WO2021169682A1 - 一种中药组合物及其制备方法和应用 - Google Patents

一种中药组合物及其制备方法和应用 Download PDF

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WO2021169682A1
WO2021169682A1 PCT/CN2021/072897 CN2021072897W WO2021169682A1 WO 2021169682 A1 WO2021169682 A1 WO 2021169682A1 CN 2021072897 W CN2021072897 W CN 2021072897W WO 2021169682 A1 WO2021169682 A1 WO 2021169682A1
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traditional chinese
chinese medicine
medicine composition
composition according
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PCT/CN2021/072897
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French (fr)
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解渤
任雪峰
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北京重生医药科技有限公司
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Priority to JP2022552204A priority Critical patent/JP7340113B2/ja
Priority to US17/802,380 priority patent/US11918620B2/en
Priority to EP21761454.4A priority patent/EP4112066A4/en
Priority to KR1020227030675A priority patent/KR102613167B1/ko
Publication of WO2021169682A1 publication Critical patent/WO2021169682A1/zh

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    • A—HUMAN NECESSITIES
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    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/233—Bupleurum
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    • A61K35/56—Materials from animals other than mammals
    • A61K35/618—Molluscs, e.g. fresh-water molluscs, oysters, clams, squids, octopus, cuttlefish, snails or slugs
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Definitions

  • the invention belongs to the field of traditional Chinese medicine, and relates to a traditional Chinese medicine composition and a preparation method thereof. Application of sclerotherapy drugs.
  • Blood lipids are the general term for various lipids in the blood. The most important ones are cholesterol and triglycerides. Triglycerides are also called neutral fats. Other important lipids also include lipoproteins, which include low-density lipoproteins and high-density lipoproteins. Density lipoprotein. The average blood cholesterol content of healthy people is between 2.8 and 5.17 mmol/L, and the average blood triglyceride content is between 0.56 and 1.7 mmol/L. Whether it is an increase in cholesterol content, an increase in triglyceride content, or an increase in both, they are collectively referred to as hyperlipidemia.
  • Atherosclerosis is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease.
  • Hyperlipidemia is the pathological basis of atherosclerosis. It is characterized by that the disease of the affected arteries starts from the intima. Generally, the accumulation of lipids and complex carbohydrates, hemorrhage and thrombosis, and then fibrous tissue proliferation and calcium deposition, and There is gradual degeneration and calcification of the arterial middle layer, which leads to thickening and hardening of the arterial wall and narrowing of the vascular lumen. The lesions often involve the muscular arteries of the major and middle muscles. Once they develop enough to block the arterial lumen, the tissues or organs supplied by the arteries will be ischemic or necrotic. Because the lipids that accumulate in the arterial intima are yellowish atherosclerotic, it is called atherosclerosis.
  • Atherosclerotic cardiovascular disease is known as the "number one killer" in developed countries, and its prevalence is rapidly increasing in developing countries. Among them, atherosclerosis caused coronary myocardial infarction and stroke deaths accounted for the main proportion. By 2035, it is estimated that more than 130 million adults (45.1%) in the United States will suffer from certain cardiovascular diseases, and the total cost of cardiovascular diseases will be as high as 1.1 trillion US dollars. The prevalence and mortality of cardiovascular diseases in China are still on the rise. There are currently 290 million patients suffering from cardiovascular diseases, and the death rate from cardiovascular diseases ranks first, accounting for more than 30% of the residents’ disease deaths. Of course, having hyperlipidemia does not necessarily mean that you will suffer from cardiovascular disease, but active treatment of hyperlipidemia is one of the important measures to prevent cardiovascular disease.
  • hypolipidemic chemicals mainly statins (Statin) and fibrates (Fibrates). Although the specific mechanisms are different, they are mainly effective through the synthesis and metabolism pathways that directly act on fat. Since the probability of blood lipid rebound is very high after drug withdrawal, chemically synthesized blood 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. In addition, the use of chemical hypolipidemic drugs cannot fundamentally prevent and control the formation and development of vascular plaque.
  • the lipid-lowering drugs based on traditional Chinese natural medicines include Guangdong Hongxing Jiangzhi Pills, Chengdu Diaozhibituo, Beijing Weixin Xuezhikang, etc. These drugs can be seen from their instructions that more or less have certain side effects.
  • the side effects of Xuezhikang are gastrointestinal discomfort, such as stomach pain, abdominal distension, heartburn, etc., which can occasionally cause serum aminotransferase and Muscle phosphokinase is reversibly increased.
  • these drugs are usually recommended to be used simultaneously with chemical lipid-lowering drugs, or mainly recommended for the elderly.
  • the purpose of the present invention is to provide a traditional Chinese medicine composition, its preparation method and its use in the preparation of drugs for preventing or treating elevated blood lipids, elevated triglycerides, elevated cholesterol, hyperlipidemia, atherosclerosis, etc. application.
  • Animal model experiments and clinical experiments show that the traditional Chinese medicine composition of the present invention has excellent effects of lowering blood lipids, lowering cholesterol, especially lowering blood triglycerides.
  • animal model experiments and clinical experiments also revealed that the traditional Chinese medicine composition of the present invention has a slow-down effect.
  • Atherosclerotic plaque is formed and has a good effect in removing atherosclerotic plaque.
  • the inventor of the present invention after long-term research on traditional Chinese medical theories and combined with clinical practice, has proposed a prevention and treatment of elevated blood lipids, elevated triglycerides, elevated cholesterol, hyperlipidemia, arterial
  • the medication regimen of atherosclerosis theory We believe that the core cause of hyperlipidemia and subsequent formation of atherosclerosis can be summarized in the logic and language of traditional Chinese medicine as: phlegm enters the blood. If it enters the context of modern medicine, it is similar to thick blood. Viscous blood is not only the cause of hyperlipidemia and atherosclerosis, but also the symptoms of phlegm in the blood. Since the phlegm in the blood of traditional Chinese medicine is manifested as the thick blood of modern medicine, we believe that its regulation treatment is the core and effective way to prevent and treat hyperlipidemia and atherosclerosis.
  • Portion drink is defined as the water from the classics in the Emperor's Internal Classic, that is, a body fluid in the circulation and metabolism.
  • the thicker body fluid is called phlegm
  • the thinner body fluid is called phlegm.
  • the "phlegm” in traditional Chinese medicine mostly refers to the viscous or thin liquid in the digestive tract, lungs, and respiratory tract. This fluid is difficult to metabolize and will continue to be produced from the digestive tract or respiratory tract even if it is excreted from the body. Come out, endlessly.
  • biochemical indicators are included under the concept of "sticky blood".
  • hyperlipidemia serum total cholesterol, low-density cholesterol, high-density cholesterol, translipoprotein, triglycerides
  • hyperglycemia fasting blood glucose, glycosylated hemoglobin, fasting insulin, C peptide, glycosylated serum protein , Fructosamine
  • platelet indicators number of platelets, platelet adhesion, platelet sedimentation, etc.
  • red blood cells number of red blood cells, red blood cell sedimentation, red blood cell adhesion, red blood cell pressure, red blood cell deformability, red blood cells
  • blood viscosity itself measurement indicators (apparent viscosity, relative viscosity, reduced viscosity, specific viscosity, etc.) and some other related indicators (fibrinogen, immunoglobulin, etc.).
  • a traditional Chinese medicine composition that effectively and long-term reduces blood lipids, especially triglycerides, and effectively prevents and treats hyperlipidemia and atherosclerosis.
  • the present invention provides a traditional Chinese medicine composition, which comprises the following raw materials in parts by weight: 10-35 parts of Bupleurum, 5-25 parts of Citrus aurantium, 3-20 parts of raw rhubarb, 3-20 parts of Radix Scutellariae, 3 parts of Radix Paeoniae Rubra -20 servings, 3-15 servings of dried ginger, 5-20 servings of leeches, 3-20 servings of licorice, 3-20 servings of Codonopsis, 3-20 servings of Baizhu, 3-25 servings of Pinellia ternata.
  • the traditional Chinese medicine composition of the present invention comprises the following raw materials in parts by weight: 20-30 parts of Bupleurum, 10-20 parts of Citrus aurantium, 5-15 parts of raw rhubarb, 5-10 parts of Radix Scutellariae, 5-15 parts of Radix Paeoniae Rubra Servings, 5-10 servings of dried ginger, 7-15 servings of leeches, 5-15 servings of licorice, 5-15 servings of Codonopsis, 5-15 servings of Baizhu, 10-20 servings of Pinellia ternata.
  • the traditional Chinese medicine composition of the present invention further comprises the following raw materials in parts by weight: 3-45 parts of raw oysters, preferably 10-35 parts. More preferably, on this basis, the traditional Chinese medicine composition of the present invention further comprises the following parts by weight of the crude drug: 3-15 parts of red yeast rice, preferably 5-12 parts.
  • the traditional Chinese medicine composition of the present invention is made from the raw materials in parts by weight as described above.
  • the traditional Chinese medicine composition of the present invention is made of the following raw materials in parts by weight: 25 parts of Bupleurum, 15 parts of Citrus aurantium, 10 parts of raw rhubarb, 6 parts of scutellaria baicalensis, 10 parts of white peony, 6 parts of dried ginger, 10 parts of leeches, 10 parts of licorice, 10 parts of Codonopsis, 10 parts of Atractylodes macrocephala, 15 parts of Pinellia ternata.
  • the traditional Chinese medicine composition of the present invention is made of the following raw materials in parts by weight: 25 parts of Bupleurum, 15 parts of Citrus aurantium, 10 parts of raw rhubarb, 6 parts of scutellaria baicalensis, 10 parts of white peony, 6 parts of dried ginger, 10 parts of leech, 10 parts of licorice, 10 parts of Codonopsis, 10 parts of Baizhu, 15 parts of Pinellia, 30 parts of raw oysters.
  • the traditional Chinese medicine composition of the present invention is made of the following raw materials in parts by weight: 25 parts of Bupleurum, 15 parts of Citrus aurantium, 10 parts of raw rhubarb, 6 parts of scutellaria baicalensis, 10 parts of white peony, 6 parts of dried ginger, 10 parts of leech, 10 parts of licorice, 10 parts of Codonopsis, 10 parts of Baizhu, 15 parts of Pinellia, 30 parts of raw oysters, 10 parts of red yeast rice.
  • parts are parts by weight, and weights are calculated based on crude drugs.
  • it can be increased or decreased according to the corresponding proportion.
  • the mass production can be in kilograms or tons, and the weight can be increased or decreased, but the proportion of the weight ratio of the crude medicinal materials between the components is different. Change.
  • Bupleurum the medicinal part is the dry root of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd. It has the effect of reconciling the exterior and interior, soothing the liver and raising yang.
  • Citrus aurantium is the dried young fruit of Rutaceae plant Lime and its cultivars or sweet orange (Immature Bitter Orange, Immature Sweet Orange, Fructus Aurantii Immaturus). It has the effect of dispelling qi and accumulating, dissipating phlegm and pimple.
  • Raw rhubarb this product is the dried roots and rhizomes of Rheum palmatum (Rheum palmum L.), Rheum tanguticum Maxim. ex Balf., or medicinal rhubarb (Rheum officinale Baill.). It has the effect of purging heat toxin, breaking stagnation, and promoting blood stasis.
  • Scutellaria baicalensis is the dried root of Scutellaria baicalnsis Geprgi, a perennial herbaceous plant in the Lamiaceae family. It has the effects of clearing away heat and dampness, purging fire and detoxification, hemostasis, and anti-fetus.
  • White peony is the dry root of the ranunculaceae plant Paeonia (Paeonia lactiflora Pall.). It has the effects of warming yang and dispelling dampness, replenishing the deficiency of the body, and strengthening the spleen and stomach.
  • Dried ginger is the dried rhizome of ginger (Zingiber oj-jicinale Rosc.). Excavate in winter, remove fibrous roots and silt, and dry in the sun or at low temperature. Those sliced fresh or dried at low temperature are called “dried ginger slices”. It has the effects of warming the middle and dispelling the cold, rejuvenating the yang and promoting the pulse, warming the lungs and transforming the drink.
  • Leech is the dried whole of leeches (Whitm.ania Pigra Whitman), leeches (Hirudo nipponica Whitman), or willow-leaf leeches (Whitmania acranutata Whitman). Catch in summer and autumn, scald to death with boiling water, dry in the sun or dry at low temperature. It has the effects of dispelling blood, clearing menstruation, and eliminating blood stasis.
