Traditional Chinese medicine compound for treating chronic obstructive pulmonary disease in stable phase and application of traditional Chinese medicine compound

Abstract

The invention belongs to the field of medicines, and particularly relates to a traditional Chinese medicine compound for treating chronic obstructive pulmonary disease in a stable phase and application thereof. The traditional Chinese medicine composition is prepared from herba epimedii, rhizoma curculiginis, radix astragali, radix salviae miltiorrhizae, lumbricus, rhizoma dioscoreae nipponicae, radix ophiopogonis, radix scutellariae, radix adenophorae, rhizoma zingiberis, cortex mori radicis, rhizoma pinelliae, rhizoma coptidis and semen ginkgo, can play the main effects of tonifying lung and kidney, reducing phlegm and removing blood stasis, and is applied to the stable phase of the chronic obstructive pulmonary disease; the traditional Chinese medicine composition has a good clinical application effect in treatment of chronic obstructive pulmonary diseases, especially lung-kidney qi deficiency syndrome and phlegm-blood stasis syndrome.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular to a Chinese medicinal compound for treating chronic obstructive pulmonary disease in the stable phase and application thereof. Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation, which is related to airway and / or alveolar abnormalities caused by exposure to harmful particles or gases. COPD seriously endangers public health, with high morbidity, disability and mortality rates, and heavy socioeconomic burden. According to statistics, in 2012, 3 million people died of COPD worldwide, accounting for 6% of the total number of deaths that year. The quality of life of COPD patients is seriously reduced, and their own physical and psychological pain and the impact on their relatives are no less than that of cancer, and they even show symptoms such as anxiety, shortness of breath, and dyspnea that are worse than those of cancer patients. A study in the United States surveyed people over 70 years old and followed up for ten years and found that COPD patients' ability to take care of themselves and their social interaction abilities were significantly lower than those of normal elderly people, and their mortality rate was significantly increased. COPD can cause a heavy socioeconomic burden.

[0003] Chronic obstructive pulmonary disease is a common disease of the respiratory system, which belongs to the category of "asthma" and "pulmonary distension" in traditional Chinese medicine. It is characterized by persistent and progressive airflow obstruction caused by abnormalities in the airways and / or alveoli. Common clinical manifestations include chronic cough, sputum, shortness of breath or dyspnea, chest tightness and wheezing. The disease has a high incidence rate, a large number of patients, high disability and mortality rates, and seriously endangers the normal life of patients.

[0004] Currently, there is a patent for combining Scutellaria baicalensis extract and Verbena officinalis extract to make an aerosol inhaler for the prevention and / or treatment of chronic obstructive pulmonary disease (patent number: CN118557647A); and for preparing a Chinese medicine composition with raw materials such as roasted Astragalus, ginseng, and Atractylodes macrocephala for slowing the progression of chronic obstructive pulmonary disease (patent number: CN118477130A).

[0005] At present, Western medicine mainly uses inhaled bronchodilators, glucocorticoids and pulmonary rehabilitation training to treat COPD in the stable stage. However, long-term use of bronchodilators may cause a series of side effects such as sinus tachycardia; long-term use of glucocorticoids may increase systemic adverse reactions and the incidence of pneumonia; pulmonary rehabilitation relies on equipment and has a limited scope of application. At present, Chinese patent medicines for the clinical treatment of COPD still lack preparations that take into account both lung and kidney deficiency syndrome and phlegm and blood stasis syndrome: for example, Jinshuibao Capsule only takes into account the former, Yupingfeng Powder and Guben Kechuan Granule only strengthen the surface and invigorate the qi, etc., which makes it difficult to achieve the effect of treating both the symptoms and the root cause. Summary of the invention

[0006] In view of the above technical defects, the present invention provides a Chinese medicine compound for treating chronic obstructive pulmonary disease in stable stage, and applies it to the treatment of lung and kidney qi deficiency syndrome and phlegm and blood stasis syndrome in stable stage of chronic obstructive pulmonary disease and the preparation of its preparation, which plays the role of tonifying lung and kidney, resolving phlegm and removing blood stasis, and has good clinical application effect. The successful application of this compound will effectively solve the problem of long-term medication and effective treatment of patients with chronic obstructive pulmonary disease in stable stage.

[0007] Specifically, the inventors solved the problem through the following technical solutions:

[0008] A Chinese medicine composition for treating chronic obstructive pulmonary disease in the stable stage, the Chinese medicine composition is made from the following Chinese medicines:

[0009] 10-20 weight parts of Epimedium, 6-12 weight parts of Curculigo, 20-60 weight parts of Astragalus, 15-20 weight parts of Salvia, 10-15 weight parts of Pheretima, 15-30 weight parts of Rhizoma Dioscoreae, 10-15 weight parts of Ophiopogon, 10-20 weight parts of Scutellaria, 15-30 weight parts of Adenophora, 10-15 weight parts of Dry Ginger, 12-30 weight parts of Morus alba, 6-10 weight parts of Pinellia, 5-10 weight parts of Coptis, and 10-20 weight parts of Ginkgo.

[0010] Furthermore, in a preferred embodiment of the present invention, the astragalus is roasted astragalus.

