Use of leech dredging network composition in preparation of medicine for preventing or treating cerebral small vessel disease

Abstract

The application belongs to the technical field of traditional Chinese medicines, and particularly discloses a use of Chuanjizhunluo in preparation of a medicine for preventing or treating cerebral small vessel disease. The Chuanjizhunluo is mainly composed of water leech, Chuanxiong Rhizoma, Salvia miltiorrhiza and Astragalus, has the effects of clearing heat and resolving toxins, promoting blood circulation to remove blood stasis, and tonifying qi and dredging collaterals. The Chuanjizhunluo can relieve anxiety, has a protective effect on the nervous system, has no damage to liver and kidney functions in the treatment process, can effectively improve general behavior performance, has an improving effect on cognitive function impairment, has a significant effect on the treatment of cerebral small vessel disease, is a safe and effective traditional Chinese medicine product for treating cerebral small vessel disease, and has a good popularization and application prospect.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to the use of the leech-infused collaterals-clearing composition in the preparation of drugs for the prevention or treatment of cerebral small vessel disease. Background Technology

[0002] Neurological disorders are diseases that occur in the central nervous system, peripheral nervous system, and autonomic nervous system, and are characterized primarily by sensory, motor, consciousness, and autonomic nerve dysfunction. Symptoms and signs of neurological disorders can manifest as altered consciousness, sensory disturbances, motor disorders, abnormal muscle tone, etc. Common symptoms include headache, dizziness, vertigo, abnormal reflexes, muscle atrophy, and urinary, fecal, and sexual dysfunction.

[0003] Cerebral small vessel disease is one of the common neurological diseases. Cerebral small vessel disease refers to a group of cerebrovascular diseases with different etiologies, mainly affecting small blood vessels in the brain. The main affected blood vessels are arterioles, microarteries, capillaries and venules. The etiologies are divided into six categories: (1) Arteriolosclerosis (also known as age-related and vascular risk factor-related cerebral small vessel disease): fibrinoid necrosis, lipid hyaline degeneration, microarteriosclerosis, microaneurysms, segmental arterial structural destruction. (2) Sporadic and hereditary cerebral amyloid angiopathy: Cerebral amyloid angiopathy refers to the progressive deposition of β-amyloid protein in the outer and middle layers of the blood vessel wall, leading to vascular damage. It mainly affects the small arteries, capillaries and veins of the pia mater and cortex, with cognitive impairment, dementia, mental symptoms, and recurrent and multiple lobar hemorrhages as the main clinical features. (3) Hereditary small vessel diseases different from cerebral amyloid angiopathy: autosomal dominant hereditary cerebral arteropathy with subcortical infarction and leukoencephalopathy, autosomal recessive hereditary cerebral arteropathy with subcortical infarction and leukoencephalopathy, Swedish hereditary multi-infarct dementia, mitochondrial encephalomyopathy with hyperlactatemia and stroke-like attacks, Fabry disease, hereditary cerebral-retinal vascular disease, hereditary vascular endothelial disease with retinopathy, nephropathy and stroke, small vessel diseases caused by COLA1 mutation, etc. (4) Inflammatory and immune-mediated small vessel diseases: such as Wegener's granulomatosis, Churg-Strauss syndrome, microarteritis, primary central nervous system vasculitis, Sneddon syndrome, central nervous system vasculitis secondary to infection, etc. (5) Venous collagen diseases. (6) Other small vessel diseases: such as radiation encephalopathy and non-amyloid microangiopathy in Alzheimer's disease, etc. The most common clinical condition is cerebral small vessel disease with arteriosclerosis, characterized by pathological changes such as lipid hyaline degeneration of the small vessel walls, atherosclerotic stenosis or occlusion, and secondary aneurysmal dilatation of small arteries. Neocortical small infarcts, vasogenic protein hyperintensities, vasogenic cavities, cerebral microvascular hemorrhage, perivascular spaces, and brain atrophy are common imaging markers of cerebral small vessel disease.

