with teeth marks on the edges, pale in color, and has a greasy coating; the pulse is slow or slippery. Diagnosis: The presence of one primary symptom and two or more secondary symptoms, consistent with the tongue and pulse findings, is sufficient for diagnosis.

[0042] 3. Inclusion criteria

[0043] ① The diagnosis meets the Western medicine diagnostic criteria for pulmonary fibrosis; ② The diagnosis meets the TCM diagnostic criteria for phlegm-stasis syndrome with qi deficiency; ③ The age is 18-80 years old, regardless of gender; ④ The subjects are aware of the content of this study and sign the informed consent form.

[0044] 4. Exclusion Criteria

[0045] ① Patients who are in the process of trying to conceive, pregnant, or breastfeeding; ② Patients with serious organic diseases of the heart, liver, kidneys, hematopoietic system, etc., or malignant tumors; ③ Patients with other lung diseases such as severe lung infection, tuberculosis, and bronchiectasis; ④ Patients who are allergic to any of the active pharmaceutical ingredients in the pharmaceutical composition of this invention; ⑤ Patients with mental illness or who are unable to cooperate in completing the clinical trial.

[0046] 5 Treatment methods

[0047] (1) Control group: The control group was treated with conventional Western medicine according to the “Diagnosis of Idiopathic Pulmonary Fibrosis - An Official ATS / ERS / JRS / ALAT Clinical Practice Guideline”.

[0048] (2) Experimental group: In addition to the treatment given to the control group, patients were given the drug prepared in Example 1 orally. Dosage: Each dose of the drug prepared by the composition of the present invention is a one-day dose, which is divided into three oral doses. The treatment course for both groups was 12 weeks.

[0049] 6 Observation Indicators

[0050] (1) Key outcome indicators

[0051] Before and after treatment, the changes in TCM syndrome scores of each group were observed.

[0052] (2) Secondary outcome indicators

[0053] Before and after treatment, monitor changes in patients' lung function (TLC, FVC, DLCO% pred), high-resolution chest CT (HRCT) score, and 6-minute walk distance (6MWD); at the same time, observe adverse reactions during treatment and assess drug safety.

[0054] 7. Statistical Methods

[0055] Data analysis was performed using SPSS 26.0 statistical software and R language. Normally distributed continuous variables were analyzed using t-tests, expressed as mean ± standard deviation (x ± s). Skewed continuous variables were analyzed using nonparametric tests, expressed as median (interquartiles) [M(P25, P75)]. Ordinal variables were analyzed using rank-sum tests. Categorical variables were expressed as frequencies (percentages), analyzed using χ² tests. All tests were two-tailed, and p < 0.05 was considered statistically significant.

[0056] 8. Treatment Results

[0057] The experimental group included 46 patients and the control group included 48 patients, for a total of 94 patients. Before treatment, there were no statistically significant differences between the two groups in terms of baseline data such as gender, age, disease course, TCM syndrome score, and pulmonary function (P>0.05), and the two groups were comparable.

[0058] (1) Comparison of TCM syndrome scores

[0059] The results (Table 1) showed no statistically significant difference in TCM syndrome scores between the two groups before treatment (P > 0.05). Within-group comparisons after treatment showed that TCM syndrome scores in both groups improved significantly after treatment compared to before treatment (P < 0.001). Between-group comparisons after treatment showed that the experimental group showed greater improvement in TCM syndrome scores than the control group (P < 0.05).

[0060] Table 1. Comparison of total scores for TCM syndromes [M(P25, P75)]

[0061]

[0062] (2) Comparison of lung function

[0063] The results (Tables 2, 3, and 4) showed no statistically significant differences in TLC, FVC, and DLCO% pred between the two groups before treatment (P > 0.05). Intra-group comparisons before and after treatment showed that TLC, FVC, and DLCO% pred were significantly higher in the experimental group after treatment than before treatment (P < 0.001); while in the control group, TLC, FVC, and DLCO% pred were all lower after treatment than before treatment (P < 0.001). Inter-group comparisons after treatment showed that TLC and FVC were significantly better in the experimental group than in the control group after treatment (P < 0.05), while there was no statistically significant difference in DLCO% pred between the two groups after treatment (P > 0.05).

