Traditional Chinese medicine composition for treating interstitial lung disease and application thereof

Abstract

The invention discloses a traditional Chinese medicine composition and application of the traditional Chinese medicine composition in preparation of medicines for treating interstitial lung diseases. The traditional Chinese medicine composition is prepared from, by weight, 5-25 parts of radix asteris, 1-15 parts of ginseng, 1-20 parts of poria cocos, 1-5 parts of pseudo-ginseng, 1-15 parts of angelica sinensis, 1-10 parts of schisandra chinensis, 1-15 parts of rhizoma anemarrhenae, 1-5 parts of cinnamon and 1-15 parts of pericarpium citri reticulatae.

Description

Technical Field

[0001] The present invention relates to a Chinese medicine composition and application thereof, and in particular to a Chinese medicine composition for treating interstitial lung disease and application thereof. Background Art

[0002] Interstitial lung disease (ILD) pulmonary fibrosis is a difficult disease of the respiratory system. Its clinical manifestations are characterized by exertional dyspnea, shortness of breath, dry cough, and wheezing. The disease mainly occurs in the pulmonary interstitium, affecting alveolar epithelial cells, pulmonary capillaries, and pulmonary arteries and veins. Complex pathogenic factors lead to alveolitis, and excessive immune inflammatory response leads to excessive repair of pulmonary interstitial fibrosis, ultimately resulting in the formation of lung scars and destruction of lung tissue, leading to significant gas exchange difficulties and ultimately respiratory failure. There are many clinical types of ILD, and the main and secondary symptoms are mixed. The pathogenesis is diverse, which greatly interferes with accurate clinical diagnosis and patient medication. Currently, the only approved drugs for the treatment of ILD are bifenidone and nintedanib, which can only relieve the patient's clinical symptoms but cannot prevent the progression of the disease. Therefore, there is an urgent need to develop safe and effective anti-pulmonary fibrosis drugs. Summary of the Invention

[0003] To solve the problems existing in the prior art, the present application provides a Chinese medicine composition for treating interstitial lung disease and its application.

[0004] The present invention adopts the following technical solutions:

[0005] A traditional Chinese medicine composition is prepared from the following traditional Chinese medicine raw materials in parts by weight: 5-25 parts of aster, 1-15 parts of ginseng, 1-20 parts of poria, 1-5 parts of panax notoginseng, 1-15 parts of angelica, 1-10 parts of schisandra, 1-15 parts of anemarrhena, 1-5 parts of cinnamon and 1-15 parts of dried tangerine peel.

[0006] Preferably, the traditional Chinese medicine composition of the present invention is prepared from the following traditional Chinese medicine raw materials in parts by weight: 10-20 parts of aster, 5-10 parts of ginseng, 5-15 parts of poria, 1-5 parts of panax notoginseng, 5-10 parts of angelica, 3-10 parts of schisandra, 5-10 parts of anemarrhena, 1-5 parts of cinnamon and 5-10 parts of tangerine peel.

[0007] More preferably, the traditional Chinese medicine composition of the present invention is made of the following traditional Chinese medicine raw materials in parts by weight: 12.5 parts of aster, 5 parts of ginseng, 7.5 parts of poria, 1.5 parts of panax notoginseng, 5 parts of angelica, 3 parts of schisandra, 5 parts of anemarrhena, 1.5 parts of cinnamon and 5 parts of tangerine peel.

