CN106511903B - 辅助利尿剂治疗老年高血压、改善依从性问题的组合物 - Google Patents
辅助利尿剂治疗老年高血压、改善依从性问题的组合物 Download PDFInfo
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Abstract
本发明公开了辅助利尿剂治疗老年高血压、改善依从性问题的组合物。该组合物由人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草制成,可以辅助噻嗪类利尿剂治疗老年高血压,有效解决服用噻嗪类利尿剂依从性不良产生的问题,并且纳入中西医结合的策略,采用中药方剂结合利尿剂来治疗高血压,起到针对利尿剂(噻嗪类)治疗高血压的减副增效的效果。
Description
技术领域
本发明涉及高血压的药物治疗技术领域,具体涉及一种辅助利尿剂治疗老年高血压、改善依从性问题的组合物及其制备方法和应用。
背景技术
高血压是目前发病率较高、并发症较多,且不容易根治的慢性病,是心脑血管疾病的第一危险因素,可直接诱发心肌梗死、心力衰竭、脑卒中、肾衰竭和猝死。积极干预高血压人群、降低血压水平,可显著减少高血压人群的心、脑、肾并发症,改善其预后。尽管许多临床证据表明降压治疗可以使高血压患者受益,但在全球范围内高血压患者的治疗率及控制率均较低,在年龄﹤60岁、60-79岁、≧80岁的人群中,血压控制达标率男性分别为38%、36%和38%,女性分别为38%、28%和23%,在我国32.2%的高血压患者接受药物治疗,控制率仅为7.6%。
合理选择降压药物不仅有利于提高高血压患者血压达标率,降低患者心血管疾病的发病率和病死率,还可预防靶器官损害(冠心病、心力衰竭、脑卒中和肾功能不全等)。高血压防治指南推荐临床常用的5类降压药物:(1)利尿剂,常用的噻嗪类利尿剂主要是氢氯噻嗪和吲达帕胺,小剂量氢氯噻嗪(6.25-12.5mg/d)对代谢影响小,与其他降压药合用降压作用明显增加,该药物适用于单纯收缩期高血压或伴心力衰竭患者,也是难治性高血压的基本治疗药物;(2)钙通道阻滞剂(calcium channel blocker,CCB),目前推荐应用长效二氢吡啶类CCB,其降压疗效好,作用平稳,无绝对禁忌证;(3)血管紧张素转化酶抑制剂(angiotensin-converting enzyme inhibitor,ACEI),适用于高血压伴慢性心力衰竭、心肌梗死后伴心功能不全、心房颤动、糖尿病肾病、肾疾病、代谢综合征等患者;(4)血管紧张素II受体拮抗剂(angiotensin II receptor blockers,ARB),目前临床上常用的ARB主要包括坎地沙坦、替米沙坦、氯沙坦、缬沙坦和厄贝沙坦等,其中坎地沙坦降压效应比较显著,而且使用剂量比较小,是ARB类药物中降压效果比较理想的药物;(5)β受体阻滞剂。
上述5类一线抗高血压药物,平均价格最便宜的是利尿剂,其次依次为β受体阻滞剂、ACEI、CCB和ARB,由于抗高血压治疗的益处主要来自血压降低本身,而对于低、中危高血压患者,目前常用的降压药物在降低血压水平方面并无显著性差异,结合我国现阶段的国情,若选择噻嗪类利尿剂、β受体阻滞剂或国产的复方降压制剂作为这类患者的初始治疗,必将节约大量成本,使有限的卫生资源利用最大。
利尿剂引起价格低廉,使用范围广,尤其对于老年高血压患者而言。常用的利尿剂可根据其作用部位或按其利尿效能的不同分类:①噻嗪类利尿剂:分为噻嗪型和噻嗪样利尿剂,噻嗪型药物的基本化学结构由苯并噻二嗪核和磺酰胺基组成,包括氢氯噻嗪和苄氟噻嗪等;噻嗪样利尿剂的化学结构含有磺酰胺基,包括氯噻酮、吲达帕胺和美托拉宗等。②襻利尿剂/袢利尿剂:主要作用于肾髓襻升支粗段皮质部,阻断钠-钾-氯共同转运体,抑制对氯化钠的主动重吸收;由于使肾髓质间液渗透压降低,影响肾脏浓缩功能,利尿作用强大,药物有呋塞米、托拉塞米、布美他尼等。③保钾利尿剂:氨苯蝶啶和阿米洛利抑制远曲小管和集合管的钠-氢共同转运体,抑制Na+再吸收和减少K+分泌,其作用不依赖醛固酮,利尿作用弱,螺内酯和依普利酮可与醛固酮受体结合,竞争性拮抗醛固酮的排钾保钠作用。
利尿剂的降压幅度是很强的,顽固性高血压常常需要用到利尿剂才能控制。另外一种情况可能使用利尿剂的情况就是对于年龄比较大的病人,例如超过70岁,体内水钠增多常常是高血压的一个重要机制,可以说必须使用利尿剂才能达到降压目标。尤其是噻嗪类利尿剂用于治疗高血压的历史已经超过50年。由于其良好的疗效和性价比,增强其他抗高血压药物的效力,并且可降低高血压相关的病残率和死亡率,至今仍是高血压治疗中获得广泛推荐的一线用药。
尽管药物疗法已使90%以上的高血压病人血压将至正常,但研究表明,不良的高血压病人服药依从性直接影响着高血压病情的发展和治疗效果。高血压服药依从性是指高血压病人对医嘱的执行程度,高血压病人的服药不依从性是指高血压病人不能按照医嘱坚持进行药物的自我管理,包括不按处方配药与服完药后不补充药物;服药药量不按医嘱(太多或太少);不规则用药,如随意改变服药时间、药量、服药间隔或漏服药物;停药太快或擅自停药或换药;服用处方药物时饮酒等。
虽然通过部分措施(如加强对服药依从性的测量,包括检测患者血、尿中药物代谢产物的浓度、药片计数、询问与问卷调查等,或者加强健康教育,简化给药方案等),可以提升患者对高血压治疗的依从性,但仍稍显不足。尤其是对于利尿剂的使用而言,基于经济学因素的考虑(①患者的危险水平,愈是高危患者,从降压治疗中愈受益;②年龄;③药物的临床疗效,血压控制水平,对临床终点事件的影响;④治疗的依从性和安全性,以及降压治疗的益处来自于血压降低本身,在降压的疗效没有显著区别的情况下,药价低廉的降压药治疗可达到理想的价效比),噻嗪类利尿剂仍是当前一线抗高血压药物,存在噻嗪型与噻嗪样利尿剂的选择性问题、患者擅自换药(如从噻嗪样换为噻嗪性利尿剂)、改变药量、服药间隔问题,老年高血压患者依从性更差。
