A pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension, its preparation method and uses.

Abstract

This invention provides a pharmaceutical composition for treating chronic obstructive pulmonary disease (COPD) complicated with pulmonary hypertension. It is a preparation made from the following raw materials in the indicated weight ratios: 12-20 parts of Trichosanthes peel, 10-20 parts of Allium macrostemon, 10-20 parts of Lysimachia christinae, 10-20 parts of Poria cocos, 10-20 parts of Paeonia suffruticosa, 6-15 parts of Prunus persica, 8-15 parts of Paeonia lactiflora, 5-15 parts of Ephedra sinica, 6-15 parts of Cinnamomum cassia, 5-20 parts of Platycodon grandiflorus, and 6-12 parts of Glycyrrhiza uralensis. This invention also provides a method for preparing this pharmaceutical composition and its uses. The pharmaceutical composition of this invention is well-formulated and can effectively improve cardiopulmonary function and reduce pulmonary artery pressure, providing an option for the clinical treatment of COPD complicated with pulmonary hypertension due to phlegm and blood stasis, with promising application prospects.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension, as well as its preparation method and uses, belonging to the field of traditional Chinese medicine. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease characterized by persistent, progressive airflow obstruction, with main clinical manifestations including chronic cough, sputum production, shortness of breath, or dyspnea. Pulmonary hypertension (PH) is a clinical and pathophysiological syndrome resulting from structural or functional changes in pulmonary vessels due to various heterogeneous diseases (etiologies) and different pathogenesis mechanisms, leading to increased pulmonary vascular resistance and pulmonary artery pressure. PH is a common complication in the development of COPD and is closely related to acute exacerbations and poor prognosis in COPD patients. The development of COPD combined with PH (COPD-PH) severely impacts patients' quality of life and can even lead to death. Statistics show that the global prevalence of COPD is approximately 10.3%, while the prevalence of COPD-PH varies considerably, and large-scale epidemiological surveys are currently lacking. According to existing studies, the prevalence of COPD-PH varies between 30% and 70%, and in patients with severe COPD, the prevalence of PH can even reach as high as 90%. Due to the incomplete understanding of its pathogenesis, there is currently no specific treatment for COPD-PH, either domestically or internationally. Most studies recommend actively treating the primary lung disease and related comorbidities. Therefore, clinical treatment remains primarily focused on COPD, including general treatment, pharmacological treatment, and non-pharmacological treatment. Pharmacological treatment mainly consists of bronchodilators, glucocorticoids, phospholipase 4 inhibitors, expectorants, and antitussives.

[0003] Traditional Chinese medicine (TCM) has shown significant efficacy in treating COPD-PH. TCM classifies COPD into categories such as "wheezing," "pulmonary distension," "asthma," and "cough" based on its clinical characteristics. COPD-PH can also be categorized within these categories. The *Ling Shu* (Spiritual Pivot) states, "The meridians are the interior, and the branches that extend horizontally are the collaterals." Collaterals, as a network system branching horizontally from the meridians, transport qi and blood laterally to the internal organs and tissues, playing a crucial role in maintaining homeostasis and vital functions. The lung collaterals are a branch of the collateral system belonging to the lungs, thus possessing both the functional characteristics of collaterals and the physiological functions of the lungs themselves. Modern research indicates that lung collaterals align with modern medical descriptions of lung physiological structure, broadly referring to structures such as the trachea, bronchi, alveolar ducts, and alveolar capillaries. PH primarily affects pulmonary arterioles with a diameter <500μm, a location consistent with the structural characteristics of "collaterals." The classic text states, "Prolonged illness enters the collaterals," "Prolonged illness often leads to blood stasis," and "When blood is not flowing smoothly, it becomes water retention." COPD's fundamental pathogenesis is lung deficiency due to prolonged illness. Insufficient lung qi weakens the collaterals, hindering the flow of fluids and blood. Over time, qi stagnation and blood stasis occur, leading to the internal generation of phlegm and blood stasis, which intertwine. If external pathogens are contracted, the struggle between the body's resistance and the pathogenic factors disrupts the flow of qi, blood, and body fluids in the collaterals, also resulting in phlegm and blood stasis. Once phlegm and blood stasis are formed, they infiltrate the damaged collaterals, creating the phenomenon of "phlegm and blood stasis lurking in the collaterals." The lungs govern all the blood vessels; if the lung collaterals are congested, the function of assisting the heart in circulating blood is impaired, potentially leading to obstruction of the heart collaterals and the development of COPD-PH. Therefore, long-term clinical practice has concluded that "phlegm and blood stasis lurking in the collaterals" is the core pathogenesis of this disease, and treatment should focus on resolving phlegm, removing blood stasis, and promoting blood circulation and unblocking the collaterals.

