Use of a traditional Chinese medicine composition in the preparation of a drug for chronic obstructive pulmonary disease

Abstract

The application relates to an application of a traditional Chinese medicine composition in a chronic obstructive pulmonary disease (COPD) medicine, wherein the traditional Chinese medicine composition comprises 10-15 parts of wind-preventing plant, 10-15 parts of perilla leaf, 2-6 parts of Ephedra, 7-9 parts of Schisandra chinensis, 7-9 parts of Ginkgo biloba, 7-9 parts of bitter almond, 7-9 parts of purple aster, 7-9 parts of dogwood fruit and 7-9 parts of lily of the valley. The traditional Chinese medicine composition can significantly improve the abnormal state of various indexes of lung function of COPD rats, and significantly inhibit the expression amount of disease marker genes such as MMP-9 and TIMP-1 in lung tissues of the COPD rats.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology and relates to a new use of a traditional Chinese medicine composition, specifically the application of a traditional Chinese medicine composition in the preparation of a drug for chronic obstructive pulmonary disease. Background Technology

[0002] Chronic obstructive pulmonary disease (COPD) is a destructive lung disease characterized by incompletely reversible airflow limitation. This airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to harmful particles or gases. COPD is a preventable and treatable chronic inflammatory airway disease. Although COPD is an airway disease, its systemic effects should not be ignored. The main symptoms include chronic cough, sputum production, shortness of breath or dyspnea, wheezing, and chest tightness. Incompletely reversible airflow limitation is a prerequisite for the diagnosis of COPD. An FEV1 / FVC ratio <70% and an FEV1 <80% of predicted value after inhalation of bronchodilators confirm incompletely reversible airflow limitation. A small number of patients may not have cough or sputum production symptoms, but only have an FEV1 / FVC ratio <70% and an FEV1 ≥80% of predicted value on pulmonary function tests; in such cases, after ruling out other diseases, COPD can also be diagnosed. Emphysema refers to a pathological state characterized by decreased elasticity of the airways distal to the terminal bronchioles, excessive inflation, increased lung volume, or simultaneous airway wall destruction. Based on its etiology, emphysema can be classified into several types: senile emphysema, compensatory emphysema, interstitial emphysema, focal emphysema, paraseptal emphysema, and obstructive emphysema. In Traditional Chinese Medicine (TCM), it is called "lung distension." External wind-cold and wind-heat are important factors inducing acute exacerbations of this disease. External wind-heat and wind-dryness can cause impaired lung function, leading to phlegm-heat accumulation in the lungs. Its pathogenesis involves qi stagnation, phlegm obstructing the airways, and phlegm and blood stasis, presenting as a deficiency-excess pattern. Acute exacerbations often present as phlegm-heat accumulation in the lungs. Given these issues, the field of TCM should actively participate in the prevention and treatment of chronic obstructive pulmonary disease (COPD) and develop appropriate prescriptions. Summary of the Invention

[0003] To solve the above-mentioned technical problems, the present invention provides an application of a traditional Chinese medicine composition in the preparation of a drug for chronic obstructive pulmonary disease. The traditional Chinese medicine composition includes: 10-15 parts of Saposhnikovia divaricata, 10-15 parts of Perilla frutescens leaf, 2-6 parts of Ephedra sinica, 7-9 parts of Schisandra chinensis, 7-9 parts of Ginkgo biloba, 7-9 parts of Prunus armeniaca, 7-9 parts of Aster tataricus, 7-9 parts of Cornus officinalis, and 7-9 parts of Magnolia biondii.

[0004] Preferably, the traditional Chinese medicine composition includes: 10-12 parts of Saposhnikovia divaricata, 10-12 parts of Perilla frutescens leaf, 4-6 parts of Ephedra sinica, 7-8 parts of Schisandra chinensis, 7-8 parts of Ginkgo biloba, 7-8 parts of bitter apricot kernel, 7-8 parts of Aster tataricus, 7-8 parts of Cornus officinalis, and 7-8 parts of Magnolia biondii.