此外,服用利尿剂亦存在一定的副作用和禁忌症。大剂量噻嗪型及噻嗪类似物有可能引起胰岛素抵抗、高血糖症、加重糖尿病及减弱口服降糖药的效能,引起血钾、血钙降低,血尿素氮、肌酐及尿酸升高。痛风、低钾血症为利尿剂使用禁忌证,重度肾功能不全不用噻嗪类利尿剂,妊娠为相对禁忌证,妊娠头7月尽量不用利尿剂,但可用于血容量过高患者。
中西医结合治疗高血压有减副增效的优点,是治疗高血压的一种有效手段,中西药合同后,西药既可以发挥近期疗效高的长处,又由于用量相应减少而减轻其毒、副作用,中药的降压作用可提高引起疗效,又具有远期降压作用,故中西药合用治疗高血压,具有见效快、疗效高、副作用少的优点,此外中西药结合治疗,也可以避免血压较大波动,使得降压平稳和缓。对于利尿剂结合中药治疗高血压,现有技术公开多种,如CN105687874A公开了一种含有氢氯噻嗪的治疗高血压的药物组合物,由氢氯噻嗪、杜仲叶、东北红豆杉、金发草、草地早熟禾组成;CN101773658A公开了一种含有吲达帕胺的药物,由吲达帕胺和中药提取物1:103组成,中药包括桂枝、赤芍、大枣、生姜、炙甘草;CN1253815A公开了一种治疗高血压、高血脂的外用制剂,由钩藤、罗布麻、绞股蓝、杜仲、阴阳莲、夏枯草、草决明、丹参、可乐定、氢氯噻嗪组成;CN101002880A公开了一种抗高血压复方制剂,包括血管紧张素II受体拮抗剂、氢氯噻嗪和知母百合浸膏颗粒药粉;CN105796773A公开了含有吲达帕胺的治疗高血压的药物组合物,由吲达帕胺、芭蕉头、白钩藤、福建柏、荠薴组成。
发明内容
针对上述现有技术,虽然采用中西医结合来治疗高血压,但仍多专注于中药对于西药的减副增效特点开发新的组方,发明人结合自身多年中医院诊治老年高血压的经验,重点考量患者服用利尿剂治疗高血压可能存在的依从性不良问题、老年高血压者药物代谢和清除、靶器官损伤和并发症问题,结合中西医合用治疗高血压的减副增效的优点,提出一种中药组合物辅助利尿剂治疗的治疗老年高血压的方案,该方案以西药利尿剂为主,尤其是噻嗪类利尿剂,结合中药的药物组合物的使用,增强老年高血压患者对高血压治疗的依从性,改善服用利尿剂时存在的依从性不良所导致的的问题,并中西医合用治疗高血压起到了减副增效的效果。
为实现上述目的,本发明采用下述技术方案:
本发明第一方面,提供一种辅助利尿剂治疗老年高血压的中药组合物,该中药组合物由以下重量份的原料制成:
人参300-500份、川芎250-350份、三七220-280份、灯盏花200-350份、附子60-90份、吴茱萸120-180份、怀牛膝80-150份、牡丹皮150-250份、郁金180-260份、黄芪220-280份、槲寄生150-250份、菟丝子100-180份、何首乌180-250份、萆薢150-250份、威灵仙80-120份、炙甘草250-350份。
优选的技术方案中,本发明所述中药组合物由以下重量份的原料制成:人参350-450份、川芎280-320份、三七220-260份、灯盏花250-280份、附子70-80份、吴茱萸140-160份、怀牛膝100-120份、牡丹皮180-220份、郁金200-240份、黄芪240-260份、槲寄生180-220份、菟丝子120-160份、何首乌200-230份、萆薢200-240份、威灵仙90-110份、炙甘草280-330份。
更优选的技术方案中,本发明所述中药组合物由以下重量份的原料制成:人参420份、川芎300份、三七250份、灯盏花250份、附子70份、吴茱萸150份、怀牛膝120份、牡丹皮200份、郁金220份、黄芪250份、槲寄生200份、菟丝子150份、何首乌200份、萆薢220份、威灵仙100份、炙甘草300份。
本发明重点考虑老年高血压患者服用利尿剂治疗高血压时可能存在的依从性不良导致的诸多问题,采用中药组合物来调和服用利尿剂(主要是噻嗪类利尿剂)依从性不良产生的问题,所述依从性不良导致的问题包括①利尿剂治疗高血压的应用经历了由大剂量使用到小剂量应用的阶段变化,现阶段越来越认识到低剂量利尿剂,不仅具有相当程度的降压作用,而且较少有大剂量利尿剂导致的生化和激素的紊乱;但虽医嘱告知患者服用小剂量,但由于个体差异或其他原因(如认知的差异等),老年高血压患者服用小剂量利尿剂(如12.5mg/d的氯噻酮)时,较服用大剂量仍降压不明显而不再遵医嘱,转而持续服用相对较大剂量利尿剂,导致一段周期内总体服药剂量大,副作用显著;②利尿剂治疗高血压本身具有一定的副作用,如导致尿液排出增多,会出现尿频,夜尿增多等情况,使尿液中钠、钾离子排出增多,使血液中钠、钾离子浓度下降,血中钾离子浓度下降会导致许多并发症,如全身乏力,肌肉无力,食欲下降,各种心律失常,患者私自减小服用剂量来降低副作用,从而产生不充分的利尿剂治疗,导致降压治疗产生抵抗;③老年高血压患者对于噻嗪类利尿剂的认知不足,尤其是对于噻嗪型利尿剂(氢氯噻嗪、苄氟噻嗪)和噻嗪样利尿剂(氯噻酮、吲达帕胺),将两者混淆服用;此外,噻嗪型利尿剂持续时间和清除半衰期短,服药间隔短,也是导致患者停换药、进而导致依从性不良的原因之一。其次,本领域内,中西医结合治疗高血压研究颇深,发明人结合老年高血压的特点(包括老年高血压患者药物代谢和清除、靶器官损伤和并发症问题),将所述老年高血压的部分问题纳入本发明方案中,采用中药方剂结合利尿剂来治疗高血压,亦起到针对利尿剂(噻嗪类)治疗高血压的减副增效的效果。
