CN101085033B - 一种治疗冠心病心绞痛的片剂及其制备方法 - Google Patents
一种治疗冠心病心绞痛的片剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种治疗冠心病心绞痛的片剂，它是由以下重量份的原料制成：黄芪15～400份、丹参10～250份、延胡索10～250份、葛根8～150份、茵陈8～150份。本发明各种组成原料简单，利用适当配比的原料彼此之间的相互作用，具有益气活血止痛、升清化浊的作用，从而达到有效治疗冠心病或心绞痛；整个产品的制备方法简单易行，易于推广应用。
Description
技术领域
本发明涉及一种治疗冠心病心绞痛的片剂，以及制备方法。
背景技术
冠心病心绞痛患者，常为时作心痛所苦，严重影响患者的生命质量和威胁患者的生命和健康，病机多为气虚血瘀、不通则痛。
发明内容
本发明所要解决的技术问题是提出一种以益气药和活血化瘀药相伍，益气活血，使气旺以运血行血，从而达到心痛缓解、心身得以舒康目的的治疗冠心病心绞痛的片剂。
本发明所提供的技术方案是：一种治疗冠心病心绞痛的片剂，它是由以下重量份的原料制成：黄芪15～400份、丹参10～250份、延胡索10～250份、葛根8～150份、茵陈8～150份。
优选的原料的重量份为：黄芪18～320份、丹参12～200份、延胡索12～200份、葛根10～120份、茵陈10～120份。
更优选的原料的重量份为：黄芪8份、丹参5份、延胡索5份、葛根3份、茵陈3份。
上述治疗冠心病心绞痛的片剂制备方法：黄芪、葛根、茵陈加水煎煮三次，每次2小时，滤过，合并滤液，减压浓缩成清膏，备用；另取丹参、延胡索加75％乙醇回流提取二次，每次2小时，滤过，滤液减压回收乙醇，加入上述清膏，搅匀，于80℃以下干燥，粉碎，加入适量辅料，混匀，压制成片，包薄膜衣即得。
本产品以益气药和活血化瘀药相伍，益气活血，使气旺以运血行血，从而达到心痛缓解、心身得以舒康的目的；又因其剂型为片剂，故命名为“心舒康片。”
上述技术方案所提到的原料，其来源及功效如下：
黄芪：为豆科植物，蒙古黄芪或膜荚黄芪的干燥根。具有补气固表，利尿托毒，排脓敛疮生肌的功能。用于气虚乏力，食少便溏，中气下陷，久泻脱肛，便血崩漏，表虚自汗，气虚水肿，，痈疽难溃，久溃不敛，血虚痿黄，内热消渴；慢性肾炎蛋白尿，糖尿病。
丹参：本品为唇形科植物丹参Salvia miltiorrhiza Bge的干燥根及根茎。具有祛淤止痛，活血通经，清心除烦的功能。用于月经不调，经闭痛经，症瘕积聚，胸腹刺痛，热痹疼痛，疮疡肿痛，心烦不眠；肝脾肿大，心绞痛。
延胡索，本品为罂粟科植物延胡索Corydalis yanhuso W.T.Wang的干燥根茎，具有活血利气止痛的功能。用于胸胁、脘腹疼痛，经闭痛经，产后瘀阻，跌扑肿痛。
葛根，本品为豆科植物野葛Pueraria lobata(Willd.)Ohwi的干燥根，具有解肌退热，生津，透疹，升阳止泻功能，用于外感发热头痛，项背强痛，口渴，消渴，麻疹不透，热痢，泄泻，高血压颈项强痛，
茵陈，本品为菊科植物滨蒿Artemisia soparia Waldst.或茵陈蒿Artemisia capillaris Thunb.的干燥地上部分，具有清湿热、退黄疸的功能，用于黄疸尿少，湿疮瘙痒，传染性黄疸型肝炎。
本发明有如下优点：各种组成原料简单，利用适当配比的原料彼此之间的相互作用，具有益气活血止痛、升清化浊的作用，从而达到有效治疗冠心病或心绞痛；整个产品的制备方法简单易行，易于推广应用。
具体实施方式
下面结合实施例来详细说明本发明。
治疗冠心病心绞痛的片剂：
配方1：黄芪680g 丹参450g 延胡索450g 葛根400g 茵陈400g