[0004] However, the treatment of chronic obstructive pulmonary disease (COPD) complicated with pulmonary arterial hypertension (PAH) is a challenging issue in the field of Traditional Chinese Medicine (TCM). Due to the complex pathological mechanisms of COPD and PAH, and their mutual influence, TCM treatment requires comprehensive consideration of multiple factors, including the patient's constitution, the severity of the disease, and the etiology and pathogenesis. The difficulty of TCM treatment is mainly reflected in the following aspects: 1. Complex pathological mechanisms: The pathological mechanisms of COPD and PAH are intertwined, requiring TCM practitioners to identify the etiology and pathogenesis, such as qi stagnation and blood stasis, phlegm-dampness obstruction, etc., which requires doctors to have a profound theoretical foundation and clinical experience in TCM. 2. Significant individual differences: Each patient's constitution, disease severity, and response to treatment are different, requiring TCM treatment to be tailored to the individual patient's specific situation. 3. Long treatment cycle: TCM treatment usually requires a long period of time to adjust and improve the patient's constitution to achieve the desired therapeutic effect, requiring good patient compliance. 4. Difficulty in efficacy evaluation: The efficacy evaluation of TCM treatment is often less intuitive than that of Western medicine, requiring a comprehensive evaluation through symptom improvement, changes in constitution, and other aspects. Summary of the Invention

[0005] This invention provides a pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension. This invention also provides a method for preparing the pharmaceutical composition and its uses.

[0006] This invention provides a pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension, which is a formulation prepared from the following active pharmaceutical ingredients in the indicated weight ratios:

[0007] Trichosanthes peel 12-20 parts, Allium macrostemon 10-20 parts, Lysimachia christinae 10-20 parts, Poria cocos 10-20 parts, Paeonia suffruticosa 10-20 parts, Prunus persica 6-15 parts, Paeonia lactiflora 8-15 parts, Ephedra sinica 5-15 parts, Cinnamomum cassia 6-15 parts, Platycodon grandiflorus 5-20 parts, Glycyrrhiza uralensis 6-12 parts.

[0008] More preferably, it is a formulation prepared from the following active pharmaceutical ingredients in the indicated weight ratios:

[0009] 15 parts of Trichosanthes peel, 15 parts of Allium macrostemon, 15 parts of Lysimachia christinae, 15 parts of Poria cocos, 15 parts of Paeonia suffruticosa, 10 parts of Prunus persica, 10 parts of Paeonia lactiflora, 10 parts of Ephedra sinica, 10 parts of Cinnamomum cassia, 15 parts of Platycodon grandiflorus, and 10 parts of Glycyrrhiza uralensis.

[0010] The ephedra is processed ephedra; the licorice is raw licorice.

[0011] The pharmaceutical composition of the present invention is prepared into a commonly used pharmaceutical formulation by adding pharmaceutically acceptable excipients or auxiliary ingredients, using the original powder of the active pharmaceutical ingredient, water or organic solvent extract as the active ingredient.

[0012] The preparations mentioned above include decoctions, oral liquids, granules, capsules, tablets, and powders.

[0013] This invention provides a method for preparing the pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension, comprising the following steps:

[0014] a. Weigh the raw materials according to the specified weight ratio;

[0015] 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 pharmaceutically acceptable excipients are added to prepare a formulation.

