WO2009135432A1 - 丹酚酸b的抗血栓应用 - Google Patents

丹酚酸b的抗血栓应用 Download PDF

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WO2009135432A1
WO2009135432A1 PCT/CN2009/071630 CN2009071630W WO2009135432A1 WO 2009135432 A1 WO2009135432 A1 WO 2009135432A1 CN 2009071630 W CN2009071630 W CN 2009071630W WO 2009135432 A1 WO2009135432 A1 WO 2009135432A1
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Prior art keywords
acid
use according
salvianolic acid
thrombus
sodium
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PCT/CN2009/071630
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English (en)
French (fr)
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韩晶岩
刘英华
吴新民
刘育英
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天津天士力制药股份有限公司
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Publication of WO2009135432A1 publication Critical patent/WO2009135432A1/zh

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    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to a new use of a traditional Chinese medicine product, in particular to the application of salvianolic acid extract danshen B in the treatment and prevention of blood clots.
  • Salvia miltiorrhiza is a traditional Chinese medicine in China. Its main water-soluble ingredients include methyl salicylate, ginseng ginseng, salvian phenol, B, C, ⁇ -stem, 3,4-dihydroxybenzaldehyde, salvianolic acid, Dan Phenol citrate, catechin, musk, protocatechuic aldehyde, protocatechuic acid, lithosperic acid, lactic acid, vitamin strontium, etc. Salicylic acid strontium is one of the main water-soluble components of Salvia miltiorrhiza.
  • Salvianolic acid compounds have a strong inhibitory effect on lipid peroxidation and scavenging of superoxide anion and hydroxyl radicals. Among them, salvianolic acid and barium are the most active. Salvianolic acid B significantly inhibited mitochondrial damage and neuronal apoptosis induced by cerebral ischemia-reperfusion injury. It can inhibit the apoptosis of PC12 cells with high expression of Caspase-3, and also inhibit the formation of B amyloid protein ( ⁇ 1-40) and the mitochondrial damage and apoptosis of PC12 cells induced by ⁇ 1-40. It is a strong antioxidant and can eliminate intracellular calcium overload.
  • Thrombosis in blood vessels is a cardiovascular determinant of the occurrence and fatality of cardiovascular and cerebrovascular diseases.
  • antithrombotic drugs are widely recognized as an effective way to reduce this risk.
  • aspirin has been commonly used for this purpose because it inhibits platelet aggregation.
  • the side effects of aspirin, which causes bleeding have prompted the development of new antithrombotic treatments.
  • Thrombosis is mainly caused by vascular endothelial damage, which is produced by the production of reactive oxygen species, and those reactive oxygen species promote the expression of selectins and adhesion molecules by platelets and leukocytes to adhere to the endothelium.
  • Superoxide dismutase (SOD), as well as vitamins C and E, have an antithrombotic effect.
  • Monoclonal antibodies against adhesion molecules have also been found to inhibit leukocyte adhesion to endothelial cells. Therefore, it is conceivable that the process of thrombus formation may be interrupted at an early stage by inhibiting the production of reactive oxygen species and the expression of adhesion molecules.
  • salvianolic acid B has a delayed thrombus attack during the study of the extract of salvianolic acid B in Salvia miltiorrhiza. Summary of the invention
  • the present invention provides a novel therapeutic use of Salvia miltiorrhiza extract.
  • the new therapeutic use is the treatment and prevention of thrombosis with salvianolic acid extract salvianolic acid B.
  • the present invention provides a new use of a medicament for preparing a medicament for treating and preventing thrombosis by using salvianolic acid extract salvianolic acid B.
  • the salvianolic acid B of the present invention is a prior art, commercially available, or can be prepared according to the prior art, and can meet pharmaceutical standards.
  • the purity is > 50%, more preferably > 90%, most preferably > 98%.
  • the medicament prepared by the present invention is a pharmaceutical preparation composition prepared by using the above-described salvia miltiorrhiza extract salvianolic acid B as a pharmaceutically active ingredient.
  • the pharmaceutical preparation composition of the present invention may contain a pharmaceutically acceptable carrier as needed, wherein salvianolic acid B is a pharmaceutically active ingredient, and the weight percentage in the preparation may be 0.1 to 99.9%, and the balance is a pharmaceutically acceptable carrier.
  • the pharmaceutical preparation composition of the present invention is in the form of a unit dosage form, which means a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral solution, granules per bag, injection Every one of them.
  • the pharmaceutical preparation composition of the present invention may be in any pharmaceutically acceptable dosage form, and includes: a tablet, a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a capsule, a hard capsule, a soft capsule, orally. Liquid, buccal, granule, granule, pill, powder, ointment, dandruff, suspension, powder, solution, injection, suppository, ointment, plaster, cream, spray, drops, patch .
  • the preparation for oral administration may contain common excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent and a wetting agent.
  • a binder such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent and a wetting agent.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
  • the solid oral composition can be prepared by a usual method such as mixing, filling, tableting or the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.
  • the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate or hydrogenated edible fats.
