Use of traditional chinese medicine composition in preparation of drug for preventing major adverse cardiac and cerebrovascular events after percutaneous coronary intervention

Abstract

Provided is the use of a traditional Chinese medicine composition in preparation of a drug for preventing major adverse cardiac and cerebrovascular events after percutaneous coronary intervention and ameliorating myocardial injury and vascular endothelial dysfunction after percutaneous coronary intervention. The traditional Chinese medicine composition is composed of total salvianolic acid and total hawthorn triterpene acid.

Description

Application of a traditional Chinese medicine composition in the preparation of a drug for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention. Technical Field

[0001] This application belongs to the field of traditional Chinese medicine technology, specifically relating to the application of a traditional Chinese medicine composition in the preparation of a drug for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention. Background Technology

[0002] Percutaneous coronary intervention (PCI) has become an important treatment for coronary heart disease since the 1980s. However, post-PCI complications such as no-reflow and slow flow, ischemia-reperfusion injury, perioperative myocardial injury, in-stent restenosis, and in-stent thrombosis are difficult to avoid, leading to an increased incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) and seriously threatening patients' lives. Post-PCI treatment requires anticoagulation, antiplatelet, and anti-inflammatory therapies. Commonly used drugs include antihypertensive drugs, lipid-lowering drugs, and antithrombotic drugs. Although these drugs have rapid onset and strong efficacy, their applications are limited, and they are accompanied by numerous adverse drug reactions.

[0003] Therefore, there is a need to develop a drug that is widely used and has mild or no adverse drug reactions. Summary of the Invention

[0004] This application provides the use of a traditional Chinese medicine composition in the preparation of a drug for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention (PCI). Following PCI, the combined use of the traditional Chinese medicine composition described in this application with conventional Western medicine treatment can improve myocardial injury and vascular endothelial dysfunction, reduce the risk of macrocephaly-associated cardiovascular events (MACCE) after PCI, and improve patient prognosis.

[0005] In a first aspect, this application provides the use of a traditional Chinese medicine composition in the preparation of a medicament for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention, wherein the traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn.

[0006] Percutaneous coronary intervention (PCI) is currently recognized as the preferred revascularization method for treating coronary artery disease. However, the hypoxia / reoxygenation process after the procedure can lead to myocardial damage due to the release of oxygen free radicals that promote inflammatory responses and cause microcirculatory disturbances. It can also cause varying degrees of damage to the local vascular endothelial function, stimulate the interaction of inflammatory factors and various cytokines, leading to restenosis of the vascular lumen, increased risk of occlusion, and increased risk of major adverse cardiovascular and cerebrovascular events (MACCE) after PCI, seriously threatening the patient's life and health.

[0007] Currently, antihypertensive drugs, lipid-lowering drugs, antiplatelet drugs, and anticoagulants are commonly used in clinical practice to improve prognosis. While these drugs are fast-acting and potent, their applications are limited, and they are accompanied by numerous adverse drug reactions. A traditional Chinese medicine composition prepared from Danshen (Salvia miltiorrhiza) and hawthorn contains total phenolic acid extracts from Danshen and total triterpenic acid extracts from hawthorn. This composition possesses the effects of promoting blood circulation, removing blood stasis, eliminating phlegm and turbidity, and reducing lipids. It may effectively improve the prognosis of PCI and reduce the risk of MACCE (major vascular endothelial cell carcinoma).

[0008] Secondly, this application provides the use of a traditional Chinese medicine composition in the preparation of a drug to improve myocardial injury after percutaneous coronary intervention, wherein the traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn.

[0009] Thirdly, this application provides the use of a traditional Chinese medicine composition in the preparation of a drug to improve vascular endothelial dysfunction after percutaneous coronary intervention, wherein the traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn.

[0010] The mass ratio of total phenolic acids from tanshinone to total triterpenoid acids from hawthorn is (1-4):(1-4). The specific values ​​in (1-4) can be selected from 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0011] Preferably, the diseases treated by the percutaneous coronary intervention include ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndrome, or stable coronary artery disease.

[0012] The traditional Chinese medicine composition is prepared by a method comprising the following steps:

[0013] (1) Mix danshen with water and decoct. After filtration, mix the filtrate with gelatin, precipitate with alcohol, concentrate, and extract with ethyl acetate to obtain an extract. Spray dry the obtained extract to obtain total phenolic acids of danshen.

[0014] Hawthorn was crushed, extracted by reflux with ethanol aqueous solution, concentrated, washed with water and dried, then mixed with ethyl acetate, extracted by reflux, filtered and collected, and dried to obtain total triterpenoids from hawthorn.

