WO2018064953A1 - Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 - Google Patents

Idhp在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用 Download PDF

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WO2018064953A1
WO2018064953A1 PCT/CN2017/104278 CN2017104278W WO2018064953A1 WO 2018064953 A1 WO2018064953 A1 WO 2018064953A1 CN 2017104278 W CN2017104278 W CN 2017104278W WO 2018064953 A1 WO2018064953 A1 WO 2018064953A1
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idhp
preparation
isopropyl ester
application
danshensu
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PCT/CN2017/104278
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English (en)
French (fr)
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郑晓晖
白亚军
贾璞
张亚军
廖莎
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西北大学
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Priority to MYPI2019001888A priority Critical patent/MY195760A/en
Priority to KR1020197013111A priority patent/KR102286297B1/ko
Priority to NZ752717A priority patent/NZ752717B2/en
Priority to AU2017340305A priority patent/AU2017340305B2/en
Application filed by 西北大学 filed Critical 西北大学
Priority to SG11201902987SA priority patent/SG11201902987SA/en
Priority to RU2019113518A priority patent/RU2719391C1/ru
Priority to JP2019518211A priority patent/JP6851652B2/ja
Priority to CA3039287A priority patent/CA3039287C/en
Priority to US16/338,801 priority patent/US10993926B2/en
Priority to PL17857834.0T priority patent/PL3524241T3/pl
Priority to EP17857834.0A priority patent/EP3524241B1/en
Priority to BR112019006957A priority patent/BR112019006957A2/pt
Publication of WO2018064953A1 publication Critical patent/WO2018064953A1/zh
Priority to IL265753A priority patent/IL265753B2/en
Priority to CY20231100274T priority patent/CY1126073T1/el

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol

Definitions

  • the invention relates to a new application of Danshensu isopropyl ester (IDHP), in particular to the application of IDHP in the preparation of medicines and health care products for preventing and treating coronary atherosclerosis-related diseases.
  • IDHP Danshensu isopropyl ester
  • the inventors explored the role of IDHP in inhibiting platelet aggregation and promoting angiogenesis, and provided a valuable theoretical basis for the prevention and treatment of new drugs and health products for coronary atherosclerosis-related diseases.
  • Coronary arteriosclerosis is a type of disease caused by coronary angiogenic atherosclerotic lesions that cause stenosis or obstruction of the vascular lumen, resulting in ischemia, hypoxia or necrosis, common coronary heart disease, stroke and myocardial infarction (MI).
  • the main pathogenesis of coronary heart disease is closely related to coronary atherosclerotic plaque instability and thrombosis. Platelet aggregation is an important factor leading to thrombosis.
  • Antiplatelet therapy plays an important role in the prevention and treatment of coronary heart disease.
  • Stroke refers to a patient with cerebrovascular disease, a high-risk disease causing acute cerebral circulation disorder due to various predisposing factors, causing cerebral artery stenosis, occlusion or rupture, clinically manifested as transient or permanent brain function.
  • Obstruction, antiplatelet therapy plays an important role in the primary and secondary prevention of stroke, and is one of the three clinically recognized treatments (surgery, anticoagulation and antiplatelet aggregation).
  • the occurrence and treatment of coronary arteriosclerosis-related diseases are closely related to angiogenesis.
  • Pathological neovascularization often occurs in atherosclerotic plaques, which can promote the development of atherosclerotic lesions, and even induce plaque hemorrhage and plaque rupture and its complications.
  • the density of neovascularization around the infarction site of ischemic stroke is directly related to the survival rate of patients with ischemic stroke, promoting angiogenesis after ischemic stroke, which is conducive to saving the ischemic penumbra.
  • Angiogenesis is also a key process in coronary reperfusion and ischemic myocardial repair.
  • pro-angiogenesis plays a significant role in the healing of myocardial infarction.
  • IDHP can significantly inhibit ADP and collagen-induced human platelet aggregation, respectively, which is the basis for the development of IDHP for the development of anti-platelet aggregation drugs.
  • IDHP can significantly promote angiogenesis in primary human umbilical vein endothelial cells (HUVEC), and IDHP significantly promoted the growth of zebrafish internode blood vessels and medial longitudinal blood vessels, indicating that IDHP can be used to prepare blood vessels. Newborn drugs.
