CN113827639B

CN113827639B - Pharmaceutical composition for preventing and treating cerebral apoplexy

Info

Publication number: CN113827639B
Application number: CN202110998177.5A
Authority: CN
Inventors: 王玮; 王健松; 廖弈秋; 黄海文; 罗志波; 张琳
Original assignee: Guangzhou Baiyunshan Pharmaceutical Holdings Co ltd Baiyunshan Pharmaceutical General Factory
Current assignee: Guangzhou Baiyunshan Pharmaceutical Holdings Co ltd Baiyunshan Pharmaceutical General Factory
Priority date: 2021-08-27
Filing date: 2021-08-27
Publication date: 2022-08-30
Anticipated expiration: 2041-08-27
Also published as: WO2023024332A1; CN113827639A

Abstract

The invention relates to a pharmaceutical composition for preventing and treating cerebral apoplexy, which comprises the following components: ginseng, monkshood, lucid ganoderma, safflower, artificial musk, bear gall, pearl, toad venom, borneol and bezoar. The composition can significantly improve neurological deficit, reduce cerebral edema, and reduce cerebral infarction area, which may be associated with the effect of the drug in reducing oxidative stress and protecting brain tissue from oxygen free radical damage.

Description

Pharmaceutical composition for preventing and treating cerebral apoplexy

Technical Field

The invention relates to the field of traditional Chinese medicines, in particular to a pharmaceutical composition for preventing and treating cerebral apoplexy.

Background

Cerebral apoplexy is a common disease in neurology, is mainly caused by brain tissue damage caused by the fact that blood cannot flow into the brain due to sudden rupture of cerebral vessels or blockage of blood vessels, has the characteristics of high morbidity, high death rate and high disability rate, and is the first death factor of residents in China. In recent years, the incidence of stroke has increased year by year and has become younger due to the increase in working and life pressure. The cerebral apoplexy comprises ischemic stroke and hemorrhagic stroke, wherein the incidence rate of the ischemic stroke is higher and accounts for about 75-90% of the total cerebral stroke. Ischemic stroke frequently occurs in a quiet state and is manifested by speech disorder, slurred speech, facial distortion, dysphagia, hemiplegia, sensory disturbance, and incontinence of urine and feces in severe patients; hemorrhagic stroke frequently occurs in an active state, and is manifested by headache, nausea, vomiting like jetting, hemiplegia and sensory disturbance, and in severe cases, disturbance of consciousness, coma and the like.

The brain damage mechanism caused by stroke is complex and is the result of the interaction of complex pathophysiological processes such as excitotoxicity, oxidative stress, inflammation, apoptosis and the like, so that the curative effect of a single medicament is limited.

Cerebral apoplexy belongs to the category of apoplexy in traditional Chinese medicine, and is mainly characterized by the basic pathogenesis of cerebral vessel obstruction or cerebral vessel hemorrhage due to the adverse flow of qi and blood, wind, fire, phlegm and stasis caused by deficiency of vital qi, diet, emotion, overstrain and internal injury, and the clinical manifestations of sudden faint, hemiplegia, facial distortion, slurred speech or aphasia and hemianesthesia. The traditional Chinese medicine compound can play a role in multiple links of cerebral apoplexy and has a good treatment effect.

The chemical drugs currently used for treating stroke are mainly thrombolytic drugs, anticoagulant drugs and neuroprotective agents. The thrombolytic drug is used for reducing thrombus and relieving the degree of vascular occlusion. Anticoagulant drugs are mainly used to improve microcirculation and restore blood flow. The nerve protective agent is mainly used for protecting nerves and delaying nerve injury. Traditional Chinese medicines are also widely used for treating cerebral apoplexy, and single medicinal materials and compound medicines mainly have the main effects of promoting blood circulation and removing blood stasis, such as angelica sinensis, pseudo-ginseng, ligusticum chuanxiong hort and the like; the compound medicine mainly comprises oral medicines such as compound red sage root tablets, yang-tonifying and five-reducing decoction, coronary heart disease-relieving capsules, qi-tonifying and heart-strengthening capsules, kidney-tonifying and qi-tonifying capsules, brain and heart disease-relieving capsules and the like, and injection preparations such as red sage root injection, compound red sage root injection and the like. However, these pharmaceutical compositions often have single efficacy, complex composition, or poor safety, and lack rigorous, systematic pharmacodynamic experiments meeting modern pharmacological requirements, making strict quality control and standardized production difficult.

