Traditional Chinese medicine composition for promoting angiogenesis after cerebral arterial thrombosis and application thereof
By combining traditional Chinese medicine compositions that 'tonify the kidneys and replenish essence' with 'activate blood circulation and resolve phlegm', the problem of existing treatments failing to promote neurovascular regeneration after ischemic stroke has been solved, achieving comprehensive improvement in neurological function recovery and a cost-effective treatment plan.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-04
- Publication Date
- 2026-04-10
AI Technical Summary
Existing Western and traditional Chinese medicine treatments for neurological function recovery after ischemic stroke have limitations. Western medicine has a single effect and cannot promote repair, while traditional Chinese medicine focuses on clearing the meridians but fails to replenish the material basis of brain damage, resulting in a bottleneck in efficacy and a lack of effective drugs to promote neurovascular regeneration.
This product utilizes a traditional Chinese medicine composition based on the holistic theory of "kidney-network-marrow" in Traditional Chinese Medicine. By combining "tonifying the kidney and replenishing essence" with "activating blood circulation and resolving phlegm," it promotes angiogenesis and is prepared into decoctions, granules, tablets, capsules, oral liquids, and extracts. The specific formula includes Rehmannia glutinosa, Rhodiola rosea, Acorus tatarinowii, Cornus officinalis, Lycium barbarum, Cuscuta chinensis, Achyranthes bidentata, and Shenqu (medicated leaven), which are used to improve cerebral blood circulation and nerve function.
It fundamentally promotes neurovascular regeneration, breaks through the bottleneck of therapeutic efficacy, improves cerebral blood flow perfusion, and enhances the recovery effect of nerve function. It is suitable for the "kidney deficiency, blood stasis, and phlegm obstruction" syndrome of ischemic stroke, and has broad clinical application prospects and is economical.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke and a preparation method and application thereof. BACKGROUND
[0002] Global stroke risk research shows that the stroke risk of Chinese population ranks first in the world, and about 2 out of 5 Chinese people may have a stroke after the age of 25. Globally, stroke is also a major cause of death and economic burden, among which ischemic stroke is the primary threat due to its high incidence, disability rate and recurrence rate. The most effective thrombolytic and recanalization therapy is still not fully applied due to strict time window and medical condition limitations. For some patients, even if they receive treatment, there is still a risk of recanalization failure or complications such as hemorrhage, and ultimately permanent neurological deficits such as hemiplegia, cognitive and swallowing disorders, which brings heavy burden to patients, families and society. In addition to ultra-early thrombolytic drugs (alteplase, tenecteplase, etc.) treatment, the drug treatment of ischemic stroke in the later stage of western medicine is mainly brain protective agents, anti-platelet drugs (such as aspirin, clopidogrel) and drugs for stabilizing plaques (such as atorvastatin, rosuvastatin, etc.). However, various brain protective agents in the acute phase have almost ended in the absence of clinical evidence. Anti-platelet drugs and drugs for stabilizing plaques only have the effect of preventing the recurrence of ischemic stroke, and have no effect on the recovery of neurological function of ischemic stroke, and have many side effects with long-term application.
[0003] Studies have shown that the key to the recovery of neurological function after cerebral ischemia lies in the repair and remodeling of neurovascular, angiogenesis and neuroregeneration (including neurogenesis and axon remodeling) are interdependent, and together constitute the functional whole of "neurovascular unit (NVU)" which is composed of neurons, glial cells, vascular cells and basement membrane. Angiogenesis is the starting link and structural basis of NVU repair, and its degree directly determines the level of neural repair and patient prognosis. Improving angiogenesis and improving cerebral blood perfusion are the core strategies to promote the recovery of neurological function. Brain tissue initiates spontaneous neurovascular repair after ischemic injury and throughout the entire course, promoting endogenous neurovascular regeneration and remodeling, especially angiogenesis, which is the only long-term effective treatment method not limited by time window. However, this self-healing ability is far from meeting the clinical rehabilitation needs. Therefore, exploring methods to promote neurovascular regeneration and repair is the fundamental strategy to break through the bottleneck of neurological function recovery, and has become the focus and difficulty in the field of global stroke research.
[0004] Traditional Chinese medicine (TCM) compound preparations have the characteristics of multiple components, multiple pathways, and multiple targets, and have small side effects. They have unique advantages in the treatment of ischemic stroke. The existing TCMs for ischemic stroke are mostly based on the theory of 'qi deficiency and blood stasis', so the treatment is mainly focused on tonifying qi and activating blood and removing blood stasis. These preparations have certain effects on improving blood circulation and eliminating pathological products, but their action levels are limited. They mainly focus on 'dredging' the collaterals blocked by blood stasis, but they pay little attention to the most fundamental damage after stroke, which is 'kidney essence deficiency' leading to 'brain marrow deficiency', i.e. the damage and repair of brain tissue itself. According to the TCM theory of 'kidney storing essence, essence generating marrow, and marrow nourishing brain', kidney essence is the material basis for the generation of brain marrow, and collaterals are the functional pathway for the nourishment of brain marrow. The existing TCMs generally 'treat collaterals but not marrow, dredge vessels but not fill essence', ignoring the fundamental aspect of 'tonifying kidney and filling essence' to promote brain marrow regeneration. This structural deficiency in treatment leads to a significant 'ceiling effect' in their efficacy.
[0005] The disadvantages of the above-mentioned prior art and their causes are analyzed as follows: 1) Limitations of existing Western medicine treatment: single action, unable to promote repair Disadvantages: The current mainstream Western medicine treatment for ischemic stroke (antiplatelet drugs + statins) can only prevent stroke recurrence, but has no effect on the recovery of damaged nerve function. The once-expected brain protective agents have generally failed in clinical trials.