[0008] Explanation of the Chinese medicine composition of the present invention: In the formula, Aster is the main drug that moistens the lungs, promotes qi, resolves phlegm and relieves cough. Ginseng greatly replenishes vital energy, enhances physical strength, and improves symptoms of qi deficiency; Poria strengthens the spleen and eliminates dampness, eliminates internal dampness, and alleviates internal phlegm and dampness obstruction; Angelica and Panax notoginseng replenish blood and invigorate blood circulation, promote blood circulation and remove blood stasis, improve blood stasis symptoms, and nourish the blood. These four are collectively the ministerial drugs. Anemarrhena is used to clear heat and purge fire, nourish yin and moisten dryness; Schisandra chinensis nourishes yin and astringes the lungs, relieves cough and shortness of breath, and helps the main and ministerial drugs to play the role of moistening the lungs and relieving cough, and nourishing the lungs and kidneys. Cinnamon can warm yang and dispel cold; Tangerine peel regulates qi and resolves phlegm, promotes the smooth flow of qi, and improves internal phlegm and dampness obstruction. These are collectively the guiding drugs. The whole formula is compact in dosage, precise in compatibility, and strengthens the body and eliminates evil, forming a comprehensive effect of replenishing qi and nourishing yin, invigorating blood circulation and removing blood stasis, and resolving phlegm and relieving cough. It regulates the pathogenesis of lung and kidney qi deficiency with phlegm and stasis and pulmonary fibrosis, aiming to improve the patient's respiratory function, alleviate symptoms, and delay the progression of the disease.

[0009] The present invention further provides a method for preparing the traditional Chinese medicine composition of the present invention, comprising the following steps: crushing ginseng and cinnamon bark, and decocting the mixture with aster, poria, notoginseng, angelica, schisandra chinensis, anemarrhena asphodeloides and tangerine peel in water; collecting volatile oil of the traditional Chinese medicine during the decocting process; collecting the decoction after the decocting process; filtering and concentrating the decoction to obtain an extract; and the extract and the collected volatile oil are the active pharmaceutical ingredients of the traditional Chinese medicine composition.

[0010] The number of times of decocting with water is 1-3 times, the amount of water added for each decoction is 6-10 times the weight of the Chinese medicine raw material, and the filtrate is concentrated to a level where each gram of extract is equivalent to 0.8-2.5g of crude drug.

[0011] The Chinese medicine composition of the present invention is in the form of a pharmaceutical preparation that can be taken orally, and includes active pharmaceutical ingredients.

[0012] Preferably, the Chinese medicine composition of the present invention is an oral preparation or an external preparation.

[0013] When preparing the Chinese medicine composition of the present invention, especially in the process of preparing the pharmaceutical preparation, pharmaceutically acceptable excipients may be added as needed, including: fillers, disintegrants, lubricants, suspending agents, adhesives, sweeteners, flavoring agents, preservatives, bases, etc.

[0014] Fillers include starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.

[0015] Among them, disintegrants include: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc.

[0016] Among them, lubricants include: magnesium stearate, sodium lauryl sulfate, talc, silicon dioxide, etc.;

[0017] Among them, suspending agents include: polyvinyl pyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc.;

[0018] Among them, the adhesives include starch slurry, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and the like.

[0019] The Chinese medicine composition disclosed in the present invention can significantly reduce pathological indicators related to inflammation, effectively reduce the area of ​​inflammatory fibrosis in lung tissue, protect the morphology and function of the lungs, and has a therapeutic effect on respiratory diseases induced by inflammation, especially interstitial lung disease. It has a significant effect on treating interstitial lung disease inflammation and fibrotic interstitial lung disease, and can delay the progression of fibrotic interstitial lung disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The total cell concentration and inflammatory cell concentration in BALF of mice in the normal control group, model control group and Chinese medicine compound group were detected. The Chinese medicine compound group, i.e. the Chinese medicine composition group of the present invention, was compared with the normal control group. ### P<0.001; compared with the model control group, * P<0.05

[0021] Figure 2 The concentrations of IL-1β, IL-6 and TNF-α inflammatory factors in BALF of mice in the normal control group, model control group and Chinese medicine compound group were detected. The Chinese medicine compound group, i.e. the Chinese medicine composition group of the present invention, was compared with the normal control group. ### P<0.001; compared with the model control group, *** P<0.001

[0022] Figure 3 The pulmonary inflammatory fibrosis area of ​​mice in the normal control group, model control group and Chinese medicine compound group was statistically analyzed. The Chinese medicine compound group, i.e., the Chinese medicine composition group of the present invention, was compared with the normal control group. ### P<0.001; compared with the model control group, * P<0.05

[0023] Figure 4 It is a panoramic picture of HE staining of lung tissue of mice in normal control group, model control group and Chinese medicine compound group. The Chinese medicine compound group is the Chinese medicine composition group of the present invention. DETAILED DESCRIPTION

[0024] The present invention is further illustrated by the following examples, but is not intended to limit the present invention.

