TWI844079B - Chinese medicine composition and its preparation method and application - Google Patents
Chinese medicine composition and its preparation method and application Download PDFInfo
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Abstract
本發明提供了一種中藥組合物及其製備方法和應用。本發明中藥組合物包括按以下重量份計的原料藥:柴胡5-35份、枳實5-30份、生大黃5-20份、黃芩1-20份、白芍3-20份、乾薑3-20份、水蛭3-25份、甘草3-20份、黨參3-20份、白術3-20份、生牡蠣 3-45 份。本發明中藥組合物具有優良的預防或治療動脈粥狀斑塊形成、缺血性心腦疾病、血脂升高、三酸甘油酯升高的良好效果。The present invention provides a Chinese medicine composition and a preparation method and application thereof. The Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 5-35 parts of bupleurum, 5-30 parts of immature bitter orange, 5-20 parts of raw rhubarb, 1-20 parts of scutellaria, 3-20 parts of white peony root, 3-20 parts of dried ginger, 3-25 parts of leech, 3-20 parts of liquorice, 3-20 parts of codonopsis, 3-20 parts of atractylodes, and 3-45 parts of raw oyster. The Chinese medicine composition of the present invention has excellent effects in preventing or treating arterial atherosclerotic plaque formation, ischemic heart and brain diseases, elevated blood lipids, and elevated triglycerides.
Description
本發明屬於中藥領域,涉及一種中藥組合物及其製備方法和該中藥組合物在製備用於預防或治療動脈粥狀斑塊形成、缺血性心臟病、血脂升高、三酸甘油酯升高的藥物中的應用。The invention belongs to the field of traditional Chinese medicine, and relates to a traditional Chinese medicine composition and a preparation method thereof, and the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating arterial atherosclerotic plaque formation, ischemic heart disease, elevated blood lipids, and elevated triglycerides.
動脈粥狀斑塊形成和硬化(atherosclerosis,AS)是冠心病、心梗、腦梗、缺血性心臟病和外周血管病的主要原因。動脈粥狀斑塊的形成機制複雜,牽扯的因素非常多,包括脂質代謝障礙,心臟平滑肌的損傷,膠原纖維增生,炎性因子聚集等等。因此斑塊形成和硬化是一個多機制,長期病變發展的結果。現有資料表明,動脈粥狀斑塊的形成從動脈內膜損傷開始,一般先有脂質和複合糖類積聚、出血,進而纖維組織增生沉著,並有動脈中層的逐漸蛻變和鈣化,導致動脈壁增厚變硬、血管腔狹窄。頸動脈粥狀硬化斑塊的成分主要有:⑴ 緻密結締組織纖維帽,主要由細胞外基質(extracellular matrix,ECM)組成,尤其是膠原纖維;⑵ 脂質核心,由脂質巨噬細胞、平滑肌細胞和ECM組成;⑶ 外膜和斑塊內的新生血管。其特點是受累病變常累及大中肌性動脈,一旦發展到足以阻塞動脈腔,則該動脈所供應的組織或器官將缺血或壞死。由於在動脈內膜積聚的脂質外觀呈黃色粥狀,因此稱為動脈粥狀硬化斑塊。Atherosclerosis (AS) is the main cause of coronary heart disease, myocardial infarction, cerebral infarction, ischemic heart disease and peripheral vascular disease. The formation mechanism of atherosclerosis is complex and involves many factors, including lipid metabolism disorders, damage to cardiac smooth muscle, collagen fiber proliferation, inflammatory factor accumulation, etc. Therefore, plaque formation and sclerosis is a multi-mechanism, long-term development of the result of the disease. Existing data show that the formation of arterial atherosclerotic plaques begins with damage to the arterial endothelium, generally followed by accumulation of lipids and complex carbohydrates, bleeding, and then proliferation and deposition of fibrous tissue, as well as gradual degeneration and calcification of the middle layer of the artery, leading to thickening and hardening of the arterial wall and narrowing of the vascular lumen. The main components of carotid atherosclerotic plaques are: (1) a dense connective tissue fibrous cap, mainly composed of extracellular matrix (ECM), especially collagen fibers; (2) a lipid core, composed of lipid macrophages, smooth muscle cells and ECM; (3) new blood vessels in the outer membrane and plaque. Its characteristic is that the affected lesions often involve large and medium muscular arteries. Once they develop to the point where the arterial lumen is blocked, the tissues or organs supplied by the artery will be ischemic or necrotic. Because the lipids accumulated in the intima of the artery appear yellow and porridge-like, they are called atherosclerotic plaques.
衛生部《2016年中國衛生統計提要》中顯示,中國人死亡原因中,約30%死於心腦血管病,而這些心腦血管病患者,絕大多數死於動脈粥狀斑塊形成導致的心腦血管疾病。中國心血管健康與疾病報告編寫組在中國循環雜誌《中國心血管健康與疾病報告2019摘要》中報告,中國心血管病患病率處於持續上升階段。推算心血管病現患人數3.30億,每5例死亡,就有2例死於心腦血管病。動脈粥狀硬化性心腦血管疾病因此被稱為人類 “頭號殺手”,是影響我國人群健康的首位致病原因。The Ministry of Health's "2016 China Health Statistics Abstract" shows that about 30% of Chinese people die from cardiovascular and cerebrovascular diseases, and the vast majority of these cardiovascular and cerebrovascular disease patients die from cardiovascular and cerebrovascular diseases caused by the formation of atherosclerotic plaques. The Chinese Cardiovascular Health and Disease Report Writing Group reported in the "China Cardiovascular Health and Disease Report 2019 Abstract" of the Chinese Journal of Circulation that the prevalence of cardiovascular disease in China is in a continuous upward stage. It is estimated that the number of people suffering from cardiovascular disease is 330 million, and 2 out of every 5 deaths are caused by cardiovascular and cerebrovascular diseases. Atherosclerotic cardiovascular and cerebrovascular diseases are therefore called the "number one killer" of humans and are the leading cause of disease affecting the health of the Chinese population.
在世界許多國家,特別是發達國家,動脈粥狀硬化性心腦血管疾病也是導致死亡的首位原因。其中,動脈粥狀硬化導致冠狀動脈心肌梗死和腦中風占主要比例。到2035年,美國預計有超過1.3億成年人(45.1%)會患有某種心血管疾病,心血管疾病的總花費將高達1.1萬億美元。In many countries around the world, especially developed countries, atherosclerotic cardiovascular and cerebrovascular diseases are also the leading cause of death. Among them, atherosclerosis leads to coronary myocardial infarction and cerebral stroke, accounting for the majority. By 2035, it is estimated that more than 130 million adults (45.1%) in the United States will suffer from some type of cardiovascular disease, and the total cost of cardiovascular disease will reach 1.1 trillion US dollars.
一般認為,血脂代謝異常、高血脂在動脈粥狀斑塊形成中具有重要作用,是核心病變基礎之一。血脂是血液中各種脂類物質的總稱,其中最重要的是膽固醇和三酸甘油酯,三酸甘油酯也稱中性脂肪,其它重要脂類還包括脂蛋白,其中又包括低密度脂蛋白和高密度脂蛋白。健康人的平均血膽固醇含量在2.8~5.17mmol/L之間,平均血三酸甘油酯含量在0.56~1.7mmol/L之間。無論是膽固醇含量增高,還是三酸甘油酯的含量增高,或是兩者皆增高,均統稱為高脂血症。It is generally believed that abnormal blood lipid metabolism and hyperlipidemia play an important role in the formation of arterial atherosclerotic plaques and are one of the core lesions. Blood lipids are a general term for various lipid substances in the blood, the most important of which are cholesterol and triglycerides. Triglycerides are also called neutral fats. Other important lipids include lipoproteins, including low-density lipoproteins and high-density lipoproteins. The average blood cholesterol level of healthy people is between 2.8 and 5.17 mmol/L, and the average blood triglyceride level is between 0.56 and 1.7 mmol/L. Whether the cholesterol level is increased, the triglyceride level is increased, or both are increased, they are collectively referred to as hyperlipidemia.
國家衛生與計劃生育委員會2019年發佈的《中國心血管健康與疾病報告2019》顯示,4億國人血脂異常,患病率達40.40%,其中高膽固醇血症患病率4.9%,高三酸甘油酯血症的患病率13.1%, 患病率水平呈現逐年增加的趨勢。這對我國治療血脂異常,降低動脈粥狀斑塊形成風險工作提出嚴峻的挑戰。The "China Cardiovascular Health and Disease Report 2019" released by the National Health and Family Planning Commission in 2019 shows that 400 million Chinese people have abnormal blood lipids, with a prevalence rate of 40.40%, including 4.9% for hypercholesterolemia and 13.1% for hypertriglyceridemia. The prevalence rate is increasing year by year. This poses a severe challenge to my country's work on treating abnormal blood lipids and reducing the risk of arterial atherosclerotic plaque formation.
目前世界上無特異有效預防治療動脈粥狀斑塊的藥物。 治療高脂血症,因此是目前臨床上,預防動脈粥狀斑塊形成主要的臨床治療措施之一。目前臨床上應用的降血脂類化藥品種較多,主要是他汀類 (Statin)和纖維酸衍生物類(Fibrates)。儘管具體機轉不同,但主要都是通過直接作用於脂肪的合成和代謝路徑起效。由於停藥後血脂反彈機率非常高,因此化學合成降血脂藥物需要長期服用,這不僅導致經濟資源的損耗,同時也大大增加了毒副作用的產生機率。例如,長期服用常常伴隨著產生不同程度的副作用,包括肌肉疼痛,肝臟以及腎臟功能損傷等。此外,化學降血脂藥的使用,並不能從根本上預防和控制血管斑塊的形成和發展,對降低動脈粥狀硬化性心腦血管疾病引起的死亡作用有限。At present, there is no specific and effective drug for the prevention and treatment of arterial atherosclerotic plaques in the world. The treatment of hyperlipidemia is therefore one of the main clinical treatment measures for the prevention of arterial atherosclerotic plaque formation. There are many types of lipid-lowering drugs currently used in clinical practice, mainly statins and fibrotic acid derivatives. Although the specific mechanisms are different, they are mainly effective by directly acting on the synthesis and metabolic pathways of fat. Since the probability of blood lipid rebound after drug withdrawal is very high, chemically synthesized lipid-lowering drugs need to be taken for a long time, which not only leads to the loss of economic resources, but also greatly increases the probability of toxic side effects. For example, long-term use is often accompanied by side effects of varying degrees, including muscle pain, liver and kidney function damage, etc. In addition, the use of chemical lipid-lowering drugs cannot fundamentally prevent and control the formation and development of vascular plaques, and has limited effect on reducing deaths caused by atherosclerotic cardiovascular and cerebrovascular diseases.