[0011] Furthermore, in a preferred embodiment of the present invention, the Chinese medicine composition is made of the following Chinese medicines:

[0012] 10 parts by weight of Epimedium, 6 parts by weight of Curculigo, 20 parts by weight of roasted Astragalus, 15 parts by weight of Salvia miltiorrhiza, 10 parts by weight of Pheretima, 15 parts by weight of Rhizoma Dioscoreae, 10 parts by weight of Ophiopogon japonicus, 10 parts by weight of Scutellaria baicalensis, 15 parts by weight of Adenophora australis, 10 parts by weight of Dried Ginger, 12 parts by weight of Morus alba, 6 parts by weight of Pinellia, 5 parts by weight of Coptis chinensis, and 10 parts by weight of Ginkgo.

[0013] Furthermore, in a preferred embodiment of the present invention, the Chinese medicine composition is made of the following Chinese medicines:

[0014] 20 parts by weight of Epimedium, 12 parts by weight of Curculigo, 60 parts by weight of roasted Astragalus, 20 parts by weight of Salvia miltiorrhiza, 15 parts by weight of Pheretima, 30 parts by weight of Rhizoma Dioscoreae, 15 parts by weight of Ophiopogon japonicus, 20 parts by weight of Scutellaria baicalensis, 30 parts by weight of Adenophora australis, 15 parts by weight of Dried Ginger, 30 parts by weight of Morus alba, 10 parts by weight of Pinellia, 10 parts by weight of Coptis chinensis, and 20 parts by weight of Ginkgo.

[0015] Furthermore, in the most preferred embodiment of the present invention, the Chinese medicine composition is made of the following Chinese medicines:

[0016] 15 parts by weight of Epimedium, 9 parts by weight of Curculigo, 40 parts by weight of roasted Astragalus, 17 parts by weight of Salvia miltiorrhiza, 12.5 parts by weight of Pheretima, 22 parts by weight of Rhizoma Dioscoreae, 12.5 parts by weight of Ophiopogon japonicus, 15 parts by weight of Scutellaria baicalensis, 23 parts by weight of Adenophora australis, 12 parts by weight of Dry Ginger, 21 parts by weight of Morus alba, 8 parts by weight of Pinellia, 7 parts by weight of Coptis chinensis, and 15 parts by weight of Ginkgo.

[0017] The second use of the present invention is to provide the use of the traditional Chinese medicine composition in the preparation of medicines for treating stable phase chronic obstructive pulmonary disease.

[0018] The third use of the present invention is to prepare a Chinese medicine preparation from the Chinese medicine composition, wherein the Chinese medicine oral preparation is any one of granules, decoctions, pills, tablets, mixtures, capsules, and powders.

[0019] The fourth use of the present invention is a method for preparing granules containing the Chinese medicinal compound of the present invention, wherein the method comprises the following steps:

[0020] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 5-10 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and use the earthworm paste for later use;

[0021] 2) Add 10-20 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, pinellia tuber, coptis root, and ginkgo, and boil for 30-40 minutes, filter, and set aside the filtrate and residue; add 4-8 times the amount of water to the residue, boil for 15-25 minutes, filter, and combine the two filtrates; set aside

[0022] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0023] 4) combining the filtrates from step 2) and step 3), concentrating at 60-70° C. to a relative density of 1.08-1.13, standing for 16-28 hours, taking the supernatant, adding earthworm paste, concentrating at 65-75° C. to a relative density of 1.25-1.35, and setting aside;

[0024] 5) Add pharmaceutically acceptable excipients in step 3) to granulate, and dry to obtain the product.

[0025] The fourth use of the present invention is a method for preparing a decoction containing the Chinese medicinal compound of the present invention, wherein the method comprises the following steps:

[0026] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 5-10 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and use the earthworm paste for later use;

[0027] 2) Add 10-20 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, pinellia tuber, coptis root, and ginkgo, and boil for 30-40 minutes, filter, and set aside the filtrate and residue; add 4-8 times the amount of water to the residue, boil for 15-25 minutes, filter, and combine the two filtrates; set aside

[0028] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0029] 4) combining the filtrates from step 2) and step 3) to obtain a decoction.

[0030] The chronic obstructive pulmonary disease is a chronic obstructive pulmonary disease of lung and kidney deficiency and phlegm and blood stasis. The raw materials used in the present invention include appropriate amounts of epimedium, curculigo, roasted astragalus, salvia, earthworm, dactylorhizoma dioscoreae, ophiopogon, scutellaria, adenophora australis, dried ginger, white mulberry bark, pinellia, coptis, and ginkgo. The present invention is based on long-term clinical practice and is aimed at the "lung and kidney deficiency and phlegm and blood stasis" syndrome in the stable period of chronic obstructive pulmonary disease. In the prescription, curculigo and epimedium warm yang and tonify the kidney, astragalus replenishes qi and raises yang, benefits the defense and consolidates the exterior, and are the main medicines; adenophora australis and ophiopogon replenish lung qi, moisten the lungs and nourish yin, as the adjuvant; and salvia is combined with blood circulation and blood stasis, pinellia ternata dries dampness and resolves phlegm, dried ginger warms the middle and resolves phlegm, earthworm, dactylorhizoma dioscoreae, mulberry bark, and ginkgo resolve phlegm and relieve asthma, coptis and scutellaria clear heat and purge fire, and the heat of curculigo, dried ginger, and pinellia is used as the adjuvant. The combination of these medicines can treat both the symptoms and the root cause, and together they have the effects of nourishing the lungs and kidneys, resolving phlegm and blood stasis, and relieving cough and asthma.

