CN1246016C - 一种治疗更年期综合征的中药复方制剂及制备方法 - Google Patents
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Abstract
本发明提供了一种治疗更年期综合征的中药复方制剂及制备方法。本发明治疗更年期综合征的中药复方制剂是以熟地黄、黄连、白芍、阿胶、及宁心安神类、清热解毒类药为活性成分与药用辅料组成的各种医学上可接受的口服制剂。该制剂不仅可弥补雌激素缺点，而且对更年期综合征有显著疗效，同时具有预防和延缓老年性疾病的作用。
Description
技术领域
本发明涉及中药复方制剂及制备方法。具体涉及一种治疗更年期综合征的中药复方制剂及制备方法。
背景技术
更年期综合征是一种发病率高、危害性大的常见病。在我国更年期人口中，更年期精神神经症状发生率高达75.1％，在绝经前已达高峰，持续7年左右；血管舒缩功能失调发生率为40.9％，高峰年龄50岁以后，持续6年左右。更年期综合征精神神经症状早期表现兴致缺失，担心微不足道的小事，或担心自己患了不治之症，甚至命在旦夕，为此焦虑激动、坐立不安、严重失眠，甚至产生自杀念头，影响患者生活质量、家庭团结、社会安宁，在发达国家该病已构成妇女致死第一原因；晚期部分妇女精神紧张可引起间隙高血压，心室收缩和舒张功能降低，冠心病的发病率和死亡率明显增加，脂质代谢失常，高血脂患者血栓形成增加，骨质疏松发病率增加。目前国内外采取西药雌激素治疗更年期综合征取得可喜成效，但同时发现口服雌激素会导致靶器官的恶性变，肝脏损害，血栓栓塞等不良反应。国内中药治疗更年期综合征，多数仍沿用辨症施治的汤剂治疗，存在服用不方便缺点，不利于进入国际市场。现有中成药中，能有效解除更年期困扰，质量稳定品种还不多。
发明内容
本发明所要解决的技术问题是提供一种具有雌激素类式生物效应的全天然中药制剂，该制剂不仅可弥补雌激素缺点，而且对更年期综合征有显著疗效，同时具有预防和延缓老年性疾病的作用。
本发明提供的治疗更年期综合征的中药复方制剂是以熟地黄、黄连、白芍、阿胶、清热解毒类、宁心安神类药为活性成分与药用辅料组成的各种医学上可接受的口服制剂。
本发明所述制剂的活性成分重量百分比组成为熟地黄25-45％，黄连8-30％，白芍8-30％，阿胶1-10％，清热解毒类药8-30％，宁心安神类药1-10％。
本发明所述口服制剂为片剂、胶囊剂、颗粒剂、丸剂等，每单位剂量制剂含盐酸小檗碱大于4.0mg，以HPLC法检测。
本发明所述的清热解毒类药选自黄芩、知母或黄柏等。
本发明所述的宁心安神类药选自茯苓、酸枣仁、合欢皮(花)、远志、琥珀、龙骨或磁石等
本发明所要解决的另一技术问题是公开上述中药复方制剂的制备方法。
本发明治疗更年期综合征的中药复方制剂的制备包括下列步骤：
(1)按处方量取熟地黄加3-6倍水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏I；
(2)按处方量分别称取黄连和白芍，将黄连粗粉碎后与白芍一起加3-6倍量水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏II；
(3)按处方量称取清热解毒类药如黄芩，加3-6倍量沸水煎煮一次，药渣再加3-6倍量水煎煮一次，合并提取液，浓缩得浸膏III；
(4)取浸膏II、III，和50％浸膏I混合喷雾干燥得浸膏粉；
(5)按处方量称取宁心安神类药如茯苓、阿胶，粉碎，过筛，得茯苓粉和阿胶粉；