配方2：黄芪1000g 丹参600g 延胡索600g 葛根300g 茵陈300g
配方3：黄芪880g 丹参600g 延胡索600g 葛根400g 茵陈400g
配方4：黄芪1200g 丹参500g 延胡索500g 葛根200g 茵陈200g
配方5：黄芪880g 丹参700g 延胡索700g 葛根200g 茵陈200g
配方6：黄芪680g 丹参450g 延胡索450g 葛根400g 茵陈400g
配方7：黄芪800g 丹参300g 延胡索300g 葛根400g 茵陈400g
配方8：黄芪880g 丹参550g 延胡索550g 葛根330g 茵陈330g
以上各种配方的五味原料中，黄芪、葛根、茵陈加水煎煮三次，每次2小时，滤过，合并滤液，减压浓缩成清膏，备用。另取丹参、延胡索加75％乙醇回流提取二次，每次2小时，滤过，滤液减压回收乙醇，加入上述清膏，搅匀，于80℃以下干燥，粉碎，加入适量辅料，混匀，压制成1000片，包薄膜衣，即得。
【性状】本品为薄膜衣片，除去包衣后显棕色至棕褐色；味微苦。
【鉴别】(1)取本品2片，除去薄膜衣，研细，加氨水2ml，密塞，放置20分钟，加乙醚20ml，超声提取20分钟，滤过，滤液蒸干，残渣加甲醇1ml使溶解，作为供试品溶液。另取延胡索乙素对照品，加甲醇制成每1ml含1mg的溶液，作为对照品溶液。照薄层色谱法(中国药典2000年版一部附录VI B)试验，吸取供试品溶液4μl，对照品溶液2μl，分别点于同一硅胶G薄层板上，以正己烷-氯仿-甲醇(7.5∶4∶1)为展开剂，展开，取出，晾干，喷以碘化铋钾试液。供试品色谱中，在与对照品色谱相应的位置上，显相同颜色的斑点。
(2)取本品2片，除去薄膜衣，研细，加甲醇20ml，超声提取20分钟，滤过，滤液蒸干，残渣加甲醇1ml使溶解，作为供试品溶液。另取葛根素对照品，加甲醇制成每1ml含1mg的溶液，作为对照品溶液。照薄层色谱法(中国药典2000年版一部附录VI B)试验，吸取上述两种溶液各4μl，分别点于同一硅胶G薄层板上，以氯仿-甲醇-水(7∶2.5∶0.25)为展开剂，展开，取出，晾干，置紫外光灯(365nm)下检视。供试品色谱中，在与对照品色谱相应的位置上，显相同颜色的荧光斑点。
【检查】应符合片剂项下有关的各项规定(中国药典2000年版一部附录I D)。
【含量测定】取本品10片，除去薄膜衣，精密称定，研细，取1g，精密称定，加甲醇超声提取2次，每次50ml、15分钟，滤过，滤液蒸干，残渣加水20ml微热使溶解，用水饱和正丁醇振摇提取4次(每次振摇2分钟)，每次20ml，合并正丁醇提取液，用氨试液洗涤3次，每次20ml，弃去氨液，正丁醇液蒸干，残渣加甲醇溶解并转移至2ml量瓶中，加甲醇至刻度，摇匀，作为供试品溶液。另取黄芪甲苷对照品适量，精密称定，加甲醇制成每1ml含1mg的溶液，作为对照品溶液。照薄层色谱法(中国药典2000年版一部附录VI B)试验，精密吸取供试品溶液5μl、对照品溶液1μl与3μl，分别交叉点于同一硅胶G薄层板上，以氯仿-甲醇-水(13∶6∶2)10℃以下放置过夜的下层溶液为展开剂，展开，展距15cm，取出，晾干，喷以10％硫酸乙醇溶液，在100℃加热至斑点显色清晰，取出，在薄层板上覆盖同样大小的玻璃板，周围用胶布固定，照薄层色谱法(中国药典2000年版一部附录VI B薄层扫描法)进行扫描，波长：λ＝505nm，测量供试品吸收度积分值与对照品吸收度积分值，计算，即得。
本品每片含黄芪以黄芪甲苷(C41H68O14)计，不得少于0.28mg。
【功能主治】益气活血、化瘀止痛、升清化浊。用于气虚瘀滞型冠心病心绞痛，症见胸痛、胸闷、心悸、气短、舌质紫暗、舌苔白、脉沉涩或虚弱等。
【用法用量】口服，一次2-3片，一日3次。
【规格】每片重0.5g
【贮藏】密闭，置阴凉干燥处。
