CN110604761B - 一种桑花片及其制备工艺与在治疗心脑血管疾病中的应用 - Google Patents
一种桑花片及其制备工艺与在治疗心脑血管疾病中的应用 Download PDFInfo
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Abstract
本发明涉及一种桑花片及其制备工艺与在治疗心脑血管疾病中的应用,所述桑花片包含如下重量份配比的原料:桑枝5‑25份,红花3‑15份,丹参3‑12份,川芎1‑9份,地龙1‑9份,黄芪3‑15份。本发明桑花片灌胃给药14天,具有明显增强小鼠耐缺氧能力;灌胃给药14、21天均能显著延长小鼠爬杆和游泳时间;灌胃给药14天,能明显对抗由垂体后叶素引起的大鼠心肌缺血(心电图改变)症状和乳酸脱氢酶同功酶I的改变,并能降低大鼠体外形成的血栓干湿重量;灌胃给药14天,能显著改善血小板的聚集和粘附功能。
Description
技术领域
本发明属于医药领域,具体涉及一种桑花片及其制备工艺与在治疗心脑血管疾病中的应用。
背景技术
心脑血管疾病是心脏血管疾病和脑血管疾病的统称,其病因主要是因为血液黏稠、高脂血症、动脉粥样硬化、高血压等导致的大脑、心脏及全身组织而引起的缺血性或出血性一类血管类疾病,主要包括:冠心病、心绞痛、脑出血和脑栓塞等。心脑血管疾病常见于中老年人,近年来,有年轻化的趋势,其具有高患病率、高致残率、高复发率、高死亡率和并发症多等特点严重威胁着人类的健康。本发明提供一种六味桑花中药组合物,其能显著提高小鼠耐缺氧能力、降低大鼠心肌缺血症状等,有望开发作为预防和/或治疗心脑血管疾病的药物。
发明内容
本发明提供一种六味桑花中药组合物,其特征在于所述中药组合物包含如下重量份配比的原料:桑枝5-25份,红花3-15份,丹参3-12份,川芎1-9份,地龙1-9份,黄芪3-15份。
本发明的另一实施方案提供一种六味桑花中药组合物,其特征在于所述中药组合物由如下重量份的原料药制成:桑枝5-25份,红花3-15份,丹参3-12份,川芎1-9份,地龙1-9份,黄芪3-15份。优选桑枝8份,红花5份,丹参4份,川芎3份,地龙3份,黄芪5份。所述六味桑花中药组合物的剂型优选片剂、胶囊剂或颗粒剂。
本发明的另一实施方案提供上述六味桑花中药组合物的制备方法,其特征在于包括如下步骤:
(1)按上述重量份,取丹参粉碎,过120目筛,得药粉备用;
(2)按上述重量份,取桑枝、红花、川芎、地龙和黄芪,加乙醇溶液浸泡1-2小时后,回流提取1-3次,每次1小时,收集提取液,浓缩、干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀即得所述六味桑花中药组合物。
步骤(2)中乙醇溶液的用量为桑枝、红花、川芎、地龙和黄芪质量之和的5-8倍,乙醇溶液选自体积分数60%-70%的乙醇溶液,所述干燥优选薄膜干燥。
本发明的另一实施方案提供一种六味桑花片的制备方法,其特征在于包括如下步骤:
(1)按上述重量份,取丹参3-12份粉碎,过120目筛,得药粉备用;
(2)按上述重量份,取桑枝5-25份,红花3-15份,川芎1-9份,地龙1-9份和黄芪3-15份,加乙醇溶液浸泡1-2小时后,回流提取1-3次,每次1小时,收集提取液,浓缩、干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀,得六味桑花中药组合物;
(3)将步骤(2)得到的六味桑花中药组合物制粒、压片,即得所述六味桑花片。