[0025] Example 1. Preparation of Chinese medicine composition 1 of the present invention

[0026] prescription:

[0027] Aster 25g, Ginseng 10g, Poria 15g, Panax notoginseng 3g, Angelica 10g, Schisandra 6g, Anemarrhena 10g, Cinnamon 3g, Tangerine peel 10g

[0028] Preparation method: Crush ginseng and cinnamon bark and decoct them with aster, poria, notoginseng, angelica, schisandra, anemarrhena, and tangerine peel for 1-2 times, while collecting volatile oil. Add 6-10 times the amount of water each time the decoction is made, filter the decoction, combine the filtrates, and concentrate the filtrates until each gram of extract is equivalent to 2.5g of crude drug. Add volatile oil to the extract to obtain the product.

[0029] Example 2: Preparation of Chinese medicine composition 2 of the present invention

[0030] prescription:

[0031] Aster 20g, Ginseng 10g, Poria 15g, Panax notoginseng 5g, Angelica 10g, Schisandra 10g, Anemarrhena 10g, Cinnamon 5g, Tangerine peel 10g

[0032] Preparation method: Crush ginseng and cinnamon bark and decoct them with aster, poria, notoginseng, angelica, schisandra, anemarrhena, and tangerine peel for 1-2 times, while collecting volatile oil. Add 6-10 times the amount of water each time decoction, filter the decoction, combine the filtrates, and concentrate the filtrates until each gram of extract is equivalent to 2.0g of crude drug. Add volatile oil to the extract to obtain the product.

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

[0034] prescription:

[0035] Aster 20g, Ginseng 12g, Poria 10g, Panax notoginseng 2g, Angelica 14g, Schisandra 10g, Anemarrhena 14g, Cinnamon 2g, Tangerine peel 16g

[0036] Preparation method: Crush ginseng and cinnamon bark and decoct them with aster, poria, notoginseng, angelica, schisandra, anemarrhena, and tangerine peel for 1-2 times, while collecting volatile oil. Add 6-10 times the amount of water each time the decoction is made, filter the decoction, combine the filtrates, and concentrate the filtrates until each gram of extract is equivalent to 1.4g of crude drug. Add volatile oil to the extract to obtain the product.

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

[0038] prescription:

[0039] Aster 25g, Ginseng 15g, Poria 20g, Panax notoginseng 5g, Angelica 15g, Schisandra 10g, Anemarrhena 15g, Cinnamon 5g, Tangerine peel 15g

[0040] Preparation method: Crush ginseng and cinnamon bark and decoct them with aster, poria, notoginseng, angelica, schisandra, anemarrhena, and tangerine peel for 1-2 times, while collecting volatile oil. Add 6-10 times the amount of water each time decoction, filter the decoction, combine the filtrates, and concentrate the filtrates until each gram of extract is equivalent to 0.8g of crude drug. Add volatile oil to the extract to obtain the product.

[0041] Example 5: Preparation of Chinese medicine composition 5 of the present invention

[0042] prescription:

[0043] Aster 25g, Ginseng 5g, Poria 5g, Panax notoginseng 5g, Angelica 5g, Schisandra 5g, Anemarrhena 5g, Cinnamon 5g, Tangerine peel 5g

[0044] Preparation method: Crush ginseng and cinnamon bark and decoct them with aster, poria, notoginseng, angelica, schisandra, anemarrhena, and tangerine peel for 1-2 times, while collecting volatile oil. Add 6-10 times the amount of water each time the decoction is made, filter the decoction, combine the filtrates, and concentrate the filtrates until each gram of extract is equivalent to 1.0g of crude drug. Add volatile oil to the extract to obtain the product.