[0006] Reason analysis: The recovery of nerve function after stroke depends on the overall repair of the neural vascular unit (NVU), a complex system involving multiple interrelated processes such as angiogenesis and nerve regeneration. The existing Western medicine has a single target, which cannot cover the complex pathological process involving multiple links and multiple targets, thus it is difficult to effectively promote the fundamental recovery of nerve function.
[0007] 2) Limitations of existing TCM treatment: treating symptoms but not the root cause, with a 'ceiling' in efficacy Disadvantages: The existing TCMs on the market are mostly based on the theory of 'tonifying qi and activating blood, removing blood stasis', which can improve blood circulation to some extent, but their efficacy in promoting nerve function recovery has a significant bottleneck ('ceiling effect'), making it difficult to meet the clinical rehabilitation needs.
[0008] Reason analysis: This type of treatment focuses on 'dredging collaterals' and 'eliminating pathogenic factors' (removing blood stasis), but generally ignores the fundamental pathogenesis of 'kidney essence deficiency and brain marrow deficiency' in stroke. The existing TCMs 'treat collaterals but not marrow, dredge vessels but not fill essence', and fail to provide a material basis for the repair of nerve tissue from the root cause, resulting in limited repair potential and inability to achieve comprehensive functional rehabilitation.
[0009] 3) Comprehensive technical gap: Lack of innovative traditional Chinese medicine for overall repair of nerve and blood vessels with "promoting angiogenesis" as the core efficacy Disadvantages: As of now, neither in the field of Western medicine nor in the field of traditional Chinese medicine, there is a drug with definite efficacy and specially used for promoting the repair of nerve and blood vessels after ischemic stroke.
[0010] Reason analysis: A successful repair strategy must organically combine "curing the root" (tonifying kidney and essence to nourish the brain marrow) with "curing the symptom" (activating blood and resolving phlegm to dredge collaterals). The existing technology fails to design drugs based on the "kidney-collaterals-marrow" theory, and thus cannot promote angiogenesis (improve the microenvironment) while consolidating the material basis for the repair of brain marrow, so it is difficult to break through the bottleneck of the recovery of nerve function.
[0011] In summary, there is an urgent need for a traditional Chinese medicine preparation based on the "kidney-collaterals-marrow" theory, which organically combines "tonifying kidney and essence" to consolidate the root with "activating blood and resolving phlegm" to dredge collaterals, and clearly takes "promoting angiogenesis" as the core efficacy. SUMMARY
[0012] In view of the deficiencies in the prior art, the purpose of the present application is to provide a traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke. This traditional Chinese medicine compound preparation based on the "kidney-collaterals-marrow" theory of traditional Chinese medicine organically combines "tonifying kidney and essence" to consolidate the root with "activating blood and resolving phlegm" to dredge collaterals, breaks through the limitation of existing therapies that can only prevent recurrence but cannot promote the recovery of nerve function, and traditional Chinese medicine therapies that have a "ceiling" in efficacy. The innovative traditional Chinese medicine composition for overall repair of nerve and blood vessels with "promoting angiogenesis" as the core efficacy has the characteristics of low price, convenience in preparation and taking, and good efficacy, so as to meet the urgent needs of long-term rehabilitation therapy for patients with ischemic stroke.
[0013] The purpose of the present application is also to provide a preparation method and application of the above-mentioned traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke.
[0014] The technical solution of the present application is as follows: The traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke comprises the following raw medicinal materials in the following weight proportions: Radix Rehmanniae Preparata 10-30 parts, Rhodiolae Crenulatae 5-20 parts, Rhizoma Acori Graminei 5-15 parts, Fructus Corni 5-15 parts, Fructus Lycii 5-20 parts, Semen Leonuri 5-20 parts, Radix Cyathulae 5-20 parts, and Massa Medicata Fermentata 5-20 parts.
[0015] Further, the traditional Chinese medicine composition comprises the following raw medicinal materials in the following weight proportions: Radix Rehmanniae Preparata 10-15 parts, Rhodiolae Crenulatae 10-20 parts, Rhizoma Acori Graminei 6-12 parts, Fructus Corni 8-12 parts, Fructus Lycii 8-12 parts, Semen Leonuri 8-12 parts, Radix Cyathulae 8-12 parts, and Massa Medicata Fermentata 10-20 parts.
[0016] The preparation method of the traditional Chinese medicine composition for promoting post-ischemic stroke angiogenesis, the traditional Chinese medicine composition is a decoction, and the preparation method of the decoction is as follows: The raw medicinal materials are weighed according to the proportion, and then soaked in 5-6 times of drinking water; After boiling with strong fire, slow boiling is performed with weak fire, and then the filtrate is collected by filtering through a 200-mesh screen; The residue is boiled again with 3-4 times of water, and then filtered in the same way; The filtrates of the two times are combined, and the decoction is obtained.
[0017] The preparation method of the traditional Chinese medicine composition for promoting post-ischemic stroke angiogenesis, the traditional Chinese medicine composition is a granule, and the preparation method of the granule is as follows: The raw medicinal materials are weighed according to the proportion, and then soaked in 6-10 times of drinking water; After boiling with strong fire, slow boiling is performed with weak fire, and then the filtrate is collected by filtering through a 200-mesh screen; The residue is boiled again with 4-8 times of water, and then filtered in the same way; The filtrates of the two times are combined, and then concentrated to a clear paste at 60 DEG C under reduced pressure; Fluidized bed granulation is adopted; Boiling drying is performed until the moisture content is less than or equal to 5%, the granules are integrated, and then packaged, and the granules are obtained.