步骤(2)中乙醇溶液的用量为桑枝、红花、川芎、地龙和黄芪质量之和的5-8倍,乙醇溶液选自体积分数60%-70%的乙醇溶液,所述干燥优选薄膜干燥。步骤(3)中所述制粒、压片为本领域常规的制粒、压片方法,任选加入药学上接受的辅料(例如填充剂、湿润剂、粘合剂、崩解剂等中的一种或几种混合)。本发明制备的上述六味桑花片的规格如下:
【性状】本品为片剂,内容物为黑褐色粉末,气微腥,味咸苦。
【功能与主治】化瘀祛风,解络止痛。适用于冠心病和脑中风患者,症见肥胖、头昏沉、懒散拒动、心前区或头暮胀等症。
【规格】每片0.6克。
【用法与用量】口服,每次2片,一日3次;四周为一疗程或遵医嘱。
本发明的另一实施方案提供上述六味桑花中药组合物或桑花片在制备预防和/或治疗心脑血管疾病药物中的应用。
本发明的另一实施方案提供上述六味桑花中药组合物或桑花片在制备预防和/或治疗心肌缺血、缺氧疾病药物中的应用。
本发明的另一实施方案提供上述六味桑花中药组合物或桑花片在制备预防和/或治疗由血小板聚集或粘附引起的疾病药物中的应用。
本发明中所述的桑枝、红花、丹参、川芎、地龙、黄芪,可以是中药材,也可以是中药饮片。
与现有技术相比,本发明的优点在于:本发明提供的六味桑花中药组合物在对小鼠耐缺氧能力的保护、小鼠应激能力的提高、大鼠心肌缺血症状的改善、血小板粘附抑制方面都发挥良好的效果,其效果优于黄芪精、地奥心血康、脑心通。
具体实施方式
为了便于对本发明的进一步理解,下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则,本发明的实施方式不限于以下内容。
实施例1
中药饮片:桑枝50g,红花30g,丹参30g,川芎10g,地龙10g,黄芪30g
(1)按上述重量份,取丹参饮片粉碎,过120目筛,得药粉备用;
(2)按上述重量份,取桑枝、红花、川芎、地龙和黄芪饮片,加体积分数60%乙醇溶液(650g)浸泡1小时后,回流提取2次,每次1小时,收集提取液,浓缩、薄膜干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀,得六味桑花中药组合物(以下简称产品A)。
实施例2
中药饮片:桑枝25g,红花15g,丹参12g,川芎9g,地龙9g,黄芪15g
(1)按上述重量份,取丹参饮片粉碎,过120目筛,得药粉备用;
(2)按上述重量份,取桑枝、红花、川芎、地龙和黄芪饮片,加体积分数70%乙醇溶液(584g)浸泡2小时后,回流提取1次,提取1小时,收集提取液,浓缩、薄膜干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀,得六味桑花中药组合物(以下简称产品B)。
实施例3
中药饮片:桑枝80g,红花50g,丹参40g,川芎30g,地龙30g,黄芪50g
(1)按上述重量份,取丹参饮片粉碎,过120目筛,得药粉备用;
(2)按上述重量份,取桑枝、红花、川芎、地龙和黄芪饮片,加体积分数65%乙醇溶液(1440g)浸泡1小时后,回流提取3次,每次1小时,收集提取液,浓缩、薄膜干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀,得六味桑花中药组合物(以下简称产品C)。
实施例4
任选取产品A、B、C中的一种与适量药学上接受的辅料(例如填充剂、湿润剂、粘合剂、崩解剂等中的一种或几种混合),按制药领域技术规范和要求(例如药典、教科书或其他现有技术中的方法)制粒、压片得六味桑花片。
规格如下:
【性状】本品为片剂,内容物为黑褐色粉末,气微腥,味咸苦。