以中國傳統天然藥物為基礎的針對心腦血管疾病的藥物,主要有通心絡膠囊、複方丹參滴丸、以及麝香保心丸等,均是市面上常見的防治冠心病、心絞痛藥物。針對血脂的有廣東宏興降脂丸、成都地奧脂必妥、北京維信血脂康等。這些藥從其說明書中可以看到,或多或少都存在一定的副作用。但更為關鍵的是,這些藥物缺乏有效和可被驗證的預防和消融動脈斑塊的作用。且從文獻報道可見,這些藥通常建議長期使用,並與化學降脂藥同時使用,或主要建議老年人使用等。Drugs for cardiovascular and cerebrovascular diseases based on traditional Chinese natural medicines mainly include Tongxinluo Capsules, Compound Danshen Pills, and Shexiang Baoxin Pills, which are all common drugs on the market for preventing and treating coronary heart disease and angina. Drugs for blood lipids include Guangdong Hongxing Jiangzhi Pills, Chengdu Di'ao Zhibituo, Beijing Weixin Xuezhikang, etc. From the instructions of these drugs, we can see that they all have certain side effects to a greater or lesser extent. But more importantly, these drugs lack effective and verifiable effects in preventing and ablating arterial plaques. And from the literature reports, it can be seen that these drugs are usually recommended for long-term use and used simultaneously with chemical lipid-lowering drugs, or are mainly recommended for use by the elderly.
因此,對於具有良好地預防和治療動脈粥狀斑塊、缺血性心臟病、血脂升高、三酸甘油酯升高等的傳統中藥藥物有強烈的臨床需求,社會和市場需求巨大。Therefore, there is a strong clinical demand for traditional Chinese medicines that have good effects in preventing and treating arterial atherosclerotic plaques, ischemic heart disease, elevated blood lipids, elevated triglycerides, etc., and the social and market demand is huge.
本發明的目的在於提供一種中藥組合物,其製備方法及其製備在用於預防或治療動脈粥狀斑塊形成、缺血性心臟病、血脂升高、三酸甘油酯升高等的藥物中的應用。臨床治療實踐顯示,本發明中藥組合物具有優良的減緩動脈粥狀斑形成,並清除動脈粥狀斑塊的效果,同時,臨床治療實踐也顯示本發明中藥組合物對於降低血脂,特別是降低血三酸甘油酯擁有良好效果。動脈粥狀斑塊形成動物模型研究顯示,本中藥組合物具有明顯的消融減小動脈斑塊的效果。The purpose of the present invention is to provide a Chinese medicine composition, a preparation method thereof and its application in drugs for preventing or treating arterial atherosclerosis, ischemic heart disease, elevated blood lipids, elevated triglycerides, etc. Clinical treatment practice shows that the Chinese medicine composition of the present invention has excellent effects of slowing down the formation of arterial atherosclerosis and clearing arterial atherosclerosis. At the same time, clinical treatment practice also shows that the Chinese medicine composition of the present invention has a good effect on lowering blood lipids, especially lowering blood triglycerides. Studies on animal models of arterial atherosclerosis formation show that the Chinese medicine composition has a significant effect of ablating and reducing arterial plaques.
本發明發明人經長期鑽研中國傳統醫學和藥材理論,並結合臨床實踐,提出了一種明顯有別於現代醫學的用於預防和治療動脈粥狀斑塊形成、缺血性心臟病、血脂升高、三酸甘油酯升高的藥物的用藥方案。我們認為,高血脂和動脈粥狀硬化形成的核心原因,用中國傳統醫學的邏輯和語言可以歸納為:痰飲入血。若進入現代醫學的語境,則類似於血液黏稠。血液黏稠既是高血脂和動脈粥狀硬化的病因,也是痰飲入血表現的病症。由於中國傳統醫學的痰飲入血表現為現代醫學的血液黏稠,因此我們認為對其的調節治療,是預防、治療高脂血症和動脈粥狀硬化的核心和有效途徑。After long-term research on traditional Chinese medicine and medicinal material theory, combined with clinical practice, the inventor of the present invention has proposed a medication regimen that is significantly different from modern medicine for the prevention and treatment of atherosclerosis, ischemic heart disease, elevated blood lipids, and elevated triglycerides. We believe that the core cause of hyperlipidemia and atherosclerosis can be summarized as phlegm entering the blood using the logic and language of traditional Chinese medicine. If it enters the context of modern medicine, it is similar to blood viscosity. Blood viscosity is both the cause of hyperlipidemia and atherosclerosis, and also a symptom of phlegm entering the blood. Since phlegm entering the blood in traditional Chinese medicine manifests as blood viscosity in modern medicine, we believe that its regulation and treatment is the core and effective way to prevent and treat hyperlipidemia and atherosclerosis.
“痰飲”在《皇帝內經》中被定義為離經之水,也就是在循環代謝中的一種體液,這種體液較黏稠的叫痰,較清稀的叫飲,合稱痰飲。中國傳統醫學中的“痰飲”多數是指在消化道和肺以及呼吸道中的黏稠或清稀的液體,這種液體難以被代謝掉,即使排出體外也又會從消化道或呼吸道繼續生成出來,綿綿不絕。這些黏稠的液體還可以從消化道、呼吸道溢出留存在皮膚下、肌肉中、骨關節中,甚至內臟和大腦中,變成各種包塊、囊腫、息肉,甚至腫瘤也被認為與痰飲留滯在個體中有關,中國傳統醫學認為很多疾病都和這種難以被身體排出體外,又難以被代謝掉的黏液有關。但中國傳統醫學對於痰飲進入血液與血液黏稠的關聯和論述欠缺。"Tanyin" is defined in Huangdi Neijing as water that has left the meridians, that is, a kind of body fluid in the circulation metabolism. The more viscous body fluid is called phlegm, and the thinner one is called drink. Together, they are called tanyin. In traditional Chinese medicine, "Tanyin" mostly refers to the viscous or thin liquid in the digestive tract, lungs, and respiratory tract. This liquid is difficult to be metabolized, and even if it is discharged from the body, it will continue to be generated from the digestive tract or respiratory tract, and it will continue to linger. These viscous liquids can also overflow from the digestive tract and respiratory tract and remain under the skin, in the muscles, in the bone joints, and even in the internal organs and brain, turning into various masses, cysts, polyps, and even tumors, which are also believed to be related to the retention of phlegm in the individual. Traditional Chinese medicine believes that many diseases are related to this kind of mucus that is difficult to be excreted and metabolized by the body. However, traditional Chinese medicine lacks the connection and discussion of phlegm entering the blood and blood viscosity.
在現代醫學中, “血液黏稠”的概念下包含了數十個生化指標。例如,高血脂的一些指標 (血清總膽固醇,低密度膽固醇,高密度膽固醇,載脂蛋白,三酸甘油酯),高血糖的一些指標 (空腹血糖,糖化血紅素,空腹胰島素,C肽,糖化血清蛋白,果糖胺),血小板的指標 (血小板數量,血小板黏附度,血小板沉降度等),紅血球的一些指標 (紅血球的數量,紅血球沉降度,紅血球黏附度,紅血球壓積量,紅血球變形性,紅血球的大小),血液黏稠度本身測定指標 (表觀黏度,相對黏度,還原黏度,比黏度等)以及一些其它相關指標 (纖維蛋白原,免疫球蛋白等)。以上這些指標都對血黏粘稠度有著比較密切的影響。血液黏稠表現不一,現代醫學尚未提供一個合理且公認的致病原因,對其的治療也停留在針對某些指標的階段,例如,通過服用藥物來控制高血脂、高血糖問題。但由於高血液黏稠度沒有從根本上解決,所以降脂、降糖效果持續時間短,需要長期服用,無法達到治癒的效果。In modern medicine, the concept of "blood viscosity" includes dozens of biochemical indicators. For example, some indicators of hyperlipidemia (serum total cholesterol, low-density cholesterol, high-density cholesterol, apolipoprotein, triglyceride), some indicators of hyperglycemia (fasting blood glucose, glycosylated hemoglobin, fasting insulin, C-peptide, glycosylated serum protein, fructosamine), platelet indicators (platelet number, platelet adhesion, platelet sedimentation, etc.), some indicators of red blood cells (red blood cell number, erythrocyte sedimentation, red blood cell adhesion, hematocrit, red blood cell deformability, red blood cell size), blood viscosity itself measurement indicators (apparent viscosity, relative viscosity, reduced viscosity, specific viscosity, etc.) and some other related indicators (fibrinogen, immunoglobulin, etc.). All of the above indicators have a close impact on blood viscosity. Blood viscosity has different manifestations. Modern medicine has not yet provided a reasonable and recognized cause of the disease. Its treatment remains at the stage of targeting certain indicators, for example, taking drugs to control high blood lipids and high blood sugar. However, since high blood viscosity has not been fundamentally solved, the lipid-lowering and blood sugar-lowering effects last for a short time and need to be taken for a long time, and the healing effect cannot be achieved.