  • Emulsifier such as lecithin, sorbitan oil Acid or gum arabic
  • non-aqueous carrier which may include edible oils
  • edible oils such as almond oil, fractionated coconut oil, oily esters of esters such as glycerol, propylene glycol or ethanol
  • preservatives such as p-hydroxybenzyl or para-hydroxybenzene Propyl methacrylate or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
  • This compound may be suspended or dissolved depending on the carrier and concentration.
  • the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration prior to charging it into a suitable vial or ampoule, and then sealing. Excipients such as a topical anesthetic, preservatives and buffers can also be dissolved in such carriers.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • the traditional Chinese medicine preparation of the present invention can be selectively added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, thio Sodium sulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, Phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof , alginate, gelatin, polyvinylpyrrolidone, g
  • the preparation of the present invention is used according to the condition of the patient at the time of use, and can be taken 1-3 times a day, 1-20 doses per time, such as: 1-20 bags or tablets or tablets, each dose of lmg-1000 mg.
  • a microcirculation dynamic observation system was used to examine the dynamic process of thrombus formation and peroxide production by using a rat model of mesenteric venous thrombosis induced by photochemical reaction.
  • flow cytometry Fluorescence Activated Cell Sorter [FACS]
  • FACS Fluorescence Activated Cell Sorter
  • mice Male SD rats weighed 200 ⁇ 250g and were purchased from the Animal Center of Peking University Medical School, certificate number SCXK 2002-0001. Rats were fed a standard mouse (Animal Center, Peking University Medical Center), the temperature was maintained at 24 ⁇ 1 °C, and the relative humidity was 50 ⁇ 1%. All animals were fasted for 12 hours before the experiment, but were free to drink. All animals were treated according to the rules of the Animal Research Committee of Peking University.
  • Hematoporphyrin was purchased from Shanghai Red Green Photosensitive Agent Research Institute (Shanghai, China). DLA was purchased from China National Institute for the Control of Pharmaceutical and Biological Products (China, Beijing). SAB was purchased from Fengshanjian Pharmaceutical Company (Kunming, China). Dihydrorhodamine 123 (DHR) and benzylamine blue were purchased from Sigma-Aldrich (USA).
  • FITC-labeled mouse anti-rat CD11b monoclonal antibody, FITC-labeled mouse anti-rat CD18 monoclonal antibody, FITC-labeled mouse IGA, ⁇ and FITC-labeled mouse IgGl and ⁇ were purchased from BD Biosciences ( United States). All other drugs used are at the highest level of the market.
  • Animals were anesthetized by intraperitoneal injection of 20% urethane (10 ml/kg body weight).
  • the right jugular vein and the left femoral vein were cannulated for injection of the drug.
  • a 2 cm incision was made in the midline of the abdominal cavity to open the abdominal cavity, and the part of the mesenteric ileum (10 to 15 cm from the end of the mesenteric) was gently turned over and hung on a self-made transparent plastic platform.
  • the mesentery was kept at 37 ° C in a constant temperature bath and kept moist by constant perfusion of physiological saline.
  • the hemodynamics of the mesenteric microcirculation was observed by transillumination using an inverted microscope (DM-IRB, Leica, Wetzlar, Germany).
  • the images were transmitted to a color monitor (J2118A, TCL, Huizhou, China) via a camera suspended from a microscope (Jk-TU53H, Toshiba, Tokyo, Japan) and used on DVD (DVR-R25, Malata, Xiamen, China) recording.
  • Jk-TU53H Toshiba, Tokyo, Japan
  • DVD DVR-R25, Malata, Xiamen, China
  • the photosensitizer HMME (1 mg/kg body weight) was injected through the femoral vein.
  • a mercury lamp using a fluorescence microscope is used as a light source (100 W) to illuminate a wavelength of 488 nm of blue light, which is focused on a single blood vessel by a 20-fold eyepiece.
  • the beam spot transmitted through the blood vessel is approximately 250 ⁇ m in diameter.
  • the irradiation was continued until the thrombus reached half of the diameter of the blood vessel, and the dynamic process of thrombosis was monitored by microscopic observation for 30 minutes.
  • Rats were randomly divided into 5 groups of 6 rats each.
  • control group all animals were subjected to basal observation for 10 minutes, and normal saline (2 ml/kg) was injected through the right jugular vein cannula, and observation was continued until the end of the experiment.
  • photochemical reaction group all animals were subjected to a 10-minute basal observation and then injected with normal saline (2 ml/kg) through the right jugular vein cannula. After 20 minutes of basal observation, HMME (1 mg/kg body weight) was injected through the left femoral vein cannula and irradiated.
  • the onset time of the thrombus that is, the interval between the start of irradiation and the appearance of the thrombus, which is judged by platelets adhering to the vessel wall.
  • the half volume of the thrombus that is, the time from the start of irradiation until the thrombus volume reaches half of the diameter of the blood vessel.
  • oxidative stress in the mesenteric venule wall of rats was determined in additional animals.
  • the fluorescent probe dihydrorhodamine DHR (10 ⁇ 1/1) was continuously added to the mesenteric perfusate. When it reacted with hydrogen peroxide (3 ⁇ 40 2 ), it was converted to rhodamin 123 (505/533 nm) at a wavelength of 488 nm. The lower excitation produces fluorescence.
