CN115475145A - 一种利鲁唑分散片及其制备方法 - Google Patents
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Abstract
本发明属于医药技术领域,具体涉及一种利鲁唑分散片及其制备方法。所述的利鲁唑分散片由利鲁唑、填充剂、粘合剂、矫味剂、崩解剂、助流剂及润滑剂组成,本发明所制备的利鲁唑分散片由粉末直接压片工艺所制备,分散时间短,溶出迅速,所需工序少,工艺简单,省时节能,批间差异小,适合放大生产。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及一种利鲁唑分散片及其制备方法。
背景技术
利鲁唑片由赛诺菲安万特公司研制开发,于1996年获FDA批准上市,规格为50mg。利鲁唑,即2-氨基-6-三氟甲氧基苯并噻唑,适用于延长肌萎缩侧索硬化(ALS)患者的生命或延长其发展至需要机械通气支持的时间。肌萎缩侧索硬化症(ALS)的发病机理尚未完全阐明,有学说认为谷氨酸(是中枢神经系统主要的兴奋型神经递质)在此疾病中是造成细胞死亡的原因,利鲁唑的作用机制尚不清楚。利鲁唑通过抑制脑内神经递质(谷氨酸及天冬氨酸)的释放,抑制兴奋性氨基酸的活性及稳定电压依赖性钠通道的失活状态来表现其神经保护作用,多种体外细胞模型均证明了利鲁唑可减少兴奋性递质的毒性作用,增加细胞的存活率。
利鲁唑为白色至微黄色结晶或结晶性粉末,无臭,在水中几乎不溶,在甲醇或乙醇中易溶,熔点为117~119.5℃。
分散片系指在水中能迅速崩解并均匀分散的制剂,水中分散后可直接饮用,也可将片剂直接置于口中含服或吞服。相对于普通片剂,具有服用方便、崩解迅速、吸收快和生物利用度高的特点。
CN111821289A公布了一种利鲁唑口崩片及其制备方法,该口崩片的组成为利鲁唑、碳酸氢钠、微晶纤维素、甘露醇及50%处方量的交联聚维酮。制备工艺为将原辅料混匀后用乙醇水溶液制粒,再经干燥、整粒得干颗粒,将干颗粒加入50%处方量的交联聚维酮和处方量的阿司帕坦混匀,再加入硬脂酸镁混匀,压片制得口崩片。该发明虽然能提高溶出速度,但是制备工艺繁琐,制备过程受湿、热因素影响,影响制剂的稳定性。
目前,利鲁唑片的生产大多通过湿法制粒后压片得到,湿法制粒需制粒、干燥、整粒及中间抽样检测等工序,设备厂房投资高,劳动强度大,时间和能源耗费高,物料有损耗,有时工人的经验决定产品的质量,使最终产品质量不稳定,批次间差异较大。
发明内容
针对现有技术存在的问题,本发明的目的是提供一种通过粉末直接压片制备利鲁唑分散片的方法,同时根据粉末直接压片法调整辅料的种类和配比,与湿法制粒工艺比,本发明所制备的利鲁唑分散片避免了物料受湿、热的影响,在不同介质中分散快,溶出迅速,稳定性好,且制备工艺简单、成本低,重现性好,批次间的差异小,可操作性强。
一方面,本发明提供了一种利鲁唑分散片,具体技术方案如下:
所述的利鲁唑分散片由利鲁唑和辅料直接压片得到,其处方组成如下:
优选的,其处方如下:
其中,主药成分为利鲁唑;
所述填充剂为微晶纤维素、预胶化淀粉、甘露醇、乳糖11SD、无水磷酸氢钙的一种或多种。
所述粘合剂为共聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲纤维素钠的一种或多种;
所述矫味剂为蔗糖、阿斯帕坦的一种或多种;
所述崩解剂为交联聚维酮、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲淀粉钠的一种或多种;
所述助流剂为微粉硅胶、气相二氧化硅、二氧化硅的一种或多种。
所述润滑剂为硬脂酸镁、氢化植物油、硬脂富马酸钠的一种或多种。
另一方面,本发明提供了一种上述所述的利鲁唑分散片的制备方法,具体步骤如下:
步骤(1):称取处方量利鲁唑与填充剂混合均匀,加入处方量粘合剂、矫味剂、崩解剂、助流剂混合均匀,最后加入处方量润滑剂混合均匀。
步骤(2):选择直径8mm的浅凹冲装压片机,调节压片速度和压力,制得药片。
相比于现有技术,本发明取得的有益效果为:
本发明所制备的利鲁唑分散片溶出快,在胃肠道分布面积大,生物利用度高;同时制备工艺简单,省时节能,且直接压片不受湿、热影响,有关物质小,结果重现性好,利于工业化的大规模生产。
附图说明
图1在pH1.0盐酸溶液的累积溶出度曲线图
图2在pH4.5醋酸盐缓冲溶液的累积溶出度曲线图
图3在pH6.8磷酸盐缓冲溶液的累积溶出度曲线图
图4在水中的累积溶出度曲线图
具体实施方式