  • HUVEC primary human umbilical vein endothelial cells
  • IDHP can significantly inhibit human platelet aggregation and promote angiogenesis, improve blood supply, and thus can treat senile vascular dementia.
  • IDHP has high safety. Combined with the above related activity studies, it is indicated that IDHP can be used to develop prevention and treatment of coronary atherosclerotic disease health products and anti-platelet aggregation. Health care products, promotion of angiogenesis health products, prevention and treatment of senile vascular dementia health products.
  • IDHP is a human body-derived substance, further indicating that by ingesting IDHP, regulating the balance state of the body, in order to achieve the purpose of prevention, health care and treatment of coronary atherosclerosis-related diseases, senile vascular dementia.
  • Figure 1 shows the effects of different concentrations of IDHP on the proliferation of human umbilical vein endothelial cells
  • Figure 2 shows the effects of different concentrations of IDHP on the migration of human umbilical vein endothelial cells
  • Figure 3 shows the effect of different concentrations of IDHP on the lumen formation of human umbilical vein endothelial cells
  • Figure 4 is the effect of IDHP on zebrafish internode blood vessel growth; wherein: A, PTK 787; B, 0.01 ⁇ M IDHP; C, 0.1 ⁇ M IDHP; D, 1.0 ⁇ M IDHP; E, 10.0 ⁇ M IDHP; F, 10 nM VEGF;
  • Figure 5 is a graph showing the results of measuring the blood vessel growth of the zebrafish by IDHP;
  • Figure 7 is a mass spectrometric identification of Danshensu isopropyl ester
  • Figure 8 shows the liquid phase identification of Danshensu isopropyl ester.
  • the health care product according to the present invention may be a soft capsule, a dropping pill, an emulsion, a tablet or a spray or the like.
  • Example 1 IDHP promotes angiogenesis in cultured human umbilical vein endothelial cells (HUVEC)
  • 1.1IDHP promotes proliferation of human umbilical vein endothelial cells (HUVEC) - CCK-8 method
  • 1.2 IDHP promotes migration of human umbilical vein endothelial cells (HUVEC) - scratch method
  • the endothelial cells were seeded on a cover plate pre-coated with gelatin in a 24-well plate to make a patch, and the inoculation density was about 10 5 /well. After the cells were attached and fused, the serum was starved for 4 hours, and the laboratory was specially prepared. The multi-channel injury tool was used for scratch damage. The coverslips were washed twice with PBS, and the drug-containing medium was added to 600 ⁇ l/well. The control group was immediately fixed with ice methanol for 0 hours, and the remaining cells were cultured for 16 hours, followed by ice methanol. Fixed, photographed under the microscope and counted. The results show (Fig. 2) that IDHP can promote the migration of human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner at 10 -10 -10 -7 M.
  • HAVEC human umbilical vein endothelial cells
  • 1.3IDHP promotes lumen formation of human umbilical vein endothelial cells (HUVEC) - Matrigel gel method
  • the tip and 96-well plate were pre-cooled at -20 ° C.
  • the Matrigel gel was placed on ice to melt it.
  • Matrigel gel (60 ⁇ L/well) was added to the pre-cooled 96-well plate to avoid the formation of bubbles and placed on ice for 5 min.
  • Matrigel level was leveled and then placed in a cell culture incubator for 30 min to solidify; endothelial cells (cell number 5 ⁇ 10 4 /well) were added to the wells containing Matrigel gel, and fresh cultures containing different concentrations of drugs were added.
  • the cells were cultured at 37 ° C for 8 h. Under the microscope, 5 fields of view were taken at 0, 3, 6 and 9 o'clock and the center of each well.
  • IDHP significantly promoted the lumen formation of primary human umbilical vein endothelial cells (HUVEC), indicating that IDHP has an activity of promoting angiogenesis in vitro.