  • the fluorescence intensity of dihydrorhodamine on the wall of the small vein was observed and recorded by a highly sensitive camera (EB CCD camera C7190, Hamamatsu, Japan) before and 30 minutes after the photochemical reaction, using IMAGE-PLUS software. Analyze.
  • the difference in fluorescence intensity between the venule wall and the extra-venous interstitial before photochemical reaction was taken as the baseline value.
  • the fluorescence intensity ratio of dihydrorhodamine (DHR) was the difference between the fluorescence intensity of the venule wall and the extra-venous interstitial at 30 minutes after photochemical reaction. The ratio to the baseline value.
  • the rat mesentery was topically applied with 0.5% toluidine blue for in vivo staining to identify mast cells surrounding the blood vessels.
  • three regions were randomly selected in the center of the illumination area to record the degranulated and non-degranulated mast cells, and the ratio of the degranulated mast cells to the total number of recorded mast cells was calculated, and the expression was degranulated mast cells. percentage(%).
  • Figure 2 shows the effect of SAB and SOD on thrombus when the rat mesenteric venule is exposed to the initial photochemical reaction. It can be seen that no thrombus was observed in the control group. After photochemical stimulation to form a thrombus, the starting time of the thrombus in the photochemical reaction group was 13.77 ⁇ 2.53 s. Obviously, pre-administration of SAB and SOD can prolong the time of photochemical reaction to trigger thromboembolism, and their starting time is: 39.00 ⁇ 4.20s and 52.85 ⁇ 6.08s.
  • Figure 3 shows the effect of SAB and SOD on the half-volume time of rat mesenteric venous thrombosis induced by photochemical reactions.
  • the half-volume time of the thrombus was 50.14 ⁇ 3.85 s, and the pre-administration of SAB did not significantly prolong the thrombus half-volume time.
  • Figure 4 depicts the area ratio of SAB and SOD to the thrombus/spleen of the rat mesenteric vein in photochemical reactions.
  • the left part shows the area ratio measurement method, and the right side is the quantitative evaluation result.
  • the area ratios were 36.32 ⁇ 3.90 and 23.21 ⁇ 5.11 at 10, 20, and 30 minutes after irradiation, respectively.
  • pre-administration of SAB or SOD can significantly reduce the area ratio of thrombus/small veins.
  • the measurement of the fluorescence intensity of the mesenteric venule wall of rats has an indicative effect on photochemical reaction-induced oxidative stress.
  • the results are shown in Fig. 5.
  • no dihydrorhodamine fluorescence was observed in the control group.
  • the fluorescence intensity increased significantly at 30 minutes after irradiation, and the administration of SAB and SOD in advance significantly inhibited the fluorescence intensity induced by photochemical reaction on the venule wall.
  • Salvianolic acid B is the main water-soluble component of Salvia miltiorrhiza. In order to explain its effect on thrombus, this experiment utilizes the thrombus induced by mesenteric photochemical reaction in rats. At the same time, the microcirculation monitoring system is used to ensure the thrombus Dynamic evaluation indicated that salvianolic acid B prolonged the onset of thrombus and inhibited photochemically induced rat mesenteric thrombosis, which may be related to inhibition of peroxide production and inhibition of mast cell degranulation. It shows that salvianolic acid B can be clinically applied to prevent and treat thrombosis.
  • FIG. 1 Effect of SAB and SOD on the initial time of mesenteric thrombosis stimulated by photochemical reactions in rats.
  • PR represents that the animals in the group are only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR represent the pre-administration of SAB and SOD before the photochemical reaction of the animals in the group. Data are expressed as "mean ⁇ standard deviation”. #P ⁇ 0.05 was compared with the photochemical reaction group.
  • Figure 3 Effect of SAB and SOD on half-volume time of rat mesenteric thrombus stimulated by photochemical reactions.
  • the animals in the group represented by PR were only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR were respectively treated with SAB and SOD before the photochemical reaction of the animals in the group.
  • Data are expressed as "mean ⁇ standard deviation”. #P ⁇ 0.05 was compared with the photochemical reaction group.
  • Figure 4 Effect of SAB and SOD on the area ratio of thrombus/spleen in rat mesenteric vein in photochemical reactions.
  • the left part shows the thrombus/venule area ratio and the right side shows the time course of the thrombus/small vein.
  • PR represents that the animals in the group are only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR represent the pre-administration of SAB and SOD before the photochemical reaction of the animals in the group. Data are expressed as "mean ⁇ standard deviation”. *P ⁇ 0.05 Compared with the control group, #P ⁇ 0.05 was compared with the photochemical reaction group.
  • FIG. 5 Effect of SAB and SOD on the ratio of dihydrorhodamine fluorescence intensity in rat mesenteric veins in photochemical reactions.
  • the control animals did not receive any treatment.
  • PR represents that the animals in the group are only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR represent the pre-administration of SAB and SOD before the photochemical reaction of the animals in the group.
  • the data is expressed as "mean ⁇ standard deviation". *P ⁇ 0.05 compared with the control group, #P ⁇ 0.05 compared with the photochemical reaction group.