药效学研究
根据国家中药6类新药治疗冠心病心绞痛中药的申报要求，本研究采用结扎健康杂种犬冠状动脉、尾静脉注射垂体后叶素Wistar大鼠心肌缺血模型及Wistar大白鼠心肌缺血再灌注损伤模型，从心肌缺血程度、范围，心梗面积、心肌酶学改变、心肌耗氧、血流动力学改变、血小板功能和血栓形成等方面，系统进行了治疗冠心病心绞痛的片剂抗心肌缺血的药效学研究。
1.抗结扎冠状动脉犬急性心肌缺血的研究
治疗冠心病心绞痛的片剂可明显减轻结扎冠状动脉犬的心肌缺血程度、范围，缩小结扎冠状动脉犬的心肌梗死面积，减少结扎冠状动脉犬心肌酶的漏出。且在抗心肌缺血的同时，不增加缺血心肌耗氧。
2.抗垂体后叶素注射引起Wistar大鼠心肌缺血的研究
治疗冠心病心绞痛的片剂可明显减轻尾静脉注射垂体后叶素大鼠II导心电图ST-T的缺血改变，降低心肌酶的漏出。
3.抗Wistar大鼠心肌缺血再灌注损伤的研究
治疗冠心病心绞痛的片剂可明显减轻心肌缺血再灌注大鼠心肌缺血程度，缩小心肌缺血再灌注大鼠的心肌梗死面积，减少心肌细胞酶的漏出，增加血清SOD活性和总抗氧化能力，降低血清MDA含量。
4.对结扎冠状动脉犬血流动力学影响的研究
治疗冠心病心绞痛的片剂可增加结扎冠状动脉犬的冠状动脉血流量和心输出量，且有一定保护结扎冠状动脉犬心脏收缩和舒张功能的作用。
5.活血化瘀作用的研究
治疗冠心病心绞痛的片剂可明显降低大鼠血小板GMP-140的血浆浓度和分子个数，抑制ADP诱导的大鼠血小板聚集，降低大鼠血液粘度，降低大鼠红细胞聚集指数，提高其变形能力。
结论：治疗冠心病心绞痛的片剂具有抗心肌缺血、减少心肌细胞酶漏出、抗脂质过氧化、抗血小板粘附聚集、降低血液粘度、抑制血栓形成、保护心脏收缩舒张功能等作用。
毒理学研究
1.治疗冠心病心绞痛的片剂小鼠、大鼠最大给药量试验
因小鼠灌胃给予治疗冠心病心绞痛的片剂，未测出LD50，故测定其最大耐受量。以最大浓度、最大容积对小鼠灌胃给药，给药后观察一周，测得其最大耐受量为361.8g生药量/kg体重，相当于临床人用量的904.5倍。证明该药用于临床研究是安全可靠的。
治疗冠心病心绞痛的片剂，因大鼠灌胃未测出LD50，故采用最大耐受量试验。以最大浓度、最大容积给大鼠灌胃给药，试验观察一周，测得其最大耐受量为158.2g生药量/kg体重，相当于临床人用量的395倍，证明该药用于临床是安全可靠的。
2.治疗冠心病心绞痛的片剂大鼠长期毒性试验
治疗冠心病心绞痛的片剂3个剂量组(28g/kg体重、14g/kg体重、7g/kg体重)，灌胃给予大鼠12周，分别为临床用量的70倍、35倍、17.5倍，未发现明显的毒副作用，停药2周后观察，亦未发现延迟性毒性反应。证明治疗冠心病心绞痛的片剂用于临床是安全的。
初步临床观察：
本研究选择冠心病(CHD)心绞痛患者60例，随机分为两组，其中心舒康组30例，血府逐瘀胶囊组30例。两组患者性别、年龄、病程、心绞痛类型、中医证型构成比、疼痛程度等基本相似，具有可比性。观察结果如下：心绞痛疗效：心舒康组、血府逐瘀胶囊组临床心绞痛总有效率分别为80.00％和86.67％，显效率均为43.33％；心电图疗效：心舒康组、血府逐瘀胶囊组总有效率分别为36.67％和33.33％；硝酸甘油消耗量：心舒康组、血府逐瘀胶囊组治疗后硝酸甘油停减率分别为23.33％和20％；血液流变学的变化：心舒康组和血府逐瘀胶囊组治疗后低切速下的血液粘度均较治疗前明显降低(P＜0.05～0.01)，心舒康组和血府逐瘀胶囊组对红细胞聚集指数、血小板聚集率均有明显抑制作用，较治疗前有显著差异(P＜0.05)，心舒康组对红细胞变形性有明显改善作用，与治疗前比较有显著差异(P＜0.01)，血府逐瘀胶囊对红细胞变形性无显著作用；对血脂水平的影响：心舒康组治疗后血清总胆固醇(TC)、甘油三酯(TG)和动脉粥样硬化指数(TC/HDL-C)均有下降趋势，高密度脂蛋白(HDL-C)有升高趋势，血府逐瘀胶囊组治疗后TC、TC/HDL-C有下降趋势，TG和HDL-C有升高趋势，但两组治疗前后比较及两组之间比较均无显著性差异。心舒康每次3粒，每日3次给药，治疗冠心病心绞痛，在改善心绞痛症状、缺血心电图改变、硝酸甘油消耗量和血液流变学方面有较好疗效，与阳性对照药血府逐瘀胶囊疗效相比显示有一定的优势。在观察期间，未发现明显毒副作用，耐受性良好。