[0015] (2) Mix the total phenolic acids of tanshinone and the total triterpenic acids of hawthorn to obtain the product.

[0016] Preferably, the decocting time is 0.5-4 hours, and the number of times is 1-4.

[0017] The simmering time can be selected as 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, etc., and the number of times can be selected as 1 time, 2 times, 3 times, 4 times, etc. Other specific values ​​within the above range can also be selected, which will not be elaborated here.

[0018] Preferably, the mass of gelatin is 1%-8% of the mass of Danshen, such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0019] Preferably, the concentration by mixing with ethanol specifically includes: mixing the filtrate with ethanol to an ethanol content of 50%-95%, letting it stand for 8-24 hours, then washing with a 50%-95% ethanol aqueous solution and letting it stand for 8-24 hours.

[0020] The mass percentage of ethanol can be selected as 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc., and the standing time can be selected as 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, etc. Other specific values ​​within the above range can be selected, which will not be elaborated here.

[0021] Preferably, after concentration, the pH is adjusted to 1-5, such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0022] Preferably, the ethyl acetate extraction is performed 1-5 times, for example, 1 time, 2 times, 3 times, 4 times, 5 times, etc.

[0023] Preferably, before spray drying, the pH is adjusted to 3-6, such as 3, 3.5, 4, 4.5, 5, 5.5, 6, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0024] Preferably, the ethanol-water solution is refluxed 1-4 times for 0.5-2 hours.

[0025] The number of times can be selected as 1, 2, 3, or 4 times, and the time can be selected as 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.4h, 1.6h, 1.8h, or 2h. Other specific point values ​​within the above range can also be selected, which will not be elaborated here.

[0026] Preferably, the ethanol aqueous solution contains 50%-95% ethanol by mass.

[0027] The ethanol mass percentage is 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, etc. Other specific values ​​within the above range can be selected, which will not be elaborated here.

[0028] Preferably, before the first drying, the process includes washing with water 1-5 times, such as 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0029] Preferably, the mixture is mixed with ethyl acetate 1 to 6 times, such as 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0030] Preferably, the dosage form of the drug includes tablets, capsules, granules, powders, injections, sprays, films, or drops.

[0031] Preferably, the drug further includes pharmaceutically acceptable excipients.

[0032] Preferably, the excipients include any one or a combination of at least two of the following: excipients, diluents, carriers, flavoring agents, binders, or fillers.

[0033] Preferably, the carrier comprises liposomes, micelles, dendritic macromolecules, microspheres, or microcapsules.

[0034] Compared with the prior art, this application has the following advantages:

[0035] Percutaneous coronary intervention (PCI) is currently recognized as the preferred revascularization method for treating coronary artery disease. However, the hypoxia / reoxygenation process after the procedure can lead to myocardial damage due to the release of oxygen free radicals that promote inflammatory responses and cause microcirculatory disturbances. It can also cause varying degrees of damage to the local vascular endothelial function, stimulate the interaction of inflammatory factors and various cytokines, leading to restenosis of the vascular lumen, increased risk of occlusion, and increased risk of major adverse cardiovascular and cerebrovascular events (MACCE) after PCI, seriously threatening the patient's life and health.

[0036] Currently, antihypertensive drugs, lipid-lowering drugs, antiplatelet drugs, and anticoagulants are commonly used in clinical practice to improve prognosis. While these drugs are fast-acting and potent, their applications are limited, and they are accompanied by numerous adverse drug reactions. A traditional Chinese medicine composition prepared from Danshen (Salvia miltiorrhiza) and hawthorn contains total phenolic acid extracts from Danshen and total triterpenic acid extracts from hawthorn. This composition possesses the effects of promoting blood circulation, removing blood stasis, eliminating phlegm and turbidity, and reducing lipids. It may effectively improve the prognosis of PCI and reduce the risk of MACCE (major vascular endothelial cell carcinoma). Attached Figure Description

[0037] Figure 1 shows the Kaplan-Meier curve of MACCE 4 years after PCI. Detailed Implementation

[0038] The technical solution of this application will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely to help understand this application and should not be regarded as specific limitations on this application.