  • Figure 6 Effect of SAB and SOD on the percentage of mast cells in the mesenchymal degranulation of the rat mesenteric.
  • the control group animals did not receive any treatment.
  • PR represents that the animals in the group are only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR represent the pre-administration of SAB and SOD before the photochemical reaction of the animals in the group.
  • the data is expressed as "mean ⁇ standard deviation”. *P ⁇ 0.05 compared with the control group, #P ⁇ 0.05 compared with the photochemical reaction group.
  • FIG. 7 Effect of SAB and SOD on the expression of adhesion molecules in granulocytes in vitro.
  • Adhesion molecule expression is expressed as fluorescence intensity on the abscissa.
  • the left side is the expression of CDllb and the expression of CD18 on the right side.
  • PR represents that the granulocytes are only stimulated by photochemical reactions.
  • SAB+PR and SOD+PR represent the institute respectively The treatment of SAB and SOD was performed in advance before the photochemical reaction of the granulocytes. Data are expressed as "mean ⁇ standard deviation". *P ⁇ 0.05 compared with the control group, #P ⁇ 0.05 compared with the photochemical reaction group.

Description

丹酚酸 B的抗血栓应用
技术领域
本发明涉及中药产品的新用途， 特别涉及丹参提取物丹酚酸 B在治疗和预防血栓中 的应用。
背景技术
丹参为中国的传统中药，其主要水溶性成分包括丹参酸甲酯，次甲丹参醌，丹参酚，乙， 丙， β-谷 醇，3,4 -二羟基苯甲醛， 丹酚酸 Α，丹酚酸 Β，儿茶精，芸香甙，原儿茶醛，原儿茶酸， 紫草酸， 乳酸，维生素 Ε等. 丹酚酸 Β是丹参的主要水溶性成分之一。
Figure imgf000003_0001
丹酚酸类化合物具有很强的抑制脂质过氧化、清除超氧阴离子和羟基自由基的作用。 其中丹酚酸 Α和 Β活性最强。 丹酚酸 B对脑缺血-再灌注损伤所致线粒体损伤和神经细 胞凋亡有明显抑制作用。 可抗 Caspase-3高表达 PC12细胞的凋亡， 还可抑制 B淀粉样蛋 白（Αβ1-40)纤维形成及 Αβ1-40所致 PC12细胞线粒体损伤和细胞凋亡。属强抗氧化药， 且能消除细胞内钙超载。
血管中的血栓是心血管是心脑血管疾病发生与致命性的决定因素。 对于易感人群来 说， 抗血栓药则被广泛地认为是一种降低这种风险有效的方法。 临床上， 阿斯匹林由于 其可以抑制血小板聚集， 因而已经普遍地应用于这种用途。 然而， 阿斯匹林易导致出血 的副作用促使人们开发出新型抗血栓的治疗方案。
血栓主要由于血管内皮损伤所致， 随着活性氧簇的产生而产生， 而那些活性氧簇则 促进血小板和白细胞表达出选择蛋白和粘附分子从而粘附于内皮。 超氧化物歧化酶 ( SOD), 以及维生素 C和 E报道具有抗血栓的作用。 抗粘附分子的单克隆抗体也发现 具有抑制白细胞粘附于内皮细胞的作用。 因此， 可以设想： 通过抑制活性氧簇的产生和 粘附分子的表达可能在早期中断血栓形成的过程。
本发明人在对丹参中的提取物丹酚酸 B进行的研究过程中， 发现丹酚酸 B具有延迟 血栓发作的作用。 发明内容
本发明提供一种丹参提取物的新的治疗用途。 所述新的治疗用途， 是用丹参提取物 丹酚酸 B治疗和预防血栓。
为此， 本发明提供一种药物新用途， 即用丹参提取物丹酚酸 B制备一种治疗和预防 血栓的药物。