[0018] The preparation method of the traditional Chinese medicine composition for promoting post-ischemic stroke angiogenesis, the traditional Chinese medicine composition is a tablet, and the preparation method of the tablet is as follows: The raw medicinal materials are weighed according to the proportion, and then soaked in 6-10 times of water; After boiling with strong fire, slow boiling is performed with weak fire, and then the filtrate is collected by filtering through a 200-mesh screen; The residue is boiled again with 4-8 times of water, and then filtered in the same way; the filtrates of the two times are combined; The extract is concentrated to a thick paste, and then vacuum dried and crushed; Microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate are added and mixed; Direct compression is adopted to compress the tablet.
[0019] The preparation method of the traditional Chinese medicine composition for promoting post-ischemic stroke angiogenesis, the traditional Chinese medicine composition is a capsule, and the preparation method of the capsule is as follows: The raw medicinal materials are crushed through a 100-mesh screen, and then accurately weighed and mixed according to the proportion; Povidone K30 ethanol solution is added to prepare soft material, and then granulated through a 20-mesh screen; Drying, integration, addition of microcrystalline silica and mixing; Filling with a capsule shell, and the capsule is obtained.
[0020] The preparation method of the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke is as follows: The raw medicinal materials are weighed according to the proportion, and then soaked in 6-10 times of water; After boiling with strong fire, slow boiling is performed with weak fire, and then the filtrate is collected by filtering through a 200-mesh screen; The residue is boiled again with 4-8 times of water, and then filtered in the same way; The filtrates obtained in the two times are combined, and then concentrated to an appropriate amount under reduced pressure at 60-65°C; Water is added to reach the theoretical amount; Filling, sterilization with steam circulation at 100°C for 30 minutes, and then an oral solution is obtained.
[0021] The preparation method of the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke is as follows: The raw medicinal materials are weighed according to the proportion, and then soaked in 6-10 times of water; Heating and reflux extraction is performed twice; The extract is combined, and then filtered through a 200-mesh filter cloth to remove the residue; The filtrate is concentrated to a thick paste under reduced pressure, and then mixed with an appropriate amount of dextrin; Vacuum drying is continued until the water content is less than or equal to 5%, and then the dried extract is obtained by pulverizing into fine powder.
[0022] The application of the traditional Chinese medicine composition or the traditional Chinese medicine composition prepared by any one of the preparation methods described above in the preparation of a medicine for preventing and / or treating ischemic stroke.
[0023] Further, the traditional Chinese medicine composition combines the functions of “tonifying kidney and filling essence” and “activating blood and resolving phlegm” to promote angiogenesis after ischemic stroke, improve blood vessel density, and improve cerebral blood flow and nerve function; the traditional Chinese medicine composition is used for preventing and / or treating the “kidney deficiency, blood stasis and phlegm obstruction” type of ischemic stroke.
[0024] Ischemic stroke belongs to the category of "stroke" in traditional Chinese medicine, and its core pathogenesis is deficiency of liver and kidney Yin essence, and the pathological products of wind, fire and phlegm are derived from it, leading to obstruction of brain collaterals and damage to brain marrow. The fundamental reason for the delayed symptoms in the recovery period is "deficiency of marrow", and the filling of marrow is closely related to kidney essence, forming a vicious cycle of "deficiency-stasis-phlegm", which is highly consistent with the damage of neurovascular unit in modern medicine. Based on the theory of "kidney-collaterals-marrow", deficiency of kidney essence leads to insufficient biochemistry, and blood stasis and phlegm further obstruct brain collaterals and damage brain marrow, so the treatment should be based on tonifying kidney and filling essence to achieve the overall repair goal of "essence filled blood sufficient, blood sufficient collaterals prosperous, and collaterals prosperous marrow growing". However, the current clinical use of Chinese patent medicines is mainly based on the theory of "qi deficiency and blood stasis", focusing on tonifying qi and activating blood, removing stasis and dredging collaterals, which can improve brain blood circulation, but there are limitations of "treating collaterals but not marrow, dredging vessels but not filling essence", and it cannot fundamentally solve the problem of brain marrow deficiency caused by kidney essence deficiency, and the effect has obvious "ceiling effect". In view of this treatment gap, the present application combines the theory of "kidney-brain correlation" with clinical practice, and proposes a basic treatment method of "tonifying kidney, activating blood and resolving phlegm", and creates a Chinese medicine composition, which is used for treating ischemic stroke with kidney deficiency, blood stasis and phlegm obstruction in the Department of Neurology of Jiangsu Provincial Hospital of Traditional Chinese Medicine, and is modified from Zuogui Pill. The composition includes Radix Rehmanniae Preparata, Rhodiolae Crenulatae, Chuanxiong Rhizoma, Caulis Lonicerae, Fructus Lycii, Herba Taxilli, Radix Cyathulae and Herba Fructus, and Radix Rehmanniae Preparata is the monarch drug for nourishing Yin and filling essence. Rhodiolae Crenulatae and Chuanxiong Rhizoma are the ministerial drugs for tonifying qi and activating blood. Caulis Lonicerae, Fructus Lycii, Herba Taxilli and Radix Cyathulae are the auxiliary drugs for assisting kidney and tonifying liver, strengthening muscles and nourishing marrow. Herba Fructus is the guide drug for regulating spleen and harmonizing the center. The drugs work together to tonify kidney and fill essence, activate blood and dredge collaterals, and resolve phlegm and open orifices. The main purpose of the whole prescription is to tonify kidney and activate blood to dredge brain collaterals, resolve blood by tonifying essence, and activate blood to dredge collaterals, so as to promote angiogenesis and improve brain blood perfusion.