[0039] Example 1

[0040] Drug preparation:

[0041] Preparation of total phenolic acid extract from Tanshinone:

[0042] Take the sliced ​​Salvia miltiorrhiza, decoct it twice with water, adding 10 times the amount of water for the first decoction and 6 times the amount of water for the second decoction, each time for 1.5 hours. Filter the decoction, combine the filtrates, and concentrate it to 1.0 g of sliced ​​Salvia miltiorrhiza per mL (relative density of 1.20 at 50℃). Add 4% gelatin solution (gelatin added at 2.0% of the sliced ​​Salvia miltiorrhiza), let it stand for 12 hours, filter the decoction, concentrate the filtrate to a relative density of 1.16 (50℃), add ethanol to a concentration of 70%, let it stand for 12 hours, filter the decoction, wash the precipitate with 60% ethanol (the amount of ethanol added is the same as the amount of ethanol added in the first alcohol precipitation), let it stand for 12 hours, filter the decoction, combine the filtrates and concentrate it to a relative density of 1.23 (50℃), adjust the pH to about 3 with dilute hydrochloric acid, and then extract it three times with an equal volume of water-saturated ethyl acetate. Combine the ethyl acetate extracts and recover the ethyl acetate. Adjust the pH of the extract to 5 with 1% sodium hydroxide. Spray dry the resulting extract to obtain the final product.

[0043] The average yield of total phenolic acids in the extract prepared by this method is greater than 2.0%.

[0044] Preparation of total triterpene acid extract from hawthorn:

[0045] Hawthorn berries were crushed into coarse powder and extracted twice by reflux with 80% ethanol. The first extraction used 8 times the ethanol volume, and the second used 4 times the ethanol volume, each time for 0.5 hours. The extracts were filtered, and the filtrates were combined. The ethanol was recovered under reduced pressure, and the extract was concentrated to a clear extract with a relative density of 1.11 (50℃). The extract was washed three times with water (10 times the volume of the extract each time) until the pH of the washings reached 6. The extract was allowed to stand, filtered, and the aqueous solution was discarded. The precipitate was spray-dried to obtain a dry powder (yield greater than 3%). Four times the volume of ethyl acetate was added to the dry powder, and the extract was warm-soaked at 60℃ for 0.5 hours. The extract was filtered, and the ethyl acetate was recovered from the filtrate to obtain a black extract, which was discarded. The residue after warm-soaking was refluxed three times with ethyl acetate, each time using 10 times the ethanol volume. The first reflux lasted 1 hour, and the second and third refluxes lasted 0.5 hours each. The extracts were filtered, and the filtrates were combined. The ethyl acetate was recovered and the extract was dried under vacuum to obtain the final product.

[0046] The yield of total triterpenic acids prepared by this method is greater than 5.0‰.

[0047] 97.5g of total phenolic acid extract from Salvia miltiorrhiza, 52.5g of total triterpenic acid extract from hawthorn, and 100g of microcrystalline cellulose were mixed together and then mixed with 40mL of ethanol to form granules. The granules were dried, filled into capsules, and made into 1000 capsules, each weighing 0.25g.

[0048] Test Example 1

[0049] Investigating the effect of the pharmaceutical composition prepared in Example 1 on major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS).

[0050] 1. Overall Experimental Design

[0051] Randomized, controlled, single-center clinical trial

[0052] 2. Inclusion criteria

[0053] The diagnostic criteria are based on the "Guidelines for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndrome" formulated by the Chinese Society of Cardiology in 2016:

[0054] ① Patients diagnosed with non-ST-elevation ACS and scheduled for PCI surgery;

[0055] ② Age between 35 and 85 years old;

[0056] ③ The patient participates voluntarily, and the patient or their family member signs an informed consent form.

[0057] 3. Exclusion criteria

[0058] Cases meeting the inclusion criteria will be excluded if they meet any of the following criteria:

[0059] ① Patients who have had a myocardial infarction, severe trauma, or major surgery within 3 months prior to admission;

[0060] ② Individuals with cerebrovascular disease and its complications;

[0061] ③ Comorbid with other heart diseases, such as rheumatic heart disease, cardiomyopathy, congenital heart disease, etc.;

[0062] ④ Hypotension, shock, severe pulmonary insufficiency, and liver and kidney dysfunction;

[0063] ⑤ Patients classified as NYHA functional class III-IV;

[0064] ⑥ If you have taken Chinese medicine or prepared Chinese medicine containing active ingredients of Danshen and hawthorn within 2 weeks before the onset of the disease, such as Danshen dripping pills, Danhong injection, Danlou tablets, hawthorn tablets, etc.

[0065] 4. Grouping and drug administration

[0066] Patients meeting the inclusion criteria signed the informed consent form for direct PCI surgery and the informed consent form for this clinical trial. Randomization was performed using the SAS system, with patients divided into a control group (n=30) and an experimental group (n=29). The control group received routine Western medicine treatment, while the experimental group received routine Western medicine treatment in addition to the medication described in Example 1, twice daily, 5 tablets each time, after breakfast and dinner, for 8 weeks post-PCI.

