Traditional Chinese medicine composition for treating unstable carotid plaque as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating unstable carotid plaque and a preparation method and application thereof. The traditional Chinese medicine composition comprises the following active pharmaceutical ingredients in parts by mass: 5-30 parts of salvia miltiorrhiza, 5-30 parts of endothelium corneum gigeriae galli, 10-50 parts of sun-dried ginseng, 3-30 parts of pseudo-ginseng, 3-15 parts of leech and 20-60 parts of pine needle. Clinical tests show that the traditional Chinese medicine composition has an anti-atherosclerosis effect in the aspect of reducing carotid plaque integral, and can effectively reduce total cholesterol and low-density lipoprotein level.

Description

Technical Field

[0001] The invention belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating unstable carotid artery plaques, and a preparation method and application thereof. Background Art

[0002] Studies have shown that local thrombosis at the site of atherosclerotic plaques or plaque rupture is the main cause of ischemic stroke and transient ischemic attack (TIA). Most scholars believe that the indicator reflecting the severity of carotid atherosclerotic plaque lesions is the biological stability of the plaque itself. Therefore, it is of great significance to study the characteristics and formation mechanism of unstable carotid plaques in order to guide treatment and reduce the occurrence of ischemic stroke and transient ischemic attack.

[0003] At present, the main western medicine treatment measures for unstable carotid plaques are: 1. Control risk factors; 2. Drug therapy (lipid regulation, antiplatelet aggregation, blood pressure and blood sugar reduction); 3. Surgical treatment (carotid endarterectomy, carotid stenting). The promotion of statins is limited by factors such as many surgical complications, high technical requirements and high risks. Statins are commonly used clinical lipid-regulating and plaque-stabilizing drugs with clear efficacy, but they also have shortcomings. The SPARCL study showed that after treatment with a 4-fold dose of atorvastatin calcium tablets (80 mg), compared with placebo, the stroke recurrence rate was only reduced by 16% in 5 years. There are also adverse reactions such as statin-related muscle symptoms, abnormal liver function, kidney damage, increased risk of diabetes and hemorrhagic stroke. Antiplatelet drugs have the disadvantages of slow onset, mild effect, inability to completely prevent clinical thrombotic events, drug resistance, single route of administration and bleeding.

[0004] Traditional Chinese medicine, based on the holistic concept and individualized syndrome differentiation and treatment, can play an important role in the diagnosis and treatment of unstable carotid plaques. It has the advantages of precision, individualization, and few adverse reactions, and has good application prospects. Therefore, it is necessary to develop a Chinese medicine composition that can effectively treat unstable carotid plaques to meet clinical drug needs. Summary of the invention

[0005] The first purpose of the present invention is to provide a traditional Chinese medicine composition for treating unstable carotid plaque. The second purpose of the present invention is to provide a method for preparing the traditional Chinese medicine composition. The third purpose of the present invention is to provide an application of the traditional Chinese medicine composition.

[0006] According to the first aspect of the present invention, a Chinese medicine composition for treating unstable carotid plaque is provided, wherein the effective ingredients include the following raw materials in parts by weight: 5-30 parts of Salvia miltiorrhiza, 5-30 parts of Gallus gallus domesticus, 10-50 parts of raw sun-dried ginseng, 3-30 parts of Panax notoginseng, 3-15 parts of leeches, and 20-60 parts of pine needles.

[0007] The present invention believes that the climate characteristics of Lingnan region are mostly humid and hot, and people like cold drinks, which can easily damage the spleen and stomach, and the water and dampness cannot be transformed. The external dampness and internal dampness combine, which aggravates the risk of phlegm and dampness causing disease. The etiology and pathogenesis of atherosclerosis are that phlegm, dampness and blood stasis promote each other, with phlegm, dampness and blood stasis as tangible lesions, forming unstable plaques.

[0008] In the formula, raw sun-dried ginseng is the main drug, which greatly replenishes vital energy, nourishes the spleen and benefits the lungs; salvia miltiorrhiza and Panax notoginseng are the assistant drugs, which promote blood circulation and remove blood stasis, remove fat and eliminate accumulation; chicken gizzard lining and pine needles are the adjuvant drugs, which strengthen the spleen and resolve phlegm, promote blood circulation and calm the mind; leech is the guiding drug, which breaks blood and removes blood stasis, unblocks the meridians and eliminates symptoms. The whole formula has the effects of strengthening the spleen and resolving phlegm, promoting blood circulation and removing blood stasis, unblocking the meridians and stabilizing plaques, and can effectively prevent and treat unstable plaques, and is used to prevent cardiovascular and cerebrovascular diseases such as atherosclerosis, ischemic stroke, and transient ischemic attack.