本发明提供了一种利鲁唑分散片及其制备方法,用于解决现有技术中产品质量不稳定,批次间差异较大的问题。
下面将对本发明实施例中的技术方案进行清晰、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素102、乳糖混合均匀,加入共聚维酮S-630、阿斯帕坦、交联羧甲纤维素钠、二氧化硅混合均匀,加入硬脂酸镁均匀;选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑分散片累积溶出度。
实施例2
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、乳糖、玉米淀粉混合均匀,加入共聚维酮S-630、阿斯帕坦、交联聚维酮XL、二氧化硅混合均匀,加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑分散片累积溶出度。
实施例3
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素101、乳糖混合均匀,加入羟丙纤维素EXF、阿斯帕坦、低取代羟丙纤维素、二氧化硅混合均匀,加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑分散片累积溶出度。
实施例4
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素102、甘露醇合均匀,加入羟丙纤维素EXF、阿斯帕坦、羧甲淀粉钠、二氧化硅混合均匀,加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑分散片累积溶出度。
对比实施例1
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素101、预胶化淀粉混合均匀,加入交联羧甲纤维素钠、二氧化硅混合均匀,加入8%聚维酮K30水溶液制粒,流化床进行干燥,将干燥后的颗粒20目筛整粒,整粒后加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑片累积溶出度。
对比实施例2
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素101、无水磷酸氢钙混合均匀,加入交联聚维酮XL、二氧化硅混合均匀,加入8%聚维酮K30水溶液制粒,流化床进行干燥,将干燥后的颗粒20目筛整粒,整粒后加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片。检测利鲁唑片累积溶出度。
对比实施例3
处方(1000片)
制备工艺:利鲁唑粉碎过筛,称取处方量的辅料、原料,将利鲁唑、微晶纤维素101、微晶纤维素102混合均匀,加入低取代羟丙纤维素、二氧化硅混合均匀,加入5%羟丙纤维素LF水溶液制粒,流化床进行干燥,将干燥后的颗粒20目筛整粒,整粒后加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑片累积溶出度。
对比实施例4
处方(1000片)
制备工艺:称取处方量的辅料、原料,将利鲁唑、微晶纤维素101、微晶纤维素102、甘露醇合均匀,加入羧甲淀粉钠、二氧化硅混合均匀,加入5%羟丙纤维素LF水溶液制粒,流化床进行干燥,将干燥后的颗粒20目筛整粒,整粒后加入硬脂酸镁均匀。选择直径8mm的浅凹冲压片,调节压片速度和压力,制得药片,检测利鲁唑片累积溶出度。
验证实施例
1.含量均匀度的检测
主要对压片过程中重量差异、硬度、脆碎度、崩解时间、含量均匀度的考察。
含量及含量均匀度测定照紫外-可见分光光度法(中国药典2020年版四部通则0401)测定。供试品溶液:取本品20片,精密称定,研细,精密称取细粉适量(约相当于利鲁唑50mg),置250ml量瓶中,加0.1mol/L盐酸溶液使利鲁唑溶解(必要时超声)并稀释至刻度,摇匀,滤过,精密量取续滤液5ml,置100ml量瓶中,用0.1mol/L盐酸溶液稀释至刻度,摇匀。对照品溶液:取利鲁唑对照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中约含10μg的溶液。测定法:取供试品溶液与对照品溶液,在254nm的波长处分别测定吸光度,计算,结果如表1所示。
表1实施例与对比实施例片剂质量检查项目对比
由表1知:实施例的崩解时间比对比实施例的崩解时间短,体外的溶出快,进而影响体内生物等效性。
