Traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, pharmaceutical preparation and application thereof

Abstract

The invention discloses a traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, a pharmaceutical preparation and application thereof, and relates to the technical field of traditional Chinese medicine, and the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 9-18 parts of ginseng, 3-6 parts of pseudo-ginseng, 9-18 parts of ligusticum wallichii, 12-24 parts of radix achyranthis bidentatae, 6-12 parts of fructus forsythiae and 9-18 parts of radix curcumae. Compared with the prior art, the traditional Chinese medicine composition has the beneficial effects that (1) atherosclerosis is an important pathological basis for occurrence of adverse cardiovascular and cerebrovascular events such as myocardial infarction and cerebral apoplexy, and the traditional Chinese medicine composition provided by the invention can effectively reduce the blood fat level and delay the progress of atherosclerotic plaques; (2) the traditional Chinese medicine composition has the advantage of good safety and can be taken for a long time.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and specifically relates to a traditional Chinese medicine composition, a pharmaceutical preparation and their applications for treating atherosclerosis and dyslipidemia. Background Art

[0002] Atherosclerosis (AS) is a chronic inflammatory disease characterized by the formation of lipid plaques in the arterial intima. Its pathological mechanism is complex. The currently most recognized lipid infiltration theory holds that dyslipidemia plays an important role in the formation and progression of AS. This pathological process includes the deposition of lipids (such as cholesterol, triglyceride) under the intima, triggering inflammatory reactions, smooth muscle cell proliferation and fibrous cap formation, and ultimately leading to plaque rupture, thrombosis and vascular occlusion, which is an important pathological basis for cardiovascular and cerebrovascular events such as myocardial infarction and stroke.

[0003] The treatment goals of AS include reversing plaque volume, changing plaque composition, reducing the risk of plaque rupture, delaying plaque progression, and reducing the risk of future adverse cardiovascular events. Research shows that there is a linear relationship between lipid levels and AS plaque volume, and lipid management is the most critical link in the management of AS. However, the efficacy of existing drug interventions for AS plaques is limited, and the residual inflammatory risk of AS cannot be eliminated. The hepatotoxicity and muscle-related adverse reactions of drugs limit the clinical benefits of patients. Finding a new method to safely and effectively reduce blood lipid levels and delay the occurrence and development of AS plaques through the combination of traditional Chinese and Western medicine is of great significance for reducing the incidence and mortality of cardiovascular diseases. Summary of the Invention

[0004] The purpose of the present invention is to provide a traditional Chinese medicine composition, a pharmaceutical preparation and their applications for treating atherosclerosis and dyslipidemia, so as to solve the problems raised in the above background art.

[0005] To achieve the above purpose, the present invention provides the following technical solutions:

[0006] A traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, comprising the following raw materials in parts by weight: 9 - 18 parts of ginseng, 3 - 6 parts of notoginseng, 9 - 18 parts of chuanxiong rhizome, 12 - 24 parts of achyranthes root, 6 - 12 parts of forsythia and 9 - 18 parts of turmeric.

[0007] As a further technical solution of the present invention: it comprises the following raw materials in parts by weight: 9 parts of ginseng, 3 parts of notoginseng, 9 parts of chuanxiong rhizome, 12 parts of achyranthes root, 6 parts of forsythia and 9 parts of turmeric.

[0008] A pharmaceutical preparation using the above traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia as an active ingredient, and the pharmaceutical preparation is prepared into a commonly used pharmaceutical dosage form by a conventional preparation method in the art.

[0009] As a further technical solution of the present invention: the pharmaceutical preparation includes decoction, capsules, tablets, pills or granules.

[0010] As a further technical solution of the present invention: the pharmaceutical preparation further includes pharmaceutically acceptable excipients.

[0011] An application of the above-mentioned traditional Chinese medicine composition in the treatment of atherosclerosis and dyslipidemia.

[0012] As a further technical solution of the present invention: the traditional Chinese medicine composition reduces blood lipid levels and reduces the formation of atherosclerotic plaques induced by hyperlipidemia.

