A traditional Chinese medicine composition for treating stable chronic obstructive pulmonary disease, and a preparation method and use thereof

Abstract

The application provides a traditional Chinese medicine composition for treating stable chronic obstructive pulmonary disease, which is prepared from the following raw materials in the following proportions: 15-45 parts of Astragalus membranaceus, 2-18 parts of Atractylodes macrocephala, 2-18 parts of Radix Stephaniae, 5-25 parts of Radix Rehmanniae Preparata, 10-30 parts of Dioscorea, 5-25 parts of Fructus Corni, 2-18 parts of Salix Pseudosalix, 2-18 parts of Cortex Moutan, 5-25 parts of Poria cocos, 5-25 parts of Radix Ginseng, 10-30 parts of Radix Epimedii Preparata, 2-18 parts of Schisandra chinensis, 1-10 parts of Periplomatula, 15-45 parts of Juglans regia, 2-18 parts of Semen Armeniacae Amarum, 2-18 parts of Platycodon grandiflorum, 5-25 parts of Fritillaria thunbergii Miq, and 100-150 parts of honey. The traditional Chinese medicine composition has a remarkable curative effect on patients with stable chronic obstructive pulmonary disease, is convenient to use, has no toxic side effects, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition for treating stable chronic obstructive pulmonary disease, its preparation method, and its uses. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease. It is a chronic, long-term disease with a progressive course. COPD is characterized by progressive and irreversible airflow limitation. Early symptoms include cough, sputum production, decreased exercise tolerance, and exertional dyspnea. The peak incidence is in winter and spring. The disease has a long course, and as it progresses, it can lead to secondary diseases such as pulmonary heart disease, heart failure, and pulmonary hypertension. Epidemiological surveys show that the prevalence of COPD among residents aged 40 and above in my country is 9.9%, and COPD-related deaths account for 9.7% of all deaths in my country, making it one of the leading causes of death from disease. COPD seriously affects patients' daily lives and health, and in severe cases, it can be life-threatening.

[0003] COPD is divided into stable and acute exacerbation phases. During the stable phase, patients' symptoms such as cough, sputum production, and shortness of breath may be stable or mild. During acute exacerbations, patients experience worsening dyspnea, increased cough, increased sputum production, and / or purulent sputum. In some cases, dyspnea may occur even at rest, and the main complaints of cough and / or sputum production may suddenly worsen. COPD management includes treatment for both the chronic stable phase and acute exacerbations. Long-term standardized management of the stable phase is the focus of treatment. Because lung function continues to decline progressively during the stable phase of COPD, and the condition is often variable and complex, treatment often employs comprehensive prevention and treatment measures, including bronchodilator therapy, rehabilitation exercises, smoking cessation and avoidance of pathogenic factors, and psychological therapy, which are adjusted according to the evolution of the disease.

[0004] Clinically, Western medicine often uses glucocorticoids, bronchodilators, expectorants and antitussives, and antioxidants to treat stable COPD, with significant clinical efficacy. However, long-term use has certain side effects and is not suitable for long-term treatment. With the development of traditional Chinese medicine, its advantages in treating stable COPD patients have gradually become apparent, and its efficacy has been clinically recognized. Traditional Chinese medicine believes that stable chronic obstructive pulmonary disease falls under the category of "lung distension," caused by external pathogens such as wind, cold, and heat invading the lungs, leading to impaired lung qi circulation and upward reversal of lung qi, resulting in cough and other symptoms. Prolonged illness, persistent symptoms, and repeated attacks lead to lung qi deficiency, weakened defensive qi, and impaired lung qi descending function. The upward reversal of lung qi obstructs the flow of qi, blood, and body fluids, resulting in phlegm and blood stasis, further hindering the flow of qi, thus causing lung distension. Patients with chronic illness and weakened constitution are susceptible to external pathogenic factors, which can trigger the onset of pre-existing conditions. Over time, the disease can also affect the spleen and kidneys. Patent CN109939172A discloses a traditional Chinese medicine composition for the stable phase of chronic obstructive pulmonary disease (COPD). It has the effects of tonifying the lung, spleen, and kidney qi, resolving phlegm, eliminating dampness, promoting diuresis, activating blood circulation, removing blood stasis, nourishing yin, and clearing heat. It can improve the pathology of COPD in the stable phase, but its improvement on specific TCM syndrome manifestations is unclear. Therefore, it is necessary to provide an effective TCM preparation to treat cough, pulmonary distension, wheezing, edema, and general weakness in the stable phase of COPD, thereby improving the quality of life of patients. Summary of the Invention

[0005] To address the above problems, this invention provides a traditional Chinese medicine composition for treating stable chronic obstructive pulmonary disease, which is a preparation made from the following raw materials in the indicated weight ratios:

[0006] Astragalus membranaceus 15-45 parts, Atractylodes macrocephala 2-18 parts, Saposhnikovia divaricata 2-18 parts, Rehmannia glutinosa 5-25 parts, Dioscorea opposita 10-30 parts, Cornus officinalis 5-25 parts, Alisma plantago-aquatica 2-18 parts, Paeonia suffruticosa 2-18 parts, Poria cocos 5-25 parts, Panax ginseng 5-25 parts, Epimedium brevicornu 10-30 parts, Schisandra chinensis 2-18 parts, Gecko 1-10 parts, Juglans regia 15-45 parts, Prunus armeniaca 2-18 parts, Platycodon grandiflorus 2-18 parts, Fritillaria cirrhosa 5-25 parts.

[0007] Furthermore, it is a formulation prepared from the following active pharmaceutical ingredients in the indicated weight ratios:

[0008] Astragalus membranaceus 20-40 parts, Atractylodes macrocephala 5-15 parts, Saposhnikovia divaricata 5-15 parts, Rehmannia glutinosa 10-20 parts, Dioscorea opposita 15-25 parts, Cornus officinalis 10-20 parts, Alisma plantago-aquatica 5-15 parts, Paeonia suffruticosa 5-15 parts, Poria cocos 10-20 parts, Panax ginseng 10-20 parts, Epimedium brevicornu 10-30 parts, Schisandra chinensis 5-15 parts, Gecko gecko 3-8 parts, Juglans regia kernel 20-40 parts, Prunus armeniaca 5-15 parts, Platycodon grandiflorus 5-15 parts, Fritillaria cirrhosa 10-20 parts.

