WO2023025228A1 - 中药组合物及其制备方法和应用 - Google Patents

中药组合物及其制备方法和应用 Download PDF

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WO2023025228A1
WO2023025228A1 PCT/CN2022/114700 CN2022114700W WO2023025228A1 WO 2023025228 A1 WO2023025228 A1 WO 2023025228A1 CN 2022114700 W CN2022114700 W CN 2022114700W WO 2023025228 A1 WO2023025228 A1 WO 2023025228A1
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parts
chinese medicine
medicine composition
traditional chinese
composition according
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PCT/CN2022/114700
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French (fr)
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解渤
任雪峰
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苏州重生医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/618—Molluscs, e.g. fresh-water molluscs, oysters, clams, squids, octopus, cuttlefish, snails or slugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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 preparation of the traditional Chinese medicine composition for preventing or treating atherosclerotic plaque formation, ischemic heart disease, elevated blood lipids, and elevated triglycerides application in medicines.
  • Atherosclerosis is the main cause of coronary heart disease, myocardial infarction, cerebral infarction, ischemic heart disease and peripheral vascular disease.
  • the formation mechanism of atherosclerotic plaque is complex, involving many factors, including lipid metabolism disorder, cardiac smooth muscle damage, collagen fiber proliferation, inflammatory factor accumulation and so on. Plaque formation and sclerosis is thus a multi-mechanism, result of long-term lesion development.
  • Existing data show that the formation of atherosclerotic plaque begins with the injury of the arterial intima. Generally, lipids and complex sugars accumulate and hemorrhage first, and then fibrous tissue proliferates and settles, and there is gradual degeneration and calcification of the arterial media, leading to arterial hyperplasia.
  • carotid atherosclerotic plaques The main components of carotid atherosclerotic plaques are: (1) dense connective tissue fibrous cap, mainly composed of extracellular matrix (ECM), especially collagen fibers; (2) lipid core, composed of lipid macrophages, smooth muscle Cell and ECM composition; (3) New blood vessels in adventitia and plaque. Its characteristic is that the involved lesions often involve large and medium muscular arteries, and once they develop enough to block the arterial lumen, the tissues or organs supplied by the arteries will be ischemic or necrotic. Atherosclerotic plaques are called atherosclerotic plaques because of the yellow ather-like appearance of lipids that accumulate in the inner lining of arteries.
  • ECM extracellular matrix
  • Atherosclerotic cardiovascular and cerebrovascular diseases are also the number one cause of death.
  • atherosclerosis leads to coronary myocardial infarction and stroke accounted for the main proportion of death.
  • 2035 more than 130 million adults (45.1%) in the United States are expected to have some kind of cardiovascular disease, and the total cost of cardiovascular disease will be as high as $1.1 trillion.
  • Blood lipid is a general term for various lipids in the blood, the most important of which are cholesterol and triglycerides, triglycerides are also called neutral fats, and other important lipids include lipoproteins, including low-density lipoproteins and high-density lipoproteins. density lipoprotein.
  • the average blood cholesterol content of healthy people is between 2.8-5.17mmol/L, and the average blood triglyceride content is between 0.56-1.7mmol/L. Whether it is an increase in cholesterol content, an increase in triglyceride content, or an increase in both, it is collectively referred to as hyperlipidemia.
  • the prevalence of hyperemia is 13.1%, and the prevalence level shows a trend of increasing year by year. This poses a severe challenge to the treatment of dyslipidemia and the reduction of the risk of atherosclerotic plaque formation in my country.
  • Drugs targeting cardiovascular and cerebrovascular diseases based on traditional Chinese natural medicines mainly include Tongxinluo Capsules, Compound Danshen Dripping Pills, and Shexiang Baoxin Pills, etc., which are common drugs for the prevention and treatment of coronary heart disease and angina pectoris on the market.
  • Tongxinluo Capsules for blood lipids, there are Guangdong Hongxing Jiangzhi Pills, Chengdu Di'ao Zhibituo, Beijing Weixin Xuezhikang, etc. It can be seen from the instructions of these medicines that there are more or less certain side effects. But more critically, these drugs lack effective and verifiable prevention and ablation of arterial plaque. And it can be seen from literature reports that these drugs are usually recommended for long-term use, and used simultaneously with chemical lipid-lowering drugs, or mainly recommended for the elderly.
  • the object of the present invention is to provide a kind of traditional Chinese medicine composition, its preparation method and its preparation in the medicine that is used for preventing or treating atherosclerotic plaque formation, ischemic heart disease, blood lipid elevation, triglyceride elevation etc. application.
  • Clinical treatment practice shows that the traditional Chinese medicine composition of the present invention has an excellent effect of slowing down the formation of atherosclerotic plaque and removing atherosclerotic plaque.
  • Triglycerides have a good effect.
  • Studies on animal models of atherosclerotic plaque formation have shown that the traditional Chinese medicine composition has an obvious effect of ablation and reduction of arterial plaque.
  • the inventors of the present invention have studied traditional Chinese medicine and medicinal material theory for a long time, combined with clinical practice, and proposed a kind of medicine for preventing and treating atherosclerotic plaque formation, ischemic heart disease, blood lipid elevation, which is obviously different from modern medicine. Medication regimen for high, elevated triglycerides.
  • phlegm enters the blood. If you enter the context of modern medicine, it is similar to blood viscosity. Blood viscosity is not only the cause of hyperlipidemia and atherosclerosis, but also a symptom of phlegm and fluid entering the blood. Since the phlegm fluid entering the blood in traditional Chinese medicine is manifested as thick blood in modern medicine, we believe that its regulation and treatment is the core and effective way to prevent and treat hyperlipidemia and atherosclerosis.
  • Portion drink is defined in the “Emperor's Internal Classic” as the water from the meridian, which is a kind of body fluid in the circulation and metabolism.
  • the thicker body fluid is called phlegm, and the thinner one is called drink, collectively called phlegm drink .
  • Most of the "phlegm drink” in traditional Chinese medicine 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 excreted, it will continue to be produced from the digestive tract or respiratory tract Come out, endlessly.
  • blood viscosity In modern medicine, dozens of biochemical indicators are included under the concept of "blood viscosity". For example, some indicators of hyperlipidemia (serum total cholesterol, low-density cholesterol, high-density cholesterol, translipoprotein, triglycerides), some indicators of hyperglycemia (fasting blood glucose, glycosylated hemoglobin, fasting insulin, C-peptide, glycosylated serum protein , fructosamine), indicators of platelets (number of platelets, degree of platelet adhesion, degree of platelet sedimentation, etc.), some indicators of red blood cells (number of red blood cells, degree of erythrocyte sedimentation, degree of adhesion of red blood cells, degree of hematocrit, degree of 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
  • the invention provides a traditional 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 traditional 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 Radix Paeoniae Alba, 5-15 parts of dried ginger, and 7-15 parts of leech; more preferably, the traditional Chinese medicine composition of the present invention
  • the product comprises 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.
  • the traditional Chinese medicine composition of the present invention is made of the above-mentioned raw materials in parts by weight.
  • the invention provides a traditional 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, 3-20 parts of Atractylodes macrocephala.
  • the Chinese medicine composition of the present invention comprises the raw material drug by following parts by weight: raw rhubarb 5-15 parts, Radix Paeoniae Alba 5-15 parts, dried ginger 5-15 parts, leech 7-15 parts, Atractylodes macrocephala 5 parts -15 parts; more preferably, the traditional Chinese medicine composition of the present invention includes the following raw materials in parts by weight: 10 parts of raw rhubarb, 10 parts of Radix Paeoniae Alba, 10 parts of dried ginger, 10 parts of leeches, and 10 parts of Atractylodes macrocephala. Further preferably, the traditional Chinese medicine composition of the present invention is made of the above-mentioned raw materials in parts by weight.