  • HUVEC primary human umbilical vein endothelial cells
  • Example 2 IDHP promotes angiogenesis in transgenic zebrafish
  • the transgenic Tg (VEGFR2:GFP) zebrafish were reared under the standard conditions of illumination for 14h/dark 10h and 28°C. When the eggs were used, healthy and mature zebrafish were taken and placed in mating ratio of male or female 1/1 or 1/2. In the cylinder, the fertilized egg is obtained from 9 to 10 the next day. After sterilizing and washing the fertilized eggs, they are transferred to zebrafish embryo culture water and cultured at 28 °C.
  • the drug solution was added to a 24-well culture plate, and 24 hpf embryos were carefully transferred to wells, 8-10 per well, and added to a total volume of 2 ml with culture water. Ensure that the final concentration of DMSO is not higher than 1%. After 24 hours of drug treatment, the embryos were observed with a fluorescence microscope and the torso and tail sections were counted. The total number of intervascular vessels was calculated, and the relative rate of ISV production in each administration group was calculated. Analysis of variance between groups was performed using SPSS software.
  • Table 1 IDHP promotes the growth of zebrafish ISV
  • Example 3 IDHP inhibits ADP and collagen-induced human platelet aggregation
  • the whole blood of the volunteers was collected and added to the anticoagulant tube, and centrifuged at 800 g for 5 min at room temperature.
  • the pale yellow supernatant was taken as platelet-rich plasma (PRP), and the remaining solution was further centrifuged at 4000 g for 10 min at room temperature, and the supernatant was taken as platelet-poor plasma. PPP).
  • PRP platelet-rich plasma
  • PPP was adjusted to 3 ⁇ 10 5 / ⁇ L with PPP, and 300 ⁇ L of adjusted PRP was added to 30 ⁇ L of PBS or different concentrations of IDHP for 3 min at 37 ° C in a blood coagulation apparatus, and then ADP or collagen was added at a final concentration of 3 ⁇ mol/L. , initiates the aggregation reaction of platelets.
  • the inhibition of platelet aggregation by IDHP and clopidogrel was determined by turbidimetry.
  • Figure 6 shows that clopidogrel significantly inhibits ADP-induced platelet aggregation in the measured concentration range (p ⁇ 0.001); IDHP significantly inhibits ADP and collagen, respectively, compared with ADP or collagen alone (Ctrl). Induction of human platelet aggregation and inhibition of collagen-induced platelet aggregation was more pronounced (P ⁇ 0.001).
  • mice ⁇ Each half was randomly divided into 6 groups. Danshensu isopropyl ester was formulated into six concentrations of solution using physiological saline: 3.145%, 2.68%, 2.4%, 2%, 1.875%, and 1.6%. The spacing between the concentrations was 1:0.9. After the animals were fasted for 12 hours, each group was administered iv, the volume was 20 mL/kg, and the administration was completed within 5 s of each animal. The doses of the six groups were 629 mg/kg, 530 mg/kg, 480 mg/kg, 400 mg/kg, 375 mg/kg, and 320 mg/kg, respectively.
  • the animal was short of breath, rapid heartbeat, jumping, convulsions, followed by slow movement and lying on the ground.
  • the poisoning phenomenon increased with the increase of the dose; the dead animals basically died within 1 min after the administration, and the undead animals returned to normal after 10 minutes.
  • the autopsy of the dead mice was observed by the naked eye. There were no abnormalities in the vital organs such as heart, liver, spleen, lung, kidney, brain, stomach and intestine.
  • the Bliss method measured LD 50 of 424 ⁇ 58 mg / kg, 95% confidence interval of 370 ⁇ 486 mg / kg, see Table 2.
  • the rabbit arteries were bled, defibrinated, washed with red blood cells with physiological saline, and then formulated into a 2% erythrocyte physiological saline solution.
  • Four sets of parallel test tubes were operated according to Table 4.
  • Danshensu is a human body-derived substance.
  • lipase is widely present in tissues containing fats, such as animals, plants and microorganisms (such as molds, bacteria, etc.), and human body contains isopropanol, which can explain danshensu isopropyl ester is a human body substance.
  • the emulsion formulation was: Danshensu isopropyl ester: 10.0 g, vitamin E: 3.0 g, refined soybean: 200.0 g, oleic acid: 15.0 g, refined protein lecithin: 25.0 g, water for injection: about 900 ml, glycerin: 2.0 g.
