Traditional Chinese medicine composition for treating carotid atherosclerosis complicated with hyperlipemia, granular preparation and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine composition for treating carotid atherosclerosis complicated with hyperlipemia, a granular preparation and a preparation method of the traditional Chinese medicine composition. The traditional Chinese medicine composition for treating carotid atherosclerosis complicated with hyperlipemia is mainly prepared from the following components in parts by weight: 8-12 parts of ligusticum wallichii, 8-12 parts of radix paeoniae rubra, 3-7 parts of coptis chinensis, 8-12 parts of red yeast rice and 3-7 parts of honey-fried licorice root. The traditional Chinese medicine composition provided by the invention can be used for treating frequently-occurring diseases and common diseases-carotid atherosclerosis complicated with hyperlipidemia in the field of prevention and treatment of cardiovascular diseases, and has a good curative effect. Moreover, the traditional Chinese medicine composition is prepared into a granular preparation in a certain manner, and the forming rate, the dissolution rate, the bulk density, the angle of repose, the moisture absorption rate and the like of the preparation are ensured, so that the drug effect of the preparation is ensured, the storage time of the product is prolonged, the acceptance degree of a patient is considered, and large-scale production is easy to realize.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and in particular to a traditional Chinese medicine composition and a granule preparation for treating carotid atherosclerosis combined with hyperlipidemia and a preparation method thereof. Background Art

[0002] Atherosclerosis (AS) is the pathological basis of cardiovascular and cerebrovascular diseases. How to effectively inhibit the formation and rupture of AS plaques and reduce the occurrence of cardiovascular events is a major clinical scientific issue and research hotspot. Elevated blood lipids are an important risk factor for AS diseases. The carotid artery is a window that reflects the formation and evolution of systemic AS diseases. The risk of stroke, myocardial infarction and death in patients with cervical AS is significantly increased.

[0003] The main strategy for the prevention and treatment of atherosclerosis is lipid-lowering. Statins are commonly used lipid-lowering drugs, but statin-enhanced lipid-lowering therapy is often accompanied by intolerable side effects. At present, there is a lack of effective Chinese medicine for the patient group of patients with carotid atherosclerosis and hyperlipidemia in clinical practice. The development of a Chinese medicine composition that can effectively prevent and treat carotid atherosclerosis and hyperlipidemia has important clinical significance and scientific value.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] One object of the present invention is to provide a Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia, which can effectively prevent and treat carotid atherosclerosis combined with hyperlipidemia and has no toxic side effects.

[0006] Another object of the present invention is to provide a Chinese medicine granule preparation for treating carotid atherosclerosis combined with hyperlipidemia.

[0007] Another object of the present invention is to provide a method for preparing a Chinese medicine granule preparation for treating carotid atherosclerosis combined with hyperlipidemia.

[0008] In order to achieve the above-mentioned object of the present invention, the present invention provides a Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia, which is mainly prepared from the following components by weight:

[0009] 8-12 parts of Chuanxiong, 8-12 parts of red peony root, 3-7 parts of Coptis chinensis, 8-12 parts of red yeast rice and 3-7 parts of roasted liquorice.

[0010] In a specific embodiment of the present invention, the Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia is mainly prepared from the following components in parts by weight:

[0011] 10 parts of Ligusticum chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of preparatory liquorice.

[0012] In a specific embodiment of the present invention, the traditional Chinese medicine composition further comprises dextrin.

[0013] Another aspect of the present invention provides a Chinese medicine granule preparation for treating carotid atherosclerosis combined with hyperlipidemia, which is prepared by using any one of the above-mentioned Chinese medicine compositions for treating carotid atherosclerosis combined with hyperlipidemia.

[0014] Another aspect of the present invention provides a method for preparing any one of the above-mentioned Chinese medicine granule preparations, comprising the following steps:

[0015] (a) weighing chuanxiong, red peony root, coptis root, red yeast rice and licorice root according to weight to obtain a mixed medicinal material; extracting the mixed medicinal material three times with water, combining the water extracts, filtering and concentrating to obtain an extract;

[0016] (b) mixing the extract with dextrin in a mass ratio of 1:(1.8-2.2), granulating, drying, and granulating to obtain the Chinese medicine granule preparation;

[0017] The relative density of the extract at 50°C is 1.2-1.25 g / cm 3 In a specific embodiment of the present invention, in the three water extractions, the solid-liquid ratio of the first extraction is 1:(10-12), and the time of the first extraction is 0.5-1h; the solid-liquid ratio of the second extraction is 1:(8-10), and the time of the second extraction is 0.5-1h; the solid-liquid ratio of the third extraction is 1:(8-10), and the time of the third extraction is 0.5-1h.

[0018] In a specific embodiment of the present invention, a fluidized bed is used for the granulation, the material temperature is 80-90° C., the inlet air temperature is 100-110° C., and the feed speed is 280-320 rpm.

[0019] In a specific embodiment of the present invention, the drying is carried out in an oven at 75-85° C., and the drying time is 1-2 hours.

[0020] In a specific embodiment of the present invention, the granules are sieved through a 10-60 mesh sieve.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) The Chinese medicine composition provided by the present invention has good therapeutic effect on the patient group of carotid atherosclerosis combined with hyperlipidemia, which is a common disease in the field of cardiovascular disease prevention and treatment;

[0023] (2) The present invention prepares the Chinese medicine composition into a granular preparation in a certain manner without changing the efficacy of the Chinese medicine composition, thereby ensuring the molding rate, dissolution rate, bulk density, angle of repose and moisture absorption rate of the preparation, and ensuring the efficacy of the preparation, extending the storage time of the product, taking into account the patient's acceptance, and being easy to achieve large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0025] Figure 1 Pathological HE-stained sections of carotid arteries of mice in each group (×200);

[0026] Figure 2 is the ratio of plaque area / vessel area in carotid artery sections of mice in each group;

[0027] Figure 3 The immunohistochemical staining of CD68 protein in the carotid artery tissue of mice in each group (×400);

[0028] Figure 4 Immunofluorescence expression of CD86 and CD206 in carotid artery tissues of mice in each group (×200);

[0029] Figure 5 The protein expressions of iNOS, Arg-1, PPARγ, and NF-κB p65 in the carotid artery tissues of mice in each group;

[0030] Figure 6 The comparison results of four blood lipids between the two groups of patients;

[0031] Figure 7 This is the comparison result of carotid intima-media thickness between the two groups of patients;

[0032] Figure 8 The comparison results of inflammation-related factors between the two groups of patients;

[0033] Fig. 9 This is the comparison result of TCM syndrome scores between the two groups of patients;

[0034] Fig.10 This is the comparison result of the efficacy of TCM syndrome between the two groups of patients;

[0035] in, Figure 1 to Figure 5In the data, Normal is the normal group, Model is the model group, Atorvastatin is the statin group, HXJD is the Chinese medicine equivalent dose group, H-HXJD is the Chinese medicine high dose group, and HXJD+Atorvastatin is the combined medication group. DETAILED DESCRIPTION

[0036] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0037] In one aspect, the present invention provides a Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia, which is mainly prepared from the following components by weight:

[0038] 8-12 parts of Chuanxiong, 8-12 parts of red peony root, 3-7 parts of Coptis chinensis, 8-12 parts of red yeast rice and 3-7 parts of roasted liquorice.