[0067] 5. Observation Indicators

[0068] ① Myocardial injury: The levels of high-sensitivity troponin (hs-cTn), a marker of myocardial injury, were detected by chemiluminescence immunoassay before treatment and 6 weeks after treatment.

[0069] ② Vascular endothelial function: Before treatment and 6 weeks after treatment, the levels of endothelin (ET)-1 and von Willebrand factor (vWF), markers of vascular endothelial function, were detected by enzyme-linked immunosorbent assay (ELISA).

[0070] ②MACCE: Follow-up for 4 years after PCI, recording the occurrence of the first MACCE in both groups, including myocardial infarction, angina pectoris, revascularization, restenosis after PCI, ischemic stroke, death, etc.

[0071] 6. Statistical methods

[0072] Data were analyzed using SPSS or Graphpad Prism software. A p-value < 0.05 was considered statistically significant.

[0073] 7. Results

[0074] 7.1 Myocardial Injury

[0075] The results are shown in Table 1.

[0076] Table 1

[0077] Note: *P < 0.05 compared to pre-treatment levels in this group; #P < 0.05 compared to the control group. Independent samples t-test was used for comparisons between groups, and paired t-test was used for comparisons within groups before and after treatment.

[0078] Compared with before treatment, the hs-cTn level in the experimental group was significantly lower (P<0.05); after treatment, the hs-cTn level in the experimental group was significantly lower than that in the control group (P<0.05).

[0079] Troponin (cTn) is specifically expressed in cardiomyocytes. During cardiomyocyte necrosis, apoptosis, cell renewal, changes in cell membrane permeability, and vesicle formation, it is released into the peripheral blood in various forms, including monomers and complexes. It is a specific marker of myocardial injury. High-sensitivity troponin (hs-cTn) detection technology can detect small amounts of free cTn released from the cytoplasm of cardiomyocytes into the peripheral blood circulation, reducing the "troponin blind zone" time and enabling earlier detection of acute myocardial infarction. The results of this study show that, compared to pre-treatment levels, the hs-cTn level in the experimental group was significantly reduced, and there was a significant difference compared to the control group, indicating that the traditional Chinese medicine composition described in this application can improve myocardial injury in PCI patients and has a cardioprotective effect.

[0080] 7.2 Vascular endothelial function

[0081] The results are shown in Table 2.

[0082] Table 2

[0083] Note: *P < 0.05 compared to pre-treatment levels in the same group. Independent samples t-tests were used for inter-group comparisons, and paired t-tests were used for intra-group comparisons before and after treatment.

[0084] Compared with before treatment, the levels of ET-1 and vWF in the experimental group were significantly reduced (P<0.05); after treatment, the levels of ET-1 and vWF in the experimental group were lower than those in the control group, showing a good decreasing trend.

[0085] Endothelin (ET)-1 and von Willebrand factor (vWF) are important biomarkers of vascular endothelial injury. ET-1 is a significant vasoactive factor that strongly constricts blood vessels, causing vasospasm, increasing blood viscosity, and promoting smooth muscle cell proliferation. vWF is an important marker of endothelial cell activation and endothelial dysfunction, and also a risk factor for assessing bleeding and thrombosis. The results of this study showed that, compared with pre-treatment levels, the levels of ET-1 and vWF in the experimental group were significantly reduced, indicating that the traditional Chinese medicine composition described in this application can improve vascular endothelial function in PCI patients and has a protective effect on vascular endothelium.

[0086] 7.3 Incidence of first MACCE in patients after PCI

[0087] At 1, 2, 3, and 4 years post-PCI follow-up, the cumulative incidence of MACCE in the control group was 10%, 20%, 23.3%, and 30.0%, respectively, while the cumulative incidence of MACCE in the experimental group was 0%, 10.34%, 10.34%, and 17.24%, respectively. The incidence of MACCE in the experimental group at each stage was lower than that in the control group.

[0088] Table 3

[0089] During the 4-year follow-up period after PCI, the treatment with the traditional Chinese medicine composition described in this application reduced the incidence of MACCE by 42.5% (30.0% in the control group and 17.24% in the experimental group), with a hazard ratio (HR) of 0.52 and a 95% confidence interval of (0.18, 1.50) (P = 0.226), showing a good decreasing trend, as shown in Figure 1.