[0009] Furthermore, it is a formulation prepared from the following active pharmaceutical ingredients in the indicated weight ratios:

[0010] Astragalus membranaceus 30 parts, Atractylodes macrocephala 10 parts, Saposhnikovia divaricata 10 parts, Rehmannia glutinosa 15 parts, Dioscorea opposita 20 parts, Cornus officinalis 15 parts, Alisma plantago-aquatica 10 parts, Paeonia suffruticosa 10 parts, Poria cocos 15 parts, Panax ginseng 15 parts, Epimedium brevicornu 20 parts, Schisandra chinensis 10 parts, Gecko 5 parts, Walnut kernels 30 parts, Bitter almonds 10 parts, Platycodon grandiflorus 10 parts, Fritillaria cirrhosa 15 parts.

[0011] Furthermore, the Rehmannia glutinosa mentioned is prepared Rehmannia glutinosa, Alisma plantago-aquatica is salted Alisma plantago-aquatica, Epimedium brevicornu is roasted Epimedium brevicornu, and Fritillaria thunbergii is Fritillaria thunbergii.

[0012] Furthermore, it is a formulation prepared by adding pharmaceutically acceptable excipients to active ingredients such as powdered active pharmaceutical ingredients, water or organic solvent extracts of active pharmaceutical ingredients.

[0013] Furthermore, the preparation is an oral preparation; the oral preparation is a decoction, pill, mixture, granule, capsule, tablet, solution, or syrup, preferably a decoction.

[0014] Furthermore, the excipients of the decoction include honey; the honey is 100-150 parts, preferably 115-135 parts, and more preferably 125 parts.

[0015] The present invention also provides a method for preparing the aforementioned composition, comprising the following steps:

[0016] (1) Weigh each raw material according to the weight ratio;

[0017] (2) The active pharmaceutical ingredient is powdered, or the active pharmaceutical ingredient is extracted with water or organic solvent, the extract is concentrated, and pharmaceutically acceptable excipients are added to prepare a formulation.

[0018] Further, the raw materials mentioned in step (2) are boiled with water, the decoction is concentrated into a clear paste, and honey is added to obtain the final product.

[0019] Finally, the present invention provides the use of the aforementioned composition in the preparation of a medicament for treating stable chronic obstructive pulmonary disease.

[0020] Furthermore, the drug is a treatment for stable chronic obstructive pulmonary disease of the lung and kidney qi deficiency type.

[0021] In Traditional Chinese Medicine (TCM), stable chronic obstructive pulmonary disease (COPD) falls under the category of "lung distension." Lung distension, a TCM term first appearing in the *Huangdi Neijing*, is characterized by a distended and unable-to-descend lung qi, hence its name. It is often caused by recurrent external pathogenic factors, prolonged illness leading to deficiency, old age, or general weakness, resulting in recurrent episodes of chronic lung disease and impaired lung function, leading to pulmonary distension and fullness. In long-term clinical practice, lung and kidney qi deficiency is a common TCM syndrome type of pulmonary distension. Symptoms of pulmonary distension caused by lung and kidney qi deficiency include cough, wheezing, edema, and general weakness. These symptoms are closely related to the lungs and seriously affect people's health. The TCM composition of this invention has the effects of tonifying the lungs and kidneys, regulating qi and relieving wheezing, and strengthening the body's foundation and stopping cough. It has shown significant clinical efficacy in the stable phase of COPD (pulmonary distension) due to lung and kidney qi deficiency.

[0022] This invention relates to a traditional Chinese medicine composition primarily used to treat lung and kidney qi deficiency syndrome in pulmonary distension, including cough, wheezing, edema, and general weakness. The condition arises from external pathogenic factors such as wind, cold, and heat invading the lungs, causing impaired lung qi circulation and upward reversal of qi flow, resulting in cough and other symptoms. Prolonged illness with recurring relapses leads to lung qi deficiency, weakened defensive qi, and impaired descending function. The upward reversal of lung qi obstructs the flow of qi, blood, and body fluids, leading to phlegm and blood stasis, further hindering the flow of qi and causing pulmonary distension. Patients with chronic illness and weakened constitution are susceptible to external pathogenic factors, which can trigger the onset of pre-existing conditions. Over time, the disease can also affect the spleen and kidneys. Lung and kidney qi deficiency impairs the body's ability to retain and process qi, commonly manifesting as a weak cough, more exhalation than inhalation, shortness of breath (wheezing and shortness of breath, especially aggravated by exertion), copious clear and thin sputum, low voice, spontaneous sweating, or urinary incontinence with coughing, a pale purple tongue, and a weak pulse. Cough and wheezing caused by lung and kidney qi deficiency are due to the invasion of cold and dampness into the yin qi. The lungs are the cover of the five viscera, and the kidney meridian enters the lungs. Therefore, when the lower body is deficient and the upper body is excessive, the airways become congested, lung qi rises high, the upper burner is blocked, and shortness of breath and inability to lie down comfortably occur. Furthermore, the *Neijing* states that water retention manifests as abdominal swelling, difficulty sitting or lying down, rattling in the throat, and chest tightness. The lungs are the upper source of water, and the kidneys are the organ that governs water. Deficiency of lung and kidney qi leads to obstruction of the water passages and abnormal distribution of body fluids, thus exacerbating symptoms such as generalized edema, palpitations, and shortness of breath. Treatment should focus on tonifying the lungs and kidneys, regulating qi, relieving asthma, and strengthening the body's foundation to stop coughing. In this formula, Astragalus membranaceus tonifies qi and strengthens the exterior, while Gecko scabra tonifies the lungs and kidneys, regulates qi, and relieves asthma; these are the principal herbs. Atractylodes macrocephala strengthens the spleen and qi, dries dampness, and promotes urination; Rehmannia glutinosa nourishes blood and yin, replenishes essence and marrow; Dioscorea opposita tonifies the spleen and stomach, tonifies the kidneys and lungs; Cornus officinalis tonifies the liver and kidneys, astringes essence and prevents leakage; Ginseng greatly tonifies primordial qi, tonifies the spleen and lungs; and Epimedium tonifies kidney yang and strengthens tendons and bones; these are the assistant herbs. Schisandra chinensis invigorates qi and generates fluids, tonifies the kidneys and calms the mind; walnut kernels tonify the kidneys and strengthen essence, warm the lungs and relieve asthma; bitter almonds resolve phlegm, stop coughing and relieve asthma; platycodon grandiflorum promotes lung function and benefits the throat; fritillaria thunbergii clears heat and moistens the lungs, resolves phlegm and stops coughing, serving as an adjuvant. Saposhnikovia divaricata dispels wind and eliminates dampness; Alisma plantago-aquatica promotes urination and clears damp heat; peony bark clears heat, cools the blood, invigorates blood and removes blood stasis; poria cocos promotes diuresis and eliminates dampness, serving as an adjuvant. This formula is based on the "theory of righteousness and evil" that "when righteous qi is abundant, evil cannot invade" and "where evil gathers, qi must be deficient." It adopts the principle of "supporting righteousness and eliminating evil" in its formulation. "The lungs are the master of qi, the kidneys are the root of qi; the lungs govern exhalation, the kidneys govern inhalation; yin and yang interact, respiration is harmonious." The entire formula primarily tonifies the lungs and kidneys, strengthens the foundation and consolidates the original qi, tonifying both yin and yang, addressing both qi and yin, and also considering phlegm, fluid retention, and blood stasis. The combined effects of these herbs tonify the lungs and kidneys, invigorate qi and relieve asthma, and consolidate the foundation and stop coughing.