(6)将步骤(4)制得的浸膏粉与步骤(5)制得的茯苓粉于沸腾制粒机中混合，加入剩余的50％浸膏I喷雾制粒，喷膏完毕加入阿胶粉混合，干燥，整粒；
(7)将步骤(6)制得的颗粒按常规方法制成各种口服制剂。
本发明所要解决的再一技术问题是公开上述中药复方制剂在制备治疗更年期综合征药物中的应用。
本发明中药复方制剂滋阴清热、安神除烦。可用于腰膝酸软、五心发热、自汗盗汗、烦躁易怒、多疑善感、心悸失眠、头昏耳鸣、舌红苔少、脉沉细数等阴虚火旺症；妇女更年期综合征见上述阴虚火旺症者。
中医理论认为：女性更年期综合征为绝经前后诸症，其发病机理主要为阴虚火旺，阴阳平衡失调。
《素问·上古天真论》在“女子七岁，肾气盛，齿更发长；二七天癸至，任脉通，太冲脉盛，故有子，……六七三阳脉衰于上，面始焦，发始白；七七任脉虚，太冲脉衰少，天癸竭，地道不通，故形坏无子也”论述中指出，肾精和天癸是生命生长发育、繁衍后代根本物质。肾精足，则肾气盛；肾精虚，则肾气衰。更年期妇女，肾精虚，天癸竭，肾气与冲、任渐衰，月经从定期来潮过度到绝经，生殖功能从降低过度到丧失，表现出阴阳平衡失调，脏腑气血不相协调。
肾精属阴，天癸属阴，任脉主人身之阴，冲脉为血海，血属阴。妇女以血为主，以血为用。更年期妇女阴精虚衰，阴不维阳，虚阳上越，出现头面潮红烘热，自汗盗汗。肾属水，心属火，正常情况下心肾相交，水火互济，才能维持人体正常生理功能。更年期肾精虚，天癸竭，水不济火，阴虚火旺导致心肾不交，心神不安，出现心烦易怒，失眠多梦阴阳升降失调见证。肾主骨，生髓，通脑，开窍于耳，肾精虚不能上荣头目脑髓，出现头目眩晕而耳鸣。腰为肾府，肾虚故见腰膝酸痛。由于阴虚火旺，故脉细数无力，舌质红少苔。综上所述，病机为阴虚火旺，阴阳平衡失调，病位在心、肾。
现代医学研究表明更年期妇女卵巢功能逐渐衰退至完全消失，性激素水平下降是更年期综合征主要病因。45-55岁妇女自然绝经，或手术切除双侧卵巢，或用放射治疗卵巢破坏引起绝经，也会导致更年期综合征发生。多数学者认为卵巢功能退化，体内雌激素(E2)水平下降，是更年期综合征病因，由此引起下丘脑——垂体——卵巢之环路失调。更年期综合征生理变化表现在两个方面，一是卵巢功能衰退，体内E2水平降落变化；二是机体老化变化。
中医治疗原则是：
阴阳相对平衡是健康标志，阴阳平衡失调是疾病产生原因，阴阳离决则生命死亡。故《素问·生气通天论》日：“生之本，本于阴阳”。根据“阴平阳秘，精神乃制，阴阳离决，精气乃绝”原则，采取“谨察阴阳所在而调之，以平为期”治疗方法，针对女性更年期综合征阴虚火旺病机，心肾不交病理，采取滋阴降火，清心除烦、宁心安神治则，调节阴阳，建立新的相对阴阳平衡内环境，治疗更年期综合征阴虚火旺。
阴虚之热，非火之有余，乃真阴之不足。更年期综合征阴虚火旺以阴虚为本，火旺为标。故本发明制剂用熟地滋补真阴作为君药；黄连、白芍、阿胶为臣药；黄芩、茯苓等清热解毒、宁心安神类药为佐药。
《本草正》日：“阴虚而神散者，非熟地之守，不足以聚之；阴虚而火升者，非熟地之重，不足以降之；阴虚而燥动，非熟地之静，不足以镇之；阴虚而刚急者，非熟地之甘，不足以缓之”。熟地滋阴补肾，肾水上济于心，水火相济，可起到降心火作用，熟地滋肾水，水足热自消，热去神自安，则阴不维阳，虚阳上越烘热、汗出得以改善；心神不安，心烦易怒、失眠多梦症状得以缓解，既解除更年期综合征病因，又解除阴虚火旺导致症状，达到标本兼故目的。黄连苦寒人心，苦能泻火，寒能清热。汗为心液，心火旺，火迫汗出，泻心火，治疗心火上炎发热，汗出；清心热，除心烦治疗心烦易怒，心神不安失眠多梦。