[0005] Most preferably, the traditional Chinese medicine composition includes: 10 parts of Saposhnikovia divaricata, 10 parts of Perilla frutescens leaf, 6 parts of Ephedra sinica, 8 parts of Schisandra chinensis, 8 parts of Ginkgo biloba, 8 parts of bitter apricot kernel, 8 parts of Aster tataricus, 8 parts of Cornus officinalis, and 8 parts of Magnolia biondii.

[0006] The term "used" can refer to any method beneficial to improving the patient's corresponding symptoms, including treatment or prevention. The composition can be made by directly grinding raw materials into powder, or by extracts or other forms obtained through conventional methods. The raw materials used can also be used by directly grinding into powder, extracts, or other processed forms.

[0007] Specifically, the aforementioned drugs include oral dosage forms, injectable dosage forms, or topical dosage forms.

[0008] The present invention relates to a traditional Chinese medicine composition for chronic obstructive pulmonary disease, which is prepared into granules, capsules, tablets or pills by adding pharmaceutically permissible excipients.

[0009] The preparation method of the traditional Chinese medicine composition of the present invention includes the following steps: the above nine ingredients (bitter almonds added to boiling water) are decocted twice with 8 times the amount of water, each time for 2 hours, filtered, the filtrates are combined, and concentrated under reduced pressure to an extract with a relative density of 1.10 to 1.15 (50±5℃).

[0010] Preferably, the preparation of the traditional Chinese medicine composition includes the following steps: volatile components of Perilla frutescens leaves and Magnolia biondii are extracted by steam distillation, encapsulated with β-cyclodextrin, and set aside. The residue is combined with Saposhnikovia divaricata, Ephedra sinica, and Prunus armeniaca, and decocted separately with water 1-3 times, 1-3 hours each time. The extracts are combined and concentrated to a clear extract with a relative density of 1.10-1.15 at 50°C. The extract is then precipitated with alcohol until the alcohol content reaches 60%-70%. The supernatant is concentrated to a clear extract with a relative density of 1.25-1.30 at 50°C for later use. Schisandra chinensis, Ginkgo biloba, Aster tataricus, and Cornus officinalis are extracted with 60%-70% ethanol 1-3 times, 1-3 hours each time. The ethanol extracts are combined and concentrated to a clear extract with a relative density of 1.25-1.30 at 50°C. The above clear extracts are combined, dried, pulverized, and the volatile oil inclusion complex is added and mixed well to obtain the final product.

[0011] Furthermore, the preparation method of the above-mentioned traditional Chinese medicine composition specifically includes the following steps: Volatile components of Perilla frutescens leaves and Magnolia biondii are extracted by steam distillation, encapsulated with β-cyclodextrin, and set aside. The residue is combined with Saposhnikovia divaricata, Ephedra sinica, and Prunus armeniaca, and decocted three times with 10 times the amount of water, each time for 1.5 hours. The extracts are combined and concentrated into a clear extract with a relative density of 1.10–1.15 at 50°C. The extract is precipitated with alcohol until the alcohol content reaches 70%. The supernatant is then concentrated to prepare a clear extract with a relative density of 1.25–1.30 at 50°C for later use. Schisandra chinensis, Ginkgo biloba, Aster tataricus, and Cornus officinalis are extracted three times with 60% ethanol, each time for 2.5 hours. The ethanol extracts are combined and concentrated to prepare a clear extract with a relative density of 1.25–1.30 at 50°C. The above clear extracts are combined, dried, pulverized, and the volatile oil inclusion complex is added and mixed well to obtain the final product.