[0023] Clinical practice has proven that the herbal composition of this invention is significantly effective for patients with stable chronic obstructive pulmonary disease (COPD) diagnosed by TCM syndrome differentiation as lung and kidney qi deficiency. It is convenient to use, has no toxic side effects, and has good prospects for clinical application.

[0024] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0025] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0026] Figure 1 HPLC chromatograms (A - mixed reference solution; B - test solution; C - negative control solution lacking Astragalus membranaceus; D - negative control solution lacking Saposhnikovia divaricata; 1-monoside; 2-loganin; 3-cicadaenin; 4-verrucous isoflavone glucoside)

[0027] Figure 2 Process flow diagram Detailed Implementation

[0028] Example 1: Preparation of the composition of the present invention

[0029] Prescription: Astragalus membranaceus 30g, Atractylodes macrocephala 10g, Saposhnikovia divaricata 10g, Rehmannia glutinosa (processed) 15g, Dioscorea opposita 20g, Cornus officinalis 15g, Alisma plantago-aquatica (processed with salt) 10g, Paeonia suffruticosa 10g, Poria cocos 15g, Panax ginseng 15g, Epimedium brevicornu (processed with salt) 20g, Schisandra chinensis 10g, Gecko 5g, Walnut kernel 30g, Prunus armeniaca 10g, Platycodon grandiflorus 10g, Fritillaria thunbergii 15g, Honey 125g.

[0030] Preparation method: Take 17 herbs including Astragalus membranaceus, Atractylodes macrocephala, Saposhnikovia divaricata, Rehmannia glutinosa (processed), Dioscorea opposita, Cornus officinalis, Alisma plantago-aquatica (processed with salt), Paeonia suffruticosa, Poria cocos, Panax ginseng, Epimedium brevicornu (processed), Schisandra chinensis, Gecko gecko, Juglans regia, Prunus armeniaca, Platycodon grandiflorus, and Fritillaria cirrhosa. First, add 6 times the amount of water and decoct for 2 hours. Second, add 4 times the amount of water and decoct for 2 hours. Filter, combine the filtrates, and concentrate the filtrate to a clear paste with a relative density of not less than 1.2 (20℃). Add honey, mix, and concentrate to make a 250g decoction paste – Gecko Gecko Nourishing Paste.

[0031] Example 2: Preparation of the composition of the present invention

[0032] Prescription: Astragalus membranaceus 20g, Atractylodes macrocephala 5g, Saposhnikovia divaricata 5g, Rehmannia glutinosa (processed) 10g, Dioscorea opposita 15g, Cornus officinalis 10g, Alisma plantago-aquatica (processed with salt) 5g, Paeonia suffruticosa 5g, Poria cocos 10g, Panax ginseng 10g, Epimedium brevicornu (processed with salt) 10g, Schisandra chinensis 5g, Gecko 3g, Walnut kernel 20g, Prunus armeniaca 5g, Platycodon grandiflorus 5g, Fritillaria thunbergii 10g, Honey 115g.

[0033] Preparation method: Same as in Example 1.

[0034] Example 3: Preparation of the composition of the present invention

[0035] Prescription: Astragalus membranaceus 40g, Atractylodes macrocephala 15g, Saposhnikovia divaricata 15g, Rehmannia glutinosa (processed) 20g, Dioscorea opposita 25g, Cornus officinalis 20g, Alisma plantago-aquatica (processed with salt) 15g, Paeonia suffruticosa 15g, Poria cocos 20g, Panax ginseng 20g, Epimedium brevicornu (processed with salt) 30g, Schisandra chinensis 15g, Gecko 8g, Walnut kernel 40g, Prunus armeniaca 15g, Platycodon grandiflorus 15g, Fritillaria thunbergii 20g, Honey 135g.

[0036] Preparation method: Same as in Example 1.