  • Licorice (Glycyrrhiza uralensis Fisch), alias: Guo Lao, Sweet Grass, Ural Licorice, Sweet Root.
  • Leguminous and licorice belong to perennial herbs.
  • the medicinal parts are roots and rhizomes. It is used for heart qi deficiency, heart palpitations, pulse congestion, spleen and stomach qi deficiency, fatigue and fatigue, to reconcile the potency of certain drugs and the reaction to the gastrointestinal tract.
  • Codonopsis is the dried root of Codonopsis pilosula, Codonopsis pilosa, or Codonopsis radicans. It has the effects of invigorating the middle, replenishing qi and promoting body fluid.
  • Atractylodes the dry rhizome of Atractylodes macrocephala Koidz. It has the effects of invigorating the spleen and replenishing qi, drying dampness and diuresis, and antiperspirant.
  • Pinellia is a dry tuber of Pinellia ternata (Thunb.) Breit. It has the effects of removing dampness, resolving phlegm, reducing adverse effects and relieving vomiting, and eliminating pimple and congestion.
  • Raw oysters are shells of Ostrea gigas Thunberg (Ostrea gigas Thunberg), Dalian Bay oyster (Ostrea talienwhanensis Cross) or Near river oyster (Ostrea rivularis Gould). It has the functions of calming the nerves, suppressing yang and replenishing yin, and softening and relieving knots.
  • Monascus is a kind of red yeast rice produced by parasitising the mycelium of Monascus purpureus Went. It has the effects of invigorating the spleen and eliminating food, promoting blood circulation and removing blood stasis.
  • the prescription of the present invention is formed in combination with clinical practice on the basis of full research on Shanghan Lunjing prescription and corresponding medicinal materials.
  • the prescription of the present invention uses Bupleurum as the noble medicine. Bupleurum dredges the vitality of the liver so that the function of the liver can be restored to normal operation. This is the key to metabolizing fat. Bupleurum is also a very good medicine for immunity, anti-inflammatory, anti-fever and cooling It can regulate the immune mechanism of the whole body, and play a key role in restoring some key hormones to re-decompose and balance blood lipids.
  • Citrus aurantium is to eliminate inflammation and harmful bacteria in the intestinal tract.
  • Citrus aurantium is also a medicinal medicine. It can be used with Bupleurum chinense to reach the upper and lower viscera, and with raw rhubarb to better sort out the intestinal function, eliminate inflammation and harmful flora in the intestine, Scutellaria baicalensis Georgi. It is also a ministerial medicine, used to reduce the secretion of gastric acid, reduce gastrin, and also to eliminate inflammation in the stomach and harmful bacteria in the intestinal tract.
  • Licorice, Codonopsis, Radix Paeoniae Alba, Atractylodes macrocephala, and Pinellia are all auxiliary drugs.
  • the use of dried ginger instead of ginger in this recipe can reduce the gastrointestinal reaction of rhubarb, making this recipe suitable for medium and long-term use to meet the treatment of hyperlipidemia , Arterial plaque treatment time requirements; the leeches included in the prescription are used to invigorate blood and break stasis, eliminate the accumulation and stickiness of various platelets and red blood cells in the human blood vessels, which is beneficial to eliminate plaque in the blood vessels; it can be increased in the prescription
  • Raw oysters are used to dissolve the astringent and underdigested substances in the human intestines and stomachs. At the same time, raw oysters can help soften the over-fatigued liver and better dissolve liver fat; red yeast rice can also be added to the prescription to increase The role of cholesterol
  • the traditional Chinese medicine composition of the present invention can obtain the pharmaceutically active substance by extraction or other methods known in the art.
  • the drug active substance can be obtained by separately extracting natural compound drug raw materials, or can be obtained by jointly extracting natural compound drug raw materials.
  • the preparation method of the traditional Chinese medicine composition of the present invention includes weighing the crude drug, adding 4-12 times the amount of water for the first time, and keeping it at 75-95°C for 30-120 minutes to obtain the first decoction; Add 3-10 times the amount of water, keep at 75-95°C for 30-120 minutes to obtain the second decoction liquid; combine the second decoction liquid, filter, and combine the filtrate.
  • the preparation method of the traditional Chinese medicine composition of the present invention includes weighing the crude drug, adding 8 times the amount of water for the first time, boiling at 80°C for 60 minutes to obtain the first decoction; adding 6 times the amount of water for the second time, boiling After incubating at 80°C for 60 minutes, the second decoction liquid is obtained; the second decoction liquid is combined, filtered, and the filtrate is combined.
  • the obtained extract can be further concentrated into an extract form, which can be a dry extract or a liquid extract. Preferably, it is concentrated under reduced pressure (-0.05Mpa, 60°C) to a relative density of 1.05-1.15 (60°C).
  • the traditional Chinese medicine composition of the present invention can be prepared by adding a pharmaceutically acceptable carrier if necessary.
  • the pharmaceutical active substance extracted or processed by the traditional Chinese medicine composition of the present invention accounts for 0.1-99.9% by weight in the preparation, and the rest is a pharmaceutically acceptable carrier.
  • the Chinese medicinal composition of the present invention can be any pharmaceutically acceptable dosage form, and these dosage forms include: decoctions, tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, Oral liquid, oral liquid, granule, granule, pill, powder, ointment, pill, suspension, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch Agent. Oral dosage forms are preferred, and decoctions, capsules, tablets, oral liquids, granules, pills, powders, pills, ointments, etc. are more preferred. Most preferred are decoctions, granules, capsules, and tablets.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of drugs for preventing or treating elevated blood lipids.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating elevated triglycerides.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of drugs for preventing or treating elevated cholesterol.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of drugs for preventing or treating hyperlipidemia.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of a medicine for preventing or controlling the formation of vascular plaque.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating atherosclerosis.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of drugs for the prevention or treatment of chronic metabolic diseases.
  • the present invention further provides a method for preventing or treating elevated blood lipids, comprising administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or treating elevated triglycerides, which comprises administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or treating elevated cholesterol, comprising administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or treating hyperlipidemia, which comprises administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or controlling the formation of vascular plaque, which comprises administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or treating atherosclerosis, which comprises administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the present invention further provides a method for preventing or treating chronic metabolic diseases, which comprises administering to a person in need thereof a preventive or therapeutically effective amount of the traditional Chinese medicine composition of the present invention as described above.
  • the traditional Chinese medicine composition of the present invention can be taken one to three times a day when in use, and when it is made into a unit dosage form, it takes 1-10 doses each time.
  • the traditional Chinese medicine composition of the present invention can be concentrated and dried to prepare dry extract powder, and then add appropriate amount of auxiliary materials to make granules (each dose contains 1250mg dry extract powder, equivalent to 20g crude drug), and it is taken once a day
  • auxiliary materials to make granules (each dose contains 1250mg dry extract powder, equivalent to 20g crude drug)
  • it is taken once a day Three times, 1-2 doses each time, or can be filled into capsules or made into tablets (each dose contains 312.5mg dry extract powder, equivalent to 5g crude drug), take one to three times a day, each time 2- 8 capsules or tablets, the specific usage and dosage can be adjusted according to the specific patient's condition.
  • the traditional Chinese medicine formula of the present invention is an innovative construction on the basis of the theory and practice of "phlegm drinking into the blood” and the theory and practice of Febrile Diseases.
  • the inventors of the present invention further optimized the component distribution ratio on the basis of fully studying and considering the properties and efficacy of each component in the formula.
  • the formula of the present invention creatively contains dried ginger and leeches, and the ratio of them has been optimized in clinical practice.
  • the traditional Chinese medicine composition of the present invention has a very obvious effect on blood viscosity. The total blood viscosity is improved through two ways.
  • the first is to reduce the viscous substance in the stomach and intestines-phlegm and drink, and reduce the blood viscosity by improving digestion and excretion of the stomach and intestines.
  • the second source is to directly metabolize the viscous organic components of the blood, including blood lipids, through metabolism.
  • the traditional Chinese medicine composition of the present invention can also reduce the aggregation degree, sedimentation degree and cut degree of red blood cells, and reduce the aggregation degree, sedimentation degree and cut degree of platelets. Clinical experiments show that the traditional Chinese medicine formula of the present invention has excellent effects of lowering blood lipids, lowering cholesterol, especially lowering blood triglycerides, and the effective rate exceeds 90%.
  • Figure 1 Comparison of oil red O staining of the aorta in the negative control group of ApoE -/- mice and the control group of atherosclerotic plaque model.
  • Figure 2 A comparative picture of the effect of the traditional Chinese medicine composition of the present invention on the formation of atherosclerotic plaques in ApoE -/- mice (full-length aortic oil red O staining).
  • D The present invention A representative picture of oil red O staining in the 1677 mg/kg dose group of the traditional Chinese medicine composition.
  • Figure 3 Comparison of the effect of the traditional Chinese medicine composition of the present invention on the formation of atherosclerotic plaque in ApoE-/- mice (HE staining of aortic arch section) HE staining of aortic arch section negative control group, model control group, positive control group, and traditional Chinese medicine combination of the present invention Comparison chart of 833mg/kg dose group and 1677mg/kg dose group.
  • Figure 4 Comparative picture of the effect of the traditional Chinese medicine composition of the present invention on the formation of atherosclerotic plaques in ApoE-/- mice (Sirius staining of aortic arch section) Comparison chart of 833mg/kg dose group and 1677mg/kg dose group.
  • Figure 5 Comparative picture of the effect of the traditional Chinese medicine composition of the present invention on the formation of atherosclerotic plaques in ApoE-/- mice (carotid artery oil red O staining) carotid artery oil red O staining negative control group, model control group, positive control group, A comparison chart of the 833 mg/kg dose group and the 1677 mg/kg dose group of the traditional Chinese medicine composition of the present invention.
  • Figure 6 The treatment result of the traditional Chinese medicine composition of the present invention on 14 patients with elevated total cholesterol and triglycerides.
  • Figure 7 The treatment results of the traditional Chinese medicine composition of the present invention on 11 patients with hypercholesterolemia, and the analysis of total cholesterol before and after treatment.
  • Figure 8 Treatment results of 88 patients with hypertriglyceridemia by the Chinese medicine composition of the present invention, and triglyceride analysis before and after treatment.
  • test methods in the following examples are conventional methods; the raw materials, reagent materials, etc. used in the following examples, unless otherwise specified, are all commercially available products.
  • the amount of solvent used in the preparation process of each test drug is a volume multiple based on the weight of the medicinal material.
  • ⁇ -cyclodextrin was added to the obtained dry extract powder A at a ratio of 4:1 to prepare dry extract powder A particles. After the granules are dried and cooled, they are bagged as granules (each bag contains 1250mg of dry extract powder of traditional Chinese medicine, which is equivalent to 20g of crude drug).
  • ⁇ -cyclodextrin was added to the obtained dry extract powder B at a ratio of 4:1 to prepare dry extract powder B particles. After the granules are dried and cooled, they are bagged as granules (each bag contains 1250mg of dry extract powder of traditional Chinese medicine, which is equivalent to 20g of crude drug).
  • Boil and extract twice in an airtight container add 8 times the amount of water for the first time, and keep it at 80 degrees Celsius for 60 minutes after boiling to get the decoction liquid; add 6 times the amount of water for the second time, keep it at 80 degrees Celsius for 60 minutes after boiling, and get the second time Decoction liquid: Combine the second decoction liquid, filter, and combine the filtrate. Concentrate under reduced pressure (-0.05Mpa, 60°C) to a relative density of 1.05-1.15 (60°C), and freeze-dried under reduced pressure to obtain dry extract powder C. The extract yield is 25% of the crude drug.
  • ⁇ -cyclodextrin was added to the obtained dry extract powder C at a ratio of 4:1 to prepare dry extract powder C particles. After the granules are dried and cooled, they are bagged as granules (each bag contains 1250mg of dry extract powder of traditional Chinese medicine, which is equivalent to 20g of crude drug).
  • Example 2 Study on the effect of the traditional Chinese medicine composition of the present invention on the mixed hyperlipidemia rat model
  • Test purpose to establish a mixed hyperlipidemia rat model and study the effect of the traditional Chinese medicine composition of the present invention on the model.
  • Test product dry extract powder A prepared in Example 1-1. Properties: brown powder; storage conditions: 2-8°C, dry.
  • Atorvastatin calcium tablets (Lipitor). Properties: white oval film-coated tablets; specification: 10mg/tablet; packaging: aluminum/aluminum blister packaging; production unit: Pfizer Pharmaceutical Co., Ltd.; storage conditions: airtight.