[0004] Cerebral small vessel disease (CBD) is a significant cerebrovascular disease leading to cognitive decline, gait and emotional disturbances, and dementia. Diffuse brain protein damage is a key imaging feature of this disease. Current clinical treatments for CBD primarily include: treatment targeting vascular risk factors, antiplatelet therapy, thrombolytic therapy, and anti-inflammatory therapy. While controlling vascular risk factors, antiplatelet therapy, and thrombolytic therapy reduce the risk of ischemic stroke, they also increase the risk of cerebral hemorrhage. A balance needs to be struck to ensure maximum treatment benefit. Effective evidence for anti-inflammatory therapy in CBD is currently lacking, although it has shown good responses to steroids or cyclophosphamide. Globally, CBD affects most middle-aged and elderly individuals, but there is currently no specific treatment. Factors influencing disease progression may be reasonable therapeutic targets, but the pathogenesis of CBD remains poorly understood. With a deeper understanding of the pathogenesis and biomarkers of CBD, it is hoped that more specific treatment methods will be developed in the future.

[0005] Traditional Chinese medicine believes that cerebral small vessel disease can be classified to some extent as cerebral collateral disease or cerebral mystic vessel disease. When the collateral vessels are blocked, collateral disease occurs, and when the mystic vessel is blocked, various diseases are easily caused. Therefore, "blockage" is the key pathogenesis of collateral disease and mystic vessel disease. When the collateral vessels and mystic vessel of the brain are blocked, the brain marrow will be deprived of nourishment, the brain marrow structure will be damaged, and ultimately the brain function will be impaired, thus triggering cerebral small vessel disease.

[0006] The Chuanzhi Tongluo Composition is made from four Chinese medicinal herbs: leech, chuanxiong (Ligusticum striatum), danshen (Salvia miltiorrhiza), and astragalus. Leech is the principal herb, possessing the functions of promoting blood circulation, removing blood stasis, and eliminating blood stasis. Chuanxiong is the assistant herb, possessing the power of growth and development, which can work synergistically with leech to reach the brain meridians, promoting blood circulation and unblocking the meridians, thus ensuring smooth flow of qi and blood and healthy organ function. Astragalus and danshen are the adjuvant herbs; astragalus treats blood stasis and stagnation by tonifying qi, while danshen promotes blood circulation, removes blood stasis, calms the mind, and nourishes the heart. Overall, the Chuanzhi Tongluo Capsule has the effects of promoting blood circulation, removing blood stasis, tonifying qi, and unblocking the meridians.

[0007] A search revealed no research or reports on the use of the leech-infused combination in the preparation of drugs for the prevention or treatment of cerebral small vessel disease. Summary of the Invention

[0008] The purpose of this invention is to discover the use of the leech-based meridian-clearing composition in the preparation of drugs for the prevention or treatment of cerebral small vessel disease. The technical solution of this invention is as follows:

[0009] The use of the leech-infused collaterals-clearing composition in the prevention or treatment of cerebral small vessel disease, wherein the leech-infused collaterals-clearing composition is made from the following ingredients: leech, chuanxiong, danshen, and astragalus.

[0010] The small vessel diseases mentioned include arteriosclerotic small vessel disease, sporadic and hereditary cerebral amyloid angiopathy, hereditary small vessel diseases different from cerebral amyloid angiopathy, inflammatory and immune-mediated small vessel diseases, venous collagen diseases, and other small vessel diseases.

[0011] The treatment methods for cerebral small vessel disease include etiological treatment, antithrombotic treatment, lipid-lowering treatment, and treatment to improve cognitive and emotional disorders.

[0012] In one embodiment of the present invention, the treatment of cerebral small vessel disease is antithrombotic therapy.

[0013] The components of the traditional Chinese medicine in the leech-infused collaterals-clearing composition of this invention are as follows (by weight):

[0014] Leech 550-650 parts by weight, Ligusticum chuanxiong 550-650 parts by weight

[0015] Salvia miltiorrhiza 350-450 parts by weight, Astragalus membranaceus 350-450 parts by weight

[0016] In one embodiment of the present invention, the traditional Chinese medicine composition comprises the following components in parts by weight:

[0017] Leech 600 parts by weight, Ligusticum chuanxiong 600 parts by weight

[0018] Salvia miltiorrhiza 400 parts by weight, Astragalus membranaceus 400 parts by weight

[0019] The aforementioned leech-based collateral-clearing composition is prepared into a clinically acceptable oral formulation using conventional processes and with the addition of clinically acceptable excipients.

[0020] The traditional Chinese medicine components are prepared into clinically acceptable oral formulations using conventional processes and with the addition of clinically acceptable excipients.

[0021] The clinically acceptable oral preparations include, but are not limited to, granules, capsules, pills, tablets, oral liquids, and mixtures; preferably, the oral preparations are capsules; more specifically, the oral preparations are leech-infused capsules.