[0025] Specifically, the beneficial effects of the present application are as follows: 1) Strong pathogenesis targeting, realizing the fundamental treatment breakthrough of "treating both the root and the branch": The present application breaks through the limitation of the existing Chinese patent medicine mainly targeting "qi deficiency and blood stasis" and focusing on "dredging collaterals and removing stasis". By "tonifying kidney and filling essence" to treat the root, it directly targets the fundamental pathogenesis of "deficiency of kidney essence and deficiency of marrow", and at the same time, it combines "activating blood and resolving phlegm" to treat the branch, clearing the pathological products of "stasis and phlegm". This treatment method of "tonifying kidney and filling essence, activating blood and resolving phlegm" realizes the fundamental change from simple "dredging collaterals" to "nourishing brain marrow" and "dredging collaterals" at the same time, aiming to break the vicious cycle of "deficiency-stasis-phlegm" and provide material basis and functional pathway for brain tissue repair, thereby breaking through the "ceiling effect" of existing treatment.
[0026] 2) The prescription is scientific and reasonable, taking into account the efficacy and clinical applicability: The prescription is based on the classical prescription "Zuogui Pill" and takes its core of nourishing yin and kidney and filling essence and marrow. The turtle shell glue and deer horn glue in the original prescription, which can cause greasy and hinder the stomach, are removed to avoid the side effects of the tonifying medicine that may hinder the function of the spleen and stomach, improve the patient's tolerance and medication compliance. At the same time, the red ginseng is innovatively added to invigorate the qi and promote blood circulation, the nine-section rhizoma belamcanda is added to resolve phlegm and open the orifices, and the six gods are added to invigorate the spleen and stomach, so that the whole prescription has the functions of invigorating the spleen and stomach, resolving phlegm and opening the orifices, and invigorating the spleen and stomach, and the prescription is rigorous, and the tonifying and eliminating are not contradictory, which is more suitable for long-term treatment of patients with ischemic stroke.
[0027] 3) The effect is clear, and it is highly consistent with the modern medical repair mechanism: The invention aims to "tonify the kidney and fill the essence, promote blood circulation to remove meridian obstruction", and ultimately achieve the purpose of "promoting angiogenesis", improving brain blood perfusion, and repairing brain marrow damage. This "tonifying kidney and filling essence-promoting blood circulation to remove meridian obstruction-promoting angiogenesis" path is highly consistent with the advanced concept of promoting "neurovascular unit" repair in modern medicine, and clearly defines the product as promoting endogenous angiogenesis and nerve repair as the core function, filling the gap in the current market for traditional Chinese medicine preparations that lack "tonifying kidney and filling essence" and clear "promoting angiogenesis" meridian function.
[0028] 4) The clinical application prospect is broad, and the drug economics advantage is significant: The invention accurately corresponds to the core syndrome of "kidney deficiency, blood stasis and phlegm obstruction" in the recovery period of stroke, and the clinical demand is huge. The selected medicinal materials are commonly used in clinical practice, widely available, and relatively low in price, effectively controlling the cost of raw materials. This advantage makes the traditional Chinese medicine composition of the invention have significant drug economics value in future large-scale production and clinical promotion, not only more comprehensive and in-depth in effect, but also can effectively reduce the economic burden of patients and the medical insurance system, and has high popularization potential in primary medical institutions, with broad market application prospect. BRIEF DESCRIPTION OF DRAWINGS
[0029] Figure 1 is the arterial spin labeling (ASL) cerebral perfusion image of the ischemic stroke patient in Example 2: (A) DWI shows left basal ganglia infarction; (B) ADC imaging shows left basal ganglia infarction; (C) ASL imaging before treatment shows reduced blood perfusion in the left cerebral hemisphere; (D) 90 days after treatment, ASL shows that the blood perfusion in the left cerebral hemisphere has recovered compared with before.
[0030] Figure 2 The detection results of the irregular stair walking experiment of Example 2: (A) model control group; (B) low-dose traditional Chinese medicine treatment group; (C) high-dose traditional Chinese medicine treatment group; (D) diltiazem treatment group.
[0031] Figure 3Detection results of the tape removal experiment of Example 2: (A) model control group; (B) low-dose traditional Chinese medicine treatment group; (C) high-dose traditional Chinese medicine treatment group; (D) butylphthalide treatment group.
[0032] Figure 4 Glut-1 / BrdU double-labeled immunofluorescence staining in the infarcted lesion peripheral region in the detection experiment of the number of neovascularization and vascular density of Example 2: (A) model control group; (B) low-dose traditional Chinese medicine treatment group; (C) high-dose traditional Chinese medicine treatment group; (D) butylphthalide treatment group.
[0033] Figure 5 BrdU / Glut-1 double-labeled blood vessel counting in the detection experiment of the number of neovascularization and vascular density of Example 2: (A) model control group; (B) low-dose traditional Chinese medicine treatment group; (C) high-dose traditional Chinese medicine treatment group; (D) butylphthalide treatment group.
[0034] Figure 6 Glut-1-labeled total blood vessel counting in the detection experiment of the number of neovascularization and vascular density of Example 2: (A) model control group; (B) low-dose traditional Chinese medicine treatment group; (C) high-dose traditional Chinese medicine treatment group; (D) butylphthalide treatment group. DETAILED DESCRIPTION
[0035] The application will be further described below in conjunction with the drawings and examples.