  • Preparation method of 0.5% sodium carboxymethyl cellulose solution accurately weigh 5.0g CMC-Na, slowly add it to a beaker containing about 800mL purified water while stirring at room temperature with a magnetic stirrer, stir until it dissolves, 2 ⁇ 8°C overnight, The next day, dilute the volume to 1000mL in the graduated cylinder and mix well, and store at 2 ⁇ 8°C for later use.
  • Isoflurane batch number 217171101, expiration date 20201101, Shenzhen Reward Life Technology Co., Ltd.;
  • TC kit batch number 20180722, 20190222, valid until 20200110, 20200820, Shanghai Kehua Biological Engineering Co., Ltd.;
  • TG kit batch number 20180822, 20190222, valid until 20200223, 20200825, Shanghai Kehua Biological Engineering Co., Ltd.;
  • HDL-C kit batch number 20181012, valid until 20191011, Shanghai Kehua Biological Engineering Co., Ltd.;
  • LDL-C kit batch number 20190212, valid until 20200226, Shanghai Kehua Biological Engineering Co., Ltd.
  • Species SD rats; grade: SPF; male, 190.2-223.9g;
  • Source and animal certificate number purchased from Guangdong Medical Laboratory Animal Center, animal production license number is SCXK (Guangdong) 2018-0002, animal certificate number 44007200066274;
  • the coat dyeing method is used to number animals with saturated picric acid, and spots are painted on different parts of the coat on the animal's body surface to show different numbers. Recognized by animal skin staining and double numbering of cages.
  • Euthanasia After modeling, the animals were eliminated and killed by carbon dioxide inhalation. After the experiment, the animals were killed by intraperitoneal injection of 20% urethane solution according to 6mL/kg body weight and bloodletting. The corpses were temporarily stored in a cadaver freezer for uniform pollution-free treatment. .
  • Quarantine observation The purchased rats were quarantined for 3 days and observed once a day. No unhealthy animals were found.
  • Feeding management The animals are kept in the SPF animal room of the Guangdong Medical Experimental Animal Center, the experimental animal use license number: SYXK (Guangdong) 2018-0002, and the animal experiment certificate number: 00219646.
  • Animal breeding conditions group breeding, 5 animals per box, breeding temperature and humidity: 20 ⁇ 26°C, 40 ⁇ 70%, using 12h:12h day and night off lighting; the breeding room conditions are always stable to ensure the reliability of the test results.
  • the animals were fed the corresponding pellets according to the requirements of the experiment, and the animals were free to eat and drink.
  • Dosage design After pre-testing, 4 SD rats were intragastrically administered with the test sample at a dose of 2000 mg/kg body weight and 5000 mg/kg body weight, and no animal deaths were found within 72 hours.
  • the adult dose of the test sample is 5g/day, calculated based on the adult body weight 60kg, and the test dose is 5 times and 10 times the recommended amount of the human body.
  • the test doses are 417 mg/kg body weight and 833 mg/kg body weight, respectively.
  • the clinical dosage of the positive drug atorvastatin calcium tablets is 10mg/day, calculated based on the adult body weight of 60kg, and 20 times the recommended amount of the human body is used as the test dose of the positive drug, that is, the test dose of the positive drug atorvastatin calcium tablets is 3.3 mg/kg weight.
  • mice After the quarantine, the animals were randomly divided into 10 negative control groups, and the rest were model groups. The model group was given the model feed for 2 weeks without fasting. After isoflurane inhalation anesthesia, blood was collected from the orbital venous sinus, centrifuged at 3000 rpm for 10 minutes, and the serum was separated to determine total cholesterol (TC), triglycerides (TG), and low-density lipoprotein. Cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels. The animals with low TG levels were eliminated, and 40 animals were randomly divided into model control group, positive control group, test sample 417mg/kg and 833mg/kg dose groups according to TG level, and 10 animals/group.
  • TC total cholesterol
  • TG triglycerides
  • HDL-C high-density lipoprotein cholesterol
  • 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.
  • the water, crude protein, crude fat, crude fiber, crude ash, calcium, phosphorus, and calcium phosphorus of the model feed must meet the national standards for maintaining feed. Provided by Guangdong Medical Laboratory Animal Center.
  • Preparation method of the test product Weigh the corresponding test product into a calibrated container, add a small amount of pure water to grind and dissolve, and then add pure water to the calibration line of the container, stir and dissolve, so that the dose concentration is 166.7mg/mL , And then diluted to a dose of 83.3mg/mL and 41.7mg/mL.
  • Preparation method of positive drug atorvastatin calcium tablet take 1 tablet of atorvastatin calcium tablet (specification: 10mg/tablet) into a calibrated container, add 0.5% CMC-Na solution to grind evenly and make up 0.5% CMC -Na solution to 60mL to make about 0.33mg/mL, shake well before use.
  • the positive control group and the test product 417mg/kg and 833mg/kg dose groups are given the corresponding dose of 10mL/kg body weight every day.
  • the negative control group and the model control group are given the same dose.
  • Volume of purified water for 67 to 68 consecutive days the first 5 animals in each group were administered for 67 days, and the last 5 animals in each group were administered for 68 days).
  • Body weight weigh the animal once at the beginning and end of the experiment; weigh the animal once a week.
  • Blood lipids after administration for 2, 4, 7 and 9 weeks (d14, d28, d52, d65), blood is collected from the orbital venous sinus under inhalation anesthesia with isoflurane, centrifuged at 3000 rpm for 10 min, serum is separated, and blood lipids, TC, TG, LDL-C, HDL-C levels.
  • the first 5 animals in each group on d66 and the last 5 animals in each group on d67 were fasted at night. On the second day, they were administered and weighed. They were anesthetized by intraperitoneal injection of 20% urethane solution 6mL/kg body weight, and blood was collected from the abdominal aorta. Take the serum and freeze it. The animals were sacrificed by bleeding, the testes and perirenal adipose tissue were weighed separately, part of the liver was fixed with neutral formaldehyde, and the rest of the liver was cryopreserved in liquid nitrogen.
  • the mean TG decreased from 3.22mmol/L in the model control group to 2.89mmol/L in the 417mg/kg group of the test sample and 2.51mmol/L in the 833mg/kg group. L, but did not reach a statistically significant difference (P value between 0.05-0.1).
  • the test sample also showed a decreasing trend for TC.
  • Organ/tissue weight and coefficient (see Table 8): Compared with the negative control group, the liver weight and its coefficient increase in the model control group were statistically different (P ⁇ 0.01); compared with the model control group Compared with the positive control group, the liver weight and its coefficient were not statistically different (P ⁇ 0.05 or 0.01); compared with the model control group, the dose of the composition of the present invention was 417mg/kg and 833mg/kg group of rat organs/ There was no statistical difference in tissue weight and its coefficient (P>0.05). Retain the organs.
  • Table 3 The effect of the traditional Chinese medicine composition of the present invention on the blood lipids of mixed hyperlipidemia rats (after modeling before administration)
  • Table 4 The effect of the traditional Chinese medicine composition of the present invention on the blood lipids of rats with mixed hyperlipidemia (administration for 2 weeks) ( m
  • Table 5 The effect of the traditional Chinese medicine composition of the present invention on the blood lipids of rats with mixed hyperlipidemia (administration for 4 weeks) ( m
  • Table 6 The effect of the traditional Chinese medicine composition of the present invention on the blood lipids of rats with mixed hyperlipidemia (administration for 7 weeks) ( m
  • Table 7 The effect of the traditional Chinese medicine composition of the present invention on the blood lipids of rats with mixed hyperlipidemia (administration for 9 weeks) ( m
  • Table 8 The effect of the traditional Chinese medicine composition of the present invention on the organ/tissue weight and its coefficient of mixed hyperlipidemia rats (
  • the Chinese medicinal composition of the present invention showed the effect of reducing TG after being administered for 2 weeks. After 4, 7, and 9 weeks of administration, the effect of reducing TG was all Statistically significant difference (P ⁇ 0.05); at the same time, the dose of 833mg/kg group also showed a preliminary effect in reducing TC, especially after 9 weeks of administration, the effect of reducing TC was statistically different (P ⁇ 0.05 ). In the 417 mg/kg group, after 4, 7, and 9 weeks of administration, the effect of reducing TG was statistically tested, and all were at the zero point of statistical test difference (P value between 0.05 and 0.10).
  • Test purpose to establish an ApoE -/- mouse atherosclerotic plaque model, and to study the effect of the traditional Chinese medicine composition of the present invention on the model's atherosclerotic plaque formation.
  • Test product dry extract powder A prepared in Example 1-1. Properties: brown powder; storage conditions: 2-8°C, dry.
  • Preparation method of 0.5% sodium carboxymethyl cellulose solution accurately weigh 5.0g CMC-Na, slowly add it to a beaker containing about 800mL purified water while stirring at room temperature with a magnetic stirrer, stir until it dissolves, 2 ⁇ 8°C overnight, The next day, dilute the volume to 1000mL in the graduated cylinder and mix well, and store at 2 ⁇ 8°C for later use.
  • Isoflurane batch number 217171101, expiration date 20201101, Shenzhen Reward Life Technology Co., Ltd.;
  • Germline level SPF grade, ApoE -/- mice; 6 ApoE mice, female, 28-35 days old; 48 ApoE mice, half male and half, 49-56 days old;
  • Identification method Use ear tag method. Before punching the number, wipe the animal ears with alcohol cotton ball and sterilize the punching machine, then punch the animal ears and hang the corresponding number plate to distinguish the animals. The number marked on the number plate is the number. The number of the animal.
  • Quarantine observation The purchased mice were quarantined for 7 days. During this period, the animals will be checked once a day. If unhealthy animals are found, they will be immediately eliminated, and healthy animals will be selected for experimentation.
  • Feeding management The animals are kept in the SPF animal room of the Guangdong Medical Experimental Animal Center, and the experimental animal use license number: SYXK ( ⁇ )2018-0002.
  • Animal breeding conditions single breeding, 1 animal/box, breeding temperature and humidity: 20 ⁇ 26°C, 40 ⁇ 70%, using 12h:12h day and night off lighting; the breeding room conditions are always stable to ensure the reliability of the test results.
  • the animals were fed the corresponding pellet feeds according to the experimental requirements, and all the feeds were provided by the Guangdong Medical Laboratory Animal Center. Animals eat and drink freely.
  • Dosage design After pre-testing, 4 SD rats (male and female) were intragastrically administered at the doses of 2000 mg/kg body weight and 5000 mg/kg body weight of the test sample. No animal deaths were found within 72 hours.
  • the adult dose of the test sample is 5g/day, calculated based on the adult body weight of 60kg, and 10 times and 20 times the recommended amount of the human body are used as the dose group of the test, then the dose of the dose group 1 and the dose group 2 They are 833mg/kg body weight and 1667mg/kg body weight.
  • the maximum clinical daily dose of the positive drug rosuvastatin calcium tablets is 20 mg, calculated at an adult weight of 60 kg, and 20 times the recommended amount of the human body is used as the test dose of the positive drug, that is, the test dose of the positive drug rosuvastatin calcium tablet is 6.6 mg/kg weight.
  • Second grouping ApoE -/- mice were randomly divided into model control group, positive control group, test sample dose 833 mg/kg group, and test sample dose 1667 mg/kg group according to TC levels. 12 per group, half male and half female.
  • 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.
  • the water, crude protein, crude fat, crude fiber, crude ash, calcium, phosphorus, and calcium phosphorus of the model feed must meet the national standards for maintaining feed. Provided by Guangdong Medical Laboratory Animal Center.
  • Preparation method of the test product Weigh the corresponding test product, add a small amount of pure water to grind and dissolve, transfer to a calibrated container, and then add pure water to the calibration line of the container, stir to dissolve, the concentration of the two groups of prepared doses is 83.35mg/mL, diluted 1 times into a dose group 1, the concentration is about 41.65mg/mL.
  • Body weight The body weight is measured once at the beginning and the end of the test. During the test, the body weight is measured once a week. Calculate the animal's weight gain for 30 days (dose D29-dose D1) and 60d (dose D60-dose D1).
  • Organ weight Measure the weight of liver, left kidney and peripheral fat of left kidney, right kidney and peripheral fat of right kidney, and calculate the organ coefficient according to the formula. The liver and right kidney were weighed and stored at -80°C.