[0031] Compared with the prior art, the present invention has achieved unexpected technical effects:

[0032] 1) In the pharmacological experiment, the composition of the present invention can improve the rat lung function, rat bronchoalveolar lavage fluid neutrophil ratio, serum LPO, IL-1β, IL-6 and MMP-9 expression and other indicators to varying degrees, alleviate symptoms, improve lung function, reduce lung and systemic inflammatory response, improve oxidative stress state and other effects, has a good therapeutic effect on model rat COPD, and has good development value.

[0033] 2) Clinical observations have confirmed that the Chinese medicine compound can significantly improve the clinical symptoms of patients with chronic obstructive pulmonary disease, improve the quality of life, reduce the frequency of acute exacerbations, and protect lung function. Compared with Western medicine treatment, the Chinese medicine compound of the present invention has a higher effective rate, and the relevant symptom scores are significantly reduced. After follow-up 1, the number of AECOPD attacks is less and the duration is improved, and the clinical application effect is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 :Represents the V of each experimental group TFrom the 4th week onwards, compared with the normal group, the VT of the model group was significantly reduced (P≤0.05), indicating that the model was successfully established; from the 8th week onwards, compared with the positive control group, Example 1-3 groups and Comparative Example 1-4 groups, V T Significantly increased (P≤0.05).

[0035] Figure 2 : It shows the changes of MV values ​​of each experimental group. From the 8th week, the MV values ​​of the positive control group and Example 1-3 groups were significantly increased compared with Comparative Example 1-4 groups (P≤0.05).

[0036] Figure 3 : It shows the comparison of IL-1β (pg / ml) content in each experimental group. It can be seen that there is a significant difference between Example 1-3 and Comparative Example 1-4 (P<0.01).

[0037] Figure 4 : It shows the comparison of IL-6 (pg / ml) content in each experimental group. It can be seen that the IL-6 content in Example 1-3 is significantly lower than that in Comparative Example 1-4, and there is a significant difference (P<0.01).

[0038] Figure 5 : It shows the comparison of the content of MMP-9 (ng / ml) in each experimental group. It can be seen that the content of MMP-9 in Example 1-3 is significantly lower than that in Comparative Example 1-4, and there is a significant difference (P<0.01).

[0039] Figure 6 : It represents the comparison of T-AOC (mM) of each experimental group. It can be seen that the content of total antioxidant capacity of the positive control group and Examples 1-3 is significantly improved compared with Comparative Examples 1-4, and there is a significant difference (P<0.01).

[0040] Figure 7 : represents the comparison of LPO (umol / L) in each experimental group. It can be seen that the content of LPO in the positive control group and Examples 1-3 is significantly reduced compared with Comparative Examples 1-4, and there is a significant difference (P<0.01). In general, the technical effect of Example 3 is better than that of other examples and the positive control group.

[0041] Figure 8 : represents the comparison of the number of monocytes in each experimental group. In terms of monocytes (unit / 200 cells), Example 3 has significant difference compared with other comparative examples (P<0.01), and the other Examples 1-2 have no difference in technical effect compared with the comparative examples.

[0042] Fig. 9: It represents the comparison of the number of lymphocytes in each experimental group. In terms of lymphocytes (per 200 cells), the positive control group and Examples 1-3 have significant differences compared with other Comparative Examples 1-4 (P<0.01).

[0043] Fig.10 : represents the comparison of neutrophils in each experimental group. In terms of neutrophils (number / 200 cells), the positive control group and Examples 1-3 have significant differences compared with other Comparative Examples 1-4 (P<0.01).

[0044] Fig.11 : It represents the comparison of TNF-α (pg·mL-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0045] Fig.12 : It represents the comparison of SFRP1 (ng·L-1) between the control group and the observation group. It can be seen that there is no significant difference between the two groups before and after treatment.

[0046] Fig.13 : It represents the comparison of IL-33 ( / ng·L-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0047] Fig.14 : It represents the comparison of TGF-β1 (μg·L-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0048] Fig.15 : It represents the comparison of MMP-9 (ng·mL-1) between the control group and the observation group. It can be seen that there is no significant difference between the two groups before and after treatment.

[0049] Fig.16 : It represents the comparison of FEV1 / % between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0050] Fig.17 : It represents the comparison between the control group and the observation group (FEV1 / FVC) / %. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0051] Fig.18: It represents the comparison of TCM syndrome scores between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0052] Fig.19 : It represents the comparison of CAT scores between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0053] Fig. 20 : It represents the comparison of the treatment effects between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.05).