[0016] The present invention also provides the use of the pharmaceutical composition in the preparation of a medicament for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension due to phlegm and blood stasis syndrome.

[0017] The *Trichosanthes kirilowii* peel is the dried, mature pericarp of *Trichosanthes kirilowii* Maxim. or *Trichosanthes rosthornii* Harms, both belonging to the Cucurbitaceae family; the *Allium macrostemon* is the dried bulb of *Allium macrostemon* Bge. or *Allium chinense* G.Don, both belonging to the Liliaceae family.

[0018] Clinical summaries have found that using Trichosanthes peel, Allium macrostemon, Lysimachia christinae, Poria cocos, Paeonia suffruticosa, Prunus persica, Paeonia lactiflora, processed Ephedra sinica, Cinnamomum cassia, Platycodon grandiflorus, and Glycyrrhiza uralensis to treat COPD-PH is effective. Trichosanthes peel is sweet and cold, entering the lung and stomach meridians. It primarily clears heat and phlegm, promotes qi circulation and relieves chest tightness, and can be used for coughs due to phlegm-heat, chest tightness, and hypochondriac pain. Allium macrostemon is warm in nature and bitter in taste, entering the lung, liver, and heart meridians. It can regulate qi, relieve chest tightness, promote yang, and disperse stagnation, and is used to treat chest pain radiating to the back, epigastric fullness, etc. The *Mingyi Bielu* records: "It enters the bones. It removes cold and heat, eliminates water retention, warms the middle and disperses stagnation. It is used topically for various sores, wind-cold, and edema." The *Bencao Beiyao* states that it "opens the orifices and treats shortness of breath due to lung qi stagnation." Lysimachia christinae is the dried whole herb of *Ardisia crenata*, a plant in the Myrsinaceae family. It is pungent and slightly bitter in taste, neutral in nature, entering the lung and liver meridians. It primarily resolves phlegm, stops coughs, and promotes blood circulation and removes blood stasis. Poria cocos is sweet and neutral in nature, primarily entering the heart and spleen meridians. It can drain dampness and promote urination, benefit the spleen and stomach, and calm the mind and spirit. The *Shennong Bencao Jing* records that it "treats chest and rib pain, anxiety, fright, palpitations, and epigastric pain... and promotes urination." The combination of Trichosanthes kirilowii peel, Allium macrostemon, Lysimachia christinae, and Poria cocos targets phlegm and dampness in COPD-PH, effectively resolving phlegm, regulating qi, strengthening the spleen, and eliminating dampness. Paeonia suffruticosa root bark is bitter, pungent, and slightly cold, entering the heart, liver, and kidney meridians. It can invigorate blood and dispel blood stasis, promoting smooth flow of qi and blood and relieving pain. The *Diannan Bencao* records that it "breaks up blood stasis, promotes blood circulation, and eliminates masses," and the *Yaoxing Lun* states that it "disperses various pains." The *Mingyi Bielu* records that peach kernel "stops cough and shortness of breath, eliminates epigastric fullness, removes sudden blood stasis, breaks up masses, unblocks meridians, and relieves pain," and the *Benjing Yi* states that it "treats blood stasis, amenorrhea, and masses." The *Diannan Materia Medica* states that peach kernels "treat blood-tinged phlegm." They are bitter, neutral in nature, and enter the heart and liver meridians. They are used to treat swelling and pain caused by blood stasis. Peony was first recorded in the *Shennong Bencao Jing* (Classic of Materia Medica), and Tao Hongjing first distinguished between red and white varieties. Currently, the medicinal material red peony is the root of various wild plants in