[0037] Example 4: Preparation of the composition of the present invention

[0038] Prescription: Astragalus membranaceus 15g, Atractylodes macrocephala 2g, Saposhnikovia divaricata 2g, Rehmannia glutinosa 5g, Dioscorea opposita 10g, Cornus officinalis 5g, Alisma plantago-aquatica 2g, Paeonia suffruticosa 2g, Poria cocos 5g, Panax ginseng 5g, Epimedium brevicornu 10g, Schisandra chinensis 2g, Gecko 1g, Walnut kernel 15g, Prunus armeniaca 2g, Platycodon grandiflorus 2g, Fritillaria thunbergii 5g, Honey 100g.

[0039] Preparation method: Same as in Example 1.

[0040] Example 5: Preparation of the composition of the present invention

[0041] Prescription: Astragalus membranaceus 45g, Atractylodes macrocephala 18g, Saposhnikovia divaricata 18g, Rehmannia glutinosa (processed) 25g, Dioscorea opposita 30g, Cornus officinalis 25g, Alisma plantago-aquatica (processed with salt) 18g, Paeonia suffruticosa 18g, Poria cocos 25g, Panax ginseng 25g, Epimedium brevicornu (processed with salt) 30g, Schisandra chinensis 18g, Gecko 10g, Walnut kernel 45g, Prunus armeniaca 18g, Platycodon grandiflorus 18g, Fritillaria thunbergii 25g, Honey 150g.

[0042] Preparation method: Same as in Example 1.

[0043] The following experimental examples illustrate the beneficial effects of the present invention.

[0044] Experimental Example 1: Preparation process of the traditional Chinese medicine composition of the present invention

[0045] 1. Experimental Instruments and Materials

[0046] 1.1 Equipment and Instruments: Ultimate 3000 High Performance Liquid Chromatograph (Thermo Fisher Scientific, USA); FA2004 0.01% Electronic Balance (Shanghai Liangping Instrument Co., Ltd.); MJN-681C Electronic Metrological Counting Balance (Ruijin Yongheng Electronic Weighing Instrument Co., Ltd.); WGL-45B Electric Heating Drying Oven (Tianjin Test Instrument Co., Ltd.); SYG-4 Digital Display Constant Temperature Water Bath (Changzhou Langyue Instrument Manufacturing Co., Ltd.); BE-1102 Rotary Evaporator (Shanghai Jiapeng Biotechnology Co., Ltd.) LHH-150SD Drug Stability Test Chamber (Shanghai Huitai Instrument Manufacturing Co., Ltd.); JHT-SDC Ultra-Clean Workbench (Jinan Jiekang Purification Equipment Factory); SPX-250B-Z Biochemical Incubator (Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); G-100S Ultrasonic Cleaner (Shenzhen Geneng Cleaning Equipment Co., Ltd.); RE-1102 Rotary Evaporator (Shanghai Jiapeng Technology Co., Ltd.); LCK2000 Decoction Machine (Tianjin Sanyan Precision Machinery Co., Ltd.).

[0047] 1.2 Reagents and reagents: Petroleum ether (batch number: 20121100801), ethyl acetate (batch number: 2021060701), chloroform (2021043001), methanol (batch number: 2022011802), formic acid (2021030201), phosphoric acid (batch number: 20121215), and chromatographic acetonitrile (batch number: 2022010701) were all produced by Chengdu Kelong Chemical Co., Ltd.; silica gel plate G (batch number: 20190506) and silica gel plate GF254 (batch number: 20190506) were produced by Qingdao Haiyang Chemical Co., Ltd.; purified drinking water (batch number: 5112006030G) was produced by China Resources Yibao Beverage (China) Co., Ltd.; and Poria cocos reference material (batch number: 121117-201910). Schisandra chinensis reference material (batch number: 120922-201610); Atractylodes macrocephala reference material (batch number: 120925-202114); Moroniside reference standard (batch number: 111998-202205, purity: 98.4%); Loganin reference standard (batch number: 111640-201808, purity: 99.0%); Icariin reference standard (batch number: 110737-202017, purity: 98.1%); Prim-O-glucosylcimifugin reference standard (batch number: 111522-202214, purity: 95.7%); Galycosin reference standard. 7-O-β-D-Glucopyranoside (batch number: 110708-201908, purity: 96.8%), 5-O-methylvisammioside (batch number: 111523-202212, purity: 97.8%), and schisandrin (batch number: 110857-201815, purity: 99.7%) were all purchased from the National Institutes for Food and Drug Control (NIFDC). All other reagents were of analytical grade.

[0048] 2. Extraction process and results

[0049] Traditional Chinese medicine prescription: Astragalus membranaceus 120g, Atractylodes macrocephala 40g, Saposhnikovia divaricata 40g, Rehmannia glutinosa (processed) 60g, Dioscorea opposita 80g, Cornus officinalis 60g, Alisma plantago-aquatica (processed with salt) 40g, Paeonia suffruticosa 40g, Poria cocos 60g, Panax ginseng 60g, Epimedium brevicornu (processed with salt) 80g, Schisandra chinensis 40g, Gecko 20g, Walnut kernel 120g, Prunus armeniaca 40g, Platycodon grandiflorus 40g, Fritillaria thunbergii 60g.

[0050] 2.1 Sample Solution Preparation: The above 17 herbs were decocted for 2 hours with 6 times the amount of water for the first time, and then decocted for 2 hours with 4 times the amount of water for the second time. The solutions were filtered, and the filtrates were combined. The filtrates were concentrated to a clear extract with a relative density of not less than 1.2 (20℃). 500g of honey was added, mixed, and concentrated to make 1000g of the final product.

[0051] 2.1.1 Preparation of test solution: Take 5.0 g of the ointment and place it in a stoppered conical flask. Add 50 mL of 50% methanol-water and weigh it. Sonicate for 30 min, cool, and weigh it again. Make up the weight loss with 50% methanol-water, shake well, let stand, filter through a 0.45 μm microporous membrane, and take the filtrate.