[0022] The uses described in this invention were discovered during the clinical application of the already marketed drug Chuanzhi Tongluo Capsules (National Drug Approval Number Z20090031). However, this invention is not limited to the above-mentioned preparation. The preparation method of the preparation described in this invention will be described in detail below.

[0023] The method for preparing the oral pharmaceutical formulation of the present invention includes the following steps:

[0024] A. Leeches are crushed into coarse powder, 2-10 times the amount of water is added, and the mixture is stirred and extracted at 37°C. After centrifugation, the supernatant is pre-filtered and sterilized through a filter membrane, then concentrated by ultrafiltration. The concentrate is then freeze-dried and crushed to obtain leech freeze-dried powder for later use.

[0025] B. Extract the three herbs, Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus, by reflux with 2-10 times the amount of 65-95% ethanol. Filter and concentrate the reflux liquid to obtain the ethanol concentrate. Add 2-6 times the amount of water to the residue of the raw herbs, decoct and extract, filter, and concentrate the filtrate to obtain the aqueous concentrate. Combine the ethanol concentrate and the aqueous concentrate, spray dry, and obtain a mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus.

[0026] C. The lyophilized leech powder obtained in step A and the mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus obtained in step B are mixed evenly and then prepared into an oral drug formulation by conventional processes or by adding pharmaceutically acceptable excipients.

[0027] Preferably, the method for preparing the oral formulation of the present invention includes the following steps:

[0028] A. Leeches are crushed into coarse powder, 6 times the amount of water is added, and the mixture is stirred at 37℃ and 100 r / min for 20 h. After centrifugation, the supernatant is pre-filtered through a 1 μm pore membrane and filtered through a 0.2 μm pore membrane for sterilization. Then, it is concentrated through an ultrafiltration membrane with a molecular weight cutoff of 6-10 kDa. The concentrate is then freeze-dried and crushed to obtain leech freeze-dried powder for later use.

[0029] B. The three herbs, Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus, were extracted twice by reflux with 6 times the amount of 80% ethanol. The extract was filtered and concentrated to a relative water density of 1.1-1.3 to obtain the ethanol concentrate. The residue was added to 4 times the amount of water of the raw herbs and decocted once. The extract was filtered and concentrated to a relative water density of 1.1-1.3 to obtain the aqueous concentrate. The ethanol concentrate and aqueous concentrate were combined and spray-dried to obtain a mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus.

[0030] C. Mix the leech freeze-dried powder obtained in step A and the mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus obtained in step B evenly, and prepare an oral drug formulation directly or by adding pharmaceutically acceptable excipients through conventional processes.

[0031] In a preferred embodiment, the leech-based meridian-clearing preparation is in the form of granules, tablets, or capsules, and its preparation method is as follows:

[0032] A. Leeches are crushed into coarse powder, 2-10 times the amount of water is added, and the mixture is stirred and extracted at 37°C. After centrifugation, the supernatant is pre-filtered and sterilized through a filter membrane, then concentrated by ultrafiltration. The concentrate is then freeze-dried and crushed to obtain leech freeze-dried powder for later use.

[0033] The preferred technical solution in step A is as follows: the water volume is 6 times the volume of the filter, the stirring time is 20 hours, and the stirring speed is 100 r / min. The centrifugation time is 30 minutes, and the centrifugation speed is 6000 r / min. Pre-filtration is performed using a 1 μm pore size membrane. Sterilization is achieved through filtration using a 0.2 μm pore size membrane. The ultrafiltration membrane used for concentration has a cutoff specification of 6-10 kDa.

[0034] B. Extract the three herbs, Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus, by reflux with 2-10 times the amount of 65-95% ethanol. Filter and concentrate the reflux liquid to obtain the ethanol concentrate. Add 2-6 times the amount of water to the residue of the raw herbs, decoct and extract, filter, and concentrate the filtrate to obtain the aqueous concentrate. Combine the ethanol concentrate and the aqueous concentrate, spray dry, and obtain a mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus.

[0035] The preferred technical solution in step B is as follows: the amount of refluxed alcohol solution is 6 times, the concentration of alcohol solution is 80%, the number of refluxes is 2, and the reflux time is 2 hours; the amount of water used to extract the residue is 4 times, the number of extractions is 1, and the extraction time is 1 hour; preferably, the relative density of the alcohol concentrate or water concentrate at 50°C is 11-1.3, more preferably 1.2.