[0036] Example 1: Preparation of various dosage forms of the traditional Chinese medicine composition in the application
[0037] 1.1 Preparation of decoction Prescription: Radix Rehmanniae 10 parts, Rhodiola 15 parts, Rhizoma Typhonii 10 parts, Fructus Corni 10 parts, Fructus Lycii 10 parts, Semen Leonuri 10 parts, Radix Cyathulae 10 parts, Massa Medicata Fermentata 15 parts.
[0038] Preparation process: the above eight kinds of medicinal materials are soaked in 5-6 times the amount of drinking water for 20-40 minutes; After boiling with strong fire, slow boiling is carried out with weak fire for 1 hour, and the filtrate is collected by filtering with a 200-mesh screen; The residue is added with 3-4 times the amount of water, and decocted for 1 hour, and filtered in the same way; The filtrates of the two times are combined, and about 300 ml of decoction is obtained.
[0039] 1.2 Preparation of granules Prescription: the same as that of Example 1.
[0040] Preparation process: the above eight kinds of medicinal materials are soaked in 6-10 times the amount of drinking water for 20-40 minutes; After boiling with strong fire, slow boiling is carried out with weak fire for 1 hour, and the filtrate is collected by filtering with a 200-mesh screen; Decoction 1 hour, filter with the same method; Combine the two filtrates, concentrate under reduced pressure at 60°C (-0.05~-0.08 MPa) to a clear paste with a relative density of 1.20±0.02 at 60°C; Fluidized bed granulation, inlet air temperature 90-100°C, outlet air temperature 40-50°C, material temperature 60-70°C, atomization pressure 0.15-0.20 MPa, sample feeding speed 70-150 r / min; Fluidized bed granulation, inlet air temperature 90-100°C, outlet air temperature 40-50°C, material temperature 60-70°C, atomization pressure 0.15-0.20 MPa, sample feeding speed 70-150 r / min;
[0041] 1.3 Tablet preparation Prescription: Radix Rehmanniae 120g, Rhodiola 100g, Nine-node Acorus 80g, Fructus Corni 90g, Fructus Lycii 120g, Semen Momordicae 80g, Radix Cyathulae 120g, Six God's Decoction 100g.
[0042] Preparation process: Take the decoction pieces (raw materials described above) according to the proportion, Extract according to the method of Example 1.2 (soak with 6-10 times the amount of drinking water for 20-40 minutes; after boiling with strong fire, slowly decoct for 1 hour with weak fire, filter with a 200 mesh screen, collect the filtrate; add 4-8 times the amount of water to the residue, decoct for 1 hour, filter in the same way; combine the two filtrates); Concentrate the extract (60~65°C, -0.05~-0.08 MPa) to a thick paste with a relative density of 1.25±0.02 at 60°C, and vacuum dry (60~70°C, -0.04~-0.09 MPa), and pulverize into fine powder; Add 70-80g of microcrystalline cellulose, 10-20g of carboxymethyl starch sodium, and 2-3g of magnesium stearate, and mix well; Use direct compression method to compress into tablets with a diameter of 8mm and a tablet weight of 0.3g, 1000 tablets; tablet hardness measurement: 5.2±0.8 kg / cm² (n=10).
[0043] 1.4 Capsule preparation Prescription: Radix Rehmanniae 150g, Rhodiola 100g, Nine-node Acorus 120g, Fructus Corni 120g, Fructus Lycii 80g, Semen Momordicae 120g, Radix Cyathulae 80g, Six God's Decoction 200g.
[0044] Preparation process: Grind the medicinal materials through a 100 mesh sieve, and accurately mix according to the proportion; Add 150-200ml of 5% povidone K30 ethanol solution with a mass percentage of 5g / 100ml to make soft material, and granulate through a 20 mesh sieve; Dry at 60°C for 2 hours, granulate, and mix with 1% micro-powder silica gel; Fill with No.0 capsule shell, 0.4g per capsule, to obtain capsule; content uniformity test: ±3.5% (in line with the pharmacopoeia requirements).
[0045] 1.5 Preparation of oral liquid Prescription: Radix Rehmanniae 100g, Rhodiola 200g, Nine-node Acorus 60g, Fructus Corni 80g, Fructus Lycii 120g, Semen Trichosanthis 80g, Radix Cyathulae 120g, Six God's Decoction 100g.
[0046] Preparation process: extract according to the method of Example 1.2 (soak with 6-10 times the amount of drinking water for 20-40 minutes; after boiling with strong fire, slowly simmer with gentle fire for 1 hour, filter with a 200-mesh screen to collect the filtrate; add 4-8 times the amount of water to the residue, and decoct for 1 hour, and filter in the same way; combine the filtrates of the two times); Concentrate the extract under reduced pressure (60-65℃, -0.05~-0.08MPa) to about 900ml, and centrifuge; Add water to adjust the total volume to 1000mL, and fill into 10mL brown oral liquid bottles, sterilize with 100℃ flow steam for 30 minutes; pH value determination: 4.8±0.2 (n=5).
[0047] 1.6 Preparation of extract Prescription: same as the prescription of Example 1.
[0048] Preparation process: soak the above eight pieces of medicinal decoction pieces (the above raw materials) with 6-10 times the amount of water for 20-40 minutes; Heat and extract twice, the first time for 1 hour, and the second time for 1 hour; Combine the extract and filter with a 200-mesh cloth to remove the residue; Concentrate the filtrate under reduced pressure (60-65℃, -0.05~-0.08MPa) to a thick paste with a relative density of 1.28±0.02 (measured at 60℃), and add an appropriate amount of dextrin; Continue vacuum drying (60-70℃, -0.04~-0.09MPa) until the moisture content is ≤5%, to obtain the dry extract; extract yield determination: 28.5%±1.5% (n=3).