生产工艺研究：
提取工艺：本产品中的药材均为中国药典所收载，对处方中药材的处理进行了研究，黄芪、丹参切2-3mn薄片，葛根切小片，延胡索、茵陈粉碎成粗粉，有利于有效成分溶出，缩短提取时间。处方中黄芪、葛根、茵陈所含的有效成份均为水溶性成份，故采用水提的方法，并采用正交试验，以提取时间、加水量、提取次数为影响因素，选择四因素三水平正交表，以提取液中黄芪甲苷的含量为评价指标，黄芪甲苷含量采用双波长薄层扫描法进行测定，经方差分析确定为黄芪、葛根、茵陈加10倍量水煎三次，每次2小时。丹参、延胡索两味药的提取采取醇提工艺设计，利于丹参酮I、丹参酮IIA、延胡索乙素脂溶性有效成分的提出。影响醇提取的因素乙醇浓度、加醇量、提取时间及提取次数通过正交试验优选，选择四因素三水平正交表。以提取液中丹参酮IIA的含量为评价指标，丹参酮IIA含量采用高效液相法进行测定，方差分析表明，选择工艺为8倍量75％乙醇提取三次，每次2小时。
浓缩与干燥：本工艺采用喷雾干燥制备浸膏粉，再行制粒。浸膏粉的含水量对制粒影响很大，并且本品为水和醇提，浸膏粉粘性大，所以必须控制水分在4.0％以内。浸膏粉的含水量与喷雾干燥时水提、醇提清膏混合后清膏的相对密度、进液速度、喷嘴离心盘转速、进风温度四个因素有直接关系。通过正交试验优化选择，选择四因素三水平正交表，试验结果以浸膏粉的含水量为评价指标，按L9(34)正交表进行试验，确定最佳喷雾条件为进液速度为6000ml/min，离心速度6000r/min，进风温度120℃，药液相对密度1.25～1.30。经验证与正交试验基本一致，说明此工艺较稳定。
制剂成型：喷雾干燥粉制成颗粒需润湿剂，经试验用低浓度乙醇制粒虽能成型。但制粒时粘性大，难以过筛，且干燥时结块、花斑，颗粒硬度大，试验证明用90％浓度的乙醇即可克服。湿颗粒用沸腾床干燥。颗粒合格率与乙醇用量、混合时间、干燥温度有直接关系，采用四因素三水平作正交试验，确定90％乙醇用量/颗粒重为2.5/10，混合时间10min，干燥温度70(℃)。
本品为片剂，黄芪、葛根、茵陈水煎及丹参、延胡索醇提所得浸膏直接制粒、压片即可，但片剂崩解时间较长，故筛选了崩解剂，羧甲基淀粉钠作为辅料崩解时间短，故选择羧甲基淀粉钠压片。
本品经沸腾制粒，压片的流动性差，必须加润滑剂加以改善，试验加入常用的滑石粉、硬脂酸镁，用测定休止角的实验方法，确定选择硬脂酸镁，用量为1.0％。
本品为全浸膏片，为降低吸湿性，同时增加制品的美感和鉴别特色，应包保护衣，选择包薄膜衣，对包衣粉、包衣液配置、操作方法及条件进行了研究。
Claims (2)
1.一种治疗冠心病心绞痛的片剂，其特征在于：其由如下重量份的原料制成：黄芪8份、丹参5份、延胡索5份、葛根3份、茵陈3份。
2.一种制备如权利要求1所述治疗冠心病心绞痛片剂的方法，其特征在于：黄芪、葛根、茵陈加水煎煮三次，每次2小时，滤过，合并滤液，减压浓缩成清膏，备用；另取丹参、延胡索加75％乙醇回流提取二次，每次2小时，滤过，滤液减压回收乙醇，加入上述清膏，搅匀，于80℃以下干燥，粉碎，加入适量辅料，混匀，压制成片，包薄膜衣即得。
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