本发明所述的丹酚酸 B是现有技术， 可以从市场上买到， 也可以根据现有技术制备， 符合药用标准即可。 优选纯度>50%， 更优选纯度 >90%， 最优选纯度 >98%。
本发明所述制备的药物， 是用上述丹参提取物丹酚酸 B作为药物活性成分制备成的 药物制剂组合物。
本发明的药物制剂组合物， 根据需要可以含有药物可接受的载体， 其中丹酚酸 B作 为药物活性成分， 其在制剂中所占重量百分比可以是 0.1-99.9%， 其余为药物可接受的载 体。 本发明的药物制剂组合物， 以单位剂量形式存在， 所述单位剂量形式是指制剂的单 位， 如片剂的每片， 胶囊的每粒胶囊， 口服液的每瓶， 颗粒剂每袋， 注射剂的每支等。
本发明的药物制剂组合物可以是任何可药用的剂型， 这些剂型包括： 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。
本发明的中药制剂， 其口服给药的制剂可含有常用的赋形剂， 诸如粘合剂、 填充剂、 稀释剂、 压片剂、 润滑剂、 崩解剂、 着色剂、 调味剂和湿润剂， 必要时可对片剂进行包 衣。
适用的填充剂包括纤维素、 甘露糖醇、 乳糖和其它类似的填充剂。 适宜的崩解剂包 括淀粉、 聚乙烯吡咯烷酮和淀粉衍生物， 例如羟基乙酸淀粉钠。 适宜的润滑剂包括， 例 如硬脂酸镁。 适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合， 填充， 压片等常用的方法制备固体口服组合物。 进行反复混合可使活 性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、 溶液、 乳剂、 糖浆剂或酏剂， 或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。 这种液体制剂可含 有常规的添加剂， 诸如悬浮剂， 例如山梨醇、 糖浆、 甲基纤维素、 明胶、 羟乙基纤维素、 羧甲基纤维素、 硬脂酸铝凝胶或氢化食用脂肪， 乳化剂， 例如卵磷脂、 脱水山梨醇一油 酸酯或阿拉伯胶； 非水性载体（它们可以包括食用油）， 例如杏仁油、 分馏椰子油、 诸如 甘油的酯的油性酯、 丙二醇或乙醇； 防腐剂， 例如对羟基苯甲酯或对羟基苯甲酸丙酯或 山梨酸， 并且如果需要， 可含有常规的香味剂或着色剂。
对于注射剂， 制备的液体单位剂型含有本发明的活性物质和无菌载体。 根据载体和 浓度， 可以将此化合物悬浮或者溶解。 溶液的制备通常是通过将活性物质溶解在一种载 体中， 在将其装入一种适宜的小瓶或安瓿前过滤消毒， 然后密封。 辅料例如一种局部麻 醉剂、 防腐剂和缓冲剂也可以溶解在这种载体中。 为了提高其稳定性， 可在装入小瓶以 后将这种组合物冰冻， 并在真空下将水除去。
本发明的中药制剂， 在制备成药剂时可选择性的加入适合的药物可接受的载体， 所 述药物可接受的载体选自： 甘露醇、 山梨醇、 焦亚硫酸钠、 亚硫酸氢钠、 硫代硫酸钠、 盐酸半胱氨酸、 巯基乙酸、 蛋氨酸、 维生素 C、 EDTA二钠、 EDTA钙钠， 一价碱金属 的碳酸盐、 醋酸盐、 磷酸盐或其水溶液、 盐酸、 醋酸、 硫酸、 磷酸、 氨基酸、 氯化钠、 氯化钾、 乳酸钠、 木糖醇、 麦芽糖、 葡萄糖、 果糖、 右旋糖苷、 甘氨酸、 淀粉、 蔗糖、 乳糖、 甘露糖醇、 硅衍生物、 纤维素及其衍生物、 藻酸盐、 明胶、 聚乙烯吡咯烷酮、 甘 油、 土温 80、 琼脂、 碳酸钙、 碳酸氢钙、 表面活性剂、 聚乙二醇、 环糊精、 β—环糊精、 磷脂类材料、 高岭土、 滑石粉、 硬脂酸钙、 硬脂酸镁等。
本发明的制剂在使用时根据病人的情况确定用法用量， 可每日服 1-3次， 每次 1-20 剂， 如： 1-20袋或粒或片， 每剂 lmg-1000mg。
以下通过实验数据证明本发明的有益效果：
丹酚酸 B对于大鼠光化学反应引起的小静脉血栓的抑制作用
本研究采用微循环动态观察系统， 以光化学反应引发的大鼠肠系膜小静脉血栓为模 型考察了丹酚酸， 简称： SAB， 对于血栓形成以及过氧化物产生的动态过程。 此外， 还 使用了流式细胞仪（荧光激活细胞分拣仪 [FACS] )， 体外考察了 SAB对于大鼠噬中性粒 细胞表达 CDllb/CD18的作用。 血管周围肥大细胞脱颗粒也进行了研究， 用以评价 SAB 的作用。 在每一个实验中， 均采用 SOD作为抗氧剂进行平行对照。
材料和方法
动物
雄性 SD大鼠重 200〜250g，购于北京大学医学部动物中心，证书号 SCXK 2002-0001。 大鼠喂标准鼠伺料（北京大学医学部动物中心）， 温度保持在 24±1 °C， 相对湿度 50±1%。 实验前， 所有动物禁食 12小时， 但可以自由饮水。 所有动物按照北京大学动物研究委员 会的规则进行处理。
试剂
血卟啉 （HMME) 购于上海红绿光敏剂研究所 （中国， 上海）。 DLA购于中国药品 生物制品检定所 （中国， 北京）。 SAB购于风山剑医药公司 （中国， 昆明）。 二氢罗达明 123(DHR)和苯甲胺蓝购于 Sigma-Aldrich公司 （美国）。 FITC标记的小鼠抗大鼠 CDllb 单克隆抗体， FITC标记的小鼠抗大鼠 CD18单克隆抗体， FITC标记的小鼠 IGA， κ和 FITC标记的小鼠 IgGl和 κ购于 BD生物科学公司 （美国）。 所有使用的其它药物均为市 售最高级别。