本发明中药组合物方中,以人参、川芎、三七、灯盏花为君药,人参补益强心、补气固脱,川芎、三七、灯盏花行气解表、活血舒筋,主扩张血管、改善血液循环和机体代谢功能;辅以附子、吴茱萸、怀牛膝、牡丹皮、郁金为臣药,强君药之治疗主证,附子、吴茱萸,温经通阳、活络行脉,怀牛膝、牡丹皮、郁金,平肝潜阳、通络活血、解阻化瘀;佐以黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙,滋肝补肾,通络降压,黄芪、槲寄生、菟丝子、何首乌,固表升阳,益精血,萆薢、威灵仙,保肝利尿,兼顾尿酸排出;炙甘草,中和附子之毒,协同附子抑制低血钾症,并付之调和药物之功效。
方中各味药的药性及与本发明治疗方案之间的关系如下:
人参,味甘、微苦,性温、平,归脾、肺经、心经,补气,固脱,生津,安神,益智,可用于调节身体免疫力、促进机体代谢、改善心血管功能和血液功能。
川芎,味辛,温,归肝、胆、心包经,活血行气,祛风止痛,可调节免疫功能、改善肺、肾功能,提高心血管功能,对中枢神经熊有明显的镇静作用。
三七,味甘、微苦,温,归心、肝、脾经,化瘀止血,消肿止痛,可用于心脑血管系统疾病的预防和治疗,其所含的皂苷类和黄酮类成分是活血化瘀有效成分,可用于调节免疫功能、抑制血小板聚集、保护肝脏。
灯盏花,味甘,微温,散寒解表,活血舒筋,可使血管扩张、动脉血流量增加,外周血管阻力降低,改善血液流变,增加心肌营养,抑制神经细胞内钙超载。
附子,性大热,味辛、味甘,有毒,归心、肾、脾经,温经通阳,振奋心阳,补益阳气。
吴茱萸,味辛、苦,热,归肝、脾、胃经,散寒止痛,疏肝下气,燥湿降逆,开郁结、降浊阴,可用于活血化瘀。
怀牛膝,味苦、酸,平,归肝,肾经,活血祛瘀,补肝肾,强筋骨,引血下行,可用于调节机体免疫、具有降压、抗炎、镇痛功效,有助于改善血液循环。
牡丹皮,味苦、辛,微寒,归心、肝、胃经,清热凉血,活血散瘀,具有降压、抗炎、镇痛功效,可保肝,增强机体免疫力。
郁金,味辛、苦,寒。归心、肝、胆经,活血止痛,行气解郁,清热凉血,清心开窍,可扩张冠状动脉,增加冠流量,改善微循环,保护肝脏。
黄芪,性味,甘,温,归肺、脾经,益卫固表,补气升阳,可增强免疫、促进机体代谢,具有改善心功能、保肝作用、镇静、抗衰老功能。
槲寄生,味苦,平,归肝、肾经,祛风湿,补肝肾,强筋骨,养血益肝肾,用于盈血亏虚、肝肾不足。
菟丝子,味辛、甘,平,归肝、肾、脾经,补阳益阴,固精缩尿,明目,可调节免疫功能、改善生殖系统功能,对心肌缺血有良好的防止作用。
何首乌,味苦、甘、涩,微温,归肝、肾经,补肝肾、益精血,解毒,具有降血脂、抗菌、抗肿瘤作用,可以改善心功能和血液功能。
萆薢,味苦,平,归肝、胃、膀胱经,利湿浊,祛风湿,舒筋通络,具有降压和抗动脉粥样硬化作用。
威灵仙,味辛、咸,温,归膀胱经,祛风湿,通经络,止痹痛。
炙甘草,味甘,平,归心、肺、脾、胃经,补脾和胃,益气复脉,可解附子毒。
本发明通过将多味中药进行配伍,药物之间共同发挥了补中固益、活脉通络、改善代谢和血液循环、滋肝补肾的作用,对于利尿剂(噻嗪类)治疗高血压具有明显的增效作用,并有效降低利尿剂使用的副效应,增效同时减副,而且方中诸药增益心、肺、肾、脾、肝,增强靶器官保护,降低老年高血压存在的靶器官损伤。
对于方中诸药的量效关系,本发明在药物布设过程中有明确的考量,方中补益药物过半,需合理调节药效关系,防止冲突、避免补之过甚;且需合理调配臣药、佐药药量效关系,使加强君药治疗主证的作用又可治疗兼证,即达到增效减副之良效。
综上所述,本方所选药材配伍相宜,组方精炼,在功能上相辅相成,疗效显著;在药性上相制相佐,毒副反应少,服用安全。
本发明的辅助利尿剂治疗老年高血压的中药组合物中,各原料组分是一个有机的整体,缺一不可。发明人在研发过程中发现,减少上述组合物中的任何一种原料组分,或以具有相似药性的原料药对本发明药物组合物的原料组分进行替换,则药物组合物整体的作用效果显著降低;在本发明的中药组合物的基础上再增加其他的原料组分,药物组合物的整体效果并未有明显的改善,甚至有药物组合物的整体效果降低的情况出现。
上述辅助利尿剂治疗老年高血压的中药组合物可直接将各原料粉碎,加水煎煮制备;也可以按照其他方法制备。在本发明的一个具体实施方式中,上述辅助利尿剂治疗老年高血压的中药组合物的制备方法为:
将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,或混合后磨成粉亦可,加水煎煮2-3次,每次煎煮时间0.3-1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉,得辅助利尿剂治疗老年高血压的中药组合物;喷雾干燥制成的细粉可以进一步与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
在本发明的一个优选的具体实施方式中,上述辅助利尿剂治疗老年高血压的中药组合物的制备方法为:
将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,或混合后磨成粉亦可,加水煎煮2次,每次煎煮时间1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉,得辅助利尿剂治疗老年高血压的药物组合物;喷雾干燥制成的细粉可以进一步与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
