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WO2013155742A1 - 六味地黄制剂在制备治疗心脏支架术后治疗药物的用途 - Google Patents

六味地黄制剂在制备治疗心脏支架术后治疗药物的用途 Download PDF

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WO2013155742A1
WO2013155742A1 PCT/CN2012/075353 CN2012075353W WO2013155742A1 WO 2013155742 A1 WO2013155742 A1 WO 2013155742A1 CN 2012075353 W CN2012075353 W CN 2012075353W WO 2013155742 A1 WO2013155742 A1 WO 2013155742A1
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dropping
group
preparation
polyethylene glycol
liuwei dihuang
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PCT/CN2012/075353
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English (en)
French (fr)
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王凤越
张艳侠
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江苏颐海药业有限责任公司
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Publication of WO2013155742A1 publication Critical patent/WO2013155742A1/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
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • 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)
    • A61K36/40—Cornaceae (Dogwood family)
    • 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)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • 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)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • 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)
    • A61K36/884—Alismataceae (Water-plantain family)
    • 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)
    • A61K36/894—Dioscoreaceae (Yam family)
    • A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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

Definitions

  • the invention relates to a new use of a traditional Chinese medicine preparation.
  • Liuwei Dihuang Pill consists of rehmannia, hawthorn, yam, peony bark, diarrhea and medlar. It can be seen from the compatibility of drugs. It is based on the combination of Bushen Yin and tonifying the liver and spleen. The formula of Liuwei Dihuang Pill has the characteristics of three supplements and three diarrhea: Liuwei Dihuang Pills reuses the radix replenishing yin and tonifying the kidney, filling the marrow and purifying the marrow.
  • Alisma is damp and diarrhea, and can reduce the nourishment of rehmannia, dilute the spleen and wet, and help the health of yam, and diarrhea and diarrhea with diarrhea, help the real yin to regain its position, Danpi clear deficiencies Heat, and the warmth of the hawthorn, the three drugs are called Sanxie, all of which are adjuvants.
  • Six flavors are combined, three supplements and three diarrhea, in which the amount of supplemental medicine is heavier than laxatives, which is mainly based on supplementation, liver, spleen and kidney, and yin and tonification.
  • kidney yin deficiency caused by weak waist and knees, dizziness, tinnitus, hand and foot fever, nocturnal emission and night sweats. After being verified by doctors of previous generations, the clinical curative effect is remarkable, and it has been passed down to this day. 'The ancestor of the prescription for yin.'
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which are used to lower cholesterol, triglycerides and phospholipids, and increase high-density lipoprotein to prevent recurrence of myocardial infarction.
  • statins which
  • the present invention provides a novel use of a Liuwei Dihuang preparation.
  • the invention relates to the use of a Liuwei Dihuang preparation for the preparation of a medicament for treating a cardiac stent.
  • Liuwei Dihuang preparation has the functions of enhancing immunity, anti-wet, anti-hypoxia, anti-low temperature, lowering blood fat, lowering blood pressure and lowering blood sugar, as follows:
  • Effects on immune function can activate cellular immunity, promote the induction of interferon by tonsil cells, and increase serum interferon levels;
  • Dilation of blood vessels has a significant antihypertensive effect on arterial stenosis hypertension
  • the effect on blood lipids can significantly reduce cholesterol, triglycerides and phospholipids, increase high-density lipoprotein, increase HDL-C/TC
  • the ratio promotes lipid metabolism, and long-term use has the effect of preventing atherosclerosis.
  • the Liuwei Dihuang preparation may be a pill, a capsule, a tablet, a soft capsule or a dropping pill, preferably a Liuwei Dihuang Pill, which is composed of a rehmannia, hawthorn, peony bark, yam, and Alisma. 6 composed of ⁇
  • the extract of the traditional Chinese medicine is obtained as a raw material, and is prepared together with a carrier as a matrix of the dropping pills, and is characterized in that:
  • the weight ratio of the extract of the 6 Chinese herbal medicines to the substrate is 1 : 1 to 8 ;
  • the dropping pill matrix has a weight average molecular weight of 6000 and a viscosity distribution of 13.6 to 14.5. Between the polyethylene glycol, the polyethylene glycol of the kind of polyethylene glycol has a weight content of 40 to 60%;
  • the condensing agent is at least one of methyl silicone oil, liquid paraffin or vegetable oil, take out the dropping pills, wash and dry.
  • the molecular weight of the invention is 6000.
  • the weight of polyethylene glycol is 40-60% PEG6000 (that is, polyethylene glycol with a weight average molecular weight of 6000).
  • the viscosity of this polyethylene glycol is between 13.6 and 14.5.
  • the dosage is the conventional dose of the Liuwei Dihuang preparation.