[0052] 2.1.2 Preparation of Reference Solutions Accurately weigh appropriate amounts of verbenafil glucoside, cimicifugain, loganin, and monoglucoside reference standards, and add methanol to prepare single reference standard stock solutions with mass concentrations of 376.36, 870.87, 851.40, and 762.80 μg / ml, respectively. Accurately measure 2.5, 1.25, 6.25, and 15 ml of each of the above stock solutions into the same 25 ml volumetric flask to prepare a mixed reference standard solution containing 37.636 μg of verbenafil glucoside, 43.5435 μg of cimicifugain, 212.85 μg of loganin, and 457.68 μg of monoglucoside per ml. Mix well to obtain the final solution.

[0053] 2.1.3 Negative Sample Preparation: Negative samples lacking Cornus officinalis, Astragalus membranaceus, and Saposhnikovia divaricata were prepared according to the formulation and process. Negative control solutions were prepared using the same method.

[0054] 2.2 Chromatographic conditions

[0055] Column: Agilent Eclipse XDB-C 18 Column (250 mm × 4.6 mm, 5 μm); Mobile phase: acetonitrile (A) - 0.2% phosphoric acid solution (B) (20:80, V / V); Gradient elution (0 → 30 min, 10% A → 30% A). Flow rate: 1.0 mL / min; Detection wavelength: 260 nm; Column temperature: 25 °C; Injection volume: 5 μL.

[0056] 2.3 Methodological Examination

[0057] 2.3.1 Specificity Test: The mixed reference solution, negative control solution, and test solution were analyzed under the specified chromatographic conditions. The chromatograms showed that the peaks of the test solution were clearly visible at the same retention times as the references, while the negative control solution showed no interfering peaks, indicating good specificity. The mixed reference solution, test solution, and negative sample solution were injected and analyzed under the chromatographic conditions described in section "2.2". The results showed that the retention times of the peaks in the samples were consistent with the corresponding retention times of the references, and the resolution and symmetry of each peak were good. The chromatographic peaks of the negative samples did not interfere with the determination, and the resolution of each peak also met the requirements. See details... Figure 1 .

[0058] 2.3.2 Linearity: Take the mixed reference solution, dilute it to prepare a series of mixed reference solutions of different concentrations, and inject and determine the solution according to the chromatographic conditions in section “2.2.1”. Record the peak area, plot the standard curve with the peak area (Y) as the ordinate and the injection amount (X, μg) as the abscissa, and obtain the regression equation for each component. See Table 1 for details.

[0059] Table 1. Results of the linear relationship examination (n=6)

[0060]

[0061] 2.3.3 Precision Test: A mixed reference solution was injected six times consecutively under the chromatographic conditions described above, and the peak areas were recorded. The RSDs of the peak areas for verrucoside, cimicifugin, loganin, and monoglobin were 0.27%, 0.30%, 0.44%, and 0.10%, respectively, indicating good instrument precision.

[0062] 2.3.4 Stability Test: The same sample solution of Huangha Peiyuan Paste (batch number: 20221201) was placed at room temperature and analyzed at 0, 2, 4, 6, 8, 12, and 24 hours. The RSDs of the peak areas of verrucoside, cimicifugin, loganin, and monoglucoside were 0.89%, 1.92%, 0.34%, and 1.09%, respectively, indicating that the sample solution had good stability within 24 hours.

[0063] 2.3.5 Repeatability Test: Six portions of raw material for Huangha Peiyuan Ointment were weighed, and six test samples were prepared according to section “2.1”. The test sample solution was prepared according to section “2.1.1”, and the samples were injected for determination. The peak areas of each chromatographic peak were measured, and the contents were calculated. The results showed that the average contents of verrucoside, cimicifugin, loganin, and monoglucoside were 93.17, 107.49, 464.01, and 977.89 μg / g, respectively, with RSDs of 1.81%, 1.80%, 0.66%, and 0.49%, respectively, indicating that the repeatability of this method was good.

[0064] 2.3.6 Recovery Test

[0065] Six portions of raw materials for Huangha Peiyuan Ointment were weighed, and appropriate amounts of reference standards of vervain isoflavone glucoside, cimicifugain, loganin, and monoglucoside were added respectively. Six test samples were prepared according to section "2.1", and the test sample solutions were prepared according to section "2.1.1". The samples were injected and the recovery rates were calculated. The average recovery rates of vervain isoflavone glucoside, cimicifugain, loganin, and monoglucoside were 98.62%, 96.32%, 97.63%, and 97.89%, respectively. See Table 2 for details.

[0066] Table 2 Results of the recovery rate experiment (n=6)

[0067]

[0068]

[0069] 2.4 Optimization of the extraction process of clam extract using orthogonal experimental design

[0070] 2.4.1 Experimental Design and Results Through preliminary experiments, the optimal process for water addition, extraction time, and number of decoctions was investigated using the single-factor method. An orthogonal design L9(3) was then employed. 4 An orthogonal experiment was conducted, with water volume (A), extraction time (B), and number of decoctions (C) as the factors of investigation, and the components verrucoside, cimicifugain, loganin, and monoglycoside as the evaluation indicators, to optimize the extraction process of *Clam Herbal Extract*. The design and results of the water extraction orthogonal experiment are shown in the table below.

[0071] The contents of verbenafil glucoside, cimicifugin, loganin, and monoglucoside were comprehensively weighted and scored, with each assigned a value of 25%. Taking verbenafil glucoside as an example, the calculation formula is as follows: Calculation Formula: X n =X i / X max ×100% (Note: X) i The results of the content of verbascoside glucoside in each orthogonal experiment; X max The maximum value of the content of verbascoside in the orthogonal experiment; comprehensive evaluation value = X n (Verbena isoflavone glucoside) × 25% + X n (Cimicifugin) × 25% + X n (Logan) × 25% + X n (Monoglycoside) × 25% × 100.