[0009] The raw material sources of the present invention are as follows:

[0010] Salvia: The dried roots and rhizomes of Salvia miltiorrhiza Bge., a plant of the genus Salvia in the family Lamiaceae.

[0011] Gallus gallus domesticus Brisson: the inner wall of the gizzard of the domestic chicken Gallus gallus domesticus Brisson, an animal of the Phasianidae family.

[0012] Raw sun-dried ginseng: the dried roots and rhizomes of Panax ginseng CAMey, a plant of the Araliaceae family.

[0013] Panax notoginseng: The dried root of Panax notoginseng (Burk.) FHChen, a plant of the genus Panax in the Araliaceae family.

[0014] Leech: The dried whole body of the leech Whitmania Pigra Whitman, the willow leech Whitmaniaacranutata Whitman, or the leech Hirudo nipponica Whitman, which are animals of the Hirudinidae family.

[0015] Pine needles: needles of Pinus armandi Franch., Pinus taiwanensis Hayata, Pinus massoniana Lamb., Pinus thunbergii Parl., Pinus tabulaeformis Carr., Pinus yunnanensis Franch., Pinus koraiensis Sieb. et Zucc. of the Pinaceae family.

[0016] In some embodiments, the active ingredients include the following raw materials in parts by weight: 20 parts of salvia miltiorrhiza, 20 parts of chicken gizzard lining, 40 parts of raw sun-dried ginseng, 20 parts of Panax notoginseng, 10 parts of leeches, and 60 parts of pine needles.

[0017] In some embodiments, pharmaceutically acceptable excipients may also be added.

[0018] In some embodiments, the excipient is at least one of a sustained-release agent, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.

[0019] In some embodiments, the dosage form of the Chinese medicine composition is pills, granules, decoctions, pastes, powders, tablets or capsules.

[0020] According to a second aspect of the present invention, a method for preparing the above-mentioned Chinese medicine composition for treating unstable carotid plaque is provided. When the dosage form of the Chinese medicine composition is a pill, the preparation method comprises the following steps:

[0021] (1) Grind the above 6 raw materials into fine powder, pass through a No. 6 sieve, and mix evenly to obtain fine drug powder;

[0022] (2) Spray water in the pill pan to moisten it, sprinkle 45% of the drug fine powder obtained in step (1), rotate the pill pan to brush off the powder particles attached to the pan wall, spray water again, sprinkle powder, repeat this cycle, and gradually increase the powder particles until they are spherical particles with a diameter of 0.8-1.2 mm. Sieve the particles between the No. 1 sieve and the No. 2 sieve to obtain pill molds;

[0023] (3) 45% of the fine drug powder obtained in step (1) is mixed with water to form a slurry with a relative density of 1.32-1.33, which is set aside; the above-mentioned pellet mold is placed in a pelletizing pot and rotated until the pellet mold rolls smoothly along the pot wall, and the slurry is sprayed in the reverse direction by the spray gun to perform pelletizing, and the material is added in a cycle, and the pellets are screened after being spheronized, and the particle size and roundness are controlled to obtain pellets with a diameter of 3-6 mm;

[0024] (4) The pellets are fully moistened, and then the remaining fine drug powder obtained in step (1) is evenly sprinkled on the pellets, and rolled in a pellet pan until the pellets are smooth, round, and compact, to obtain water pills;

[0025] (5) Dry the water pellets at a temperature below 80°C for 1-2 hours to ensure that the water content of the water pellets does not exceed 9%;

[0026] (6) After the pellets are dried, a pellet picker is used to separate qualified pellets from deformed pellets to obtain pellets of uniform size and round shape.

[0027] According to a third aspect of the present invention, there is provided use of the above-mentioned traditional Chinese medicine composition for treating unstable carotid plaques in the preparation of a medicament for treating unstable carotid plaques.

[0028] According to a fourth aspect of the present invention, there is provided use of the above-mentioned Chinese medicine composition for treating unstable carotid artery plaque in the preparation of a medicament for preventing and / or treating atherosclerosis or ischemic stroke or transient ischemic attack.

[0029] The beneficial effects of the present invention include:

[0030] (1) The results of the clinical single-blind trial showed that the Chinese medicine composition of the present invention has a therapeutic effect on improving unstable plaques of carotid atherosclerosis.

[0031] (2) The results of the clinical double-blind trial showed that the Chinese medicine composition of the present invention has an anti-atherosclerotic effect in reducing the carotid artery plaque score and can effectively reduce the levels of total cholesterol and low-density lipoprotein. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with specific examples, but the embodiments of the present invention are not limited thereto. The materials involved in the following examples can be obtained from commercial channels, and the methods not specifically described are all conventional methods known in the art.