  • Liuwei Dihuang preparation has a promoting effect on the rehabilitation of patients after cardiac stenting, which on the one hand improves blood rheology, reduces whole blood viscosity, and significantly lowers cholesterol, triglyceride and phospholipid, and increases High-density lipoprotein can prevent the recurrence of myocardial infarction. On the other hand, it also increases the body's immunity and anti-wet effect, and improves the body's function, so that the drug can exert better therapeutic effect.
  • the hydrochloric acid solution is crystallized and used; the distilled aqueous solution and the peony bark residue, the hawthorn dregs, the remaining barium, and the rehmannia root, the yam and the diarrhea are boiled three times, each time 1 Hour, filter, combine the filtrate, concentrate to a thick paste; add the above-mentioned fine powder and hawthorn thick paste, mix, low-temperature drying, pulverize into fine powder, add the above-mentioned peony bark extract, and mix to obtain Liuwei Dihuang powder;
  • the matrix is made of polyethylene glycol 6000. (weight average molecular weight), the viscosity of the polyethylene glycol is 14%, and the weight percentage of the polyethylene glycol having a molecular weight of 6000 is 50%;
  • the peony bark is distilled to extract the volatile oil, and the volatile oil of the peony bark is obtained.
  • the aqueous solution is collected after 8 hours of distillation; the hawthorn is added 70%.
  • the ethanol is refluxed and extracted twice, each time for 2 hours, the extract is combined, filtered, and the filtrate is reserved; the rehmannia root, yam, and diarrhea are boiled twice with water, and the first time added 8 times the amount of water for 2 hours, the second Add 6 times the amount of water to cook 1 hour, the decoction was combined, filtered, and the filtrate was combined with the above distilled aqueous solution, concentrated under reduced pressure to a clear density of 1.15 to 1.20, and allowed to cool, add ethanol to make the alcohol content up to 70%, stir well, static Set After 48 hours, the supernatant was combined with the above extract of Hawthorn, and the ethanol was recovered under reduced pressure until it was tasteless.
  • the hardness is expressed in the attached table by placing the dropping pill on a glass plate and pressing it with a finger to observe the change in morphology.
  • '+ 'It means that the tap is deformed
  • ' ++ ' means to force the deformation
  • ' +++ ' means that it is not deformed by force.
  • Method of administration and dosage Liuwei Dihuang Dropping Pills Group 0.85g/Kg/d, administered intragastrically three times a day, the control group 0.40mg/Kg/d, administered intragastrically three times a day; for one month in a row;
  • the Liuwei Dihuang Dropping Pill group can significantly reduce the levels of TC, TG, and LDL-C in the hyperlipidemia model ( P ⁇ 0.05 or P ⁇ 0.01), and in the aspect of increasing HDL-C, the Liuwei Dihuang Dropping Pill group was superior to the fenofibrate group.
  • the high fat model group was P ⁇ 0.05; Compared with the high fat model group, the Liuwei Dihuang Drop Pill Group and the fenofibrate control group were compared with the high fat model group (P ⁇ 0.05). ** The Liuwei Dihuang Dropping Pill Group and the fenofibrate control group were compared with the high fat model group. P ⁇ 0.01 .
  • mice 80 female mice, weighing 18 to 22 g.
  • Grouping and dose design dose, 0.85g / Kg / d.
  • the trials were randomly divided into 8 groups according to their body weight, each group 10 animals, each 2 groups is a large group, a total of four groups, respectively, a group of immunization: plaque, hemolysin determination; immune two groups: organ index, mouse peritoneal macrophage phagocytosis chicken red blood cell test; immunity Three groups: NK Activity, leaching test; four groups of immunization: DTH test.
  • Experimental data statistical method experimental data to SPSS The software performs one-way analysis of variance. After the homogeneity test of variance, the experimental data of variance was analyzed by LSD method, and the experimental data of variance was statistically analyzed by Tambane method.
  • DTH test The abdominal skin of mice is treated with an electric razor for a hair removal process, with a range of about 3 cm. *3cm, then evenly sensitize with 50 ⁇ L of DNFB solution; after 5 days, apply evenly on the right side of the mouse with 10 ⁇ l of DNFB solution for attack. twenty four After the hour, the mice were sacrificed by cervical dislocation. The left and right ears were cut out, and the ear piece with a diameter of 8 mm was removed by a puncher to calculate the weight difference between the left and right ears.
  • Antibody-producing cell assay The cervical spine of the animal was dissected, the spleen was taken, ground with a glass homogenizer, and filtered through four layers of gauze, centrifuged (1000 rpm for 10 min), using Hank's Wash twice. Splenocytes were suspended in 8 mL of Hank's solution.
  • the surface medium (1g agarose plus double distilled water 100mL) was heated and dissolved, and then placed in a 45 °C water bath to keep warm, with the same amount Mix the pH of 7.2 ⁇ 7.4, 2 times the concentration of Hank's solution, dispense small tubes, 0.5mL per tube, then add 50 ⁇ L 10% SRBC, 25 ⁇ L to the tube
  • the spleen cell suspension was quickly mixed, poured onto a 6 cm plate of a brushed agar layer, incubated in a carbon dioxide incubator for 1.5 h, and then diluted with SA buffer (1:10). ), after continuing to incubate for 1.5 h, count the number of hemolysis plaques.