[0049] Example 2: Clinical efficacy observation 1) General information: all cases were from ischemic stroke patients treated in the outpatient and inpatient departments of the Encephalopathy Center of Jiangsu Province Hospital of Traditional Chinese Medicine from July 2024 to October 2025. A total of 116 patients were included in this clinical observation, including 52 cases in the control group and 64 cases in the traditional Chinese medicine treatment group. There was no significant difference in age, gender, and disease duration between the 2 groups (P>0.05).
[0050] 2) Treatment method: the patients in the control group are given the standard treatment scheme of Western medicine: the conventional application of anti-platelet drugs (aspirin or clopidogrel) and statins, and the selection of antihypertensive drugs, hypoglycemic drugs and the like according to the condition. The patients in the traditional Chinese medicine treatment group are treated with the decoction of Example 1 on the basis of the standard treatment of Western medicine, the decoction of Example 1 is decocted with water to 300 mL, and is taken twice a day in the morning and evening, 1 dose / d, and is continuously taken for 8 weeks.
[0051] 3) Comparison of NIHSS score and MBI score of nerve function: there is no obvious difference between the control group and the traditional Chinese medicine treatment group in the comparison of NIHSS score and MBI score before treatment (P>0.05); after treatment, the NIHSS scores of the patients in the two groups are lower than those before treatment, and the NIHSS score (5.07±1.28) of the traditional Chinese medicine treatment group is obviously lower than that (6.95±1.39) of the control group, and the difference is significant (P<0.05), while the MBI scores of the patients in the two groups are increased compared with those before treatment, and the MBI score (79.23±7.74) of the traditional Chinese medicine treatment group is obviously higher than that (62.19±8.23) of the control group, and the difference is statistically significant (P<0.05), and the specific comparison is shown in Table 1.
[0052] Table 1 Comparison of NIHSS and MBI scores before and after treatment (x±s, points)
[0053] Note: compared with the control group after treatment, #P<0.001; compared with the control group before treatment, ΔP>0.05; compared with before treatment, ▲P<0.05 4) Comparison of clinical treatment effect: after treatment, the total effective rate of the control group is 55.76%, and the total effective rate of the traditional Chinese medicine treatment group is 76.56%, and the curative effects of the two groups are obviously different (P<0.05, see Table 2 for details), which shows that the curative effect of the traditional Chinese medicine composition decoction of the application is obviously better than that of the conventional treatment of Western medicine.
[0054] Table 2 Comparison of clinical treatment effect
[0055] Note: compared with the control group after treatment, #P<0.05 5) Comparison of TCM syndrome scores: there is no obvious difference in the comparison of TCM syndrome scores of the patients in the two groups before treatment (P>0.05). After treatment, the TCM syndrome scores of the patients in the two groups are obviously lower than those before treatment (P<0.05), and the score (7.90±1.60) of the patients in the traditional Chinese medicine treatment group is lower than that (11.1±3.19) of the patients in the control group, and the difference is statistically significant (P<0.05), and the details are shown in Table 3.
[0056] Table 3 Comparison of TCM disease diagnosis scores of the patients in the two groups (x±s, points)
[0057] Note: Compared with the control group after treatment, P<0.001; compared with the control group before treatment, P>0.05; compared with before treatment, P<0.05
[0058] 6) Improvement of cerebral blood perfusion (arterial spin labeling imaging ASL evaluation): The cerebral blood flow (CBF) was detected by ASL imaging to evaluate the cerebral tissue blood perfusion and recovery of ischemic stroke patients. Figure 1 The magnetic resonance DWI (A) and ADC (B) imaging of the ischemic stroke patient showed left basal ganglia cerebral infarction, and the ASL imaging before treatment showed reduced blood perfusion of the left cerebral hemisphere (C), and the ASL imaging after 8 weeks of treatment showed that the blood perfusion of the left cerebral hemisphere was recovered (D).
[0059] Healthy side: There was no statistical difference in CBF before and after treatment in both groups (P>0.05), indicating that the treatment did not affect the perfusion of normal brain regions (Table 4).
[0060] Affected side: The CBF of both groups was improved after treatment (P<0.001), but the improvement in the traditional Chinese medicine treatment group was significantly greater than that in the control group, and the difference between the two groups was statistically significant (P<0.001, Table 5).
[0061] Affected side / healthy side CBF (rCBF): The rCBF of the traditional Chinese medicine treatment group increased from 0.5 to 0.9, close to the normal level, which was significantly better than that of the control group (0.5 to 0.7) (P<0.001, Table 6).
[0062] Reperfusion efficiency: The reperfusion efficiency of the traditional Chinese medicine treatment group was 87.5%, which was significantly higher than that of the control group (44.2%) (P<0.001, Table 7).
[0063] In summary, the traditional Chinese medicine composition of the present application can promote the recovery of blood perfusion in the affected brain tissue, and its efficacy is better than that of conventional treatment.
[0064] Table 4 Comparison of healthy side CBF of patients in two groups before and after treatment
[0065] Table 5 Comparison of affected side CBF of patients in two groups before and after treatment
[0066] Table 6 Comparison of rCBF of patients in two groups before and after treatment
[0067] Table 7 Comparison of reperfusion efficiency of patients in two groups
[0068] Example 3: Animal pharmacology experiment
[0069] 1) Animal model and experimental method Experimental animals: 8 to 10 weeks old adult male C57BL / 6J mice, weighing 25 to 30 grams, aged 2.5 to 3 months, provided by Zhejiang Provincial Academy of Medical Sciences Experimental Animal Center, license number: SCXK (Zhe) 2008-0033.