中药成分复杂,一种药材中既有水溶性成分,又有油溶性或醇溶性成分,且有些活性成分在高温下容易失活,因此通过选择合适的提取方法和提取工艺对中药有效成分进行提取分离,可以最大限度的提取出有效成分并保证有效成分的活性,从而保证产品的临床效果。
经试验验证,采用上述制备方法,可以最大限度的提取出中药组合物中的有效成分并保证有效成分的活性,从而保证产品的临床效果。
上述中药组合物在制备辅助利尿剂治疗老年高血压的药物制剂中的应用也是本发明保护的范围。
本发明所述老年性高血压系指年龄大于65岁,血压值持续或非同日3次以上超过标准血压诊断标准,即收缩压≥140mmHg(18.6kPa)和(或)舒张压≥90mmHg(12kPa)者。
老年人体内水钠增多常常是其高血压的一个重要机制,往往必须使用利尿剂才能达到降压目标。
老年人中常有药代动力学的变化,一般情况下,随年龄的增加,体内脂肪量增加,而水分、血浆容量、肌肉总量降低,导致脂溶性药物的分布容积降低。由于肝肾功能常有降低,老年高血压患者的药物代谢和排出率降低。因此,在使用噻嗪类利尿剂应考虑减量。
老年人肝脏对药物的清除率低。老年人α受体阻滞药和拉贝洛尔的药代动力学无降低,而β受体的敏感性降低,但α受体功能正常。在降压的速度方面,不宜快速降低血压。主要原因在于老年人脑循环和其他循环系统的功能需要在较高循环压力情况下维持正常,虽然对降压治疗可以进行自身调节和适应,但常需要数天才能适应。因此,即使在需要快速降压的老年人中,开始降压幅度也不宜超过25%。
除了降压治疗外,老年人一般靶器官损害和并发症较多,需注重多重干预,个体化治疗。
本发明所述利尿剂,优选为噻嗪类利尿剂:作用于远曲小管,阻断钠-氯共同转运体,减少Na+和Cl-重吸收,促进Na+、Cl-和水的排出,由于使远曲小管的钠负荷增高,促进Na+-K+交换,故也排泄K+;而且血容量的减少促进了醛固酮的分泌,进一步排泄钾,噻嗪类利尿剂对尿液的浓缩过程没有影响,利尿作用中等,该类药物又可分为噻嗪型和噻嗪样利尿剂,噻嗪型药物的基本化学结构由苯并噻二嗪核和磺酰胺基组成,包括氢氯噻嗪和苄氟噻嗪等;噻嗪样利尿剂的化学结构不同于噻嗪型,但含有磺酰胺基,同样作用于远曲小管,包括氯噻酮、吲达帕胺和美托拉宗(该药还作用于近曲小管)等。
所述辅助利尿剂治疗,意指与利尿剂药物联用或合用,包括将所述中药组合物与利尿剂分别制成药物制剂,联合服用;或者将中药组合物与利尿剂混合制备药物制剂。
本发明的第二方面,公开了一种治疗老年高血压的药物组合物,该药物组合物由利尿剂与上述中药组合物制备而成,中药组合物各组分的重量份为人参300-500份、川芎250-350份、三七220-280份、灯盏花200-350份、附子60-90份、吴茱萸120-180份、怀牛膝80-150份、牡丹皮150-250份、郁金180-260份、黄芪220-280份、槲寄生150-250份、菟丝子100-180份、何首乌180-250份、萆薢150-250份、威灵仙80-120份、炙甘草250-350份,利尿剂选自氢氯噻嗪12.5-25份、氯噻酮12.5-25份、吲达帕胺1.5-2.5份中的一种。
优选的技术方案中,本发明所述治疗老年高血压的药物组合物由以下重量份的原料制成:人参420份、川芎300份、三七250份、灯盏花250份、附子70份、吴茱萸150份、怀牛膝120份、牡丹皮200份、郁金220份、黄芪250份、槲寄生200份、菟丝子150份、何首乌200份、萆薢220份、威灵仙100份、炙甘草300份、选自氢氯噻嗪12.5份、氯噻酮12.5份、吲达帕胺1.5份中的一种的利尿剂。
在本发明的一个具体实施方式中,上述治疗老年高血压的药物组合物的制备方法为:
将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,或混合后磨成粉亦可,加水煎煮2-3次,每次煎煮时间0.3-1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉,将利尿剂药物与该细粉混合得所述药物组合物;药物组合物可以进一步与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
本发明第三方面,提供一种药物制剂,由上述中药组合物或上述药物组合物,和药学上可接受的辅料制备而成。
上述药物制剂可以制成各种药物剂型,如丸剂、颗粒剂、胶囊剂、片剂、散剂或口服液等。
所述药学上可接受的辅料为药物制剂中的常规辅料,如:崩解剂、润滑剂、黏合剂等;优选为甘油、丁二醇、海藻糖、甜菜碱、淀粉、羧甲基纤维素钠、麦芽糊精中的一种或多种。
本发明取得了以下有益效果:
(1)本发明所述中药组合物可有效调节机体代谢机能,改善血液循环、增强机体代谢,对于老年高血压患者所服过大剂量的利尿剂(噻嗪类),通过“排”的手段,部分降低利尿剂浓度,中和或缓解患者因依从性不良服用大剂量利尿剂带来的损害;另一方面,本发明所述中药组合物可扩张血管、活血通络,从另一手段对老年高血压患者进行降压,辅助利尿剂提高降压效果,解决了患者服用小剂量利尿剂时降压不明显的问题;第三方面,本发明所述中药组合物可延长噻嗪型利尿剂持续时间和增强清除半衰期,从而增长服药间隔,而对噻嗪样利尿剂影响不大,通过中药组合物来弥补药物选择间的不足,增加药物适用度,从而提升患者的依从性;此外,老年患者对于中药认可度增加,也从一定程度上解决老年高血压患者利用中药辅助利尿剂治疗高血压时存在的依从性不良问题。