  • mice were removed from the eye and collected at 2000 r/min for 10 min. The serum was separated, and the serum was diluted with physiological saline. The serum of different dilutions was placed in a micro-hemagglutination plate, 100 ⁇ L per well, and then 100 ⁇ L of 0.5% (V/V) SRBC was added. The suspension was mixed, placed in a humidified flat plate, and incubated at 37 ° C for 3 h to observe the degree of hemagglutination.
  • V/V 0.5%
  • mice NK cell activity (Lactate dehydrogenase LDH assay): The target cells were subcultured 24 hours before the test, washed three times with Hank's solution before use, and the cell concentration was adjusted with RPMI 1640 complete medium. 4* 10 5 /mL. The spleen cell suspension was washed twice with Hank's solution and centrifuged for 10 min (1000 r/min) each time. Discard the supernatant and bounce the cytoplasm. Add 0.5 mL of sterilized water for 20 seconds.
  • red blood cells After lysing the red blood cells, add 0.5 mL of 2 times Hank's solution and 8 mL of Hank's solution, centrifuge for 10 min (1000 r/min), and resuspend with 1 mL of complete medium. 1% glacial acetic acid was diluted and counted. The number of viable cells was counted by phenol blue staining (should be above 95%), and the cell concentration was adjusted to 2*10 7 cells/mL.
  • target cells and effector cells (50:1 target ratio) and add to 96-well culture plates; target cells naturally release wells plus target cells and culture medium 100 ⁇ L each, target cells maximal release wells plus target cells and 1% 100 ⁇ L of NP40, each of which has three parallel wells, and cultured in a 37 ° C, 5% CO 2 incubator for 4 hours, then centrifuge the plate (1500 r / min) for 5 min, and take 100 ⁇ L of supernatant from each well.
  • a 96-well culture plate 100 ⁇ L of LDH substrate solution was added at the same time for 3 min, and 30 ⁇ L of 1 mol/L HCl was added to each well, and the optical density value (OD) was measured at 490 nm of the microplate reader to calculate the activity of NK cells.
  • mice in the drug-administered group was significantly higher than that in the control group, and the statistical difference was statistically significant ( P ⁇ 0.01), the results are shown in Table 7.