[0033] Example 1

[0034] The preparation method of the Chinese medicine pill for treating unstable carotid artery plaque of this embodiment comprises the following steps:

[0035] (1) Weigh 20 kg of Salvia miltiorrhiza, 20 kg of Gallus gallus domesticus, 40 kg of raw sun-dried ginseng, 20 kg of Panax notoginseng, 10 kg of Leech, and 60 kg of pine needles, grind the above 6 raw drugs into fine powder using a crushing and grinding device, pass through a No. 6 sieve, and mix well to obtain drug fine powder.

[0036] (2) Spray a small amount of water in the pill pan to moisten it, sprinkle about 45% of the fine drug powder obtained in step (1), rotate the pill pan, brush off the powder particles attached to the pan wall, spray water again, sprinkle powder, and repeat this cycle several times to gradually increase the powder particles until they become spherical particles with a diameter of about 1 mm. Sieve the particles between the No. 1 sieve and the No. 2 sieve to obtain pill molds.

[0037] (3) About 45% of the fine drug powder obtained in step (1) is mixed with water to form a mixed slurry with a relative density of 1.32, which is set aside and stirred evenly when used; the pill mold is placed in a panning pot and rotated for a while, until the pill mold rolls smoothly along the pot wall, the spray gun is sprayed with the mixed slurry in the reverse direction to pan the pills, and the material is continuously added in a cycle according to the principle of "less → more → less", and the pill mold and the mixed slurry are rolled, kneaded, turned, and bumped. If the pills stick to the pot during the panning process, about 5% of the fine drug powder obtained in step (1) can be added and stirred to overcome the problem. The rotation speed of the panning pot is controlled at about 45 revolutions per minute, and the pills are screened after rounding, and the particle size and roundness are well controlled to obtain pills with a diameter of 3-6 mm.

[0038] (4) The pellets are fully moistened, and then the remaining fine drug powder obtained in step (1) is evenly sprinkled on the pellets in multiple times, and the pellets are continued to be rolled in the pan for a certain period of time until the surface of the pellets is smooth, round and compact, and then they can be taken out to obtain water pills.

[0039] (5) Use FG-230 type boiling drying bed to control the temperature below 80℃ and dry for 1.5 hours to make the water content of the water pills not exceed 9%.

[0040] (6) To ensure that the pellets are round, uniform in size, and accurate in dosage, after the pellets are dried, a vertical pellet picker is used to separate qualified pellets from deformed pellets, thus obtaining pellets of uniform size and roundness.

[0041] Example 2

[0042] The preparation method of the Chinese medicinal pills for treating unstable carotid plaques in this embodiment is basically the same as that in Example 1, except that, in step (1), 30 kg of salvia miltiorrhiza, 30 kg of chicken gizzard lining, 50 kg of raw sun-dried ginseng, 30 kg of Panax notoginseng, 15 kg of leeches, and 50 kg of pine needles are weighed.

[0043] Example 3

[0044] The preparation method of the Chinese medicinal pills for treating unstable carotid plaques in this embodiment is basically the same as that in Example 1, except that, in step (1), 5 kg of salvia miltiorrhiza, 5 kg of chicken gizzard lining, 10 kg of raw sun-dried ginseng, 3 kg of Panax notoginseng, 3 kg of leeches, and 20 kg of pine needles are weighed.

[0045] Next, in order to explore the therapeutic effect of the Chinese medicine composition for treating unstable carotid plaques of the present invention on unstable carotid atherosclerotic plaques, the following clinical trials were conducted.

[0046] 1. Single-blind trial

[0047] From December 2013 to December 2015, 90 prospective single-center, single-blind, placebo-controlled trials were completed.

[0048] 1. Basic Information

[0049] 1. Treatment group: 60 cases, 30 males and 30 females, aged 63.30±6.59 years. Diseases: Past history: 14 cases of stroke, 4 cases of TIA, 35 cases of hypertension, 18 cases of diabetes, 38 cases of hyperlipidemia, 9 cases of coronary heart disease, and 16 cases of hyperuricemia.

[0050] 2. Control group: 30 cases, 12 males and 18 females. Age 63.63±6.76 years. Diseases: 9 cases of stroke, 3 cases of TIA, 23 cases of hypertension, 8 cases of diabetes, 17 cases of hyperlipidemia, 2 cases of coronary heart disease, and 11 cases of hyperuricemia.

[0051] There was no significant difference in gender, age, and disease severity between the treatment group and the control group (P>0.05).

[0052] (II) Treatment methods

[0053] 1. Two groups of basic treatments: including regulation of blood pressure, blood sugar, nerve nutrition, myocardial drugs, coronary artery dilation drugs, etc.

[0054] 2. Control group: atorvastatin calcium tablets (produced by Pfizer Pharmaceuticals Co., Ltd., national medicine standard number J20030048) 20 mg, once a night;

[0055] 3. Treatment group: In addition to atorvastatin calcium tablets, the Chinese medicine pills prepared in Example 1 were taken twice a day, after breakfast and dinner, 6 g each time.