黄连与熟地配伍，降心火，下济于肾，使心肾交通，水火相济，熟地滋阴降火功能得以有效发挥。白芍苦降酸收，收敛浮越之阳下归其宅，又能滋阴。阿胶补血养血。白芍、阿胶与熟地配伍，可增强熟地滋补真阴力量，肾精足，则腰酸肢软，头目眩晕症状得以缓解。黄芩清热泻肺，辅佐黄连，增强清热之力。又肺为肾之上源，清肺亦所以清肾也。有资料报导，黄芩与黄连配伍，对更年期综合征潮热、汗出具有良好的治疗作用；黄芩取其清热燥湿、泻火解毒、清上中焦之活，知母、黄柏等亦为苦寒之药，可泻相火，退虚热，可代黄芩之功。肾为先天之本，脾为后天之本；茯苓健脾，为熟地补肾精提供源泉；茯苓宁心安神，又可控制更年期失眠多梦症状；凡安神药如酸枣仁、合欢皮(花)、远志、琥珀、龙骨、磁石等皆可用。全方六味药合用，共同起到滋阴降火、清心除烦、宁心安神作用，从而建立新的阴阳相对平衡内环境，解除更年期综合征困挠。
本发明制剂中各活性成分药材主要含生物碱、甙类、维生素类、微量元素类有效成分，在水中有一定溶解度，故选择水浸提煎煮工艺。为保证浸膏中所含活性物质的量，本发明采用正交试验优选了各提取条件，使提取浸膏中小檗碱含量最佳。
黄芩中含黄芩酶，能使黄芩甙水解，从而降低浸膏中黄芩甙的含量，本发明在提取浸膏时将黄芩单独进行水提，首先采用100℃沸水直接加到黄芩药材中提取，可在短时间内破坏黄芩酶而减少黄芩甙的损失。
为保证本发明制剂的稳定性，减少浸膏粉的吸湿性，增加流动性以适合工业化生产，在本发明制剂的制备中采用在浸膏粉及阿胶粉的混合粉中加入茯苓粉，大大降低了半成品的吸湿性。
用本发明方法制得的各种口服制剂，活性成分含量高，质量稳定，成品率高。
用本发明制剂(更年青胶囊)进行有关毒性学和药效学以及临床试验，结果显示：
I.毒理学试验
急毒试验：小鼠灌服急毒试验表明，更年青胶囊无明显毒性，LD50求不出。小鼠尾静脉给药急毒试验，LD50＞16.0388/kg体重。
长毒试验：给大鼠灌服本品25.0g/kg、12.5g/kg、5.0g/kg(分别相当于临床日剂量50、25和5倍)180天，检查8项血液学指标，9项血液生化学指标及10多种组织脏器病理形态。结果说明，更年青对大白鼠的生长发育，造血功能和血液生化学均无明显的毒性影响，对大白鼠的心、肝、脾、肺、肾、子宫、卵巢、睾丸、垂体、脑等组织的组织形态学检查，各项指标均未发现异常变化及损伤性毒性变化，本品长期服用毒性小，临床量用药安全。
II.药效学试验
动物药效学试验证明，更年青胶囊对内分泌具有可靠的有效的双向调节作用。给更年期大鼠灌服更年青4周后，明显降低大鼠血清LH、FSH、T含量(P＜0.05-0.001)，对E2无影响(P＞0.05)，与更年期空白对照组比较(P＜0.05-0.01)；给切除双侧卵巢雌性幼年小鼠灌服更年青15天，去势幼鼠子宫重量有非常明显增重作用(P＜0.001)，与灌服生理盐水对照组比较(P＜0.001)，有极显著差异。更年青对阴虚小鼠，cAMP有非常明显降低作用(P＜0.001)，为更年青纠正“虚症”提供了科学依据。更年青对用甲状腺素处理的小鼠，其耐缺氧生存时间、游泳耗竭时间、睡眠时间均明显延长(P＜0.05-0.001)。对毛果芸香碱所致大鼠足趾汗液分泌，更年青亦有明显的对抗作用。更年青对环磷酰胺所致小鼠体液免疫功能低下和对可的松抑制小鼠RES吞噬功能，均有明显的对抗作用，提示本品有增强免疫功能的作用。
III.临床试验
1.I期临床试验