  • Mouse peritoneal macrophage phagocytosis chicken red blood cell test the phagocytic index of erythrocyte phagocytosis in the peritoneal macrophages of the mice in the administration group was significantly higher than that in the control group, and the statistical difference was statistically significant (P ⁇ 0.01). However, the phagocytic rate of erythrocyte phagocytosis in the peritoneal macrophages of the mice in the administration group was not statistically significant compared with the control group. The results are shown in Table 9.
  • Phagocytosis rate % Phagocytic index Control group 10 9.03 ⁇ 1.08 0.13 ⁇ 0.01 G 10 10.50 ⁇ 1.20 0.16 ⁇ 0.02**
  • NK cell activity assay The NK cell activity was significantly enhanced in the drug-administered group, and the difference was statistically significant compared with the control group ( P ⁇ 0.01), and the results are shown in Table 10.

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Abstract

本发明公开了六味地黄制剂在制备治疗心脏支架术后治疗药物的用途。

Description

六味地黄制剂在制备治疗心脏支架术后治疗药物的用途 技术领域
本发明涉及一种传统中药制剂的新用途。
背景技术
六味地黄丸由熟地、山茱萸、山药、牡丹皮、泽泻和茯苓组成，从药物配伍上可以看到，其是以补肾阴和补肝脾结合，并以补肾阴为主。六味地黄丸的配方具有三补三泻的特点：六味地黄丸重用熟地滋阴补肾、填精益髓，是为君药，山茱萸补养肝肾，并能涩精，取肝肾同源之意，山药补益脾阴，亦能固肾，共为臣药，三药配合，肾肝脾三阴并补，是为三补，但熟地黄用量是山萸肉和山药之和，故仍以补肾为主。泽泻利湿而泄肾浊，并能减熟地黄之滋腻，茯苓淡渗脾湿，并助山药之健运，与泽泻共泻肾浊，助真阴得复其位，丹皮清泄虚热，并制山茱萸之温涩，三药称为三泻，均为佐药。六味合用，三补三泻，其中补药用量重于泻药，是以补为主，肝脾肾三阴并补，以补肾阴为主。其主要用于肾阴虚引起的腰膝酸软、头晕耳鸣、手脚心发热、遗精盗汗等症状，经过历代医家的验证，临床疗效显著，从而留传至今，被誉为 '补阴 方药之祖 ' 。
心脏支架术后病人需要长期服用抗凝药物（如氯吡格雷），同时还需要服用他汀类药物，其用于降低胆固醇、甘油三酯和磷脂，增加高密度脂蛋白，以防止心肌梗塞复发。同时，由于心脏支架术后病人常常还存在免疫力低下的问题，因此，还需要服用药物提高人体免疫机能。这样，使得病人服用药物过多，且由于他汀类药物存在肌肉溶解的风险，肌肉酸痛、无力更是常见的副作用，因此，迫切需要找到一个替代药品。
 技术问题
心脏支架术后病人需要长期服用抗凝药物（如氯吡格雷），同时还需要服用他汀类药物，其用于降低胆固醇、甘油三酯和磷脂，增加高密度脂蛋白，以防止心肌梗塞复发。同时，由于心脏支架术后病人常常还存在免疫力低下的问题，因此，还需要服用药物提高人体免疫机能。这样，使得病人服用药物过多，且由于他汀类药物存在肌肉溶解的风险，肌肉酸痛、无力更是常见的副作用，因此，迫切需要找到一个替代药品。
 技术解决方案
本发明提供了一种六味地黄制剂的新用途。
本发明涉及六味地黄制剂在制备治疗心脏支架术后治疗药物的用途。
申请人在研究中发现，六味地黄制剂同时具有增强免疫、抗疲惫、耐缺氧、抗低温、降血脂、降血压、降血糖的作用，具体如下：
抗疲惫、抗低温、耐缺氧作用与人参相似；
对免疫功能的影响：能激活细胞免疫，促进扁桃体细胞诱生干扰素，提高血清干扰素水平；
扩张血管，对动脉狭窄性高血压有明显的降压作用；
改善血液流变性，降低全血粘度、血浆粘度、纤维蛋白原，抑制梗死心脏中氧自由基的天生，缩小梗死面积，防治冠心病、心肌梗塞；
对血脂的影响，可明显降低胆固醇、甘油三酯和磷脂，增加高密度脂蛋白，增大 HDL-C/TC 的比值，促进脂质代谢，长期服用有防止动脉粥样硬化的作用。