痰飲進入血液引發血液黏稠,會大大增加高血脂和血糖發生的風險,進而引發動脈粥狀硬化,堵塞血管,再而引發心腦腎疾病。我們據此理論,在醫學臨床實踐中,開發了高效和長效用於預防或粥狀動脈斑塊形成、缺血性心臟病、血脂升高、三酸甘油酯升高的中藥組合物。Phlegm and drink enter the blood and cause blood viscosity, which greatly increases the risk of high blood lipids and blood sugar, and then causes arteriosclerosis, blockage of blood vessels, and then causes heart, brain and kidney diseases. Based on this theory, we have developed a highly effective and long-lasting Chinese medicine combination for the prevention or formation of atherosclerotic plaques, ischemic heart disease, elevated blood lipids, and elevated triglycerides in medical clinical practice.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:生大黃3-20份、白芍3-20份、乾薑3-20份、水蛭3-25份;優選地,本發明中藥組合物包含按以下重量份計的原料藥:生大黃5-15份、白芍5-15份、乾薑5-15份、水蛭7-15份;更優選地,本發明中藥組合物包含按以下重量份計的原料藥:生大黃10份、白芍10份、乾薑10份、水蛭10份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a Chinese medicine composition, which includes the following raw materials in parts by weight: 3-20 parts of raw rhubarb, 3-20 parts of white peony root, 3-20 parts of dried ginger, and 3-25 parts of leech; preferably, the Chinese medicine composition of the present invention includes the following raw materials in parts by weight: 5-15 parts of raw rhubarb, 5-15 parts of white peony root, 5-15 parts of dried ginger, and 7-15 parts of leech; more preferably, the Chinese medicine composition of the present invention includes the following raw materials in parts by weight: 10 parts of raw rhubarb, 10 parts of white peony root, 10 parts of dried ginger, and 10 parts of leech. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials in parts by weight as described above.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:生大黃3-20份、白芍3-20份、乾薑3-20份、水蛭3-25份、白術3-20份;優選地,本發明中藥組合物包含按以下重量份計的原料藥:生大黃5-15份、白芍5-15份、乾薑5-15份、水蛭7-15份、白術5-15份;更優選的,本發明中藥組合物包括按以下重量份計的原料藥:生大黃10份、白芍10份、乾薑10份、水蛭10份、白術10份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a Chinese medicine composition, which includes the following raw materials in parts by weight: 3-20 parts of raw rhubarb, 3-20 parts of white peony root, 3-20 parts of dried ginger, 3-25 parts of leech, and 3-20 parts of Atractylodes macrocephala; preferably, the Chinese medicine composition of the present invention includes the following raw materials in parts by weight: 5-15 parts of raw rhubarb, 5-15 parts of white peony root, 5-15 parts of dried ginger, 7-15 parts of leech, and 5-15 parts of Atractylodes macrocephala; more preferably, the Chinese medicine composition of the present invention includes the following raw materials in parts by weight: 10 parts of raw rhubarb, 10 parts of white peony root, 10 parts of dried ginger, 10 parts of leech, and 10 parts of Atractylodes macrocephala. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials in parts by weight as described above.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:柴胡5-35份、枳實5-30份、生大黃3-20份、白芍3-20份、乾薑3-20份、水蛭3-25份、白術3-20份;優選地,本發明中藥組合物包含按以下重量份計的原料藥:柴胡15-30份、枳實10-20份、生大黃5-15份、白芍5-15份、乾薑5-15份、水蛭7-15份、白術5-15份;更優選地,本發明中藥組合物包含按以下重量份計的原料藥:柴胡20份、枳實15份、生大黃10份、白芍10份、乾薑10份、水蛭10份、白術10份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a traditional Chinese medicine composition, which comprises the following raw materials in parts by weight: 5-35 parts of bupleurum, 5-30 parts of immature bitter orange, 3-20 parts of raw rhubarb, 3-20 parts of white peony root, 3-20 parts of dried ginger, 3-25 parts of leech, and 3-20 parts of atractylodes macrocephala; preferably, the traditional Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 15-30 parts of bupleurum, 10-20 parts of immature bitter orange, 5-15 parts of raw rhubarb, 5-15 parts of white peony root, 5-15 parts of dried ginger, 7-15 parts of leech, and 5-15 parts of atractylodes macrocephala; more preferably, the traditional Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 20 parts of bupleurum, 15 parts of immature bitter orange, 10 parts of raw rhubarb, 10 parts of white peony root, 10 parts of dried ginger, 10 parts of leech, and 10 parts of atractylodes macrocephala. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials according to the weight proportions as mentioned above.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:柴胡5-35份、枳實5-30份、生大黃3-20份、白芍3-20份、乾薑3-20份、水蛭3-25份、甘草3-20份、白術3-20份、生牡蠣 3-45 份;優選地,其包含按以下重量份計的原料藥:柴胡15-30份、枳實10-20份、生大黃5-15份、白芍5-15份、乾薑5-15份、水蛭7-15份、甘草5-15份、白術5-15份、生牡蠣10-35 份;更優選地,其包含按以下重量份計的原料藥:柴胡20份、枳實15份、生大黃10份、白芍10份、乾薑10份、水蛭10份、甘草10份、白術10份、生牡蠣30 份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a Chinese medicine composition, which comprises the following raw materials in parts by weight: 5-35 parts of bupleurum, 5-30 parts of immature bitter orange, 3-20 parts of raw rhubarb, 3-20 parts of white peony root, 3-20 parts of dried ginger, 3-25 parts of leech, 3-20 parts of liquorice, 3-20 parts of atractylodes macrocephala, and 3-45 parts of raw oyster; preferably, it comprises the following raw materials in parts by weight: 15-30 parts of bupleurum, 10-20 parts of immature bitter orange, 5-15 parts of raw rhubarb, 5-15 parts of white peony root, 5-15 parts of dried ginger, 7-15 parts of leech, 5-15 parts of liquorice, 5-15 parts of atractylodes macrocephala, 10-35 parts of raw oyster More preferably, it comprises the following raw materials in parts by weight: 20 parts of bupleurum, 15 parts of immature bitter orange, 10 parts of raw rhubarb, 10 parts of white peony root, 10 parts of dried ginger, 10 parts of leech, 10 parts of liquorice, 10 parts of atractylodes macrocephala, and 30 parts of raw oyster. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials in parts by weight as described above.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:柴胡5-35份、枳實5-30份、生大黃3-20份、黃芩1-20份、白芍3-20份、乾薑3-20份、水蛭3-25份、甘草3-20份、黨參3-20份、白術3-20份、生牡蠣 3-45 份;優選地,本發明中藥組合物,包含按以下重量份計的原料藥:柴胡15-30份、枳實10-20份、生大黃5-15份、黃芩2-10份、白芍5-15份、乾薑5-15份、水蛭7-15份、甘草5-15份、黨參5-15份、白術5-15份、生牡蠣10-35 份;更優選地,本發明中藥組合物,包含按以下重量份計的原料藥:柴胡20份、枳實15份、生大黃10份、黃芩3份、白芍10份、乾薑10份、水蛭10份、甘草10份、黨參10份、白術10份、生牡蠣30 份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a Chinese medicine composition, which comprises the following raw materials in parts by weight: 5-35 parts of bupleurum, 5-30 parts of immature bitter orange, 3-20 parts of raw rhubarb, 1-20 parts of scutellaria, 3-20 parts of white peony root, 3-20 parts of dried ginger, 3-25 parts of leech, 3-20 parts of liquorice, 3-20 parts of codonopsis, 3-20 parts of atractylodes, 3-45 parts of raw oyster parts; preferably, the Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 15-30 parts of bupleurum, 10-20 parts of immature bitter orange, 5-15 parts of raw rhubarb, 2-10 parts of scutellaria, 5-15 parts of white peony root, 5-15 parts of dried ginger, 7-15 parts of leech, 5-15 parts of liquorice, 5-15 parts of codonopsis pilosula, 5-15 parts of atractylodes macrocephala, and 10-35 parts of raw oyster; more preferably, the Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 20 parts of bupleurum, 15 parts of immature bitter orange, 10 parts of raw rhubarb, 3 parts of scutellaria, 10 parts of white peony root, 10 parts of dried ginger, 10 parts of leech, 10 parts of liquorice, 10 parts of codonopsis pilosula, 10 parts of atractylodes macrocephala, and 30 parts of raw oyster. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials according to the weight proportions as mentioned above.
本發明提供一種中藥組合物,其包括按以下重量份計的原料藥:生大黃3-20份、乾薑3-20份、白芍3-20份、水蛭3-25份、甘草3-20份、生牡蠣 3-45 份、丹皮3-20份、桃仁2-15份;優選地,本發明中藥組合物,其包含按以下重量份計的原料藥:生大黃5-15份、乾薑5-15份、丹皮5-15份、桃仁3-12份、白芍5-15份、水蛭7-15份、甘草5-15份、生牡蠣10-35 份;更優選地,本發明中藥組合物,其包括按以下重量份計的原料藥:生大黃10份、乾薑10份、白芍10份、水蛭10份、甘草10份、生牡蠣30份、丹皮10份、桃仁6份。進一步優選地,本發明中藥組合物由按如上所述重量份的原料藥製成。The present invention provides a Chinese medicine composition, which comprises the following raw materials in parts by weight: 3-20 parts of raw rhubarb, 3-20 parts of dried ginger, 3-20 parts of white peony root, 3-25 parts of leech, 3-20 parts of liquorice, 3-45 parts of raw oyster, 3-20 parts of moutan bark, and 2-15 parts of peach kernel; preferably, the Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 5-15 parts of raw rhubarb, 5-15 parts of dried ginger, 5-15 parts of moutan bark, 3-12 parts of peach kernel, 5-15 parts of white peony root, 7-15 parts of leech, 5-15 parts of liquorice, 10-35 parts of raw oyster, 10-35 parts of moutan bark ... More preferably, the Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 10 parts of raw rhubarb, 10 parts of dried ginger, 10 parts of white peony root, 10 parts of leech, 10 parts of liquorice, 30 parts of raw oyster, 10 parts of moutan bark, and 6 parts of peach kernel. Further preferably, the Chinese medicine composition of the present invention is prepared from the raw materials in parts by weight as described above.
以上組成中,份為重量份,重量是以生藥計算的。在生產時可按照相應比例增大或減少,如大規模生產可以以公斤為單位,或以噸為單位,重量可以增大或者減小,但各組成之間的生藥材重量配比的比例不變。In the above composition, parts are by weight, and the weight is calculated based on the raw materials. During production, the proportion can be increased or decreased accordingly. For example, large-scale production can be measured in kilograms or tons. The weight can be increased or decreased, but the weight ratio of the raw materials in each component remains unchanged.
本發明相關原料藥介紹如下:The raw materials related to the present invention are introduced as follows:
柴胡,藥用部位為傘形科植物柴胡或狹葉柴胡的乾燥根 (Bupleurum chinense DC.或Bupleurum scorzonerifolium Willd.)。有和解表裡,疏肝升陽之功效。Bupleurum, the medicinal part of which is the dried root of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd., is a plant of the Umbelliferae family. It has the effects of reconciling the exterior and interior, soothing the liver and raising yang.
枳實,為芸香科植物酸橙及其栽培變種或甜橙的乾燥幼果(Immature Bitter Orange、Immature Sweet Orange、Fructus Aurantii Immaturus)。有破氣消積,化痰散痞之功效。Citrus aurantium is the dried young fruit of the plant bitter orange and its cultivated varieties or sweet orange (Immature Bitter Orange, Immature Sweet Orange, Fructus Aurantii Immaturus) of the Rutaceae family. It has the effects of breaking up qi and eliminating stagnation, resolving phlegm and dispersing abdominal distension.
生大黃,本品為蓼科植物掌葉大黃(Rheum palmatum L.),唐古特大黃(Rheum tanguticum Maxim. ex Balf.),或藥用大黃(Rheum officinale Baill.)的乾燥根及根莖。有瀉熱毒,破積滯,行瘀血之功效。Raw rhubarb is the dried root and rhizome of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., or Rheum officinale Baill., which are plants of the Polygonaceae family. It has the effects of dispelling heat and toxins, breaking up stagnation, and promoting the flow of blood stasis.
黃芩,唇形科多年生草本植物黃芩(Scutellaria baicalnsis Geprgi) 的乾燥根。有清熱燥濕、瀉火解毒、止血、安胎等功效。Scutellaria baicalensis is the dried root of Scutellaria baicalnsis Geprgi, a perennial herb of the Lamiaceae family. It has the effects of clearing away heat and dampness, purging fire and detoxifying, stopping bleeding, and calming the fetus.
白芍,為毛莨科植物芍藥(Paeonia lactiflora Pall.)的乾燥根。具溫陽祛濕、補體虛、健脾胃等功效。White peony root is the dried root of Paeonia lactiflora Pall., a plant of the Ranunculaceae family. It has the effects of warming the yang and removing dampness, replenishing the body, and strengthening the spleen and stomach.
乾薑,為姜科植物薑(Zingiber oj-jicinale Rosc.)的乾燥根莖。冬季採挖,除去鬚根和泥沙,曬乾或低溫乾燥。趁鮮切片曬乾或低溫乾燥者稱為“乾薑片”。有溫中散寒,回陽通脈,溫肺化飲等功效。Dried ginger is the dried rhizome of the ginger plant Zingiber oj-jicinale Rosc. It is dug in winter, the roots and mud are removed, and it is dried in the sun or at low temperature. The slices that are sliced and dried in the sun or at low temperature while fresh are called "dried ginger slices". It has the effects of warming the middle and dispersing cold, restoring yang and unblocking meridians, warming the lungs and transforming drinks.
水蛭,為水蛭科動物螞蟥(Whitm.ania Pigra Whitman),水蛭(Hirudo nipponica Whitman)或柳葉螞蟥(Whitmania acranutata Whitman)的乾燥全體。夏、秋二季捕捉,用沸水燙死,曬乾或低溫乾燥。具有破血通經,逐瘀消症的功效。Leeches are the dried whole body of the Hirudinidae leech (Whitmania Pigra Whitman), Hirudo nipponica Whitman or Whitmania acranutata Whitman. They are caught in summer and autumn, killed by boiling water, and dried in the sun or at low temperatures. They have the effects of breaking blood, unblocking menstruation, removing blood stasis and relieving symptoms.