  • Sections of the aortic arch, HE staining showed that the model control group showed certain histological changes compared with the negative control group, mainly manifested by the accumulation of foam cells under the intima of the aortic arch and the formation of intimal plaques (Figure 3). There was no significant difference between the positive control group and the model control group. However, in the aortic arch of the 833 mg/kg dose group and 1667 mg/kg group of the traditional Chinese medicine composition of the present invention, only subintimal foam cell aggregation was seen, without the formation of intimal plaque (Figure 3). The aortic arch section and Sirius staining showed that the model control group and the negative control group had obvious collagen fiber proliferation in the intimal plaque and adventitia.
  • the traditional Chinese medicine composition of the present invention has obvious effects of reducing the formation of atherosclerotic plaque and reducing the weight gain of model animals in animal experiments.
  • the treatment period for all patients is one to three courses (one course of treatment is 14 days), and each person takes 2 times a day. According to different conditions, 1 or 2 bags of granules are taken each time. Each bag of granules contains 1250mg of dry extract powder A, B or C.
  • the traditional Chinese medicine composition of the present invention has an effective rate of 45% for patients with single hypercholesterolemia (Table 15 and Figure 7), and the effective rate for reducing single hypertriglyceridemia is close to 90% (Table 15 and Figure 7). 8).
  • the traditional Chinese medicine composition of the present invention has an excellent curative effect on patients with severe hyperlipidemia, especially patients with severe blood triglycerides (triglycerides>5.6 mmol/L).
  • Table 15 Summary of blood total cholesterol and triglyceride measurement results of 113 cases of hyperlipidemia before and after treatment
  • Example 6 A typical case of atherosclerosis treatment
  • Yang male, attended Beijing Tongyitang Clinic (1st floor, Building 4, Zhongguancun Life Science Park, Changping District, Beijing) in 2019.
  • Yang had plaques formed in bilateral common carotid arteries and right supraclavicular arteries.
  • plaques in the right supraclavicular artery were formed.
  • the left common carotid artery formed multiple plaques, with a maximum length of 3.5mm and a thickness of 1.6mm; the diameter of the right vertebral artery was 2.8mm, the average blood flow velocity was 0.21m/s, and the blood flow was 77ml/min.
  • each bag of granules contains 1250mg dry extract powder A.
  • the right common carotid atherosclerotic plaque became smaller and disappeared, and the largest decrease was 10.0mm long and 1.8mm thick; the right supraclavicular atherosclerotic plaque disappeared, and the vertebral artery diameter Increased (3.2mm), blood flow velocity (0.21m/s) and blood flow increased significantly (blood flow from before treatment to 135ml/min after treatment.
  • Wang male, 40 years old, attended Beijing Tongyitang Clinic (1st Floor, Building 4, Zhongguancun Life Science Park, Changping District, Beijing) in 2018. At the time of treatment, Wang had bilateral common carotid artery atherosclerotic plaques and left and right necks. The arteries all have plaques of about 1.6 mm.
  • each bag of granules contains 1250mg dry extract powder A. After six courses of treatment (3 months of treatment), there was no obvious plaque formation in the left and right common carotid arteries, and the original diagnosis of hardened plaque disappeared.

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Abstract

本发明提供了一种中药组合物及其制备方法和应用。本发明中药组合物包括按以下重量份计的原料药：柴胡10-35份、枳实5-25份、生大黄3-20份，黄芩3-20份、白芍3-20份、干姜3-15份、水蛭5-20份、甘草3-20份、党参3-20份、白术3-20份、半夏3-25份。本发明中药组合物具有优良的降低血脂，降低胆固醇，特别是降低血甘油三酯的效果；本发明中药组合物也具有减缓动脉粥样斑块形成，清除动脉粥样斑块，预防和治疗动脉粥样硬化的良好效果。

Description

一种中药组合物及其制备方法和应用 技术领域
本发明属于中药领域，涉及一种中药组合物及其制备方法和该中药组合物在制备用于预防或治疗血脂升高、甘油三酯升高、胆固醇升高、高脂血症、动脉粥样硬化药物中的应用。
背景技术
血脂是血液中各种脂类物质的总称，其中最重要的是胆固醇和甘油三脂，甘油三脂也称中性脂肪，其它重要脂类还包括脂蛋白，其中又包括低密度脂蛋白和高密度脂蛋白。健康人的平均血胆固醇含量在2.8～5.17mmol/L之间，平均血甘油三酯含量在0.56～1.7mmol/L之间。无论是胆固醇含量增高，还是甘油三脂的含量增高，或是两者皆增高，均统称为高脂血症。
国家卫生与计划生育委员会2015年初发布的《中国居民营养与慢性病调查报告》显示，2012年中国成人血脂异常患病率40.40％，相比2002年的患病率水平出现大幅度增加，其中高胆固醇血症患病率4.9％，高甘油三酯血症的患病率13.1％。呈现为国民血脂异常的普遍暴露状态，这对我国血脂异常防治工作提出更为严峻的挑战。
动脉粥样硬化(atherosclerosis，AS)是冠心病、脑梗死、外周血管病的主要原因。高脂血症为动脉粥样硬化的病变基础，其特点是受累动脉病变从内膜开始，一般先有脂质和复合糖类积聚、出血及血栓形成，进而纤维组织增生及钙质沉着，并有动脉中层的逐渐蜕变和钙化，导致动脉壁增厚变硬、血管腔狭窄。病变常累及大中肌性动脉，一旦发展到足以阻塞动脉腔，则该动脉所供应的组织或器官将缺血或坏死。由于在动脉内膜积聚的脂质外观呈黄色粥样，因此称为动脉粥样硬化。
动脉粥样硬化性心血管疾病被称为发达国家的“头号杀手”，在发展中国家患病率正迅速增加。其中，动脉粥样硬化导致冠状动脉心肌梗死和卒中死亡占主要比例。到2035年，美国预计有超过1.3亿成年人(45.1％)会患有某种心血管疾病，心血管疾病的总花费将高达1.1万亿美元。中国心血管病患病率及死亡率仍处于上升阶段，心血管病现患病人数2.9亿，心血管病死亡率居首位，占居民疾病死亡构成的30％以上。当然，有高脂血症并不意味着一定会患心血管疾病，但积极治疗高脂血症，却是预防心血管疾病的重要措施之一。
合理的饮食及适当的锻炼是控制预防血脂升高，从而减少动脉粥样硬化性心血管疾病危害的有效和必要的措施。然而在饮食锻炼无效时，药物治疗成为必不可少的手段。
目前临床上应用的降血脂类化药品种较多，主要是他汀类(Statin)和贝特类(Fibrates)。尽管具体机理不同，但主要都是通过直接作用于脂肪的合成和代谢通路起效。由于停药后血脂反弹几率非常高，因此化学合成降血脂药物需要长期服用，这不仅导致经济资源的损耗，同时也大大增加了毒副作用的产生几率。例如，长期服用常常伴随着产生不同程度的副反应，包括肌肉疼痛，肝脏以及肾脏功能损伤等。此外，化学降血脂药的使用，并不能从根本上预防和控制血管斑块的形成和发展。
以中国传统天然药物为基础的降脂类药物有广东宏兴降脂丸、成都地奥脂必妥、北京维信血脂康等。这些药从其说明书中可以看到，或多或少都存在一定的副作用，例如血脂康的副作用表现为胃肠道不适，如胃痛、腹胀、胃部灼热等，偶可引起血清氨基转移酶和肌磷酸激酶可逆性升高。且从文献报道可见，这些药通常建议与化学降脂药同时使用，或主要建议老年人使用等。
因此，对于具有良好地预防和治疗血脂升高、甘油三酯升高、胆固醇升高、高脂血症的传统中药药物仍有强烈的临床需求。同时，目前，尚未有以中国传统天然药物为基础的预防和控制血管斑块形成、治疗动脉粥样硬化的药物。因此，社会和市场需求巨大。
发明内容
本发明的目的在于提供一种中药组合物，其制备方法及其在制备预防或治疗血脂升高、甘油三酯升高、胆固醇升高、高脂血症、动脉粥样硬化等的药物中的应用。动物模型实验和临床实验显示，本发明中药组合物具有优良的降低血脂，降低胆固醇，特别是降低血甘油三酯的效果，同时，动物模型实验和临床实验也揭示本发明中药组合物，具有减缓动脉粥样斑块形成，并清除动脉粥样斑块的良好效果。
本发明发明人经长期钻研中国传统医学理论并结合临床实践，提出了一种明显有别于现代医学的预防和治疗血脂升高、甘油三酯升高、胆固醇升高、高脂血症、动脉粥样硬化理论的用药方案。我们认为，高血脂和随后的动脉粥样硬化形成的核心原因，用中国传统医学的逻辑和语言可以归纳为：痰饮入血。若进入现代医学的语境，则类似于血液粘稠。血液粘稠既是高血脂和动脉粥样硬化的病因，也是痰饮入血表现的病症。由于中国传统医学的痰饮入血表现为现代医学的血液粘稠，因此我们认为对其的调节治疗，是预防、治疗高脂血症和动脉粥样硬化的核心和有效途径。