[0039] The Chinese medicine composition provided by the present invention can have a good therapeutic effect on a patient group suffering from a frequently-occurring and common disease in the field of cardiovascular disease prevention and treatment, namely, carotid atherosclerosis combined with hyperlipidemia.

[0040] Chuanxiong, pungent, warm, enters the liver and gallbladder meridians, can be used to promote blood circulation and qi, dispel wind and relieve pain, and has certain effects on headaches, irregular menstruation, and promoting blood circulation and qi. Red peony root, bitter, slightly cold, enters the liver meridian, has the effects of clearing heat and cooling blood, promoting blood circulation and removing blood stasis. Coptis chinensis, bitter, cold in nature, enters the heart, spleen, stomach, liver, gallbladder, and large intestine meridians, has the effects of clearing heat and drying dampness, purging fire and detoxifying. Red yeast rice, sweet in nature and warm, can help digestion and harmonize the stomach, promote blood circulation and relieve pain, strengthen the spleen, and dry the stomach. Roasted licorice, flat in nature, slightly warm, is good at tonifying the spleen and stomach, tonifying the middle and relieving urgency, and replenishing qi and restoring the pulse. The Chinese medicine composition of the present invention is prepared by compounding Chuanxiong, red peony root, coptis root, red yeast rice and licorice root in proportion. Chuanxiong is pungent, fragrant, warm and dry, and has a good nature of moving around. It can not only promote blood circulation and remove blood stasis, but also promote qi circulation and relieve stagnation, and can move qi upward to the head and reach the sea of ​​blood downward, and relieve depression in the middle, so it is a "blood-qi medicine"; red peony root is bitter and cold in nature, can clear away heat and cool blood, promote blood circulation and relieve pain, and can control the warm and dry nature of Chuanxiong. The two medicines complement each other in medicinal properties when used together, and play the effect of promoting blood circulation and removing blood stasis; coptis root is very bitter and cold, can clear away heat, purge fire and detoxify , Coptis chinensis can purge qi and heat, while red peony root can clear nutrient heat. The combination of the two medicines can synergistically enhance the heat-clearing effect; Red yeast rice is sweet and warm in nature, and is good at breaking blood and activating blood circulation, lowering fat and clearing turbidity. It has a wide range of pharmacological effects such as lowering blood lipids, blood sugar, and blood pressure. When used together with red peony root and Chuanxiong, they can achieve the functions of mutual dependence, mutual assistance, and mutual promotion; Roasted licorice is mild and slightly warm in nature, and can tonify the middle and relieve urgency. The combination of these medicines is good at activating blood circulation and detoxifying, and can achieve the prevention and treatment of carotid atherosclerosis combined with hyperlipidemia.

[0041] For example, in different embodiments, the amounts of each component in the Chinese medicine composition can be as follows by weight:

[0042] The dosage of Chuanxiong can be 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, or any value between two of them or a range consisting of any two of them;

[0043] The dosage of red peony root can be 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, or any two of them or a range consisting of any two of them;

[0044] The dosage of Coptis chinensis can be 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, or any two of them or a range consisting of any two of them;

[0045] The amount of red yeast rice can be 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, or any value between them or a range consisting of any two of them;

[0046] The dosage of licorice root can be 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, or any point value between any two of them or a range consisting of any two of them.

[0047] In a specific embodiment of the present invention, the Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia is mainly prepared from the following components in parts by weight:

[0048] 10 parts of Ligusticum chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of preparatory liquorice.

[0049] The present invention further optimizes the ratio of Chuanxiong, red peony root, coptis root, red yeast rice and licorice. When the dosage of the five components meets the above conditions, it is more helpful to take into account the content and ratio of the main active ingredients of each traditional Chinese medicine in the case of co-extraction, which is beneficial to exerting the efficacy.

[0050] In a specific embodiment of the present invention, the Chinese medicine composition further comprises dextrin.

[0051] For Chinese medicine compositions, whether liquid or solid dosage forms, most still have obvious bitterness. In order to improve patient acceptance and improve patient compliance, some components can be added to eliminate or cover bitterness to achieve corresponding effects. However, the introduction of other components may affect drug efficacy on the one hand, resulting in greater difficulty in product quality control, and on the other hand, change drug dissolution and affect bioavailability. The present invention further cooperates with the granulation method of granular preparations through the introduction of dextrin, takes into account the excellent forming rate, dissolution rate, bulk density, angle of repose and moisture absorption rate of granular preparations, and ensures the stability, drug efficacy and medication compliance of the preparation.

[0052] Another aspect of the present invention provides a Chinese medicine granule preparation for carotid atherosclerosis combined with hyperlipidemia, which is prepared by using any one of the above-mentioned Chinese medicine compositions for carotid atherosclerosis combined with hyperlipidemia.

[0053] Another aspect of the present invention provides a method for preparing any one of the above-mentioned Chinese medicine granule preparations, comprising the following steps:

[0054] (a) weighing chuanxiong, red peony root, coptis root, red yeast rice and licorice root according to weight to obtain a mixed medicinal material; extracting the mixed medicinal material three times with water, combining the water extracts, filtering and concentrating to obtain an extract;

[0055] (b) mixing the extract and dextrin in a mass ratio of 1:(1.8-2.2), granulating, drying, and granulating to obtain a Chinese medicine granule preparation;

[0056] The relative density of the extract at 50°C is 1.2-1.25 g / cm 3 .

[0057] The preparation method of the Chinese medicine granule preparation of the present invention has the advantages of easy granulation and large-scale production. At the same time, the prepared granules have suitable forming rate, dissolution rate, bulk density, repose angle and moisture absorption rate, etc., and the long-term stability of the granule preparation is improved, which is helpful to improve the storage stability of the granule preparation and ensure the long-term drug effect.

[0058] The introduction of dextrin can, on the one hand, improve the adhesion and drug adhesion when mixed with the extract; on the other hand, it can improve the solubility of the granular preparation in water, and can also reduce the bitterness of the pharmaceutical composition to a certain extent. However, studies have found that when the amount of dextrin is too high, the viscosity is too high, the size of the obtained particles is large, and the molding rate is too low; and the excessive introduction of dextrin is likely to increase the hygroscopicity of the particles, affecting the storage stability; and when the amount of dextrin is too low, the viscosity is relatively low, the size of the obtained particles is small, which also leads to a low molding rate, and there is less dextrin, the degree of masking the bitterness is low, and the dissolution rate of the particles is insufficient, affecting the efficacy. In the preparation of the granular preparation of the Chinese medicine composition of the present invention, the mass ratio of the extract to dextrin can be 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2 or any point value between the two or any range composed of the two, and the ratio is adjusted within the above range, which helps to take into account the multi-faceted performance of the granular preparation.