甘草(Glycyrrhiza uralensis Fisch),別名:國老、甜草、烏拉爾甘草、甜根子。豆科、甘草屬多年生草本,藥用部位是根及根莖。用於心氣虛,心悸怔忡,脈結代,以及脾胃氣虛,倦怠乏力,調和某些藥物的烈性及對胃腸道的反應。Licorice (Glycyrrhiza uralensis Fisch), also known as Guolao, sweet grass, Ural licorice, sweet root, is a perennial herbaceous plant of the Leguminosae family and the genus Glycyrrhiza. Its medicinal parts are the roots and rhizomes. It is used to treat heart qi deficiency, palpitations, irregular pulse, spleen and stomach qi deficiency, fatigue, and to adjust the potency of certain drugs and their effects on the gastrointestinal tract.
黨參,為桔梗科植物黨參、素花黨參、或川黨參等的乾燥根。有補中,益氣,生津的功效。Dangshen is the dried root of Dangshen, Dangshen with white flowers, or Dangshen with Sichuan in the Campanulaceae family. It has the effects of nourishing the middle, replenishing qi, and promoting the production of body fluids.
白術,菊科植物白術(Atractylodes macrocephala Koidz.)的乾燥根莖。有健脾益氣,燥濕利水,止汗的功效。Atractylodes macrocephala is the dried rhizome of Atractylodes macrocephala Koidz. It has the effects of strengthening the spleen and replenishing qi, drying dampness and promoting diuresis, and stopping sweating.
生牡蠣,為牡蠣科動物長牡蠣(Ostrea gigas Thunberg),大連灣牡蠣(Ostrea talienwhanensis Crosse) 或近江牡蠣(Ostrea rivularis Gould)的貝殼。有重鎮安神,潛陽補陰,軟堅散結之功效。Raw oysters are the shells of the Ostrea gigas Thunberg, Ostrea talienwhanensis Crosse or Ostrea rivularis Gould species of the Ostrea family. They have the effects of calming the nerves, nourishing the yang and tonifying the yin, and softening and dispersing lumps.
丹皮(Tree Peony Bark),又名牡丹皮,中藥名,為毛茛科芍藥屬植物多年生落葉小灌木植物牡丹Paeonia suffruticosa Andr.的乾燥根皮。有抗炎,抑制血小板,中樞抑制作用及抗動脈粥狀硬化等作用。Tree Peony Bark, also known as Peony Bark, is a Chinese medicine name. It is the dried root bark of Paeonia suffruticosa Andr., a perennial deciduous shrub of the Ranunculaceae family. It has anti-inflammatory, platelet inhibition, central nervous system inhibition and anti-atherosclerosis effects.
桃仁,為薔薇科植物桃Prunus persica(L.)Batsch或山桃Prunus davidiana (Carr.)Franch.的乾燥成熟種子。具有活血祛瘀,潤腸通便,止咳平喘的功效。Peach kernel is the dried mature seed of Prunus persica (L.) Batsch or Prunus davidiana (Carr.) Franch. of the Rosaceae family. It has the effects of promoting blood circulation and removing blood stasis, moistening the intestines and relieving constipation, and relieving cough and asthma.
本發明的藥方是在對傷寒論經方及相應藥材充分研究的基礎上,結合臨床實踐形成的。中醫理論中,缺血性心腦血管疾病屬於“眩暈”“胸痹”的範疇。最常見的原因是氣滯血瘀或氣血不足,血液推動乏力而導致的血流運行不暢,從而導致心腦血管供血、供氧不足而出現胸悶、胸痛、眩暈的症狀。本藥主要立方是為了去痰飲,痰飲是內邪之首,動脈斑塊的主要病理就是由於血液黏稠,脂肪代謝障礙和動脈炎性反應引發的疾病,為了清除動脈斑塊,清除血中痰飲是主要工作。本方通過組方中藥藥物達到解除血液黏稠的狀態,行氣導滯降濁,逐漸清除動脈斑塊,達到顯著改善缺血性心腦疾病的症狀的療效。The prescription of the present invention is formed on the basis of a thorough study of the Shanghan Lun prescription and the corresponding medicinal materials, combined with clinical practice. In the theory of traditional Chinese medicine, ischemic cardiovascular and cerebrovascular diseases belong to the category of "vertigo" and "chest pain". The most common cause is qi stagnation and blood stasis or qi and blood deficiency, which leads to poor blood flow due to weak blood propulsion, resulting in insufficient blood supply and oxygen supply to the cardiovascular and cerebrovascular vessels, resulting in symptoms of chest tightness, chest pain, and dizziness. The main purpose of this medicine is to remove phlegm and drink, which is the first of the internal evils. The main pathology of arterial plaques is due to blood viscosity, fat metabolism disorders and arterial inflammatory reactions. In order to remove arterial plaques, removing phlegm and drink in the blood is the main task. This prescription uses a combination of Chinese medicinal herbs to relieve blood viscosity, promote qi circulation, remove stagnation and reduce turbidity, gradually clear arterial plaques, and achieve a therapeutic effect that significantly improves the symptoms of ischemic heart and brain diseases.
本方以生大黃和柴胡共同為君藥,以乾薑、生白術、黨參為臣藥,以水蛭、生牡蠣、白芍、枳實、黃芩,或丹皮,桃仁為佐藥,以甘草為使藥。This prescription uses raw rhubarb and bupleurum as the main medicines, dried ginger, raw white atractylodes, and dangshen as the assistant medicines, leech, raw oyster, white peony root, immature bitter orange, scutellaria, or moutan bark and peach kernel as the adjuvant medicines, and licorice as the guiding medicine.
本發明的中藥組合物可通過提取或本領域其他已知方式來獲得藥物活性物質。所述藥物活性物質可以通過分別提取天然複方藥物原料得到,也可以通過共同提取天然複方藥物原料得到。The Chinese medicine composition of the present invention can obtain the active pharmaceutical ingredients by extraction or other known methods in the art. The active pharmaceutical ingredients can be obtained by extracting the natural compound pharmaceutical raw materials separately or by extracting the natural compound pharmaceutical raw materials together.
優選的,通過煎煮法製備。更優選的,本發明中藥組合物的製備方法包括稱取原料藥,第一次加水4-12倍量,在70-95℃,優選70-85℃保溫30-120分鐘,得到第一次煎煮液;第二次加水3-10倍量,在70-95℃,優選70-85℃保溫30-120分鐘,得到第二次煎煮液;合併二次煎煮液,濾過,合併濾液。更優選的,本發明中藥組合物的製備方法包括稱取原料藥,第一次加水8倍量,煮沸後在80℃或75℃保溫60分鐘,得到第一次煎煮液;第二次加水6倍量,煮沸後在80℃或75℃保溫60分鐘,得到第二次煎煮液;合併二次煎煮液,濾過,合併濾液。獲得的提取物可進一步濃縮製成浸膏形式,可以是乾浸膏也可以是流浸膏。優選減壓(-0.05Mpa, 60℃)濃縮至相對密度 1.05-1.15(60℃)。Preferably, the preparation is by decoction. More preferably, the preparation method of the Chinese medicine composition of the present invention comprises weighing the raw material drug, adding 4-12 times of water for the first time, keeping warm at 70-95°C, preferably 70-85°C for 30-120 minutes, to obtain a first decoction; adding 3-10 times of water for the second time, keeping warm at 70-95°C, preferably 70-85°C for 30-120 minutes, to obtain a second decoction; combining the two decoctions, filtering, and combining the filtered liquids. More preferably, the preparation method of the Chinese medicine composition of the present invention comprises weighing the raw material drug, adding 8 times the amount of water for the first time, boiling and keeping it at 80°C or 75°C for 60 minutes to obtain the first decoction; adding 6 times the amount of water for the second time, boiling and keeping it at 80°C or 75°C for 60 minutes to obtain the second decoction; combining the two decoctions, filtering, and combining the filtrate. The obtained extract can be further concentrated to an extract form, which can be a dry extract or a fluid extract. It is preferably concentrated under reduced pressure (-0.05Mpa, 60°C) to a relative density of 1.05-1.15 (60°C).
本發明中藥組合物,視需要還可以加入藥學上可接受的載體製成製劑。本發明中藥組合物提取或加工獲得的藥物活性物質在製劑中所占重量百分比為0.1-99.9%,其餘為藥學上可接受的載體。The Chinese medicine composition of the present invention can be added with a pharmaceutically acceptable carrier as needed to prepare a preparation. The weight percentage of the active pharmaceutical ingredient extracted or processed from the Chinese medicine composition of the present invention in the preparation is 0.1-99.9%, and the rest is a pharmaceutically acceptable carrier.
本發明中藥組合物可以是任何可藥用的劑型,這些劑型包括:湯劑、錠劑、糖衣錠劑、薄膜衣錠劑、腸溶衣錠劑、膠囊劑、硬膠囊劑、軟膠囊劑、口服液、口含劑、顆粒劑、沖劑、丸劑、散劑、膏劑、丹劑、懸浮劑、粉劑、溶液劑、注射劑、栓劑、軟膏劑、硬膏劑、霜劑、噴霧劑、滴劑、貼劑。優選口服劑型,進一步優選湯劑、膠囊劑、錠劑、口服液、顆粒劑、丸劑、散劑、丹劑、膏劑等。最優選湯劑、顆粒劑、膠囊劑、錠劑。The Chinese medicine composition of the present invention can be in any pharmaceutically acceptable dosage form, including decoctions, tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, liquids, pills, powders, ointments, pills, suspensions, powders, solutions, injections, suppositories, soft ointments, hard plasters, creams, sprays, drops, and patches. Oral dosage forms are preferred, and decoctions, capsules, tablets, oral liquids, granules, pills, powders, pills, pastes, etc. are further preferred. Decoctions, granules, capsules, and tablets are most preferred.
本發明進一步提供所述的中藥組合物在製備預防或控制血管斑塊形成的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in preparing a drug for preventing or controlling the formation of vascular plaques.
本發明進一步提供所述的中藥組合物在製備預防或治療動脈粥狀斑塊的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of a medicine for preventing or treating arterial atherosclerotic plaque.
本發明進一步提供所述的中藥組合物在製備預防或治療動脈粥狀斑塊缺血性心腦疾病的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of drugs for preventing or treating arterial atherosclerotic plaque ischemic heart and brain diseases.
本發明進一步提供所述的中藥組合物在製備預防或治療血脂升高的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of a drug for preventing or treating hyperlipidemia.
本發明進一步提供所述的中藥組合物在製備預防或治療三酸甘油酯升高的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of a drug for preventing or treating elevated triglycerides.
本發明進一步提供所述的中藥組合物在製備預防或治療膽固醇升高的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of a drug for preventing or treating elevated cholesterol.
本發明進一步提供所述的中藥組合物在製備預防或治療高脂血症的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of a drug for preventing or treating hyperlipidemia.
本發明進一步提供所述的中藥組合物在製備預防或治療慢性代謝疾病的藥物中的應用。The present invention further provides the use of the Chinese medicine composition in the preparation of medicines for preventing or treating chronic metabolic diseases.