采取随机对照单盲对照法，以更年青胶囊为治疗组观察100例，西药尼尔雌醇为对照组观察30例，比较两组治疗3月后，更年期综合征K评分变化、E2变化，和对乳房、阴道付反应。结果K评分：更年青胶囊P＜0.001，尼尔雌醇P＜0.01；E2前者略上升、后者略下降；付反应前者无，后者有4人阴道分泌物增多。有效率：更年青胶囊95％，尼尔雌醇90％。结果确定更年青胶囊有效安全日治疗量相当原生药34克，疗程三月，用药15天后开始显效。结果说明更年青胶囊治疗更年期综合征是安全的有效中药制剂。
2.II期临床试验
北京中医药大学东直门医院、上海中医药大学曙光医院、四川省人民医院、第三军医大学西南医院、重庆医科大学第一附属医院，自1998年9月至1999年2月，进行了临床试验，以更年安片为对照品，采取随机对照、双摸拟、双盲法共观察临床病例405例，其中治疗组305例，对照组100例。治疗组口服更年青胶囊，4粒，3次/日，共30天，对照组口服更年安片4片，3次/日，共30天，服药前，服药结束当日，对血清E2、FSH、LH、阴道细胞成熟指数、甲皱微循环、阴虚火旺证评分进行试验观察和一月随访，治疗组还进行了安全性指标各项(心电图、肝、肾功能三大常规)检测。结果显示：治疗组显愈率65.36％，总有效率96.10％：对照组显愈率40.00％，总有效率86.00％，两组比较P＜0.001，差有非常显著意义，治疗组相关安全性检查未见新的异常。
本发明中药复方制剂以熟地、白芍、阿胶滋补肾阴，黄连、黄芩清心降火除烦，茯苓宁心安神，六味药合用，具有滋阴降火，安神除烦功能。本发明中药制剂为更年期综合征患者提供了疗效可靠，服用方便、安全、价廉的治疗药物。
具体实施方式
实施例1 胶囊剂制备方法：
配方：熟地黄 25％
黄连 25％
白芍 20％
阿胶 7％
黄芩 15％
合欢皮 8％
(1)将熟地黄加4倍水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏I；
(2)将黄连粗粉碎后与白芍一起加5倍量水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏II；
(3)将黄芩加4倍量沸水煎煮一次，药渣再加3倍量水煎煮一次，合并提取液，浓缩得浸膏III；
(4)取浸膏II、III，和50％浸膏I混合喷雾干燥得浸膏粉；
(5)将合欢皮、阿胶粉碎后，分别过80目筛，得合欢皮粉和阿胶粉；
(6)将制得的浸膏粉与合欢皮粉于沸腾制粒机中混合，加入剩余的50％浸膏I喷雾制粒，喷膏完毕加入阿胶粉混合，干燥，整粒；
(7)将所得颗粒装胶囊。
实施例2 颗粒剂制备：
配方： 熟地黄 43％
黄连 15％
白芍 25％
阿胶 4％
黄柏 10％
茯苓 3％
分装1000袋
(1)取熟地黄加5倍水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏I；
(2)将黄连粗粉碎后与白芍一起加4倍量水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏II；
(3)将黄柏加5倍量沸水煎煮一次，药渣再加6倍量水煎煮一次，合并提取液，浓缩得浸膏III；
(4)取浸膏II、III，和50％浸膏I混合喷雾干燥得浸膏粉；
(5)将茯苓、阿胶粉碎后，分别过40目筛，得茯苓粉和阿胶粉；
(6)将制得的浸膏粉与茯苓粉于沸腾制粒机中混合，加入剩余的50％浸膏I喷雾制粒，喷膏完毕加入阿胶粉混合，干燥，整粒；
(7)将制得的颗粒装袋。
实施例3 片剂的制备
配方： 熟地黄 32％
黄连 20％
白芍 15％
阿胶 8％
知母 20％
酸枣仁 6％
压制成1000片