[0056] The efficacy of both groups was observed after taking the medicine for 3 consecutive months.

[0057] (III) Observation indicators

[0058] 1. Carotid artery ultrasound examination

[0059] All patients were uniformly examined using Hitachi Avius color Doppler ultrasound detector with a probe frequency of 10MHz. The patients were placed in a supine position and the bilateral common carotid arteries (CCA), carotid bifurcation (BIF), internal carotid artery origin (ICA), and external carotid artery (ECA) were examined by two-dimensional method before and 3 months after treatment. The carotid intima-media thickness (IMT) was measured, and the morphology, size, number, location, and nature of plaques were recorded.

[0060] 2. Serum marker detection

[0061] Before treatment and 3 months after treatment, fasting venous blood was drawn in the morning to test serum TC, TG, LDL, HDL, hsCRP, homocysteine ​​(Hcy), liver and kidney function, coagulation, cardiac enzymes, etc.

[0062] 3. Number of cardiovascular and cerebrovascular events

[0063] Cardiovascular and cerebrovascular events refer to events that produce vascular atherosclerosis, leading to organ lesions such as coronary heart disease and cerebral stroke. During the three-month follow-up, the occurrence of acute cerebral infarction, cerebral hemorrhage, and acute myocardial infarction events were recorded, and symptoms such as dizziness, headache, chest tightness, and chest pain were recorded. Calculated by case, if a patient had a stroke, a TIA, and an angina pectoris, it would be recorded as 3 cases. The number of fatal cardiovascular and cerebrovascular events and the survival period from the occurrence of cardiovascular and cerebrovascular events to death were recorded, and the endpoint events were recorded.

[0064] 4. Safety evaluation

[0065] Whether there is severe damage to liver and kidney function (alanine aminotransferase, aspartate aminotransferase, creatinine or urea nitrogen higher than 3 times the reference upper limit); whether there is related myopathy such as muscle soreness, increased cardiac enzymes (creatine kinase or creatine kinase isoenzyme higher than 3 times the reference upper limit); whether there is bleeding tendency such as nose bleeding, skin, mucous membrane and visceral bleeding; whether there are gastrointestinal discomfort symptoms such as nausea, vomiting, abdominal pain, diarrhea, etc.

[0066] (IV) Efficacy analysis

[0067] 1. Efficacy standards

[0068] Effective: Carotid IMT, Crouse score and plaque area were reduced compared with those before treatment; the number of unstable carotid plaques converted to stable plaques increased.

[0069] Stable: There is no obvious change in the plaque, but no cardiovascular or cerebrovascular events occur.

[0070] Ineffective: The number of plaques increases or the area increases.

[0071] 2. Treatment results

[0072] The treatment group was superior to the control group in reducing carotid intima-media thickness (IMT), plaque score, plaque area, total cholesterol, and triglycerides, all of which were significantly different (P < 0.05). Comparison of liver function, renal function, and cardiac enzymes between the two groups showed that there was no significant statistical significance in terms of safety between the two groups (P > 0.05).

[0073] 3. Clinical observation results

[0074] (1) Changes of IMT in the two groups before and after treatment

[0075] The comparison results of IMT changes between the two groups before and after treatment are shown in Table 1:

[0076] Table 1 Comparison of IMT changes between the two groups before and after treatment (mm)

[0077]

[0078] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to IMT based on professional knowledge analysis, and were used as covariates to analyze the changes in IMT after treatment in the treatment and control groups using covariance analysis.

[0079] As shown in Table 1, the IMT of the treatment group decreased after treatment compared with that before treatment, while the IMT of the control group did not improve after treatment compared with that before treatment, but there was no statistical significance (P>0.05). After treatment, the treatment group was superior to the control group in reducing IMT, with a significant difference (P<0.05).

[0080] (2) Comparison of plaque score changes before and after treatment

[0081] The comparison results of the changes in plaque scores between the two groups before and after treatment are shown in Table 2:

[0082] Table 2 Comparison of plaque score changes between the two groups before and after treatment

[0083]

[0084] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to plaque score based on professional knowledge analysis, and they were used as covariates to analyze the changes in plaque score between the treatment group and the control group after treatment using covariance analysis.

[0085] As shown in Table 2, the plaque score of the treatment group decreased after treatment compared with that before treatment, while the plaque score of the control group did not improve after treatment compared with that before treatment, but there was no statistical significance (P>0.05). After treatment, the treatment group was superior to the control group in reducing the plaque score, with a significant difference (P<0.05).