  • the 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 Citrus aurantii, 3-20 parts of raw rhubarb, 3-20 parts of white peony root, dried ginger 3-20 parts, 3-25 parts of leech, 3-20 parts of Baizhu; 5-15 parts of Rhubarb, 5-15 parts of Radix Paeoniae Alba, 5-15 parts of Dried Ginger, 7-15 parts of Leech, 5-15 parts of Atractylodes Rhizome; more preferably, the Chinese medicine composition of the present invention comprises the following raw materials in parts by weight : Bupleurum 20 parts, Citrus aurantium 15 parts, raw rhubarb 10 parts, white peony root 10 parts, dried ginger 10 parts, leech 10 parts, Atractylodes macrocephala 10 parts. Further preferably, the traditional Chinese medicine composition of the present invention is made of the above-mentioned raw materials in parts by weight.
  • the 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 Citrus aurantii, 3-20 parts of raw rhubarb, 3-20 parts of white peony root, dried ginger 3-20 parts, 3-25 parts of leech, 3-20 parts of licorice, 3-20 parts of Atractylodes macrocephala, 3-45 parts of raw oyster; preferably, it contains the following raw materials in parts by weight: 15-30 parts of Bupleurum , 10-20 parts of Citrus aurantium, 5-15 parts of raw rhubarb, 5-15 parts of white peony, 5-15 parts of dried ginger, 7-15 parts of leech, 5-15 parts of licorice, 5-15 parts of Atractylodes macrocephala, 10 raw oysters -35 parts; more preferably, it comprises the raw material drug by following parts by weight: 20 parts of Bupleurum bupleuri, 15 parts of Citrus aurantium, 10 parts of raw rhubarb
  • the invention provides a traditional Chinese medicine composition, which includes the following raw materials in parts by weight: 5-35 parts of Bupleurum, 5-30 parts of Citrus aurantium, 3-20 parts of raw rhubarb, 1-20 parts of Scutellaria baicalensis, 3 parts of white peony -20 parts, 3-20 parts of dried ginger, 3-25 parts of leeches, 3-20 parts of licorice, 3-20 parts of Codonopsis pilosula, 3-20 parts of Atractylodes macrocephala, 3-45 parts of raw oysters; preferably, the Chinese medicine composition of the present invention , comprising the following raw materials in parts by weight: 15-30 parts of Bupleurum bupleuri, 10-20 parts of Citrus aurantii, 5-15 parts of raw rhubarb, 2-10 parts of Scutellaria baicalensis, 5-15 parts of white peony root, 5-15 parts of dried ginger 7-15 parts, 7-15 parts of leeches, 5-15 parts of licorice, 5-15 parts of Codonopsis
  • the invention provides a traditional Chinese medicine composition, which includes 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 licorice 20 parts, 3-45 parts of raw oysters, 3-20 parts of paeonol, 2-15 parts of peach kernels; 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 paeonol, 3-12 parts of peach kernel, 5-15 parts of white peony, 7-15 parts of leech, 5-15 parts of licorice, 10-35 parts of raw oyster; more preferably,
  • the traditional 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 leeches, 10 parts of licorice, 30 parts of raw oysters
  • parts are parts by weight, and the weight is calculated based on crude drugs. It can be increased or decreased according to the corresponding proportion during production.
  • the unit of kilogram or ton can be used for large-scale production, and the weight can be increased or decreased, but the weight ratio of raw medicinal materials between the components is not the same. Change.
  • Bupleurum the medicinal part is the dried root of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd. It has the effects of reconciling the exterior and interior, soothing the liver and promoting yang.
  • Citrus aurantium is the dry young fruit of Rutaceae lime and its cultivars or sweet orange (Immature Bitter Orange, Immature Sweet Orange, Fructus Aurantii Immaturus). It has the effects of dispelling qi and eliminating stagnation, resolving phlegm and dissipating ruffian.
  • Raw rhubarb this product is the dry root and rhizome of Rheum palmatum L., Rheum tanguticum Maxim.ex Balf., or medicinal rhubarb (Rheum officinale Baill.). It has the effects of purging heat and poison, breaking stagnant stagnation, and promoting blood stasis.
  • Scutellaria baicalensis the dry 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 detoxification, stopping bleeding, and preventing miscarriage.
  • Radix Paeoniae Alba is the dry root of Paeonia lactiflora Pall. It has the effects of warming the yang and removing dampness, replenishing the deficiency, and invigorating the spleen and stomach.
  • Dried ginger is the dry rhizome of Zingiber oj-jicinale Rosc. Excavated in winter, remove fibrous roots and sediment, and dry in the sun or at low temperature. Those who take fresh slices and dry them in the sun or at low temperature are called “dried ginger slices”. It has the effects of warming the middle and dispelling the cold, returning to the yang and dredging the veins, warming the lungs and transforming the drink.
  • Leeches are the dried whole body of leeches (Whitm.ania Pigra Whitman), leeches (Hirudo nipponica Whitman) or willow leaf leeches (Whitmania acranutata Whitman) of the leech family. It is caught in summer and autumn, scalded to death with boiling water, and dried in the sun or at low temperature. It has the effects of removing blood stasis and promoting menstrual flow, removing blood stasis and eliminating symptoms.
  • Licorice (Glycyrrhiza uralensis Fisch), alias: old country, sweet grass, Ural licorice, sweet root.
  • Legumes and licorice are perennial herbs, and the medicinal parts are roots and rhizomes. It is used for deficiency of heart qi, palpitations, intermittent pulse, deficiency of spleen and stomach qi, fatigue and fatigue, and to reconcile the potency of certain drugs and the reaction to the gastrointestinal tract.
  • Codonopsis Codonopsis is the dry root of Codonopsis Codonopsis, Suhua Codonopsis, or Sichuan Codonopsis. It has the effects of nourishing the middle, replenishing qi, and promoting body fluid.
  • Atractylodes macrocephala the dry rhizome of Atractylodes macrocephala Koidz. It has the effects of invigorating the spleen and replenishing qi, drying dampness and diuresis, and antiperspirant.
  • Raw oysters are the shells of Ostrea gigas Thunberg, Ostrea talienwhanensis Crosse or Ostrea rivularis Gould. It has the effects of calming the nerves, suppressing yang and nourishing yin, softening and resolving hard masses.
  • Tree Peony Bark also known as Moutan Bark, the name of traditional Chinese medicine, is the dry root bark of the perennial deciduous small shrub plant Paeonia suffruticosa Andr. of the family Ranunculaceae Paeoniae. It has anti-inflammation, inhibition of platelets, central nervous system inhibition and anti-atherosclerosis.
  • Peach kernel is the dry mature seed of Prunus persica (L.) Batsch or Prunus davidiana (Carr.) Franch. It has the effects of promoting blood circulation and removing blood stasis, moistening the intestines and laxative, relieving cough and relieving asthma.
  • the prescription of the present invention is formed on the basis of sufficient research on Shanghanlunjing prescriptions and corresponding medicinal materials, combined with clinical practice.
  • ischemic cardiovascular and cerebrovascular diseases belong to the category of "vertigo" and "chest pain”.
  • the most common cause is stagnation of qi and blood stasis or insufficient qi and blood, and poor blood flow caused by weak blood push, which leads to insufficient blood supply and oxygen supply to the cardiovascular and cerebrovascular vessels, resulting in symptoms of chest tightness, chest pain, and dizziness.
  • the main prescription of this medicine is to remove phlegm, and phlegm is the first of internal evils.