[0012] Specifically, the aforementioned drug is selected from granules, and its preparation method includes:

[0013] Volatile components were extracted from 277.8g of Perilla frutescens leaves and 222.2g of Magnolia biondii using steam distillation. These components were then encapsulated with β-cyclodextrin for later use. The residue was combined with 277.8g of Saposhnikovia divaricata, 166.7g of Ephedra sinica, and 222.2g of Prunus armeniaca. Each was decocted separately with 10 times the amount of water three times, 1.5 hours each time. The extracts were combined and concentrated to a clear extract with a relative density of 1.10–1.15 at 50°C. Alcohol precipitation was performed until the alcohol content reached 70%. The supernatant was then concentrated to a concentration suitable for 50°C. Prepare a clear extract with a relative density of 1.25–1.30. Extract 222.2g of Schisandra chinensis, 222.2g of Ginkgo biloba, 222.2g of Aster tataricus, and 222.2g of Cornus officinalis with 60% ethanol three times, 2.5 hours each time. Combine the ethanol extracts and concentrate them to prepare a clear extract with a relative density of 1.25–1.30 at 50℃. Combine the above clear extracts, dry them, pulverize them, add volatile oil inclusion complexes, mix well, add appropriate amounts of dextrin and sucralose, mix well, and make granules.

[0014] The herbal composition of this invention can significantly improve lung function indicators in COPD rats, including significantly increasing tidal volume (VT), expiratory volume per minute (MV), peak expiratory flow (PEF), and the FEV0.3 / FVC ratio. The high-dose group showed comparable therapeutic effects to the positive control drug. Furthermore, the herbal composition of this invention can significantly inhibit the expression levels of disease marker genes such as MMP-9 and TIMP-1 in the lung tissue of COPD rats. This demonstrates that the herbal composition of this invention has a significant therapeutic effect on COPD. Attached Figure Description

[0015] Figure 1 The lung function (MV, VT, and PEF) of rats in each experimental group was modeled from 0 to 16 weeks.

[0016] Figure 2The lung function (FVC, FEV0.3, and FEV0.3 / FVC) of rats in each experimental group was modeled 16 weeks after birth.

[0017] Figure 3 The expression levels of MMP-9 and TIMP-1 genes in the lung tissue of rats in each experimental group were detected 16 weeks after modeling. Detailed Implementation

[0018] As mentioned above, the present invention aims to provide an application of a traditional Chinese medicine composition in the preparation of drugs for COPD. The following will describe this in detail with reference to specific experiments.

[0019] Unless otherwise specified, all experiments in the following experiments were conducted under standard conditions or conditions recommended by the manufacturer. Active pharmaceutical ingredients (APIs) or excipients, as well as reagents or instruments whose manufacturers are not specified, are all commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention.

[0021] Example 1: Preparation of the traditional Chinese medicine composition granules of the present invention

[0022] In this embodiment, the traditional Chinese medicine composition is made from the following raw materials: Saposhnikovia divaricata 277.8g, Perilla frutescens leaf 277.8g, Ephedra sinica 166.7g, Schisandra chinensis 222.2g, Ginkgo biloba 222.2g, Prunus armeniaca 222.2g, Aster tataricus 222.2g, Cornus officinalis 222.2g, and Magnolia biondii 222.2g.

[0023] The traditional Chinese medicine composition granules are prepared according to the following method:

[0024] Volatile components of Perilla frutescens leaves and Magnolia biondii were extracted by steam distillation and encapsulated with β-cyclodextrin for later use. The residue was combined with Saposhnikovia divaricata, Ephedra sinica, and Prunus armeniaca, and decocted three times with 10 times the amount of water, each time for 1.5 hours. The extracts were combined and concentrated to a clear extract with a relative density of 1.10–1.15 at 50°C. The extract was then precipitated with alcohol until the alcohol content reached 70%. The supernatant was concentrated to a clear extract with a relative density of 1.25–1.30 at 50°C for later use. Schisandra chinensis, Ginkgo biloba, Aster tataricus, and Cornus officinalis were extracted three times with 60% ethanol, each time for 2.5 hours. The ethanol extracts were combined and concentrated to a clear extract with a relative density of 1.25–1.30 at 50°C. The above extracts were combined, dried, pulverized, and encapsulated with volatile oils. The mixture was then mixed to obtain the herbal composition. Appropriate amounts of dextrin and sucralose were added to the herbal composition, mixed well, and granulated to obtain 1000g of granules.

[0025] Experimental Example 2: The therapeutic effect of a traditional Chinese medicine composition on a rat COPD model induced by cigarette smoke combined with LPS.