[0045] Example 6. Preparation of capsules

[0046] The extracts prepared in Examples 1-5 are dried and mixed with volatile oil, and appropriate amounts of auxiliary materials or additives are added, followed by mixing, granulation, drying, total mixing, and filling.

[0047] Experimental Example 1: Therapeutic effect of the composition of the present invention on pulmonary fibrosis

[0048] 1 Materials and Methods

[0049] 1.1 Materials

[0050] 1.1.1 Animals: 45 SPF male C57BL / 6 mice, aged 6-8 weeks, purchased from Beijing Weitonglihua Animal Experiment Technology Co., Ltd., animal qualification certificate number:

[0051] No. 110011241110667382. They were kept in an SPF animal room at Tianjin Pharmaceutical Technology Co., Ltd. under the following conditions: room temperature of 23-25°C, humidity of 40%-60%, standard feed, free access to food and water, and adaptive feeding for 3 days.

[0052] 1.1.2 Drugs and Reagents: The present invention was prepared according to Example 1. According to the "Equivalent Dose Ratio Table for Humans and Animals Based on Body Surface Area", the clinical dose was converted to a mouse daily dose of 12.61 g / kg, which was used as the dosage for this experiment.

[0053] Bleomycin hydrochloride for injection was purchased from Nippon Kayaku Co., Ltd. (batch number: 340840); interleukin-1β (IL-1β; batch number: 120228003184421202), interleukin-6 (IL-6; batch number: 12022700202681202), and tumor necrosis factor-α (TNF-α; batch number: 120228003104841202) were all purchased from Jianglai Biological.

[0054] 1.1.3 Instruments: Semi-automatic rotary microtome, Leica, Germany (model: HistoCoreMULTICUT); tissue embedding machine, Leica, Germany (model: HistoCore Arcadia);

[0055] Tissue dehydrator, Leica, Germany (model: HistoCore Pearl); automatic staining machine, Leica, Germany (model: ST5010); upright microscope, Nikon, Japan (model:

[0056] Ci-L); inverted microscope, Nikon Corporation, Japan (model: TS2); automatic cell counter, Countstar (model: Countstar BioTech); Mutiskan FC basic microplate reader, Thermo

[0057] (Model: 51119080); fully automatic slide scanner, 3D Histech (Model: PannoramicMIDI).

[0058] 1.2 Grouping and modeling: C57BL / 6 mice were randomly divided into three groups according to the random number table method, namely, normal control group, model control group, and Chinese medicine compound group, with 15 mice in each group.

[0059] The mouse pulmonary fibrosis model was replicated by intratracheal injection of bleomycin: the experimental mice were weighed, and the mice were anesthetized and the modeling dose was calculated based on their body weight. The anesthetized mice were placed in a supine position with their trunks fixed, the neck exposed, the neck disinfected with alcohol, and the neck hair shaved with a surgical blade. The surgical blade cut the neck skin about 0.5 cm along the midline of the neck. Forceps were used to separate the neck muscles and expose the trachea. An insulin injection needle was used to draw up the corresponding dose of bleomycin solution and inject it into the lungs along the trachea. The normal control group was injected with normal saline through the trachea. The mice were picked up and patted on the back to evenly distribute the modeling agent. The incision was sutured and the local skin was treated with anti-infection.

[0060] 1.3 Intervention Dosage Method According to the "Equivalent Dose Ratio Table for Humans and Animals Based on Body Surface Area", the dosage for mice was converted from clinical doses. The dosage for the Chinese medicine compound group was the daily dosage of raw medicine for mice.

[0061] The drug concentration was 12.61g / kg, prepared into a solution with a concentration of 0.68g / mL. Mice in the TCM compound group were gavaged daily at a dose of 0.2mL / 10g, while the normal and model control groups were gavaged with normal saline at the same dose. Intervention began on the first day after modeling in all groups and continued daily for a total of 7 days.