[0054] Fig.21 : It shows the incidence of AECOPD in the control group and the observation group after 1 year of follow-up. It can be seen that there are significant differences in the number of attacks and duration between the two groups (P<0.01). DETAILED DESCRIPTION

[0055] The following are only a few examples. During the research, the inventors have repeatedly conducted experiments and obtained the same or similar results. The method is effective and feasible, and has good clinical application value. The Chinese medicine component formula for treating chronic obstructive pulmonary disease with lung and kidney qi deficiency of the present invention has the effects of nourishing the lung and kidney, relieving asthma, and resolving phlegm and activating blood circulation, and is effectively used for the treatment of chronic obstructive pulmonary disease in the stable stage. The present invention repeatedly studied the efficacy of the Jinshui Yifei prescription obtained in each embodiment in treating rats with chronic obstructive pulmonary disease, and achieved satisfactory therapeutic effects. The relevant research data are as follows:

[0056] Example 1: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0057]

[0058]

[0059] The preparation process is:

[0060] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 5 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is still hot, and set aside the earthworm paste;

[0061] 2) Add 10 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, 8 parts by weight of Pinellia ternata, Coptis chinensis, and Ginkgo biloba, and boil for 30 minutes, filter, and set aside the filtrate and residue; add 4 times the amount of water to the residue, boil for 15 minutes, filter, and combine the two filtrates; set aside

[0062] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0063] 4) combining the filtrates from step 2) and step 3), concentrating at 60-70° C. to a relative density of 1.08, standing for 16 hours, taking the supernatant, adding earthworm paste, concentrating at 65-75° C. to a relative density of 1.25, and setting aside;

[0064] 5) Add pharmaceutically acceptable excipients in step 3) to granulate, and dry to obtain the product.

[0065] Example 2: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0066]

[0067]

[0068] The preparation process is:

[0069] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 10 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and use the earthworm paste for later use;

[0070] 2) Add 20 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, 8 parts by weight of Pinellia ternata, Coptis chinensis, and Ginkgo biloba, and boil for 40 minutes, filter, and set aside the filtrate and residue; add 8 times the amount of water to the residue, boil for 25 minutes, filter, and combine the two filtrates; set aside

[0071] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0072] 4) combining the filtrates from step 2) and step 3), concentrating at 60-70° C. to a relative density of 1.13, standing for 16-28 hours, taking the supernatant, adding earthworm paste, concentrating at 65-75° C. to a relative density of 1.35, and setting aside;

[0073] 5) Add pharmaceutically acceptable excipients in step 3) to granulate, and dry to obtain the product.

[0074] Example 3: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0075]

[0076]

[0077] The preparation process is:

[0078] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 7 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and set aside the earthworm paste;

[0079] 2) Add 15 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, 8 parts by weight of Pinellia ternata, Coptis chinensis, and Ginkgo biloba, decoct for 35 minutes, filter, and set aside the filtrate and residue; add 6 times the amount of water to the residue, decoct for 20 minutes, filter, and combine the two filtrates; set aside

[0080] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0081] 4) combining the filtrates from step 2) and step 3), concentrating at 60-70° C. to a relative density of 1.10, standing for 16-28 hours, taking the supernatant, adding earthworm paste, concentrating at 65-75° C. to a relative density of 1.30, and setting aside;

[0082] 5) Add pharmaceutically acceptable excipients in step 3) to granulate, and dry to obtain the product.

[0083] Example 4: A decoction for treating stable chronic obstructive pulmonary disease and its preparation

[0084]

[0085]

[0086] The preparation process is:

[0087] 1) Crush the earthworm and pass it through a 16-mesh sieve, add 7 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and set aside the earthworm paste;

[0088] 2) Add 15 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, 8 parts by weight of Pinellia ternata, Coptis chinensis, and Ginkgo biloba, and boil for 30-40 minutes, filter, and set aside the filtrate and residue; add 6 times the amount of water to the residue, boil for 30 minutes, filter, and combine the two filtrates; set aside

[0089] 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside;

[0090] 4) combining the filtrates from step 2) and step 3) to obtain a decoction.

[0091] Comparative Example 1: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0092]

[0093] The preparation process is the same as that of Example 3.

[0094] Comparative Example 2: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0095]

[0096] The preparation process is the same as that of Example 3.

[0097] Comparative Example 3: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0098]

[0099] The preparation process is the same as that of Example 3.

[0100] Comparative Example 4: A granule for treating stable chronic obstructive pulmonary disease and its preparation

[0101]

[0102]

[0103] The preparation process is the same as that of Example 3.

[0104] Verification Example 1: Experimental study on rats of the drug of the present invention in treating chronic obstructive pulmonary disease

[0105] 1.1 Animals

[0106] SPF grade SD rats, half male and half female, 2 months old, weighing 210±10 g (experimental unit use license number: SYXK(Beijing)2023-0053, Xiyuan Hospital, China Academy of Chinese Medical Sciences).

[0107] 1.2 Bacteria

[0108] Klebsiella pneumoniae (KP) (strain number: 46114) was purchased from the National Institutes for Food and Drug Control, China Medical Bacteria Collection Center. The bacterial concentration was adjusted to 10 × 10 8 CFU (Colony Forming Unit) / ml suspension.