Disclosure of Invention

Based on the above, the invention aims to provide a composition for preparing a medicament for preventing and treating cerebral apoplexy.

CN108057066B discloses a Chinese medicinal composition for preventing and treating unstable angina pectoris, which is prepared from radix Ginseng, radix Aconiti lateralis Preparata, Ganoderma, flos Carthami, artificial Moschus, fel Ursi, Margarita, Bufonis venenum, Borneolum Syntheticum and calculus bovis (calculus bovis is generally cultivated in vitro because of the small amount of natural calculus bovis). The inventor surprisingly finds that the traditional Chinese medicine composition can relieve angina pectoris and has good treatment effect on cerebral apoplexy, particularly ischemic cerebral apoplexy, and a large amount of test data recorded in the invention prove that: the composition can effectively improve neurological deficit, reduce cerebral infarction area, relieve brain edema degree, resist oxidative stress injury, relieve symptoms of cerebral apoplexy from various angles, and block disease course progress through reasonable compatibility of the traditional Chinese medicine components; and is safe and reliable, and has no toxic and side effects on human bodies.

The specific technical scheme is as follows:

the application of a composition in preparing a medicament for preventing and treating cerebral apoplexy is disclosed, wherein the composition mainly comprises the following components in parts by weight:

in some embodiments of the invention, the composition consists essentially of the following components in parts by weight:

in some embodiments of the invention, the medicament is prepared from the composition and pharmaceutically acceptable excipients.

In some embodiments of the invention, the pharmaceutical may be prepared according to methods conventional in the art. The medicine is a composition formed by crushing and mixing raw material medicines, or an extract obtained by mixing and extracting the raw material medicines independently. Optionally, the extract is further refined and purified. Wherein the extraction method comprises decocting extraction, reflux extraction, immersion extraction, ultrasonic extraction, percolation extraction, microwave extraction, etc.; the purification method comprises water extraction and alcohol precipitation, alkali dissolution and acid precipitation and various column chromatography purification methods, such as a macroporous resin column, a silica gel column, a reversed phase column and the like.

In some embodiments of the present invention, the dosage form of the drug is tablet, capsule, granule, pill, oral liquid or drop pill. The composition can be made into corresponding tablets, capsules, granules, pills, oral liquids or dripping pills by adding appropriate pharmaceutically acceptable auxiliary materials according to the conventional preparation process of required dosage forms.

The pharmaceutically acceptable auxiliary materials refer to conventional pharmaceutical auxiliary materials in the pharmaceutical field, and are selected from one or more of fillers, binders, disintegrating agents, lubricants, suspending agents, wetting agents, pigments, essences, solvents, surfactants or flavoring agents. The filler is selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose or glucose; the adhesive is selected from cellulose derivatives, alginate, starch, water, dextrin, gelatin, polyvinylpyrrolidone or the like; the disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or croscarmellose sodium; the lubricant is selected from stearic acid, polyethylene glycol, calcium carbonate, sodium bicarbonate, superfine silica gel powder, talcum powder or magnesium stearate; the suspending agent is selected from silica gel micropowder, Cera flava, cellulose, and solid polyethylene glycol; the wetting agent is selected from glycerol, tween-80, ethoxylated hydrogenated castor oil or lecithin; the solvent is selected from ethanol, liquid polyethylene glycol, isopropanol, tween-80, glycerol, propylene glycol or vegetable oil, and the vegetable oil is selected from soybean oil, castor oil, peanut oil, blend oil, etc.; the surfactant is selected from sodium dodecyl benzene sulfonate, stearic acid, polyoxyethylene-polyoxypropylene copolymer, sorbitan fatty acid or polysorbate (Tween) and the like; the correctant is selected from aspartame, sucralose, essence, steviosin, acesulfame potassium, citric acid or saccharin sodium.