2.有关物质检测结果
有关物质的检测
有关物质照高效液相色谱法(中国药典2020年版四部通则0512)测定。供试品溶液:取本品细粉适量,加流动相使利鲁唑溶解并稀释制成每1ml中约含利鲁唑0.5mg的溶液,滤过,取续滤液。对照溶液:精密量取供试品溶液1ml,置100ml量瓶中,用流动相稀释至刻度,摇匀。色谱条件:用十八烷基硅烷键合硅胶为填充剂;以甲醇-水(70:30)为流动相;检测波长为221nm;进样体积10为μl。系统适用性要求:理论板数按利鲁唑峰计算不低于2000。测定法:精密量取供试品溶液与对照溶液,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,结果记录在表2中。
表2实施例与对比实施例有关物质含量
实施例 | 单杂(%) | 总杂(%) |
实施例1 | 0.018 | 0.098 |
实施例2 | 0.009 | 0.074 |
实施例3 | 0.012 | 0.071 |
实施例4 | 0.016 | 0.083 |
对比实施例1 | 0.076 | 0.114 |
对比实施例2 | 0.045 | 0.136 |
对比实施例3 | 0.066 | 0.145 |
对比实施例4 | 0.058 | 0.126 |
由表2知,实施例单个杂质和总杂小于对比实施例,所得产品质量稳定。
3.溶出度的测定
溶出度的检测
溶出度照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)测定。采用第二法装置,以0.1mol/L的盐酸溶液900ml为溶出介质,转速每分钟50转,依法操作,经5min、10min、15min、20min、30min、45min时分别取样。供试品溶液:取溶出液适量,滤过,精密量取续滤液5ml,置25ml量瓶中,用0.1mol/L的盐酸溶液稀释至刻度,摇匀;对照品溶液:取利鲁唑对照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中约含10μg的溶液。分别取供试品溶液和对照品溶液,照紫外-可见分光光度法(中国药典2020年版四部通则0401),在254nm的波长处分别测定吸收度,计算每片在不同时间的溶出量,溶出结果如表3~6所示。
表3在pH1.0的盐酸溶液的溶出度
表4在pH4.5的醋酸盐缓冲溶液的溶出度
表5在pH6.8磷酸盐缓冲溶液的溶出度
表6在水溶液的溶出度
由表3、4、5、6知,在四种介质中,实施例在30min时溶出均达到85%以上,但对比实施例在pH6.8磷酸盐缓冲溶液和水中,在30min时溶出均未达到85%以上,对比实施例溶出速度慢。
综上,本发明与现有技术相比,所制备的利鲁唑分散片在不同介质中的溶出速度快,生物利用度高,且产品质量好,制备工艺简单,生产能耗低,适合放大生产。
Claims (10)
1.一种利鲁唑分散片,其特征在于,由利鲁唑、填充剂、粘合剂、矫味剂、崩解剂、助流剂、润滑剂组成,并通过粉末直接压片制备而成。
4.根据权利要求3所述的利鲁唑分散片,其特征在于,所述填充剂为微晶纤维素、预胶化淀粉、甘露醇、乳糖11SD、无水磷酸氢钙的一种或多种。
5.根据权利要求3所述的利鲁唑分散片,其特征在于,所述粘合剂为共聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲纤维素钠的一种或多种。
6.根据权利要求3所述的利鲁唑分散片,其特征在于,所述矫味剂为蔗糖、阿斯帕坦的一种或多种。
7.根据权利要求3所述的利鲁唑分散片,其特征在于,所述崩解剂为交联聚维酮、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲淀粉钠的一种或多种。
8.根据权利要求3所述的利鲁唑分散片,其特征在于,所述助流剂为微粉硅胶、气相二氧化硅、二氧化硅的一种或多种。
9.根据权利要求3所述的利鲁唑分散片,其特征在于,所述润滑剂为硬脂酸镁、氢化植物油、硬脂富马酸钠的一种或多种。
10.一种根据权利要求1~9任一项所述的利鲁唑分散片的制备方法,其特征在于,所述制备方法包括以下步骤:
步骤(1):称取处方量利鲁唑与填充剂混合均匀,加入处方量粘合剂、矫味剂、崩解剂、助流剂混合均匀,最后加入处方量润滑剂混合均匀;
步骤(2):选择直径8mm的浅凹冲装压片机,调节压片速度和压力,制得药片。
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