the peony group. Red peony is bitter, slightly cold in nature, and enters the liver meridian. It can invigorate blood, remove blood stasis, clear heat, and cool the blood, and is mainly used for stagnation-related hypochondriac pain, hernia, and abdominal masses. Tao Hongjing stated in *Collected Annotations on the Materia Medica*: "Red peony has a slight purgative effect; it is commonly used to stop pain, and its effect is no less than that of angelica." Miao Xiyong also believed in *Commentary on the Materia Medica*: "The red color of the tree peony is mainly used to break up and disperse stagnation, promote bowel movements, and specifically enters the blood aspect of the liver, thus treating abdominal pain caused by pathogenic factors." The combination of peony bark, peach kernels, and red peony has a strong effect in invigorating blood, removing blood stasis, and relieving pain, specifically targeting blood stasis in COPD-PH. "When blood circulation is impaired, it becomes water retention." Phlegm and blood stasis, two pathological products, influence each other in the body, forming a vicious cycle. Trichosanthes peel, Allium macrostemon, Lysimachia christinae, Poria cocos, Paeonia suffruticosa, Prunus persica, and Paeonia lactiflora can work together to invigorate blood and resolve phlegm. The *Shennong Bencao Jing* classifies Ephedra as a medium-grade herb, stating that it "treats stroke, cold, headache, malaria, promotes sweating, removes pathogenic heat, stops cough, and eliminates chills and fever." Modern physicians believe that Ephedra has the effects of inducing sweating, relieving exterior syndromes, and clearing the lungs and relieving asthma, making it an essential medicine for these purposes. Processing it makes its properties milder and its dispersing power weaker, but its lung-moistening, asthma-relieving, and cough-suppressing effects are stronger. Cinnamon twig is the dried young branch of Cinnamomum cassia, a plant in the Lauraceae family. It is pungent, sweet, and warm, and enters the heart, lung, and bladder meridians. It can induce sweating, relieve muscle tension, warm and unblock the meridians, assist yang qi, and calm the ascending qi. It is often used to treat wind-cold exterior syndromes, chest pain, and phlegm retention.Cheng Wuji stated that it "relieves abdominal distension, harmonizes the skin surface, disperses blood stasis in the lower abdomen, and benefits lung qi." The *Ben Cao Jing Shu* also states that it "primarily benefits liver and lung qi." When combined with ephedra, cinnamon twig enhances its diaphoretic, exterior-releasing, lung-clearing, and asthma-relieving effects, thus treating cough and asthma symptoms during acute exacerbations of COPD-PH. The *Ben Cao Qiu Zhen* states that platycodon "both guides other herbs upwards and lowers qi," while the *Ben Cao Shu Gou Yuan* believes it primarily "enters the Qi aspect of the Lung Meridian of Hand-Taiyin," mainly... It treats "sore throat, lung heat, shortness of breath, and cough." The combination of Platycodon grandiflorus and Ephedra sinica, one ascending and the other descending, promotes the flow of lung qi, restores the normal dispersing and descending functions of the lungs, and relieves cough and asthma. Licorice root, sweet and neutral in nature, can harmonize the middle jiao, relieve urgency, moisten the lungs, and coordinate the effects of other herbs, serving as an adjuvant. Currently, there are no reports of using Trichosanthes kirilowii peel, Allium macrostemon, Lysimachia christinae, Poria cocos, Paeonia suffruticosa, Prunus persica kernel, Paeonia lactiflora, processed Ephedra sinica, Cinnamomum cassia twig, Platycodon grandiflorus, and licorice root to treat phlegm-stasis syndrome in COPD-PH.