In some embodiments of the present invention, the composition and the prepared medicine thereof are used for preventing and treating cerebral apoplexy, wherein the cerebral apoplexy is ischemic cerebral apoplexy.

In some embodiments of the present invention, the composition and the prepared medicine thereof improve neurological deficit, and/or reduce cerebral infarction area, and/or reduce the degree of edema of brain tissues, and/or resist oxidative stress injury. In some embodiments of the invention, the combating oxidative stress damage is reducing MDA levels, increasing GSH levels and SOD activity (P < 0.05).

The invention has the beneficial effects that:

the composition disclosed by the invention can effectively improve the neurological deficit, reduce the cerebral infarction area, relieve the hydropsy degree of brain tissues, resist oxidative stress injury, relieve the symptoms of cerebral apoplexy from various angles and block the progress of the disease course through the reasonable compatibility of the traditional Chinese medicine components; the quality is controllable, and the standardized production is convenient; and is safe and reliable, and has no toxic and side effects on human bodies.

Detailed Description

The following are specific embodiments of the present invention, which are presented for the purpose of further describing the invention and are not intended to limit the invention thereto.

Example 1

The test drugs of the experimental group of this example consist of the following components in parts by weight:

example 2

example 3

example 4

example 5

example 6

and (3) pharmacodynamic study: effect on cerebral ischemia reperfusion model rats

1. Experimental method

1.1 animal grouping and drug intervention

After 160 male SD rats (body mass 240 +/-20 g) are fed adaptively for 1-2, the rats are randomly divided into 8 groups, namely a sham operation group, a model group and examples 1, 2, 3, 4, 5 and 6 (wherein, the medicines of the groups in the examples are crushed according to the prescription amount, sieved and mixed, and are made into a suspension by a sodium carboxymethyl cellulose solution suspension, and the suspension is evenly shaken before administration), and 8 groups are provided, wherein, corresponding medicines are administered to each group of 20 rats every day (the groups in the examples 1, 2, 3, 4, 5 and 6 are respectively administered according to the crude drug amount of 57, 63, 67, 71, 83 and 89 mg/Kg of body weight, and the sham operation group and the model group are administered with the same amount of the sodium carboxymethyl cellulose solution). Are administered for 4 weeks. And molding on the 2 nd day after the dosing is finished.

1.2 preparation of cerebral ischemia reperfusion model rat

Before operation, the patient is fasted for 12 hours, and water is freely drunk. Each group of rats was anesthetized by intraperitoneal injection of chloral hydrate, and was fixed on an operating table in the lateral position, and the anal temperature of the rats was maintained at 37 + -1 deg.C during the experiment. The operation is carried out according to the following steps: preparing skin, and disinfecting skin; the middle incision of the neck exposes the common carotid artery, the internal carotid artery is separated bluntly, the common carotid artery and the internal carotid artery are clamped and closed, a nylon thread is slowly and softly pushed towards the intracranial direction of the internal carotid artery through the main incision of the external carotid artery, the bifurcation of the common carotid artery is taken as a mark, slight resistance is met when the nylon thread is pushed about 18mm, namely, the thinner middle cerebral artery is reached and stopped, the middle cerebral artery is blocked by ligation, the local cerebral blood flow is fully blocked, a wound is sutured, the nylon thread with the length of about 3cm is kept outside the body, and an iodine disinfection operation area is formed. Reperfusion was achieved by pulling out the occlusion wire about 10min after 1h of ischemia. The sham operation group: the treatment was performed in the same treatment group without ligation. A transcranial Doppler blood flow analyzer is adopted to monitor the cerebral blood flow condition in the operation process.