[0086] (3) Comparison of plaque area changes before and after treatment

[0087] The comparison results of the changes in plaque area between the two groups before and after treatment are shown in Table 3:

[0088] Table 3 Comparison of plaque area changes between the two groups before and after treatment (cm 2 )

[0089]

[0090] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to plaque area based on professional knowledge analysis, and they were used as covariates to analyze the changes in plaque area between the treatment group and the control group after treatment using covariance analysis.

[0091] As shown in Table 3, the plaque area of ​​the treatment group decreased after treatment compared with that before treatment, while the plaque area of ​​the control group did not improve after treatment compared with that before treatment, but there was no statistical significance (P>0.05). After treatment, the treatment group was better than the control group in reducing the plaque area, with a significant difference (P<0.05).

[0092] (4) Comparison of changes in total cholesterol (TC) before and after treatment

[0093] The comparison results of total cholesterol changes in the two groups before and after treatment are shown in Table 4:

[0094] Table 4 Comparison of total cholesterol changes between the two groups before and after treatment (mmol / L)

[0095]

[0096] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to TC based on professional knowledge analysis, and they were used as covariates to analyze the changes in TC after treatment in the treatment and control groups using covariance analysis.

[0097] As shown in Table 4, total cholesterol in both groups decreased after treatment compared with before treatment, but there was no statistical significance (P>0.05). After treatment, the treatment group was superior to the control group in reducing total cholesterol, with a significant difference (P<0.05).

[0098] (5) Comparison of triglyceride (TG) changes before and after treatment

[0099] The comparison results of triglyceride changes in the two groups before and after treatment are shown in Table 5:

[0100] Table 5 Comparison of triglyceride changes between the two groups before and after treatment (mmol / L)

[0101]

[0102] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to TG based on professional knowledge analysis, and they were used as covariates to analyze the changes in TG in the treatment and control groups after treatment using covariance analysis.

[0103] As shown in Table 5, the triglyceride levels of the two groups decreased after treatment compared with those before treatment, but there was no statistical significance (P>0.05). After treatment, the treatment group was superior to the control group in reducing triglyceride, with a significant difference (P<0.05).

[0104] (6) Comparison of changes in low-density lipoprotein (LDL) before and after treatment

[0105] The comparison results of low-density lipoprotein changes in the two groups before and after treatment are shown in Table 6:

[0106] Table 6 Comparison of low-density lipoprotein changes between the two groups before and after treatment (mmol / L)

[0107]

[0108]

[0109] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to LDL based on professional knowledge analysis, and they were used as covariates to analyze the changes in LDL after treatment in the treatment and control groups using covariance analysis.

[0110] As shown in Table 6, the low-density lipoprotein in both groups decreased after treatment compared with before treatment, and the difference in the control group after treatment was statistically significant (P < 0.05).

[0111] (7) Comparison of changes in high-density lipoprotein (HDL) before and after treatment

[0112] The comparison results of high-density lipoprotein changes in the two groups before and after treatment are shown in Table 7:

[0113] Table 7 Comparison of changes in high-density lipoprotein between the two groups before and after treatment (mmol / L)

[0114]

[0115] Note: * indicates the results of covariance analysis. Because there were differences in hsCRP, red blood cells, prothrombin time, plaque score and number of plaques between the two groups before treatment, these factors were related to HDL based on professional knowledge analysis, and they were used as covariates to analyze the changes in HDL after treatment in the treatment and control groups using covariance analysis.

[0116] As shown in Table 7, the high-density lipoprotein levels in the two groups after treatment tended to increase compared with those before treatment, which was statistically significant (P < 0.05).

[0117] In summary, the above test results show that the Chinese medicine composition of the present invention has a therapeutic effect on improving unstable plaques of carotid atherosclerosis.

[0118] 2. Double-blind trial

[0119] From March 1, 2017, to September 18, 2018, a prospective, single-center, randomized, double-blind, placebo-controlled trial of 118 patients was completed.

[0120] 1. Diagnostic criteria

[0121] 1. Diagnosis of carotid artery plaque

[0122] According to the "Carotid Ultrasound Examination Standards for Healthy Physical Examination Populations", the standards for unstable carotid plaques when using carotid color Doppler ultrasound are as follows:

[0123] Plaques were defined as localized ≥1.5 mm;

[0124] Unstable plaque: Ultrasound echo shows homogeneous hypoechoic plaques, irregular and ulcerative plaques.

[0125] Stable plaques: homogeneous isoechoic plaques and heterogeneous plaques with strong echoes.

[0126] 2. Diagnosis of carotid stenosis: According to the "Guidelines for the Diagnosis and Treatment of Carotid Stenosis", when angiography is used to examine the carotid artery lumen, the NASCET method is used to measure the degree of stenosis:

[0127] The stenosis degree of the NASCET method = (1-B / A) × 100% (if the entire internal carotid artery is narrowed after bifurcation, the contralateral carotid artery is taken for comparison), where A represents the basic inner diameter = the inner diameter of the lumen at the normal point beyond the carotid dilatation; B represents the measurement reference = the width of the carotid artery at the narrowest point.