【功能与主治】化瘀祛风,解络止痛。适用于冠心病和脑中风患者,症见肥胖、头昏沉、懒散拒动、心前区或头暮胀等症。
【规格】每片0.6克。
【用法与用量】口服,每次2片,一日3次;四周为一疗程或遵医嘱。
实施例5
中药饮片:桑枝50g,红花30g,丹参30g,川芎10g,地龙10g,黄芪30g
按上述重量份,取桑枝、红花、丹参、川芎、地龙和黄芪饮片,加体积分数60%乙醇溶液(650g)浸泡1小时后,回流提取2次,每次1小时,收集提取液,浓缩、薄膜干燥后,粉碎,过120目筛得细粉(以下简称产品D)。
实施例7
为进一步临床应用,按照《药品注册管理办法》的规定,我们对六味桑花中药组合物进行了主要药效作用的实验研究,其结果如下。
一、实验材料
1、试药:产品A-D按照实施例1-4记载的方法,由本医院药剂科制剂室制备,批号20181015;临用前用蒸馏水配成不同浓度备用;实验采用的剂量分别是小鼠:1.0g/kg;大鼠:0.6g/kg。
2、阳性对照药:地奥心血康胶囊为市购产品,批号:201805054,成都地奥制药集团有限公司生产,临用前用蒸馏水配成所需浓度,批准文号:国药准字Z10910051;黄芪精,批号:2018010401,江苏扬子江药业集团有限公司生产,批准文号:国药准字Z32020370。
3、试剂:垂体后叶素注射液,6u/ml×10支,批号:20181004,上海禾丰制药有限公司;盐酸异丙肾上腺素注射液(ISO),批号:20180614,上海禾丰制药有限公司;钠石灰、黄凡士林、戊巴比妥钠、ADP、阿氏稀释液、枸椽酸钠等试剂为市购。
4、仪器:IVC(独立换气笼盒)饲养系统(上海绍丰实验动物设备有限公司);CBV-1500A高性能无菌实验台(上海瑞仰净化装备有限公司);台式离心机;德国Sartorius电子天平(感量10mg);Olympus生物显微镜(日本);LMB-2B型二道生理记录仪(成都仪器厂生产);XSN-RⅡ型血栓形成一血小板粘附两用仪(无锡电子仪器厂生产);XN-2型血液粘度自动计时仪(上海医科大学生产);BS631型血小板聚集仪(上海医科大学生产);电磁流量计(由日本光电公司产);RM-6280型多道智能生理信号采集、处理系统(由日本光电公司和成都仪器厂合作生产)。
5、实验动物:昆明种小鼠,雄雌各半,体质量18~22g;SD大鼠,体质量180~220g,均由中国人民解放军空军军医大学实验动物中心提供,动物合格证号:scxk(军)2012-005号。
二、实验项目和观察指标
1、六味桑花中药组合物对小鼠耐缺氧能力的保护作用
观察指标:小鼠耐缺氧存活时间(min)。
2、六味桑花中药组合物不同治疗时间对小鼠应激能力的影响
观察指标:a.爬杆时间(min);b.游泳时间(min)。
3、六味桑花中药组合物对垂体后叶素所致大鼠心肌缺血的影响
观察指标:a.ST段出现率、T波改变(低平或增高等)、心律不齐和心率等指标;b.血浆乳酸脱氢酶同功酶;c.体外血栓形成:血栓长度(mm)、血栓湿重(mg)、血栓干重(mg)。
4、六味桑花中药组合物对大鼠血小板聚集和粘附功能的影响
观察指标:a.测定1min、5min和最大聚集百分率(%);b.血小板粘附率(%)、血小板粘附抑制率(%)。
5、六味桑花中药组合物对血瘀大鼠血液流变学的影响
观察指标:测定全血比粘度(高、低切变率)、血浆比粘度、红细胞压积百分率、红细胞聚集指数等指标。
三、实验方法和结果