[0019] The pharmaceutical composition of this invention differs significantly from the traditional Gualou Xiebai Banxia Decoction. Firstly, in terms of composition, the composition of this invention is more diverse than that of the traditional Gualou Xiebai Banxia Decoction, covering more complex pathological mechanisms. Secondly, the traditional Gualou Xiebai Banxia Decoction primarily functions to invigorate Yang, dissipate stagnation, resolve phlegm, and relieve chest tightness, suitable for treating chest pain with significant phlegm accumulation. The pharmaceutical composition of this invention not only has the effects of resolving phlegm and regulating Qi, but also enhances the effects of promoting blood circulation and removing blood stasis, making it more suitable for pulmonary hypertension due to phlegm and blood stasis, resulting in a more comprehensive therapeutic effect.

[0020] In this invention, Trichosanthes peel excels at clearing heat and resolving phlegm, relieving chest congestion and dispersing stagnation; Allium macrostemon is pungent and warm, entering the lung meridian and reaching the chest, promoting qi circulation and relieving stagnation, and together they serve as the principal herbs. Dioscorea opposita stops cough and resolves phlegm, invigorates blood and removes blood stasis; Poria cocos promotes diuresis and eliminates dampness, strengthens the spleen and resolves dampness; Paeonia suffruticosa, Prunus persica, and Paeonia lactiflora invigorate blood and disperse stasis, together they serve as the assistant herbs, working in conjunction with the principal herbs to enhance the effects of resolving phlegm, removing blood stasis, and unblocking the meridians. Ephedra sinica (processed) clears the lungs and relieves asthma, opening up congested lung qi; Cinnamomum cassia warms and unblocks the meridians, assisting yang and transforming qi; Platycodon grandiflorus clears the lungs, stops cough, and resolves phlegm, these three herbs together serve as the adjuvant herbs. Glycyrrhiza uralensis harmonizes all the herbs, making the formula balanced, and performs the function of adjuvant and guiding herbs. The entire formula works together to resolve phlegm, remove blood stasis, invigorate blood and unblock the meridians, and has a good therapeutic effect on chronic obstructive pulmonary disease complicated with pulmonary hypertension due to phlegm and blood stasis syndrome.

[0021] The pharmaceutical composition of the present invention is well-formulated and can effectively improve cardiopulmonary function and reduce pulmonary artery pressure, providing an option for the clinical treatment of chronic obstructive pulmonary disease complicated with pulmonary hypertension and phlegm and blood stasis syndrome, with good application prospects.

[0022] 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.

[0023] 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

[0024] Figure 1 RVSP plot (A: RVSP waveform; B: RVSP histogram; *P<0.05, ***P<0.001);

[0025] Figure 2 HE staining of lung tissue and WT% (A: HE staining of lung tissue at 40x; B: WT% bar chart; *P<0.05, ***P<0.001);

[0026] Figure 3 RVHI bar chart (*P<0.05, ***P<0.001). Detailed Implementation

[0027] Example 1: Preparation of the pharmaceutical composition of the present invention

[0028] Prescription: Trichosanthes peel 15g, Allium macrostemon 15g, Lysimachia christinae 15g, Poria cocos 15g, Paeonia suffruticosa 15g, Prunus persica 10g, Paeonia lactiflora 10g, Ephedra sinica (processed) 10g, Cinnamomum cassia 10g, Platycodon grandiflorus 15g, Glycyrrhiza uralensis 10g.

[0029] 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 before taking.

[0030] Example 2: Preparation of the pharmaceutical composition of the present invention

[0031] Prescription: Trichosanthes peel 12g, Allium macrostemon 10g, Lysimachia christinae 10g, Poria cocos 10g, Paeonia suffruticosa 10g, Prunus persica 6g, Paeonia lactiflora 8g, Ephedra sinica (processed) 6g, Cinnamomum cassia 8g, Platycodon grandiflorus 8g, Glycyrrhiza uralensis 6g.

[0032] Preparation method: Same as in Example 1.

[0033] Example 3: Preparation of the pharmaceutical composition of the present invention

[0034] Prescription: Trichosanthes peel 20g, Allium macrostemon 20g, Lysimachia christinae 20g, Poria cocos 12g, Paeonia suffruticosa 12g, Prunus persica 12g, Paeonia lactiflora 12g, Ephedra sinica (processed) 15g, Cinnamomum cassia 15g, Platycodon grandiflorus 12g, Glycyrrhiza uralensis 12g.

[0035] Preparation method: Same as in Example 1.

[0036] The beneficial effects of the present invention will be illustrated by the following research.

[0037] Example 1: Clinical trial of the pharmaceutical composition of the present invention for the treatment of chronic obstructive pulmonary disease complicated with pulmonary hypertension.