[0109] 1.3 Cigarettes

[0110] Daqianmen cigarettes, produced by Shanghai China Tobacco, tar content: 10mg, nicotine content in smoke: 0.8mg, CO content: 11mg, cigarette length: 75mm, filter length: 25mm, packaging form: strip box and soft box, number of cigarettes in a single box: 20.

[0111] 1.4 Modeling, grouping, and drugs

[0112] 1.4.1 Modeling

[0113] The rat model of stable COPD was established by cigarette smoking combined with repeated infection with Klebsiella pneumoniae. Eight cigarettes were used each time in the first and second weeks of cigarette smoking, and 15 cigarettes were used each time in the third to twelfth weeks, twice a day, 40 minutes per time, with at least 3 hours between two smokings, for a total of 12 weeks. 6×10 Klebsiella pneumoniae liquid was instilled into the nasal cavity from the first to the eighth week. 8 CFU / ml, 0.1ml, once every 5 days.

[0114] 1.4.2 Experimental drugs

[0115] Aminophylline tablets (Henan Yonghe Pharmaceutical Co., Ltd., national medicine standard H41020984 0.1g / tablet), the drug was ground before use, and physiological saline was added to make a 1.0mg / ml suspension; granules prepared in Examples 1-4 of the present invention and Comparative Examples 1-4. Calculated on the basis of a human weight of 70kg, the dosage for rats is 14.43g / kg of the raw drug (Examples 1-3 and Comparative Examples 1-4).

[0116] 1.4.3 Grouping and Dosing

[0117] Rats were randomly divided into a normal group, a model group, a positive control group, an embodiment 1 group, an embodiment 2 group, an embodiment 3 group, a comparative example 1 group, a comparative example 2 group, a comparative example 3 group, and a comparative example 4 group, with 8 rats in each group. All rats were intragastrically administered, the normal group was given the same dose of physiological saline, and the positive control group (aminophylline control test) was intragastrically administered with 54 mg / kg / d, once a day, at 9:00 am.

[0118] 1.5 Index detection

[0119] 1.5.1 Pulmonary function: Starting from the day before modeling (recorded as week 0), pulmonary function was measured monthly, that is, at the end of the 4th, 8th, 12th, 16th and 20th weeks, the rats were placed in a closed body scanning box, and their pulmonary function parameters, including tidal volume (VT), peak expiratory flow (PEF), and maximum minute ventilation (MV), were recorded using a connected computer after their breathing stabilized.

[0120] 1.5.2 Changes in serum cytokines IL-1β, IL-6, MMP-9, T-AOC, and LPO expression: After the 20th week, the subjects were anesthetized with 2.8 ml / kg of 10% chloral hydrate, blood was collected from the abdominal aorta, and serum was collected by centrifugation at 2500 rpm for 15 min and stored at -80°C to detect changes in the following indicators: IL-1β, IL-6, and MMP-9 were detected using enzyme-linked immunosorbent assay (ELISA) kits, serum T-AOC changes were detected using total antioxidant capacity (T-AOC) detection kits (ABTS method), and LPO expression changes were detected using lipid peroxide (LPO) kits. The detection methods were carried out according to the instructions of the kits.

[0121] 1.5.3 Classification and counting of cells in alveolar lavage fluid sediment: remove the lungs, ligate the right main bronchus, separate the left lung, and use 4°C pre-cooled PBS to perfuse the left lung. Draw 3 ml of PBS each time and inject it into the left lung for lavage. The lavage fluid after withdrawal is filtered through sterile gauze and injected into a centrifuge tube. Repeat this process 3 times until the withdrawal rate reaches more than 80%. Centrifuge at 3000rpm for 10min, freeze the supernatant for later use, evenly spread the sediment on a slide, fix with neutral formaldehyde, dehydrate in gradients, stain with HE, and cover with glycerol. Observe under a microscope. Count 200 neutrophils, macrophages, and lymphocytes in each section, and calculate the number of each type of cell.

[0122] 1.6 Statistical analysis

[0123] GraphPad Prism 6.0 statistical software was used for data processing. Measurement data were expressed as mean ± standard deviation (X ± S). Paired t test was used for comparison between groups. Kruskal-Wallis rank sum test was used for intra-group comparison between multiple groups. If the data did not conform to normal distribution, one-way analysis of variance was used if the data conformed to normal distribution and variance was homogeneous. The difference was statistically significant when P < 0.05.

[0124] 1.7 Results Analysis

[0125] Figure 1 :Represents the V of each experimental group T From the 4th week onwards, compared with the normal group, the VT of the model group was significantly reduced (P≤0.05), indicating that the model was successfully established; from the 8th week onwards, compared with the positive control group, Example 1-3 groups and Comparative Example 1-4 groups, V T However, in general, the changes in Vt of each group in the embodiment were more obvious than those of the positive control group, indicating that the drug combination of the present invention has a definite effect and is superior to commercially available western medicine.

[0126] Figure 2: It shows the changes of MV values ​​of each experimental group. From the 8th week, the MV values ​​of the positive control group and Example 1-3 groups were significantly increased compared with the comparative example 1-4 groups (P≤0.05). Among them, the MV value of the normal group did not change much after the 8th week, which may be due to the fact that the development is close to maturity.