肠系膜微循环的观察
动物采用腹腔注射 20%乌拉坦 （10ml/kg体重） 进行麻醉。 右颈静脉和左股静脉进 行插管以便注射药物。 腹腔中线切 2cm的切口打开腹腔， 肠系膜回肠部分 （距肠系膜尾 端 10〜15cm的位置）轻轻外翻，挂在自制的透明塑料平台上。肠系膜在恒温槽保持 37°C 并通过不断灌注生理盐水保持湿润。 使用倒置的显微镜 （DM-IRB, Leica, Wetzlar, 德 国） 通过透射照明法观察肠系膜微循环血流动力学。 图像通过悬挂于显微镜上的摄像机 (Jk—TU53H， 东芝， 东京， 日本） 传输至彩色监视器 （J2118A, TCL, 惠州， 中国） 上， 并使用 DVD (DVR-R25, 万利达， 厦门， 中国） 进行记录。 在本研究中， 选择那 些单一的、 无分支且无明显弯曲的、 直径为 25〜45μηι长度为 200μηι的血管测定各项参 数。
血栓的诱发
本实验中采用了光化学血栓法。
简言之， 进行 10分钟基础观察后， 通过股静脉注射光敏剂 HMME ( lmg/kg体重）。 采用荧光显微镜的汞灯作光源 （100W) 照射波长 488nm蓝光光线， 通过 20倍目镜聚焦 于单个的血管上。 透射于血管上的光束点直径大约为 250μηι。 持续照射直至血栓的达到 血管直径的一半， 通过显微镜观察 30分钟监视血栓形成的动态过程。
给药
大鼠随机分成 5组， 每组 6只。 对照组中， 所有动物进行 10分钟的基础观察后， 通 过右侧的颈静脉插管注射生理盐水 （2 ml/kg)， 持续观察直至实验结束。 光化学反应组， 所有动物进行 10分钟的基础观察后通过右侧的颈静脉插管注射生理盐水 （2 ml/kg)， 进 行 20分钟的基础观察后通过左侧股静脉插管注射 HMME ( 1 mg/kg体重） 并进行照射。 在 SAB+光化学反应和 SOD+光化学反应组， 所有进行 10分钟的基础观察后通过右侧颈 静脉注射 SAB ( 10 mg/kg体重） 或 SOD ( 12000单位 /kg体重） 代替生理盐水进行基础 观察， 10分钟后继续通过左侧股静脉注射 HMME ( 1 mg/kg体重）进行照射。 DLA、 SAB 和 SOD溶于生理盐水中。 在照射开始后， 持续观察 30分钟。
血栓形成动态的评价
本实验中， 测定了下列参数用以评价形成的血栓。（a) 血栓起始时间， 即从照射开始 至血栓出现之间的间隔时间，后者通过粘附于血管壁上的血小板进行判断。（b) 血栓的半 体积时间， 即从照射开始至血栓体积到达血管直径的一半的时间。 （c) 血栓 /小静脉的面 积比， 即血栓与小静脉的面积比， 使用 Image-Pro-Plus软件 （Media Cybemetrics公司， 美国）， 在 200μηι长的小静脉范围内， 分别在照射前以及照射后 10、 20和 30分钟时进 行测定。
小静脉壁的氧化应激的可视化观察
如前所述， 大鼠肠系膜小静脉壁的氧化应激在另外的动物中测定。 简言之， 肠系膜 的灌流液中连续加入荧光探针二氢罗达明 DHR ( 10μηιο1/1), 当其与过氧化氢（¾02)反 应便转化成罗达明 123 (505/533 nm) 并在 488nm波长下激发产生荧光。 观察到小静脉 壁上二氢罗达明的荧光强度，分别在光化学反应前和反应后的 30分钟时通过高灵敏的摄 像机 （EB CCD camera C7190， 滨松， 日本） 进行记录， 并采用 IMAGE-PLUS软件进行 分析。 将光化学反应前小静脉壁和静脉外间质的荧光强度差作为基线值， "二氢罗达明 (DHR)荧光强度比" 为光化学反应后 30分钟时小静脉壁与静脉外间质的荧光强度差与 基线值的比值。
肥大细胞脱颗粒在另外的动物中测定。
血管周围肥大细胞脱颗粒率的计数
在观察后 30分钟时， 大鼠肠系膜局部应用 0.5 %甲苯胺蓝进行活体染色来鉴定血管 周围的肥大细胞。在 20倍的目镜下， 在光照区域的中心随机选择三个区域记录脱颗粒和 未脱颗粒的肥大细胞， 计算脱颗粒的肥大细胞与所记录肥大细胞总数的比值， 表达为脱 颗粒的肥大细胞百分率 （％)。
统计
统计学差异采用单因素方差分析法进行计算。 P<0.05为具有显著性。 数据表示为平 均值 ±标准差。
结果
图 2表示当大鼠肠系膜小静脉暴露于光化学反应初始时， SAB和 SOD对于血栓的 作用。 可以看到， 对照组没有观察到血栓。 经过光化学刺激形成血栓， 光化学反应组血 栓的起始时间为 13.77±2.53s。 显然， 预先给予 SAB和 SOD可以延长光化学反应引发血 栓的时间， 它们的起始时间为别为： 39.00±4.20s和 52.85±6.08s。
图 3 表示了 SAB和 SOD对于光化学反应引发的大鼠肠系膜小静脉血栓半体积时间 的影响。光化学组血栓半体积时间为 50.14±3.85s， 而预先给予 SAB没有显著地延长血栓 半体积时间。