  • Danshensu isopropyl ester 10.4g
  • starch 6.3g
  • polyethylene glycol (molecular weight 6000) 26.5g
  • preparation of prescription Danshensu isopropyl ester and polyethylene glycol 6000 is heated to 80 ° C to melt, add starch and sodium carboxymethyl starch, mix well, drip into liquid paraffin coolant (1 ⁇ 5 ° C), made 1000 pills, pill weight 45mg, remove the surface oil trace, that is.

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Abstract

丹参素异丙酯（IDHP）在制备预防和治疗冠状动脉粥样硬化疾病的药物或保健品中的应用，同时可用于抗血小板聚集、促进血管新生、以及制备预防和治疗老年血管性痴呆的药物和保健品。

Description

IDHP在制备预防和治疗冠状动脉粥样硬化疾病药物或保健品中的应用
本申请要求于2016年10月08日提交中国专利局、申请号为201610876752.3、发明名称为“IDHP制备预防和治疗冠状动脉粥样硬化疾病药物的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及丹参素异丙酯(IDHP)的新应用，具体涉及IDHP在制备预防和治疗冠状动脉粥样硬化相关性疾病药物和保健品中的应用。
背景技术
β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯(丹参素异丙酯，IDHP)是发明人应用代谢物组学研究技术，采用HPLC-MS、GC-MS、GC-FTIR、MS、NMR等技术手段，在复方丹参滴丸、冠心丹参片、丹参饮等复方丹参方和“君-使”对药的研究过程中，从众多的代谢产物及其系列的改性物中，筛选并合成的活性化合物。
发明内容
发明人探索IDHP在抑制血小板聚集、促进血管新生等方面的作用，为预防和治疗冠状动脉粥样硬化相关性疾病新药及保健品开发提供有价值的理论依据。
冠状动脉硬化疾病是冠状动脉血管发生动脉粥样硬化病变而引起血管腔狭窄或阻塞，造成缺血、缺氧或坏死而导致一类疾病，常见冠心病、脑卒中及心肌梗塞(心梗)。冠心病主要发病机制与冠状动脉粥样硬化斑块不稳定及血栓形成密切相关，血小板聚集是导致血栓形成的重要因素，抗血小板治疗在冠心病预防及治疗方面起着重要作用。脑卒中是指脑血管疾病的病人，因各种诱发因素引起脑内动脉狭窄，闭塞或破裂，而造成急性脑血液循环障碍的一种高危疾病，临床上表现为一过性或永久性脑功能 障碍，抗血小板治疗在脑卒中的一级和二级预防中起着重要作用，是目前临床公认的三大治疗手段(手术、抗凝和抗血小板聚集)之一。同时，冠状动脉硬化相关性疾病分发生、治疗又与血管新生息息相关。动脉粥样硬化斑块内常出现病理性新生血管，它们可以促进粥样硬化病变的发展，甚至诱发斑块内出血和斑块破裂及其并发症。发生缺血性脑卒中梗死部位周围新生血管的密度与缺血性脑卒中患者的存活率直接相关，促进缺血性脑卒中后血管新生，有利于挽救缺血半暗带。血管新生也是冠状动脉再灌注及缺血心肌修复的关键过程。此外，促血管新生在心梗的愈后方面作用显著。发明人研究发现IDHP可分别显著抑制ADP或胶原诱导的人血小板聚集，同时发现IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)血管新生，这说明IDHP可用于制备预防和治疗冠状动脉粥样硬化疾病药物。
发明人研究发现IDHP可分别显著抑制ADP及胶原诱导的人血小板聚集，该发现为将IDHP用于开发抗血小板聚集药物奠定了基础。