[0059] Through research, it was found that the viscosity of the concentrated extract has a certain influence on the subsequent granulation process. After concentration, the viscosity of the liquid changes significantly. If the concentration degree of the water extract is too high, the viscosity of the liquid extract obtained is too large, and the size of the obtained particles is larger; if the concentration degree of the water extract is too low, the viscosity of the liquid extract obtained is too small, and the size of the obtained particles is smaller; the forming rate is low. The present invention adjusts the relative density of the extract and combines it with a certain proportion of dextrin. It can form particles in one step without adding other substances, which significantly improves production efficiency; at the same time, in the granulation process, it helps to form particles of moderate size, ensure the particle forming rate, and ensure the various properties of the particles. For example, in different embodiments, the relative density of the extract of the present invention at 50°C can be 1.2g / cm 3 , 1.21g / cm 3 , 1.22g / cm 3 , 1.23g / cm 3 , 1.24g / cm 3 , 1.25g / cm 3 Or a range consisting of any two of them.

[0060] In the granule preparation process of the present invention, the granules can be smoothly prepared only by compounding the extract and dextrin without adding additional auxiliary agents. In addition, the present invention reduces the content of dextrin at the same dose through compounding the extract and dextrin, which is convenient for patients to take, shortens the subsequent drying time, avoids the loss of active ingredients, and ensures the granule yield and low hygroscopicity.

[0061] In a specific embodiment of the present invention, in the three water extractions, the solid-liquid ratio of the first extraction is 1:(10-12), and the time of the first extraction is 0.5-1h; the solid-liquid ratio of the second extraction is 1:(8-10), and the time of the second extraction is 0.5-1h; the solid-liquid ratio of the third extraction is 1:(8-10), and the time of the third extraction is 0.5-1h.

[0062] With reference to the relevant detection index components of Chinese medicinal materials in the "Chinese Pharmacopoeia", the extraction conditions are explored according to the content of the index components and the solid yield obtained by extraction. The solid-liquid ratio and extraction time of the three water extractions of the present invention are regulated to ensure the content of active ingredients of each component, so as to give full play to the compatibility effect and ensure the solid yield obtained by extraction. It should be noted that the solid-liquid ratio in the present invention is defined according to the ratio of g:mL. For example, in different embodiments, the solid-liquid ratio of the first extraction can be 1:10, 1:10.5, 1:11, 1:11.5, 1:12 or a range consisting of any two thereof; the time of the first extraction can be 0.5h, 0.6h, 0.8h, 1h or a range consisting of any two thereof; the solid-liquid ratio of the second extraction can be 1:8, 1:8.5, 1:9, 1:9.5, 1:10 or a range consisting of any two thereof; the time of the second extraction can be 0.5h, 0.6h, 0.8h, 1h or a range consisting of any two thereof; the solid-liquid ratio of the third extraction can be 1:8, 1:8.5, 1:9, 1:9.5, 1:10 or a range consisting of any two thereof; the time of the third extraction can be 0.5h, 0.6h, 0.8h, 1h or a range consisting of any two thereof. Under the extraction conditions of the present invention, if the extraction time is further extended, not only the time cost will be increased, but also the impurities (ineffective ingredients) will increase, the proportion of active ingredients in the extract will be reduced, and the efficacy will be reduced.

[0063] In a specific embodiment of the present invention, a fluidized bed is used for granulation. In the fluidized bed granulation, the material temperature is 80-90° C., the inlet air temperature is 100-110° C., the feed speed is 280-320 rpm, and the atomization pressure is 0.1-0.2 MPa.

[0064] For example, in different embodiments, in fluidized bed granulation, the material temperature can be 80°C, 82°C, 85°C, 88°C, 90°C or any two thereof; the air inlet temperature can be 110°C, 112°C, 115°C, 118°C, 112°C or any two thereof; the feed rate can be 280rpm, 290rpm, 300rpm, 310rpm, 320rpm or any two thereof; the atomization pressure can be 0.1MPa, 0.12MPa, 0.15MPa, 0.18MPa, 0.2MPa or any two thereof. By adjusting the conditions of fluidized bed granulation within the above range and matching the corresponding material ratio, the particle forming rate and particle performance can be guaranteed.

[0065] In a specific embodiment of the present invention, in step (b), drying is carried out in an oven at 75-85° C., and the drying time is 1-2 hours.

[0066] In a specific embodiment of the present invention, the granules are sieved through a 10-60 mesh sieve.

[0067] In actual operation, 10-mesh sieve and 60-mesh sieve are used for granulation.

[0068] Example 1

[0069] This embodiment provides a method for preparing a Chinese medicine composition and a granule preparation thereof for treating carotid atherosclerosis combined with hyperlipidemia. The Chinese medicine composition is mainly prepared from the following components in parts by weight:

[0070] 10 parts of Ligusticum chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of preparatory liquorice.

[0071] The preparation method of the granule preparation of the Chinese medicine composition comprises the following steps:

[0072] (1) Weigh Chuanxiong, red peony root, coptis root, red yeast rice and licorice according to the proportion, mix them, add water at a solid-liquid ratio of 1:12, decoct and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:10, decoct and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:10, decoct and extract for 1 hour, collect the water extract; combine the three water extracts, filter, and concentrate under reduced pressure at a concentration pressure of 0.25 MPa and a concentration temperature of 70°C to obtain an extract, the relative density of the extract at 50°C is 1.22 g / cm 3 .

[0073] (2) The extract and dextrin were mixed evenly at a mass ratio of 1:2; then, granules were made using a fluidized bed with a 12-mesh sieve (during granulation, the material temperature was 85°C, the inlet air temperature was 105°C, the feed rate was 300 rpm, and the atomization pressure was 0.1 MPa). After being dried in an oven at 80°C for 1 h, granules were sized using a 10-mesh sieve and a 60-mesh sieve. Granules that passed through the 10-mesh sieve but not the 60-mesh sieve were taken as the finished granule preparation.

[0074] Example 2 Group

[0075] This example is carried out with reference to Example 1, except that the extraction conditions of step (1) are different, and the specific differences are as follows:

[0076] Example 2a: The mixture was boiled and extracted for 0.5 h at a solid-liquid ratio of 1:10, and the water extract was collected; the mixture was boiled and extracted for 0.5 h at a solid-liquid ratio of 1:8, and the water extract was collected; the mixture was boiled and extracted for 0.8 h at a solid-liquid ratio of 1:8, and the water extract was collected; the subsequent concentration was the same as in Example 1;

[0077] Example 2b: The mixture was boiled and extracted for 1.5 hours at a solid-liquid ratio of 1:12, and the water extract was collected; the mixture was boiled and extracted for 1.5 hours at a solid-liquid ratio of 1:10, and the water extract was collected; the mixture was boiled and extracted for 1.5 hours at a solid-liquid ratio of 1:10, and the water extract was collected; the subsequent concentration was the same as in Example 1;

[0078] Example 2c: Add water at a solid-liquid ratio of 1:15, decoct and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:12, decoct and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:12, decoct and extract for 1 hour, collect the water extract; subsequent concentration is the same as in Example 1;

[0079] Example 2d: Add water at a solid-liquid ratio of 1:8 and boil for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:8 and boil for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:8 and boil for 1 hour, collect the water extract; subsequent concentration is the same as in Example 1;

[0080] Example 2e: Add water at a solid-liquid ratio of 1:12, boil and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:10, boil and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:10, boil and extract for 1 hour, collect the water extract; then add water at a solid-liquid ratio of 1:10, boil and extract for 1 hour, collect the water extract; subsequent concentration is the same as Example 1.