本發明進一步提供一種預防或控制血管斑塊形成的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or controlling the formation of vascular plaques, comprising administering an effective amount of the Chinese medicinal composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療動脈粥狀斑塊的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating arterial atherosclerotic plaques, comprising administering an effective amount of the Chinese medicine composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療動脈粥狀斑塊性缺血性心腦疾病的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating arteriosclerotic ischemic heart and brain diseases, comprising administering an effective amount of the Chinese medicine composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療血脂升高的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating elevated blood lipids, comprising administering an effective amount of the Chinese medicine composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療三酸甘油酯升高的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating elevated triglycerides, comprising administering an effective amount of the Chinese medicinal composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療膽固醇升高的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating elevated cholesterol, comprising administering an effective amount of the Chinese medicinal composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療高脂血症的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating hyperlipidemia, comprising administering an effective amount of the Chinese medicine composition of the present invention as described above to a person in need thereof.
本發明進一步提供一種預防或治療慢性代謝性疾病的方法,包括給予有此需要的人預防或治療有效量的如上所述的本發明中藥組合物。The present invention further provides a method for preventing or treating chronic metabolic diseases, comprising administering an effective amount of the Chinese medicine composition of the present invention as described above to a person in need thereof.
本發明中藥組合物在使用時可每日服用一到三次14天為一個療程,動脈粥狀斑塊病人的治療需要6-12各療程,在每個療程間停藥3天。製成單位劑量形式時,每次服用1-10劑。本發明中藥組合物經過水煎後,可濃縮乾燥製得乾浸膏粉,再加入適量賦型劑,製成顆粒劑,每日服用一到三次,每次服用1-2劑,或者也可以裝入膠囊或製成錠劑,每日服用一到三次,每次服用2-8粒膠囊或錠劑,具體用法用量可根據具體病人情況酌情調整。The Chinese medicine composition of the present invention can be taken once to three times a day for 14 days as a course of treatment. The treatment of patients with arterial atheroma requires 6-12 courses of treatment, and the drug is stopped for 3 days between each course of treatment. When it is made into a unit dose form, 1-10 doses are taken each time. After being decocted in water, the Chinese medicine composition of the present invention can be concentrated and dried to obtain a dry extract powder, and then an appropriate amount of a molding agent is added to make granules, which can be taken once to three times a day, 1-2 doses each time, or can be put into capsules or made into tablets, which can be taken once to three times a day, 2-8 capsules or tablets each time. The specific usage and dosage can be adjusted according to the specific patient conditions.
本發明的中藥配方,是在“痰飲入血”和傷寒論理論和實踐基礎上的創新性構建。本發明發明人在充分研究考慮中藥材組分性質和功效的基礎上,結合臨床實踐而形成了本配方,並確定了組分配比。本發明中藥組合物對預防動脈粥狀斑塊發生和進展,消融動脈粥狀軟斑塊臨床效果明顯。臨床治療實踐也顯示,本發明中藥配方具有優良的降低血脂,特別是對重度血三酸甘油酯升高(三酸甘油酯>5.6 mmol/L)的病例,降低血三酸甘油酯的效果尤其明顯。The Chinese medicine formula of the present invention is an innovative construction based on the theory and practice of "phlegm and drink entering the blood" and the theory of typhoid fever. The inventors of the present invention have formed this formula and determined the composition ratio based on a full study and consideration of the properties and efficacy of the components of Chinese medicinal materials, combined with clinical practice. The Chinese medicine composition of the present invention has obvious clinical effects on preventing the occurrence and progression of arterial atherosclerotic plaques and ablating arterial atherosclerotic soft plaques. Clinical treatment practice also shows that the Chinese medicine formula of the present invention has excellent blood lipid lowering effect, especially for cases with severe elevated blood triglycerides (triglycerides>5.6 mmol/L), the effect of lowering blood triglycerides is particularly obvious.
下面結合具體實施方式對本發明進行進一步的詳細描述,給出的實施例僅為了闡明本發明,而不是為了限制本發明的範圍。The present invention is further described in detail below in conjunction with specific implementations. The embodiments given are only for illustrating the present invention, not for limiting the scope of the present invention.
下述實施例中的試驗方法,如無特殊說明,均為常規方法;下述實施例中所用的原料、試劑材料等,如無特殊說明,均為市售購買產品。The experimental methods in the following examples are conventional methods unless otherwise specified; the raw materials, reagent materials, etc. used in the following examples are commercially available products unless otherwise specified.
本申請說明書中,如果沒有特殊說明,各受試藥物的製備過程中溶劑的用量都是以藥材重量為基準的體積倍數。In this application manual, unless otherwise specified, the amount of solvent used in the preparation of each test drug is based on the volume multiple of the drug weight.
實施例1 本發明中藥組合物的製備Example 1 Preparation of the Chinese medicine composition of the present invention
樣品A:稱取如下原料藥:柴胡20份、枳實15份、生大黃10份、白芍10份、乾薑10份、水蛭10份、白術10份,置密閉容器內煮提兩次,第一次加水8倍量,煮沸後75攝氏度保溫60分鐘,得到煎煮液;第二次加水6倍量,煮沸後70攝氏度保溫60分鐘,得第二次煎煮液;合併二次煎煮液,濾過,合併濾液。濾液等體積分為14份,提供7天的用量,4攝氏度保存。Sample A: Weigh the following raw materials: 20 parts of Bupleurum, 15 parts of Citrus aurantium, 10 parts of Rhubarb, 10 parts of White Peony, 10 parts of Ginger, 10 parts of Leech, 10 parts of Atractylodes macrocephala, and boil them twice in a sealed container. For the first time, add 8 times the amount of water, boil and keep warm at 75 degrees Celsius for 60 minutes to obtain a decoction; for the second time, add 6 times the amount of water, boil and keep warm at 70 degrees Celsius for 60 minutes to obtain a second decoction; combine the two decoctions, filter, and combine the filtrate. The filtrate is divided into 14 equal volumes, which can provide a 7-day supply and is stored at 4 degrees Celsius.
樣品B:稱取如下原料藥:柴胡20g、枳實15g、生大黃10g、黃芩3g、白芍10g、乾薑10g、水蛭10g、甘草10g、黨參10g、白術10g、生牡蠣30g,置密閉容器內煮提兩次,第一次加水8倍量,煮沸後75攝氏度保溫60分鐘,得到煎煮液;第二次加水6倍量,煮沸後70攝氏度保溫60分鐘,得第二次煎煮液;合併二次煎煮液,濾過,合併濾液。濾液等體積分為14份,提供7天的用量,4攝氏度保存。Sample B: Weigh the following raw materials: 20g of Bupleurum, 15g of Citrus aurantium, 10g of Rhubarb, 3g of Scutellaria, 10g of White Peony, 10g of Dried Ginger, 10g of Hirudo, 10g of Licorice, 10g of Codonopsis pilosula, 10g of Atractylodes macrocephala, 30g of Oyster, and boil them twice in a sealed container. For the first time, add 8 times the amount of water, boil and keep warm at 75 degrees Celsius for 60 minutes to obtain a decoction; for the second time, add 6 times the amount of water, boil and keep warm at 70 degrees Celsius for 60 minutes to obtain a second decoction; combine the two decoctions, filter, and combine the filtrate. The filtrate is divided into 14 equal volumes, providing a 7-day supply, and stored at 4 degrees Celsius.
樣品C:稱取如下原料藥:柴胡20g、枳實15g、生大黃10g、白芍10g、乾薑10g、水蛭10g、甘草10g、白術10g、生牡蠣30g,置密閉容器內煮提兩次,第一次加水8倍量,煮沸後75攝氏度保溫60分鐘,得到煎煮液;第二次加水6倍量,煮沸後70攝氏度保溫60分鐘,得第二次煎煮液;合併二次煎煮液,濾過,合併濾液。濾液等體積分為14份,提供7天的用量,4攝氏度保存。Sample C: Weigh the following raw materials: 20g of Bupleurum, 15g of Citrus aurantium, 10g of Rhubarb, 10g of White Peony Root, 10g of Dried Ginger, 10g of Hirudo, 10g of Liquorice, 10g of Atractylodes macrocephala, and 30g of Oyster, and boil them twice in a sealed container. For the first time, add 8 times the amount of water, boil and keep warm at 75 degrees Celsius for 60 minutes to obtain a decoction; for the second time, add 6 times the amount of water, boil and keep warm at 70 degrees Celsius for 60 minutes to obtain a second decoction; combine the two decoctions, filter, and combine the filtrate. The filtrate is divided into 14 portions of equal volume, providing a 7-day supply, and stored at 4 degrees Celsius.
樣品D:稱取如下原料藥:生大黃10g、白芍10g、乾薑10g、水蛭10g、甘草10g、丹皮10g、桃仁6g、生牡蠣30g,置密閉容器內煮提兩次,第一次加水8倍量,煮沸後75攝氏度保溫60分鐘,得到煎煮液;第二次加水6倍量,煮沸後70攝氏度保溫60分鐘,得第二次煎煮液;合併二次煎煮液,濾過,合併濾液。濾液等體積分為14份,提供7天的用量,4攝氏度保存。Sample D: Weigh the following raw materials: 10g of raw rhubarb, 10g of white peony root, 10g of dried ginger, 10g of leech, 10g of liquorice, 10g of moutan bark, 6g of peach kernel, and 30g of raw oyster. Boil them twice in a sealed container. Add 8 times the amount of water for the first time, boil and keep warm at 75 degrees Celsius for 60 minutes to obtain a decoction. Add 6 times the amount of water for the second time, boil and keep warm at 70 degrees Celsius for 60 minutes to obtain a second decoction. Combine the two decoctions, filter, and combine the filtrate. Divide the filtrate into 14 portions of equal volume, which can provide a 7-day supply and are stored at 4 degrees Celsius.
實施例2:動脈粥狀硬化治療典型病例Example 2: Typical case of atherosclerosis treatment
實施例2-1:Embodiment 2-1:
陳某,男,2021年期間,在浙江湖州瑞博中醫門診部(浙江省湖州市梅州路 322號)就診,就診時,陳某雙側頸總動脈硬化斑塊形成,明顯的有6個斑塊,大小分別為斑塊1(15.2*1.6mm)、斑塊2(10.7*2.0mm)、斑塊3(10.2*2.1mm)、斑塊4(5.5*1.0mm)、斑塊5(5.8*1.6mm)和斑塊6(5.5*1.7mm)。早晚飯後,各服用如上實施例樣品B準備的濾液一份。經過7個療程 (14天/每療程)的治療,雙側頸總動脈硬化斑塊變小或消失,其中斑塊4、5、6三個斑塊完全消失,另外三個斑塊1、2、3顯著減小,大小分別減小為8.8*2.4mm、7*2.4mm和6.8*1.7mm。Chen, male, was treated at the Ruibo TCM Clinic in Huzhou, Zhejiang (No. 322, Meizhou Road, Huzhou City, Zhejiang Province) in 2021. At the time of treatment, Chen had sclerotic plaques in both lateral common carotid arteries, with 6 obvious plaques, sized as plaque 1 (15.2*1.6mm), plaque 2 (10.7*2.0mm), plaque 3 (10.2*2.1mm), plaque 4 (5.5*1.0mm), plaque 5 (5.8*1.6mm) and plaque 6 (5.5*1.7mm). After breakfast and dinner, take one portion of the filtrate prepared in Sample B as described above. After 7 courses of treatment (14 days/each course), the sclerotic plaques in the bilateral common carotid arteries became smaller or disappeared, among which plaques 4, 5, and 6 disappeared completely, and the other three plaques 1, 2, and 3 were significantly reduced in size to 8.8*2.4mm, 7*2.4mm, and 6.8*1.7mm, respectively.