[0128] 3. Plaque area: Measure the three diameters of each plaque separately, select the two diameters with the largest values ​​as the product of length and width, and the sum of the plaque areas of the carotid arteries on both sides is the total plaque area of ​​the patient.

[0129] 4. Plaque score: Crouse score is used, with the sum of the maximum thickness of each plaque in each blood vessel as the plaque score of the blood vessel, and the sum of the scores of both carotid arteries as the plaque score of each patient.

[0130] (II) Relevant standards

[0131] 1. Inclusion criteria

[0132] (1) Patients who meet the diagnostic criteria for carotid atherosclerosis and have a single maximum IMT > 1.5 mm in at least one arterial segment can be diagnosed as having a plaque.

[0133] (2) Ultrasound shows that carotid atherosclerotic plaques are unstable plaques.

[0134] (3) Those who can take medication for a long time.

[0135] (4) Aged 18 to 80 years old.

[0136] (5) Those who agree to participate in the clinical research and sign the informed consent form.

[0137] (6) Meet the diagnostic criteria for hyperlipidemia.

[0138] (7) No history of stroke or a history of stroke with no sequelae or few sequelae, with an mRS score of less than or equal to 2 points.

[0139] 2. Exclusion criteria

[0140] (1) mRS score was greater than or equal to 3 points before enrollment;

[0141] (2) Carotid artery stenosis ≥50%;

[0142] (3) definite or suspected diagnosis of vasculitis;

[0143] (4) Accompanied by infection, tumor, heart, liver, and kidney dysfunction (liver and kidney function is more than twice the upper limit of normal, and heart function grade is greater than or equal to grade 2);

[0144] (5) Combined with acute myocardial infarction and unstable angina;

[0145] (6) Patients with acute stroke;

[0146] (7) Severe stenosis or occlusion of intracranial blood vessels distal to the responsible lesion;

[0147] (8) Pregnant or lactating women;

[0148] (9) Known allergy to the trial drug.

[0149] 3. Criteria for excluding patients

[0150] After entering the clinical trial observation, patients who were mistakenly included because they did not meet the inclusion criteria and patients who met the inclusion criteria but did not take the medicine after inclusion can be regarded as excluded patients.

[0151] 4. Criteria for determination of dropout or loss to follow-up

[0152] (1) Those who were lost to follow-up within 6 months of treatment;

[0153] (2) those who voluntarily requested to withdraw from treatment within 6 months;

[0154] (3) Failure to take the study drug as required, taking less than 2 / 3 of the dose;

[0155] (4) Failure to complete the inspection and assessment within the required time;

[0156] (5) Patients who met the inclusion criteria specified in the clinical trial protocol but failed to complete the trial for some reason.

[0157] All of the above can be regarded as patients who dropped out or were lost to follow-up, including patients who dropped out voluntarily and patients who were identified as dropped out by doctors.

[0158] 5. Termination criteria

[0159] (1) Severe adverse reactions occurred during treatment;

[0160] (2) Patients who develop other serious illnesses or die during treatment.

[0161] (III) Grouping and sample size

[0162] The subjects were divided into an experimental group and a control group at a ratio of 1:1 according to the random block method, with 60 cases in each group; the grouping results were stored in opaque envelopes.

[0163] (IV) Experimental drugs and treatments

[0164] 1. Basic treatment for the two groups: Basic treatment was in accordance with the 2014 Chinese Guidelines for Secondary Prevention of Ischemic Stroke / Transient Ischemic Attack.

[0165] 2. Experimental group: The subjects took the Chinese medicine pills prepared in Example 1 twice a day, after breakfast and dinner, 6 g each time, and 10 mg / day of atorvastatin at the same time.

[0166] 3. Control group: Take placebo twice a day, 6 g each time, after breakfast and dinner, and take atorvastatin 10 mg / day at the same time. The placebo is composed of maltodextrin, powdered sugar, starch, and liquid caramel (all food grade), and the mass ratio of the four is 4.5:2.9:2.9:1. The appearance, taste and weight of the placebo are consistent with those of the Chinese medicine pills in Example 1.

[0167] The efficacy of both groups was observed after taking the medicine for 6 consecutive months.

[0168] (V) Observation indicators

[0169] 1. Carotid artery ultrasound examination

[0170] All patients were examined by two ultrasound physicians from the Ultrasound Department of our hospital. Hitachi Vius color Doppler ultrasound detector was used with a probe frequency of 10 MHz. The patients were placed in a supine position and the two-dimensional method was used to examine the bilateral common carotid arteries (CCA), carotid bifurcation (BIF), internal carotid artery origin (ICA), and external carotid artery (ECA) before and after 6 months of treatment. Carotid IMT was measured, and the morphology, size, number, location, and nature of plaques were recorded.