  • the main pathogenesis of arterial plaque is the disease caused by blood viscosity, lipodystrophy and arterial inflammatory reaction.
  • clear blood Phlegm drinking is the main work.
  • this prescription achieves the state of relieving blood viscosity, conducts Qi conduction stagnation and lowers turbidity, gradually removes arterial plaques, and achieves the curative effect of significantly improving the symptoms of ischemic heart and brain diseases.
  • raw rhubarb and Bupleurum are used as monarch drugs
  • dried ginger raw Atractylodes macrocephala
  • Codonopsis pilosula are used as ministerial drugs
  • leeches raw oysters
  • white peony root white peony root
  • citrus aurantium scutellaria baicalensis
  • paeonol peach kernels are used as adjuvant drugs
  • licorice is used as adjuvant drugs. medicine.
  • the traditional Chinese medicine composition of the present invention can obtain pharmaceutical active substances through extraction or other known methods in the art.
  • the pharmaceutical active substance can be obtained by extracting natural compound drug raw materials separately, or by jointly extracting natural compound drug raw materials.
  • the preparation method of the traditional Chinese medicine composition of the present invention comprises weighing the crude drug, adding 4-12 times the amount of water for the first time, and incubating at 70-95°C, preferably 70-85°C, for 30-120 minutes to obtain the first decoction Boil liquid; add 3-10 times the amount of water for the second time, keep warm at 70-95°C, preferably 70-85°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 comprises weighing the crude 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 decoction for the first time; adding water for the second time 6 times the amount, boiled and kept at 80°C or 75°C for 60 minutes to obtain the second decoction; combine the second decoction, filter, and combine the filtrates.
  • the obtained extract can be further concentrated into the form of extract, which can be dry extract or liquid extract. It is preferably 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 also be prepared by adding pharmaceutically acceptable carriers if necessary.
  • the pharmaceutical active substance extracted or processed from 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 medicine composition of the present invention can be any pharmaceutically acceptable dosage form, and these dosage forms include: decoction, tablet, sugar-coated tablet, film-coated tablet, enteric-coated tablet, capsule, hard capsule, soft capsule, Oral liquids, buccal preparations, granules, granules, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches agent. Oral dosage forms are preferred, and decoctions, capsules, tablets, oral liquids, granules, pills, powders, elixirs, ointments, etc. are more preferred. Decoctions, granules, capsules and tablets are most preferred.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines 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 atherosclerotic plaque.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating atherosclerotic plaque-ischemic heart and brain diseases.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating hyperlipidemia.
  • 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 medicaments for preventing or treating elevated cholesterol.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating hyperlipidemia.
  • the present invention further provides the application of the traditional Chinese medicine composition in the preparation of medicines for preventing or treating chronic metabolic diseases.
  • the present invention further provides a method for preventing or controlling the formation of vascular plaque, which comprises administering a preventive or therapeutic effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating atherosclerotic plaque, comprising administering a preventive or therapeutically effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating atherosclerotic ischemic heart and brain diseases, which comprises administering a preventive or therapeutic effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating elevated blood lipids, comprising administering a preventive or therapeutically effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating elevated triglycerides, comprising administering a preventive or therapeutically effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating elevated cholesterol, which comprises administering a preventive or therapeutically effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating hyperlipidemia, comprising administering a preventive or therapeutic effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the present invention further provides a method for preventing or treating chronic metabolic diseases, comprising administering a preventive or therapeutically effective amount of the above-mentioned traditional Chinese medicine composition of the present invention to a person in need.
  • the traditional Chinese medicine composition of the present invention can be taken one to three times a day for 14 days as a course of treatment, and the treatment of patients with atherosclerotic plaque requires 6-12 courses of treatment, and the drug is stopped for 3 days between each course of treatment.
  • 1-10 doses are administered each time.
  • the traditional Chinese medicine composition of the present invention can be concentrated and dried to obtain dry extract powder, and then an appropriate amount of auxiliary materials can be added to make granules, which can be taken one to three times a day, 1-2 doses each time, or can be packed into Capsules or tablets, take one to three times a day, 2-8 capsules or tablets each time, the specific usage and dosage can be adjusted according to the actual situation of the patient.
  • the traditional Chinese medicine formula of the present invention is an innovative construction based on the theory and practice of "phlegm drink enters the blood" and Treatise on Febrile Diseases.
  • the inventors of the present invention have formed the formula and determined the proportion of the components on the basis of fully studying and considering the properties and efficacy of the components of the Chinese herbal medicines, combined with clinical practice.
  • the traditional Chinese medicine composition of the invention has obvious clinical effects on preventing the occurrence and progression of atherosclerotic plaques and ablating atherosclerotic plaques.
  • Clinical treatment practice also shows that the traditional Chinese medicine formula of the present invention has an excellent effect of lowering blood lipids, especially for cases with severe elevated blood triglycerides (triglyceride>5.6mmol/L), the effect of lowering blood triglycerides is particularly obvious.
  • Fig. 1 has shown the body weight change of mice after applying various doses of A sample group of the present invention and model control group;
  • Fig. 2 has shown the body weight change of mice after applying various doses of the B sample group of the present invention and the model control group;
  • Fig. 3 has shown the body weight change of mice after applying various doses of the C sample group of the present invention and the model control group;
  • Fig. 4 has shown the body weight change of mice after applying various doses of D sample group of the present invention and model control group;
  • Figure 5 shows the plaque area and arterial lumen area ratio of mice after applying each sample group of the present invention, model control group and rosuvastatin positive group;
  • Figure 6 shows the number of atherosclerotic plaques in mice after applying each sample group, model control group and rosuvastatin positive group of the present invention
  • Figure 7 shows the changes in the atherosclerotic plaques of mice after applying various doses of A and B sample groups of the present invention, normal group 1, model group 1, and rosuvastatin intervention group 1;
  • Figure 8 shows the changes in the atherosclerotic plaques of mice after application of various doses of C and D sample groups of the present invention, normal group 2, model group 2, and rosuvastatin intervention group 2;
  • Figure 9 shows the plaque area and arterial lumen area ratio of mice after applying the A sample group of the present invention by different doses
  • Figure 10 shows the plaque area and arterial lumen area ratio of mice after applying the B sample group of the present invention by different doses
  • Figure 11 shows the plaque area and arterial lumen area ratio of mice after applying the C sample group of the present invention by different doses
  • Fig. 12 shows the ratio of plaque area to arterial lumen area of mice after applying the D sample group of the present invention according to different doses.
  • test methods in the following examples are conventional methods; the raw materials, reagent materials, etc. used in the following examples, unless otherwise specified, are commercially available products.
  • the amount of solvent used in the preparation process of each test drug is the volume multiple based on the weight of the medicinal material.
  • Sample A Weigh the following raw materials: 20 parts of Bupleurum, 15 parts of Citrus aurantium, 10 parts of raw rhubarb, 10 parts of white peony, 10 parts of dried ginger, 10 parts of leech, 10 parts of Atractylodes macrocephala, boil them twice in a closed 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; Cook the liquid, filter, and combine the filtrates. Divide the filtrate into 14 equal volumes, provide a 7-day supply, and store at 4°C.
  • Sample B Weigh the following raw materials: Bupleurum 20g, Citrus aurantium 15g, Raw Rhubarb 10g, Scutellaria baicalensis 3g, Paeoniae Alba 10g, Dried ginger 10g, Leech 10g, Licorice 10g, Codonopsis 10g, Atractylodes macrocephala 10g, Raw oyster 30g, put in airtight Boil twice in the container, add 8 times the amount of water for the first time, heat it at 75 degrees Celsius for 60 minutes after boiling, and get the decoction liquid; liquid; combine the second decoction liquid, filter, and combine the filtrate. Divide the filtrate into 14 equal volumes, provide a 7-day supply, and store at 4°C.