[0038] 1 Case Data

[0039] A total of 110 patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension were enrolled and randomly divided into an experimental group and a control group, with 55 patients in each group. During the treatment period, 5 patients dropped out of the experimental group and 1 patient dropped out of the control group, for a total of 6 dropouts. Ultimately, 50 patients were enrolled in the experimental group and 54 patients in the control group, with no statistically significant difference in dropout rates between the two groups (χ²). 2 =1.587, P=0.208), a total of 104 patients.

[0040] 2 Diagnostic criteria

[0041] 2.1 Diagnostic criteria for chronic obstructive pulmonary disease

[0042] The diagnostic criteria for COPD are based on the Global Strategy for Diagnosis, Treatment and Prevention of Chronic Obstructive Lung Disease (GOLD 2022) published by the Global Initiative for Chronic Obstructive Lung Disease (GILD 2022) and the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Lung Disease (2021 Revised Edition) published by the Chinese Society of Respiratory Diseases. These criteria primarily rely on a history of exposure to risk factors, clinical symptoms, signs, and pulmonary function tests, excluding other diseases, and making a comprehensive diagnosis. Among these, a persistent airflow limitation (FEV1 / FVC <70% after inhalation of a bronchodilator) is a necessary condition for a definitive diagnosis of COPD.

[0043] 2.2 Diagnostic criteria for pulmonary hypertension

[0044] Referring to the "Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension in China (2021 Edition)" jointly issued by the Chinese Society of Respiratory Diseases and the Chinese Medical Doctor Association, and the "2022 ESC / ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension" jointly issued by the European Society of Cardiology and the European Society of Respiratory Medicine (ESC / ERS), pulmonary artery pressure is estimated based on a peak tricuspid regurgitation flow greater than 2.8 m / s measured by echocardiography, i.e., a pulmonary artery pressure of 40 mmHg is the threshold for pulmonary hypertension.

[0045] 2.3 Traditional Chinese Medicine Syndrome Differentiation

[0046] The following syndrome diagnostic criteria are formulated with reference to the "Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease with Traditional Chinese Medicine (2011 Edition)" and the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs (Trial Implementation)" issued by the Pulmonary Disease Professional Committee of the Internal Medicine Branch of the China Association of Traditional Chinese Medicine:

[0047] Phlegm-stasis syndrome: Main symptoms: cough, wheezing, copious white and sticky phlegm, sticky mouth, cyanotic lips. Secondary symptoms: chest tightness and pain, purplish complexion. Tongue and pulse: dark red or purplish tongue with ecchymosis, choppy and deep pulse.

[0048] 3. Inclusion criteria

[0049] ① Patients diagnosed with COPD-PH as described above; ② Patients who meet the above TCM syndrome differentiation criteria; ③ Patients aged 18-85 years, regardless of gender; ④ Subjects who are aware of and agree to participate in the trial.

[0050] 4 Exclusion Criteria

[0051] ① Patients who are in the process of trying to conceive, pregnant, or breastfeeding; ② Patients diagnosed with other serious lung diseases; ③ Patients with serious primary diseases of the liver, kidneys, and hematopoietic system, or those with malignant tumors; ④ Patients who are allergic to the investigational drugs.

[0052] 5 Treatment Methods

[0053] (1) Control group: The routine Western medicine treatment plan was given in accordance with the Global Strategy for Diagnosis, Treatment and Prevention of Chronic Obstructive Pulmonary Disease (GOLD2022) and the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease (2021 Revised Edition).

[0054] (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, to be taken orally in three divided doses. The treatment course for both groups was 2 weeks.

[0055] 6 Observation Indicators

[0056] (1) Key outcome indicators

[0057] Before and after treatment, the changes in TCM syndrome scores of each group were observed.

[0058] (2) Secondary outcome indicators

[0059] Before and after treatment, monitor changes in patients' lung function (FEV1, FVC, FEV1 / EVC), echocardiography (pulmonary artery systolic pressure), and cardiac function classification.