(1)按处方量取熟地黄加3倍水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏I；
(2)按处方量分别称取黄连和白芍，将黄连粗粉碎后与白芍一起加6倍量水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏II；
(3)按处方量称取知母，加5倍量沸水煎煮一次，药渣再加6倍量水煎煮一次，合并提取液，浓缩得浸膏III；
(4)取浸膏II、III，和50％浸膏I混合喷雾干燥得浸膏粉；
(5)将酸枣仁、阿胶粉碎后，分别过60目筛，得酸枣仁粉和阿胶粉；
(6)将制得的浸膏粉与酸枣仁粉于沸腾制粒机中混合，加入剩余的50％浸膏I喷雾制粒，喷膏完毕加入阿胶粉混合，干燥，整粒；
(7)将制得的颗粒压片。
Claims (4)
1、一种治疗更年期综合征的中药复方制剂，其特征在于该制剂由重量百分比组成为熟地黄25-45％，黄连8-30％，白芍8-30％，阿胶1-10％，清热解毒类药8-30％，宁心安神类药1-10％为原料制得的活性成分与其他药用辅料组成的各种医学上可接受的口服制剂；其中清热解毒类药为黄芩、知母或黄柏，宁心安神类药为茯苓、酸枣仁、合欢皮或花、远志、琥珀、龙骨或磁石。
2、一种如权利要求1所述的治疗更年期综合征的中药复方制剂，其特征在于其中所述的口服制剂为片剂、胶囊剂、颗粒剂或丸剂，每单位剂量制剂含盐酸小檗碱大于4.0mg，以HPLC法检测。
3、一种如权利要求1所述的治疗更年期综合征的中药复方制剂的制备方法，其特征在于该制剂由下列步骤制得：
(1)按配比取熟地黄加3-6倍水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏I；
(2)按配比分别称取黄连和白芍，将黄连粗粉碎后与白芍一起加3-6倍量水浸泡过夜，煎煮二次，合并提取液，浓缩得浸膏II；
(3)按配比称取清热解毒类药，加3-6倍量沸水煎煮一次，药渣再加3-6倍量水煎煮一次，合并提取液，浓缩得浸膏III；
(4)取浸膏II、III，和50％浸膏I混合喷雾干燥得浸膏粉；
(5)按配比称取宁心安神类药、阿胶，粉碎，分别过筛，得宁心安神类药粉和阿胶粉；
(6)将步骤(4)制得的浸膏粉与步骤(5)制得的宁心安神类药粉于沸腾制粒机中混合，加入剩余的50％浸膏I喷雾制粒，喷膏完毕加入阿胶粉混合，干燥，整粒；
(7)将步骤(6)制得的颗粒按常规方法制成各种口服制剂。
4、一种如权利要求1所述的中药复方制剂在制备治疗更年期综合征药物中的应用。
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| CN103961457B (zh) * | 2013-12-31 | 2016-01-20 | 贵阳新天药业股份有限公司 | 用于治疗妇女更年期阴道出血的药物组合物及其制备方法 |
| CN104800553B (zh) * | 2015-04-30 | 2018-01-26 | 东阿阿胶股份有限公司 | 一种治疗更年期失眠症的中药组合物及其制备方法 |
| CN105343474A (zh) * | 2015-12-09 | 2016-02-24 | 赵爱良 | 一种治疗男性更年期综合征的胶囊剂及制备方法 |
| CN108210827A (zh) * | 2016-12-12 | 2018-06-29 | 景东旭 | 清心安神汤 |
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