實施例2-2:Embodiment 2-2:
李某,女,65歲,2020-2021年期間,在浙江湖州瑞博中醫門診部(浙江省湖州市梅州路 322號)就診,就診時,李某雙側頸總動脈硬化斑塊形成,明顯的有4個斑塊,大小分別為斑塊1(12.1*2.6mm)、斑塊2(10.2*2.0mm)、斑塊3(10.0*1.9mm)和斑塊4(5.6*2.0mm)。早晚飯後,各服用如上實施例樣品B準備的濾液一份。經過12個療程 (14天/每療程)的治療,雙側頸總動脈硬化斑塊變小或消失,其中斑塊2、4這兩個斑塊完全消失,剩下的兩個斑塊1和3顯著減小,大小分別減小為3.9*2.5mm和 2.6*2.1mm。Li, female, 65 years old, was treated at the Ruibo TCM Clinic in Huzhou, Zhejiang (No. 322, Meizhou Road, Huzhou City, Zhejiang Province) during 2020-2021. At the time of treatment, Li had sclerotic plaques in both lateral common carotid arteries, with 4 obvious plaques, sized as plaque 1 (12.1*2.6mm), plaque 2 (10.2*2.0mm), plaque 3 (10.0*1.9mm) and plaque 4 (5.6*2.0mm). After meals in the morning and evening, take one portion of the filtrate prepared in Sample B as described above. After 12 courses of treatment (14 days/each course), the sclerotic plaques of the bilateral common carotid arteries became smaller or disappeared, among which plaques 2 and 4 completely disappeared, and the remaining two plaques 1 and 3 were significantly reduced in size, reduced to 3.9*2.5mm and 2.6*2.1mm respectively.
實施例 3 本發明中藥組合物對 ApoE-/-小鼠動脈粥狀斑塊形成的影響研究Example 3 Study on the effect of the Chinese medicine composition of the present invention on the formation of arterial atherosclerotic plaques in ApoE-/- mice
3.1. 試驗目的:以ApoE-/-小鼠建立動脈粥狀硬化模型,探究受試樣品治療動脈粥狀硬化的效果。3.1. Purpose of the experiment: To establish an atherosclerosis model using ApoE-/- mice and to investigate the efficacy of the test samples in treating atherosclerosis.
3.2. 供試品3.2. Test Articles
3.2.1. CS001-樣品A;實施例 1-1 中製得的乾浸膏粉 樣品1。性狀:棕色粉末;保存條件:2—8℃,乾燥。3.2.1. CS001-Sample A; Dry extract powder sample 1 prepared in Example 1-1. Properties: brown powder; Storage conditions: 2-8℃, dry.
3.2.2. CS001-樣品B;實施例 1-1 中製得的乾浸膏粉 樣品2。性狀:棕色粉末;保存條件:2—8℃、乾燥。3.2.2. CS001-Sample B; Dry extract powder sample 2 prepared in Example 1-1. Properties: brown powder; Storage conditions: 2-8℃, dry.
3.2.3. CS001-樣品C;實施例 1-1 中製得的乾浸膏粉 樣品3。性狀:棕色粉末;保存條件:2—8℃、乾燥。3.2.3. CS001-Sample C; Dry extract powder sample 3 prepared in Example 1-1. Properties: brown powder; Storage conditions: 2-8℃, dry.
3.2.4. CS001-樣品D;實施例 1-1 中製得的乾浸膏粉 樣品4。性狀:棕色粉末;保存條件:2—8℃、乾燥。3.2.4. CS001-Sample D; Dry extract powder sample 4 prepared in Example 1-1. Properties: brown powder; Storage conditions: 2-8℃, dry.
3.3 對照品:瑞舒伐他汀鈣片(可定);形狀:粉紅色薄膜衣錠;規格/純度:10 mg/錠;包裝:鋁塑泡包裝;生產單位:阿斯利康藥業(中國)有限公司; 保存條件: 密封、乾燥。3.3 Reference substance: Rosuvastatin calcium tablets (optional); Shape: pink film-coated tablets; Specification/purity: 10 mg/tablet; Packaging: aluminum-plastic blister pack; Manufacturer: AstraZeneca Pharmaceuticals (China) Co., Ltd.; Storage conditions: sealed and dry.
3.4 試驗用溶劑、乳化劑及其它介質:3.4 Test solvents, emulsifiers and other media:
名稱:純淨水Name: Purified Water
生產廠家:珠海百試通生物科技有限公司;Manufacturer: Zhuhai Baishitong Biotechnology Co., Ltd.
3.5 主要儀器與試劑3.5 Main instruments and reagents
離心機,型號:TG16WS;湖南湘儀實驗室儀器開發有限公司產品;Centrifuge, model: TG16WS; product of Hunan Xiangyi Laboratory Instrument Development Co., Ltd.;
ME104E電子分析天平,感量:0.1mg,瑞士梅特勒托利多公司;ME104E electronic analytical balance, sensitivity: 0.1 mg, Mettler Toledo, Switzerland;
電子天平,感量:0.1g,型號:JE2001;上海浦春計量儀器有限公司。Electronic balance, sensitivity: 0.1g, model: JE2001; Shanghai Puchun Metrology Instrument Co., Ltd.
TC、TG、HDL-C、LDL-C 試劑盒:上海科華生物工程股份有限公司TC, TG, HDL-C, LDL-C reagent kit: Shanghai Kehua Bioengineering Co., Ltd.
3.6 實驗系統3.6 Experimental system
動物信息: ApoE-/-小鼠、SPF級、160只、雌性、2月齡;Animal information: ApoE-/- mice, SPF grade, 160, female, 2 months old;
動物來源: ApoE-/-小鼠購自江蘇集萃藥康生物科技股份有限公司(生產許可證號:SCXK(蘇)2018-0008)。動物合格證號:99822700020300、320727210100778554,實驗證明號:00293582。Animal source: ApoE-/- mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd. (production license number: SCXK (Su) 2018-0008). Animal qualification certificate number: 99822700020300, 320727210100778554, experimental certificate number: 00293582.
選用理由:委託方要求。Reason for selection: Required by the client.
飼養管理:動物飼養在珠海百試通生物科技有限公司實驗動物中心SPF級動物房。動物飼養條件:群養4隻/籠,飼養溫度與濕度:20~26℃,40~70%,採用12h:12h晝夜間斷照明;飼養室條件始終保持穩定,以保證試驗結果的可靠性。試驗期間動物均按實驗要求餵以相應顆粒飼料,普通飼料由江蘇美迪森生物醫藥有限公司提供。動物自由進食飲水。Feeding and management: The animals were raised in the SPF animal house of the experimental animal center of Zhuhai Baishitong Biotechnology Co., Ltd. Animal feeding conditions: 4 animals/cage, feeding temperature and humidity: 20-26℃, 40-70%, 12h:12h day and night intermittent lighting; the feeding room conditions were always kept stable to ensure the reliability of the test results. During the test, the animals were fed with corresponding pellet feed according to the experimental requirements, and the ordinary feed was provided by Jiangsu Medison Biomedicine Co., Ltd. Animals had free access to food and water.
識別方法:採用打耳標標記法,耳標編號籠具雙重編號標記識別。Identification method: ear tagging is used, and the ear tag numbering cage has double numbering marks for identification.
安樂死:50mg/kg舒泰50和10mg/kg速眠新Ⅱ聯合麻醉後采血處死,屍體暫存於屍體冷凍櫃,珠海百試通生物科技有限公司統一進行無公害化處理。Euthanasia: The animals were anesthetized with 50 mg/kg of Shutai 50 and 10 mg/kg of Sumenxin II, and then blood was collected for killing. The bodies were temporarily stored in a body freezer and handled in a pollution-free manner by Zhuhai Baishitong Biotechnology Co., Ltd.
檢疫觀察:對購入動物檢疫7天。期間每日檢查動物一次,如發現不健康的動物立即剔除,選用健康動物進行實驗。Quarantine observation: Purchased animals are quarantined for 7 days. During this period, the animals are checked once a day. If unhealthy animals are found, they are immediately removed and healthy animals are selected for experiments.
3.7 劑量設計與分組3.7 Dosage Design and Grouping
劑量設計依據:委託方要求。Dosage design basis: client's requirements.
3.8 實驗方法3.8 Experimental methods
3.8.1. 供試品溶液配製:3.8.1. Preparation of test solution:
3.8.1.1. 樣品A3.8.1.1. Sample A
樣品A超高劑量(0.521g/ml):準確稱量2.13g樣品A,加入15ml的純淨水,攪拌均勻,得0.521g/ml樣品A超高劑量懸浮液。Sample A ultra-high dose (0.521 g/ml): Accurately weigh 2.13 g of sample A, add 15 ml of pure water, stir evenly, and obtain 0.521 g/ml sample A ultra-high dose suspension.
樣品A高劑量(0.261g/ml):取 4ml樣品A超高劑量懸浮液,加入4ml的純淨水,攪拌均勻,得0.261g/ml樣品A高劑量懸浮液。Sample A high dose (0.261g/ml): Take 4ml of sample A ultra-high dose suspension, add 4ml of pure water, stir evenly to obtain 0.261g/ml sample A high dose suspension.
樣品A中劑量(0.13g/ml):取 2ml樣品A超高劑量懸浮液,加入6ml的純淨水,攪拌均勻,得0.13g/ml樣品A中劑量懸浮液。Medium dose of sample A (0.13 g/ml): Take 2 ml of the ultra-high dose suspension of sample A, add 6 ml of pure water, stir evenly, and obtain a medium dose suspension of sample A at 0.13 g/ml.
樣品A低劑量(0.065g/ml):取1ml樣品A超高劑量懸浮液,加入7ml的純淨水,攪拌均勻,0.065g/ml樣品A低劑量懸浮液。Sample A low dose (0.065g/ml): Take 1ml of sample A ultra-high dose suspension, add 7ml of pure water, stir evenly, and the result is 0.065g/ml sample A low dose suspension.
3.8.1.2. 樣品B3.8.1.2. Sample B
樣品B超高劑量(0.521g/ml):準確稱量2.7g樣品B,加入15ml的純淨水,攪拌均勻,得0.521g/ml樣品B超高劑量懸浮液。Sample B ultra-high dose (0.521 g/ml): Accurately weigh 2.7 g of sample B, add 15 ml of pure water, stir evenly, and obtain 0.521 g/ml sample B ultra-high dose suspension.
樣品B高劑量(0.261g/ml):取 4ml樣品B超高劑量懸浮液,加入4ml的純淨水,攪拌均勻,得0.261g/ml樣品B高劑量懸浮液。Sample B high dose (0.261g/ml): Take 4ml of sample B ultra-high dose suspension, add 4ml of pure water, stir evenly to obtain 0.261g/ml sample B high dose suspension.