1.3 measurement of index

1.3.1 behavioral deficiency: closely observing the conditions of each group of animals within 24h of ischemia reperfusion, and evaluating the behavior defect by referring to a Zea Longa score standard, wherein 0 is normal and has no nerve injury symptom; 1 is divided into the contralateral forelimb which cannot be fully extended; 2, turning to the opposite side during crawling; 3, the body is inclined towards the opposite side when walking; 4, the patient cannot walk spontaneously and loses consciousness.

1.3.2 cerebral infarction volume and brain water content: after 24h of reperfusion after administration, each group of animals was sacrificed, the whole brains of 10 rats were taken, the wet weight of brain tissue was weighed, sliced, stained in 2% triphenyltetrazolium chloride (TTC) solution for 30min, fixed, and the pale area (infarct zone, unstained) and the non-pale area (normal zone) were separated, and the brain infarct volume (%) -infarct zone range wet weight/brain tissue wet weight × 100%. Drying the dyed brain tissue in an oven to constant weight, weighing the dry weight, and calculating the water content of the brain according to the following formula: brain water (%) is (brain tissue wet weight-brain tissue dry weight)/brain tissue wet weight × 100%.

1.3.3 oxidative stress indicators: after 24h of reperfusion after dosing, each group of animals was sacrificed, 10 of the rats were taken, the brains were rapidly weighed, and a 10% brain tissue homogenate was prepared with physiological saline. Centrifuging at low temperature, collecting supernatant, and detecting Malondialdehyde (MDA), reduced Glutathione (GSH) content and superoxide dismutase (SOD) activity in brain tissue by kit instruction method.

2. Results of the experiment

2.1 comparison of behavioral impairment scores in groups of rats

Compared with the sham operation group, the behavioral score of the rats in the model group is obviously higher. The behavioral scores of rats given the example drug were significantly reduced (P <0.05) compared to the model group, indicating that the example drug can ameliorate neurological deficit. The results are shown in Table 1.

Table 1 comparison of behavioral deficit scores (n ═ 20) for groups of rats

Group of	Behavioural scoring (score)
		Artificial operation group	0
Model set	3.40±0.55
		EXAMPLE 1 group	2.61±0.44*
EXAMPLE 2 group	2.33±0.29*
		EXAMPLE 3 group	2.47±0.27*
EXAMPLE 4 group	2.63±0.38*
		EXAMPLE 5 group	2.52±0.31*
EXAMPLE 6 group	2.35±0.45*

Note: p <0.05 in comparison with model group

2.2 comparison of the cerebral infarction volume and brain Water content of rats in each group

The brain tissue of the rats in the sham operation group has no infarction; compared with the sham operation group, the brain water content of the rats in the model group is obviously higher (P < 0.05). The cerebral infarction volume and brain water content of rats given the example drug were significantly decreased (P <0.05) compared to the model group, indicating that the example drug can reduce cerebral infarction volume and brain water content caused by ischemia. The results are shown in Table 2.

Table 2 comparison of cerebral infarct volume and brain water content (%, n is 10) for each group of rats

Note: p <0.05 in comparison with model group

2.3 comparison of oxidative stress indicators in rats of various groups

Compared with a sham operation group, the brain tissue of the rat in the model group has obviously higher MDA content and obviously lower GSH content and SOD activity (P is less than 0.05). Compared with the model group, the rats given the example drug have obviously reduced MDA content and obviously improved GSH content and SOD activity (P <0.05), which indicates that the example drug can reduce oxidative stress injury. The results are shown in Table 3.