[0081] By testing the solid yield and index component content in the combined water extract obtained by different extraction processes of Example 1 and Example 2, it was found that the solid yield and index component content of the water extract obtained by the extraction process of Example 1 were the best, followed by Example 2a, while Examples 2b to 2e could not take into account both the solid yield and index component content, and the effects were not as good as those of Example 1 and Example 2a.

[0082] Specifically, by comparing Example 1 and Example 2b, it can be seen that when the extraction time is extended, the yield of the index component does not change significantly; by comparing Example 1 and Example 2c, it can be seen that when the amount of water is increased, the yield of the index component does not increase significantly. At the same time, due to the increase in the amount of water, the subsequent concentration time increases, which is more likely to cause the loss of effective ingredients; by comparing Example 1 and Example 2d, it can be seen that when the amount of water is reduced, the yield of the index component decreases; by comparing Example 1 and Example 2e, it can be seen that the yield of the index component does not change significantly when the number of extractions is increased.

[0083] Example 3 Group

[0084] This example is carried out with reference to Example 1, except that the relative density of the extract obtained by vacuum concentration in step (1) is different, as shown below:

[0085] Example 3a: The relative density of the obtained extract at 50°C is 1.20 g / cm 3 ;

[0086] Example 3b: The relative density of the obtained extract at 50°C is 1.25 g / cm 3 ;

[0087] Example 3c: The relative density of the obtained extract at 50°C is 1.15 g / cm 3 ;

[0088] Example 3d: The relative density of the obtained extract at 50°C is 1.30 g / cm 3 .

[0089] By testing the particle forming rates obtained by granulating with different extract densities in Example 1 and Example 3, it was found that the particle forming rate obtained under the extract density condition of Example 1 was higher, the particle forming rate obtained under the extract density condition of Examples 3a to 3c was also higher, but the particle forming rate obtained under the extract density condition of Example 3d was lower.

[0090] According to the above test results, the relative density of the extract at 50°C is regulated to be between 1.2 and 1.25 g / cm 3The range of the molding rate of the obtained particles can be guaranteed. By comparing Example 1 and Example 3c, it can be seen that when the relative density of the extract is low, although the molding rate is relatively high, the obtained particles have relatively poor fluidity and are easy to absorb moisture; by comparing Example 1 and Example 3d, it can be seen that when the relative density of the extract is high, although it is easy to form, the viscosity is large and the particle size is large, resulting in a low molding rate.

[0091] Example 4 Group

[0092] This example is carried out with reference to Example 1, except that the type or amount of auxiliary materials used in step (2) is different, and the specific differences are as follows:

[0093] Example 4a: The mass ratio of the extract to dextrin is 1:1.8, and the rest remains unchanged;

[0094] Example 4b: The mass ratio of the extract to dextrin is 1:2.2, and the rest remains unchanged;

[0095] Example 4c: The mass ratio of the extract to dextrin is 1:1.5, and the rest remains unchanged;

[0096] Example 4d: The mass ratio of the extract to dextrin is 1:2.5, and the rest remains unchanged;

[0097] Example 4e: The dextrin in Example 1 was replaced with an equal weight of lactose, and the rest remained unchanged;

[0098] Example 4f: The dextrin in Example 1 is replaced by an equal weight of soluble starch, and the rest remains unchanged;

[0099] Example 4g: The dextrin in Example 1 was replaced by an equal weight of microcrystalline cellulose, and the rest remained unchanged;

[0100] Example 4h: The dextrin in Example 1 was replaced with an equal weight of mannitol, and the rest remained unchanged.

[0101] The finished granule preparations obtained by using different excipients in Example 1 and Example 4 were comprehensively evaluated using moisture absorption rate, forming rate, dissolution rate, bulk density, angle of repose, and economy as indicators.

[0102] In the calculation method of comprehensive evaluation index, comprehensive evaluation index = (20 / maximum formability value) × formability value + (15 / maximum bulk density value) × bulk density value + (minimum angle of repose value × 15) / angle of repose value + (20 / maximum solubility value) × solubility value + (minimum moisture absorption value × 20) / moisture absorption value + (minimum economic value × 10) / economic value.

[0103] Among them, molding rate: refer to the double screening method under the granule particle size item under Part 4 of the 2020 edition of the Chinese Pharmacopoeia, and pass the prepared granule product through a No. 1 sieve and a No. 5 sieve. The particles that can pass through the No. 1 sieve and cannot pass through the No. 5 sieve are qualified particles. Molding rate (%) = (grid particle weight / total particle amount) × 100. Maximum molding value: the maximum value among the five groups of molding rate values ​​measured.

[0104] Bulk density: Take 4g of formed granules and weigh them, then put them into a measuring cylinder, and vibrate them up and down to make the granules compact. Read the mL number near the scale, i.e. the volume, and calculate the bulk density. Bulk density = (granule weight / granule volume) × 100%. Maximum bulk density value: the maximum value among the five groups of bulk density values ​​measured.

[0105] Angle of repose: Use the serial funnel method, use an iron stand to connect three funnels in series and fix them on a flat coordinate paper, 1 cm above the coordinate paper, pour the particles along the funnel wall into the highest funnel, and stop when the top of the particle cone on the coordinate paper touches the bottom of the funnel. Record the diameter of the cone bottom as 2R, calculate the angle of repose α, α = arctan (H / R), repeat the measurement 5 times, and calculate the average value. Minimum angle of repose value: the minimum value among the five groups of angle of repose values ​​measured.

[0106] Dissolution rate: Dry a 50mL centrifuge tube to constant weight, accurately weigh 1g of granules into the centrifuge tube, add 20mL of boiling water, stir and shake, centrifuge at 4000r / min for 10min, discard the supernatant, dry the residue at 80℃ to constant weight, accurately weigh the mass, and calculate the dissolution rate, dissolution rate (%) = (dissolved granule mass / total granule mass) × 100%. Maximum solubility value: the maximum value among the five groups of solubility values ​​measured.

[0107] Moisture absorption rate: Place a desiccator with saturated sodium chloride at room temperature for 48 hours, and make the relative humidity in the desiccator 75%. Accurately weigh 1g of the prepared granules into a weighing bottle with constant weight, and dry to constant weight. Remove the bottle cap of the granules with constant weight and place them in a desiccator with saturated sodium chloride. After 48 hours, accurately weigh them. Moisture absorption rate (%) = (weight of granules after moisture absorption - weight of granules before moisture absorption) / weight of granules before moisture absorption × 100%. Minimum moisture absorption rate value: the minimum value among the five groups of moisture absorption values ​​measured.

[0108] Economy: The unit price of 1 kg of each auxiliary material. Minimum economy: The lowest value among the unit prices of the five auxiliary materials.

[0109] According to the above-mentioned comprehensive evaluation index calculation method, the present invention adopts the extract and dextrin in a ratio of 1: (1.8-2.2), which is more helpful to ensure the moisture absorption rate, molding rate, dissolution rate, bulk density, angle of repose and economy of the finished granule preparation. Preferably, the extract and dextrin are used in a ratio of 1:2.