[0072] Table 3 Factor Level Table

[0073]

[0074] Table 4. Orthogonal experimental design and results of extraction process

[0075]

[0076] Table 5. Results of the extraction process variance analysis

[0077]

[0078] The comprehensive evaluation results in Tables 4 and 5 show that among the three factors affecting extraction, the number of decoctions (C) was statistically significant, while the amount of water added (A) and extraction time (B) showed no significant difference. In the experiment, the highest comprehensive score was achieved with A2B3C2. Regarding the amount of water added and extraction time, the three levels of conditions had no significant effect on the content of the four components. Considering the principles of energy conservation and consumption reduction in large-scale production, and taking into account the formulation production equipment, the optimal extraction process was selected as A2B2C2, i.e., an 8-fold increase in water volume, an extraction time of 2 hours, and two decoctions. Process validation was then conducted.

[0079] Pilot-scale production using this extraction process revealed that a large amount of water was required, resulting in a long time needed to concentrate the liquid to the specified density. Therefore, the water addition ratio was adjusted. Based on the experimental results and pilot-scale production, the final extraction process for Huangha Peiyuan Gao (a traditional Chinese medicine extract) was determined to be: extraction twice, 2 hours each time, with 6 times the amount of water added for the first extraction and 4 times the amount of water added for the second extraction.

[0080] Based on actual production conditions, the final optimized extraction process for Huangha Peiyuan Paste is as follows: extraction twice, 2 hours each time, with 6 times the amount of water added for the first extraction and 4 times the amount of water added for the second extraction.

[0081] 3. Formulation process research

[0082] The preparation process of the decoction paste adopts the traditional process route of decoction, concentration, paste collection, and packaging.

[0083] The types and amounts of excipients for Huangha Peiyuan Paste are being screened.

[0084] 3.1 Selection of Auxiliary Materials

[0085] Honey and sucrose are commonly used as excipients in decoction pastes. Based on the kidney-tonifying, qi-boosting, yin-nourishing, and lung-moistening effects of Huangha Peiyuan Paste, and considering the properties of honey (tonifying the middle jiao, moistening dryness, relieving pain, and detoxifying), honey was chosen as an excipient for Huangha Peiyuan Paste.

[0086] 3.2 Examination of the dosage of excipients

[0087] The ratio of clear paste to added honey was investigated. The taste results are shown in the table below.

[0088] Table 6. Experimental results of the ratio of ointment to excipients.

[0089]

[0090] The results showed that the paste made with a 1:1 ratio of clear paste to honey had a suitable taste, with a slightly sour and astringent flavor, and a sweet and slightly bitter taste. Therefore, the ratio of clear paste to honey is 1:1.

[0091] 3.3 Main Equipment

[0092] Table 7 Main Preparation Equipment and Manufacturers

[0093]

[0094] 3.4 Process Validation

[0095] To verify the feasibility and stability of the preparation process of Huangha Peiyuan Paste, a verification of the preparation process of Huangha Peiyuan Paste was conducted.

[0096] This validation primarily aimed to verify the formulation process conditions that affect the quality of Huangha Peiyuan Gao (a traditional Chinese medicine paste). The formulation process was confirmed through monitoring and verifying the results of three pilot-scale production batches.

[0097] Verification objective: To evaluate the production system elements and various process variables that may affect product quality in the preparation process of Huangha Peiyuan Gao (a traditional Chinese medicine), to confirm the feasibility of the production system and the stability of the production process, and to ensure that products that meet the quality standards of Huangha Peiyuan Gao can be produced according to this preparation process specification.

[0098] 4. Prescription, preparation method, and process flow diagram

[0099] 4.1 Prescription

[0100] One dose of a doctor's prescription, when decocted into a paste, yields approximately 250 grams. 1000 preparation units are calculated as 1000 grams. The prescription is as follows:

[0101]

[0102] 4.2 Manufacturing Method

[0103] The above 17 herbs are decocted for 2 hours with 6 times the amount of water for the first time, and for 2 hours with 4 times the amount of water for the second time. Filter, combine the filtrates, and concentrate the filtrate to a clear extract with a relative density of not less than 1.2 (20℃). Add 500g of honey, mix, concentrate, and make 1000g.

[0104] 4.3 Process Flow Diagram

[0105] Figure 2 .

[0106] In summary, the modern Chinese medicine preparations prepared according to the drug dosage ratio and process method of this invention have high content of active ingredients and stable quality.

[0107] Experimental Example 2: Clinical efficacy of the composition of the present invention

[0108] 1. Clinical Data

[0109] The experimental group consisted of 62 patients who met the diagnostic criteria for pulmonary distension (COPD stable phase) and were diagnosed with lung and kidney qi deficiency syndrome by traditional Chinese medicine differentiation, and were admitted to the Department of Pulmonary Diseases of Nanchong Municipal Hospital of Traditional Chinese Medicine from April 2021 to September 2023. There were 32 male cases and 30 female cases.

[0110] 1.1 Diagnostic criteria

[0111] 1.1.1 Diagnostic Criteria

[0112] Characterized by shortness of breath, difficulty breathing, even open-mouth breathing with shoulder elevation, nasal flaring, inability to lie flat, and cyanosis of the lips. Often has a history of chronic cough, asthma, tuberculosis, palpitations, etc., and is triggered by external pathogens or fatigue. Presents with a barrel chest. Percussion of the chest reveals hyperresonance, a reduced or absent cardiac dullness border, and a downward displacement of the liver dullness border. Lung breath sounds are decreased, and dry or wet rales or wheezing may be heard. Hepatomegaly, lower extremity edema, and jugular venous distension may also be present. In cases with concurrent infection, the total white blood cell count and neutrophils may be elevated. If necessary, serum potassium, sodium, and carbon dioxide combining power, chest X-ray, electrocardiogram, cardiac and pulmonary function tests, and blood gas analysis should be performed.