[0036] C. Mix the lyophilized leech powder obtained in step A with the mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus obtained in step B evenly, add an appropriate amount of dextrin and mix well, then granulate by dry method to obtain granules; compress the granules into tablets and coat them with enteric coating to obtain tablets; or fill the granules into enteric-coated capsules to obtain capsules.

[0037] In another embodiment, the dosage form of the present invention is a pill, and its preparation method includes the following steps:

[0038] A. Leeches are crushed into coarse powder, 2-10 times the amount of water is added, and the mixture is stirred and extracted at 37°C. After centrifugation, the supernatant is pre-filtered and sterilized through a filter membrane, then concentrated by ultrafiltration. The concentrate is then freeze-dried and crushed to obtain leech freeze-dried powder for later use.

[0039] The preferred technical solution in step A is as follows: the amount of water used is 6 times, the stirring time is 20 hours, the stirring speed is 100 r / min, the centrifugation time is 30 minutes, the centrifugation speed is 6000 r / min, the 1 μm pore size membrane is used for pre-filtration, the 0.2 μm pore size membrane is used for filtration and sterilization, and the ultrafiltration membrane for concentration has a cutoff specification of 6-10 kDa.

[0040] B. Extract the three herbs, Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus, by reflux with 2-10 times the amount of 65-95% ethanol. Filter and concentrate the reflux liquid to obtain the ethanol concentrate. Add 2-6 times the amount of water to the residue of the raw herbs and decoct to extract. Filter and concentrate the filtrate to obtain the aqueous concentrate. Combine the ethanol concentrate and the aqueous concentrate, spray dry, and obtain a mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus.

[0041] The preferred technical solution in step B is as follows: the amount of refluxed alcohol solution is 6 times, the concentration of alcohol solution is 80%, the number of refluxes is 2, and the reflux time is 2 hours; the amount of water used to extract the residue is 4 times, the number of extractions is 1, and the extraction time is 1 hour; preferably, the relative density of the alcohol concentrate or water concentrate at 50°C is 11-13, more preferably 1.2.

[0042] C. Mix the freeze-dried powder of leeches obtained in step A and the mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus obtained in step B evenly, add dextrin, mix well to make pills, dry them, coat them with enteric coating and polish them to obtain pills.

[0043] During the clinical application of Chuanzhi Tongluo, the inventor found that it has an obvious effect on the treatment of cerebral small vessel disease. Subsequently, it was confirmed by relevant pharmacodynamic studies that Chuanzhi Tongluo is an effective prescription for the treatment of cerebral small vessel disease: it can effectively improve general behavioral performance and has an improvement effect in case of cognitive function impairment. It has a protective effect on the nervous system, and has no damage to liver and kidney functions during the treatment process, and has a significant effect on the treatment of cerebral small vessel disease. The specific implementation manners of the treatment of cerebral small vessel disease according to the present invention will be explained in detail below. Specific implementation manners

[0044] The present invention will be further described below in combination with tables and specific implementation manners so that the public can have a more in-depth understanding of the invention content. It is not a limitation of the present invention. Any equivalent substitution in the art according to the disclosed content of the present invention belongs to the protection scope of the present invention.

[0045] 1 Instruments and materials:

[0046] The test substance is Chuanzhi Tongluo Capsule (produced by Lunan Hepu Pharmaceutical Co., Ltd.); Shu Tai 50-Xylazine Hydrochloride Injection, Shu Tai 50, batch number: 7UX8A, purchased from Virbac S.A.; Xylazine Hydrochloride, batch number: 20201118, purchased from Jilin Huamu Health Products Co., Ltd.

[0047] 2 Experimental animals:

[0048] Healthy male SPF-grade SD rats, with a body weight of 250 - 300 g, provided by Lunan Pharmaceutical Group Co., Ltd., animal license number: SYXK (Lu) 20180008. All animals were adaptively fed for 2 weeks before the experiment, the temperature was controlled at (23 - 25) °C, the relative humidity was (40 - 60)%, natural light, good ventilation, and the animals were allowed to eat, drink water and move freely. Before the experiment, all adaptively fed animals were tested for limb balance, and 40 animals with flexible limb movement and no movement coordination障碍 were selected.