在推荐的实施例中，所述的六味地黄制剂可以是丸剂、胶囊、片剂、软胶囊或滴丸，优选使用六味地黄滴丸，其是以由熟地、山茱萸、牡丹皮、山药、泽泻和茯苓组成的 6 味中药的提取物为原料，与作为滴丸基质的载体共同制备获得，其特征在于：
1 ）所述 6 味中药的提取物与所述基质的重量比为 1 ： 1 ～ 8 ；
2 ）所述 6 味中药的提取物采用药典或部颁标准中所规定的方法获得；
3 ）所述滴丸基质为重均分子量为 6000 、粘度分布在 13.6 ～ 14.5 之间的聚乙二醇，该种聚乙二醇中，分子量为 6000 的聚乙二醇的重量含量为 40 ～ 60% ；
4 ）按照上述比例准确称取提取物和基质，置于加热容器内加热使熔融，搅拌均匀，而后置入滴丸机内，在 75 ℃～ 100 ℃，滴入 30 ℃～ -8 ℃的冷凝剂中，所述冷凝剂为甲基硅油、液体石蜡或植物油中的至少一种，取出滴丸，洗净、干燥后获得。
 有益效果
经研究发现，同样的 PEG6000 （亦即，重均分子量为 6000 的聚乙二醇），因其是 PEG1 ～ PEG+ ∞的混合体，呈正态分布，这其中，以分子量为 6000 的 PEG 含量最大，一般在 5% 左右。而本发明选用分子量为 6000 的聚乙二醇重量含量在 40 ～ 60% 的 PEG6000 （亦即，重均分子量为 6000 的聚乙二醇），这种聚乙二醇的粘度分布在 13.6 ～ 14.5 之间，聚合度最高，以其作为滴丸基质，可获得圆整度高、硬度高，且融散时间控制在 5 ～ 15 分钟之间的滴丸，确保药品可以真正速效、高效地发挥药理作用。
在将六味地黄制剂用于心脏支架术后病人康复治疗之时，其给药剂量为六味地黄制剂常规给药剂量。
鉴于六味地黄制剂上述的功能，因此，六味地黄制剂对于心脏支架术后病人的康复具有促进作用，其一方面改善血液流变性，降低全血粘度，并明显降低胆固醇、甘油三酯和磷脂，增加高密度脂蛋白，从而可以防止心肌梗塞复发，另一方面，它还同时具有增加人体免疫、抗疲惫作用，提高人体机能，使得药物可以发挥更好的疗效。
 本发明的实施方式
下面结合实施例对本发明做进一步的描述，但不构成对本发明的任何限制。
实施例 1
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、取茯苓 350g 粉碎成细粉；山茱萸加乙醇回流提取二次，每次 1 小时，滤过，药渣备用，滤液回收乙醇，浓缩至稠膏状；牡丹皮用水蒸气蒸馏，蒸馏液加入 1mol/L 盐酸溶液使结晶，备用；蒸馏后的水溶液及牡丹皮药渣、山茱萸药渣、剩余茯苓、及熟地黄、山药和泽泻加水煎煮三次，每次 1 小时，滤过，合并滤液，浓缩至稠膏状；加入上述茯苓细粉及山茱萸稠膏，混匀，低温干燥，粉碎成细粉，加入上述牡丹皮提取物，混匀即得六味地黄粉末；
3 、按照 1:2 的比例添加六味地黄提取物和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 14% ，且分子量为 6000 的聚乙二醇重量百分比含量为 50% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 80 ～ 85 ℃，然后以适当的速度，滴入 10 ～ 5 ℃的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得。
实施例 2
1 、取熟地黄 1408g ，牡丹皮 528g ，山药 704g ，山茱萸 704g ，泽泻 528g 和茯苓 528g ；
2 、牡丹皮蒸馏提取挥发油，获得牡丹皮挥发油，蒸馏 8 小时后的水溶液另器收集；山茱萸加 70% 的乙醇回流提取二次，每次 2 小时，合并提取液，滤过，滤液备用；熟地黄、山药、泽泻加水煎煮两次，第一次加 8 倍量水煎煮 2 小时，第二次加 6 倍量水煎煮 1 小时，合并煎液，滤过，滤液与上述蒸馏后的水溶液合并，减压浓缩至相对密度为 1.15 ～ 1.20 的清膏，放冷，加乙醇使含醇量达 70% ，搅匀，静置 48 小时，取上清液与上述山茱萸提取液合并，减压回收乙醇到无醇味，备用；茯苓加水煮沸后，于 80 ℃温浸二次，每次加 6 倍量水，温浸 1.5 小时，合并浸出液，滤过，滤液减压浓缩至相对密度为 1.15 ～ 1.20 （ 50 ℃）的清膏，与上述备用液合并，浓缩至相对密度为 1.30(50 ℃ ) 的稠膏，减压干燥，粉碎成细粉，获得提取物粉末；取牡丹皮挥发油和提取物粉末备用；
3 、按照 1:8 的比例添加六味地黄提取物（由牡丹皮挥发油和提取物粉末组成）和基质，并混匀，基质选用聚乙二醇 6000 （重均分子量），该种聚乙二醇的粘度为 14% ，且分子量为 6000 的聚乙二醇重量百分比含量为 60% ；
4 、将混合物料加热至熔融，搅拌均匀；
5 、将上述物料加入滴丸机，保持温度为 95 ～ 100 ℃，然后以适当的速度，滴入 0 ～ -8 ℃的甲基硅油中，待收缩成型后取出，去掉甲基硅油，干燥即得。
表 1 六味地黄滴丸的测试数据
项目 圆整率 硬度 融散时限（分钟）
实施例 1 92 +++ <5
实施例 2 92 +++ <5