[0110] Example 5 Group

[0111] This example is carried out with reference to Example 1, except that the dosages of Chuanxiong, red peony root, coptis root, red yeast rice and licorice root are different, and the specific differences are as follows:

[0112] Example 5a: comprising 8 parts of Chuanxiong, 8 parts of red peony root, 3 parts of coptis root, 8 parts of red yeast rice and 3 parts of licorice root by weight;

[0113] Example 5b: comprising 12 parts of Chuanxiong, 12 parts of red peony root, 7 parts of coptis root, 12 parts of red yeast rice and 7 parts of licorice root by weight;

[0114] Example 5c: comprising 5 parts of Chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of licorice root by weight;

[0115] Example 5d: comprising 15 parts of Chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of licorice root by weight;

[0116] Example 5e: comprising, by weight, 10 parts of Chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 5 parts of red yeast rice and 5 parts of licorice root;

[0117] Example 5f: The composition comprises 10 parts of Chuanxiong, 10 parts of red peony root, 5 parts of Coptis chinensis, 15 parts of red yeast rice and 5 parts of pre-fried liquorice root, by weight.

[0118] Experimental Example 1

[0119] The stability of the finished granule preparation of Example 1 was studied by long-term stability test and accelerated stability test. The stability test verified that the stability of the finished granule preparation obtained by the granulation conditions of Example 1 of the present invention was significantly better than that of the other Examples 2-4.

[0120] Long-term stability test: The long-term stability test adopts the method of retaining samples under conditions close to the actual storage of drugs. The pilot samples of the finished granule preparation are placed in commercial packaging (polyester / aluminum / polyethylene composite film for drug packaging) and placed at room temperature for 6 months. Samples are taken for inspection at 0, 3, and 6 months, and samples are taken 3 times in total for 6 months. The results show that the pilot samples of the finished granule preparation prepared in Example 1 of the present invention have high long-term stability.

[0121] The finished granule preparations after packaging are brown-yellow granules after 0, 3, and 6 months; they have a slight odor and a slightly bitter taste.

[0122] According to the thin layer chromatography method (General Chapter 0502 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia"), after 0, 3, and 6 months of testing, the position and fluorescence of the main spots of the solution prepared from the pilot sample of the finished granule preparation were consistent with those of the paeoniflorin reference substance, chuanxiong reference medicinal material, red yeast rice reference medicinal material, berberine hydrochloride reference substance, coptis chinensis reference medicinal material, and licorice reference medicinal material, respectively. The standard substances were all purchased from China Food and Drug Inspection Institutes.

[0123] The filling volume difference of the finished granule preparations was determined as follows: 10 bags of the finished granule preparations were randomly selected, the packaging was removed, the weight of the contents of each bag was accurately weighed, and the weight of the contents of each bag was compared with the labeled filling volume. The results showed that the filling volume differences of the three batches of finished granule preparations were within the limit (±5%), which met the requirements of the pharmacopoeia.

[0124] The particle size is determined according to the particle size and particle size distribution determination method in the "Pharmacopoeia of the People's Republic of China (2020 Edition)"; the moisture content is determined according to the moisture determination method in the "Pharmacopoeia of the People's Republic of China (2020 Edition)"; the total aerobic bacteria, total mold and yeast counts of the finished granule preparation are tested according to the method of microbial limit inspection of non-sterile products in Part IV 1105 of the 2020 edition of the "Chinese Pharmacopoeia", and Escherichia coli is tested.

[0125] The results of long-term stability test of the granule preparation are shown in Table 1.

[0126] Table 1 Long-term stability test results of finished granule preparations

[0127] Inspection indicators 0 months 3 months 6 months Temperature(℃) 26 23 25 Humidity (%RH) 30 48 52 Difference in filling volume Comply with regulations Comply with regulations Comply with regulations granularity 1.6％ 1.6％ 1.6％ Moisture 2.3％ 2.3％ 1.8％ Total aerobic bacteria <10cfu / g <10cfu / g <10cfu / g Total mold and yeast count <10cfu / g <10cfu / g <10cfu / g Escherichia coli Not detected Not detected Not detected

[0128] Accelerated stability test: The accelerated stability test adopts the method of retaining samples under high temperature and high humidity conditions. The pilot samples of the finished granule preparations are placed in commercial packaging (polyester / aluminum / polyethylene composite film for drug packaging) and then placed in a comprehensive drug stability test box. The test was conducted for 6 months at a temperature of 40℃±2℃ and a relative humidity of 75%±5%. For the accelerated stability test, samples were taken at 0, 1, 2, 3, and 6 months for inspection, with a total of 5 samples taken for 6 months. The results showed that the finished granule preparations were inspected according to the quality standards during the accelerated stability test period, and the results were in compliance with the regulations. The properties of the packaged Huoxue Jiedu Optimized Granules remained unchanged after 0, 1, 2, 3, and 6 months, all of which were brown-yellow granules; the odor was slight and the taste was slightly bitter. The position and fluorescence of the main spots of the test sample should be consistent with those of the paeoniflorin reference substance, Chuanxiong reference medicinal material, Monascus reference medicinal material, berberine hydrochloride reference substance, Coptis chinensis reference medicinal material, and Licorice reference medicinal material, respectively. The results of the inspection of filling volume difference, particle size, moisture content, and microbial limit are shown in Table 2.

[0129] Table 2 Accelerated stability test results of finished granule preparations

[0130]

[0131]

[0132] Experimental Example 2

[0133] The finished granule preparation of Example 1 was subjected to acute toxicity and chronic toxicity tests.

[0134] SPF SD rats were used as research subjects, and acute toxicity tests (single-dose toxicity tests) and long-term toxicity tests (6-month repeated-dose toxicity tests) of the pilot products of the granule preparations were carried out. Normative experimental research was carried out in accordance with the innovative Chinese medicines - Chinese medicine compound preparations in the "Classification and Application Material Requirements for Registration of Traditional Chinese Medicines".

[0135] Long-term toxicity test: SD rats were randomly divided into solvent control group, low-dose group (12.5 times the intended clinical dose), medium-dose group (25 times the intended clinical dose), and high-dose group (50 times the intended clinical dose). The drugs were administered for 6 consecutive months. The basic conditions of the animals, hematological indicators, blood biochemistry tests, organ tissue indexes, and pathological tissue examinations were tested at the 13th and 26th weeks of administration, and the recovery of various indicators after the recovery period was observed. Results: No toxic symptoms or obvious abnormalities in the experimental rats were found, and no abnormalities were found in the pathological sections. Acute toxicity test: The drug was administered twice within 24 hours, equivalent to 134 times the intended clinical dose, and no obvious toxicity was found.

[0136] Among them, the proposed clinical dosage is: 40g of crude drug / day.