[0070] Experimental drugs: The traditional Chinese medicine composition extract prepared by the extract preparation method of Example 1.6 described above.
[0071] Experimental animal modeling (photochemical embolism focal cerebral ischemia model): The mice were injected with rose Bengal (10 mg / kg body weight, 5 mg / ml normal saline) through the tail vein, and were completely anesthetized by intraperitoneal injection of ketamine-xylazine solution. Then the complete skull was exposed, and a 4 mm diameter illumination cold light source (Zeiss, CL1500HAL, 150 W, 3000K) was used to irradiate 2.5 mm lateral to the Bregma to cover the right sensory motor cortex for five minutes. Finally, the head skin was bonded with 3M adhesive, and placed on a heating plate for constant temperature preservation until complete recovery, and then returned to the mouse cage.
[0072] Experimental animal grouping and administration method: After 72 hours of cerebral ischemia, the animals were divided into the following groups: model control group 10 (equal volume of normal saline), low-dose traditional Chinese medicine treatment group 10 (ZGTL-L, 1.7g / kg), high-dose traditional Chinese medicine treatment group 10 (ZGTL-H, 3.4g / kg) and 10 (100mg / kg). The solution of the traditional Chinese medicine treatment group is to prepare the traditional Chinese medicine composition extract with normal saline, and the administration method is gavage, once a day. In order to identify proliferating cells, 5-bromo-20-deoxyuridine (BrdU, Sigma Company, USA, 50mg / kg) was injected intraperitoneally to each animal every day. All interventions started on the 3rd day after ischemia induction and lasted for 30 days. Behavioral tests were performed before ischemia induction and on the 3rd, 7th, 14th and 30th day after ischemia induction to assess the motor and sensory function of the mice. On the 30th day after ischemia induction, immunofluorescence staining was used to observe angiogenesis and vascular density. 2) Detection index and result
[0073] Irregular parallel ladder walking experiment: 1 week before surgery, the animals were trained to walk on a horizontal ladder, with random intervals to prevent the mice from learning and remembering. The interval between the small iron rods was changed constantly as the experiment progressed. After several training sessions, a Sony camera was used to record the video. Postoperative recording was performed once a week, and the analysis was conducted using a double-blind principle. Specific analysis measures: complete palm grip of the forelimbs on the iron rod indicates correct; direct stepping, wrist contact, and a few finger contacts are all errors; the same applies to the hindlimb footpalm. The error rate was used as the statistical result for statistical analysis.
[0074] The irregular ladder walking experiment is shown in Figure 2 There was no significant difference in the error rate of each group of mice before modeling. On the 3rd day after modeling, the error rate of all groups increased sharply, indicating that the stroke model successfully induced severe motor coordination dysfunction. As the recovery time increased, each group showed different recovery trajectories. The recovery of the model control group (A) was the slowest, and the error rate was still significantly higher than that of the other groups on the 30th day, indicating that its spontaneous functional repair ability was limited. The positive control drug, D, showed a stable recovery trend, and the error rate was significantly lower than that of the model control group on the 30th day (P<0.05). Both the low- and high-dose traditional Chinese medicine treatment groups showed improvement, and the error rate was significantly lower than that of the model group on the 30th day (P<0.01), with no significant difference from the D group. The above results show that the traditional Chinese medicine composition of the present embodiment can significantly promote the recovery of motor coordination function in ischemic stroke mice.
[0075] Sticker removal experiment: Cut medical adhesive tape into 3mm x 3mm size, and use ophthalmic forceps to attach it to the center of the mouse's palm. Then place the mouse in a transparent glass device and record the time it takes for the mouse to perceive and tear off the tape. The maximum recording time is 2 minutes. Before each recording, let the mouse adapt to the transparent glass device for a few minutes to reduce the time error caused by the mouse's discomfort with the new environment. All experimental animals were tested on one side and then on the other side. Preoperative experiments were performed 3 times, and the average of 3 times was used as the baseline for subsequent postoperative results. Postoperative recording was performed once a week, and the analysis was conducted using a double-blind principle.
[0076] The detection results are shown in Figure 3As shown, before modeling, the sticker removal time in all groups was similar to the baseline level. On day 3 after modeling, the removal time in all groups was significantly prolonged, indicating that the stroke model successfully induced significant sensorimotor dysfunction. During the subsequent recovery process, the groups showed different recovery patterns. The model control group (A) recovered the slowest, with its removal time remaining at a high level throughout the observation period, and still significantly longer than other groups on day 30, suggesting limited spontaneous recovery ability. The butylphthalide positive control group (D) showed a stable recovery trend, with a removal time significantly shorter than the model control group on day 30. Both low- and high-dose traditional Chinese medicine treatment groups showed improvement effects, with sticker removal time significantly shorter than the model group on day 30 (P<0.01), and no significant difference from the butylphthalide group. These results indicate that the traditional Chinese medicine composition of this invention can significantly promote the recovery of motor coordination function in mice with ischemic stroke.
[0077] Angiogenesis and vascular density detection: To determine the potential role of the herbal composition of the present invention in angiogenesis, Glut-1 and BrdU labeled blood vessels were detected by immunofluorescence staining 30 days after cerebral ischemia to assess angiogenesis and vascular formation.