“痰饮”在《皇帝内经》中被定义为离经之水，也就是在循环代谢中的一种体液，这种体液较粘稠的叫痰，较清稀的叫饮，合称痰饮。中国传统医学中的“痰饮”多数是指在消化道和肺以及呼吸道中的粘稠或清稀的液体，这种液体难以被代谢掉，即使排出体外也又会从消化道或呼吸道继续生成出来，绵绵不绝。这些粘稠的液体还可以从消化道、呼吸道溢出留存在皮肤下、肌肉中、骨关节中，甚至内脏和大脑中，变成各种包块、囊肿、息肉，甚至肿瘤也被认为与痰饮留注在机体中有关，中国传统医学认为很多疾病 都和这种难以被身体排出体外，又难以被代谢掉的粘液有关。但中国传统医学没有论述过痰饮进入血液之中留存并导致血液黏稠。
在现代医学中，“血液粘稠”的概念下包含了数十个生化指标。例如，高血脂的一些指标(血清总胆固醇，低密度胆固醇，高密度胆固醇，转脂蛋白，甘油三酯)，高血糖的一些指标(空腹血糖，糖化血红蛋白，空腹胰岛素，C肽，糖化血清蛋白，果糖胺)，血小板的指标(血小板数量，血小板粘附度，血小板沉降度等)，红血球的一些指标(红血球的数量，红血球沉降度，红血球粘附度，红血球积压度，红细胞变形性，红细胞的大小)，血液粘稠度本身测定指标(表观粘度，相对粘度，还原粘度，比粘度等)以及一些其它相关指标(纤维蛋白原，免疫球蛋白等)。以上这些指标都对血液粘稠度有着比较密切的影响，但依然不是全部。血液粘稠表现不一，现代医学尚未提供一个合理且公认的致病原因，对其的治疗也停留在针对某些指标的阶段，例如，通过服用药物来控制高血脂、高血糖问题。但由于高血液粘稠度没有从根本上解决，所以降脂、降糖效果持续时间短，需要长期服用，无法达到治愈的效果。
痰饮进入血液引发血液粘稠，会大大增加高血脂和血糖发生的风险，进而引发动脉粥状硬化，堵塞血管，再而引发心脑肾疾病。我们据此理论，在医学临床实践中，开发了高效和长效降低血脂，特别是降低甘油三脂，有效预防和治疗高脂血症和动脉粥样硬化的中药组合物。
本发明提供一种中药组合物，其包括按以下重量份计的原料药：柴胡10-35份、枳实5-25份、生大黄3-20份，黄芩3-20份、白芍3-20份、干姜3-15份、水蛭5-20份、甘草3-20份、党参3-20份、白术3-20份、半夏3-25份。
优选地，本发明中药组合物包括按以下重量份计的原料药：柴胡20-30份、枳实10-20份、生大黄5-15份，黄芩5-10份、白芍5-15份、干姜5-10份、水蛭7-15份、甘草5-15份、党参5-15份、白术5-15份、半夏10-20份。
更优选地，本发明中药组合物还进一步包括按以下重量份计的原料药：生牡蛎3-45份，优选10-35份。更优选地，在此基础上，本发明中药组合物还进一步包括按以下重量份计的原料药：红曲3-15份，优选5-12份。
优选地，本发明中药组合物由按如上所述重量份的原料药制成。
更优选地，本发明中药组合物由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份。
更优选地，本发明中药组合物由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份、生牡蛎30份。
更优选地，本发明中药组合物由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份、生牡蛎30份、红曲10份。
以上组成中，份为重量份，重量是以生药计算的。在生产时可按照相应比例增大或减少，如大规模生产可以以公斤为单位，或以吨为单位，重量可以增大或者减小，但各组成之间的生药材重量配比的比例不变。
本发明相关原料药介绍如下：
柴胡，药用部位为伞形科植物柴胡或狭叶柴胡的干燥根(Bupleurum chinense DC.或Bupleurum scorzonerifolium Willd.)。有和解表里，疏肝升阳之功效。
枳实，为芸香科植物酸橙及其栽培变种或甜橙的干燥幼果(Immature Bitter Orange、Immature Sweet Orange、Fructus Aurantii Immaturus)。有破气消积，化痰散痞之功效。
生大黄，本品为蓼科植物掌叶大黄(Rheum palmatum L.)，唐古特大黄(Rheum tanguticum Maxim.ex Balf.)，或药用大黄(Rheum officinale Baill.)的干燥根及根茎。有泻热毒，破积滞，行瘀血之功效。
黄芩，唇形科多年生草本植物黄芩(Scutellaria baicalnsis Geprgi)的干燥根。有清热燥湿、泻火解毒、止血、安胎等功效。
白芍，为毛莨科植物芍药(Paeonia lactiflora Pall.)的干燥根。具温阳祛湿、补体虚、健脾胃等功效。
干姜，为姜科植物姜(Zingiber oj-jicinale Rosc.)的干燥根茎。冬季采挖，除去须根和泥沙，晒干或低温干燥。趁鲜切片晒干或低温干燥者称为“干姜片”。有温中散寒，回阳通脉，温肺化饮等功效。
水蛭，为水蛭科动物蚂蟥(Whitm.ania Pigra Whitman)，水蛭(Hirudo nipponica Whitman)或柳叶蚂蟥(Whitmania acranutata Whitman)的干燥全体。夏、秋二季捕捉，用沸水烫死，晒干或低温干燥。具有破血通经，逐瘀消症的功效。
甘草(Glycyrrhiza uralensis Fisch)，别名：国老、甜草、乌拉尔甘草、甜根子。豆科、甘草属多年生草本，药用部位是根及根茎。用于心气虚，心悸怔忡，脉结代，以及脾胃气虚，倦怠乏力，调和某些药物的烈性及对胃肠道的反应。
党参，为桔梗科植物党参、素花党参、或川党参等的干燥根。有补中，益气，生津的功效。
白术，菊科植物白术(Atractylodes macrocephala Koidz.)的干燥根茎。有健脾益气，燥湿利水，止汗的功效。
半夏，为天南星科植物半夏(Pinellia ternata(Thunb.)Breit.)的干燥块茎。有燥湿化痰，降逆止呕，消痞散结之功效。
生牡蛎，为牡蛎科动物长牡蛎(Ostrea gigas Thunberg)，大连湾牡蛎(Ostrea talienwhanensis Crosse)或近江牡蛎(Ostrea rivularis Gould)的贝壳。有重镇安神，潜阳补阴，软坚散结之功效。
红曲，为曲霉科真菌红曲霉(Monascus purpureus Went.)的菌丝体寄生在粳米上而成的红曲米。具有健脾消食，活血化瘀之功效。
本发明的药方是在对伤寒论经方及相应药材充分研究的基础上，结合临床实践形成的。本发明药方以柴胡为君药，柴胡疏通肝脏的气机，使得肝脏的功能得以恢复正常运转，这是代谢脂肪的关键所在，柴胡还是非常好的免疫、消炎、退烧、降温的药物，其可以对全身的免疫机制进行调节，并在恢复一些关键的激素重新分解平衡血脂方面起到关键作用，对甲状腺素的功能恢复也有很好的作用；生大黄为臣药，生大黄起到通肠道、消除肠道的炎症和有害菌群的关键作用，枳实也是臣药，配合柴胡通达脏腑上下，配合生大黄更好地梳理肠道功能，消除肠道中的炎症和有害菌群，黄芩也是臣药，用来降低胃酸的分泌、减少胃泌素，同时也用于消除胃中的炎症和肠道中的有害菌群；甘草、党参、白芍、白术、半夏都是辅助药物，用来去除肠胃中的多余粘液，减少血液粘稠物质的来源，减低血液粘度；本方中使用干姜，而非生姜，可以减少大黄的肠胃反应，使得此方剂适宜中长期服用，满足治疗高血脂、动脉斑块的治疗时间要求；方剂中包括的水蛭用来活血破淤，消除人体血管中的各种血小板、红血球的集聚堆积和粘黏，有利于消除血管中的斑块；方剂中可增加生牡蛎，用来消解人体肠胃中的积涩的未充分消化物质，同时生牡蛎可以帮助软化过于疲劳的肝脏，将肝的脂肪更好的消解掉；方剂中还可增加红曲，用于增加降解胆固醇的作用，但其不是关键成分。
本发明的中药组合物可通过提取或本领域其他已知方式来获得药物活性物质。所述药物活性物质可以通过分别提取天然复方药物原料得到，也可以通过共同提取天然复方药物原料得到。
优选的，通过水提法制备。更优选的，本发明中药组合物的制备方法包括称取原料药，第一次加水4-12倍量，在75-95℃保温30-120分钟，得到第一次煎煮液；第二次加水3-10倍量，在75-95℃保温30-120分钟，得到第二次煎煮液；合并二次煎煮液，滤过，合并滤液。更优选的，本发明中药组合物的制备方法包括称取原料药，第一次加水8倍量，煮沸80℃保温60分钟，得到第一次煎煮液；第二次加水6倍量，煮沸后80℃保温60分钟，得到第二次煎煮液；合并二次煎煮液，滤过，合并滤液。获得的提取物可进一步浓缩制成浸膏形式，可以是干浸膏也可以是流浸膏。优选减压(-0.05Mpa,60℃)浓缩至相对密度1.05-1.15(60℃)。
本发明中药组合物，视需要还可以加入药学上可接受的载体制成制剂。本发明中药组合物提取或加工获得的药物活性物质在制剂中所占重量百分比为0.1-99.9％，其余为药学上可接受的载体。
本发明中药组合物可以是任何可药用的剂型，这些剂型包括：汤剂、片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。优选口服剂型，进一步优选汤剂、胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。最优选汤剂、颗粒剂、胶囊剂、片剂。
本发明进一步提供所述的中药组合物在制备预防或治疗血脂升高的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或治疗甘油三酯升高的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或治疗胆固醇升高的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或治疗高脂血症的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或控制血管斑块形成的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或治疗动脉粥样硬化的药物中的应用。
本发明进一步提供所述的中药组合物在制备预防或治疗慢性代谢疾病的药物中的应用。
本发明进一步提供一种预防或治疗血脂升高的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或治疗甘油三酯升高的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或治疗胆固醇升高的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或治疗高脂血症的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或控制血管斑块形成的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或治疗动脉粥样硬化的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明进一步提供一种预防或治疗慢性代谢性疾病的方法，包括给予有此需要的人预防或治疗有效量的如上所述的本发明中药组合物。
本发明中药组合物在使用时可每日服用一到三次，制成单位剂量形式时，每次服用1-10剂。本发明中药组合物经过水煎后，可浓缩干燥制得干浸膏粉，再加入适量辅料，制成颗粒剂(每剂含1250mg干浸膏粉,相当于生药20g)，每日服用一到三次，每次服用1-2剂，或者也可以装入胶囊或制成片剂(每剂含312.5mg干浸膏粉,相当于生药5g)，每日服用一到三次，每次服用2-8粒胶囊或片剂，具体用法用量可根据具体病人情况酌情调整。
本发明的中药配方，是在“痰饮入血”和伤寒论理论和实践基础上的创新性构建。本发明发明人在充分研究考虑配方中各组分性质和功效的基础上，进一步优化了组分配比。特别是，本发明组方创造性地包含干姜和水蛭，并在临床实践中优化了它们的配比。本发明中药组合物对血液粘稠有非常明显的作用，通过两个途径改善总血粘稠度，第一是通过改善肠胃消化和排泄减少肠胃中的粘稠物质—痰饮，减少血液粘稠的来源，第二 是通过新陈代谢作用直接代谢掉血液粘稠的有机组成部分，包括血脂。本发明中药组合物还能减少红血球聚集度、沉降度、切度，减少血小板的聚集度和沉降度、切度。临床实验显示，本发明中药配方具有优良的降低血脂，降低胆固醇，特别是降低血甘油三酯的效果，有效率超过90％。对于重度血甘油三酯升高(甘油三酯>5.6mmol/L)，效果显著，在较短时间内(14天，治疗一个疗程)就可以降低90％以上。本发明中药组方具有的优良效果，也经第三方机构开展的动物模型实验得以证实。此外，实验显示本发明中药组合物也具有特异性地减缓动脉粥样斑块形成，并清除动脉粥样斑块的良好效果。
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1：ApoE -/- 小鼠阴性对照组与动脉粥样斑块模型对照组主动脉全长油红O染色对比图片。A.阴性对照组油红O染色代表性图片；B.造模后模型对照组油红O染色代表性图片。
图2：本发明中药组合物对ApoE -/- 小鼠动脉粥样斑块形成影响对比图片(主动脉全长油红O染色)。A.阴性对照组油红O染色代表性图片；B.模型对照组油红O染色代表性图片；C.本发明中药组合物833mg/kg剂量组油红O染色代表性图片；D.本发明中药组合物1677mg/kg剂量组油红O染色代表性图片。