[0127] Figure 3 : It shows the comparison of IL-1β (pg / ml) content in each experimental group. It can be seen that there is a significant difference between Example 1-3 and Comparative Example 1-4 (P<0.01).

[0128] Figure 4 : It shows the comparison of IL-6 (pg / ml) content in each experimental group. It can be seen that the IL-6 content in Example 1-3 is significantly lower than that in Comparative Example 1-4, and there is a significant difference (P<0.01).

[0129] Figure 5 : It shows the comparison of the content of MMP-9 (ng / ml) in each experimental group. It can be seen that the content of MMP-9 in Example 1-3 is significantly lower than that in Comparative Example 1-4, and there is a significant difference (P<0.01).

[0130] Figure 6 : It represents the comparison of T-AOC (mM) of each experimental group. It can be seen that the content of total antioxidant capacity of the positive control group and Examples 1-3 is significantly improved compared with Comparative Examples 1-4, and there is a significant difference (P<0.01).

[0131] Figure 7 : represents the comparison of LPO (umol / L) in each experimental group. It can be seen that the content of LPO in the positive control group and Examples 1-3 is significantly reduced compared with Comparative Examples 1-4, and there is a significant difference (P<0.01). In general, the technical effect of Example 3 is better than that of other examples and the positive control group.

[0132] Figure 8 : represents the comparison of the number of monocytes in each experimental group. In terms of monocytes (units / 200 cells), Example 3 has a significant difference (P<0.01) compared with other comparative examples, and the remaining Examples 1-2 have no difference in technical effects compared with the comparative examples, which further illustrates that the composition and dosage of Example 3 of the present invention are more appropriate.

[0133] Fig. 9: It represents the comparison of the number of lymphocytes in each experimental group. In terms of lymphocytes (cells / 200 cells), the positive control group and Examples 1-3 have significant differences (P<0.01) compared with other comparative examples 1-4. It can be seen that in terms of the number of lymphocytes, the composition and dosage of the present invention and the drug in the positive control group can stimulate the body to produce an immune response and increase the number of lymphocytes.

[0134] Fig.10 : represents the comparison of neutrophils in each experimental group. In terms of neutrophils (number / 200 cells), the positive control group and Examples 1-3 have significant differences compared with other Comparative Examples 1-4 (P<0.01).

[0135] 1.8 Conclusion

[0136] The granules prepared in Examples 1-3 of the present invention and the positive control group can improve the rat lung function to varying degrees, such as the ratio of neutrophils in the rat bronchoalveolar lavage fluid and the expression of serum LPO, IL-1β, IL-6, and MMP-9. The granules of Examples 1-3 are particularly significant, showing a therapeutic effect with significant differences compared with the positive control group in some individual indicators.

[0137] In summary, the granules of Examples 1-3 have good therapeutic effects in treating COPD, can alleviate symptoms, improve lung function, reduce lung and systemic inflammatory responses, improve oxidative stress, etc. The effect of the granules of Example 3 is particularly significant and has a high clinical application value.

[0138] Verification Example 2: Clinical Trial of the Drugs of the Embodiments of the Present Invention in Treating Chronic Obstructive Pulmonary Disease

[0139] 2.1 Clinical patient sources and basic information

[0140] A total of 138 patients with stable COPD of lung and kidney qi deficiency type who visited Xiyuan Hospital of China Academy of Chinese Medical Sciences from June 2020 to May 2023 were selected. According to the order of visit, the patients were randomly divided into a control group and an observation group by random number table method, with 69 cases in each group. This study was approved by the Medical Ethics Committee of Xiyuan Hospital of China Academy of Chinese Medical Sciences, and all patients signed informed consent. There was no significant difference in gender, disease severity, height, weight, etc. between the two groups before the experiment (P>0.05), and they were comparable.

[0141] 2.2 Diagnostic criteria

[0142] 2.2.1 Western medicine diagnostic criteria: Refer to the diagnostic criteria for stable COPD in the "Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease (2021 Revised Edition)". ① Shortness of breath, repeated coughing, and expectoration; ② Forced expiratory volume in the first second (FEV1) / forced vital capacity (FVC) after inhalation of bronchodilators < 70%.

[0143] 2.2.2 TCM syndrome differentiation standards: Refer to the syndrome differentiation standards for lung and kidney qi deficiency in the "Guidelines for Clinical Research of New Chinese Medicines (Trial)", and the clinical manifestations are: chest tightness, wheezing, cough, shortness of breath, obvious fatigue, pale tongue with thin white coating, dull tongue, deep and thin pulse, cough and sputum.

[0144] 2.3 Inclusion criteria

[0145] ① Meet the above diagnostic criteria for stable COPD; ② TCM syndrome type is lung and kidney deficiency, phlegm and blood stasis; ③ Age over 18 years old; ④ Participate in the study for the first time and sign the informed consent form.

[0146] 2.4 Exclusion criteria

[0147] ① Patients with lung diseases such as lung infection and lung malignancy; ② Patients with mental illness or impaired consciousness who cannot cooperate with the study; ③ Pregnant or lactating women; ④ Patients who are allergic to the Chinese medicine ingredients in this study; ⑤ Patients with low willingness to participate in the study or poor compliance.