[0113] 1.1.2 Disease Diagnostic Criteria

[0114] 1.1.2.1 COPD Diagnosis and Staging Criteria for Stable Phase: Referencing the 2020 Global Conference on Chronic Obstructive Pulmonary Disease (GOLD), the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease (2013 Revised Edition) formulated by the Chronic Obstructive Pulmonary Disease Group of the Chinese Medical Association, and the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease at the Primary Care Level (Practical Version 2018) formulated by the Chinese Medical Association.

[0115] (1) Diagnostic criteria for COPD: Forced expiratory volume in one second / forced vital capacity (FEV1 / FVC) <70% after inhalation of bronchodilator; chest X-ray / chest CT scan excludes other diseases;

[0116] (2) Stability phase criteria: The patient’s symptoms such as cough, sputum, and shortness of breath are stable or mild, and the condition has basically recovered to the state before the acute exacerbation.

[0117] 1.1.2.2 Diagnostic criteria for pulmonary distension in Traditional Chinese Medicine: Refer to the diagnostic points of "pulmonary distension" in the National Planning Textbook of Traditional Chinese Medicine Internal Medicine for General Higher Education.

[0118] 1.1.2.3 Diagnostic criteria for Lung and Kidney Qi Deficiency Syndrome: Based on the "Diagnostic Criteria for Traditional Chinese Medicine Syndromes of Chronic Congestive Lung Disease (2011 Edition)," the "Guidelines for Diagnosis and Treatment of Common Diseases in Traditional Chinese Medicine (TCM) - TCM Diseases and Syndromes Section," and the "Reference Standards for Differentiation of Deficiency Syndromes in Traditional Chinese Medicine," Lung and Kidney Qi Deficiency Syndrome is defined as follows: ① Wheezing and shortness of breath, aggravated by exertion; ② Fatigue or spontaneous sweating, aggravated by exertion; ③ Susceptibility to colds and aversion to wind; ④ Soreness and weakness of the lower back and knees; ⑤ Tinnitus, dizziness, or puffy face; ⑥ Frequent urination, nocturia, or cough with urinary incontinence; ⑦ Pale tongue with white coating, and a deep, thready, or weak pulse. A diagnosis can be made if two of the following criteria are met: ①②③, plus two of the following criteria: ④⑤⑥⑦.

[0119] 1.2 Inclusion Criteria

[0120] Those who meet all of the following criteria: (1) meet the diagnostic criteria and staging criteria for COPD; (2) meet the TCM diagnostic criteria for lung and kidney qi deficiency; (3) meet the TCM diagnostic criteria for lung distension; (4) are grouped into group C (mMRC 0-1, CAT < 10) or group D (mMRC ≥ 2, CAT ≥ 10) (refer to the 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD)); (5) have a pulmonary function classification of moderate to very severe, and have a pulmonary function FEV1 percentage of predicted value < 80%; (6) are 40 years old ≤ age ≤ 89 years old; (7) are informed by the subject or their representative or family member and voluntarily sign the informed consent form.

[0121] 1.3 Exclusion Criteria

[0122] Patients meeting any of the following criteria: (1) those with bronchial asthma, bronchiectasis, pulmonary interstitial fibrosis, or other chronic lung diseases; (2) those with chronic cough and wheezing caused by fungi, tuberculosis, tumors, irritant gases, silicosis, allergies, or other factors, as confirmed by examination; (3) those with severe respiratory failure [whose blood oxygen partial pressure (PaO2) is still <50 mmHg after oxygen therapy and non-invasive assisted ventilation, with or without carbon dioxide partial pressure (PaCO2) >70 mmHg], pulmonary encephalopathy requiring invasive mechanical ventilation, or those unable to complete pulmonary function tests; (4) those with severe cardiovascular diseases: acute coronary syndrome, acute heart failure, severe pulmonary hypertension, severe congenital heart disease without surgery, active endocarditis, subacute myocarditis or pericarditis, or those whose blood pressure is still not well controlled after antihypertensive treatment. Patients with high blood pressure (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg), severe arrhythmia, or resting heart rate >120 beats / min (including instantaneous rise); (5) patients with acute pulmonary embolism or pulmonary infarction; (6) patients with acute cerebrovascular disease or epilepsy; (7) patients with severe infection; (8) patients with renal insufficiency and serum creatinine exceeding the upper limit of normal; (9) patients with liver insufficiency and serum transaminase >2 times the upper limit of normal; (10) patients with malignant tumors; (11) patients with severe hematopoietic system diseases; (12) patients with acquired immunodeficiency syndrome (HIV); (13) patients with severe mental illness; (14) patients who have used immunomodulators routinely for more than 1 month within the past 6 months; (15) pregnant or lactating women; (16) patients who have participated in or are currently participating in other clinical trials within the past 3 months.

[0123] 2. Treatment methods

[0124] Experimental group: The drug of the composition of the present invention was administered, specifically as follows: Astragalus membranaceus 30g, Atractylodes macrocephala 10g, Saposhnikovia divaricata 10g, Rehmannia glutinosa 15g, Dioscorea opposita 20g, Cornus officinalis 15g, Alisma plantago-aquatica 10g, Paeonia suffruticosa 10g, Poria cocos 15g, Panax ginseng 15g, Epimedium brevicornu 20g, Schisandra chinensis 10g, Gecko 5g, Walnut kernel 30g, Prunus armeniaca 10g, Platycodon grandiflorus 10g, Fritillaria thunbergii 15g.

[0125] The specific administration method is as follows: The above-mentioned composition is extracted by decoction. For the first decoction, add 6 times the amount of water and decoct for 2 hours. For the second decoction, add 4 times the amount of water and decoct for 2 hours. Filter, combine the filtrates, and concentrate the filtrate to a clear extract with a relative density of not less than 1.2 (20℃). Add 125g of honey, mix, and concentrate to obtain 250g of the final product. For oral administration, one dose is given every six days, twice daily, with each dose being 20ml, equivalent to 20g of raw herbs. The efficacy is statistically analyzed after 12 weeks of continuous use.