[0064] Table 2. Comparison of TLC in pulmonary function between the two groups [M(P25, P75), elution]

[0065]

[0066] Table 3 Comparison of FVC between the two groups [M(P25, P75), elution]

[0067]

[0068] Table 4 Comparison of DLCO% and pred in the two groups of pulmonary function ( ±s,%)

[0069]

[0070] (3) Comparison of HRCT scores

[0071] The results (Table 5) showed no statistically significant difference in HRCT scores between the experimental and control groups before treatment (P > 0.05). Intra-group comparisons before and after treatment showed a significant decrease in HRCT scores in the experimental group (P < 0.001) and a significant increase in HRCT scores in the control group (P < 0.001). Inter-group comparisons after treatment showed that the HRCT score in the experimental group was lower than that in the control group, but the difference was not statistically significant (P = 0.056).

[0072] Table 5 Comparison of HRCT scores between the two groups [M (P25, P75)]

[0073]

[0074] (4) 6MWD comparison

[0075] The results showed that there was no statistically significant difference in 6MWD between the two groups before treatment (P>0.05); after 12 weeks of treatment, the 6MWD of both groups was significantly longer than before treatment, and the 6MWD of the experimental group was significantly longer than that of the control group, with a statistically significant difference (P<0.05), indicating that the drug composition of the present invention can effectively improve the exercise endurance of patients.

[0076] Table 6 Comparison of 6MWD between the two groups

[0077]

[0078] (5) Safety evaluation

[0079] During the treatment, no significant adverse reactions were observed in either group of patients, and no abnormalities were found in liver and kidney function tests, blood routine tests, etc., indicating that the pharmaceutical composition of the present invention has good safety.

[0080] In summary, the pharmaceutical composition of the present invention is well-formulated and can effectively improve the TCM syndrome of patients with pulmonary fibrosis due to phlegm-stasis and qi deficiency, improve lung function, improve HRCT score, improve exercise endurance, inhibit the process of pulmonary fibrosis, and has good safety. It provides a new option for the clinical treatment of pulmonary fibrosis due to phlegm-stasis and qi deficiency and has good application prospects.

Claims

1. A traditional Chinese medicine composition for treatment and / or adjuvant treatment, characterized in that: It is prepared from the following raw materials in the indicated weight ratios: Astragalus membranaceus 12-18 parts, processed Ephedra sinica 8-12 parts, apricot kernel 12-18 parts, licorice 8-12 parts, earthworm 8-12 parts, red peony root 8-12 parts, Fritillaria thunbergii 8-12 parts, Perilla frutescens seed 8-12 parts, and Scutellaria baicalensis 12-18 parts.

2. The traditional Chinese medicine composition for treating or / and adjuvant treatment of pulmonary fibrosis according to claim 1, characterized in that: It is prepared from the following raw materials in the indicated weight ratios: Astragalus membranaceus 15 parts, processed ephedra floss 10 parts, apricot kernel 15 parts, licorice root 10 parts, earthworm 10 parts, red peony root 10 parts, fritillaria thunbergii 10 parts, perilla seed 10 parts, scutellaria baicalensis 15 parts.

3. The traditional Chinese medicine composition for treating and / or adjuvant treatment of pulmonary fibrosis according to claim 1 or 2, characterized in that: It is prepared into a commonly used oral formulation by adding pharmaceutically acceptable excipients or auxiliary ingredients, using the original drug powder, water or organic solvent extract as the active ingredient.

4. The traditional Chinese medicine composition for treating or / and adjuvant treatment of pulmonary fibrosis according to claim 3, characterized in that: The oral preparations include decoctions, oral liquids, granules, capsules, tablets, and powders.

5. A method for preparing a traditional Chinese medicine composition for treating or / and adjuvant treating pulmonary fibrosis as described in any one of claims 1-4, characterized in that: It includes the following steps: a. Weigh the raw materials according to the specified weight ratio; b. The active pharmaceutical ingredient is directly ground into powder, or the active pharmaceutical ingredient is decocted with water or extracted with organic solvents, the extract is concentrated, and then pharmaceutically acceptable excipients or auxiliary ingredients are added to prepare commonly used pharmaceutical preparations.

6. Use of the traditional Chinese medicine composition according to any one of claims 1-4 in the preparation of a medicament for the treatment and / or adjuvant treatment of pulmonary fibrosis.

7. The use according to claim 6, characterized in that: The aforementioned medication is for treating pulmonary fibrosis caused by phlegm and blood stasis in the meridians combined with qi deficiency.

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