[0148] 2.5 Treatment methods

[0149] Control group: given conventional western medicine treatment, tiotropium bromide powder inhalation (Boehringer Ingelheim Pharmaceuticals Co., Ltd., Germany, approval number: National Medicine Standard H20140933; batch number: 20200802, 20200902; specification: 18 μg / inhalation) inhalation, once a day, 1 inhalation each time, the course of treatment is 12 weeks. Observation group: the granules of Example 3 group, taken with boiled water, once a day, the control group and the observation group took the drugs for 12 consecutive weeks.

[0150] 2.6 Efficacy criteria

[0151] The evaluation was conducted in accordance with the Guiding Principles for Clinical Research of New Chinese Medicines. The specific evaluation is as follows:

[0152] Markedly effective: After treatment, clinical symptoms and signs disappeared or basically disappeared, and the syndrome score decreased by ≥80%.

[0153] Effective: Clinical symptoms and signs improved, and syndrome scores decreased by ≥30% and <80%.

[0154] Ineffective: Clinical symptoms and signs slightly improved, or no improvement or aggravation, and the syndrome score decreased

[0155] <30%.

[0156] Total effective rate = (number of markedly effective + effective) cases / total number of cases × 100%.

[0157] 2.7 Observation indicators

[0158] 2.7.1 Symptom score

[0159] Before and after treatment, symptoms such as cough, sputum, wheezing, shortness of breath, and spontaneous sweating were scored according to the severity of the symptoms according to the grading and quantitative standards for COPD and its related diseases in the "Guidelines for Clinical Research of New Chinese Medicines (Trial)". 0 point means no symptoms, 1 point means mild symptoms, 2 points means moderate symptoms, and 3 points means severe symptoms.

[0160] 2.7.2 Pulmonary function indicators

[0161] The pulmonary function tester (MINATO, model: AS-507) was used to detect the pulmonary function indicators FVC (forced vital capacity), FEV1 (forced expiratory volume in 1 second) and FEV1 / FVC (ratio of forced expiratory volume in 1 second to forced vital capacity).

[0162] 2.7.3 Occurrence of AECOPD

[0163] The frequency and duration of AECOPD (acute exacerbation of chronic obstructive pulmonary disease) were recorded during the 1-year follow-up.

[0164] 2.8 Statistical analysis

[0165] GraphPadPrism6 statistical software was used for data processing. The quantitative data were in accordance with normal distribution. The data were expressed as t-tests, and the count data were tested with chi-square tests. P < 0.05 was considered statistically significant.

[0166] 2.9 Results Analysis

[0167] Table 1 Comparison of efficacy between the two groups of patients

[0168]

[0169] Fig.11 : It represents the comparison of TNF-α (pg·mL-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0170] Fig.12: It represents the comparison of SFRP1 (ng·L-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0171] Fig.13 : It represents the comparison of IL-33 ( / ng·L-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0172] Fig.14 : It represents the comparison of TGF-β1 (μg·L-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0173] Fig.15 : It represents the comparison of MMP-9 (ng·mL-1) between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0174] Fig.16 : It represents the comparison of FEV1 / % between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0175] Fig.17 : It represents the comparison between the control group and the observation group (FEV1 / FVC) / %. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0176] Fig.18 : It represents the comparison of TCM syndrome scores between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0177] Fig.19 : It represents the comparison of CAT scores between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0178] Fig. 20 : It represents the comparison of the treatment effects between the control group and the observation group. It can be seen that there was no significant difference between the two groups before treatment. After treatment, there was a significant difference between the control group and the observation group (P<0.01).

[0179] Fig.21: It shows the incidence of AECOPD in the control group and the observation group after one year of follow-up. It can be seen that there are significant differences in the number of attacks and duration between the two groups (P<0.01). Among the follow-up personnel, 62 cases were followed up in the control group and 64 cases were followed up in the observation group.

[0180] 2.10 Conclusion

[0181] Compared with western medicine treatment, the treatment efficiency of the granules of Example 3 of the present invention is higher, the relevant symptom scores are significantly reduced, and the lung function indexes are significantly improved. After follow-up 1, the number of AECOPD attacks using the granules of Example 3 was less and the duration was shorter, and the inter-group comparison (P<0.01). It is suggested that the granules of Example 3 of the present invention can significantly alleviate the occurrence of COPD and improve the quality of life of COPD patients. The product has been used in our hospital for decades. This prescription is mainly effective in tonifying the lungs and kidneys, resolving phlegm and removing blood stasis, and has a good clinical application effect.

Claims

1. A Chinese medicine composition for treating stable chronic obstructive pulmonary disease, characterized in that: The Chinese medicine composition is made from the following Chinese medicines: 10-20 weight parts of Epimedium, 6-12 weight parts of Curculigo, 20-60 weight parts of Astragalus, 15-20 weight parts of Salvia, 10-15 weight parts of Pheretima, 15-30 weight parts of Rhizoma Dioscoreae, 10-15 weight parts of Ophiopogon, 10-20 weight parts of Scutellaria, 15-30 weight parts of Adenophora, 10-15 weight parts of Dry Ginger, 12-30 weight parts of Morus alba, 6-10 weight parts of Pinellia, 5-10 weight parts of Coptis, and 10-20 weight parts of Ginkgo.