[0013] Compared with the prior art, the beneficial effects of the present invention are: ① Atherosclerosis is an important pathological basis for the occurrence of adverse cardiovascular and cerebrovascular events such as myocardial infarction and stroke. The traditional Chinese medicine composition provided by the present invention can effectively reduce blood lipid levels and delay the progression of atherosclerotic plaques; ② The traditional Chinese medicine composition of the present invention has the advantage of good safety and can be taken for a long time. Description of the Drawings

[0014] Figure 1 It is a graph showing the results of the influence of the traditional Chinese medicine composition in the animal experiment of the present invention on the serum lipid levels of mice;

[0015] Figure 2 It is a graph showing the results of the influence of the traditional Chinese medicine composition in the animal experiment of the present invention on Oil Red O staining of mice and the proportion of plaque area;

[0016] Figure 3 It is a graph showing the results of the influence of the traditional Chinese medicine composition in the animal experiment of the present invention on HE staining of mice and the proportion of plaque area;

[0017] Figure 4 It is a graph showing the results of the influence of the traditional Chinese medicine composition in the animal experiment of the present invention on Masson staining of mice and the proportion of collagen content. Detailed Embodiments

[0018] Next, the technical solutions in the embodiments of the present invention will be described clearly and completely. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0019] A traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, comprising the following raw materials in parts by weight: 9 parts of ginseng, 3 parts of notoginseng, 9 parts of chuanxiong, 12 parts of achyranthes bidentata, 6 parts of forsythia and 9 parts of curcuma aromatica.

[0020] The formula of the Chinese medicine composition of the present invention is as follows:

[0021] Atherosclerosis combined with dyslipidemia falls under the categories of "turbid paste," "turbid blood," and "pulse accumulation" in Traditional Chinese Medicine. Disharmony in the blood vessels and internal accumulation of turbid toxins are the primary pathogenesis. Qi deficiency and weak blood circulation are the root causes of this disharmony. Sluggish blood flow leads to the internal generation of blood stasis and turbid toxins, which adhere to the vessel walls and damage the collaterals, representing the symptoms of the disease. Internal accumulation of turbid toxins further exacerbates vascular congestion, promoting the progression of AS plaques. Therefore, treatment should focus on invigorating Qi, activating blood circulation, and detoxifying. This prescription, with ginseng and Panax notoginseng as the main ingredients, establishes a foundation for invigorating Qi and activating blood circulation. Ginseng has a sweet and slightly bitter flavor and a slightly warm nature. It enters the spleen, lung, heart, and kidney meridians. It not only tonifies vital Qi to strengthen the body, but also tonifies the Qi of the spleen and lungs to aid in the transformation of dampness, resolve phlegm, and reduce turbidity. It also promotes fluid production, calms the mind, improves intelligence, and strengthens the body, making it a key herb for invigorating Qi and strengthening the body. Panax notoginseng is sweet, slightly bitter, and warm. It enters the liver, stomach, and heart meridians, and has the properties of dissolving blood stasis, arresting bleeding, and activating blood circulation and alleviating pain. The "Supplement to Compendium of Materia Medica" states that "ginseng is the best for replenishing qi, and Panax notoginseng is the best for replenishing blood." The combination of the two can tonify both qi and blood, dissolve blood stasis and dredge the meridians, and improve the underlying qi deficiency and blood stasis in patients with atherosclerosis and dyslipidemia. Chuanxiong, along with Curcuma zedoaria, and Achyranthes bidentata, serve as assistant herbs. Chuanxiong, a "blood-activating qi herb," enters the liver, gallbladder, and pericardium meridians, promoting blood circulation and qi movement, dispelling wind and relieving pain. The "Compendium of Materia Medica" states that Chuanxiong "has a pungent flavor and a yang nature, with qi that is mobile and free from yin coagulation and stickiness. Although it enters the blood, it can dispel all forms of wind and regulate all qi." Curcuma zedoaria promotes qi and relieves depression, activates blood circulation and relieves pain, and promotes bile secretion and reduces jaundice. Achyranthes bidentata has both attacking and tonic properties, nourishing the liver and kidneys while removing blood stasis and dredging the meridians, guiding blood downward. The three herbs synergistically enhance the qi-activating and blood-activating effects of ginseng and Panax notoginseng. The bitter and cold Fructus Forsythiae (Forsythia suspensa) supplements the body with a clearing effect, detoxifying the heart and eliminating inflammatory reactions within blood vessels, while also dispersing blood stasis and Qi accumulation. The six herbs work synergistically to invigorate Qi, activate blood circulation, dispel stasis, and detoxify, demonstrating excellent clinical efficacy.

[0022] Experimental Example 1: Pharmacodynamic study of the Chinese herbal composition of the present invention in preventing and treating atherosclerosis combined with dyslipidemia

[0023] animal

[0024] 8-week-old SPF-grade ApoE - / - Forty mice and ten C57BL / 6J mice were purchased from Spefox (Beijing) Biotechnology Co., Ltd., with the experimental animal production license number: SCXK (Beijing) 2019-0010; they were kept in the Experimental Animal Center of Xiyuan Hospital, China Academy of Chinese Medical Sciences, with the experimental animal use license number: SYXK (Beijing) 2023-0053.