(2)本发明所述中药组合物不仅可以化瘀通阻,而且可以舒筋通络、活血软脉,与利尿剂可以有效配合互补,增强降压效果;第二,老年人肝脏对药物的清除率低,主要原因在于老年人脑循环和其他循环系统的功能需要在较高循环压力情况下维持正常,虽然对降压治疗可以进行自身调节和适应,但常需要数天才能适应,尤其是在有肾功能损害的情况下,会致药物蓄积而进一步导致损害,通过本发明药物组合物有效增强代谢功能的情况下,药物蓄积产生的损伤降低;第三,服用利尿剂会对血钾系统代谢产生不利影响,本发明中药组合物在增强代谢的同时,合理调配保钾药物,有效降低服用利尿剂产生的低钾血症;此外,本发明中药组合物兼顾加强尿酸排泄,进一步减轻和缓解长期服用利尿剂产生的高尿酸问题。
(3)老年高血压患者一般靶器官损害和并发症较多,而且服用利尿剂本身易影响肾功能,本发明所述中药组合物增益心、肺、肾、脾、肝,滋肝补肾、强心健脾,有效的增强靶器官保护,降低老年高血压存在的靶器官损伤。
(4)理想的降压药物应符合以下条件:①平稳,有效;②安全性好,不良反应少;③服用简便,依从性好;④价格低廉,经济性好;本发明所述复方制剂具有该特点,为老年高血压的治疗提供了一种有效且经济的手段。
具体实施方式
下面通过具体实例对本发明进行进一步的阐述,应该说明的是,下述说明仅是为了解释本发明,并不对其内容进行限定。
实施例1:
辅助利尿剂治疗老年高血压的中药组合物,该中药组合物由以下重量份的原料制成:人参420份、川芎300份、三七250份、灯盏花250份、附子70份、吴茱萸150份、怀牛膝120份、牡丹皮200份、郁金220份、黄芪250份、槲寄生200份、菟丝子150份、何首乌200份、萆薢220份、威灵仙100份、炙甘草300份,每一重量份为1mg。
将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,加水煎煮2次,每次煎煮时间1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉。
实施例2本发明所述中药组合物辅助利尿剂降压药理作用研究
动物:成年雄性自发性高血压大鼠(SHR)102只、正常血压Wistar-Kyoto(WKY)大鼠6只,体重210.0~270.0g,购自北京维通利华实验动物技术有限公司,适应性饲养于正压净化通风动物房内1周后开始试验。
动物分组及给药:
102只SHR大鼠适应性根据随机数字表进行分组,分别为模型组、对照组、中药单方组、氢氯噻嗪实验组、氯噻酮实验组、吲达帕胺实验组;
氢氯噻嗪实验组又分为氢氯噻嗪复方1组、氢氯噻嗪复方2组、氢氯噻嗪复方3组、氢氯噻嗪复方4组、氢氯噻嗪组,每组6只;
氯噻酮实验组又分为氯噻酮复方1组、氯噻酮复方2组、氯噻酮复方3组、氯噻酮复方4组、氯噻酮组,每组6只;
吲达帕胺实验组又分为吲达帕胺复方1组、吲达帕胺复方2组、吲达帕胺复方3组、吲达帕胺复方4组、吲达帕胺组,每组6只;
WKY大鼠(对照组)和模型组每日上午灌胃10.0ml/kg的0.5%羧甲基纤维素钠,中药单方组每日上午灌胃实施例1制备的中药组合物,
氢氯噻嗪复方1组:2.5mg/kg/d氢氯噻嗪(相当于人用剂量6.25g/d)+实施例1中药组合物,氢氯噻嗪复方2组:5mg/kg/d氢氯噻嗪(相当于人用剂量12.5mg/d)+实施例1中药组合物,氢氯噻嗪复方3组:10mg/kg/d氢氯噻嗪(相当于人用剂量25mg/d)+实施例1中药组合物,氢氯噻嗪复方4组:50mg/kg/d氢氯噻嗪(相当于人用剂量125mg/d)+实施例1中药组合物、氢氯噻嗪组5mg/kg/d;
氯噻酮复方1组:2.5mg/kg/d氯噻酮(相当于人用剂量6.25g/d)+实施例1中药组合物,氯噻酮复方2组:5mg/kg/d氯噻酮(相当于人用剂量12.5mg/d)+实施例1中药组合物,氯噻酮复方3组:10mg/kg/d氯噻酮(相当于人用剂量25mg/d)+实施例1中药组合物,氯噻酮复方4组:50mg/kg/d氯噻酮(相当于人用剂量125mg/d)+实施例1中药组合物,氯噻酮组5mg/kg/d;
吲达帕胺复方1组:0.08mg/kg/d吲达帕胺(相当于人用剂量0.6mg/d)+实施例1中药组合物,吲达帕胺复方2组:0.15mg/kg/d吲达帕胺(相当于人用剂量1.25mg/d)+实施例1中药组合物,吲达帕胺复方3组:0.3mg/kg/d吲达帕胺(相当于人用剂量2.5mg/d)+实施例1中药组合物,吲达帕胺复方4组:1.5mg/kg/d吲达帕胺(相当于人用剂量12.5mg/d)+实施例1中药组合物,吲达帕胺组0.15mg/kg/d。
血压、电解质测定:所有SHR和WKY大鼠每日灌胃给药1次,给药1h后使用BP系列动物无创血压计测量血压,观察并分析各组血压变化情况。连续给药50天后,进行腹主动脉取血,3500-4000r/min离心10min,取上清检测血清电解质(Na+、K+)。
统计学处理:采用SigmaStat软件进行统计处理,血清电解质数据采用单因素方差分析,血压数据分析采用重复双因素方差分析,组间比较采用SNK Test分析,以P<0.05为差异具有统计学意义。
实验结果,与模型组相比,本发明所述中药组合物结合利尿剂使用,可以有效降低SHR的收缩压(SBP)和舒张压(DBP)(PP<0.05或P<0.01),降压结果见表1-表3所示。血清电解质含量的影响见表4所示,与模型组相比,本发明所述中药组合物结合利尿剂使用,可以有效控制利尿剂对于钾的影响。
表1模型组、对照组、中药单方组、氢氯噻嗪实验组对SHR血压(收缩压)的影响
单位mmHg,n=6;与模型组比较,*P<0.05,**P<0.01
表2模型组、对照组、中药单方组、氯噻酮实验组对SHR血压(收缩压)的影响
单位mmHg,n=6;与模型组比较,*P<0.05,**P<0.01