图 4描述了 SAB和 SOD对于光化学反应中大鼠肠系膜静脉的血栓 /小静脉的面积比。 左边的部分显示了面积比率的测定方法， 右侧则是其量化的评价结果。 在光化学反应组 中， 照射后 10、 20和 30分钟时， 面积比率分别为 36.32±3.90和 23.21±5.11。 照射后 20 分钟时， 预先给予 SAB或 SOD能显著减少血栓 /小静脉的面积比，
大鼠肠系膜小静脉壁荧光强度的测定对于光化学反应诱发的氧化应激具有指示性的 作用，结果见图 5。如图所示，对照组没有观察到二氢罗达明荧光。相反在光化学反应组， 荧光强度在照射后 30分钟时显著增加，预先给予 SAB和 SOD则可以明显地抑制小静脉 壁上光化学反应诱发的荧光强度。
观察 30分钟后，对光化学反应诱发的大鼠肠系膜血管周围间质脱颗粒的肥大细胞百 分率进行了测定。 结果表明， 光化学反应刺激能够明显增加脱颗粒的肥大细胞百分率 (46.64±7.65 )， 而对照组则为 28.75±2.27。 预先给予 SAB可以明显地抑制化学反应诱发 的大鼠肠系膜中肥大细胞脱颗粒， 而 SOD则没有观察到该作用， 见图 6。
进行了体外实验测定了 SAB或 SOD对于光化学反应诱发的大鼠粒细胞中 CDllb和 CD18表达的作用，结果见图 7。显然，体外光化学反应刺激能够引起大鼠粒细胞中 CDllb 和 CD18 表达的增加。 预先给予 SOD 能够显著抑制光化学反应诱发的大鼠粒细胞中 CDllb的表达， 但是 SAB没有这种作用 （A部分）。 另一方面， 预先给予 SAB和 SOD 能够显著抑制光化学反应诱发的大鼠嗜中性粒细胞中 CD18的表达。
结论
丹酚酸 B是丹参中主要的水溶性成份， 为了说明其对于血栓的作用， 本实验利用了 大鼠肠系膜光化学反应诱发的血栓。 同时， 使用了微循环监视系统， 保证了对于血栓的 动态评价， 说明了丹酚酸 B延长血栓起始时间， 可以抑制光化学引发的大鼠肠系膜血栓， 该作用可能与其抑制过氧化物产生和抑制肥大细胞脱颗粒作用相关。 表明丹酚酸 B可以 临床上应用于预防和治疗血栓。
附图说明
图 1. SAB的化学结构。
图 2. SAB和 SOD对于光化学反应刺激的大鼠肠系膜血栓初始时间的影响。 PR代表 所在组动物只受到光化学反应的刺激。 SAB+PR和 SOD+PR分别代表所在组动物光化学 反应前预先给予 SAB和 SOD治疗。 数据以 "平均值±标准差"的方式表达。 #P<0.05与光 化学反应组比较。
图 3. SAB和 SOD对于光化学反应刺激的大鼠肠系膜血栓半体积时间的影响。 PR代 表所在组动物只受到光化学反应的刺激 SAB+PR和 SOD+PR分别代表所在组动物光化学 反应前预先给予 SAB和 SOD治疗。 数据以 "平均值±标准差"的方式表达。 #P<0.05与光 化学反应组比较。
图 4. SAB和 SOD对于光化学反应中大鼠肠系膜静脉的血栓 /小静脉的面积比的影响。 左边的部分显示了血栓 /小静脉面积比率的测定方法， 右侧则是血栓 /小静脉的时间进程。 PR代表所在组动物只受到光化学反应的刺激。 SAB+PR和 SOD+PR分别代表所在组动物 光化学反应前预先给予 SAB和 SOD治疗。数据以 "平均值±标准差"的方式表达。 *P<0.05 与对照组比较， #P<0.05与光化学反应组比较。
图 5. SAB和 SOD对于光化学反应中大鼠肠系膜静脉的二氢罗达明荧光强度比率的 影响。 对照组动物不进行任何治疗。 PR代表所在组动物只受到光化学反应的刺激。 SAB+PR和 SOD+PR分别代表所在组动物光化学反应前预先给予 SAB和 SOD治疗。 数 据以"平均值 ±标准差 "的方式表达。*P<0.05与对照组比较， #P<0.05与光化学反应组比较。
图 6. SAB和 SOD对于大鼠肠系膜周围间质脱颗粒的肥大细胞百分率的影响。 对照 组动物不进行任何治疗。 PR代表所在组动物只受到光化学反应的刺激。 SAB+PR和 SOD+PR分别代表所在组动物光化学反应前预先给予 SAB和 SOD治疗。数据以"平均值 ±标准差"的方式表达。 *P<0.05与对照组比较， #P<0.05与光化学反应组比较。
图 7. SAB和 SOD对于体外粒细胞中粘附分子表达的影响。 粘附分子表达以横坐标 上的荧光强度表示。 左侧为 CDllb的表达， 右侧 CD18的表达。 对照组粒细胞不进行任 何治疗。 PR代表所在粒细胞只受到光化学反应的刺激。 SAB+PR和 SOD+PR分别代表所 在组粒细胞在光化学反应前预先给与 SAB和 SOD治疗。数据以 "平均值±标准差"的方式 表达。 *P<0.05与对照组比较， #P<0.05与光化学反应组比较。
具体实施方式
以下通过实施例进一步说明本发明， 但不作为对本发明的限制。
实施例 1
病例 1
女 65岁， 清晨突发脑血栓， 通过 CT、 核磁共振显示脑干区有梗塞， 使用丹酚酸 B注射 液救治， 5天一个疗程， 第 1个疗程用完， 腿可以运动了； 第 2个疗程用完， 可以搀扶走 路， 第 3个疗程， 拄拐杖能够行走。

Claims

权利要求书
1、 丹酚酸 B在制备一种治疗和预防血栓药物中的应用。
2、 权利要求 1的应用， 其特征在于， 所述丹酚酸 B能延长血栓起始时间。