[0060] 7 Statistical Methods

[0061] Data analysis was performed using SPSS 22.0 statistical software and R language. Normally distributed continuous variables were analyzed using t-tests, and expressed as mean (standard deviation). Skewed continuous variables were analyzed using nonparametric tests, and expressed as median (interquartiles). Ordinal variables were analyzed using rank-sum tests. Categorical variables were expressed as frequency (percentage). All tests were two-tailed, and p < 0.05 was considered statistically significant.

[0062] 8 Treatment Results

[0063] The experimental group included 50 patients and the control group included 54 patients, for a total of 104 patients. There were no statistically significant differences in gender and age between the two groups before treatment (P>0.05), and the two groups were comparable.

[0064] (1) Comparison of TCM syndrome scores

[0065] The results (Table 1) showed that the TCM syndrome scores of both groups were significantly better after treatment than before treatment (P < 0.001). Comparing the two groups after treatment, the experimental group showed greater symptom improvement than the control group (P < 0.05).

[0066] Table 1. Comparison of total scores for TCM syndromes [M(P25, P75)]

[0067]

[0068] (2) Comparison of lung function

[0069] The results (Tables 2, 3, and 4) showed that, based on intergroup comparisons, there were statistically significant differences in pulmonary function FEV1, FVC, and FEV1 / FVC between the two groups before treatment (P > 0.05), indicating comparability between the groups. After treatment, the experimental group showed better FEV1, FVC, and FEV1 / FVC than the control group (P < 0.05).

[0070] Table 2 Comparison of FEV1 in lung function between the two groups [M(P25, P75), escalation]

[0071]

[0072] Table 3 Comparison of FVC between the two groups [M(P25, P75), elution]

[0073]

[0074] Table 4 Comparison of FEV1 / FVC between the two groups [M(P25, P75), %)

[0075]

[0076] (3) Comparison of echocardiographic data (pulmonary artery systolic blood pressure)

[0077] The results (Table 5) showed that, based on intra-group comparisons, the pulmonary artery systolic blood pressure in both groups decreased after treatment compared to before treatment, with statistically significant differences (P < 0.05). Based on inter-group comparisons, there was no statistically significant difference in pulmonary artery systolic blood pressure between the two groups before treatment (P > 0.05), indicating comparability between the groups; however, after treatment, the pulmonary artery systolic blood pressure in the experimental group was lower than that in the control group, with a statistically significant difference (P < 0.05).

[0078] Table 5 Comparison of pulmonary artery systolic blood pressure between the two groups [M (P25, P75), mmHg]

[0079]

[0080] (4) Comparison of cardiac function classification

[0081] The results (Table 6) showed that, based on intragroup comparisons, the cardiac function classification improved in both groups after treatment compared to before treatment, with statistically significant differences (P < 0.001). Based on intergroup comparisons, there was no statistically significant difference in cardiac function classification between the two groups before treatment (P > 0.05), indicating that the groups were comparable; however, compared to the control group after treatment, the improvement in cardiac function in the experimental group was better than that in the control group (P < 0.05).

[0082] Table 6 Comparison of cardiac function classification between the two groups [M(P25, P75)]

[0083]

[0084] In summary, the pharmaceutical composition of the present invention is well-formulated and can effectively improve cardiopulmonary function and reduce pulmonary artery pressure, providing an option for the clinical treatment of chronic obstructive pulmonary disease complicated with pulmonary hypertension due to phlegm and blood stasis, and has good application prospects.

[0085] Experimental Example 2: Animal Experimental Study on the Treatment of Pulmonary Hypertension with the Pharmaceutical Composition of the Present Invention

[0086] 1. Materials and Methods

[0087] (1) Experimental animals: 120 male Sprague-Dawley (SD) rats aged 6-8 weeks and weighing 200±20g.

[0088] (2) Experimental drugs and instruments: Sildenafil citrate tablets, Pfizer Pharmaceuticals Co., Ltd., National Drug Approval Number: H20020528, 100mg / tablet; The drugs used in the intervention group were the drugs prepared as described in Example 1, purchased from Sichuan Xinlvse Pharmaceutical Technology Development Co., Ltd.; pressure sensor; small animal anesthesia machine.