注，附表中的硬度表示方法，是采用将滴丸置于玻璃板上，用手指按压之，观察其形态变化。这其中，' + '表示轻按即变形，' ++ '表示用力按之变形，' +++ '表示用力按之不变形。
试验例 1
取 SD 大鼠 40 只，随机分成 4 组，分别为正常对照组（ I ）、高脂模型组（ II ）、六味地黄滴丸组（ III ，实施例 1 中制得）和非诺贝特对照组（ IV ）；高脂模型组、六味地黄滴丸组和非诺贝特对照组脂肪乳剂采用灌胃法造模；
服用方法及服用剂量：六味地黄滴丸组 0.85g/Kg/d ，每日灌胃给药三次，对照组 0.40mg/Kg/d ，每日灌胃给药三次；连续服用一个月；
对高脂血症大鼠血脂和血液流变学的影响
实验结果如表 2 中所示。
表 2 对高脂血症大鼠血脂和血液流变学的影响
组别 TC TG HDL-C LDL-C
正常对照组 2.95 ± 0.15 1.04 ± 0.08 2.02 ± 0.12 0.85 ± 0.05
高脂模型组 3.88 ± 0.14* 1.69 ± 0.05** 1.65 ± 0.10** 1.95 ± 0.11**
六味地黄滴丸组 3.15 ± 0.09** 1.05 ± 0.10** 2.12 ± 0.05** 1.55 ± 0.10*
非诺贝特对照组 3.32 ± 0.19* 1.12 ± 0.11** 1.50 ± 0.06 1.51 ± 0.15*
* 高脂模型组和正常对照组相比较 P<0.05 ， ** 高脂模型组和正常对照组相比较 P<0.01 ； * 六味地黄滴丸组、非诺贝特对照组与高脂模型组相比较 P<0.05 ， ** 六味地黄滴丸组、非诺贝特对照组与高脂模型组相比较 P<0.01 。
结果，六味地黄滴丸组能显著降低高脂血模型的 TC 、 TG 、 LDL-C 的水平（ P<0.05 或 P<0.01 ），且在升高 HDL-C 方面，六味地黄滴丸组优于非诺贝特组。
对高脂血症大鼠全血粘度、血浆粘度的影响
实验结果如表 3 中所示。
表 3 对高脂血症大鼠全血粘度、血浆粘度的影响
组别 全血粘度 血浆粘度
5S-1 200S-1
正常对照组 13.4 ± 0.2 6.0 ± 0.3 1.68 ± 0.01
高脂模型组 17.6 ± 1.2* 6.4 ± 0.5 1.96 ± 0.05*
六味地黄滴丸组 10.5 ± 1.0** 5.1 ± 0.6* 1.04 ± 0.38**
非诺贝特对照组 14.2 ± 0.5* 5.8 ± 0.3* 1.85 ± 0.15
* 高脂模型组和正常对照组相比较 P<0.05 ； * 六味地黄滴丸组、非诺贝特对照组与高脂模型组相比较 P<0.05 ， ** 六味地黄滴丸组、非诺贝特对照组与高脂模型组相比较 P<0.01 。
结果显示，六味地黄滴丸组可显著降低全血粘度和血浆粘度。
试验例 2
1 材料和方法
1.1 样品：实施例 2 中制得的六味地黄滴丸；
1.2 实验动物：雌性小白鼠 80 只，体重 18 ～ 22g 。
1.3 分组及剂量设计：给药剂量， 0.85g /Kg/d 。试验按体重随机分成 8 小组，每小组 10 只动物，每 2 小组为一个大组，共四大组，分别为免疫一组：空斑、溶血素测定；免疫二组：脏器指数、小鼠腹腔巨噬细胞吞噬鸡红细胞试验；免疫三组： NK 活性、淋转试验；免疫四组： DTH 试验。
1.4 仪器与试剂：
1.4.1 仪器： 8mm 直径打孔器、微量血凝试验板、 2-16K 通用离心机、 MODEL680 酶标仪、 96 孔培养板、 Co-150CO2 培养箱、分光光度计、倒置显微镜、电子天平、显微镜。
1.4.2 试剂：注射用墨汁、刀豆蛋白（ ConA ）、 MTT 、 DNFB 、丙酮、麻油、 SRBC 、生理盐水、鸡红细胞、羊红细胞、甲醇、 Giemsa 染液、 YAC-1 细胞、 Hanks 液（ PH7.2-7.4 ）、 RPMI1640 完全培养液、乳酸锂、碘硝基氯化四氮唑（ INT ）、吩嗪二甲酯硫酸盐（ PMS ）、 NAD 、 Tris-HCl 缓冲液（ pH8.2 ）、 1%NP40 、台酚兰、 1mol/L 盐酸、酸性异丙醇等。
1.5 实验数据统计方法：实验数据以 SPSS 软件进行单因素方差分析。经方差齐性检验，方差齐的实验数据采用 LSD 法进行统计分析，方差不齐的实验数据采用 Tambane 法进行统计分析。
1.6 试验方法：连续灌胃 30 天后，分别进行以下试验。
1.6.1 迟发型变态反应（ DTH ）检测：小鼠腹部皮肤用电动剃毛刀进行脱毛处理，范围约 3cm *3cm ，后用 DNFB 溶液 50μL 均匀涂抹致敏； 5 天后，再用 DNFB 溶液 10μ l 均匀涂抹于小鼠右耳两面进行攻击。 24 小时后颈椎脱臼处死小鼠，剪下左右两耳，用打孔器取下直径 8mm 的耳片称重，计算左右耳重量差值。
1.6.2 抗体生成细胞和血清溶血素测定：每鼠腹腔注射 2% （ V/V ） SRBC 悬液 0.2mL 进行免疫。 5 天后，摘除眼球采血做血清溶血素检测，并将动物颈椎脱臼处死，取脾脏进行抗体生成细胞检测。