[0090] The cumulative incidence of MACCE in the experimental group was lower than that in the control group during the 4-year follow-up period, showing a good decreasing trend. These results indicate that the traditional Chinese medicine composition described in this application may improve patient prognosis by reducing the occurrence of major adverse cardiovascular and cerebrovascular events after PCI by alleviating myocardial and vascular endothelial damage.

[0091] Percutaneous coronary intervention (PCI) is currently recognized as the preferred revascularization method for treating coronary artery disease. However, the hypoxia / reoxygenation process after the procedure can lead to myocardial damage due to the release of oxygen free radicals that promote inflammatory responses and microcirculatory disturbances. It can also cause varying degrees of damage to local vascular endothelial function, stimulate the interaction of inflammatory factors and various cytokines, resulting in restenosis of the vascular lumen, increased risk of occlusion, and a higher risk of major adverse cardiovascular and cerebrovascular events (MACCE), seriously threatening patients' lives and health. Currently, antihypertensive drugs, lipid-lowering drugs, antiplatelet drugs, and anticoagulants are commonly used clinically to improve prognosis. While these drugs are fast-acting and potent, their applications are limited, and they are accompanied by numerous adverse drug reactions. The traditional Chinese medicine composition described in this application is prepared from Danshen (Salvia miltiorrhiza) and hawthorn, and its components are total phenolic acid extracts of Danshen and total triterpenic acid extracts of hawthorn. It has the effects of promoting blood circulation, removing blood stasis, eliminating phlegm and turbidity, and reducing lipids, and may effectively improve the prognosis of PCI and reduce the risk of MACCE. In summary, the traditional Chinese medicine composition described in this application can improve myocardial injury and vascular endothelial dysfunction, reduce the risk of MACCE after PCI, and improve patient prognosis, making it worthy of clinical promotion.

[0092] The applicant declares that this application illustrates the use of a traditional Chinese medicine composition in the preparation of a drug for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention through the above embodiments. However, this application is not limited to the above embodiments, i.e., it does not mean that this application must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this application, equivalent substitutions of the raw materials of the product, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this application.

[0093] The preferred embodiments of this application have been described in detail above. However, this application is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this application, various simple modifications can be made to the technical solution of this application, and these simple modifications all fall within the protection scope of this application.

[0094] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this application will not describe the various possible combinations separately.

Claims

The application of a traditional Chinese medicine composition in the preparation of a drug for preventing major adverse cardiovascular and cerebrovascular events after percutaneous coronary intervention, wherein, The traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn. The application of a traditional Chinese medicine composition in the preparation of a drug for improving myocardial injury after percutaneous coronary intervention, wherein, The traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn. The application of a traditional Chinese medicine composition in the preparation of a drug for improving vascular endothelial dysfunction after percutaneous coronary intervention, wherein, The traditional Chinese medicine composition includes total phenolic acids from tanshinone and total triterpenoid acids from hawthorn. The application according to any one of claims 1-3, wherein, The mass ratio of total phenolic acids from tanshinone to total triterpenic acids from hawthorn is (1-4):(1-4). The application according to any one of claims 1-4, wherein, The diseases treated by percutaneous coronary intervention include ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndrome, or stable coronary artery disease. The application according to any one of claims 1-5, wherein, The traditional Chinese medicine composition is prepared by a method comprising the following steps: (1) Mix danshen with water and decoct. After filtration, mix the filtrate with gelatin, precipitate with alcohol, concentrate, and extract with ethyl acetate to obtain an extract. Spray dry the obtained extract to obtain total phenolic acids of danshen. Hawthorn was crushed, extracted by reflux with ethanol aqueous solution, concentrated, washed with water and dried, then mixed with ethyl acetate, extracted by reflux, filtered and collected, and dried to obtain total triterpenoids from hawthorn. (2) Mix the total phenolic acids of tanshinone and the total triterpenic acids of hawthorn to obtain the product. According to the application of claim 6, wherein, The concentration process also includes adjusting the pH to 1-5; Preferably, prior to spray drying, the pH is adjusted to 3-6; Preferably, the mass of gelatin is 1-8% of the mass of Danshen. The application according to any one of claims 1-7, wherein, The dosage forms of the drug include tablets, capsules, granules, powders, injections, sprays, films, or drops. The application according to any one of claims 1-8, wherein, The drug also includes pharmaceutically acceptable excipients. According to the application of claim 9, wherein, The excipients include any one or a combination of at least two of the following: excipients, diluents, carriers, flavoring agents, binders, or fillers. According to the application of claim 10, wherein, The carrier includes liposomes, micelles, dendritic macromolecules, microspheres, or microcapsules.

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