[0049] 3 Experimental methods

[0050] 3. Installing the mold and administering medicine

[0051] Preparation of cerebral small vessel disease model [[ID=3`1]]

[0052] Construction of rat cerebral small vessel model

[0053] The in vitro injection method using syngeneic microemboli was employed. Autologous thrombus preparation: Blood was collected from the left ventricle of rats and completely dried in an 80℃ drying oven. The dried blood clots were finely ground and passed through a 200μm sieve to prepare emboli. A 10g / L suspension was prepared with saline for modeling. Rats were anesthetized by intraperitoneal injection of 50-xeraphosphine hydrochloride injection (0.4mL / kg), fixed in a supine position, and the neck fur was removed. After routine skin disinfection, a midline incision was made, and the left common carotid, internal carotid, and external carotid arteries were bluntly dissected and exposed. The cardiac end of the common carotid artery was temporarily clamped, and the distal end of the external carotid artery was ligated. 0.3mL of turbid fluid was retrogradely injected into the internal carotid artery from the proximal end of the external carotid artery. The common carotid artery was immediately opened to restore blood flow, allowing the emboli to pass through the internal carotid artery into the anterior and middle cerebral arteries and their collateral branches. The proximal end of the external carotid artery was ligated, and the anterior neck incision was sutured and disinfected. Successful model establishment was defined as the appearance of epileptic seizures, limb paralysis, and abnormal movements in rats, while also recording rat mortality. Thirty rats were randomly selected for model establishment. Of the 30 rats, 3 died during surgery and 1 died post-surgery, resulting in a model establishment success rate of 86.7%. The remaining 26 rats successfully established the model.

[0054] 3.2 Grouping and administration of experimental animals

[0055] Twenty-six rats that successfully developed the model were randomly divided into two groups: a model group and a leech-treated group (n=13 each). Rats not involved in the model were placed in the normal control group. Rats were administered physiological saline three times daily (morning, noon, and evening, 4 hours apart) at a dose of 50 mL / kg body weight. The treatment group was administered leech-treated solution at a dose of 65 mL / kg body weight. This treatment was continued for four weeks. During the experiment, the animals were provided with normal environmental conditions, and all animals were allowed free movement and food. They were weighed every other day, and the dosage was adjusted as needed based on changes in body weight.

[0056] Example 1: Effects of Hirudo medicinalis on Morris water maze in rats with cerebral small vessel disease.

[0057] 1. Morris water maze experiment

[0058] Rats in each group underwent the Morris water maze test at 7, 14, and 28 days after modeling to assess their learning and memory functions. The water maze was a 120cm diameter cylinder, painted black, filled with opaque milky-white water at a depth of 40cm. Four entry points (A (East), B (South), C (West), and D (North)) were marked on the maze walls, dividing the pool into four quadrants. A 9cm diameter, 39cm high circular transparent platform was placed 33cm from the center of each quadrant, with the top of the platform 1cm below the water surface. The Morris water maze test included: ① Escape test. Experimental rats were placed in the water from entry points A, B, C, and D, facing the pool wall. The time required for them to find and climb onto the platform within 2 minutes (escape latency) was recorded. If the rats did not find the platform within 2 minutes, they were guided to the platform, stayed there for 10 seconds, and then returned to their cages. The escape latency at this time was recorded as 120 seconds. The test was repeated 4 times for each rat within 1 day, and the average value was used for subsequent analysis. The latency is expressed as an average value in seconds.

[0059] ② In the spatial exploration experiment, the four platforms in the pool were first removed. Then, rats from each group were placed into the water from points A, B, C, and D on the pool wall. The number of times the rats crossed the original platform area within 2 minutes was observed. The test was repeated twice for each rat within 1 day, and the average value was included in the subsequent analysis as the number of times the platform was crossed, in units of times per minute.

[0060] 2. Results

[0061] The escape latency and number of times rats crossed platforms in the Morris water maze were recorded in each group. The results are shown in Table 1.

[0062] Table 1. Latency period and number of platform crossings in the Morris water maze for rats in each group

[0063]

[0064]

[0065] Note: Compared with the model group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0066] Table 1 shows that, compared with the control group, the escape latency in the Morris water maze was significantly prolonged (P<0.01) and the number of times rats crossed platforms was significantly reduced (P<0.05) 7, 14 and 28 days after modeling; compared with the model group, the escape latency in the Morris water maze was significantly shortened (P<0.01) and the number of times rats crossed platforms was significantly increased (P<0.05) 7, 14 and 28 days after modeling in the leech-treated group.