1.6.2 .1 抗体生成细胞检测：将动物颈椎脱臼处死，取脾脏，用玻璃匀浆器磨碎，并通过四层纱布过滤，离心（ 1000 转 /10min ） , 用 Hank's 液洗两遍。将脾细胞悬浮于 8mLHank's 液中。将表层培养基（ 1g 琼脂糖加双蒸水 100mL ）加热溶解后，放入 45 ℃ 水浴保温，与等量的 pH7.2 ～ 7.4 、2 倍浓度的 Hank's 液混合，分装小试管，每管 0.5mL ，再向管内加入 50μL 10%SRBC 、 25μL 脾细胞悬液，迅速混匀，倾倒于已刷琼脂薄层的 6cm 平皿上，放入二氧化碳培养箱中温育 1.5h ，然后用 SA 缓冲液稀释的补体（ 1 ： 10 ）加入，继续温育 1.5h 后，计数溶血空斑数。
1.6.2 .2 血清溶血素的测定：将小鼠摘除眼球采血，于 2000r/min 离心 10min 分离血清，用生理盐水将血清倍比稀释，将不同稀释度的血清分别置于微量血凝板内，每孔 100μL ，再加入 100μL0.5% （ V/V ）的 SRBC 悬液，混匀，装入湿润的平盘内加盖，于 37 ℃ 温箱孵育 3h ，观察血球凝集程度。
1.6.3 小鼠腹腔巨噬细胞吞噬鸡红细胞实验（半体内法）和脏器 / 体重比值：每鼠腹腔注射 20% 鸡红细胞悬液 1mL 。间隔 30min ，颈椎脱臼处死动物，将其仰位固定于鼠板上，正中剪开腹壁皮肤，经腹腔注入生理盐水 2mL ，转动鼠板 1min 。然后吸出腹腔洗液 1mL ，平均分滴于 2 片载玻片上，放入垫有湿纱布的搪瓷盒内，移置 37 ℃ 孵箱温育 30min 。孵毕，于生理盐水中漂洗，以除去未贴片细胞，晾干，以 1 ： 1 丙酮甲醇溶液固定， 4% （ V/V ） Giemsa- 磷酸缓冲液染色 3min ，再用蒸馏水漂洗晾干。在油镜下阅片计数，计算吞噬率和吞噬指数。并解剖动物取出脾脏和胸腺，用滤纸吸干血迹后称重。
1.6.4 ConA 诱导的小鼠淋巴细胞转化试验和小鼠 NK 细胞活性测定（乳酸脱氢酶 LDH 测定法）：颈椎脱臼法处死小鼠，无菌取脾，置于盛有适量无菌 Hanks 液的小平皿中，用镊子轻轻将脾撕碎，经 200 目筛网过滤，制成单细胞悬液，将细胞悬液分为两部分，分别用于 ConA 诱导的小鼠淋巴细胞转化试验和小鼠 NK 细胞活性测定。
1.6.4 .1 ConA 诱导的小鼠淋巴细胞转化试验：用 Hank's 液洗涤细胞悬液 2 次，每次离心 10min （ 1000r/min ），然后将细胞悬浮于 1mL 的完全培养液中，台酚兰染色计数活细胞数（ 95% 以上），调整细胞浓度为 3* 106 个 /mL 。将每份细胞悬液分两孔加入 24 孔培养板中，每孔 1mL ，一孔加 75μlConA 液，另一孔为对照，置培养箱中培养 72h 。培养结束前 4h ，每孔吸去上清液 0.7mL ，加入 0.7mL 不含小牛清的 RPMI 1640 培养液，同时加入 MTT 50μl/ 孔，继续培养 4h 。培养结束后，每孔加入 1mL 酸性异丙醇，吹打混匀，使紫色结晶完全溶解。然后分装到 96 孔培养板，每孔做 3 个平行孔，用酶标仪以 570nm 波长测定光密度值。
1.6.4 .2 小鼠 NK 细胞活性测定（乳酸脱氢酶 LDH 测定法）：试验前 24 小时将靶细胞传代培养，用前以 Hank's 液洗 3 次，用 RPMI 1640 完全培养液调整细胞浓度为 4* 105 个 /mL 。用 Hank's 液洗涤脾细胞悬液 2 次，每次离心 10min （ 1000r/min ）。弃上清液将细胞浆弹起，加入 0.5mL 灭菌水 20 秒，裂解红细胞后再加入 0.5mL2 倍 Hank's 液及 8mLHank's 液，离心 10min （ 1000r/min ），用 1mL 完全培养液重悬，用 1% 冰醋酸稀释后计数，台酚兰染色计数活细胞数（应在 95% 以上），调整细胞浓度为 2* 107 个 /mL 。取靶细胞和效应细胞各 100μL （效靶比为 50 ： 1 ），加入 96 孔培养板中；靶细胞自然释放孔加靶细胞和培养液各 100μL ，靶细胞最大释放孔加靶细胞和 1%NP40 各100μL ，上述各项均设三个平行孔，于 37 ℃ 、 5% CO2 培养箱中培养 4 小时，然后将培养板离心（ 1500r/min ） 5min ，每孔吸取上清液 100μL 置于 96 孔培养板中，同时加入 LDH 基质液 100μL ，反应 3min ，每孔中加入 1mol/L 的 HCl30μL ，在酶标仪 490nm 处测定光密度值（ OD ），计算 NK 细胞活性。
2 结果：
2.1 脏器 / 体重比值的测定：给药组胸腺指数明显高于对照组，经统计差异有统计学意义（ P<0.05 ），结果见表 4 。
表 4 胸腺指数、脾指数的测定（ eq \x\to(x) ± S ）
组别 动物数（只） 胸腺指数（ % ） 脾指数（ % ）
对照组 10 0.28 ± 0.05 0.40 ± 0.10
给药组 10 0.39 ± 0.08* 0.36 ± 0.05
* 与对照组比较 P<0.05
2.3 细胞免疫功能测定