表3模型组、对照组、中药单方组、吲达帕胺实验组对SHR血压(收缩压)的影响
单位mmHg,n=6;与模型组比较,*P<0.05,**P<0.01
时间/天 | 模型组 | 对照组 | 吲达帕胺复方1组 | 吲达帕胺复方2组 | 吲达帕胺复方3组 | 吲达帕胺复方4组 | 吲达帕胺组 | 中药单方组 |
0 | 166.1±10.2 | 115.5±10.0** | 169.5±11.1 | 160.7±8.9 | 165.3±9.2 | 164.6±10.3 | 168.5±12.5 | 163.3±11.4 |
1 | 165.9±13.6 | 126.1±10.2** | 161.3±11.6* | 154.6±9.4** | 156.4±9.1** | 151.5±12.5** | 160.4±11.3* | 161.9±15.1 |
2 | 168.5±9.9 | 119.0±8.1** | 155.4±10.7** | 139.7±9.6** | 142.1±9.8** | 133.8±11.8** | 153.2±10.4** | 159.3±14.3* |
5 | 171.1±12.1 | 112.9±13.3** | 140.7±10.1** | 128.9±9.6** | 130.7±9.8** | 123.0±13.2** | 141.5±9.3** | 157.7±8.7** |
10 | 179.7±11.6 | 120.4±11.7** | 133.5±10.3** | 118.5±13.5** | 120.0±10.4** | 111.9±14.9** | 130.3±10.1** | 152.7±10.5** |
15 | 185.3±11.9 | 116.5±9.6** | 130.1±9.8** | 123.3±9.7** | 115.6±11.0** | 115.5±11.0** | 132.7±11.7** | 149.1±12.4** |
25 | 196.0±8.7 | 128.3±11.7** | 125.6±10.9** | 123.7±9.1** | 119.2±13.7** | 109.9±14.0** | 124.6±11.4** | 137.2±10.4** |
50 | 218.8±10.6 | 123.1±10.1** | 119.3±11.6** | 113.1±11.6** | 118.4±9.2** | 115.6±12.6** | 120.3±10.6** | 125.5±8.6** |
表4模型组、中药单方组、实验组对SHR血清电解质含量的影响
单位:mmol/L,n=6;与模型组比较,**P<0.01;与氢氯噻嗪组比较,#P<0.05,##P<0.01
模型组 | 氢氯噻嗪复方1组 | 氢氯噻嗪复方2组 | 氢氯噻嗪复方3组 | 氢氯噻嗪复方4组 | 氢氯噻嗪组 | 中药单方组 | |
K+ | 6.9±0.5 | 6.5±0.3## | 6.8±0.3## | 6.7±0.2## | 6.3±0.5# | 5.5±0.3** | 6.7±0.3 |
Na+ | 140.0±2.3 | 139±2.2 | 136±2.5 | 137±1.8 | 136±2.1 | 135±2.6 | 138.9±2.6 |
模型组 | 氯噻酮复方1组 | 氯噻酮复方2组 | 氯噻酮复方3组 | 氯噻酮复方4组 | 氯噻酮组 | 中药单方组 | |
K+ | 6.9±0.5 | 6.6±0.3## | 6.6±0.5## | 6.7±0.3## | 6.1±0.6# | 5.6±0.3** | 6.7±0.3 |
Na+ | 140.0±2.3 | 138±1.5 | 137±2.2 | 136±2.4 | 136±2.3 | 137±1.9 | 138.9±2.6 |
模型组 | 吲达帕胺复方1组 | 吲达帕胺复方2组 | 吲达帕胺复方3组 | 吲达帕胺复方4组 | 吲达帕胺组 | 中药单方组 | |
K+ | 6.9±0.5 | 6.4±0.5## | 6.7±0.4## | 6.9±0.3## | 6.2±0.4# | 5.8±0.2** | 6.7±0.3 |
Na+ | 140.0±2.3 | 139±1.9 | 136±2.3 | 138±2.1 | 137±2.0 | 135±2.6 | 138.9±2.6 |
由上述表1-表3可以看出,虽然本发明所述中药组合物具有部分降压效果(中药单方组),但仍较氢氯噻嗪组、氯噻酮组、吲达帕胺组均较差,其降压效果较为缓慢,并不适宜单独直接作为降压药使用,而中药组合物与利尿剂合用时,可以有效增强利尿剂的降压效果(复方组Vs利尿剂组)。并且由于老年高血压患者肝肾功能常有降低,对于药物的自身调节和适应性差,常需要数天才能适应利尿剂得以发挥利尿剂的降压效应,而结合复方组Vs利尿剂组的时间轴来看,通过加入本发明所述中药组合物,可以加强机体对于利尿剂的调节和适应性,增强机体对于利尿剂降压的“敏感性”,使其更快的发挥降压效果(复方组Vs利尿剂组)。
通过各种利尿剂不同剂量的复方组试验,可以看出,本发明所述中药组合物对于低剂量组(复方2组)和中剂量组(复方3组)影响相差不大。但对于极低剂量组(复方1组)的降压效果提升明显,可使得极低剂量组的降压效果达到常规低剂量利尿剂(氢氯噻嗪组、氯噻酮组、吲达帕胺组)的降压效果;并且本发明所述中药组合物对于高剂量组(复方4组)亦有明显的改善作用,在试验周期内动物并未有明显的异常举动表征,并且对于利尿剂产生的低钾效应有明显的改良(参见表4,复方4组的K+虽然低于复方1组-复方3组,但较利尿剂组有明显提高),这一点对于高血压患者克服依从性不良问题至为重要,由于个体差异或其他原因,老年高血压患者服用低剂量利尿剂时因降压不明显而不再遵医嘱,持续服用相对较大剂量利尿剂,导致总体服药剂量大、副作用显著,而且利尿剂治疗高血压本身具有一定的副作用,患者私自减小服用剂量来降低副作用,从而产生不充分的利尿剂治疗,导致降压治疗产生抵抗;通过本发明所述中药组合物,可以调和低剂量/极低剂量、以及高剂量利尿剂服用带来的问题,部分的降低由于患者依从性不良产生的恶化效果。