[0137] Experimental Example 3

[0138] Animal experiments

[0139] According to the difference in feeding feed, administration of drugs and dosage, the experimental animals were divided into normal control group, model group, atorvastatin group, high-dose granule preparation group (referred to as high-dose Chinese medicine group), equivalent dose granule preparation group (referred to as equivalent dose Chinese medicine group), equivalent dose granule preparation combined with atorvastatin group (referred to as combined medication group), and the granule preparation was the granule preparation prepared in Example 1. The corresponding drugs were administered by gavage for 12 weeks. After one week of adaptive feeding with ordinary basic feed, the normal control group was fed with ordinary basic feed; the remaining groups were fed with high-cholesterol and high-fat feed for 2 weeks. The latter formula is made by adding 0.25% cholesterol and 15% fat to ordinary basic feed and mixing them thoroughly. In the third week of the experiment, all groups of mice except the normal control group were cannulated in the right carotid artery to establish the CAS model, and sterile operation was maintained throughout the animal modeling process. This experiment was divided into 6 groups: C57BL / 6J mice were used as the normal control group (referred to as the normal group), ApoE - / -The mice were randomly divided into the model group, atorvastatin group (referred to as statin group), granule preparation equivalent dose group (referred to as Chinese medicine equivalent dose group), granule preparation high dose group (referred to as Chinese medicine high dose group), granule preparation equivalent dose combined with atorvastatin group (referred to as combined medication group). The experiment started with drug intervention from the 9th week and lasted for 12 weeks. The intervention measures of each group were as follows:

[0140] (1) Normal group: fed with basic diet and given an equal volume of purified water;

[0141] (2) Model group: fed with high-fat diet + carotid artery cannula, given an equal volume of purified water;

[0142] (3) statin group: high-fat diet + carotid artery cannulation, and atorvastatin calcium (10 mg / kg / d);

[0143] (4) Chinese medicine equivalent dose group: high-fat diet + carotid artery cannula, and granular preparation (5.2 g / kg / d);

[0144] (5) High-dose Chinese medicine group: fed with high-fat diet + carotid artery cannula, and given granular preparation (10.4 g / kg / d);

[0145] (6) Combined medication group: high-fat diet + carotid artery cannula, granular preparation (5.2 g / kg / d) + atorvastatin calcium (10 mg / kg / d).

[0146] Index detection

[0147] Specimen preparation and sampling

[0148] Sampling of carotid atherosclerotic blood vessels: After 12 weeks of continuous administration, 1% sodium pentobarbital 50 mg / kg was injected intraperitoneally for anesthesia, and the mice were eyeballed and blood was collected. The centrifuge tube was placed at room temperature for 2 hours. After the blood coagulated into blood clots and shrank, it was centrifuged at 3000rpm for 10 minutes, and the supernatant was taken into a clean centrifuge tube and stored in a -80℃ refrigerator for later use. The mice after blood samples were collected were separated and the right common carotid artery was cut along the anterior midline of the neck with tissue scissors, and the normal saline was quickly rinsed until there was no blood residue. The common carotid artery at the cannula was taken, 1 / 3 of which was immersed in 10% formaldehyde solution for fixation, and the other 2 / 3 was divided into two parts, quickly frozen in liquid nitrogen, and then packaged and quickly transferred to a -80℃ refrigerator for storage. In this part of the experiment, the carotid artery fixed with 10% formaldehyde was stained with HE and oil red, and the remaining carotid artery tissues were quickly immersed in liquid nitrogen and later transferred to a -80℃ refrigerator for storage.

[0149] General condition: The survival status, physical appearance, behavioral activities, mental state, eating, drinking, fur, breathing, mouth, eyes, nose, urine and feces of each group of mice were observed daily, and they were weighed every 5 days.

[0150] Serological testing:

[0151] Blood lipid determination: The serum blood lipids (TC, TG, LDL-C, HDL-C) of mice were determined by enzymatic method using a fully automatic biochemical analyzer.

[0152] Elisa method was used to detect the levels of serum inflammation-related factors hs-CRP, TNF-α, TGF-β1, iNOS and Arg-1 in each group of mice.

[0153] HE staining was used to observe the pathological morphology of carotid artery tissue. Immunohistochemistry was used to detect the expression of common protein CD68 of mouse carotid macrophages. Immunofluorescence was used to detect the expression of M1 macrophage marker protein CD86 and M2 macrophage marker protein CD206. Western Blot was used to detect the expression of iNOS, Arg-1, PPARγ and NF-κB p65 proteins in mouse carotid artery tissue.

[0154] The specific results are as follows:

[0155] (1) Blood lipid levels: Compared with the model group, the statin group, high-dose Chinese medicine group, and combination group could reduce TC, TG, and LDL-C levels (P<0.05), while the combination group could increase HDL-C level (P<0.05). The equivalent dose of Chinese medicine group could reduce TG and LDL-C levels (P<0.05).

[0156] (2) HE staining results show: Figure 1 The carotid artery pathological HE staining sections of mice in each group. Figure 2 The ratio of plaque area to blood vessel area in carotid artery sections of mice in each group (Note: *P<0.05 vs. normal group, **P<0.01 vs. normal group; # P<0.05vs. model group, ## P<0.01vs. model group; ▲ P<0.05vs.statin group); the normal group had intact carotid artery lumen structure and no plaque deposition, while the other groups showed varying degrees of intimal thickening, plaque deposition, and a large number of monocytes, macrophages / foam cells gathered on the plaque surface, and even plaque rupture, bleeding and thrombosis. After drug intervention, there was a different degree of relief compared with the model group. Compared with the model group, the proportion of plaque area to vascular area in the statin group, high-dose Chinese medicine group, and combination group was reduced (P<0.05); compared with the statin group, the combination group could further reduce the proportion of plaque area to vascular area (P<0.05).

[0157] (3) Elisa detection of serum inflammation-related factors: Compared with the model group, the statin group, high-dose Chinese medicine group, and combination drug group could reduce the levels of hs-CRP, TNF-α, and iNOS (P<0.05), and increase the levels of TGF-β1 and Arg-1 (P<0.05). The equivalent dose of Chinese medicine group could reduce the level of TNF-α (P<0.05), and increase the level of Arg-1 (P<0.05).

[0158] (4) Immunohistochemical staining results showed: Figure 3 The immunohistochemical staining of CD68 protein in the carotid artery tissue of mice in each group; compared with the model group, the expression of CD68 protein in the carotid artery of mice in the statin group, high-dose Chinese medicine group, and combination drug group was significantly reduced (P<0.05); compared with the statin group, the combination drug group could further reduce the CD68 level (P<0.05).

[0159] (5) Immunofluorescence staining results showed: Figure 4 The immunofluorescence expression of CD86 and CD206 in the carotid artery tissue of mice in each group; CD86 immunofluorescence showed that compared with the model group, the expression of CD86 protein in the statin group, the equivalent dose of Chinese medicine group, the high dose of Chinese medicine group, and the combination group decreased to varying degrees (P<0.05). The results of CD206 immunofluorescence showed that compared with the model group, the expression of CD206 in the statin group, the high dose of Chinese medicine group, and the combination group increased to varying degrees (P<0.05).

[0160] (6) Western Blot results show: Figure 5 The results show that the expression of iNOS, Arg-1, PPARγ, and NF-κB p65 proteins in the carotid artery tissue of mice in each group; compared with the model group, the statin group, the high-dose Chinese medicine group, and the combined drug group could down-regulate the expression of iNOS (P<0.05); compared with the model group, the statin group, the equivalent dose of Chinese medicine group, the high-dose Chinese medicine group, and the combined drug group could up-regulate the expression of Arg-1 (P<0.05); compared with the model group, the statin group, the equivalent dose of Chinese medicine group, the high-dose Chinese medicine group, and the combined drug group could up-regulate the expression of PPARγ (P<0.05); compared with the model group, the statin group, the high-dose Chinese medicine group, and the combined drug group could down-regulate the expression of NF-κB p65 (P<0.05). Compared with the statin group, the combined drug group could further up-regulate the expression of Arg-1 and PPARγ (P<0.05).