[0078] like Figure 4 As shown, in the area surrounding cerebral infarction, the model control group (A) showed Glut-1 / BrdU double-labeled neovascularization (…). Figure 5 ) and Glut-1 markers total vascular ( Figure 6 The lowest number of blood vessels indicated limited spontaneous angiogenesis capacity. The butylphthalide positive control group (D) showed a promoting effect on angiogenesis, with significantly higher numbers of new blood vessels and total microvessel density compared to the model control group. The low-dose and high-dose traditional Chinese medicine treatment groups showed significantly higher numbers of new blood vessels labeled with Glut-1 / BrdU and total Glut-1 labeled vessels compared to the control group, while the high-dose group was comparable to the butylphthalide group. These results demonstrate that the traditional Chinese medicine composition of this invention can promote angiogenesis and increase vascular density after ischemic stroke.
[0079] The present invention has been disclosed above with reference to preferred embodiments, but these are not intended to limit the present invention. Anyone skilled in the art can make various changes or modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be defined by the scope of the claims in this application.
Claims
1. A traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: Prepared Rehmannia root 10-30 parts, Rhodiola rosea 5-20 parts, Acorus tatarinowii 5-15 parts, Cornus officinalis 5-15 parts, Lycium barbarum 5-20 parts, Cuscuta chinensis 5-20 parts, Achyranthes bidentata 5-20 parts, and Shenqu 5-20 parts.
2. The traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: Prepared Rehmannia Root 10-15 parts, Rhodiola Rosea 10-20 parts, Acorus tatarinowii 6-12 parts, Cornus officinalis 8-12 parts, Lycium barbarum 8-12 parts, Cuscuta chinensis 8-12 parts, Achyranthes bidentata 8-12 parts, and Shenqu (medicated leaven) 10-20 parts.
3. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is a decoction, and the preparation method of the decoction is as follows: Weigh the raw materials according to the proportions and soak them in 5 to 6 times the amount of drinking water. Bring to a boil over high heat, then simmer over low heat. Filter the liquid through a 200-mesh sieve and collect the filtrate. Add 3 to 4 times the amount of water to the dregs and boil them, then filter them using the same method. Combine the two filtrates to obtain the decoction.
4. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is in the form of granules, and the preparation method of the granules is as follows: Weigh the raw materials according to the proportions and soak them in 6 to 10 times the amount of drinking water. Bring to a boil over high heat, then simmer over low heat. Filter the liquid through a 200-mesh sieve and collect the filtrate. Add 4 to 8 times the amount of water to the dregs and boil them, then filter them using the same method. Combine the two filtrates and concentrate under reduced pressure at 60°C to obtain a clear extract; Fluidized bed granulation is used; Boil and dry until the moisture content is ≤5%, granulate, and package to obtain granules.
5. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is in the form of tablets, and the tablet preparation method is as follows: Weigh the raw materials according to the specified ratio and soak them in 6-10 times the amount of water. Bring to a boil over high heat, then simmer over low heat. Filter the liquid through a 200-mesh sieve and collect the filtrate. Add 4 to 8 times the amount of water to the dregs and decoct again, then filter using the same method; combine the two filtrates. The extract was concentrated into a thick paste, vacuum dried, and then pulverized. Add microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate, and mix well; The tablets are formed using the direct compression method.
6. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is in the form of capsules, and the preparation method of the capsules is as follows: The raw materials are pulverized through a 100-mesh sieve and accurately weighed and mixed according to the specified ratio; Add povidone K30 ethanol solution to prepare a soft mass, then granulate it through a 20-mesh sieve; Dry, granulate, and mix with micronized silica gel; The capsule shell is filled to obtain a capsule.
7. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is an oral liquid, and the preparation method of the oral liquid is as follows: Weigh the raw materials according to the proportions and soak them in 6-10 times the amount of drinking water. Bring to a boil over high heat, then simmer over low heat. Filter the liquid through a 200-mesh sieve and collect the filtrate. Add 4-8 times the amount of water to the dregs and boil them, then filter them using the same method. Combine the two filtrates and concentrate them under reduced pressure at 60-65℃ to an appropriate volume; Add water to the theoretical volume; Fill the container and sterilize it with flowing steam at 100°C for 30 minutes to obtain the oral liquid.
8. The method for preparing the traditional Chinese medicine composition for promoting angiogenesis after ischemic stroke as described in claim 1 or 2, characterized in that, The traditional Chinese medicine composition is an extract, and the preparation method of the extract is as follows: Weigh the raw material and soak it in 6-10 times the amount of water; Extract twice by heating and reflux; Combine the extracts and filter them through a 200-mesh filter cloth to remove the residue; Concentrate the filtrate under reduced pressure to a thick paste, add an appropriate amount of dextrin and mix well; Continue vacuum drying until the moisture content is ≤5%, then pulverize into fine powder to obtain dry extract.
9. The use of the traditional Chinese medicine composition according to claim 1 or 2, or the traditional Chinese medicine composition prepared by the preparation method according to claims 3-8, in the preparation of a medicament for the prevention and / or treatment of ischemic stroke.
10. The application according to claim 9, characterized in that: The traditional Chinese medicine composition organically combines "tonifying the kidney and replenishing essence" to strengthen the body's foundation with "activating blood circulation and resolving phlegm" to unblock the meridians, thereby promoting angiogenesis after ischemic stroke, increasing vascular density, and improving cerebral blood flow and nerve function. The traditional Chinese medicine composition is used to prevent and / or treat the "kidney deficiency, blood stasis, and phlegm obstruction" syndrome of ischemic stroke.