发明人研究发现IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)血管新生，同时IDHP对斑马鱼节间血管和背部纵侧血管的生长具有显著地促进作用，这说明IDHP可用于制备促进血管新生的药物。
IDHP可显著抑制人血小板聚集和促进血管新生，改善血运，从而可以治疗老年血管性痴呆。
经过小鼠急性、慢性毒性试验以及溶血实验，发明人发现IDHP具有较高安全性，结合上述相关活性研究发现，说明IDHP可用于开发预防和治疗冠状动脉粥样硬化相疾病保健品、抗血小板聚集保健品、促进血管新生保健品、预防和治疗老年血管性痴呆保健品。
发明人研究发现IDHP为人体内源性物质，进一步说明通过摄入IDHP，调节体内平衡状态，以达到预防、保健与治疗冠状动脉粥样硬化相关性疾病、老年血管性痴呆的目的。
附图说明
图1为不同浓度IDHP对人脐带静脉内皮细胞增殖的影响；
图2为不同浓度IDHP对人脐带静脉内皮细胞迁移的影响；
图3为不同浓度IDHP对人脐带静脉内皮细胞管腔形成的影响；
图4为IDHP对斑马鱼节间血管生长的影响；其中：A，PTK 787；B，0.01μM IDHP；C，0.1μM IDHP；D，1.0μM IDHP；E，10.0μM IDHP；F，10nM VEGF；
图5为IDHP促斑马鱼节间血管生长的测定结果图；
图6为IDHP对ADP及胶原诱导的正常人血小板聚集的影响(n＝16)；
图7为丹参素异丙酯质谱鉴定；
图8为丹参素异丙酯液相鉴定。
具体实施方式
本发明IDHP化合物的结构式如下式所示，其制备方法可参见CN 200410026205.3，但不限于该文献记载的范围。
Figure PCTCN2017104278-appb-000001
本发明所述的保健品可以是软胶囊、滴丸、乳剂、片剂或喷雾等。
实施例1：IDHP促进体外培养的人脐带静脉内皮细胞(HUVEC)血管新生
1.1IDHP促进人脐带静脉内皮细胞(HUVEC)增殖—CCK-8法
人脐带静脉内皮细胞接种于96孔板中，密度约2,500个/孔。种板24h后，换取新鲜含药培养基，100μl/孔，继续培养48h；药物处理结束前2小时，避光条件下在培养液中加入CCK-8试剂，每孔10μl。继续培养2h后，用酶标仪测定450nm处吸光值，计算细胞增殖率。图1结果显示，与空白对照组相比，IDHP在10-9-10-7M时显著促进血管内皮细胞增 殖(P<0.01)。
1.2IDHP促进人脐带静脉内皮细胞(HUVEC)的迁移—划痕法
将内皮细胞接种于24孔板内由明胶预包被的盖玻片上使之爬片，接种密度约105个/孔，待细胞贴壁并融合后，撤血清饥饿4h，用被实验室特制的多通道损伤工具进行划痕损伤，PBS清洗两遍盖玻片，并加入含药培养基，600μl/孔，0小时对照组立刻用冰甲醇固定，其余组细胞继续培养16h后，用冰甲醇固定，显微镜下观察拍照并统计。结果显示(图2)，IDHP在10-10-10-7M时，可剂量依赖性的促进人脐带静脉内皮细胞(HUVEC)的迁移。
1.3IDHP促进人脐带静脉内皮细胞(HUVEC)的管腔形成—Matrigel胶法
将枪头和96孔板于-20℃预冷，将Matrigel胶放冰上使之融化，取Matrigel胶(60μL/孔)加入到预冷的96孔板中，避免形成气泡，冰上放置5min，使Matrigel液面水平，然后放入细胞培养箱30min使之凝固；取内皮细胞(细胞数5×104/孔)加入到含Matrigel胶的孔中，再加入含不同浓度的药物的新鲜培养基，37℃培养8h；在显微镜下观察，每孔选取0，3，6，9点钟及正中心共5个视野，观察小管数目及管状结构完整性并拍照统计。结果显示，与Ctrl对照组相比，IDHP可显著促进原代人脐带静脉内皮细胞(HUVEC)的管腔形成，说明IDHP在体外具有促进血管新生的活性。
实施例2：IDHP促进转基因斑马鱼的血管新生