从表1-表3复方组试验可以看出,本发明所述中药组合物对于噻嗪类利尿剂适用性良好,对于氢氯噻嗪(噻嗪型利尿剂)、氯噻酮(噻嗪样利尿剂)、吲达帕胺(噻嗪样利尿剂)三种噻嗪类利尿剂均有较好的辅助降压效果,且对于三者降压效果相近,说明本发明所述中药组合物可以相应的延长噻嗪型利尿剂降压的持续时间,增强短效利尿剂的长效性,但本发明所述中药组合物对于长效利尿剂(氯噻酮、吲达帕胺)影响不明显。
实施例3
一种治疗高血压的药物组合物,由如下重量份配比的原料药组成:
人参420g、川芎300g、三七250g、灯盏花250g、附子70g、吴茱萸150g、怀牛膝120g、牡丹皮200g、郁金220g、黄芪250g、槲寄生200g、菟丝子150g、何首乌200g、萆薢220g、威灵仙100g、炙甘草300g、氢氯噻嗪12.5g。
该治疗高血压的药物组合物的制备方法:
a.人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,加水煎煮2次,每次煎煮时间1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉;
b.将氢氯噻嗪与上述细粉混匀,得本发明药物组合物。
c.本发明药物组合物与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒,制成颗粒剂。
共制备1000袋,每袋约重5g。
实施例4
一种治疗高血压的药物组合物,由如下重量份配比的原料药组成:
人参420g、川芎300g、三七250g、灯盏花250g、附子70g、吴茱萸150g、怀牛膝120g、牡丹皮200g、郁金220g、黄芪250g、槲寄生200g、菟丝子150g、何首乌200g、萆薢220g、威灵仙100g、炙甘草300g、氯噻酮12.5g。
该治疗高血压的药物组合物的制备方法:
a.人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,加水煎煮2次,每次煎煮时间1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉;
b.将氢氯噻嗪与上述细粉混匀,得本发明药物组合物。
c.本发明药物组合物与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
共制备1000袋,每袋重5g。
实施例5
一种治疗高血压的药物组合物,由如下重量份配比的原料药组成:
人参420g、川芎300g、三七250g、灯盏花250g、附子70g、吴茱萸150g、怀牛膝120g、牡丹皮200g、郁金220g、黄芪250g、槲寄生200g、菟丝子150g、何首乌200g、萆薢220g、威灵仙100g、炙甘草300g、吲达帕胺1.5g。
该治疗高血压的药物组合物的制备方法:
a.人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,加水煎煮2次,每次煎煮时间1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉;
b.将氢氯噻嗪与上述细粉混匀,得本发明药物组合物。
c.本发明药物组合物与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
共制备1000袋,每袋重5g。
实施例6对实施例3-5制备的药物组合物进行了临床试验,结果如下:
研究对象:筛选在我中医药大学附属医院53例原发性老年高血压患者进行本项研究,均符合1999年WHO诊断标准,且符合以下条件:①初次确诊或确诊不超过半年未治疗且收缩压≥140mmHg(老年高血压患者多以单纯收缩期高血压为主,因此舒张压未纳入考量,舒张压范围距中值偏大);②无严重急慢性并发症。将符合条件的53例患者按照服药类型为观察组和对照组,其中对照组25例,服用氢氯噻嗪或吲达帕胺(12例服用氢氯噻嗪,13例服用吲达帕胺),观察组28例,服用实施例3-5所述颗粒剂(11例服用实施例3所述氢氯噻嗪复方颗粒,2例服用实施例4所述氯噻酮复方颗粒,15例服用实施例5所述吲达帕胺复方颗粒)。患者在性别、年龄、体重指数、病程、血压水平等很一般资料方面比较差异无统计学意义(P>0.05)。
治疗方法:①对照组:在对患者进行高血压健康知识教育的基础上应用氢氯噻嗪或吲达帕胺治疗,均告知采用低剂量,氢氯噻嗪每日12.5--25mg,吲达帕胺每日1.5-2.5mg;②观察组:在对患者进行高血压健康知识教育的基础上应用实施例3-5所述的颗粒剂,每次1袋,每日1-2次,两组均以1周为一个观察阶段。观察指标:①安全性指标:包括血常规、大便常规、肝功能、肾功能检查、心电图;②疗效性指标:治疗前后血压水平,血压复常率(收缩压≤120mmHg,舒张压≤90mmHg)。③高血压症发生情况。