图3：本发明中药组合物对ApoE-/-小鼠动脉粥样斑块形成影响对比图片(主动脉弓切片HE染色)主动脉弓切片HE染色阴性对照组、模型对照组、阳性对照组、本发明中药组合物833mg/kg剂量组和1677mg/kg剂量组对比图。
图4：本发明中药组合物对ApoE-/-小鼠动脉粥样斑块形成影响对比图片(主动脉弓切片天狼星染色)主动脉弓切片天狼星染色阴性对照组、模型对照组、阳性对照组、本发明中药组合物833mg/kg剂量组和1677mg/kg剂量组对比图。
图5：本发明中药组合物对ApoE-/-小鼠动脉粥样斑块形成影响对比图片(颈动脉油红O染色)颈动脉油红O染色阴性对照组、模型对照组、阳性对照组、本发明中药组合物833mg/kg剂量组和1677mg/kg剂量组对比图。
图6：本发明中药组合物对14例总胆固醇和甘油三酯共同升高的患者的治疗结果。A.治疗前后总胆固醇分析；B.治疗前后甘油三酯分析。
图7：本发明中药组合物对11例高胆固醇血症患者的治疗结果，治疗前后总胆固醇分析。
图8：本发明中药组合物对88例高甘油三酯血症患者的治疗结果，治疗前后甘油三酯分析。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为了阐明本发明，而不是为了限制本发明的范围。
下述实施例中的试验方法，如无特殊说明，均为常规方法；下述实施例中所用的原料、试剂材料等，如无特殊说明，均为市售购买产品。
本申请说明书中，如果没有特殊说明，各受试药物的制备过程中溶剂的用量都是以药材重量为基准的体积倍数。
实施例1本发明中药组合物的制备
实施例1-1：
称取如下原料药：柴胡25g、枳实15g、生大黄10g、黄芩6g、白芍10g、干姜6g、水蛭10g、甘草10g、党参10g、白术10g、半夏15g、生牡蛎30g，置密闭容器内煮提两次，第一次加水8倍量，煮沸后80摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后80摄氏度保温60分钟，得第二次煎煮液；合并二次煎煮液，滤过，合并滤液。减压(-0.05Mpa,60℃)浓缩至相对密度1.05-1.15(60℃)，减压冷冻干燥得干浸膏粉A，提取得膏率为生药量的25％。
在获得的干浸膏粉A中以4:1的比例加入β-环糊精，制得干浸膏粉A颗粒。颗粒干燥冷却后，装袋作为颗粒剂(每袋含中药干浸膏粉1250mg，相当于生药20g)。
实施例1-2：
称取如下原料药：柴胡25g、枳实15g、生大黄10g、黄芩6g、白芍10g、干姜6g、水蛭10g、甘草10g、党参10g、白术10g、半夏15g，置密闭容器内煮提两次，第一次加水8倍量，煮沸后80摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后80摄氏度保温60分钟，得第二次煎煮液；合并二次煎煮液，滤过，合并滤液。减压(-0.05Mpa,60℃)浓缩至相对密度1.05-1.15(60℃)，减压冷冻干燥得干浸膏粉B，提取得膏率为生药量的25％。
在获得的干浸膏粉B中以4:1的比例加入β-环糊精，制得干浸膏粉B颗粒。颗粒干燥冷却后，装袋作为颗粒剂(每袋含中药干浸膏粉1250mg，相当于生药20g)。
实施例1-3：
称取如下原料药：柴胡25g、枳实15g、生大黄10g、黄芩6g、白芍10g、干姜6g、水蛭10g、甘草10g、党参10g、白术10g、半夏15g、红曲10g、生牡蛎30g。置密闭容器内煮提两次，第一次加水8倍量，煮沸后80摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后80摄氏度保温60分钟，得第二次煎煮液；合并二次煎煮液，滤过，合并滤液。减压(-0.05Mpa,60℃)浓缩至相对密度1.05-1.15(60℃)，减压冷冻干燥得干浸膏粉C，提取得膏率为生药量的25％。
在获得的干浸膏粉C中以4:1的比例加入β-环糊精，制得干浸膏粉C颗粒。颗粒干燥冷却后，装袋作为颗粒剂(每袋含中药干浸膏粉1250mg，相当于生药20g)。
实施例2本发明中药组合物对混合型高脂血症大鼠模型的影响研究
2.1试验目的：建立混合型高脂血症大鼠模型，研究本发明中药组合物对该模型的影响。
2.2供试品：实施例1-1中制得的干浸膏粉A。性状：棕色粉末；保存条件：2—8℃、干燥。
2.3对照品：阿托伐他汀钙片(立普妥)。性状：白色椭圆形薄膜衣片；规格：10mg/片；包装：铝/铝水泡眼包装；生产单位：辉瑞制药有限公司；保存条件：密闭。
2.4试验用溶媒、乳化剂及其它介质：
2.4.1羧甲基纤维素钠
保存条件：常温；
0.5％羧甲基纤维素钠溶液配制方法：准确称量5.0g CMC-Na，磁力搅拌器室温边搅拌边缓慢加入装有约800mL纯净水的烧杯中，搅拌至溶解，2～8℃过夜，第二天量筒中定容至1000mL后混匀，2～8℃保存备用。
2.4.2名称：纯净水
生产单位：广东省医学实验动物中心比较医学实验室。
2.5.主要仪器与试剂
BS-3000A电子分析天平，感量：0.1g，上海友声衡器有限公司；
BS224S电子分析天平，感量：0.1mg，赛多利斯科学仪器(北京)科技有限公司；
5418台式高速离心机，德国EPPENDORF；
7020型全自动生化分析仪，日本株式会社日立高新技术；
异氟烷：批号217171101，失效日期20201101，深圳市瑞沃德生命科技有限公司；
乌拉坦：批号20160920，有效期至20210920，国药集团化学试剂有限公司；
氯化钠注射液，批号：H18052802-2，广东科伦药业有限公司；
麻醉用20％乌拉坦溶液：称取20.0g乌拉坦，加氯化钠注射液至100mL，混匀，0.2μm滤膜除菌；
TC试剂盒：批号20180722、20190222，有效期至20200110、20200820，上海科华生物工程股份有限公司；
TG试剂盒：批号20180822、20190222，有效期至20200223、20200825，上海科华生物工程股份有限公司；
HDL-C试剂盒：批号20181012，有效期至20191011，上海科华生物工程股份有限公司；
LDL-C试剂盒：批号20190212，有效期至20200226，上海科华生物工程股份有限公司。
2.6实验系统
种系：SD大鼠；级别：SPF级；雄性，190.2～223.9g；
来源和动物合格证号：购自广东省医学实验动物中心，动物生产许可证号为SCXK(粤)2018-0002，动物合格证号44007200066274；
识别方法：采用被毛染色法，使用饱和苦味酸对动物进行编号，在动物体表不同部位的被毛涂染斑点，以示不同号码。以动物皮肤染色和笼具双重编号标记识别。
动物福利：本试验涉及的与动物试验相关的内容和程序将遵从实验动物使用和管理的相关法律法规及本机构实验动物伦理委员会的相关规定，保证实验动物的福利。
安死术：造模后淘汰动物采用二氧化碳吸入致死，试验结束后的动物20％乌拉坦溶液按照6mL/kg体重腹腔注射麻醉后放血处死，尸体暂存于尸体冷冻柜，统一进行无公害化处理。
检疫观察：对购入大鼠检疫3天，每天观察1次，未发现不健康的动物。
饲养管理：动物饲养在广东省医学实验动物中心SPF级动物房，实验动物使用许可证号：SYXK(粤)2018-0002，动物实验证明号：00219646。动物饲养条件：群养，5只/箱，饲养温度与湿度：20～26℃，40～70％，采用12h:12h昼夜间断照明；饲养室条件始终保持稳定，以保证试验结果的可靠性。试验期间动物按实验要求喂相应颗粒饲料，动物自由进食饮水。
2.7剂量设计与分组
剂量设计：经预试，受试样品2000mg/kg体重、5000mg/kg体重剂量下分别灌胃4只SD大鼠，72h内未见动物死亡。受试样品的成人剂量为5g/日，按成人体重60kg计算，以人体推荐量的5倍、10倍作为试验的剂量，则试验剂量分别为417mg/kg体重和833mg/kg体重。阳性药阿托伐他汀钙片临床用量为10mg/日，按成人体重60kg计算，以20倍人体推荐量作为阳性药的试验剂量，即阳性药阿托伐他汀钙片试验剂量为3.3mg/kg体重。
分组：检疫结束后，动物随机分为阴性对照组10只，其余为模型组。模型组给予模型饲料2周后，不禁食，异氟烷吸入麻醉后，眼眶静脉窦采血，3000rpm离心10min，分离血清，测定总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平。淘汰TG水平较低的动物，选取40只根据TG水平随机分为模型对照组，阳性对照组、受试样品417mg/kg和833mg/kg组剂量组，10只/组。
表1 剂量设计与分组情况表
Figure PCTCN2021072897-appb-000001
Figure PCTCN2021072897-appb-000002
2.8试验方法
2.8.1高脂高胆固醇模型饲料：在维持饲料中添加20.0％蔗糖、5％猪油、1.0％胆固醇、0.1％胆酸钠，适量的酪蛋白、碳酸氢钙、石粉等。除了粗脂肪外，模型饲料的水分、粗蛋白、粗脂肪、粗纤维、粗灰分、钙、磷、钙：磷均要达到维持饲料的国家标准。由广东省医学实验动物中心提供。
2.8.2供试品配制方法：称取相应供试品至已标定容器中，加少量纯净水研磨溶解，再补足纯净水至容器的标定刻度线，搅拌溶解，使剂量浓度为166.7mg/mL，依次倍比稀释成剂量83.3mg/mL、41.7mg/mL。
2.8.3阳性药阿托伐他汀钙片配制方法：取1片阿托伐他汀钙片(规格：10mg/片)至已标定容器中，加0.5％CMC-Na溶液研磨均匀后补足0.5％CMC-Na溶液至60mL使成约0.33mg/mL，用前摇匀。
2.8.4造模方法：阴性对照组给予维持饲料，其余各组给予模型饲料至试验结束。其中除阴性对照组外，其余各组给药期d30～d36期间用西方高脂饲料。
2.8.5给药方法：造模成功后，阳性对照组及供试品417mg/kg和833mg/kg剂量组每天按10mL/kg体重灌胃相应剂量药液，阴性对照组和模型对照组给予同体积的纯净水，连续67～68天(每组前5只动物给药67天，每组后5只动物给药68天)。
2.8.6检测指标
2.8.6.1一般状态：每天观察动物的临床情况1次，至试验结束。
2.8.6.2体重：实验开始、实验结束称量动物体重1次；每周测量体重1次。
2.8.6.3血脂：给药满2、4、7、9周(d14、d28、d52、d65)，不禁食异氟烷吸入麻醉眼眶静脉窦采血，3000rpm离心10min，分离血清，测定血脂TC、TG、LDL-C、HDL-C水平。
2.8.6.4d66每组前5只动物、d67每组后5只动物晚上禁食，第2天给药、称重，按20％乌拉坦溶液6mL/kg体重腹腔注射麻醉，腹主动脉采血，取血清冻存。动物放血处死，取睾丸和肾周脂肪组织分别称重，取部分肝脏中性甲醛固定，其余肝脏液氮冷冻保存。
2.9数据统计方法：所有数据采用
Figure PCTCN2021072897-appb-000003
表示，应用SPSS 21.0软件进行统计分析；采用组间两两比较的单因素方差分析方法，检验水平α＝0.05。
2.10结果
2.10.1一般观察：试验期间动物体形、被毛、皮肤、粪便、肌肉张力、步态、精神、呼吸等未见异常反应。
2.10.2体重(见表2)：试验期间，各组动物体重无统计学差异(P>0.05)。
2.10.3血脂(见表3～7)
2.10.3.1造模后给药前血脂(见表3)：与阴性对照组相比，模型对照组大鼠造模后给药前的血清TC、TG、LDL-C值升高有统计学差异(P<0.05或0.01)；与模型对照组相比，各组大鼠造模后给药前的血脂四项指标均无统计学差异(P>0.05)。
2.10.3.2给药满2周血脂(见表4)：与阴性对照组相比，模型对照组大鼠给药满2周的血清TC、TG、LDL-C值升高有统计学差异(P<0.05或0.01)；与模型对照组相比，阳性对照组大鼠给药满2周的血清TC、TG、HDL-C、LDL-C值降低均无统计学差异(P>0.05)；与模型对照组相比，受试样品剂量417mg/kg和833mg/kg组大鼠给药满2周后，血清各指标均无统计学差异(P>0.05)。与模型对照组相比，TG均值均有所降低，由模性对照组的3.22mmol/L降低到受试样品剂量417mg/kg组的2.89mmol/L和剂量833mg/kg组的2.51mmol/L，但未达到统计学上的显著差异(P值介于0.05-0.1)。
2.10.3.3给药满4周血脂(见表5)：与阴性对照组相比，模型对照组大鼠给药满4周的血清TC、TG、LDL-C值升高有统计学差异(P<0.05或0.01)；与模型对照组相比，阳性对照组大鼠给药满4周的血清TC和LDL-C值降低均有接近统计学差异的改变(P＝0.10(TC)和P＝0.05(LDL-C))；与模型对照组相比，受试样品剂量833mg/kg组大鼠给药满4周后，TG和LDL-C值的降低，有统计学的显著差异(P<0.05)。受试样品剂量417mg/kg组大鼠给药满4周后，TG和LDL-C值的降低，没达到统计学上的显著差异(P>0.05)，但仍旧表现出降低的趋势，TG由模型对照组的3.03mmol/L降低到2.32mmol/L(P＝0.05)。同时，受试样品对TC也表现出降低的趋势，TC由模型对照组的3.44mmol/L降低到2.72mmol/L(剂量417mg/kg组，P＝0.08)和2.75mmol/L(剂量833mg/kg组，P＝0.09)。