[0026] 1. Experimental Materials

[0027] 1.1 Animals

[0028] Sixty male Wistar rats, SPF grade, weighing 200±20g.

[0029] Housing environment: SPF-grade animal room, with environmental conditions controlled at 21℃~25℃, relative humidity 40%~70%, 12-hour light with alternating light and dark, and free access to food. After one week of acclimatization, modeling begins.

[0030] 1.2 Drugs

[0031] The traditional Chinese medicine composition prepared in Example 1 was provided by Jiangsu Kangyuan Pharmaceutical Co., Ltd.; dexamethasone acetate tablets (Chenxin Pharmaceutical Co., Ltd., batch number 08050204).

[0032] 1.3 Instruments

[0033] Laboratory animal mass exposure chamber (DSI, Mass Dosing, USA), conscious small animal respiratory and pulmonary function testing system (DSI, Whole-Body Plethysmograph, USA), real-time quantitative PCR system (Roche, Switzerland) 480II), Micro UV / Vis Spectrophotometer (Thermo Fisher Scientific, NanoDrop, USA) TM One, electronic balance (Sartorius Scientific Instruments, model BS224S); electronic balance (G&G, model TC3K).

[0034] 2. Dosage design

[0035] The daily dosage of the traditional Chinese medicine composition is 166g of raw herbs / day, calculated based on body surface area:

[0036] The equivalent dose for rats is 166g / 60kg × 6.2 = 17.15g crude drug / kg. Following a 1 / 4:1 / 2:1 dosing regimen, the low dose is 4.30g crude drug / kg and the medium dose is 8.60g crude drug / kg. Administer by gavage at a dose of 0.2mL / 10g, once daily.

[0037] The daily dose of dexamethasone is 1.5 mg / day. Based on the body surface area calculation method, the equivalent dose for rats is 1.5 mg / 60 kg × 6.2 = 0.155 mg / kg.

[0038] The main indicators measured included tidal volume (VT), expiratory volume per minute (MV), peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory volume in 0.3 seconds (FEV0.3), and the FEV0.3 / FVC ratio. The expression levels of MMP-9 and TIMP-1 marker genes in lung tissue were also measured.

[0039] 3. Experimental Methods

[0040] Wistar rats were acclimatized for 7 days with free access to food and water. Then, two stages of rat modeling were performed.

[0041] Phase 1: Eight rats were randomly selected as the control group. The remaining rats were given LPS solution at 1 mg / kg via nasal instillation twice a week for 8 weeks. The control group rats were given an equal volume of physiological saline. Except for the control group, all other rats were exposed to cigarette smoke. An plexiglass fumigation chamber was used, with each fumigation session consisting of 10 cigarettes, lasting 30 minutes each time, twice a day, with an interval of ≥3 hours, for 8 weeks.

[0042] Phase Two: After the first phase of modeling, tidal volume (VC), minute ventilation (MV), and peak expiratory flow (PEF) were measured in each rat. The rats were then randomly divided into a model group, a dexamethasone control group, and high, medium, and low dose groups of the traditional Chinese medicine composition, with 10 rats in each group. From week nine, drug administration and modeling were continued for eight weeks. Tissue samples were collected at the experimental endpoint in week 16. Before sampling, rats were anesthetized with isoflurane and underwent endotracheal intubation and pulmonary function evaluation. Evaluation indicators included forced vital capacity (FVC), forced expiratory volume in 0.3 seconds (FEV0.3), and the FEV0.3 / FVC ratio. After pulmonary function evaluation, samples were dissected, and lung tissue samples were collected for the detection of TIMP-1 and MMP-9 levels.

[0043] 4. Statistical Methods

[0044] All data presented in the experimental results graphs represent the mean ± standard deviation. For experiments with three or more groups, one-way or two-way ANOVA was used. A p-value < 0.05 was considered significant, with the significance increasing progressively with the asterisk: *P < 0.05, **P < 0.01, ***P < 0.001. A p-value ≥ 0.05 was considered insignificant, expressed as ns. All statistical analyses were performed using Graphpad software.