  • Sample C Weigh the following raw materials: bupleurum 20g, citrus aurantium 15g, raw rhubarb 10g, white peony root 10g, dried ginger 10g, leech 10g, licorice 10g, atractylodes macrocephala 10g, raw oyster 30g, boil and extract twice in a closed 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; Cook the liquid, filter, and combine the filtrates. Divide the filtrate into 14 equal volumes, provide a 7-day supply, and store at 4°C.
  • Sample D Weigh the following raw materials: 10g of raw rhubarb, 10g of white peony, 10g of dried ginger, 10g of leech, 10g of licorice, 10g of paeonol, 6g of peach kernel, and 30g of raw oyster. Add 8 times the amount of water, 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, and heat it at 70 degrees Celsius for 60 minutes after boiling to obtain the second decoction; combine the second decoctions, filter and combine the filtrates. Divide the filtrate into 14 equal volumes, provide a 7-day supply, and store at 4°C.
  • Example 2 Typical cases of atherosclerosis treatment
  • Animal source ApoE -/- mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. (production license number: SCXK (Su) 2018-0008). Animal certificate number: 99822700020300, 320727210100778554, experiment certificate number: 00293582.
  • Feeding management Animals were kept in the SPF grade animal room of the Experimental Animal Center of Zhuhai Baishitong Biotechnology Co., Ltd.
  • Animal feeding conditions 4 animals/cage in groups, feeding temperature and humidity: 20-26°C, 40-70%, with 12h:12h day and night intermittent lighting; the conditions in the feeding room are always kept stable to ensure the reliability of the test results.
  • the animals were fed with the corresponding pellet feed according to the experimental requirements, and the common feed was provided by Jiangsu Medison Biomedical Co., Ltd. Animals had free access to food and water.
  • Ear tagging method is adopted, and the ear tag number cage is identified with double number marks.
  • Quarantine observation Quarantine for purchased animals for 7 days. During this period, the animals were checked once a day, and any unhealthy animals were found to be removed immediately, and healthy animals were selected for experiments.
  • Dosage design basis request of the entrusting party.
  • Super high dose of sample A (0.521g/ml): Accurately weigh 2.13g of sample A, add 15ml of purified water, and stir well to obtain a 0.521g/ml super high dose suspension of sample A.
  • Sample A high dose (0.261g/ml): Take 4ml of sample A super high dose suspension, add 4ml of purified water, stir evenly to obtain 0.261g/ml sample A high dose suspension.
  • Sample A low dose (0.065g/ml): Take 1ml of sample A super high dose suspension, add 7ml of purified water, stir well, 0.065g/ml sample A low dose suspension.
  • Sample B ultra-high dose (0.521g/ml): Accurately weigh 2.7g of sample B, add 15ml of pure water, stir well, and obtain 0.521g/ml sample B ultra-high dose suspension.
  • Sample B high dose (0.261g/ml): take 4ml of sample B super high dose suspension, add 4ml of purified water, stir well, and obtain 0.261g/ml sample B high dose suspension.
  • Sample B low dose (0.065g/ml): Take 1ml of sample B ultra-high dose suspension, add 7ml of purified water, stir well, 0.065g/ml sample B low dose suspension.
  • Super high dose of sample C (0.521g/ml): Accurately weigh 1.23g of sample C, add 15ml of purified water, and stir well to obtain a 0.521g/ml super high dose suspension of sample C.
  • Sample C high dose (0.261g/ml): Take 4ml of sample C ultra high dose suspension, add 4ml of purified water, stir evenly to obtain 0.261g/ml sample C high dose suspension.
  • Sample C low dose (0.065g/ml): Take 1ml of sample C super high dose suspension, add 7ml of purified water, stir well, 0.065g/ml sample C low dose suspension.
  • Super high dose of sample D (0.521g/ml): Accurately weigh 2.22g of sample D, add 15ml of purified water, and stir well to obtain a 0.521g/ml super high dose suspension of sample D.
  • Sample D high dose (0.261g/ml): take 4ml of sample D ultra high dose suspension, add 4ml of purified water, stir evenly to obtain 0.261g/ml sample D high dose suspension.
  • Sample D low dose (0.065g/ml): take 1ml sample D super high dose suspension, add 7ml of purified water, stir well, 0.065g/ml sample D low dose suspension.
  • Rosuvastatin (0.33mg/ml): Take 1 tablet of rosuvastatin, grind it into powder, add 30ml of purified water, stir to dissolve, shake well before administration Dose design and grouping
  • 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 content, 10 crude protein, crude fat, crude fiber, crude ash, calcium, phosphorus, calcium phosphorus of the model feed must meet the national standards for maintaining feed. Provided by the Experimental Animal Center of Zhuhai Baishitong Company.
  • mice in the positive control group and each test sample group were given the corresponding drug solution by gavage at 20mL/kg body weight every day, and the model control group was given the same volume of purified water, once a day, for 60 days in a row .
  • Table 1 The mice in the positive control group and each test sample group were given the corresponding drug solution by gavage at 20mL/kg body weight every day, and the model control group was given the same volume of purified water, once a day, for 60 days in a row .
  • Body weight body weight was measured once at the beginning of the test and at the end of the test, and once a week during the test. Calculate the weight gain of animals after administration for 30 days (administration D29-administration D1) and 60 days after administration (administration D60-administration D1).
  • TC and TG levels 30 days, 60 days and 90 days after modeling, each animal was not fasted, blood was collected from the fundus venous plexus after anesthesia, centrifuged at 3000 rpm for 10 minutes, serum was separated, and TC and TG levels were measured.
  • LDL and HDL levels On the 60th and 90th days of modeling, each animal was not fasted, blood was collected from the fundus venous plexus after anesthesia, centrifuged at 3000rpm for 10min, the serum was separated, and the levels of LDL and HDL were measured.
  • CRP C-reactive protein
  • Tissue preservation After blood collection, animals were sacrificed by exsanguination and serum was collected. All experimental animals were grossly dissected, and heart, liver, kidney and brain tissues were collected. Among them, the heart, some liver, kidney and brain tissues were fixed as tissue samples, and the remaining tissues were cryopreserved. Histopathological examination should be performed when other tissues and organs change in volume, color, texture, etc.
  • the body weight of the rosuvastatin positive group and each sample group decreased from the second week, and the body weight changes in some weeks had statistical differences (P ⁇ 0.05).
  • the impact of rosuvastatin positive group on body weight was more obvious than that of each sample treatment group.
  • no dose-response relationship was observed in each sample treatment group, indicating that changes in body weight had nothing to do with the administered dose.
  • the TC value of the mice in the ultra-high dose group of sample A was higher than that of the model control group at D30, with a statistical difference (P ⁇ 0.05). There was no statistical difference in the TC values of mice in other administration groups compared with the model control group at each time point (P>0.05).
  • the TG value of the mice in the ultra-high dose group of sample A was higher than that of the model control group at D30, with a statistical difference (P ⁇ 0.05).
  • the TG value of the 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 of the model control group at D60, with a statistical difference (P ⁇ 0.05).
  • the HDL value of the mice in the sample A ultra-high dose group was higher than that of the model control group at D60, and the HDL-C value of the mice in the rosuvastatin group was lower than that of the model control group at D30, with a statistical difference (P ⁇ 0.05).
  • the HDL-C value of the mice in the ultra-high dose group of D was higher than that of the model control group at D30, with a statistical difference (P ⁇ 0.05).