2.10.3.4给药满7周血脂(见表6)：与阴性对照组相比，模型对照组大鼠给药满7周的血清TC、LDL-C值升高有统计学差异(P<0.01)，TG值有升高趋势，但无统计学差异(P>0.05)；阳性对照组大鼠给药满7周的血清TC值为3.03mmol/L，与模型对照组相比有所降低(3.55mmol/L)，但降低无统计学差异(P＝0.10)；与模型对照组相比，受试样品剂量417mg/kg和833mg/kg组大鼠给药满7周的血清TG的降低具有显著性或接近于显著性的统计学差异(受试样品417mg/kg和833mg/kg组P值分别为P＝0.05和P＝0.04)。同时，受试样品833mg/kg组，LDL-C的降低同样具有显著的统计学差异(P<0.05)。
2.10.3.5给药满9周血脂(见表7)：与阴性对照组相比，模型对照组大鼠给药满9周的血清TC、TG、LDL-C值升高有统计学差异(P<0.01)；与模型对照组相比，阳性对照组大鼠给药满9周的血清TC、TG、LDL-C值降低均无统计学差异(P>0.05)；与模型对照组相比，受试样品剂量417mg/kg组给药满9周的血脂四项指标均无统计学差异 (P>0.05)。然而，受试样品剂量833mg/kg组给药满9周的血脂TC，TG和LDL-C三项指标的降低均具有明显的统计学差异(P<0.05)
2.10.4脏器/组织重量及系数(见表8)：与阴性对照组相比，模型对照组大鼠肝脏重量及其系数增大有统计学差异(P<0.01)；与模型对照组相比，阳性对照组大鼠肝脏重量及其系数均无统计学差异(P<0.05或0.01)；与模型对照组相比，本发明组合物剂量417mg/kg和833mg/kg组大鼠脏器/组织重量及其系数均无统计学差异(P>0.05)。留存脏器。
表2 本发明中药组合物对混合型高脂血症大鼠体重的影响(
Figure PCTCN2021072897-appb-000004
g，n＝
Figure PCTCN2021072897-appb-000005
注：采用重复测量的分析方法进行统计分析。
续表2 本发明中药组合物对混合型高脂血症大鼠体重的影响(
Figure PCTCN2021072897-appb-000006
g，n＝
Figure PCTCN2021072897-appb-000007
注：采用重复测量的分析方法进行统计分析。
表3 本发明中药组合物对混合型高脂血症大鼠血脂的影响(造模后给药前)(
Figure PCTCN2021072897-appb-000008
Figure PCTCN2021072897-appb-000009
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01，“ #”P在0.05-0.10间
表4 本发明中药组合物对混合型高脂血症大鼠血脂的影响(给药满2周)(
Figure PCTCN2021072897-appb-000010
m
Figure PCTCN2021072897-appb-000011
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01，“ #”P在0.05-0.10间
表5 本发明中药组合物对混合型高脂血症大鼠血脂的影响(给药满4周)(
Figure PCTCN2021072897-appb-000012
m
Figure PCTCN2021072897-appb-000013
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01，“#”P在0.05-0.10间
表6 本发明中药组合物对混合型高脂血症大鼠血脂的影响(给药满7周)(
Figure PCTCN2021072897-appb-000014
m
Figure PCTCN2021072897-appb-000015
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01，“ #”P在0.05-0.10间
表7 本发明中药组合物对混合型高脂血症大鼠血脂的影响(给药满9周)(
Figure PCTCN2021072897-appb-000016
m
Figure PCTCN2021072897-appb-000017
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01
表8 本发明中药组合物对混合型高脂血症大鼠脏器/组织重量及其系数的影响(
Figure PCTCN2021072897-appb-000018
Figure PCTCN2021072897-appb-000019
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01
2.11结果总结：
1)各组动物体重无统计学差异(P>0.05)。
2)模型对照组和阴性对照组比较，造模后给药前、给药满2、4、9周的大鼠血清TC、TG、LDL-C值均升高(P<0.05或0.01)，混合型高脂血症大鼠模型成立；
3)阳性对照组与模型对照组比较，在各个时间点，尽管在降低大鼠血清总胆固醇显示一定的效果，然而差异均不具有显著差异，表明本阳性对照药品阿托伐他汀对本混合型高脂血症大鼠模型的降低血脂作用不明显，不是理想的阳性对照药品。
4)本发明中药组合物，特别是剂量833mg/kg组，在给药满2周后，即显示出降低TG的效果，在给药满4、7、9周后，降低TG的效果均具有统计学上的显著差异(P<0.05)；同时，剂量833mg/kg组在降低TC上也显示初步效果，特别是在给药满9周后，降低TC的效果具有统计学差异(P<0.05)。剂量417mg/kg组，在给药满4、7、9周后，降低TG的效果在统计学检验上，均处于上统计检验差异零界点上(P值在0.05到0.10间)。
5)模型对照组和阴性对照组比较，大鼠肝脏重量及其系数增大(P<0.01)；受试样品组与模型对照组比较，大鼠脏器/组织重量及其系数均无统计学差异(P>0.05)。留存脏器待移交委托方。
6)结论：在本实验条件下，本发明中药组合物的动物实验显现明显的降血脂，降低胆固醇效果，特别是对降低血甘油三酯的效果尤为显著。同时，降血脂效果与剂量有一定相关性。
实施例3本发明中药组合物对ApoE -/-小鼠动脉粥样斑块形成的影响研究
3.1试验目的：建立ApoE -/- 小鼠动脉粥样斑块模型，研究本发明中药组合物对该模型动脉粥样斑块形成的影响。
3.2供试品：实施例1-1中制得的干浸膏粉A。性状：棕色粉末；保存条件：2—8℃、干燥。
3.3对照品：瑞舒伐他汀钙片(可定)；性状：粉红色薄膜衣片；规格/纯度：10mg/片；包装：铝塑泡包装；生产单位：阿斯利康药业(中国)有限公司；保存条件：密封、干燥。
3.4试验用溶媒、乳化剂及其它介质：
3.4.1羧甲基纤维素钠
保存条件：常温；
0.5％羧甲基纤维素钠溶液配制方法：准确称量5.0g CMC-Na，磁力搅拌器室温边搅拌边缓慢加入装有约800mL纯净水的烧杯中，搅拌至溶解，2～8℃过夜，第二天量筒中定容至1000mL后混匀，2～8℃保存备用。
3.4.2名称：纯净水
生产单位：广东省医学实验动物中心比较医学实验室。
3.5主要仪器与试剂
BS-3000A电子分析天平，感量：0.1g，上海友声衡器有限公司；
BS224S电子分析天平，感量：0.1mg，赛多利斯科学仪器(北京)科技有限公司；
5418台式高速离心机，德国EPPENDORF；
7020型全自动生化分析仪，日本株式会社日立高新技术；
异氟烷：批号217171101，失效日期20201101，深圳市瑞沃德生命科技有限公司；
乌拉坦：批号20160920，有效期至20210920，国药集团化学试剂有限公司；
氯化钠注射液，批号：H18052802-2，广东科伦药业有限公司；
麻醉用20％乌拉坦溶液：称取20.0g乌拉坦，加氯化钠注射液至100mL，混匀，0.2μm滤膜除菌；
TC、TG、HDL-C、LDL-C试剂盒：上海科华生物工程股份有限公司；
质控血清：Randox Laboratories Limited
3.6实验系统
种系级别：SPF级，ApoE -/- 小鼠；6只ApoE小鼠，雌性，28～35日龄；48只ApoE小鼠，雌雄各半，49～56日龄；
识别方法：采用耳标法，打孔号前先用酒精棉球擦拭动物耳朵和打孔机消毒，然后在动物耳朵上打孔悬挂相应的号码牌来区分动物，号码牌上标记数字即为该动物的编号。
动物福利：本试验涉及的与动物试验相关的内容和程序将遵从实验动物使用和管理的相关法律法规及本机构实验动物伦理委员会的相关规定，保证实验动物的福利。
安死术：试验结束后的动物异氟烷吸入麻醉后摘眼球采血，采血后颈椎脱臼处死取材，尸体暂存于尸体冷冻柜，待本中心统一进行无公害化处理。
检疫观察：对购入小鼠检疫7d。期间每日检查动物一次，如发现不健康的动物立即剔除，选用健康动物进行实验。
饲养管理：动物饲养在广东省医学实验动物中心SPF级动物房，实验动物使用许可证号：SYXK(粤)2018-0002。动物饲养条件：单养，1只/箱，饲养温度与湿度：20～26℃，40～70％，采用12h:12h昼夜间断照明；饲养室条件始终保持稳定，以保证试验结果的可靠性。试验期间动物均按实验要求喂以相应颗粒饲料，所有饲料均由广东省医学实验动物中心提供。动物自由进食饮水。
3.7剂量设计与分组
剂量设计：经预试，受试样品2000mg/kg体重、5000mg/kg体重剂量下分别灌胃4只SD大鼠(雌雄各半)，72h内未见动物死亡。根据委托方提供信息，受试样品的成人剂量为5g/日，按成人体重60kg计算，以人体推荐量的10倍、20倍作为试验的剂量组，则剂量1组和剂量2组的剂量分别为833mg/kg体重和1667mg/kg体重。阳性药瑞舒伐他汀钙片临床每日最大剂量20mg，按成人体重60kg计算，以20倍人体推荐量作为阳性药的试验剂量，即阳性药瑞舒伐他汀钙片试验剂量为6.6mg/kg体重。
分组：检疫合格后，常规饲养1周，第1次分组(造模期)，6只ApoE -/- 小鼠为阴性对照组，给予维持饲料。其它48只ApoE -/- 小鼠为模型组，给予21％高脂饲料喂养1个月采血测定血脂四项。第2次分组(给药期)：ApoE -/- 小鼠按照TC水平随机分为模型对照组、阳性对照组、受试样品剂量833mg/kg组、受试样品剂量1667mg/kg组，12只/组，雌雄各半。
表9 剂量设计与分组情况表
Figure PCTCN2021072897-appb-000020
3.8试验方法
3.8.1高脂高胆固醇模型饲料：在维持饲料中添加20.0％蔗糖、5％猪油、1.0％胆固醇、0.1％胆酸钠，适量的酪蛋白、碳酸氢钙、石粉等。除了粗脂肪外，模型饲料的水分、粗蛋白、粗脂肪、粗纤维、粗灰分、钙、磷、钙：磷均要达到维持饲料的国家标准。由广东省医学实验动物中心提供。
3.8.2供试品配制方法：称取相应供试品，加少量纯净水研磨溶解，转移至已标定容器中，再补足纯净水至容器的标定刻度线，搅拌溶解，配制剂量2组浓度为83.35mg/mL，稀释1倍成剂量1组，浓度约为41.65mg/mL。
3.8.3阳性药瑞舒伐他汀钙片配制方法：取1片瑞舒伐他汀钙片(规格：10mg/片)加0.5％CMC-Na溶液研磨均匀后，转移至已标定容器中，补足0.5％CMC-Na溶液至30mL使成约0.33mg/mL，用前摇匀。
3.8.4造模方法：阴性对照组给予维持饲料，其余各组给予21％高脂饲料至试验结束。
3.8.5给药方法：阳性对照组、受试样品剂量833mg/kg组、受试样品剂量1667mg/kg组小鼠每天按20mL/kg体重灌胃给予相应的药液，阴性对照组和模型对照组给予同体积的纯净水，1次/d，连续60d。
3.8.6检测指标：
1)一般状态：每天观察并记录小鼠的一般临床状态1次。
2)体重：试验开始及试验结束测量体重1次，试验期间，每周测量体重1次。计算动物给药30d增重(给药D29-给药D1)、给药60d增重(给药D60-给药D1)。
3)TC、TG、LDL-C、HDL-C水平：造模期结束，各动物不禁食，异氟烷吸入麻醉后，眼眶静脉丛取血，低温离心机3000r/min，离心10min，分离血清测定总胆固醇TC、甘油三酯TG、高密度脂蛋白HDL-C、低密度脂蛋白LDL-C水平，剩余的血清-80℃ 冰箱保存。
4)脏器重量：测量肝脏，左肾及左肾周边脂肪，右肾及右肾周边脂肪重量，按照公式计算脏器系数。肝脏，右肾称量后-80℃保存。
Figure PCTCN2021072897-appb-000021
5)病理检查：实验结束后，仰卧位固定小鼠,迅速打开小鼠胸腔,用生理盐水经左心室全身灌流,再用4％多聚甲醛灌流固定。取心脏起至下髂动脉分支处的整条动脉,储存于4％多聚甲醛固定液，进行处理并油红O染色。快速分离主动脉弓连同心脏、和颈总动脉(右侧)，用4％多聚甲醛固定。颈总动脉进行油红O染色，主动脉弓进行HE染色和天狼星染色。
3.9数据统计方法：所有数据采用
Figure PCTCN2021072897-appb-000022
表示，应用SPSS 21.0软件进行统计分析；采用组间两两比较的单因素方差分析方法，检验水平α＝0.05。
3.10结果
3.10.1一般临床观察：试验过程中，阴性对照组2#于给药30d死亡，解剖可见左肾肿大，左肾上半部分呈乳白色，下半部呈暗红色。纵向剖开左肾可见左肾内部存在较大腔体，腔内充满乳白色乳状液体及清液。可见右肾干瘪萎缩，右肾附近可见聚集性血凝块。膀胱内可见乳白色脂肪状液体，聚集于膀胱出口，约占据膀光内体积一半。腹腔其余脏器大体解剖肉眼未见明显异常，胸腔大体解剖肉眼未见明显异常，胸主动脉肉眼未见斑块。判断：体内胆固醇聚集及高血脂症为ApoE基因敲除小鼠的正常表现，推断该小鼠死亡原因为因动物个体差异，脂肪代谢异常，胆固醇积累过多。其余动物体型、被毛、皮肤、粪便、肌肉张力、步态、精神、呼吸等未见异常反应。