[0089] 2. Experimental methods and procedures

[0090] Rats were randomly divided into a normal group, a model group, low-, medium-, and high-dose intervention groups, and a sildenafil group. The dosage administered via gavage was as follows: the low-, medium-, and high-dose intervention groups received 6.08 g / kg, 12.15 g / kg, and 24.10 g / kg body weight of the drug prepared in Example 1, respectively; the sildenafil group received 20 mg / kg body weight of sildenafil; and the normal and model groups received an equal volume of physiological saline. This was administered once daily for 3 consecutive weeks.

[0091] Except for the normal control group, all other groups were treated with a single subcutaneous injection of 60 mg / kg of lysimachia christinae for 3 weeks to establish a PH rat model. At the end of the third week, after the second administration, rats were anesthetized by inhalation of 2% isoflurane, and a pressure sensor was connected via the right external jugular vein to measure the right ventricular systolic pressure (RVSP). After the test, rat heart and lung tissues were collected, routinely stained with hematoxylin and eosin (HE), and observed under an optical microscope to measure the percentage of pulmonary arteriolar wall thickness (WT%). The rat heart was harvested, all atrial tissue was removed, and the right ventricle (RV) and left ventricle (LV) were separated along the interventricular septum (S) and weighed separately. The ratio of RV / (LV+S) is called the right ventricular hypertrophy index (RVHI), used to assess the degree of right ventricular hypertrophy.

[0092] 3 Results

[0093] The effects of the pharmaceutical composition of the present invention on right ventricular systolic blood pressure (RVSP), pulmonary arteriole wall thickness percentage (WT%), and right ventricular hypertrophy index (RVHI) in rats are shown in the figure. Figure 1 , Figure 2 , Figure 3 .

[0094] In summary, the pharmaceutical composition of the present invention can reverse pulmonary arteriole remodeling and right ventricular hypertrophy in a PH rat model and reduce right ventricular systolic pressure, showing promising application prospects.

Claims

1. A pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension, characterized in that: It is a preparation made from the following raw materials in the indicated weight ratios: Trichosanthes peel 12-20 parts, Allium macrostemon 10-20 parts, Lysimachia christinae 10-20 parts, Poria cocos 10-20 parts, Paeonia suffruticosa 10-20 parts, Prunus persica 6-15 parts, Paeonia lactiflora 8-15 parts, Ephedra sinica 5-15 parts, Cinnamomum cassia 6-15 parts, Platycodon grandiflorus 5-20 parts, Glycyrrhiza uralensis 6-12 parts.

2. The pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension according to claim 1, characterized in that: It is a preparation made from the following raw materials in the indicated weight ratios: 15 parts of Trichosanthes peel, 15 parts of Allium macrostemon, 15 parts of Lysimachia christinae, 15 parts of Poria cocos, 15 parts of Paeonia suffruticosa, 10 parts of Prunus persica, 10 parts of Paeonia lactiflora, 10 parts of Ephedra sinica, 10 parts of Cinnamomum cassia, 15 parts of Platycodon grandiflorus, and 10 parts of Glycyrrhiza uralensis.

3. The pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension according to claim 1 or 2, characterized in that: The ephedra is processed ephedra; the licorice is raw licorice.

4. The pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension according to claim 1 or 2, characterized in that: It is prepared into a commonly used pharmaceutical formulation by adding pharmaceutically acceptable excipients or auxiliary ingredients to the original powder of the active pharmaceutical ingredient, water or organic solvent extract as the active ingredient.

5. The pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension according to claim 4, characterized in that: The preparations mentioned are decoctions, oral liquids, granules, capsules, tablets, and powders.

6. A method for preparing a pharmaceutical composition for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension as described in any one of claims 1-5, 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 pharmaceutically acceptable excipients are added to prepare a formulation.

7. Use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a medicament for treating chronic obstructive pulmonary disease complicated with pulmonary hypertension due to phlegm and blood stasis syndrome.

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