  • P>0.05 there was no statistical difference in the HDL values of mice in other administration groups at each time point
  • mice in sample B low-dose group and sample B ultra-high-dose group were lower than those of the model control group at D60, with statistical difference (P ⁇ 0.05).
  • CRP value of mice in sample C medium dose group, sample C high dose group, sample C super high dose group, sample D low dose group, sample D medium dose group, sample D high dose group, sample D super high dose group mice at D60 It was lower than the model control group, with statistical difference (P ⁇ 0.05), and there was no statistical difference in the CRP values of mice in other administration groups at each time point compared with the model control group (P>0.05).
  • the hearts, livers, kidneys, and brains of ApoE -/- mice in the model control group showed varying degrees of inflammatory reactions.
  • the degree of lesion was close to that of the model control group. No other pathological changes were observed in each group.
  • the degree of atherosclerotic plaque formation in the positive treatment group and each sample treatment group showed a tendency to alleviate, and the plaque area decreased, and the average plaque area of some groups was the same as that of the model.
  • the control group there was a significant difference (P ⁇ 0.01 or P ⁇ 0.05).
  • the mice in the four dose groups of sample B showed a more obvious dose-effect relationship on the area of atherosclerotic plaque in the arterial arch ( FIG. 8 ). No significant dose-effect relationship was observed in other groups. No significant dose-response relationship was observed for the number of atheromas in each group.
  • experimental samples A, B, C, and D all showed relatively obvious effects of preventing and ablating arterial plaque.
  • sample B showed an obvious dose-effect relationship for the removal of arterial plaque.
  • sample B has the effect of significantly lowering the blood TG value.
  • Sample D showed an obvious effect of inhibiting inflammatory response.
  • the CRP value was significantly reduced in each dose group.

Abstract

一种中药组合物及其制备方法和应用。中药组合物包括按以下重量份计的原料药：柴胡5-35份、枳实5-30份、生大黄5-20份、黄芩1-20份、白芍3-20份、干姜3-20份、水蛭3-25份、甘草3-20份、党参3-20份、白术3-20份、生牡蛎3-45份。中药组合物具有优良的预防或治疗动脉粥样斑块形成、缺血性心脑疾病、血脂升高、甘油三酯升高的良好效果。

Description

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动脉粥样斑块形成、缺血性心脏病、血脂升高、甘油三酯升高的药物中的应用。
背景技术
动脉粥样斑块形成和硬化(atherosclerosis，AS)是冠心病、心梗、脑梗、缺血性心脏病和外周血管病的主要原因。动脉粥样斑块的形成机制复杂，牵扯的因素非常多，包括脂质代谢障碍，心脏平滑肌的损伤，胶原纤维增生，炎性因子聚集等等。因此斑块形成和硬化是一个多机制，长期病变发展的结果。现有资料表明，动脉粥样斑块的形成从动脉内膜损伤开始，一般先有脂质和复合糖类积聚、出血，进而纤维组织增生沉着，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。颈动脉粥样硬化斑块的成分主要有：⑴致密结缔组织纤维帽，主要由细胞外基质(extracellular matrix，ECM)组成，尤其是胶原纤维；⑵脂质核心，由脂质巨噬细胞、平滑肌细胞和ECM组成；⑶外膜和斑块内的新生血管。其特点是受累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斑块。
卫生部《2016年中国卫生统计提要》中显示，中国人死亡原因中，约30％死于心脑血管病，而这些心脑血管病患者，绝大多数死于动脉粥样斑块形成导致的心脑血管疾病。中国心血管健康与疾病报告编写组在中国循环杂志《中国心血管健康与疾病报告2019摘要》中报告，中国心血管病患病率处于持续上升阶段。推算心血管病现患人数3.30亿，每5例死亡，就有2例死于心脑血管病。动脉粥样硬化性心脑血管疾病因此被称为人类“头号杀手”，是影响我国人群健康的首位致病原因。
在世界许多国家，特别是发达国家，动脉粥样硬化性心脑血管疾病也是导致死亡的首位原因。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。
一般认为，血脂代谢异常、高血脂在动脉粥样斑块形成中具有重要作用，是核心病变基础之一。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2019年发布的《中国心血管健康与疾病报告2019》显示，4亿国人血脂异常，患病率达40.40％，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％，患病率水平呈现逐年增加的趋势。这对我国治疗血脂异常，降低动脉粥样斑块形成风险工作提出严峻的挑战。
目前世界上无特异有效预防治疗动脉粥样斑块的药物。治疗高脂血症，因此是目前临床上，预防动脉粥样斑块形成主要的临床治疗措施之一。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，对降低动脉粥样硬化性心脑血管疾病引起的死亡作用有限。
以中国传统天然药物为基础的针对心脑血管疾病的药物，主要有通心络胶囊、复方丹参滴丸、以及麝香保心丸等，均是市面上常见的防治冠心病、心绞痛药物。针对血脂的有广东宏兴降脂丸、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。但更为关键的是，这些药物缺乏有效和可被验证的预防和消融动脉斑块的作用。且从文献报道可见，这些药通常建议长期使用，并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动脉粥样斑块、缺血性心脏病、血脂升高、甘油三酯升高等的传统中药药物有强烈的临床需求，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，其制备方法及其制备在用于预防或治疗动脉粥样斑块形成、缺血性心脏病、血脂升高、甘油三酯升高等的药物中的应用。临床治疗实践显示，本发明中药组合物具有优良的减缓动脉粥样斑形成，并清除动脉粥样斑块的效果，同时，临床治疗实践也显示本发明中药组合物对于降低血脂，特别是降低血甘油三酯拥有良好效果。动脉粥样斑块形成动物模型研究显示，本中药组合物具有明显的消融减小动脉斑块的效果。
本发明发明人经长期钻研中国传统医学和药材理论，并结合临床实践，提出了一种明显有别于现代医学的用于预防和治疗动脉粥样斑块形成、缺血性心脏病、血脂升高、甘油三酯升高的药物的用药方案。我们认为，高血脂和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。但中国传统医学对于痰饮进入血液与血液黏稠的联系和论述欠缺。
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。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，开发了高效和长效用于预防或粥样动脉斑块形成、缺血性心脏病、血脂升高、甘油三酯升高的中药组合物。