3、权利要求 1的应用， 其特征在于， 所述丹酚酸 B被制备成药物制剂组合物用于人类血 栓疾病。
4、 权利要求 3的应用， 其特征在于， 所述药物制剂组合物， 以丹酚酸 B作为药物活性成 分， 同时含有药物可接受的载体， 其中丹酚酸 B在制剂中所占重量百分比是 0.1-99.9%， 其余为药物可接受的载体。
5、 权利要求 3的应用， 其特征在于， 所述药物制剂组合物， 在使用时根据病人的情况确 定用法用量， 可每日服 1-3次， 每次 1-20剂， 每剂 lmg-1000mg。
6、 权利要求 4的应用， 其特征在于， 所述药物可接受的载体选自： 甘露醇、 山梨醇、 焦 亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素 C、 EDTA 二钠、 EDTA钙钠， 一价碱金属的碳酸盐、 醋酸盐、 磷酸盐或其水溶液、 盐酸、 醋酸、 硫酸、 磷酸、 氨基酸、 氯化钠、 氯化钾、 乳酸钠、 木糖醇、 麦芽糖、 葡萄糖、 果糖、 右 旋糖苷、 甘氨酸、 淀粉、 蔗糖、 乳糖、 甘露糖醇、 硅衍生物、 纤维素及其衍生物、 藻酸 盐、 明胶、 聚乙烯吡咯烷酮、 甘油、 土温 80、 琼脂、 碳酸钙、 碳酸氢钙、 表面活性剂、 聚乙二醇、 环糊精、 β—环糊精、 磷脂类材料、 高岭土、 滑石粉、 硬脂酸钙、 硬脂酸镁。
7、 权利要求 5的应用， 其特征在于， 所述药物制剂组合物是注射剂。
8、 权利要求 1的应用， 其特征在于， 丹酚酸 Β的纯度 >50%。
9、 权利要求 1的应用， 其特征在于， 丹酚酸 Β的纯度 >90%。
10、 权利要求 1的应用， 其特征在于， 丹酚酸 Β的纯度 >98%。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006582A (zh) * 2012-11-20 2013-04-03 陆文萍 一种丹酚酸a冻干粉针及其制备药物用途
CN110563677A (zh) * 2019-08-23 2019-12-13 惠州市九惠制药股份有限公司 一种丹酚酸b及其粉雾剂胶囊和制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102861128B (zh) * 2012-07-30 2014-10-08 邵文远 丹参多酚酸有效部位在制备治疗皮肤病制剂中的应用
CN116590395A (zh) * 2023-04-06 2023-08-15 广东医科大学附属医院 Hdac10作为靶点在制备stat3相关疾病药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080111200A (ko) * 2007-06-18 2008-12-23 계명대학교 산학협력단 단삼 추출물을 포함하는 혈전 형성 예방용 기능성 식품 및 약학 조성물

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2294680T3 (es) * 2004-03-01 2008-04-01 B. Braun Melsungen Ag Hidroxietilalmidon.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080111200A (ko) * 2007-06-18 2008-12-23 계명대학교 산학협력단 단삼 추출물을 포함하는 혈전 형성 예방용 기능성 식품 및 약학 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Proceedings of the ninth China national academic congress on cardiovascular pharmacology, 2007", article WU HONGLI ET AL.: "Study of the effect of salvianolic acid B on vascular endothelial cells damage induced by hydrogen peroxide and mechanism thereof.", pages: 101 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103006582A (zh) * 2012-11-20 2013-04-03 陆文萍 一种丹酚酸a冻干粉针及其制备药物用途
CN103006582B (zh) * 2012-11-20 2015-02-18 江西青峰药业有限公司 一种丹酚酸a冻干粉针及其制备药物用途
CN110563677A (zh) * 2019-08-23 2019-12-13 惠州市九惠制药股份有限公司 一种丹酚酸b及其粉雾剂胶囊和制备方法

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