1、六味桑花中药组合物对小鼠耐缺氧能力的保护作用:450只昆明种小鼠末次给药后随机分为常压、常压+ISO和低压三种条件下进行实验。①常压:动物置密封干燥器(其内放100g钠石灰)中,观察动物在常压下的死亡时间;②常压+ISO:动物皮下注射20mg.kg-1ISO 15分钟再置常压下的干燥器中,记录动物死亡时间;③低压:将小鼠放入密封干燥器后,立即抽负压至-40kPa;并一直维持-40kPa值,记录10分钟内动物死亡数。结果见表1,六味桑花中药组合物灌胃给药14天,具有明显增强小鼠耐缺氧能力(P<0.05或P<0.01)。
注:aP<0.05,bP<0.01,与对照组比较。
2、桑花中药组合物不同治疗时间对小鼠应激能力的影响:180只昆明种雄性小鼠随机分成5组,依次(7d、14d、21d三个时间点)给药后,各组动物同时试爬杆三次,每次在杆时间最长1分钟,之后正式爬杆,记录在杆时间(min)。动物爬杆后次日再给药一次,立即标记投入泳缸中做游泳实验,实验时小鼠尾部负重10%体重的橡皮泥。观察游泳时间(min)。结果见表2,产品A、C灌胃给药14、21天,能显著延长小鼠爬杆和游泳时间(P<0.05或P<0.01)。
注:aP<0.05,bP<0.01,与对照组比较。
注:aP<0.05,bP<0.01,与对照组比较。
3、桑花中药组合物对垂体后叶素所致大鼠心肌缺血的影响:60只SD大鼠随机分成5组,于末次给药后10分钟内腹腔注射(ip)30mg/kg 1%戊巴比妥钠麻醉,四肢仰卧位固定于鼠板上,分离颈总动脉(A)和颈外静脉(V),并分别插管。颈总A接二导生理记录仪血压传感器测血压;颈外V给药。连接标准Ⅱ导联测正常心电图后,再从颈外V插管注入0.5u/kg垂体后叶素(100μl容量),10秒钟内注完,立即开始记录心电图,连续观察5分钟内ST段出现率(包括ST段抬高或下降及融合等)、T波改变(低平或增高等)、心律不齐和心率等指标。之后从颈总A放血两份。一份测血浆乳酸脱氢酶同功酶(LDH1、LDH2、LDH3、LDH4和LDH5);另一份做体外血栓形成实验。结果见表3~5。桑花中药组合物给药14天,能明显对抗由垂体后叶素引起的心肌缺血症状,说明桑花中药组合物对心肌缺血症状具有明显保护作用,并能降低大鼠体外形成的血栓干湿重量。
注:aP<0.05,bP<0.01,与缺血前比较;cP<0.05,dP<0.01,与对照组比较。
注:aP<0.05,bP<0.01,与对照组比较。
注:aP<0.05,bP<0.01,与对照组比较。
4、桑花中药组合物对大鼠血小板聚集和粘附功能的影响:50只雄性SD大鼠随机分5组后断尾采血1m1,3.6%枸椽酸钠抗凝贮于4℃冰箱备用。动物给药14天,于末次给药后10min,ip 30mg/kg 1%戊巴比妥钠麻醉,仰卧固定,颈A插管,每鼠取2ml和1ml两份血样,分别测血小板聚集和粘附功能。①血小板聚集功能:抗凝血1000r/min离心10min制备成富血小板血浆(PPP);以3000r/min离心15min,制备贫血小板血浆(PRP);取0.45ml PRP调至“0”,取0.45ml PPP置BS631型聚集仪的比色皿中,加入0.9%(mg/ml)浓度的ADP溶液50μl,开机测1min、5min和最大聚集百分率(%),结果见表6。②血小板粘附功能:给药前后抗凝血各1ml,装入球形瓶中,安在血小板粘附化的旋转盘上,3r/min旋转15min,然后取出旋转未接触和旋转接触后的血液,以阿氏稀释液计算血小板总数,按公式[(接触前血小板数一接触后血小板数)/接触后血小板数]×100%计算血小板粘附率(%),再以公式[(对照组粘附率一治疗组粘附率)/对照组粘附率]×100计算血小板粘附抑制率(%)。实验结果表明桑花中药组合物能显著改善血小板的聚集和粘附功能(表7)。