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：生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份；优选地，本发明中药组合物包含按以下重量份计的原料药：生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份；更优选地，本发明中药组合物包含按以下重量份计的原料药：生大黄10份、白芍10份、干姜10份、水蛭10份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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：生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份、白术3-20份；优选地，本发明中药组合物包含按以下重量份计的原料药：生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份、白术5-15份；更优选的，本发明中药组合物包括按以下重量份计的原料药：生大黄10份、白芍10份、干姜10份、水蛭10份、白术10份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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5-35份、枳实5-30份、生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份、白术3-20份；优选地，本发明中药组合物包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份、白术5-15份；更优选地，本发明中药组合物包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、白芍10份、干姜10份、水蛭10份、白术10份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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5-35份、枳实5-30份、生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份、甘草3-20份、白术3-20份、生牡蛎3-45份；优选地，其包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份、甘草5-15份、白术5-15份、生牡蛎10-35份；更优选地，其包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、白芍10份、干姜10份、水蛭10份、甘草10份、白术10份、生牡蛎30份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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5-35份、枳实5-30份、生大黄3-20份、黄芩1-20份、白芍3-20份、干姜3-20份、水蛭3-25份、甘草3-20份、党参3-20份、白术3-20份、生牡蛎3-45份；优选地，本发明中药组合物，包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、黄芩2-10份、白芍5-15份、干姜5-15份、水蛭7-15份、甘草5-15份、党参5-15份、白术5-15份、生牡蛎10-35份；更优选地，本发明中药组合物，包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、黄芩3份、白芍10份、干姜10份、水蛭10份、甘草10份、党参10份、白术10份、生牡蛎30份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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：生大黄3-20份、干姜3-20份、白芍3-20份、水蛭3-25份、甘草3-20份、生牡蛎3-45份、丹皮3-20份、桃仁2-15份；优选地，本发明中药组合物，其包含按以下重量份计的原料药：生大黄5-15份、干姜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、生牡蛎10-35份；更优选地，本发明中药组合物，其包括按以下重量份计的原料药：生大黄10份、干姜10份、白芍10份、水蛭10份、甘草10份、生牡蛎30份、丹皮10份、桃仁6份。进一步优选地，本发明中药组合物由按如上所述重量份的原料药制成。
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。
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。
丹皮(Tree Peony Bark)，又名牡丹皮，中药名，为毛茛科芍药属植物多年生落叶小灌木植物牡丹Paeonia suffruticosa Andr.的干燥根皮。有抗炎，抑制血小板，中枢抑制作用及抗动脉粥样硬化等作用。
桃仁，为蔷薇科植物桃Prunus persica(L.)Batsch或山桃Prunus davidiana(Carr.)Franch.的干燥成熟种子。具有活血祛瘀，润肠通便，止咳平喘的功效。
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。中医理论中，缺血性心脑血管疾病属于“眩晕”“胸痹”的范畴。最常见的原因是气滞血瘀或气血不足，血液推动乏力而导致的血流运行不畅，从而导致心脑血管供血、供氧不足而出现胸闷、胸痛、眩晕的症状。本药主要立方是为了去痰饮，痰饮是内邪之首，动脉斑块的主要病机就是由于血液黏稠，脂肪代谢障碍和动脉炎性反应引发的疾病，为了清除动脉斑块，清除血中痰饮是主要工作。本方通过组方中药药物达到解除血液粘稠的状态，行气导滞降浊，逐渐清除动脉斑块，达到显著改善缺血性心脑疾病的症状的疗效。
本方以生大黄和柴胡共同为君药，以干姜、生白术、党参为臣药，以水蛭、生牡蛎、白芍、枳实、黄芩，或丹皮，桃仁为佐药，以甘草为使药。
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70-95℃，优选70-85℃保温30-120分钟，得到第一次煎煮液；第二次加水3-10倍量，在70-95℃，优选70-85℃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，煮沸后在80℃或75℃保温60分钟，得到第一次煎煮液；第二次加水6倍量，煮沸后在80℃或75℃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斑块的药物中的应用。
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斑块缺血性心脑疾病的药物中的应用。
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斑块的方法，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斑块性缺血性心脑疾病的方法，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14天为一个疗程，动脉粥样斑块病人的治疗需要6-12各疗程，在每个疗程间停药3天。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中药材组分性质和功效的基础上，结合临床实践而形成了本配方，并确定了组分配比。本发明中药组合物对预防动脉粥样斑块发生和进展，消融动脉粥样软斑块临床效果明显。临床治疗实践也显示，本发明中药配方具有优良的降低血脂，特别是对重度血甘油三酯升高(甘油三酯>5.6mmol/L)的病例，降低血甘油三酯的效果尤其明显。
附图说明
图1显示了应用本发明的A样品组各种不同剂量与模型对照组之后小鼠的体重变化；
图2显示了应用本发明的B样品组各种不同剂量与模型对照组之后小鼠的体重变化；
图3显示了应用本发明的C样品组各种不同剂量与模型对照组之后小鼠的体重变化；
图4显示了应用本发明的D样品组各种不同剂量与模型对照组之后小鼠的体重变化；
图5显示了应用本发明各样品组、模型对照组和瑞舒伐他汀阳性组之后小鼠的斑块面积与动脉管腔面积比；
图6显示了应用本发明各样品组、模型对照组和瑞舒伐他汀阳性组之后小鼠的动脉粥样斑块数目；
图7显示了应用本发明的A、B样品组各种不同剂量、正常组1、模型组1、和瑞舒伐他汀干预组1之后小鼠的动脉粥样斑块变化情况；
图8显示了应用本发明的C、D样品组各种不同剂量、正常组2、模型组2、和瑞舒伐他汀干预组2之后小鼠的动脉粥样斑块变化情况；
图9显示了按不同剂量应用本发明的A样品组之后小鼠的斑块面积与动脉管腔面积比；
图10显示了按不同剂量应用本发明的B样品组之后小鼠的斑块面积与动脉管腔面积比；
图11显示了按不同剂量应用本发明的C样品组之后小鼠的斑块面积与动脉管腔面积比；
图12显示了按不同剂量应用本发明的D样品组之后小鼠的斑块面积与动脉管腔面积比。
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
样品A：称取如下原料药：柴胡20份、枳实15份、生大黄10份、白芍10份、干姜10份、水蛭10份、白术10份，置密闭容器内煮提两次，第一次加水8倍量，煮沸后75摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后70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。滤液等体积分为14份，提供7天的用量，4摄氏度保存。
样品B：称取如下原料药：柴胡20g、枳实15g、生大黄10g、黄芩3g、白芍10g、干姜10g、水蛭10g、甘草10g、党参10g、白术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75摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后70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。滤液等体积分为14份，提供7天的用量，4摄氏度保存。
样品C：称取如下原料药：柴胡20g、枳实15g、生大黄10g、白芍10g、干姜10g、水蛭10g、甘草10g、白术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75摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后70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。滤液等体积分为14份，提供7天的用量，4摄氏度保存。