[0126] 3. Observation of therapeutic effects

[0127] 3.1 Efficacy criteria

[0128] Traditional Chinese Medicine (TCM) syndrome differentiation and efficacy evaluation criteria (referring to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines"):

[0129] ①Significant effect: Clinical symptoms and signs are significantly improved, namely wheezing, cough, sputum production; shortness of breath, fatigue, spontaneous sweating, soreness of the waist and knees, tinnitus; symptoms of cold, wheezing, frequent urination, and nocturia disappear or are mostly relieved, and the syndrome score is reduced by ≥70%;

[0130] ② Effective: Clinical symptoms and signs have improved, namely wheezing, cough, sputum production; shortness of breath, fatigue, spontaneous sweating, soreness of the waist and knees, tinnitus; symptoms of cold, wheezing, frequent urination, and nocturia are partially relieved, and the syndrome score is reduced by ≥30%;

[0131] ③ Ineffective: Clinical symptoms and signs show no significant improvement or even worsen, such as wheezing, coughing, expectoration; shortness of breath, fatigue, spontaneous sweating, soreness of the lower back and knees, tinnitus; symptoms of cold, wheezing, frequent urination, and nocturia are not relieved, and the syndrome score decreases by less than 30%.

[0132] The specific syndrome scoring criteria are shown in Table 8.

[0133] Table 8 Traditional Chinese Medicine Syndrome Scoring Table

[0134]

[0135]

[0136] 3.2 Treatment Efficacy

[0137] Table 9 Treatment Efficacy

[0138] Experimental group (62 people) 52 10 0 100％

[0139] Note: Cure rate = (Significantly effective cases / Total cases) * 100%; Overall effective rate = (Significantly effective cases + Effective cases) / Total cases * 100%

[0140] Experimental Conclusion: Before treatment, all COPD patients in the stable phase participating in the clinical study exhibited varying degrees of clinical characteristics of TCM syndromes, including wheezing, shortness of breath, fatigue, spontaneous sweating, lower back and knee weakness, tinnitus, and dizziness. After treatment with the TCM composition of this invention, the TCM syndrome scores decreased, significantly improving symptoms such as wheezing, cough, and sputum production in the stable phase of COPD, improving patients' quality of life, and preventing the disease from progressing to an acute exacerbation. The TCM formula of this invention is rationally formulated and has significant efficacy in treating stable phase (pulmonary distension) of chronic obstructive pulmonary disease caused by lung and kidney qi deficiency.

Claims

1. A traditional Chinese medicine composition for treating stable chronic obstructive pulmonary disease, characterized in that: It is a preparation made from the following raw materials in the indicated weight ratios: Astragalus membranaceus 20-40 parts, Atractylodes macrocephala 5-15 parts, Saposhnikovia divaricata 5-15 parts, Rehmannia glutinosa 10-20 parts, Dioscorea opposita 15-25 parts, Cornus officinalis 10-20 parts, Alisma plantago-aquatica 5-15 parts, Paeonia suffruticosa 5-15 parts, Poria cocos 10-20 parts, Panax ginseng 10-20 parts, Epimedium brevicornu 10-30 parts, Schisandra chinensis 5-15 parts, Gecko gecko 3-8 parts, Juglans regia kernel 20-40 parts, Prunus armeniaca 5-15 parts, Platycodon grandiflorus 5-15 parts, Fritillaria cirrhosa 10-20 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that: It is a preparation made from the following raw materials in the indicated weight ratios: Astragalus membranaceus 30 parts, Atractylodes macrocephala 10 parts, Saposhnikovia divaricata 10 parts, Rehmannia glutinosa 15 parts, Dioscorea opposita 20 parts, Cornus officinalis 15 parts, Alisma plantago-aquatica 10 parts, Paeonia suffruticosa 10 parts, Poria cocos 15 parts, Panax ginseng 15 parts, Epimedium brevicornu 20 parts, Schisandra chinensis 10 parts, Gecko 5 parts, Walnut kernels 30 parts, Bitter almonds 10 parts, Platycodon grandiflorus 10 parts, Fritillaria cirrhosa 15 parts.

3. The traditional Chinese medicine composition according to any one of claims 1 to 2, characterized in that: The Rehmannia glutinosa mentioned is prepared Rehmannia glutinosa, Alisma plantago-aquatica is salted Alisma plantago-aquatica, Epimedium is roasted Epimedium, and Fritillaria thunbergii is Fritillaria thunbergii.

4. The traditional Chinese medicine composition according to claim 1, characterized in that: It is a preparation made from active pharmaceutical ingredients, such as powdered active pharmaceutical ingredients or water extracts of active pharmaceutical ingredients, plus pharmaceutically acceptable excipients. The preparation is an oral preparation; The oral preparations include decoctions, pills, mixtures, granules, capsules, tablets, solutions, and syrups.

5. The traditional Chinese medicine composition according to claim 4, characterized in that: The oral preparation is a decoction.

6. The traditional Chinese medicine composition according to claim 5, characterized in that: The excipients of the decoction include honey; the honey is 100-150 parts.

7. The traditional Chinese medicine composition according to claim 6, characterized in that: The honey is 115-135 parts.

8. The traditional Chinese medicine composition according to claim 7, characterized in that: The honey was 125 portions.

9. A method for preparing the composition according to any one of claims 1 to 8, characterized in that: It includes the following steps: (1) Weigh each raw material according to the weight ratio; (2) The active pharmaceutical ingredient is powdered, or the active pharmaceutical ingredient is extracted with water, the extract is concentrated, and pharmaceutically acceptable excipients are added to prepare a formulation.

10. The method according to claim 9, characterized in that: In step (2), the raw materials are boiled with water, the decoction is concentrated into a clear paste, and honey is added to obtain the final product.

11. Use of the composition according to any one of claims 1 to 8 in the preparation of a medicament for treating stable chronic obstructive pulmonary disease.

12. The use according to claim 11, characterized in that: The drug is used to treat stable chronic obstructive pulmonary disease (COPD) of the lung and kidney qi deficiency type.

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