[0025] Drugs and high-fat feed

[0026] Shenqi Yangxin Recipe: 9 parts ginseng, 3 parts Panax notoginseng, 9 parts Chuanxiong, 12 parts Achyranthes, 6 parts Forsythia, and 9 parts Curcuma. Ginseng, Chuanxiong, Achyranthes, Forsythia, and Curcuma were purchased from Beijing Kangrentang Pharmaceutical Co., Ltd. [Ginseng Formula Granules (Beijing Kangrentang Pharmaceutical Co., Ltd., batch number: 23023281), Chuanxiong Formula Granules (Beijing Kangrentang Pharmaceutical Co., Ltd., batch number: 24008491), Forsythia Formula Granules (Beijing Kangrentang Pharmaceutical Co., Ltd., batch number: 23018951), Achyranthes Formula Granules (Beijing Kangrentang Pharmaceutical Co., Ltd., batch number: 24012561), Curcuma Formula Granules (Beijing Kangrentang Pharmaceutical Co., Ltd., batch number: 23015951)]. Panax notoginseng powder was purchased from China National Traditional Chinese Medicine Co., Ltd. (batch number: 740711102).

[0027] Atorvastatin calcium tablets were purchased from Pfizer Inc. (Batch No.: National Medicine Standard H20051407).

[0028] High-fat feed (containing 21% fat and 0.15% cholesterol) was purchased from Beijing Keao Xieli Feed Co., Ltd. [Production license number: SCXK (Tianjin) 2020-0004]

[0029] Model building and grouping

[0030] Feed ApoE with a high-fat diet - / - The AS model was established in mice. All mice were adaptively housed for 7 days. - / - Mice were fed a high-fat diet for 14 weeks to establish the AS model, and C57BL / 6J mice were fed a normal diet for 14 weeks. - / - Mice were randomly divided into four groups (n=10) using a random number table: a model group (Model group), an atorvastatin group (ATV group), a low-dose Shenqi Yangxin Fang group (SQYX-L group), and a high-dose Shenqi Yangxin Fang group (SQYX-H group). Ten C57BL / 6J mice served as a normal control group (Control group). Starting from the 16th week of the experiment, the corresponding drugs were administered orally for 8 weeks. The mice were weighed once a week, and the specific drug dosage was adjusted based on their body weight. During this period, a high-fat diet was maintained to maintain the model.

[0031] Drug administration and dosage: The drug dosage for mice was calculated according to the conversion method of drug dosage between mice and humans in "Experimental Animals and Animal Experiment Techniques". The dosage for the SQYX-L group was 2507.70 mg / Kg / d, and that for the SQYX-H group was 5015.40 mg / Kg / d. Shenqi Yangxin Fang was dissolved in pure water, and the drug was fully dissolved by ultrasonic oscillation. After autoclaving, it was stored at 4°C for later use. The dosage for the ATV group was 2.60 mg / Kg / d. Atorvastatin calcium tablets were crushed and dissolved in pure water, and the drug was fully dissolved by ultrasonic oscillation. After autoclaving, it was stored at 4°C for later use. The Control group and the Model group were given intragastric administration of the same volume of pure water. Mice in each group started drug intervention after the modeling was completed, and their weights were measured once a week. The drug dosage was adjusted according to the weight change. Drug intervention was continued for 8 weeks.

[0032] Index detection

[0033] Specimen preparation and sampling

[0034] Sampling of atherosclerotic blood vessels: After the last drug administration, the mice were fasted for 12 h without water restriction. The mice were weighed, anesthetized by intraperitoneal injection of 1% pentobarbital sodium (40 mg / kg), blood was collected by eye socket puncture, and the blood was collected in a centrifuge tube and left to stand at room temperature for 2 h. After the blood coagulated into a clot and shrank, it was centrifuged at 3000 rpm at 4°C for 15 min, and the supernatant was taken and placed in a clean centrifuge tube and stored at -80°C in the refrigerator for later use.

[0035] After blood collection, the mice were fixed in the supine position on the operating table, and the thoracic and abdominal viscera were exposed. 4°C normal saline was injected from the apex of the heart until the liver, lung lobes, and limbs of the mice turned white. The heart, aorta, and kidneys were retained, and other thoracic and abdominal viscera, trachea, esophagus, and fat tissues were removed. The aortic arch was bluntly dissected to the bifurcation of the common iliac artery. The subclavian artery, left common carotid artery, and brachiocephalic trunk artery were dissected upward at the aortic arch, the heart was separated at the root of the ascending aorta, the renal artery was dissected and cut at the kidney, and the common iliac artery was cut at the root. It was fixed in 4% paraformaldehyde fixative and stored at room temperature for gross oil red O staining; after the aortic samples were fixed in 4% paraformaldehyde fixative, the samples embedded in paraffin for sectioning were used for HE staining, Masson staining, and immunohistochemical staining. The remaining aortic tissues were placed in a cryopreservation box and quickly frozen in liquid nitrogen, and then transferred to a -80°C refrigerator for storage and later use after the sampling was completed.