2.3.1 ConA 诱导的小鼠脾淋巴细胞转化试验：样品给药组淋转 OD 差值明显高于对照组，经统计差异有统计学意义（ P<0.01 ），结果见表 5 。
表 5 ConA 诱导的小鼠脾淋巴细胞转化试验（ eq \x\to(x) ± S ）
组别 动物数（只） OD 差值
对照组 10 0.072 ± 0.02
给药组 10 0.185 ± 0.05**
** 与对照组比较 P<0.01
2.3.2 迟发性变态反应试验：给药组左右耳肿胀度差值明显高于对照组，经统计差异有统计学意义（ P<0.01 ），结果见表 6 。
表 6 DTH 测定结果（ eq \x\to(x) ± S ）
组别 动物数（只） 左右耳肿胀度差值（ g ）
对照组 10 0.022 ± 0.05
给药组 10 0.031 ± 0.02**
** 与对照组比较 P<0.01
2.4 体液免疫功能测定：
2.4.1 血清溶血素试验：给药组小鼠抗体积数明显高于对照组，经统计差异有统计学意义（ P<0.01 ），结果见表 7 。
表 7 血清溶血素试验（ eq \x\to(x) ± S ）
组别 动物数（只） 抗体积数
对照组 10 70.5 ± 22.2
给药组 10 102.2 ± 18.5* ）
** 与对照组比较 P<0.01
2.4.2 抗体生成细胞检测试验：给药组溶血空斑数明显高于对照组，经统计差异有统计学意义（ P<0.01 ），结果见表 8 。
表 8 抗体生成细胞检测试验（ eq \x\to(x) ± S ）
组别 动物数（只） 溶血空斑数（ *103 个 / 全脾）
对照组 10 2.95 ± 0.55
给药组 10 5.68 ± 1.20**
） * 与对照组比较 P<0.01
2.5 巨噬细胞功能测定：
小鼠腹腔巨噬细胞吞噬鸡红细胞试验：给药组小鼠腹腔巨噬细胞吞噬鸡红细胞吞噬指数明显高于对照组，经统计差异有统计学意义（ P<0.01 ），而给药组小鼠腹腔巨噬细胞吞噬鸡红细胞吞噬率与对照组相比，均无统计学意义，结果见表 9 。
表 9 巨噬细胞吞噬试验（ eq \x\to(x) ± S ）
组别 动物数（只） 吞噬率（ % ） 吞噬指数
对照组 10 9.03 ± 1.08 0.13 ± 0.01
给药组 10 10.50 ± 1.20 0.16 ± 0.02**
** 与对照组比较 P<0.01
2.6 NK 细胞活性测定：给药组能明显增强 NK 细胞活性，与对照组相比，差异有统计学意义（ P<0.01 ），结果见表 10 。
表 10 NK 细胞活性测定（ eq \x\to(x) ± S ）
组别 动物数（只） NK 细胞活性（ % ）
对照组 10 7.230 ± 4.18
给药组 10 16.50 ± 2.21**
** 与对照组比较 P<0.01
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (2)

  1. 六味地黄制剂在制备治疗心脏支架术后治疗药物的用途
    .
  2. 根据权利要求六味地黄 1 中所述的用途，其特征在于：所述的制剂为滴丸，其是以由熟地、山茱萸、牡丹皮、山药、泽泻和茯苓组成的 6 味中药的提取物为原料，与作为滴丸基质的载体共同制备获得，其特征在于：
    1 ）所述 6 味中药的提取物粉末与所述基质的重量比为 1 ： 1 ～ 8 ；
    2 ）所述 6 味中药的提取物粉末采用药典或部颁标准中所规定的方法获得；
    3 ）所述滴丸基质为重均分子量为 6000 、粘度分布在 13.6 ～ 14.5 之间的聚乙二醇，该种聚乙二醇中，分子量为 6000 的聚乙二醇重量含量在 40 ～ 60% ；
    4 ）按照上述比例准确称取提取物和基质，置于加热容器内加热使熔融，搅拌均匀，而后置入滴丸机内，在 75 ℃～ 100 ℃，滴入 30 ℃～ -8 ℃的冷凝剂中，所述冷凝剂为甲基硅油、液体石蜡或植物油中的至少一种，取出滴丸，洗净、干燥后获得。
PCT/CN2012/075353 2012-04-16 2012-05-11 六味地黄制剂在制备治疗心脏支架术后治疗药物的用途 WO2013155742A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1544042A (zh) * 2003-11-12 2004-11-10 北京正大绿洲医药科技有限公司 六味地黄滴丸及其制备方法
CN1634542A (zh) * 2004-11-12 2005-07-06 康国忠 六味地黄滴心丸制剂及其制备方法
CN1666763A (zh) * 2004-03-08 2005-09-14 张言军 六味地黄滴丸

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CN1544042A (zh) * 2003-11-12 2004-11-10 北京正大绿洲医药科技有限公司 六味地黄滴丸及其制备方法
CN1666763A (zh) * 2004-03-08 2005-09-14 张言军 六味地黄滴丸
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