CN111110639B - 一种含有苯磺酸氨氯地平的药物组合物 - Google Patents
一种含有苯磺酸氨氯地平的药物组合物 Download PDFInfo
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Abstract
本发明公开了一种苯磺酸氨氯地平组合物,包括以下重量份的成分:苯磺酸氨氯地平5重量份、填充剂55~76重量份、乙基甲基纤维素5~10重量份、精氨酸1~5重量份、崩解剂1~1.5重量份、润滑剂0.05~0.1重量份。本发明添加乙基甲基纤维素、精氨酸,从而大幅度提高了药物的溶出度及稳定性;本发明不适用粘合剂,因此,避免了水分对苯磺酸氨氯地平影响;本方法工艺操作简便,设备要求不高,生产成本低,适合工业化生产。
Description
技术领域
本发明涉及医药领域,特别是指一种含有苯磺酸氨氯地平组合物。
背景技术
钙拮抗剂(CAS)是公认有效的抗高血压药和动脉扩张药,它通过阻滞心肌和血管平滑肌细胞上的特异性L型钙通道而阻止Ca2+进入细胞内,从而舒张血管平滑肌,扩张外周小动脉,减低外周阻力,使血压下降。此外,钙拮抗剂还能通过降低心脏后负荷,增加冠脉血流量,有助于改善心肌缺血,缓解心绞痛。
苯磺酸氨氯地平为20世纪80年代中期由美国辉瑞制药有限公司研制成功的第三代1,4二氢吡啶类钙离子拮抗剂,其化学名称为3-乙基-5-甲基-2-(2-氨乙氧甲基)-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸酯苯磺酸盐。其作用温和而持久,服用方便,不良反应轻微,临床用于治疗高血压、心绞痛及高血压或冠心病并发的心力衰竭等。该药已在全球多个国家上市,得到广泛应用。
但是苯磺酸氨氯地平原料稳定性差,遇湿易吸潮,对光和温度很敏感的特性,使得我们在实际制备苯磺酸氨氯地平时面临严峻的考验。苯磺酸氨氯地平通常口服起始剂量为5mg,每日一次,最大不超过10mg,每日一次。瘦小者、体质虚弱者、老年患者或肝功能受损者从2.5mg,每日一次开始用药;合用其他抗高血压药者也从此剂量开始用药。目前片剂由于制剂工艺和配方的原因,导致苯磺酸氨氯地平稳定性差,在制剂生产过程或贮存过程中有关物质均有明显增加,给临床应用带来安全性隐患。
CN101161241A公开一种苯磺酸氨氯地平片的制备工艺,由苯磺酸氨氯地平、填充剂、崩解剂、润滑剂等作为主要成分,采用粉碎后过筛,流化床制粒,喷雾干燥后旋转压片制成。但是湿法制粒后,产品稳定性差,易变色,溶出度慢。
发明内容
本发明提出一种含有苯磺酸氨氯地平组合物,解决了苯磺酸氨氯地平制剂稳定性差的问题,得到稳定性好、溶出迅速、质量可靠的苯磺酸氨氯地平片剂。
本发明的技术方案是这样实现的:
一种苯磺酸氨氯地平组合物,包括以下重量份的成分:
所述的药物组合物制备为片剂。
所述崩解剂为羧甲淀粉钠、羧甲纤维素钠、羟丙纤维素其中的一种或多种。
所述填充剂为淀粉、微晶纤维素、可压性淀粉中的一种或多种。
所述的润滑剂为硬脂酸镁、微粉硅胶和滑石粉中的一种。
一种苯磺酸氨氯地平片剂的制备方法,包括如下步骤:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量填充剂、崩解剂、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入润滑剂混合均匀,直接压片,即得。
与现有技术相比,本发明的有益效果为:
1、本发明添加乙基甲基纤维素、精氨酸,从而大幅度提高了药物的溶出度及稳定性;
2、本发明不适用粘合剂,因此,避免了水分对苯磺酸氨氯地平影响;
3、本方法工艺操作简便,设备要求不高,生产成本低,适合工业化生产。
具体实施方式
以下实施例进一步描述本发明的有益效果,实施例仅用于例证的目的,不限制本发明的范围,同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
试验例
有关物质取本品细粉适量(约相当于氨氯地平50mg),置50ml量瓶中,加流动相约40ml,超声约30分钟使苯磺酸氨氯地平溶解,取出,放冷,用流动相稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液;精密量取适量,用流动相定量稀释制成每1ml中约含氨氯地平2μg的溶液,作为对照溶液。照含量测定项下的色谱条件,精密量取供试品溶液与对照溶液各20μl,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的3倍。
溶出度取本品,照溶出度与释放度测定法(中国药典2015版四部通则0931第二法),以盐酸溶液(0.9→1000)500ml为溶出介质,转速为每分钟75转,依法操作,经30分钟时,取溶液适量,滤过,取续滤液作为供试品溶液。另取苯磺酸氨氯地平对照品适量,精密称定,加甲醇适量溶解后用溶出介质稀释制成每1ml中约含氨氯地平10μg的溶液,作为对照品溶液。照含量测定项下的方法测定,计算每片的溶出量。限度为标示量的80%,应符合规定。