[0067] Example 2: Effects of Hirudo medicinalis on the platform jumping test in a rat model of cerebral small vessel disease.

[0068] 1. Diving platform experiment

[0069] Rats in each group underwent a jumping platform test on day 26 of modeling. The experimental setup consisted of an acrylic box with a copper grid at the bottom and a 3.5 cm high, 6.5 cm diameter rubber mat inside, serving as a safety platform for the rats to avoid electric shocks. During the experiment, the rats were placed in the box and allowed to acclimatize for 5 minutes, followed by the application of 36V AC current. The reaction time to jump onto the rubber mat after receiving electrical stimulation and the number of incorrect jumps within 3 minutes were recorded as learning indicators. On day 27 of modeling, the test was repeated. The rats were first placed in the box for 3 minutes, then placed on the rubber mat. The latency to jump off the mat for the first time and the number of jumps within 3 minutes were recorded as memory indicators.

[0070] 2. Results

[0071] The latency and number of errors in the jumping test for each group of rats are shown in Table 2.

[0072] Table 2. Reaction time, experimental latency, and number of errors of rats in each group when jumping off the platform.

[0073]

[0074] Note: Compared with the model group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0075] Table 2 shows that, compared with the control group, the model group rats had significantly increased reaction time and number of errors within 3 minutes (P<0.01) and significantly shortened latency (P<0.01); compared with the model group rats, the leech-treated group rats had significantly reduced number of errors (P<0.05) and significantly increased latency (P<0.05).

[0076] The above experimental results indicate that the leech-based treatment for cerebral small vessel disease (CBD) in rats prepared according to this invention can effectively improve the general behavioral performance of these rats. Morris water maze test results showed that the escape latency of the rats significantly increased, while the number of platform crossings significantly decreased. The platform jumping test results showed that the reaction time and the number of errors within 3 minutes significantly increased, while the latency significantly shortened, indicating a significant decline in cognitive function in the rats. Simultaneously, the Morris water maze test results showed that the escape latency of the leech-based treatment group was significantly shortened, and the number of platform crossings significantly increased. The platform jumping test results showed that the number of errors and the latency significantly increased in the leech-based treatment group. Therefore, leech-based treatment can improve the cognitive function of rats with CBD, demonstrating a significant therapeutic effect on CBD.

Claims

1. The use of the leech-infused collaterals-clearing composition in the preparation of a drug for improving cognitive function in cerebral small vessel disease, wherein the leech-infused collaterals-clearing composition is made from the following components in parts by weight: Leech 600 parts by weight, Ligusticum chuanxiong 600 parts by weight Salvia miltiorrhiza 400 parts by weight, Astragalus membranaceus 400 parts by weight; The preparation method of the leech-infused collaterals-clearing composition is as follows: A. Leeches are crushed into coarse powder, 2-10 times the amount of water is added, and the mixture is stirred and extracted at 37°C. After centrifugation, the supernatant is pre-filtered and sterilized through a filter membrane, then concentrated by ultrafiltration. The concentrate is then freeze-dried and crushed to obtain leech freeze-dried powder for later use. The water volume was 6 times the normal volume, the stirring time was 20 hours, the stirring speed was 100 r / min, the centrifugation time was 30 minutes, and the centrifugation speed was 6000 r / min. 1 μm pore size membrane pre-filtration was used. B. Extract the three herbs, Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus, by reflux with 2-10 times the amount of 65-95% ethanol. Filter and concentrate the reflux liquid to obtain the ethanol concentrate. Add 2-6 times the amount of water to the residue of the raw herbs, decoct and extract, filter, and concentrate the filtrate to obtain the aqueous concentrate. Combine the ethanol concentrate and the aqueous concentrate, spray dry, and obtain a mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus. The volume of refluxed alcohol solution was 6 times, the concentration of alcohol solution was 80%, the reflux was performed twice, and the reflux time was 2 hours; the volume of water used to extract the residue was 4 times, the extraction was performed once, and the extraction time was 1 hour. C. Mix the lyophilized leech powder obtained in step A with the mixed powder of Ligusticum chuanxiong, Salvia miltiorrhiza, and Astragalus membranaceus obtained in step B evenly, add an appropriate amount of dextrin and mix well, then granulate by dry method to obtain granules; compress the granules into tablets and coat them with enteric coating to obtain tablets; or fill the granules into enteric-coated capsules to obtain capsules.

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