注:bP<0.01,与对照组比较。
注:bP<0.01,与对照组比较。
5、桑花中药组合物对血瘀大鼠血液流变学的影响:48只雄性SD大鼠,随机分组给药14天后,除正常组外,其余各组动物皮下注射0.1%肾上腺素(Adr)0.2m1/只,约3~4小时将动物浸入2℃冷水中(头在水面上)5min,如此操作2次,造成血瘀动物模型;次日给药后ip1%戊巴比妥钠麻醉,行颈A插管取血5ml,测全血比粘度(高、低切变率)、血浆比粘度、红细胞压积百分率、红细胞聚集指数等指标。结果表明桑花中药组合物对血瘀大鼠高切变率、低切变率、RBC聚积指数、血浆比粘度与对照组比较有明显改善(表8)。
注:bP<0.01,与正常组比较;dP<0.01,与模型组比较。
注:aP<0.05,bP<0.01,与正常组比较;cP<0.05,dP<0.01,与模型组比较。
结论:本发明桑花中药组合物灌胃给药14天,具有明显增强小鼠耐缺氧能力(P<0.05或P<0.01);灌胃给药14、21天均能显著延长小鼠爬杆和游泳时间(P<0.05或P<0.01);灌胃给药14天,能明显对抗由垂体后叶素引起的大鼠心肌缺血(心电图改变)症状和乳酸脱氢酶同功酶I的改变,并能降低大鼠体外形成的血栓干湿重量(P<0.05或P<0.01);灌胃给药14天,能显著改善血小板的聚集和粘附功能。
Claims (9)
1.一种六味桑花中药组合物,其特征在于所述中药组合物由如下重量份的原料药制成:桑枝5-25份,红花3-15份,丹参3-12份,川芎1-9份,地龙1-9份,黄芪3-15份。
2.权利要求1所述的六味桑花中药组合物的制备方法,其特征在于包括如下步骤:
(1)按重量份,取丹参粉碎,过120目筛,得药粉备用;
(2)按重量份,取桑枝、红花、川芎、地龙和黄芪,加乙醇溶液浸泡1-2小时后,回流提取1-3次,每次1小时,收集提取液,浓缩、干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀即得所述六味桑花中药组合物。
3.权利要求2所述的制备方法,其特征在于步骤(2)中乙醇溶液的用量为桑枝、红花、川芎、地龙和黄芪质量之和的5-8倍,乙醇溶液的体积分数为60%-70%,所述干燥选自薄膜干燥。
4.权利要求1所述的六味桑花中药组合物,其特征在于所述六味桑花中药组合物的剂型选自片剂、胶囊剂或颗粒剂。
5.一种六味桑花片的制备方法,其特征在于包括如下步骤:
(1)按重量份,取丹参3-12份粉碎,过120目筛,得药粉备用;
(2)按重量份,取桑枝5-25份,红花3-15份,川芎1-9份,地龙1-9份和黄芪3-15份,加乙醇溶液浸泡1-2小时后,回流提取1-3次,每次1小时,收集提取液,浓缩、干燥后,粉碎,过120目筛得细粉,与步骤(1)得到的药粉混匀,得六味桑花中药组合物;
(3)将步骤(2)得到的六味桑花中药组合物制粒、压片,即得所述六味桑花片。
6.权利要求5所述的制备方法,其特征在于步骤(2)中乙醇溶液的用量为桑枝、红花、川芎、地龙和黄芪质量之和的5-8倍,乙醇溶液的体积分数为60%-70%,所述干燥选自薄膜干燥。
7.权利要求1、4任一项所述的六味桑花中药组合物在制备预防和/或治疗心脑血管疾病药物中的应用。
8.权利要求1、4任一项所述的六味桑花中药组合物在制备预防和/或治疗心肌缺血、缺氧疾病药物中的应用。
9.权利要求1、4任一项所述的六味桑花中药组合物在制备预防和/或治疗由血小板聚集或粘附引起的疾病药物中的应用。
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