[0045] 5. Experimental Results

[0046] (1) Evaluation of the effects of the tested traditional Chinese medicine composition on respiratory function in COPD rats

[0047] Non-invasive lung function was assessed in rats at weeks 0, 8, and 16 during the experiment. The measured parameters were tidal volume (VT), expiratory volume per minute (MV), and peak expiratory flow (PEF). Comparison from weeks 0 to 16 showed that VT, MV, and PEF increased with age in all experimental groups. Pre-treatment assessment at week 8 showed that the model group had significantly lower lung function parameters than the control group (P < 0.01), indicating successful modeling. Assessments at week 16 and after 8 weeks of treatment showed that the model group's parameters remained significantly lower than the control group. However, compared to the model group, the tested herbal composition dose-dependently increased MV, VT, and PEF in COPD rats. The high-dose and medium-dose groups showed significant differences in all three parameters compared to the model group (P < 0.01), and the high-dose group's therapeutic effect was comparable to the positive control drug. (See attached results). Figure 1 .

[0048] Furthermore, after 8 weeks of treatment with different drugs, compared with the model group, the tested traditional Chinese medicine composition could increase the FEV0.3 / FVC ratio in COPD rats in a dose-dependent manner. The statistical analysis results of the high-dose and medium-dose groups showed significant differences compared with the model group (P<0.01), and the treatment effect of the high-dose group was comparable to that of the positive control drug. (See related results for further details.) Figure 2 .

[0049] (2) Detection and analysis of COPD marker expression levels in lung tissue and bronchoalveolar lavage fluid

[0050] The gene expression levels of MMP-9 and TIMP-1 in lung tissue samples from different experimental groups were detected by real-time quantitative PCR. The results showed that, compared with the control group, the gene expression levels of MMP-9 and TIMP-1 in the lung tissue of COPD rats were significantly increased (P<0.001). Conversely, compared with the model group, the tested traditional Chinese medicine composition could dose-dependently reduce the expression levels of MMP-9 and TIMP-1 in the lung tissue of COPD rats. Statistical analysis of the high-dose and medium-dose groups showed significant differences compared with the model group (P<0.01), and the inhibitory effect of the high-dose group on the above gene expression levels was comparable to that of the positive control drug. (See attached results). Figure 3 .

[0051] 6. Experimental Conclusions

[0052] The traditional Chinese medicine composition significantly improved lung function indicators in COPD rats, including significantly increasing tidal volume (VT), expiratory volume per minute (MV), peak expiratory flow (PEF), and the FEV0.3 / FVC ratio. The high-dose group showed comparable therapeutic effects to the positive control drug. Furthermore, the traditional Chinese medicine composition significantly inhibited the expression levels of disease marker genes such as MMP-9 and TIMP-1 in the lung tissue of COPD rats. This demonstrates that the traditional Chinese medicine composition of this invention has a significant therapeutic effect on COPD.

[0053] The above embodiments of the present invention are merely examples to clearly illustrate the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a drug for chronic obstructive pulmonary disease, characterized in that, By weight, the traditional Chinese medicine composition is made from the following raw materials: 10-15 parts of Saposhnikovia divaricata, 10-15 parts of Perilla frutescens leaf, 2-6 parts of Ephedra sinica, 7-9 parts of Schisandra chinensis, 7-9 parts of Ginkgo biloba, 7-9 parts of bitter apricot kernel, 7-9 parts of Aster tataricus, 7-9 parts of Cornus officinalis, and 7-9 parts of Magnolia biondii.

2. The application according to claim 1, characterized in that, By weight, the traditional Chinese medicine composition is made from the following raw materials: 10-12 parts of Saposhnikovia divaricata, 10-12 parts of Perilla frutescens leaf, 4-6 parts of Ephedra sinica, 7-8 parts of Schisandra chinensis, 7-8 parts of Ginkgo biloba, 7-8 parts of bitter apricot kernel, 7-8 parts of Aster tataricus, 7-8 parts of Cornus officinalis, and 7-8 parts of Magnolia biondii.