样品D：称取如下原料药：生大黄10g、白芍10g、干姜10g、水蛭10g、甘草10g、丹皮10g、桃仁6g、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75摄氏度保温60分钟，得到煎煮液；第二次加水6倍量，煮沸后70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。滤液等体积分为14份，提供7天的用量，4摄氏度保存。
实施例2：动脉粥样硬化治疗典型病例
实施例2-1：
陈某，男，2021年期间，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，陈某双侧颈总动脉硬化斑块形成，明显的有6个斑块，大小分别为斑块1(15.2*1.6mm)、斑块2(10.7*2.0mm)、斑块3(10.2*2.1mm)、斑块4(5.5*1.0mm)、斑块5(5.8*1.6mm)和斑块6(5.5*1.7mm)。早晚饭后，各服用如上实施例样品B准备的滤液一份。经过7个疗程(14天/每疗程)的治疗，双侧颈总动脉硬化斑块变小或消失，其中斑块4、5、6三个斑块完全消失，另外三个斑块1、2、3显著减小，大小分别减小为8.8*2.4mm、7*2.4mm和6.8*1.7mm。
实施例2-2：
李某，女，65岁，2020-2021年期间，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，李某双侧颈总动脉硬化斑块形成，明显的有4个斑块，大小分别为斑块1(12.1*2.6mm)、斑块2(10.2*2.0mm)、斑块3(10.0*1.9mm)和斑块4(5.6*2.0mm)。早晚饭 后，各服用如上实施例样品B准备的滤液一份。经过12个疗程(14天/每疗程)的治疗，双侧颈总动脉硬化斑块变小或消失，其中斑块2、4这两个斑块完全消失，剩下的两个斑块1和3显著减小，大小分别减小为3.9*2.5mm和2.6*2.1mm。
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：以ApoE -/-小鼠建立动脉粥样硬化模型，探究受试样品治疗动脉粥样硬化的效果。
3.2.供试品
3.2.1.CS001-样品A；实施例1-1中制得的干浸膏粉样品1。性状：棕色粉末；保存条件：2—8，干燥。
3.2.2.CS001-样品B；实施例1-1中制得的干浸膏粉样品2。性状：棕色粉末；保存条件：2—8、干燥。
3.2.3.CS001-样品C；实施例1-1中制得的干浸膏粉样品3。性状：棕色粉末；保存条件：2—8、干燥。
3.2.4.CS001-样品D；实施例1-1中制得的干浸膏粉样品4。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：
名称：纯净水
生产厂家：珠海百试通生物科技有限公司；
3.5主要仪器与试剂
离心机，型号：TG16WS；湖南湘仪实验室仪器开发有限公司产品；
ME104E电子分析天平，感量：0.1mg，瑞士梅特勒托利多公司；
电子天平，感量：0.1g，型号：JE2001；上海浦春计量仪器有限公司。
TC、TG、HDL-C、LDL-C试剂盒：上海科华生物工程股份有限公司
3.6实验系统
动物信息：ApoE -/-小鼠、SPF级、160只、雌性、2月龄；
动物来源：ApoE -/-小鼠购自江苏集萃药康生物科技股份有限公司(生产许可证号：SCXK(苏)2018-0008)。动物合格证号：99822700020300、320727210100778554，实验证明号：00293582。
选用理由：委托方要求。
饲养管理：动物饲养在珠海百试通生物科技有限公司实验动物中心SPF级动物房。动物饲养条件：群养4只/笼，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，普通饲料由江苏美迪森生物医药有限公司提供。动物自由进食饮水。
识别方法：采用打耳标标记法，耳标编号笼具双重编号标记识别。
安死术：50mg/kg舒泰50和10mg/kg速眠新Ⅱ联合麻醉后采血处死，尸体暂存于尸体冷冻柜，珠海百试通生物科技有限公司统一进行无公害化处理。
检疫观察：对购入动物检疫7天。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。
3.7剂量设计与分组
剂量设计依据：委托方要求。
3.8实验方法
3.8.1.供试品溶液配制：
3.8.1.1.样品A
样品A超高剂量(0.521g/ml)：准确称量2.13g样品A，加入15ml的纯净水，搅拌均匀，得0.521g/ml样品A超高剂量混悬液。
样品A高剂量(0.261g/ml)：取4ml样品A超高剂量混悬液，加入4ml的纯净水，搅拌均匀，得0.261g/ml样品A高剂量混悬液。
样品A中剂量(0.13g/ml)：取2ml样品A超高剂量混悬液，加入6ml的纯净水，搅拌均匀，得0.13g/ml样品A中剂量混悬液。
样品A低剂量(0.065g/ml)：取1ml样品A超高剂量混悬液，加入7ml的纯净水，搅拌均匀，0.065g/ml样品A低剂量混悬液。
3.8.1.2.样品B
样品B超高剂量(0.521g/ml)：准确称量2.7g样品B，加入15ml的纯净水，搅拌均匀，得0.521g/ml样品B超高剂量混悬液。
样品B高剂量(0.261g/ml)：取4ml样品B超高剂量混悬液，加入4ml的纯净水，搅拌均匀，得0.261g/ml样品B高剂量混悬液。
样品B中剂量(0.13g/ml)：取2ml样品B超高剂量混悬液，加入6ml的纯净水，搅拌均匀，得0.13g/ml样品B中剂量混悬液。
样品B低剂量(0.065g/ml)：取1ml样品B超高剂量混悬液，加入7ml的纯净水，搅拌均匀，0.065g/ml样品B低剂量混悬液。
3.8.1.3.样品C
样品C超高剂量(0.521g/ml)：准确称量1.23g样品C，加入15ml的纯净水，搅拌均匀，得0.521g/ml样品C超高剂量混悬液。
样品C高剂量(0.261g/ml)：取4ml样品C超高剂量混悬液，加入4ml的纯净水，搅拌均匀，得0.261g/ml样品C高剂量混悬液。
样品C中剂量(0.13g/ml)：取2ml样品C超高剂量混悬液，加入6ml的纯净水，搅拌均匀，得0.13g/ml样品C中剂量混悬液。
样品C低剂量(0.065g/ml)：取1ml样品C超高剂量混悬液，加入7ml的纯净水，搅拌均匀， 0.065g/ml样品C低剂量混悬液。
3.8.1.4.样品D
样品D超高剂量(0.521g/ml)：准确称量2.22g样品D，加入15ml的纯净水，搅拌均匀，得0.521g/ml样品D超高剂量混悬液。
样品D高剂量(0.261g/ml)：取4ml样品D超高剂量混悬液，加入4ml的纯净水，搅拌均匀，得0.261g/ml样品D高剂量混悬液。
样品D中剂量(0.13g/ml)：取2ml样品D超高剂量混悬液，加入6ml的纯净水，搅拌均匀，得0.13g/ml样品D中剂量混悬液。
样品D低剂量(0.065g/ml)：取1ml样品D超高剂量混悬液，加入7ml的纯净水，搅拌均匀，0.065g/ml样品D低剂量混悬液。
3.8.2.对照品溶液配制
瑞舒伐他汀(0.33mg/ml)：取1片瑞舒伐他汀，研磨成粉末，加入30ml纯化水，搅拌溶解即可，给药前摇匀剂量设计与分组
3.8.3.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、10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。由珠海百试通公司实验动物中心提供。
3.8.4造模方法：SPF级ApoE -/-小鼠160只，饲养于SPF级屏障中。检疫3天合格后，适应性饲养14d。所有ApoE -/-小鼠均给予高脂饲料喂养30天。30天后以TC为分组指标随机区组分为模型对照组1和2、瑞舒伐他汀组(阳性组1和2)、样品A,B,C,D各四组(低剂量组、中剂量组、高剂量组、超高剂量组)，8只/组。所有ApoE -/-小鼠在造模后，继续给予高脂饲料喂养30天，然后恢复到正常维持饲料。
3.8.5给药方法：阳性对照组、各受试样品组小鼠每天按20mL/kg体重灌胃给予相应的药液，模型对照组给予同体积的纯净水，1次/d，连续60d。分组：表1
表1各组给药表
Figure PCTCN2022114700-appb-000001
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：
TC、TG水平:于造模30d、60d和90d，各动物不禁食，麻醉后眼底静脉丛采血，3000rpm离心10min，分离血清，测定TC、TG水平。
LDL、HDL水平：于造模60d和90d，各动物不禁食，麻醉后眼底静脉丛采血，3000rpm离心10min，分离血清，测定LDL、HDL水平。
C-reactive protein(CRP)水平:于造模30d和90d，各动物不禁食，麻醉后眼底静脉丛采血，3000rpm 离心10min，分离血清，测定CRP水平。
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。取主动脉弓进行HE染色和天狼星染色。
组织保留:动物采血后，放血处死，收集血清。所有的试验动物进行大体解剖，收集心脏，肝脏，肾脏和脑部组织。其中心脏，和部分肝脏，肾脏和脑部组织进行组织标本固定，剩余组织冷冻保存。其它组织器官如出现体积、颜色、质地等改变时，进行组织病理学检查。
3.9数据统计方法：所有数据采用
Figure PCTCN2022114700-appb-000002
表示，应用SPSS 21.0软件进行统计分析；采用秩和检验进行统计分析。百分率的比较采用秩和检验进行统计分析。检验水平α＝0.05。
3.10结果
3.10.1.日常观察：各组小鼠在试验过程中均未出现死亡情况与异常反应。
3.10.2.体重(见图1-4)：
与模型对照组比较，瑞舒伐他汀阳性组、及各样品组，体重自第二周起，都有所降低,其中一些周的体重改变，具有统计学差异(P＜0.05)。其中，瑞舒伐他汀阳性组对体重的影响，相比各样品处理组，都更为明显。然而，体重的改变，在各样品处理组中，都没有观察到剂量反应关系，表明体重的改变与给药剂量无关。
3.10.3.TC值、TG值、CRP值、LDL值、HDL值(见表2-4)：
表2：受试样品对各组小鼠的体重影响(
Figure PCTCN2022114700-appb-000003
g，n＝8)
Figure PCTCN2022114700-appb-000004
注：采用单因素方差分析分析；与模型对照组比较，“*”P＜0.05和“**”P＜0.01.