樣品B中劑量(0.13g/ml):取 2ml樣品B超高劑量懸浮液,加入6ml的純淨水,攪拌均勻,得0.13g/ml樣品B中劑量懸浮液。Medium dose of sample B (0.13 g/ml): Take 2 ml of the ultra-high dose suspension of sample B, add 6 ml of pure water, stir evenly, and obtain a medium dose suspension of sample B with a concentration of 0.13 g/ml.
樣品B低劑量(0.065g/ml):取1ml樣品B超高劑量懸浮液,加入7ml的純淨水,攪拌均勻,0.065g/ml樣品B低劑量懸浮液。Sample B low dose (0.065g/ml): Take 1ml of sample B ultra-high dose suspension, add 7ml of pure water, stir evenly, and the result is 0.065g/ml sample B low dose suspension.
3.8.1.3. 樣品C3.8.1.3. Sample C
樣品C超高劑量(0.521g/ml):準確稱量1.23g樣品C,加入15ml的純淨水,攪拌均勻,得0.521g/ml樣品C超高劑量懸浮液。Sample C ultra-high dose (0.521g/ml): Accurately weigh 1.23g of sample C, add 15ml of pure water, stir evenly, and obtain 0.521g/ml sample C ultra-high dose suspension.
樣品C高劑量(0.261g/ml):取 4ml樣品C超高劑量懸浮液,加入4ml的純淨水,攪拌均勻,得0.261g/ml樣品C高劑量懸浮液。Sample C high dose (0.261g/ml): Take 4ml of sample C ultra-high dose suspension, add 4ml of pure water, stir evenly to obtain 0.261g/ml sample C high dose suspension.
樣品C中劑量(0.13g/ml):取 2ml樣品C超高劑量懸浮液,加入6ml的純淨水,攪拌均勻,得0.13g/ml樣品C中劑量懸浮液。Medium dose of sample C (0.13 g/ml): Take 2 ml of the ultra-high dose suspension of sample C, add 6 ml of pure water, stir evenly, and obtain a medium dose suspension of sample C at 0.13 g/ml.
樣品C低劑量(0.065g/ml):取1ml樣品C超高劑量懸浮液,加入7ml的純淨水,攪拌均勻,0.065g/ml樣品C低劑量懸浮液。Sample C low dose (0.065g/ml): Take 1ml of sample C ultra-high dose suspension, add 7ml of pure water, stir evenly, and the result is 0.065g/ml sample C low dose suspension.
3.8.1.4. 樣品D3.8.1.4. Sample D
樣品D超高劑量(0.521g/ml):準確稱量2.22g樣品D,加入15ml的純淨水,攪拌均勻,得0.521g/ml樣品D超高劑量懸浮液。Sample D ultra-high dose (0.521 g/ml): Accurately weigh 2.22 g of sample D, add 15 ml of pure water, stir evenly, and obtain 0.521 g/ml sample D ultra-high dose suspension.
樣品D高劑量(0.261g/ml):取 4ml樣品D超高劑量懸浮液,加入4ml的純淨水,攪拌均勻,得0.261g/ml樣品D高劑量懸浮液。Sample D high dose (0.261g/ml): Take 4ml of sample D ultra-high dose suspension, add 4ml of pure water, stir evenly to obtain 0.261g/ml sample D high dose suspension.
樣品D中劑量(0.13g/ml):取 2ml樣品D超高劑量懸浮液,加入6ml的純淨水,攪拌均勻,得0.13g/ml樣品D中劑量懸浮液。Medium dose of sample D (0.13 g/ml): Take 2 ml of the ultra-high dose suspension of sample D, add 6 ml of pure water, stir evenly, and obtain a medium dose suspension of sample D of 0.13 g/ml.
樣品D低劑量(0.065g/ml):取1ml樣品D超高劑量懸浮液,加入7ml的純淨水,攪拌均勻,0.065g/ml樣品D低劑量懸浮液。Sample D low dose (0.065g/ml): Take 1ml of sample D ultra-high dose suspension, add 7ml of pure water, stir evenly, and the result is 0.065g/ml sample D low dose suspension.
3.8.2. 對照品溶液配製3.8.2. Preparation of reference solution
瑞舒伐他汀(0.33mg/ml):取1錠瑞舒伐他汀,研磨成粉末,加入30ml純化水,攪拌溶解即可,給藥前搖勻劑量設計與分組Rosuvastatin (0.33 mg/ml): Take 1 tablet of rosuvastatin, grind it into powder, add 30 ml of purified water, stir to dissolve, and shake well before administration. Dosage design and grouping
3.8.3. 高脂高膽固醇模型飼料:在維持飼料中添加 20.0%蔗糖、5%豬油、1.0%膽固醇、0.1%膽酸鈉,適量的酪蛋白、碳酸氫鈣、石粉等。除了粗脂肪外,模型飼料的水分、 10 粗蛋白、粗脂肪、粗纖維、粗灰分、鈣、磷、鈣:磷均要達到維持飼料的國家標準。由 珠海百試通公司實驗動物中心提供。3.8.3. High-fat and high-cholesterol model feed: Add 20.0% sucrose, 5% lard, 1.0% cholesterol, 0.1% sodium cholate, appropriate amount of casein, calcium bicarbonate, stone powder, etc. to the maintenance feed. Except for crude fat, the moisture, crude protein, crude fat, crude fiber, crude ash, calcium, phosphorus, calcium: phosphorus of the model feed should meet the national standards for maintenance feed. Provided by Zhuhai Baishitong Company Experimental Animal Center.
3.8.4 造模方法:SPF級ApoE-/-小鼠160隻,飼養於SPF 級環境設施中。檢疫3天合格後,適應性飼養14d。所有ApoE-/-小鼠均給予高脂飼料餵養30天。30天后以TC為分組指標隨機區組分為模型對照組1 和 2、瑞舒伐他汀組 (陽性組1 和 2)、樣品A, B, C, D各四組 (低劑量組、中劑量組、高劑量組、超高劑量組),8只/組。所有ApoE-/-小鼠在造模後,繼續給予高脂飼料餵養30天,然後恢復到正常維持飼料。3.8.4 Modeling method: 160 SPF-level ApoE-/- mice were raised in an SPF-level environment. After passing the quarantine for 3 days, they were adaptively raised for 14 days. All ApoE-/- mice were fed a high-fat diet for 30 days. After 30 days, they were randomly divided into model control groups 1 and 2, rosuvastatin groups (positive groups 1 and 2), and four groups of samples A, B, C, and D (low-dose group, medium-dose group, high-dose group, and ultra-high-dose group), with 8 mice per group. After modeling, all ApoE-/- mice were fed a high-fat diet for 30 days and then returned to normal maintenance diet.
3.8.5 給藥方法:陽性對照組、各受試樣品組小鼠每天按 20 mL/kg 體重灌胃給予相應的藥液,模型對照組 給予同體積的純淨水,1 次/d,連續 60 d。分組:表1
3.8.6 檢測指標:3.8.6 Testing indicators:
1)一般狀態:每天觀察並記錄小鼠的一般臨床狀態 1 次。1) General condition: Observe and record the general clinical condition of mice once a day.
2)體重:試驗開始及試驗結束測量體重 1 次,試驗期間,每週測量體重 1 次。計算動物給藥 30 d 增重(給藥 D29-給藥 D1)、給藥 60 d 增重(給藥 D60-給藥 D1)。2) Body weight: Measure body weight once at the beginning and end of the experiment, and once a week during the experiment. Calculate the weight gain of animals after 30 days of medication (D29-D1) and 60 days of medication (D60-D1).
3)TC、TG、LDL-C、HDL-C 水平:3) TC, TG, LDL-C, HDL-C levels:
TC、TG水平:於造模30d、60d和90d,各動物不禁食,麻醉後眼底靜脈叢采血,3000rpm離心10min,分離血清,測定TC、TG水平。TC and TG levels: On days 30, 60 and 90 after modeling, the animals were not fasted, and blood was collected from the fundus venous plexus after anesthesia. The blood was centrifuged at 3000 rpm for 10 min, and the serum was separated to measure the TC and TG levels.
LDL、HDL水平:於造模60d和90d,各動物不禁食,麻醉後眼底靜脈叢采血,3000rpm離心10min,分離血清,測定LDL、HDL水平。LDL and HDL levels: On days 60 and 90 after modeling, the animals were not fasted, and blood was collected from the fundus venous plexus after anesthesia. The blood was centrifuged at 3000 rpm for 10 min, and the serum was separated to measure the LDL and HDL levels.
C- reactive protein(CRP)水平: 於造模30d和90d,各動物不禁食,麻醉後眼底靜脈叢采血,3000rpm離心10min,分離血清,測定CRP水平。C-reactive protein (CRP) level: At 30 and 90 days after modeling, the animals were not fasted, and blood was collected from the fundus venous plexus after anesthesia. The blood was centrifuged at 3000 rpm for 10 min, and the serum was separated to measure the CRP level.
病理檢查:實驗結束後,仰臥位固定小鼠, 迅速打開小鼠胸腔, 用生理鹽水經左心室全身灌流, 再用 4%多聚甲醛灌流固定。取主動脈弓進行 HE 染色和天狼星紅染色。Pathological examination: After the experiment, the mice were fixed in a supine position, the chest cavity was quickly opened, and the whole body was perfused with physiological saline through the left ventricle, and then fixed with 4% paraformaldehyde. The aortic arch was taken for HE staining and Sirius red staining.
組織保留: 動物采血後,放血處死,收集血清。所有的試驗動物進行大體解剖,收集心臟,肝臟,腎臟和腦部組織。其中心臟,和部分肝臟,腎臟和腦部組織進行組織標本固定,剩餘組織冷凍保存。其它組織器官如出現體積、顏色、質地等改變時,進行組織病理學檢查。Tissue preservation: After blood was collected from the animals, they were bled and killed, and serum was collected. All experimental animals were subjected to gross autopsy, and heart, liver, kidney and brain tissues were collected. The heart, and part of the liver, kidney and brain tissues were fixed as tissue specimens, and the remaining tissues were frozen and preserved. Other tissues and organs were subjected to tissue pathological examination when changes in volume, color, texture, etc. occurred.
3.9 數據統計方法: 所有數據採用( )表示,應用SPSS 21.0軟件進行統計分析;採用順位和檢驗進行統計分析。百分率的比較採用順位和檢驗進行統計分析。檢驗水平α=0.05。 3.9 Data Statistical Method: All data are collected using ( ) indicates that the statistical analysis was performed using SPSS 21.0 software; the rank sum test was used for statistical analysis. The comparison of percentages was performed using the rank sum test. The test level α = 0.05.
3.10結果3.10 Results
3.10.1. 日常觀察:各組小鼠在試驗過程中均未出現死亡情況與異常反應。3.10.1. Daily observation: No deaths or abnormal reactions occurred in any group of mice during the experiment.