[0036] Detection of blood lipid levels

[0037] Collect the blood samples of mice using 1.5 ml EP tubes, place them at room temperature for 2 hours, then put them into a pre-cooled centrifuge and centrifuge at 3000 rpm at 4°C for 15 minutes to collect the serum. Use an automatic biochemical analyzer to detect the levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) in the serum.

[0038] Oil Red O staining

[0039] Isolate the intact aorta of mice and fix it overnight in 4% paraformaldehyde solution. Longitudinally cut the aorta to expose the intimal surface, stain the aorta with Oil Red O staining solution for 30 minutes, then rinse it successively with 60% isopropanol and double-distilled water, fix it, and take a complete aorta image with the endothelial surface facing up. Finally, use Image J to calculate the area of atherosclerosis.

[0040] HE staining

[0041] Take mouse aorta tissue, fix it overnight in 4% paraformaldehyde solution, and prepare tissue specimens according to the steps of fixation, dehydration, wax infiltration, embedding, sectioning and baking, and rehydration. Then, perform hematoxylin staining, eosin staining, dehydration, clearing, and mounting in sequence to complete HE staining. Observe the sections under a microscope, take pictures, and use Image J to quantitatively analyze the plaque size.

[0042] Masson staining

[0043] The specimen preparation process is the same as that of HE staining. Take the prepared sections and stain them successively with Weigert iron hematoxylin staining solution, differentiate with 1% hydrochloric acid ethanol differentiation solution, blue with Masson bluing solution, infiltrate with ponceau fuchsin staining solution, wash with weak acid working solution and phosphomolybdic acid solution, stain with aniline blue staining solution, wash with weak acid working solution, and finally dehydrate, clear, and mount to complete Masson staining.

[0044] Statistical methods

[0045] All data are expressed as mean ± standard deviation. Use GraphPad Prism 9.0 software for statistical analysis. For multiple comparisons, apply one-way analysis of variance and then perform Bonferroni post hoc test. p < 0.05 indicates statistical significance.

[0046] The specific results are as follows:

[0047] (1) Effects of the Traditional Chinese Medicine Composition on Blood Lipid Levels in Mice

[0048] Figure 1 were the levels of TC, TG, LDL-C, and HDL-C in mice of each group (Note: Compared with the Control group, ** p < 0.01. Compared with the Model group, # p < 0.05, ## p < 0.01. Compared with the ATV group, △ p < 0.05, △△ p < 0.01). Compared with the Model group, the levels of TC, TG, and LDL-C in the ATV group and the SQYX-L group were all decreased (p < 0.05), and the level of HDL-C was increased (P < 0.05); the level of TG in the SQYX-H group was decreased and the level of HDL-C was increased (P < 0.05). Compared with the ATV group, there was no significant difference in blood lipid levels in the SQYX-L group (P > 0.05). The results suggest that Shenqi Yangxin Decoction can decrease the levels of TC, TG, and LDL-C and increase the level of HDL-C, and the curative effect of its low-dose group is equivalent to that of the ATV group.

[0049] (2) Effects of the Traditional Chinese Medicine Composition on Gross Oil Red O Staining of Aorta in Mice

[0050] Figure 2 were the gross Oil Red O staining of aorta and the proportion of plaque area in mice of each group (Note: Compared with the Control group, ** p < 0.01. Compared with the Model group, # p < 0.05, ## p < 0.01). The intima of the aorta in Control group mice was smooth and flat, and only trace lipid deposition and red staining were seen. Compared with the Control group, the intima of the aorta in Model group mice was less smooth, and lipid plaques with dense red staining were visible, mainly distributed at the aortic arch, abdominal aorta, and arterial bifurcations. The proportion of the lipid plaque area in the whole aortic area increased significantly (p < 0.01). Only scattered granular lipid depositions were seen in the ATV group and different-dose groups of Shenqi Yangxin Decoction. Compared with the Model group, the proportion of lipid area of aortic plaques in the ATV group and the SQYX-L group was decreased (p < 0.05). Compared with the ATV group, there was no significant difference in the aortic plaque area in the SQYX-L group (P > 0.05). The results suggest that Shenqi Yangxin Decoction can inhibit lipid deposition on the inner wall of the aorta, and the curative effect of its low-dose group is equivalent to that of the ATV group.