[0171] 2. Serological testing

[0172] Before treatment and 6 months after treatment, fasting venous blood was drawn in the morning and urine was collected for testing of blood lipids, blood and urine routine, liver and kidney function, coagulation function, creatine kinase, etc.

[0173] 3. Number of cardiovascular and cerebrovascular events

[0174] Cardiovascular and cerebrovascular events refer to events that produce vascular atherosclerosis, leading to organ lesions such as coronary heart disease and cerebral stroke. During the six-month follow-up, the occurrence of acute cerebral infarction, cerebral hemorrhage, and acute myocardial infarction events were recorded, and symptoms such as dizziness, headache, chest tightness, and chest pain were recorded. Calculated by case, if a patient had a stroke, a TIA, and an angina pectoris, it would be recorded as 3 cases. The number of fatal cardiovascular and cerebrovascular events and the survival period from the occurrence of cardiovascular and cerebrovascular events to death were recorded, and the endpoint events were recorded.

[0175] 4. Safety evaluation

[0176] Whether there is severe damage to liver and kidney function (alanine aminotransferase, aspartate aminotransferase, creatinine or urea nitrogen higher than 3 times the reference upper limit); whether there is related myopathy such as muscle soreness, increased cardiac enzymes (creatine kinase or creatine kinase isoenzyme higher than 3 times the reference upper limit); whether there is bleeding tendency such as nose bleeding, skin, mucous membrane and visceral bleeding; whether there are gastrointestinal discomfort symptoms such as nausea, vomiting, abdominal pain, diarrhea, etc.

[0177] (VI) Overall incidence of adverse reactions / events

[0178] 1. Divided into general adverse reactions / events and serious adverse events. General adverse reactions / events: mild symptoms or certain damage to important organs and tissues, easy to recover; serious adverse events: damage to important organs, disability, cancer, life-threatening, sequelae, or requiring hospitalization, and hospitalized patients need to extend their hospitalization period.

[0179] 2. For various adverse reactions that occur during treatment, according to previous studies, the adverse reactions that need to be observed include: gastrointestinal reactions, allergic reactions, liver damage, muscle damage, coagulation function, bleeding tendency, etc. The observers should record them and analyze the reasons.

[0180] 7. Outcome indicators

[0181] 1. Main outcome measures

[0182] Changes in carotid IMT, Crouse score, plaque area, and number of unstable carotid plaques after 6 months of treatment.

[0183] 2. Secondary efficacy outcome indicators

[0184] a. Changes in blood lipids after 6 months of treatment;

[0185] b. Whether cardiovascular and cerebrovascular events occurred during treatment and follow-up.

[0186] (VIII) Experimental results

[0187] Finally, 118 subjects were included, 59 in the experimental group and 59 in the control group.

[0188] 1. Comparison of carotid artery ultrasound indicators before and after treatment between the two groups

[0189] The intra-group comparison results of carotid artery color Doppler ultrasound indicators before and after treatment in the two groups are shown in Table 8:

[0190] Table 8 Comparison of carotid artery color Doppler ultrasound indicators before and after treatment in the two groups

[0191]

[0192] As can be seen from Table 8, the intra-group comparison of carotid ultrasound indicators before and after treatment in the experimental group and the control group showed that the Crouse score of the experimental group decreased after treatment compared with that before treatment, and the difference was statistically significant (P < 0.05). The carotid IMT and plaque area decreased compared with those before treatment, but the difference was not statistically significant (P > 0.05). After treatment, the bilateral IMT of the control group decreased compared with that before treatment (P < 0.05), the plaque score decreased compared with that before treatment, and the plaque area increased compared with that before treatment, but the difference was not statistically significant (P > 0.05). There was no significant change in the number of unstable plaques in the two groups before and after treatment.

[0193] 2. Comparison of blood lipid changes between the two groups before and after treatment

[0194] The comparison results of blood lipid changes in the two groups before and after treatment are shown in Table 9:

[0195] Table 9 Comparison of blood lipid changes in the two groups before and after treatment

[0196]

[0197] As can be seen from Table 9, total cholesterol in the experimental group decreased after treatment compared with before treatment, with a statistically significant difference (P < 0.05), triglycerides slightly increased, and low-density lipoprotein decreased compared with before treatment, with no statistically significant difference between the two (P > 0.05). Total cholesterol and triglycerides in the control group decreased compared with before treatment, and low-density lipoprotein slightly increased, with no statistically significant difference between the three (P > 0.05).