[0161] Conclusion: This study established a mouse model of carotid atherosclerosis and intervened with the Chinese medicine composition, confirming the effectiveness of the Chinese medicine composition in lowering blood lipids and anti-atherosclerosis. At the same time, related indicators such as inflammation-related factors, macrophage phenotype and PPARγ / NF-κB signaling pathway were detected. The results showed that the Chinese medicine composition of the present invention may regulate macrophage polarization through the PPARγ / NF-κB signaling pathway, thereby exerting an anti-atherosclerotic effect.

[0162] According to the above method, the granule preparations of Examples 5a to 5f were verified by animal experiments. Examples 5a to 5b have certain effects of lowering blood lipids and resisting atherosclerosis, but the effects are weaker than those of Example 1; the effects of Examples 5c to 5f are even weaker than those of Examples 5a to 5b.

[0163] Experimental Example 4

[0164] Clinical Trials

[0165] 1. Research subjects

[0166] The research subjects were 60 patients (30 cases in each group) from the outpatient department and ward of the Department of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, who met the diagnostic criteria and exclusion criteria for hyperlipidemia combined with carotid atherosclerosis. They were then randomly divided into two groups, the control group was treated with atorvastatin, and the experimental group was treated with the Chinese medicine composition of Example 1 on the basis of the treatment of the control group, and both were treated for 12 weeks.

[0167] 2. Diagnostic criteria

[0168] (1) For hyperlipidemia, refer to the Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults (2016 Revised Edition) published by the Joint Committee for the Revision of the Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults;

[0169] (2) With reference to the "Chinese Consensus on the Diagnosis and Treatment of Head and Neck Atherosclerosis", vascular ultrasound examination confirmed that the diagnosis criteria for carotid atherosclerosis were met;

[0170] (3) Syndrome differentiation: The diagnostic criteria for heat-toxic blood stasis syndrome were formulated with reference to the 2016 “Practical Diagnostic Criteria for Blood Stasis Syndrome” and the 2011 “Quantitative Diagnostic Criteria for Syndrome Differentiation of Toxin-induced Pathogenesis in Stable Coronary Heart Disease”. The specific diagnostic criteria are as follows:

[0171] Main symptoms: vertigo;

[0172] Secondary symptoms: chest tightness, bitter taste in the mouth, dry stool;

[0173] Tongue: Dark red tongue, or with ecchymosis, yellow fur; sublingual veins are purple or crimson;

[0174] Pulse: The pulse is rough and rapid;

[0175] Complexion: complexion or lips and nails are dark purple.

[0176] Two of these are sufficient for diagnosis.

[0177] Quantitative points are scored based on the presence or absence of symptoms and the severity of the symptoms (mild, moderate, severe), with 0, 3, 6, and 9 points representing no symptoms, mild, moderate, and severe symptoms, respectively. Tongue coating and pulse are not scored.

[0178] 3. Inclusion criteria

[0179] (1) 40 years old < age < 75 years old;

[0180] (2) Meet the diagnostic criteria for primary hyperlipidemia, and meet any of the following: TC ≥ 5.2 mmol / L; LDL-C ≥ 3.4 mmol / L; TG ≥ 1.7 mmol / L;

[0181] (3) Vascular ultrasound examination confirmed that the diagnosis criteria for carotid atherosclerosis were met, with carotid intima-media thickness (IMT) and carotid stenosis <50%;

[0182] (4) According to TCM diagnosis, it is a syndrome of blood stasis and toxicity;

[0183] (5) Although taking lipid-lowering drugs, they have stopped taking them for 2 weeks or more;

[0184] (6) Volunteer to participate in this study and sign the informed consent.

[0185] 4. Case Exclusion Criteria

[0186] (1) Patients with confirmed coronary heart disease, or with uncontrolled hypertension (sitting diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg), or diabetes mellitus (glycosylated hemoglobin (HbA1c) ≥8.5%), or with uncontrolled heart failure (NYHA grade ≥III) and arrhythmia accompanied by clinical symptoms or hemodynamic disorders;

[0187] (2) Patients with hyperlipidemia caused by drugs (phenothiazines, β-blockers, adrenocortical steroids, and certain contraceptives, etc.), or who are currently taking hormones, thyroid hormone treatment drugs, and other drugs that affect blood lipid metabolism;

[0188] (3) Patients with major diseases of the liver, kidney and blood system, major infectious diseases, active rheumatic and immune diseases, malignant tumors and mental illness;

[0189] (4) Those who have had severe trauma or major surgery in the past six months, or have a tendency to bleed;

[0190] (5) Pregnant or lactating women, or those who are allergic to the trial drug or its ingredients;

[0191] (6) Participants in other clinical trials.

[0192] 5. Treatment options

[0193] (1) Conventional treatment: During the observation period, both the experimental group and the control group were given nutritional guidance, exercise advice, and a series of chronic disease management methods such as weight loss, smoking cessation, and alcohol restriction in accordance with the Expert Consensus on Nutritional Prescriptions for Cardiovascular Diseases. In addition, other complication-related drug treatments such as antihypertensive and blood sugar control were given according to their actual conditions.

[0194] (2) Treatment plan for the control group: Oral atorvastatin calcium tablets, 10 mg each time, once a day, taken around 8 pm.

[0195] (3) Treatment plan for the experimental group: that is, Chinese medicine composition granules + atorvastatin treatment. The experimental group was treated with Chinese medicine composition granules on the basis of atorvastatin basic western medicine treatment. Chinese medicine composition granules (prepared according to the method of Example 1) were taken once in the morning and evening, and 13g of granules each time (corresponding to 20g of crude drug).

[0196] (4) Treatment cycle: The treatment cycle for both groups was 12 weeks.

[0197] During the trial, it is prohibited to use other Western medicines, Chinese herbal medicine slices or Chinese patent medicine preparations with lipid-regulating effects. If other diseases are combined, corresponding treatment can be given, but it cannot affect the efficacy observation of this study. The researcher needs to record the reason for using the drug, the name of the drug, the dosage, etc. in detail in the case observation form.

[0198] 6. Detection indicators

[0199] (1) Baseline characteristics: Demographic data such as patient age, gender, BMI, blood pressure, and smoking status were recorded.

[0200] (2) Main efficacy indicators: changes in LDL-C and carotid intima-media thickness (IMT) before and after treatment.

[0201] (3) Secondary efficacy indicators: changes in TC, TG, HDL-C, and TCM symptom scores before and after treatment.

[0202] (4) Inflammation-related factors: changes in serum hs-CRP, TNF-α, iNOS, TGF-β1, and Arg-1 before and after treatment.

[0203] (5) Safety indicators: blood routine, liver and kidney function, urine routine and incidence of adverse reactions.

[0204] 7. Efficacy evaluation criteria

[0205] (1) Criteria for determining the efficacy of TCM syndromes: Refer to the 2013 “General Principles for Clinical Research of New Chinese Medicines” and use the integral method to determine the efficacy of TCM syndromes.

[0206] Therapeutic index (n) = [(pre-treatment score - post-treatment score) / pre-treatment score] × 100%

[0207] Clinical cure: TCM clinical symptoms and signs disappear or basically disappear, and the syndrome score decreases by ≥90%.

[0208] Markedly effective: Clinical symptoms and signs of TCM were significantly improved, and the syndrome score was reduced by ≥70%.