2. The Chinese medicine composition according to claim 1, characterized in that The astragalus is roasted astragalus.

3. The Chinese medicine composition according to claim 2, characterized in that: The Chinese medicine composition is made from the following Chinese medicines: 10 parts by weight of Epimedium, 6 parts by weight of Curculigo, 20 parts by weight of roasted Astragalus, 15 parts by weight of Salvia miltiorrhiza, 10 parts by weight of Pheretima, 15 parts by weight of Rhizoma Dioscoreae, 10 parts by weight of Ophiopogon japonicus, 10 parts by weight of Scutellaria baicalensis, 15 parts by weight of Adenophora australis, 10 parts by weight of Dried Ginger, 12 parts by weight of Morus alba, 6 parts by weight of Pinellia, 5 parts by weight of Coptis chinensis, and 10 parts by weight of Ginkgo.

4. The Chinese medicine composition as claimed in claim 2, characterized in that The Chinese medicine composition is made from the following Chinese medicines: 20 parts by weight of Epimedium, 12 parts by weight of Curculigo, 60 parts by weight of roasted Astragalus, 20 parts by weight of Salvia miltiorrhiza, 15 parts by weight of Pheretima, 30 parts by weight of Rhizoma Dioscoreae, 15 parts by weight of Ophiopogon japonicus, 20 parts by weight of Scutellaria baicalensis, 30 parts by weight of Adenophora australis, 15 parts by weight of Dried Ginger, 30 parts by weight of Morus alba, 10 parts by weight of Pinellia, 10 parts by weight of Coptis chinensis, and 20 parts by weight of Ginkgo.

5. The Chinese medicine composition according to claim 2, characterized in that: The Chinese medicine composition is made from the following Chinese medicines: 15 parts by weight of Epimedium, 9 parts by weight of Curculigo, 40 parts by weight of roasted Astragalus, 17 parts by weight of Salvia miltiorrhiza, 12.5 parts by weight of Pheretima, 22 parts by weight of Rhizoma Dioscoreae, 12.5 parts by weight of Ophiopogon japonicus, 15 parts by weight of Scutellaria baicalensis, 23 parts by weight of Adenophora australis, 12 parts by weight of Dry Ginger, 21 parts by weight of Morus alba, 8 parts by weight of Pinellia, 7 parts by weight of Coptis chinensis, and 15 parts by weight of Ginkgo.

6. Use of the Chinese medicine composition according to any one of claims 1 to 5 in the preparation of a medicament for treating chronic obstructive pulmonary disease in the stable phase.

7. A Chinese medicine preparation prepared from the Chinese medicine composition according to any one of 1 to 5, characterized in that: The Chinese medicine oral preparation is any one of granules, decoctions, pills, tablets, mixtures, capsules and powders.

8. A method for preparing the granules as claimed in claim 7, characterized in that: The method comprises the following steps: 1) Crush and sieve the earthworm, add 5-10 times the amount of rice wine and soak for 12 hours, heat it in water to dissolve it, filter it with a 100-mesh sieve while it is hot, and obtain the earthworm paste for later use; 2) Add 10-20 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, pinellia tuber, coptis root, and ginkgo, decoct for 30-40 minutes, filter, and set aside the filtrate and residue; add 4-8 times the amount of water to the residue, decoct for 15-25 minutes, filter, and combine the secondary filtrates for later use; 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside; 4) combining the filtrates from step 2) and step 3), concentrating at 60-70° C. to a relative density of 1.08-1.13, standing for 16-28 hours, taking the supernatant, adding earthworm paste, concentrating at 65-75° C. to a relative density of 1.25-1.35, and setting aside; 5) Add pharmaceutically acceptable excipients in step 3) to granulate, and dry to obtain the product.

9. A method for preparing the decoction as claimed in claim 7, characterized in that: The method comprises the following steps: 1) Crush the earthworm and pass it through a 16-mesh sieve, add 5-10 times the amount of rice wine and soak it for 12 hours, heat it in water to dissolve it, filter it through a 100-mesh sieve while it is hot, and use the earthworm paste for later use; 2) Add 10-20 times the amount of water to Adenophora australis, dried ginger, white mulberry bark, pinellia tuber, coptis root, and ginkgo, and boil for 30-40 minutes, filter, and set aside the filtrate and residue; add 4-8 times the amount of water to the residue, boil for 15-25 minutes, filter, and combine the two filtrates; set aside 3) crushing epimedium, curculigo, ophiopogon, roasted astragalus, salvia miltiorrhiza, rhizoma dioscoreae, and scutellariae, adding 75% ethanol and refluxing extraction twice, combining the filtrates and setting aside; 4) combining the filtrates from step 2) and step 3) to obtain a decoction.

10. The chronic obstructive pulmonary disease according to any one of claims 1 to 7 is of the type of deficiency of both lung and kidney and phlegm and blood stasis.

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