[0198] Subgroup analysis was also conducted on whether or not lipid-lowering drugs were taken. Among the subjects taking lipid-lowering drugs, there were 51 subjects in the experimental group and 51 subjects in the control group. The changes in blood lipids of the subjects taking lipid-lowering drugs in the two groups before and after treatment were compared. The results are shown in Table 10:

[0199] Table 10 Comparison of blood lipid changes before and after treatment in the two groups of subjects taking lipid-lowering drugs

[0200]

[0201] As can be seen from Table 10, total cholesterol, triglycerides and low-density lipoprotein in both groups after treatment were lower than those before treatment. The total cholesterol and low-density lipoprotein in the experimental group after treatment were significantly different from those before treatment (P < 0.05), and the triglyceride was not significantly different from that before treatment (P > 0.05). The total cholesterol and triglyceride in the control group after treatment were significantly different from those before treatment (P < 0.05), and the low-density lipoprotein was not significantly different from that before treatment (P > 0.05).

[0202] Traditional statins target low-density lipoprotein, and generally achieve lipid-lowering and plaque-stabilizing effects by reducing low-density lipoprotein content. However, the results of this study found that on the basis of both groups using statins to lower lipids, the low-density lipoprotein in the experimental group decreased more significantly after treatment, suggesting that the Chinese medicine composition of the present invention has a lipid-lowering effect, and the action pathway is similar to that of statins.

[0203] In summary, the above experiments show that the Chinese medicine composition of the present invention has an anti-atherosclerotic effect in reducing the carotid artery plaque score, and can effectively reduce the levels of total cholesterol and low-density lipoprotein.

Claims

1. A Chinese medicine composition for treating unstable carotid artery plaque, characterized in that: The effective ingredients include the following raw materials in parts by weight: 5-30 parts of salvia miltiorrhiza, 5-30 parts of chicken gizzard lining, 10-50 parts of sun-dried ginseng, 3-30 parts of notoginseng, 3-15 parts of leech and 20-60 parts of pine needles.

2. The Chinese medicine composition for treating unstable carotid plaque according to claim 1, characterized in that: The effective ingredients include the following raw materials in parts by weight: 20 parts of salvia miltiorrhiza, 20 parts of chicken gizzard lining, 40 parts of sun-dried ginseng, 20 parts of notoginseng, 10 parts of leeches and 60 parts of pine needles.

3. The Chinese medicine composition for treating unstable carotid plaque according to claim 1 or 2, characterized in that: Pharmaceutically acceptable excipients may also be added.

4. The Chinese medicine composition for treating unstable carotid plaque according to claim 3, characterized in that: The auxiliary material is at least one of a sustained-release agent, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant, and a lubricant.

5. The Chinese medicine composition for treating unstable carotid plaque according to claim 1 or 2, characterized in that: The dosage form of the Chinese medicine composition is pills, granules, decoction, paste, powder, tablet or capsule.

6. A method for preparing the Chinese medicine composition for treating unstable carotid plaque according to any one of claims 1 to 5, characterized in that: When the dosage form of the Chinese medicine composition is a pill, the preparation method thereof comprises the following steps: (1) Grind the above 6 raw materials into fine powder, pass through a No. 6 sieve, and mix evenly to obtain fine drug powder; (2) Spray water in the pill pan to moisten it, sprinkle 45% of the drug fine powder obtained in step (1), rotate the pill pan to brush off the powder particles attached to the pan wall, spray water again, sprinkle powder, repeat this cycle, and gradually increase the powder particles until they are spherical particles with a diameter of 0.8-1.2 mm. Sieve the particles between the No. 1 sieve and the No. 2 sieve to obtain pill molds; (3) 45% of the fine drug powder obtained in step (1) is mixed with water to form a slurry with a relative density of 1.32-1.33, which is set aside; the above-mentioned pellet mold is placed in a pelletizing pot and rotated until the pellet mold rolls smoothly along the pot wall, and the slurry is sprayed in the reverse direction by the spray gun to perform pelletizing, and the feed is added in a cycle until the pellets are spheronized and then screened to obtain pellets with a diameter of 3-6 mm; (4) The pellets are fully moistened, and then the fine drug powder obtained in the remaining step (1) is evenly sprinkled on the pellets, and rolled in a pellet pan to obtain water pills; (5) Dry the water pellets at a temperature below 80°C for 1-2 hours to ensure that the water content of the water pellets does not exceed 9%; (6) After drying, a pill picker is used to separate qualified pellets from deformed pellets to obtain round pellets.

7. Use of the Chinese medicine composition for treating unstable carotid plaques according to any one of claims 1 to 5 in the preparation of a medicament for treating unstable carotid plaques.

8. Use of the Chinese medicine composition for treating unstable carotid plaque according to any one of claims 1 to 5 in the preparation of a medicament for preventing and / or treating atherosclerosis, ischemic stroke or transient ischemic attack.

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