含量测定照高效液相色谱法(中国药典2015版四部通则0512)测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂(WonCract ODS-2柱,4.6mm×250mm,5μm或效能相当的色谱柱);以乙腈-甲醇-0.7%三乙胺溶液(取三乙胺7.0ml,加水至1000ml,用磷酸调节pH值至3.0±0.1)(15:35:50)为流动相;检测波长为237nm。取苯磺酸氨氯地平对照品5mg,加浓过氧化氢溶液5ml,置70℃加热10~30分钟,作为系统适用性溶液,取系统适用性溶液20μl注入液相色谱仪,记录色谱图,氨氯地平峰保留时间约为18分钟,氨氯地平峰与氨氯地平杂质D峰(相对保留时间约0.5)的分离度应大于4.5,理论板数按氨氯地平峰计算不低于3000。
测定法取本品5片,置500ml量瓶中,加流动相适量,超声处理30分钟使苯磺酸氨氯地平溶解,放冷,用流动相稀释至刻度,摇匀,滤过,精密量取续滤液20μl注入液相色谱仪,记录色谱图。另取苯磺酸氨氯地平对照品适量,精密称定,加流动相溶解并定量稀释制成每1ml中含氨氯地平0.05mg的溶液,同法测定。按外标法以峰面积计算,并将结果与0.7211
分子式:C20H23ClN2O5 分子量:406.9
2-[2-氨基乙氧基]-4-(2-氯苯基)6-甲基-3,5-吡啶二羧酸-5-甲酯,3-乙酯
试验例1:处方筛选试验
分别取苯磺酸氨氯地平5g(含量99.9%,总杂0.06%),按下述处方(见表1)制得含有苯磺酸氨氯地平片剂,检测溶出度及有关物质,结果见表2:
表1苯磺酸氨氯地平片处方(单位:g)
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量微晶纤维素、羧甲淀粉钠、乙基甲基纤维素(根据处方要求添加)、精氨酸(根据处方要求添加)、苯磺酸氨氯地平原料药进行混合后,再加入硬脂酸镁混合均匀,直接压片,即得。
表2试验结果
试验结果表明:采用本发明处方制备的苯磺酸氨氯地平片剂中均未检测到杂质D,且有关物质含量低于0.1%,优于其他处方例。
试验例2:影响因素试验
分别取实施例1和2及对比例(市售苯磺酸氨氯地平片)的苯磺酸氨氯地平片,测定有关物质及溶出度,结果见表3。
表3苯磺酸氨氯地平片有关物质含量测定试验数据
从表3中可以看出:本发明实施例1和2制备的苯磺酸氨氯地平片相对于对比例市售的苯磺酸氨氯地平片稳定性好,在高温5天、10天及强光10天的有关物质的含量明显低于对比例有关物质的含量,说明本发明的制剂处方和制备方法对其稳定性有较大的改善;本发明实施例1和2制备的苯磺酸氨氯地平片在5min内溶出达到90%以上,比对比例高出10%左右,说明本发明的制剂处方和制备方法对其溶出度有一定的提高。
制备例
实施例1
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量微晶纤维素、羟甲淀粉钠、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入硬脂酸镁混合均匀,直接压片,即得。
实施例2
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量淀粉、羧甲纤维素、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入滑石粉混合均匀,直接压片,即得。
实施例3
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量微晶纤维素、羟丙纤维素、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入硬脂酸镁混合均匀,直接压片,即得。
实施例4
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量可压性淀粉、羟丙纤维素、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入滑石粉混合均匀,直接压片,即得。
实施例5
制备方法:
1)将苯磺酸氨氯地平原料药过100目筛,所述辅料过60目筛;
2)按处方量可压性淀粉、羧甲淀粉钠、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入硬脂酸镁混合均匀,直接压片,即得。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种苯磺酸氨氯地平片剂组合物,其特征在于,所述片剂组合物包括以下重量份的成分:
苯磺酸氨氯地平 5重量份
填充剂微晶纤维素 69.95重量份
乙基甲基纤维素 5重量份
精氨酸 1重量份
崩解剂羧甲淀粉钠 1重量份
润滑剂硬脂酸镁 0.05重量份。
2.一种苯磺酸氨氯地平片剂组合物,其特征在于,所述片剂组合物包括以下重量份的成分:
苯磺酸氨氯地平 5重量份
填充剂微晶纤维素 60.95重量份
乙基甲基纤维素 10重量份
精氨酸 5重量份
崩解剂羧甲淀粉钠 1重量份
润滑剂硬脂酸镁 0.05重量份。
3.根据权利要求1或2所述的组合物,其特征在于,所述片剂的制备方法为:
1)将苯磺酸氨氯地平原料药过100目筛,辅料过60目筛;
2)按处方量填充剂、崩解剂、乙基甲基纤维素、精氨酸、苯磺酸氨氯地平原料药进行混合后,再加入润滑剂混合均匀,直接压片,即得。
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