临床疗效结果:统计结果见表5,治疗前两组的收缩压和舒张压水平比较差异无统计学意义(P>0.05);治疗后两组的收缩压和舒张压水平均较治疗前明显降低,差异具有统计学意义(P<0.05);观察组患者在收缩压和舒张压改善程度方面明显优于对照组,差异具有统计学意义(P<0.05)。本试验中全部受试者于治疗前后分别进行安全性指标检测,结果未发现明显异常改变,本研究中观察组的高血压症发生率为3.5%明显低于对照组的21.7%,差异具有统计学意义(P<0.05)。
表5 药物组合物临床试验效果
注:*表示与治疗前比较P<0.05;#表示与对照组治疗后比较P<0.05
在跟进的询问与问卷调查中,观察组共计22份结果(22/28),基本均能良好服药,对照组共计15份结果(15/23),有3份明确表示过程中增加剂量,存在换药情况。本发明将中药组合物与利尿剂结合起来,可以避免噻嗪类利尿剂的常见的高血压症反应,并提高对高血压的治疗效果,并且临床试验结果表明,口服本发明组合物的患者,在降低血压水平方面要优于单纯应用噻嗪类利尿剂者,并且本发明药物组合物在改善噻嗪类药物高血压症反应方面比单纯应用氢氯噻嗪者效果显著。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术的技术人员在本发明批露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (12)
1.一种辅助利尿剂治疗老年高血压的中药组合物,该中药组合物由以下重量份的原料制成:
人参300-500份、川芎250-350份、三七220-280份、灯盏花200-350份、附子60-90份、吴茱萸120-180份、怀牛膝80-150份、牡丹皮150-250份、郁金180-260份、黄芪220-280份、槲寄生150-250份、菟丝子100-180份、何首乌180-250份、萆薢150-250份、威灵仙80-120份、炙甘草250-350份;
所述利尿剂为噻嗪类利尿剂。
2.根据权利要求1所述的中药组合物,其特征在于,所述中药组合物由以下重量份的原料制成:人参350-450份、川芎280-320份、三七220-260份、灯盏花250-280份、附子70-80份、吴茱萸140-160份、怀牛膝100-120份、牡丹皮180-220份、郁金200-240份、黄芪240-260份、槲寄生180-220份、菟丝子120-160份、何首乌200-230份、萆薢200-240份、威灵仙90-110份、炙甘草280-330份。
3.根据权利要求1所述的中药组合物,其特征在于,所述中药组合物由以下重量份的原料制成:人参420份、川芎300份、三七250份、灯盏花250份、附子70份、吴茱萸150份、怀牛膝120份、牡丹皮200份、郁金220份、黄芪250份、槲寄生200份、菟丝子150份、何首乌200份、萆薢220份、威灵仙100份、炙甘草300份。
4.权利要求1-3任一项所述的中药组合物的制备方法,其特征在于,步骤如下:
将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,或混合后磨成粉,加水煎煮2-3次,每次煎煮时间0.3-1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉,得辅助利尿剂治疗老年高血压的中药组合物。
5.权利要求4所述的中药组合物的制备方法,其特征在于,加水煎煮2次,每次煎煮时间1h。
6.权利要求4所述的中药组合物的制备方法,其特征在于,喷雾干燥制成的细粉进一步与适量麦芽糊精混合均匀,挤压法造粒,干燥,整粒,过筛得颗粒。
7.一种治疗老年高血压的药物组合物,其特征在于,药物组合物由利尿剂与中药组合物制备而成,中药组合物各组分的重量份为人参300-500份、川芎250-350份、三七220-280份、灯盏花200-350份、附子60-90份、吴茱萸120-180份、怀牛膝80-150份、牡丹皮150-250份、郁金180-260份、黄芪220-280份、槲寄生150-250份、菟丝子100-180份、何首乌180-250份、萆薢150-250份、威灵仙80-120份、炙甘草250-350份,利尿剂选自氢氯噻嗪12.5-25份、氯噻酮12.5-25份、吲达帕胺1.5-2.5份中的一种;
制备方法为:将人参、川芎、三七、灯盏花、附子、吴茱萸、怀牛膝、牡丹皮、郁金、黄芪、槲寄生、菟丝子、何首乌、萆薢、威灵仙、炙甘草按重量份磨成粉混合,或混合后磨成粉,加水煎煮2-3次,每次煎煮时间0.3-1h,合并滤液,滤液浓缩至相对密度1.05-1.12,喷雾干燥制成细粉,将利尿剂药物与该细粉混合得所述药物组合物。
8.根据权利要求7所述的药物组合物,其特征在于,药物组合物由以下重量份的原料制成:人参420份、川芎300份、三七250份、灯盏花250份、附子70份、吴茱萸150份、怀牛膝120份、牡丹皮200份、郁金220份、黄芪250份、槲寄生200份、菟丝子150份、何首乌200份、萆薢220份、威灵仙100份、炙甘草300份、选自氢氯噻嗪12.5份、氯噻酮12.5份、吲达帕胺1.5份中的一种的利尿剂。
9.一种治疗老年高血压的药物制剂,由权利要求7或8所述的药物组合物和药学上可接受的辅料制备而成。
10.如权利要求9所述的药物制剂,其特征在于,所述药学上可接受的辅料为崩解剂、润滑剂或黏合剂。
11.如权利要求10所述的药物制剂,其特征在于,所述药学上可接受的辅料为甘油、丁二醇、海藻糖、甜菜碱、淀粉、羧甲基纤维素钠、麦芽糊精中的一种或多种。
12.如权利要求9所述的药物制剂,其特征在于,所述药物制剂的剂型为丸剂、胶囊剂、片剂、散剂、颗粒剂或口服液中的一种。
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