3.10.2. 體重(見圖1-4):3.10.2. Weight (see Figure 1-4):
與模型對照組比較,瑞舒伐他汀陽性組、及各樣品組,體重自第二周起,都有所降低, 其中一些周的體重改變,具有統計學差異(P<0.05)。其中,瑞舒伐他汀陽性組對體重的影響,相比各樣品處理組,都更為明顯。然而,體重的改變,在各樣品處理組中,都沒有觀察到劑量反應關係,表明體重的改變與給藥劑量無關。Compared with the model control group, the weight of the rosuvastatin-positive group and each sample group decreased from the second week, and the weight changes in some weeks were statistically different (P < 0.05). Among them, the effect of rosuvastatin-positive group on weight was more obvious than that of each sample treatment group. However, no dose-response relationship was observed in the changes in weight in each sample treatment group, indicating that the changes in weight were not related to the dosage.
3.10.3. TC值、TG值、CRP值、LDL值、HDL值(見表2-4): 3.10.3. TC value, TG value, CRP value, LDL value, HDL value (see Table 2-4):
3.10.3.1. TC值:3.10.3.1. TC value:
樣品A超高劑量組小鼠在D30時TC值高於模型對照組,具有統計學差異(P<0.05)。其餘各給藥組小鼠在各時間點TC值與模型對照組比較,均無統計學差異(P>0.05)。The TC value of mice in the ultra-high dose group of sample A was higher than that of the model control group at D30, with statistical difference (P < 0.05). There was no statistical difference in the TC value of mice in the other drug groups compared with the model control group at each time point (P > 0.05).
3.10.3.2. TG值:3.10.3.2. TG value:
樣品A超高劑量組小鼠在D30時TG值高於模型對照組,具有統計學差異(P<0.05)。樣品A高劑量組、樣品B低劑量組、樣品B中劑量組、樣品B超高劑量組小鼠在D60時TG值低於模型對照組,具有統計學差異(P<0.05)。其餘各給藥組小鼠在各時間點TG值與模型對照組比較,均無統計學差異(P>0.05)。The TG value of mice in the sample A ultra-high dose group was higher than that in the model control group at D30, with statistical differences (P < 0.05). The TG value of mice in the sample A high dose group, sample B low dose group, sample B medium dose group, and sample B ultra-high dose group was lower than that in the model control group at D60, with statistical differences (P < 0.05). There was no statistical difference in the TG value of mice in the other drug groups compared with the model control group at each time point (P > 0.05).
3.10.3.3. LDL值:3.10.3.3. LDL value:
樣品A中劑量組、樣品A高劑量組、樣品A超高劑量組、樣品B低劑量組、樣品B中劑量組、樣品B高劑量組、樣品B超高劑量組小鼠在D30時LDL值高於模型對照組,具有統計學差異(P<0.05),樣品A超高劑量組、樣品B超高劑量組小鼠在D60時LDL值高於模型對照組,具有統計學差異(P<0.05),其餘各給藥組小鼠在各時間點LDL值與模型對照組比較,均無統計學差異(P>0.05)。The LDL values of mice in the medium dose group of sample A, high dose group of sample A, ultra-high dose group of sample A, low dose group of sample B, medium dose group of sample B, high dose group of sample B, and ultra-high dose group of sample B at D30 were higher than those in the model control group, with statistical differences (P<0.05). The LDL values of mice in the ultra-high dose group of sample A and ultra-high dose group of sample B were higher than those in the model control group at D60, with statistical differences (P<0.05). There were no statistical differences in the LDL values of mice in the other drug groups compared with the model control group at each time point (P>0.05).
3.10.3.4. HDL值3.10.3.4. HDL value
樣品A超高劑量組小鼠在D60時HDL值高於模型對照組,瑞舒伐他汀組小鼠在D30時HDL-C值低於模型對照組,具有統計學差異(P<0.05),樣品D超高劑量組小鼠在D30時HDL-C值高於模型對照組,具有統計學差異(P<0.05)。其它各給藥組小鼠在各時間點HDL值與模型對照組比較,均無統計學差異(P>0.05)。The HDL value of mice in the ultra-high-dose group of sample A was higher than that of the model control group at D60, and the HDL-C value of mice in the rosuvastatin group was lower than that of the model control group at D30, with statistical differences (P < 0.05). The HDL-C value of mice in the ultra-high-dose group of sample D was higher than that of the model control group at D30, with statistical differences (P < 0.05). There was no statistical difference in the HDL values of mice in other drug groups compared with the model control group at each time point (P > 0.05).
3.10.3.5. CRP值:3.10.3.5. CRP value:
樣品B低劑量組、樣品B超高劑量組小鼠在D60時CRP值低於模型對照組,具有統計學差異(P<0.05)。樣品C中劑量組、樣品C高劑量組、樣品C超高劑量組、樣品D低劑量組、樣品D中劑量組、樣品D高劑量組、樣品D超高劑量組小鼠在D60時CRP值低於模型對照組,具有統計學差異(P<0.05),其餘各給藥組小鼠在各時間點CRP值與模型對照組比較,均無統計學差異(P>0.05)。The CRP values of mice in the sample B low-dose group and the sample B ultra-high-dose group were lower than those in the model control group at D60, with statistical differences (P < 0.05). The CRP values of mice in the sample C medium-dose group, the sample C high-dose group, the sample C ultra-high-dose group, the sample D low-dose group, the sample D medium-dose group, the sample D high-dose group, and the sample D ultra-high-dose group were lower than those in the model control group at D60, with statistical differences (P < 0.05). There were no statistical differences in the CRP values of mice in the other drug groups compared with the model control group at each time point (P > 0.05).
3.10.4 病理檢測結果3.10.4 Pathological test results
模型對照組ApoE-/-小鼠的心、肝、腎、腦均出現不同程度的炎症反應,樣品A,B, C 和D,各劑量組小鼠的心、肝、腎、腦的炎性病變程度與模型對照組接近。各個組,均未觀察到其它病理改變。The heart, liver, kidney, and brain of ApoE-/- mice in the model control group showed varying degrees of inflammatory response. The degree of inflammatory lesions in the heart, liver, kidney, and brain of mice in samples A, B, C, and D were close to those in the model control group. No other pathological changes were observed in any group.
3.10.5.動脈弓動脈粥狀斑塊HE染色檢查結果 (表5,圖5-12)。3.10.5. HE staining examination results of arterial arch arterial atherosclerotic plaques (Table 5, Figure 5-12).
表5, 動脈弓部動脈粥狀斑塊面積及數量((Avg.,n=8)HE染色) Table 5. Area and number of atheromatous plaques in the arterial arch (Avg., n=8) HE staining)
與模型對照組比較,陽性處理組,及各樣品處理組小鼠在動脈弓粥狀斑塊形成的病變程度均呈現減輕的趨勢,斑塊面積都有所減少,部分組平均斑塊面積與模型對照組相比 具有顯著性差異(P<0.01 or P<0.05)。其中與模型對照組比較,樣品B的四個劑量組小鼠在動脈弓的粥狀斑塊面積上呈現較為明顯的劑量效應關係 (圖8)。其它組劑量效應關係未明顯觀察到。粥狀斑塊數在各組中未觀察到明顯的劑量效應關係。Compared with the model control group, the degree of atherosclerotic plaque formation in the positive treatment group and the mice in the sample treatment groups showed a trend of reduction, and the plaque area was reduced. The average plaque area of some groups was significantly different from that of the model control group (P < 0.01 or P < 0.05). Compared with the model control group, the four dose groups of sample B showed a more obvious dose-effect relationship in the area of atherosclerotic plaques in the arterial arch (Figure 8). No obvious dose-effect relationship was observed in other groups. No obvious dose-effect relationship was observed in the number of atherosclerotic plaques in each group.
結論Conclusion
在本實驗條件下,實驗樣品A,B,C,D均顯示出較為明顯的預防和消融動脈斑塊的效果。其中,樣品B對於動脈斑塊的清除呈現明顯的劑量效應關係。此外,樣品B具有明顯降低血TG值的效果。樣品D顯示明顯的抑制炎性反應的效果,與模型對照組相比,CRP值在各劑量組均顯著性降低。Under the experimental conditions, the experimental samples A, B, C, and D all showed obvious effects in preventing and ablating arterial plaques. Among them, sample B showed an obvious dose-effect relationship in the removal of arterial plaques. In addition, sample B had an effect of significantly reducing blood TG values. Sample D showed an obvious effect of inhibiting inflammatory response. Compared with the model control group, the CRP value in each dose group was significantly reduced.
無without
圖1顯示了應用本發明的A樣品組各種不同劑量與模型對照組之後小鼠的體重變化; 圖2顯示了應用本發明的B樣品組各種不同劑量與模型對照組之後小鼠的體重變化; 圖3顯示了應用本發明的C樣品組各種不同劑量與模型對照組之後小鼠的體重變化; 圖4顯示了應用本發明的D樣品組各種不同劑量與模型對照組之後小鼠的體重變化; 圖5顯示了應用本發明各樣品組、模型對照組和瑞舒伐他汀陽性組之後小鼠的斑塊面積與動脈管腔面積比; 圖6顯示了應用本發明各樣品組、模型對照組和瑞舒伐他汀陽性組之後小鼠的動脈粥狀斑塊數目; 圖7顯示了應用本發明的A、B樣品組各種不同劑量、正常組1、模型組1、和瑞舒伐他汀干預組1之後小鼠的動脈粥狀斑塊變化情況; 圖8顯示了應用本發明的C、D樣品組各種不同劑量、正常組2、模型組2、和瑞舒伐他汀干預組2之後小鼠的動脈粥狀斑塊變化情況; 圖9顯示了按不同劑量應用本發明的A樣品組之後小鼠的斑塊面積與動脈管腔面積比; 圖10顯示了按不同劑量應用本發明的B樣品組之後小鼠的斑塊面積與動脈管腔面積比; 圖11顯示了按不同劑量應用本發明的C樣品組之後小鼠的斑塊面積與動脈管腔面積比; 圖12顯示了按不同劑量應用本發明的D樣品組之後小鼠的斑塊面積與動脈管腔面積比。 Figure 1 shows the weight changes of mice after applying various doses of the sample group A of the present invention and the model control group; Figure 2 shows the weight changes of mice after applying various doses of the sample group B of the present invention and the model control group; Figure 3 shows the weight changes of mice after applying various doses of the sample group C of the present invention and the model control group; Figure 4 shows the weight changes of mice after applying various doses of the sample group D of the present invention and the model control group; Figure 5 shows the ratio of plaque area to arterial lumen area of mice after applying each sample group of the present invention, the model control group and the rosuvastatin positive group; Figure 6 shows the number of arterial atheromatous plaques in mice after applying various sample groups of the present invention, model control group and rosuvastatin positive group; Figure 7 shows the changes in arterial atheromatous plaques in mice after applying various different doses of sample groups A and B of the present invention, normal group 1, model group 1, and rosuvastatin intervention group 1; Figure 8 shows the changes in arterial atheromatous plaques in mice after applying various different doses of sample groups C and D of the present invention, normal group 2, model group 2, and rosuvastatin intervention group 2; Figure 9 shows the ratio of plaque area to arterial lumen area in mice after applying sample group A of the present invention at different doses; Figure 10 shows the ratio of plaque area to arterial lumen area of mice after applying the B sample group of the present invention at different doses; Figure 11 shows the ratio of plaque area to arterial lumen area of mice after applying the C sample group of the present invention at different doses; Figure 12 shows the ratio of plaque area to arterial lumen area of mice after applying the D sample group of the present invention at different doses.
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