3. The application according to claim 1, characterized in that, This traditional Chinese medicine composition is made from the following raw materials: 10 parts of Saposhnikovia divaricata, 10 parts of Perilla frutescens leaf, 6 parts of Ephedra sinica, 8 parts of Schisandra chinensis, 8 parts of Ginkgo biloba, 8 parts of bitter apricot kernel, 8 parts of Aster tataricus, 8 parts of Cornus officinalis, and 8 parts of Magnolia biondii.

4. The application according to claim 1, 2 or 3, characterized in that... This traditional Chinese medicine composition can be prepared into decoctions, granules, capsules, tablets or pills by adding pharmaceutically permissible excipients.

5. The application according to claim 1, 2 or 3, characterized in that, The preparation of the traditional Chinese medicine composition includes the following steps: Volatile components of Perilla frutescens leaves and Magnolia biondii were extracted by steam distillation and encapsulated with β-cyclodextrin for later use. The residue was combined with Saposhnikovia divaricata, Ephedra sinica, and Prunus armeniaca, and decocted separately with water 2-3 times, 1-3 hours each time. The extracts were combined and concentrated to a clear extract with a relative density of 1.10-1.15 at 50℃. The extract was then precipitated with alcohol until the alcohol content reached 60%-70%. The supernatant was concentrated to a clear extract with a relative density of 1.25-1.30 at 50℃ for later use. Schisandra chinensis, Ginkgo biloba, Aster tataricus, and Cornus officinalis were extracted with 60%-70% ethanol 2-3 times, 1-3 hours each time. The alcohol extracts were combined and concentrated to a clear extract with a relative density of 1.25-1.30 at 50℃. The above extracts were combined, dried, pulverized, and the volatile oil encapsulation compound was added and mixed well to obtain the final product.

6. The application according to claim 1, 2 or 3, characterized in that, The preparation of the traditional Chinese medicine composition includes the following steps: Volatile components of Perilla frutescens leaves and Magnolia biondii were extracted by steam distillation and encapsulated with β-cyclodextrin for later use. The residue was combined with Saposhnikovia divaricata, Ephedra sinica, and Prunus armeniaca, and decocted three times with 10 times the amount of water, each time for 1.5 hours. The extracts were combined and concentrated to a clear extract with a relative density of 1.10-1.15 at 50°C. The extract was then precipitated with alcohol until the alcohol content reached 70%. The supernatant was concentrated to a clear extract with a relative density of 1.25-1.30 at 50°C for later use. Schisandra chinensis, Ginkgo biloba, Aster tataricus, and Cornus officinalis were extracted three times with 60% ethanol, each time for 2.5 hours. The ethanol extracts were combined and concentrated to a clear extract with a relative density of 1.25-1.30 at 50°C. The above extracts were combined, dried, pulverized, and the volatile oil encapsulation compound was added and mixed well to obtain the final product.

7. The application according to claim 1, 2 or 3, characterized in that, The drug is selected from granules, and its preparation method includes the following steps: Volatile components were extracted from 277.8g of Perilla frutescens leaves and 222.2g of Magnolia biondii using steam distillation. These components were then encapsulated with β-cyclodextrin for later use. The residue was combined with 277.8g of Saposhnikovia divaricata, 166.7g of Ephedra sinica, and 222.2g of Prunus armeniaca. Each was decocted separately with 10 times the amount of water three times, 1.5 hours each time. The extracts were combined and concentrated to a clear extract with a relative density of 1.10–1.15 at 50°C. Alcohol precipitation was performed until the alcohol content reached 70%. The supernatant was then concentrated to a concentration suitable for 50°C. Prepare a clear extract with a relative density of 1.25–1.

30. Extract 222.2g of Schisandra chinensis, 222.2g of Ginkgo biloba, 222.2g of Aster tataricus, and 222.2g of Cornus officinalis with 60% ethanol three times, 2.5 hours each time. Combine the ethanol extracts and concentrate them to prepare a clear extract with a relative density of 1.25–1.30 at 50℃. Combine the above clear extracts, dry them, pulverize them, add volatile oil inclusion complexes, mix well, add appropriate amounts of dextrin and sucralose, mix well, and make granules.

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