转基因Tg(VEGFR2:GFP)系斑马鱼在照明14h/黑暗10h、28℃标准条件下饲养，用卵时，取健康性成熟的斑马鱼，按雌雄1/1或1/2的比例放入交配缸内，次日9～10时获得受精卵。对受精卵进行消毒和清洗后，移入斑马鱼胚胎培养水中，28℃下培养。
将药物溶液加入到24孔培养板中，将24hpf的胚胎小心转移至孔中，每孔8-10个，用培养水加至总体积为2ml。保证DMSO的终浓度不高于1％。药物处理24h后，采用荧光显微镜观察胚胎，计数躯干与尾部的节 间血管总数，计算各给药组的ISV相对生成率。采用SPSS软件进行各组间方差分析。
结果显示，浓度分别为0.01,0.1和1.0μM的IDHP对斑马鱼节间血管和背部纵侧血管的生长具有显著地促进作用(图4)，血管总数和长度明显增加(表1)。根据公式：相对生成率(％)＝(给药组血管总长－PTK787对照组血管总长)÷正常对照组血管总长×100计算相对生成率，药物间呈现良好的剂量依赖关系(图5)。
表1 IDHP对斑马鱼ISV生长的促进作用
Figure PCTCN2017104278-appb-000002
注：***代表与对照相比，p<0.001
实施例3：IDHP抑制ADP及胶原诱导的人血小板聚集
采集志愿者全血加入抗凝管中，室温800g离心5min，取淡黄色上清即为富含血小板血浆(PRP)，将余液继续以4000g室温离心10min，取上清即为贫血小板血浆(PPP)。
以PPP调节PRP至3×105/μL，取300μL调节后的PRP加入30μL的PBS或不同浓度的IDHP于血液凝聚仪中37℃温育3min后，加入终浓度为3μmol/L的ADP或胶原，启动血小板的凝聚反应。采用比浊法测定IDHP及氯吡格雷对血小板聚集的抑制作用。图6结果显示，氯吡格雷在所测浓度范围内，可显著抑制ADP诱导的血小板聚集(p<0.001)；与ADP或胶 原单独作用组(Ctrl)相比，IDHP可分别显著抑制ADP及胶原诱导的人血小板聚集，且对胶原诱导的血小板聚集的抑制作用更为显著(P<0.001)。
实施例4：丹参素异丙酯(IDHP)毒理学研究
4.1快速给药小鼠急性毒性试验
选小白鼠60只，♀
Figure PCTCN2017104278-appb-000003
各半，随机分为6组。将丹参素异丙酯用生理盐水配成6种浓度的溶液：3.145％、2.68％、2.4％、2％、1.875％和1.6％。各浓度间的间距为1：0.9。动物禁食12h后，各组分别iv给药，容积20mL/kg，每只动物5s内完成给药。6个组的剂量分别为629mg/kg、530mg/kg、480mg/kg、400mg/kg、375mg/kg和320mg/kg。iv后，动物呼吸急促、心跳加快、跳跃、抽搐，随后运动迟缓、卧地。中毒现象随给药剂量的增加而增加；死亡动物基本在给药后1min内死亡，未死的动物在10min后恢复正常。对死亡小鼠进行尸检，肉眼观察，小鼠的心、肝、脾、肺、肾、脑、胃、肠等重要脏器均未见异常。Bliss法测定LD50为424±58mg/kg，95％可信区间为370～486mg/kg，见表2。
表2 丹参素异丙酯的LD50测定(Bliss’s)法本底死亡率：0％
Figure PCTCN2017104278-appb-000004
显著性指数：G＝0.1760 X50＝－0.3722 Sx＝0.0158 G较小，省略
异质性检查：Chi2＝6.90 Chi2.05＝9.64 Sb＝2.7993 无异质性
回归方程式为：Y(Probit)＝9.8687+13.0795×log(D) r＝0.8716
LD50＝424.4±39.7(mg/kg)
Feiller异质性校正：Sx＝0.0229 Sb＝3.6778
LD50＝424.4±57.9(mg/kg)
95％可信区间为370.4～486.2mg/kg
4.2慢速给药小鼠急性毒性试验
试验用小鼠在实验室饲养1天后挑选体重合格者，按体重和性别随机分组，每组10只，雌雄各半，根据预摸结果，全死剂量为2.4g/kg。小鼠采用尾静脉给药，小鼠按体重计算给药量，给药剂量依次为2.4g/kg、2.2g/kg、2.0g/kg、1.8g/kg，并计算给药速度，在10分钟内给药完毕，给药后观察小鼠反应情况并记录14天内小鼠死亡率。