3.10.2造模期数据
3.10.2.1造模期体重(表10)：造模期各组动物体重无统计学差异(p＞0.05)。
3.10.2.2造模期血脂四项(表11)：与阴性对照组(♂)比较，模型组(♂)动物血清TC、TG、HDL-C、LDL-C水平提高(p＜0.01)，模型组(♀)动物血清TC水平提高(p＜0.05)。
3.10.3给药期数据
3.10.3.1给药期体重(表12)：给药期各组动物体重无统计学差异(p＞0.05)；与阴性对照组(♂)比较，模型对照组(♂)动物给药30d、给药60d增重增加(p＜0.05)；与模型对照组(♂)比较，阳性对照组(♂)、受试样品833mg/kg剂量组(♂)、受试样品1667mg/kg剂量组(♂)动物给药30d、给药60d增重减少(p＜0.05)。
3.10.3.2给药60d脏器重量及指数(表13、14)：与阴性对照组(♂)比较，模型对照组(♂)动物肝脏、右肾周脂肪重量及系数提高(p＜0.05 or 0.01)，左肾及右肾系数下降(p＜0.05 or 0.01)，模型对照组(♀)动物左肾及右肾重量、左肾系 数下降(p＜0.05 or 0.01)；与模型对照组(♂)比较，阳性对照组(♂)动物、受试样品833mg/kg剂量组(♂)动物左肾重量下降(p＜0.05)；与模型对照组(♀)比较，受试样品833mg/kg剂量组(♀)动物右肾重量下降(p＜0.05)。
3.10.4病理检查结果：主动脉全长油红O染色显示，高脂饲料喂养ApoE -/-小鼠主动脉分叉部位布满红染斑块样物质，模型组与阴性对照组相比粥样斑块明显增加(图1),同时本发明中药组合物的833mg/kg和1677mg/kg剂量组，在给药60天后，主动脉油红O染色与模型对照组比较，均显示出明显降低动脉粥样斑块形成的效果(图2)。主动脉弓切片，HE染色显示，模型对照组较阴性对照组可见一定的组织学变化，主要表现为主动脉弓内膜下泡沫细胞聚集、内膜斑块形成(图3)。阳性对照组与模型对照组比较未见明显差异。然而，本发明中药组合物的833mg/kg剂量组、1667mg/kg组的主动脉弓仅见内膜下泡沫细胞聚集，未有内膜斑块的形成(图3)。主动脉弓切片，天狼星染色显示，模型对照组与阴性对照组比较，内膜斑块部位、外膜均有明显胶原纤维增生。本发明中药组合物处理组，特别是1667mg/kg组，仅见少量外膜胶原纤维增生，内膜未有胶原纤维增生(图4)。图5颈动脉油红O染色显示可见，管腔内红色脂滴形成，在本发明中药组合物的833mg/kg剂量组、1667mg/kg组均明显低于模型对照组和他汀干预组。本发明中药组合物的1667mg/kg组，颈动脉管腔内仅见微量红色脂滴(图5)。
表10 造模期体重数据(
Figure PCTCN2021072897-appb-000023
g)
Figure PCTCN2021072897-appb-000024
表11 造模期血脂四项数据(
Figure PCTCN2021072897-appb-000025
g)
Figure PCTCN2021072897-appb-000026
表12 给药期体重数据(
Figure PCTCN2021072897-appb-000027
g)
Figure PCTCN2021072897-appb-000028
续表12 给药期体重数据(
Figure PCTCN2021072897-appb-000029
g)
Figure PCTCN2021072897-appb-000030
注：与阴性对照组(♂)比较， #p＜0.05；与模型对照组(♂)比较， ■p＜0.05。
表13 给药60d脏器重量
Figure PCTCN2021072897-appb-000031
Figure PCTCN2021072897-appb-000032
注：与阴性对照组(♂)比较， #p＜0.05， ##p＜0.01；与模型对照组(♂)比较， ■p＜0.05；与模型对照组(♀)比较， *p＜0.05。
表14 给药60d脏器系数数据
Figure PCTCN2021072897-appb-000033
Figure PCTCN2021072897-appb-000034
注：与阴性对照组(♂)比较， #p＜0.05， ##p＜0.01；与模型对照组(♂)比较， ■p＜0.05；与模型对照组(♀)比较， *p＜0.05。
3.11结果总结
本发明中药组合物在动物实验中显现明显的降低动脉粥样硬化斑块形成和降低模型动物体重增加的效果。
实施例4高脂血症治疗临床试验
临床试验病例来自于浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)和北京同義堂诊所(北京市昌平区中关村生命科学园4号楼1层)。
我们收集了前期在如上两个诊所应用本发明干浸膏粉A、B或C治疗高脂血症的病例资料，其中总胆固醇(>6.2mmol/L)和甘油三酯(>1.7mmol/L)共同升高的病例为14例,总胆固醇单一升高的病例为11例，甘油三酯单一升高的病例为88例(表15)。
所有病人治疗期为一到三个疗程(一个疗程14天)，每人每日2次，根据不同病情，每次服用颗粒剂1或2袋，每袋颗粒剂含有1250mg干浸膏粉A、B或C。
以总胆固醇或甘油三酯水平降低10％作为有效性指标,在14例总胆固醇和甘油三酯共同升高的病例中，接近79％的患者总胆固醇有效降低，93％的患者甘油三酯有效降低，10位患者两者同时有效降低(表15和图6)。
本发明中药组合物对单一总胆固醇升高血症患者，降低的有效率为45％(表15和图7)，对单一高甘油三脂血症降低的有效率接近90％(表15和图8)。其中，本发明中药组合物对重度高脂血症患者，特别是重度血甘油三酯(甘油三酯>5.6mmol/L)病例，具有优良的疗效。
表15 113例高血脂病例治疗前后血总胆固醇和甘油三酯测定结果汇总
Figure PCTCN2021072897-appb-000035
注：组间比较，独立样本T检验“ ▲”P<0.05，“ ▲▲”P<0.01
实施例5：高脂血症治疗典型病例
实施例5-1：
邵某，男，2016年在浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)就诊，就诊时血液呈现为乳白色，甘油三脂达到33.4mmol/L,总胆固醇为6.71mmol/L。日服用颗粒剂两次，每次2袋，每袋颗粒剂含有1250mg干浸膏粉A。经过一个疗程的治疗(14天)，甘油三脂降到0.62mmol/L，总胆固醇降到4.41mmol/L，均恢复到正常值水平。
实施例5-2：
陈某，女，2016年在浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)就诊。陈某长期服用他汀类降血脂药，在就诊时血液甘油三脂为8.31mmol/L,总胆固醇为6.59mmol/L，均超过正常值，特别是血甘油三酯远超正常水平。日服用颗粒剂两次，每次2袋，每袋颗粒剂含有1250mg干浸膏粉A。经过一个疗程的治疗(14天)，甘油三脂降到1.01mmol/L，总胆固醇也降到4.77mmol/L，均恢复到正常值水平。
实施例5-3：
黄某，男，2017年在浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)就诊。戴某在就诊时血液甘油三脂为8.05mmol/L,总胆固醇为5.51mmol/L，均超过正常值，尤以甘油三酯升高为主。日服用颗粒剂两次，每次1袋，每袋颗粒剂含有1250mg干浸膏粉B。经过两个疗程治疗后，甘油三脂降到1.45mmol/L，回到正常水平。
实施例5-4：
俞某，男，2018年在浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)就诊。陈某在就诊时血液甘油三脂为7.13mmol/L,总胆固醇为4.51mmol/L，诊断为高甘油三酯血症。日服用颗粒剂两次，每次1袋，每袋颗粒剂含有1250mg干浸膏粉B。经过两个疗程治疗后，甘油三脂降到1.75mmol/L，基本回到正常水平。总胆固醇未有变化。
实施例5-5：
沈某，男，2017年在浙江湖州瑞博中医门诊部(浙江省湖州市梅州路322号)就诊。许某在就诊时血液甘油三脂为0.95mmol/L,总胆固醇为7.22mmol/L，诊断为高胆固醇血症。日服用颗粒剂两次，每次1袋，每袋颗粒剂含有1250mg干浸膏粉C。经过三个疗程治疗后，总胆固醇降到正常水平内4.91mmol/L。甘油三酯未有明显变化。
实施例6：动脉粥样硬化治疗典型病例
实施例6-1：
杨某，男，2019年在北京同義堂诊所(北京市昌平区中关村生命科学园4号楼1层)就诊，就诊时，杨某双侧颈总动脉及右侧锁骨上动脉硬化斑块形成，右侧颈总动脉形成多处斑块，最大着长16.5mm，厚3.9mm；同时右侧锁骨上动脉斑块形成。左侧颈总动脉形成多处斑块，最大着长3.5mm，厚1.6mm；右侧椎动脉管径2.8mm,平均血流速度0.21m/s，血流量77ml/min。
日服用颗粒剂两次，每次2袋，每袋颗粒剂含有1250mg干浸膏粉A。经过八个疗程，四个月的治疗，右侧颈总动脉硬化斑块变小和消失，最大着降低为长10.0mm，厚1.8mm；右侧锁骨上动脉硬化斑块消失，椎动脉管径变大(3.2mm)，血流速度(0.21m/s)和血流量均有明显提升(血流量从治疗前的到治疗后的135ml/min。
实施例6-2：
王某，男，40岁，2018年在北京同義堂诊所(北京市昌平区中关村生命科学园4号楼1层)就诊，就诊时，王某双侧颈总动脉动脉硬化斑块形成，左右颈动脉都有大约1.6mm的斑块形成。
日服用颗粒剂两次，每次2袋，每袋颗粒剂含有1250mg干浸膏粉A。服用六个疗程后(3个月的治疗)，左右侧颈总动脉均未见明显斑块形成，原诊断硬化斑块消失。

Claims (18)

  1. 一种中药组合物，其特征在于包括按以下重量份计的原料药：柴胡10-35份、枳实5-25份、生大黄3-20份，黄芩3-20份、白芍3-20份、干姜3-15份、水蛭5-20份、甘草3-20份、党参3-20份、白术3-20份、半夏3-25份。
  2. 根据权利要求1所述的中药组合物，其特征在于包括按以下重量份计的原料药：柴胡20-30份、枳实10-20份、生大黄5-15份，黄芩5-10份、白芍5-15份、干姜5-10份、水蛭7-15份、甘草5-15份、党参5-15份、白术5-15份、半夏10-20份。
  3. 根据权利要求1所述的中药组合物，其特征在于还进一步包括按以下重量份计的原料药：生牡蛎3-45份，优选10-35份。
  4. 根据权利要求3所述的中药组合物，其特征在于还进一步包括按以下重量份计的原料药：红曲3-15份，优选5-12份。
  5. 根据权利要求2所述的中药组合物，其特征在于由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份。
  6. 根据权利要求3所述的中药组合物，其特征在于由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份、生牡蛎30份。
  7. 根据权利要求4所述的中药组合物，其特征在于由按以下重量份计的原料药制成：柴胡25份、枳实15份、生大黄10份，黄芩6份、白芍10份、干姜6份、水蛭10份、甘草10份、党参10份、白术10份、半夏15份、生牡蛎30份、红曲10份。
  8. 根据权利要求1-7中任一项所述的中药组合物，其特征在于其为口服制剂。
  9. 根据权利要求8所述的中药组合物，其特征在于其为汤剂、颗粒剂、片剂或胶囊。
  10. 根据权利要求1-7中任一项所述的中药组合物的制备方法，其特征在于该制备方法包括称取原料药，第一次加水4-12倍量，在75-95℃保温30-120分钟，得到第一次煎煮液；第二次加水3-10倍量，在75-95℃保温30-120分钟，得到第二次煎煮液；合并二次煎煮液，滤过，合并滤液。
  11. 根据权利要求10所述的中药组合物的制备方法，其特征在于该制备方法包括称取原料药，第一次加水8倍量，煮沸80℃保温60分钟，得到第一次煎煮液；第二次加 水6倍量，煮沸后80℃保温60分钟，得到第二次煎煮液；合并二次煎煮液，滤过，合并滤液。
  12. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗血脂升高的药物中的应用。
  13. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗甘油三酯升高的药物中的应用。
  14. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗胆固醇升高的药物中的应用。
  15. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗高脂血症的药物中的应用。
  16. 根据权利要求1-7中任一项所述的中药组合物在制备预防或控制动脉粥样斑块形成的药物中的应用。
  17. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗动脉粥样硬化的药物中的应用。
  18. 根据权利要求1-7中任一项所述的中药组合物在制备预防或治疗慢性代谢性疾病的药物中的应用。
PCT/CN2021/072897 2020-02-26 2021-01-20 一种中药组合物及其制备方法和应用 WO2021169682A1 (zh)

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