[0062] 1.4 Detection indicators and methods

[0063] 1.4.1 Determination of total cell count in alveolar lavage fluid: Fix the limbs of mice in supine position, cut the mouse skin with small scissors to expose the organs and trachea, insert a tracheal tube into the trachea, and use a syringe to draw PBS for lavage twice. The lavage fluid is placed in an EP tube and centrifuged for storage. The precipitate is used to count the total cell number and inflammatory cell number.

[0064] 1.4.2 Expression of inflammatory factors in bronchoalveolar lavage fluid The inflammatory factors IL-6, TNF-α, and IL-1β were detected in the supernatant of bronchoalveolar lavage fluid using ELISA kits, and the detection procedures were performed according to the instructions.

[0065] 1.4.3 Lung Fibrosis Area: The left lung of the mouse was fixed in formalin for 24-48 hours, removed, placed in an embedding cassette, and placed in an automatic dehydrator for dehydration according to the programmed program. The lung was then paraffin-embedded the next day. Paraffin sections were made using a semi-automatic rotary microtome, with a thickness of 5 μm. The slides were placed in an automatic stainer for H&E staining. After staining, the slides were removed and mounted with an appropriate amount of neutral resin. The prepared sections were trimmed and photographed using a pathology slide scanner. Fibrosis area was then counted using dedicated image viewing software.

[0066] 1.4.4 Statistical Methods: Measurement data were expressed as x ± s. If the data conformed to a normal distribution and met homogeneity of variance, one-way analysis of variance was used for comparisons between multiple groups. If the data showed a skewed distribution or did not meet homogeneity of variance, a nonparametric test with rank transformation was used. A P value of < 0.05 was considered statistically significant.

[0067] 2 Results

[0068] 2.1 Detection of cell count in alveolar lavage fluid The average cell concentration of mice in the normal control group was 0.35*10^6, the average cell concentration of mice in the model control group after the end of drug administration was 5.14*10^6, and the average cell concentration of the TCM compound group after the end of drug administration was 2.80*10^6. The total cell count of the lungs induced by BLM was significantly reduced after treatment with the TCM compound. The total cells were classified and counted, and monocytes, macrophages, lymphocytes and neutrophils were counted. The results showed that the concentrations of the three types of cells in the alveolar lavage fluid increased significantly after BLM modeling. After repeated administration of TCM, the cell concentrations were reduced to varying degrees, among which neutrophils and lymphocytes showed significant differences (see Table 1, Figure 1 ).

[0069] Table 1. Detection of total cell and inflammatory cell concentrations in mouse BALF

[0070]

[0071] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, * P<0.05

[0072] 2.2 Detection of inflammatory factors in alveolar lavage fluid The average IL-6 concentration of mice in the model control group was 638.92 pg / ml after the end of medication, which was significantly higher than 263.27 pg / ml in the normal control group. The average IL-6 concentration of the Chinese medicine compound group was 288.54 pg / ml after the end of medication, which can significantly reduce the IL-6 concentration in BLM-induced lung lavage fluid.

[0073] The average IL-1β concentration in the model control group after drug administration was 112.14 pg / ml, significantly higher than the 27.94 pg / ml in the normal control group. The average IL-1β concentration in the TCM compound group after drug administration was 21.37 pg / ml. The TCM compound significantly reduced IL-1β concentration in BLM-induced lung lavage fluid.

[0074] The average TNF-α concentration of the model control group mice after the end of the drug administration was 181.34 pg / ml, which was significantly higher than that of the normal control group (75.15 pg / ml). The average TNF-α concentration of the Chinese medicine compound group after the end of the drug administration was 82.20 pg / ml, which can significantly reduce the TNF-α concentration in the lung lavage fluid induced by BLM (see Table 2, Figure 2 ).

[0075] Table 2. Detection of inflammatory factor concentrations in mouse BALF

[0076]

[0077]

[0078] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, *** P<0.001

[0079] 2.3 Statistics of Inflammatory Fibrosis Area in Lung Tissue After BLM modeling, significant inflammatory cell infiltration and extracellular matrix deposition occurred in the lungs. The inflammatory fibrosis area of ​​the sections was counted. The results showed that the average inflammatory fibrosis area of ​​the model control group mice after the end of drug administration was 11.95%, while the average inflammatory fibrosis area of ​​the TCM compound group after the end of drug administration was 6.10%. The TCM compound can reduce the area of ​​inflammatory fibrosis induced by BLM, with a significant difference (see Table 3, Figure 3 , Figure 4 ).