[0209] Effective: TCM clinical symptoms and signs improved, and syndrome scores decreased by ≥30%.

[0210] Ineffective: There is no significant improvement in TCM clinical symptoms and signs, or they may even get worse, and the syndrome score is reduced by less than 30%.

[0211] (2) Hyperlipidemia: The standards are formulated in accordance with the Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China (2016 Revised Edition) and the Guidelines for Clinical Research of New Chinese Medicines:

[0212] Significant effect: LDL-C decreased by ≥20%, TC decreased by ≥40%, or TG decreased by ≥20%, or HDL-C increased by ≥0.26mmol / L (10mg / dl);

[0213] Effective: TC decreased by 20% to 40%, or TG decreased by 10% to 20%, or HDL-C increased by 0.104 to 0.26 mmol / L (4 to 10 mg / dl);

[0214] Invalid: The above TG, TC, and HDL-C indicators did not meet the effective standards.

[0215] 8. Statistical methods

[0216] SPSS 20.0 software was used for statistical analysis. When comparing the measurement data between groups, the normality test was first performed. If the data obeyed the normal distribution, the t test of group design data was used. If the data did not obey the normal distribution, the Wilcoxon rank sum test was used. The chi-square test was used for the comparison of count data between groups. P < 0.05 was considered statistically significant.

[0217] result:

[0218] (1) Comparison of baseline characteristics: There was no statistically significant difference in gender, age, BMI, systolic blood pressure, diastolic blood pressure, etc. between the two groups (P>0.05), indicating that the baseline levels of the two groups were consistent.

[0219] (2) Four blood lipid items: Figure 6 Comparison of the four blood lipids of the two groups of patients (Note: Compared with the group before treatment: # P<0.05, ##P<0.01; compared with the control group: *P<0.05, **P<0.01); compared with before treatment, the levels of TC, TG, and LDL-C in the experimental group decreased (P<0.05), and the level of HDL-C increased (P<0.05); the level of TG in the control group decreased (P<0.05). Inter-group comparison showed that compared with the control group, the levels of TC, TG, and LDL-C in the experimental group were lower (P<0.05).

[0220] (3) Carotid intima-media thickness (cIMT): Figure 7 Comparison of carotid intima-media thickness between the two groups of patients (Note: Compared with the group before treatment: # P<0.05, ## Compared with before treatment, the carotid intima-media thickness in both the experimental and control groups was significantly reduced (P<0.05).

[0221] (4) Inflammation-related factors: Figure 8 Comparison of inflammation-related factors between the two groups of patients (Note: Compared with the group before treatment: # P<0.05, ## P<0.01; compared with the control group: *P<0.05, **P<0.01); compared with before treatment, hs-CRP, TNF-α and iNOS levels in the experimental group and the control group decreased after 12 weeks of medication (P<0.05), and TGF-β1 and Arg-1 levels increased (P<0.05). Inter-group comparison showed that compared with the control group, the iNOS level in the experimental group was lower (P<0.05), and the Arg-1 level was higher (P<0.05).

[0222] (5) TCM syndrome score: Fig. 9 Comparison of TCM syndrome scores between the two groups of patients (Note: Compared with the group before treatment: ## P<0.01; compared with the control group: **P<0.01); compared with before treatment, the TCM syndrome score of the experimental group was significantly reduced (P<0.05); and was better than that of the control group (P<0.05).

[0223] (6) TCM syndrome efficacy: Fig.10 The total effective rate of the experimental group was better than that of the control group (80% vs 42.3%, P<0.05).

[0224] Conclusion: The Chinese medicine composition of the present invention can reduce the thickness of the intima-media of the carotid artery, reduce the blood lipid level and the expression of inflammatory factors, regulate lipid metabolism, inhibit inflammatory response, and improve the patient's traditional Chinese medicine symptoms, indicating that the Chinese medicine composition of the present invention exerts anti-AS effects through lipid-regulating and anti-inflammatory effects. During the entire study period, no adverse reactions such as liver and kidney damage and allergies occurred, confirming the clinical effectiveness and safety of the Chinese medicine composition of the present invention in the treatment of carotid atherosclerosis combined with hyperlipidemia.

[0225] From the above test results, it can be seen that the Chinese medicine composition provided by the present invention can have a good therapeutic effect on the patient group of carotid atherosclerosis combined with hyperlipidemia, which is a common disease in the field of cardiovascular disease prevention and treatment. In addition, the present invention, without changing the efficacy of the Chinese medicine composition, makes the Chinese medicine composition into a granular preparation in a certain way to ensure the molding rate, dissolution rate, bulk density, repose angle and moisture absorption rate of the preparation, thereby ensuring the efficacy of the preparation, extending the storage time of the product, taking into account the patient's acceptance, and easily realizing large-scale production.

[0226] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia, It is characterized in that The invention is mainly prepared from the following components by weight: 8-12 parts of chuanxiong, 8-12 parts of red peony root, 3-7 parts of coptis root, 8-12 parts of red yeast rice and 3-7 parts of roasted liquorice root.

2. The Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia according to claim 1, It is characterized in that The invention is mainly prepared from the following components by weight: 10 parts of chuanxiong, 10 parts of red peony root, 5 parts of coptis root, 10 parts of red yeast rice and 5 parts of roasted liquorice root.

3. The Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia according to claim 1, It is characterized in that The traditional Chinese medicine composition also includes dextrin.

4. Chinese medicine granule preparation for the treatment of carotid atherosclerosis combined with hyperlipidemia, It is characterized in that The invention is mainly prepared from the Chinese medicine composition for treating carotid atherosclerosis combined with hyperlipidemia as described in any one of claims 1 to 3.

5. The method for preparing the Chinese medicine granule preparation for treating carotid atherosclerosis combined with hyperlipidemia according to claim 4, It is characterized in that The steps include: (a) weighing chuanxiong, red peony root, coptis root, red yeast rice and licorice root according to weight to obtain a mixed medicinal material; extracting the mixed medicinal material three times with water, combining the water extracts, filtering and concentrating to obtain an extract; (b) mixing the extract with dextrin in a mass ratio of 1:(1.8-2.2), granulating, drying and granulating to obtain the Chinese medicine granule preparation; The relative density of the extract at 50°C is 1.2-1.25 g / cm 3 .

6. The preparation method according to claim 5, It is characterized in that In the three water extractions, the solid-liquid ratio of the first extraction is 1:(10-12); the solid-liquid ratio of the second extraction is 1:(8-10); and the solid-liquid ratio of the third extraction is 1:(8-10).

7. The preparation method according to claim 5, It is characterized in that In the three water extractions, the first extraction time is 0.5 to 1 hour; the second extraction time is 0.5 to 1 hour; and the third extraction time is 0.5 to 1 hour.

8. The preparation method according to claim 5, It is characterized in that The granulation is carried out in a fluidized bed, the material temperature is 80-90° C., the inlet air temperature is 100-110° C., and the feed speed is 280-320 rpm.

9. The preparation method according to claim 5, It is characterized in that In step (b), the drying is carried out in an oven at 75 to 85° C., and the drying time is 1 to 2 hours.

10. The preparation method according to claim 5, It is characterized in that The granules are sieved through a 10-60 mesh sieve.

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