静脉给药后主要毒性反应为中枢抑制，呼吸衰竭等表现。死亡多在给药期间内发生，死亡解剖未见内脏有异常改变，观察14天，再计算小鼠死亡率，Bliss法测定LD50＝2.048g/kg±0.085g/kg，95％可信限＝1.965～2.135g/kg，结果见表3：
表3 小鼠尾静脉给药丹参素异丙酯的LD50测定(Bliss法)
Figure PCTCN2017104278-appb-000005
4.3溶血试验
家兔动脉取血，去纤维蛋白，用生理盐水洗涤红细胞后配制成2％的红细胞生理盐水溶液。按表4进行操作每组平行试管4支。
表4
Figure PCTCN2017104278-appb-000006
Figure PCTCN2017104278-appb-000007
操作完成后，37±0.5℃水浴，于0.5h、1h、2h、3h每组分别各取一支试管，3000rpm离心15min，观察红细胞的溶血情况，同时，光镜下观察红细胞形态。
试验结果表明，红细胞形态完整，无明显的溶血现象，提示丹参素异丙酯无溶血作用。
实施例5：丹参素异丙酯内源性研究
脂肪酶催化丹参素与异丙醇合成丹参素异丙酯：
Figure PCTCN2017104278-appb-000008
具体实施可参考以下方案，但不限于该方案：
丹参素(5.0毫克，0.025毫摩尔)，异丙醇(0.3毫克，0.005毫摩尔)，水(1.5毫升)，脂肪酶(5毫克)，密闭37℃摇床(220转/分钟)温浴24小时，取100微升反应液，加入100微升乙酸乙酯，振摇20秒，取有机相做液相与质谱分析。质谱结果([M-1]＝239.0965)见图7；液相结果见图8。
液相检测条件：甲醇：0.2％甲酸水＝3:7；流速：0.6毫升/分钟；色谱柱：C18(zorbax)，250毫米，5微米，4.6毫米(内径)；柱温：25℃。
结合发明人前期研究发现丹参素为人体内源性物质，同时，脂肪酶广泛存在于含有脂肪的动、植物和微生物(如霉菌、细菌等)组织中，且人体内含有异丙醇，从而可以说明丹参素异丙酯为人体内源性物质。
实施例6：丹参素异丙酯乳剂
乳剂配方为：丹参素异丙酯：10.0g，维生素E：3.0g，精制大豆：200.0g，油酸：15.0g，精制蛋白卵磷脂：25.0g，注射用水：约900ml，甘油：2.0g。
实施例7：丹参素异丙酯滴丸
丹参素异丙酯：10.4g，淀粉：6.3g，羧甲基淀粉钠：1.8g，聚乙二醇(分子量6000)：26.5g，制备时取处方量丹参素异丙酯与聚乙二醇6000加热至80℃熔化，加入淀粉和羧甲基淀粉钠，混合均匀，滴入液体石蜡冷却剂中(1～5℃)，制成1000丸，丸重45mg，除去表面油迹，即得。
前面已经详述了本发明，包括其优选的实施方案。但是，应当明白，考虑到本发明公开的内容，本领域的技术人员可在本发明的精神实质范围内对本发明进行改变和/或改进，也属于本发明的范围。

Claims (10)

  1. 丹参素异丙酯在制备预防和治疗冠状动脉粥样硬化疾病药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的冠状动脉粥样硬化疾病为脑卒中、冠心病或心梗中的一种或几种。
  3. 丹参素异丙酯在制备预防和治疗冠状动脉粥样硬化疾病保健品中的应用。
  4. 根据权利要求3所述的应用，其特征在于，所述的冠状动脉粥样硬化疾病为脑卒中、冠心病或心梗中的一种或几种。
  5. 丹参素异丙酯在制备抗血小板聚集药物中的应用。
  6. 丹参素异丙酯在制备抗血小板聚集保健品中的应用。
  7. 丹参素异丙酯在制备促进血管新生药物中的应用。
  8. 丹参素异丙酯在制备促进血管新生保健品中的应用。
  9. 丹参素异丙酯在制备预防和治疗老年血管性痴呆药物中的应用。
  10. 丹参素异丙酯在制备预防和治疗老年血管性痴呆保健品中的应用。
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