表3：各组小鼠TC值、TG值(
Figure PCTCN2022114700-appb-000005
n＝8)
Figure PCTCN2022114700-appb-000006
注：采用单因素方差分析分析；与模型对照组比较，“*”P＜0.05和“**”P＜0.01.
表4：各组小鼠CRP值、LDL值、HDL值(
Figure PCTCN2022114700-appb-000007
n＝8)
Figure PCTCN2022114700-appb-000008
注：采用单因素方差分析分析；与模型对照组比较，“*”P＜0.05和“**”P＜0.01.
3.10.3.1.TC值：
样品A超高剂量组小鼠在D30时TC值高于模型对照组，具有统计学差异(P＜0.05)。其余各给药组小鼠在各时间点TC值与模型对照组比较，均无统计学差异(P>0.05)。
3.10.3.2.TG值：
样品A超高剂量组小鼠在D30时TG值高于模型对照组，具有统计学差异(P＜0.05)。样品A高剂量组、样品B低剂量组、样品B中剂量组、样品B超高剂量组小鼠在D60时TG值低于模型对照组，具有统计学差异(P＜0.05)。其余各给药组小鼠在各时间点TG值与模型对照组比较，均无统计学差异(P>0.05)。
3.10.3.3.LDL值：
样品A中剂量组、样品A高剂量组、样品A超高剂量组、样品B低剂量组、样品B中剂量组、样品B高剂量组、样品B超高剂量组小鼠在D30时LDL值高于模型对照组，具有统计学差异(P＜0.05)，样品A超高剂量组、样品B超高剂量组小鼠在D60时LDL值高于模型对照组，具有统计学差异(P＜0.05)，其余各给药组小鼠在各时间点LDL值与模型对照组比较，均无统计学差异(P>0.05)。
3.10.3.4.HDL值
样品A超高剂量组小鼠在D60时HDL值高于模型对照组，瑞舒伐他汀组小鼠在D30时HDL-C值低于模型对照组，具有统计学差异(P＜0.05)，样品D超高剂量组小鼠在D30时HDL-C值高于模型对照组，具有统计学差异(P＜0.05)。其它各给药组小鼠在各时间点HDL值与模型对照组比较，均无统计学差异(P>0.05)。
3.10.3.5.CRP值：
样品B低剂量组、样品B超高剂量组小鼠在D60时CRP值低于模型对照组，具有统计学差异(P＜0.05)。样品C中剂量组、样品C高剂量组、样品C超高剂量组、样品D低剂量组、样品D中剂量组、样品D高剂量组、样品D超高剂量组小鼠在D60时CRP值低于模型对照组，具有统计学差异(P＜0.05)，其余各给药组小鼠在各时间点CRP值与模型对照组比较，均无统计学差异(P>0.05)。
3.10.4病理检测结果
模型对照组ApoE -/-小鼠的心、肝、肾、脑均出现不同程度的炎症反应，样品A，B,C和D，各剂量组小鼠的心、肝、肾、脑的炎性病变程度与模型对照组接近。各个组，均未观察到其它病理改变。
3.10.5.动脉弓动脉粥样斑块HE染色检查结果(表5，图5-12)。
表5，动脉弓部动脉粥样斑块面积及数量((Avg.，n＝8)HE染色)
Figure PCTCN2022114700-appb-000009
与模型对照组比较，阳性处理组，及各样品处理组小鼠在动脉弓粥样斑块形成的病变程度均呈现减轻的趋势，斑块面积都有所减少，部分组平均斑块面积与模型对照组相比具有显著性差异(P<0.01 or P<0.05)。其中与模型对照组比较，样品B的四个剂量组小鼠在动脉弓的粥样斑块面积上呈现较为明显的剂量效应关系(图8)。其它组剂量效应关系未明显观察到。粥样斑块数在各组中未观察到明显的剂量效应关系。
结论
在本实验条件下，实验样品A，B，C，D均显示出较为明显的预防和消融动脉斑块的效果。其中，样品B对于动脉斑块的清除呈现明显的剂量效应关系。此外，样品B具有明显降低血TG值的效果。样品D显示明显的抑制炎性反应的效果，与模型对照组相比，CRP值在各剂量组均显著性降低。

Claims (24)

  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5-35份、枳实5-30份、生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份、白术3-20份。
  2. 根据权利要求1所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份、白术5-15份。
  3. 根据权利要求2所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、白芍10份、干姜10份、水蛭10份、白术10份。
  4. 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5-35份、枳实5-30份、生大黄3-20份、白芍3-20份、干姜3-20份、水蛭3-25份、甘草3-20份、白术3-20份、生牡蛎3-45份。
  5. 根据权利要求4所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、白芍5-15份、干姜5-15份、水蛭7-15份、甘草5-15份、白术5-15份、生牡蛎10-35份。
  6. 根据权利要求5所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、白芍10份、干姜10份、水蛭10份、甘草10份、白术10份、生牡蛎30份。
  7. 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5-35份、枳实5-30份、生大黄3-20份、黄芩1-20份、白芍3-20份、干姜3-20份、水蛭3-25份、甘草3-20份、党参3-20份、白术3-20份、生牡蛎3-45份。
  8. 根据权利要求7所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡15-30份、枳实10-20份、生大黄5-15份、黄芩2-10份、白芍5-15份、干姜5-15份、水蛭7-15份、甘草5-15份、党参5-15份、白术5-15份、生牡蛎10-35份。
  9. 根据权利要求8所述的中药组合物，其特征在于包含按以下重量份计的原料药：柴胡20份、枳实15份、生大黄10份、黄芩3份、白芍10份、干姜10份、水蛭10份、甘草10份、党参10份、白术10份、生牡蛎30份。
  10. 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：生大黄3-20份、干姜3-20份、白芍3-20份、水蛭3-25份、甘草3-20份、生牡蛎3-45份、丹皮3-20份、桃仁2-15份。
  11. 根据权利要求10所述的中药组合物，其特征在于包含按以下重量份计的原料药：生大黄5-15份、干姜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、生牡蛎10-35份。
  12. 根据权利要求11所述的中药组合物，其特征在于包含按以下重量份计的原料药：生大黄10份、干姜10份、白芍10份、水蛭10份、甘草10份、生牡蛎30份、丹皮10份、桃仁6份。
  13. 根据权利要求1-12中任一项所述的中药组合物，其特征在于其为口服制剂。
  14. 根据权利要求13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。
  15. 根据权利要求1-12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70-95℃，优选70-85℃保温30-120分钟，得到第一次煎煮液；第二次加水3-10倍量，在70-95℃，优选70-85℃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。
  16. 根据权利要求15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，煮沸后在80℃或75℃保温60分钟，得到第一次煎煮液；第二次加水6倍量，煮沸后在80℃或75℃或70℃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。
  17. 根据权利要求1-12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。
  18. 根据权利要求1-12中任一项所述的中药组合物在制备预防或治疗动脉粥样斑块的药物中的应用。
  19. 根据权利要求1-12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性缺血性心脑疾病的药物中的应用。
  20. 根据权利要求1-12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。
  21. 根据权利要求1-12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。
  22. 根据权利要求1-12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。
  23. 根据权利要求1-12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。
  24. 根据权利要求1-12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。
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