[0051] (3) Effects of the Traditional Chinese Medicine Composition on HE and Masson Staining in Mice

[0052] Figure 3 were the pathological HE staining sections of aorta and the ratio of plaque area / vascular area in mice of each group,Figure 4 Aortic pathological Masson staining sections and the ratio of collagen fiber content to vascular area for each group of mice (Note: Compared with the Control group, ** p < 0.01. Compared with the Model group, # p < 0.05, ## p < 0.01). The aortic lumen structure of the Control group was intact, the cells were arranged tightly, the intima was smooth, the media thickness was uniform, and no plaque deposition was seen. Compared with the Control group, the aortic lesions in the Model group were more severe, with plaques protruding into the lumen, accompanied by inflammatory cell infiltration, having a larger lipid core, reduced collagen fiber content, a thinner fibrous cap, and a significantly increased proportion of plaque area (p < 0.01). Compared with the Model group, the aortic plaque deposition in each treatment group was reduced to varying degrees, with a small amount of inflammatory cells and lipid cores visible, an increase in collagen fiber content (P < 0.05), and a decrease in the proportion of plaque area in the ATV group and the SQYX-L group (P < 0.05). Compared with the ATV group, there was no significant difference in the proportion of plaque area and collagen fiber content in the SQYX-L group (P > 0.05). The results suggest that Shenqi Yangxin Prescription can inhibit plaque formation, reduce inflammatory cell infiltration and lipid deposition, and increase collagen fiber content, and the curative effect of its low-dose group is comparable to that of the ATV group.

[0053] Conclusion: In this study, by establishing an atherosclerotic mouse model and intervening with a traditional Chinese medicine composition, the effectiveness of the traditional Chinese medicine composition in reducing blood lipid levels and delaying atherosclerosis was confirmed.

[0054] In addition, it should be noted that on the basis of the above basic drug ratios, those skilled in the art have conducted multiple groups of experiments within the ratio ranges of 9 - 18 parts of ginseng, 3 - 6 parts of notoginseng, 9 - 18 parts of chuanxiong rhizome, 12 - 24 parts of achyranthes root, 6 - 12 parts of forsythia fruit, and 9 - 18 parts of turmeric root-tuber, and the technical effects required for different drug ratios can all be supported by experiments.

[0055] A pharmaceutical preparation with the above-mentioned traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia as an active ingredient, and the pharmaceutical preparation is prepared into a commonly used pharmaceutical dosage form by a conventional preparation method in the art. The pharmaceutical preparation includes decoction, capsule, tablet, pill or granule, and is preferably used for granule. The pharmaceutical preparation also includes pharmaceutically acceptable excipients.

[0056] An application of the above traditional Chinese medicine composition in the treatment of atherosclerosis and dyslipidemia. The traditional Chinese medicine composition reduces blood lipid levels and reduces the formation of atherosclerotic plaques induced by hyperlipidemia.

[0057] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, in any aspect, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention. Any reference signs in the claims should not be construed as limiting the claims involved.

[0058] In addition, it should be understood that although this specification is described in terms of embodiments, not every embodiment only includes an independent technical solution. This narrative manner of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, characterized in that, It comprises the following raw materials in parts by weight: 9-18 parts of ginseng, 3-6 parts of notoginseng, 9-18 parts of chuanxiong rhizome, 12-24 parts of achyranthes root, 6-12 parts of forsythia fruit and 9-18 parts of turmeric root-tuber.

2. A traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia, characterized in that, It comprises the following raw materials in parts by weight: 9 parts of ginseng, 3 parts of notoginseng, 9 parts of chuanxiong rhizome, 12 parts of achyranthes root, 6 parts of forsythia fruit and 9 parts of turmeric root-tuber.

3. A pharmaceutical preparation with the traditional Chinese medicine composition for treating atherosclerosis and dyslipidemia as described in claim 1 or 2 as an active ingredient, characterized in that, The pharmaceutical preparation is prepared into a pharmaceutically common dosage form by a conventional preparation method in the art.

4. The pharmaceutical preparation according to claim 3, characterized in that, The pharmaceutical preparation includes decoction, capsule, tablet, pill or granule.

5. The pharmaceutical preparation according to claim 4, characterized in that, The pharmaceutical preparation further includes pharmaceutically acceptable excipients.

6. Use of the traditional Chinese medicine composition according to claim 1 or 2 in the treatment of atherosclerosis and dyslipidemia.

7. The application according to claim 6, characterized in that, The traditional Chinese medicine composition reduces blood lipid levels and reduces the formation of atherosclerotic plaques induced by hyperlipidemia.

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