[0080] Table 3. Inflammatory fibrosis area in mice lungs

[0081]

[0082] Note: Compared with the normal control group, ### P<0.001; compared with the model control group, * P<0.05

[0083] In summary, the Chinese herbal formula of the present invention significantly reduced the concentrations of total cells, neutrophils, and lymphocytes in mouse BALF, as well as inflammation-related pathological indicators such as inflammatory factors IL-6, TNF-α, and IL-1β. It also effectively reduced the area of ​​inflammatory fibrosis in lung tissue and protected the morphology and function of the lungs. In summary, the Chinese herbal formula of the present invention exhibits a favorable anti-inflammatory effect and can effectively alleviate the progression of pulmonary fibrosis in interstitial lung disease.

Claims

1. A Chinese medicine composition, characterized in that The traditional Chinese medicine composition is prepared from the following traditional Chinese medicine raw materials in parts by weight: 5-25 parts of aster, 1-15 parts of ginseng, 1-20 parts of poria, 1-5 parts of panax notoginseng, 1-15 parts of angelica, 1-10 parts of schisandra, 1-15 parts of anemarrhena, 1-5 parts of cinnamon and 1-15 parts of dried tangerine peel.

2. The Chinese medicine composition according to claim 1, characterized in that The traditional Chinese medicine composition is prepared from the following traditional Chinese medicine raw materials in parts by weight: 10-20 parts of aster, 5-10 parts of ginseng, 5-15 parts of poria, 1-5 parts of panax notoginseng, 5-10 parts of angelica, 3-10 parts of schisandra, 5-10 parts of anemarrhena, 1-5 parts of cinnamon and 5-10 parts of dried tangerine peel.

3. The Chinese medicine composition according to claim 1, characterized in that The traditional Chinese medicine composition is prepared from the following traditional Chinese medicine raw materials in parts by weight: 12.5 parts of aster, 5 parts of ginseng, 7.5 parts of poria, 1.5 parts of panax notoginseng, 5 parts of angelica, 3 parts of schisandra, 5 parts of anemarrhena, 1.5 parts of cinnamon and 5 parts of dried tangerine peel.

4. The method for preparing the Chinese medicine composition according to claim 1-3, characterized in that: The method comprises the following steps: crushing ginseng and cinnamon bark, adding water to decoct the mixture together with aster, poria, notoginseng, angelica, schisandra, rhizoma anemarrhenae and tangerine peel; collecting volatile oil of the Chinese medicinal materials during the decoction; collecting the decoction liquid after the decoction; filtering and concentrating the decoction liquid to obtain an extract; and the extract and the collected volatile oil are the active pharmaceutical ingredients of the Chinese medicinal composition.

5. The preparation method according to claim 4, characterized in that The number of times of adding water for decoction is 1-3 times, and the amount of water added for each decoction is 6-10 times the weight of the Chinese medicine raw material.

6. The Chinese medicine composition according to any one of claims 1 to 3, characterized in that: It is a pharmaceutical preparation that can be taken orally and includes the active pharmaceutical ingredient.

7. The Chinese medicine composition according to claim 6, characterized in that The pharmaceutical preparation is an oral preparation or an external preparation.

8. Use of the Chinese medicine composition according to claims 1-3 in the preparation of a medicament for treating respiratory diseases induced by inflammation.

9. The use according to claim 8, wherein the inflammation-induced respiratory disease is interstitial lung disease.

10. The use according to claim 8, wherein the interstitial lung disease comprises inflammatory interstitial lung disease and / or fibrotic interstitial lung disease.

11. Use of the traditional Chinese medicine composition according to claims 1-3 in the preparation of a medicament for delaying the progression of fibrotic interstitial lung disease.

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