Table 3 comparison of oxidative stress index (n ═ 10) for each group of rats

Group of	MDA(μmol/mg Prot)	GSH(μg/mg Prot)	SOD(μU/mg Prot)
				Artificial operation group	9.13±0.76*	46.84±6.92*	69.05±8.14*
Model set	56.30±7.18	27.80±3.21	30.43±4.85
				EXAMPLE 1 group	45.51±3.92*	33.41±3.35*	41.74±6.32*
EXAMPLE 2 group	41.42±4.55*	35.50±5.24*	46.21±4.49*
				EXAMPLE 3 group	39.21±3.26*	36.45±4.06*	45.35±6.12*
EXAMPLE 4 group	40.25±5.47*	36.37±2.81*	38.72±4.50*
				EXAMPLE 5 group	43.07±4.84*	34.01±5.65*	36.19±5.33*
EXAMPLE 6 group	39.84±3.27*	33.79±3.34*	45.84±3.26*

Note: p <0.05 in comparison with model group

3. Conclusion of the experiment

The risk factors (hypertension, hyperglycemia and the like) and ischemia of the stroke can cause the activation of a Reactive Oxygen Species (ROS) related enzyme system, a large amount of ROS are generated and far exceed the endogenous clearance capacity of an antioxidant defense system of an organism, and oxidative stress occurs.

Compared with the model group, the behavioral score, the cerebral infarction volume, the brain water content and the MDA content in the brain tissue of the rat in the drug group are obviously reduced, and the GSH content and the SOD activity in the brain tissue are obviously improved (P is less than 0.05), so that the drug in the embodiment can improve the neurological deficit, reduce the cerebral edema degree and reduce the cerebral infarction area, and the effect of the drug in the embodiment is probably related to the effect of the drug in reducing oxidative stress and protecting the brain tissue from oxygen free radical injury. The pharmaceutical composition of the invention relieves the symptoms of cerebral apoplexy from various angles and blocks the progress of the course of disease through the reasonable compatibility of the traditional Chinese medicine components; and is safe and reliable, and has no toxic and side effects on human bodies.

In conclusion, the pharmaceutical composition provided by the invention can obviously reduce oxidative stress injury of animals in an ischemic stroke model, improve neurological deficit and protect brain tissues, and is suitable for preventing and treating ischemic stroke.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. The application of a composition in preparing medicines for preventing and treating cerebral arterial thrombosis; the medicament improves neurological deficit, and/or reduces cerebral infarction area, and/or reduces the degree of edema of brain tissues, and/or resists oxidative stress injury; the composition is prepared from the following components in parts by weight:

150-350 parts of ginseng

80-200 parts of monkshood

60-120 parts of lucid ganoderma

50-100 parts of safflower

10-60 parts of artificial musk

10-60 parts of bear gall

10-60 parts of pearl

10-60 parts of toad venom

5-50 parts of borneol

5-50 parts of bezoar.

2. The use of the composition according to claim 1 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein the composition is prepared from the following components in parts by weight:

200-300 parts of ginseng

100-150 parts of monkshood

80-100 parts of lucid ganoderma

60-80 parts of safflower

20-40 parts of artificial musk

20-40 parts of bear gall

20-40 parts of pearl

20-40 parts of toad venom

10-30 parts of borneol

10-30 parts of bezoar.

3. Use of the composition according to any one of claims 1-2 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein the bezoar bovis used in the composition is in vitro cultured bezoar bovis.

4. Use of the composition according to any one of claims 1-2 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein the medicament is prepared from the composition according to any one of claims 1-2 and pharmaceutically acceptable excipients.

5. The composition of claim 4, wherein the composition is in the form of tablet, capsule, granule, pill, or oral liquid.

6. The use of the composition according to claim 4 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein the medicament is in the form of drop pill.

7. The use of the composition according to any one of claims 1-2 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein the medicament is a mixture of pulverized raw materials.

8. The use of the composition according to any one of claims 1-2 in the preparation of a medicament for preventing and treating ischemic stroke, wherein the medicament is an extract obtained by mixing and extracting each of the raw materials, or an extract obtained by mixing and extracting each of the raw materials separately.

9. The use of the composition according to claim 8 for the preparation of a medicament for the prevention and treatment of ischemic stroke, wherein said extract is further purified.