CN1296045C - 二氢麦角碱及其衍生物的口腔崩解片及其制备工艺 - Google Patents
二氢麦角碱及其衍生物的口腔崩解片及其制备工艺 Download PDFInfo
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- CN1296045C CN1296045C CNB2005100552065A CN200510055206A CN1296045C CN 1296045 C CN1296045 C CN 1296045C CN B2005100552065 A CNB2005100552065 A CN B2005100552065A CN 200510055206 A CN200510055206 A CN 200510055206A CN 1296045 C CN1296045 C CN 1296045C
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- dihydroergotoxine
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Abstract
本发明提供了一种能有兴奋多巴胺和5-羟色胺受体,阻断α-肾上腺受体的效应和扩血管作用的口腔崩解片,其含有二氢麦角碱或二氢麦角碱衍生物作为药物的活性成分。以二氢麦角碱或二氢麦角碱衍生物为原料,采用各种制剂学方法,添加填充剂、崩解剂、矫味剂、助流剂、润滑剂等为辅料,再经过特定的制备方法制备。本发明的口腔崩解片脆碎度良好,崩解迅速,口感好,无砂砾感;具有携带、储藏、运输和服用方便等特点;特别之处是可以在无水条件下服用并快速起效,从而改善患者的依从性,提高药物的疗效。
Description
技术领域
本发明涉及一种能有兴奋多巴胺和5-羟色胺受体,阻断α-肾上腺受体的效应和扩血管作用的二氢麦角碱及二氢麦角碱衍生物的口腔崩解片。本发明还设计该制剂的制备方法。
背景技术
双氢麦角碱为麦角毒碱类α-肾上腺素受体阻滞剂,具有兴奋多巴胺和5-羟色胺受体,阻断α-肾上腺受体的效应。能抑制血管运动中枢及兴奋迷走中枢,使外周血管舒张,血压降低,心律减慢,对中枢有镇痛作用;动物试验表明双氢麦角碱能改变脑的神经传递,并且它能改善受损害的脑代谢功能,并缩短脑循环时间,此效应可反应在脑电活动的改变上,改善脑血流及脑电图,在脑电图(EEG)的功率谱上有显著变化。无催产作用。
临床主要使用双氢麦角毒碱甲磺酸盐,该品系由等量的甲磺酸双氢麦角高碱、甲磺酸双氢麦角克碱和甲磺酸双氢麦角开碱[甲磺酸双氢-α-麦角开碱:甲磺酸双氢-β-麦角开碱(2∶1)]所组成的混合物。
口腔崩解片是近年来新发展的一种剂型,具有携带服用方便等特点,并非常适合于吞咽困难的患者,如老年人和婴幼儿等。现有的参考文献没有完全公开一种与本发明相同或类似的二氢麦角碱及其衍生物的口腔崩解片的制备处方和制备方法。
本发明的目的在于提供二氢麦角碱及其衍生物的口腔崩解片制剂就和制备方法。该口腔崩解片具有优异的口腔崩解特性和适当的强度。从二氢麦角碱的适用证和和适用对象而言,将二氢麦角碱制成口腔崩解片能较好地改进患者的依从性,提高治疗效果。
发明内容
本发明的目的在于改进现有的二氢麦角碱及其衍生物在口服剂型方面的不足,向广大患者和医务工作者提供一种服用方便、吸收起效快、生物利用度高的二氢麦角碱及其衍生物口腔崩解片制剂。本发明涉及服用时不必饮水、在口腔中仅需几十秒即可迅速崩解或溶解、随唾液下咽即可完成服药的二氢麦角碱及其衍生物的口腔崩解片及其制备方法。
一、处方
本发明所述及的二氢麦角碱及二氢麦角碱衍生物的口腔崩解片,包括原料药物,共需要以下9类原、辅材料,其中:不作包衣处理时,则不使用包衣材料,泡腾剂为酌情可选用辅料,也可不用。处方如下:
药物原料(0.1-10)%
粘合剂(0-5)%
填充剂(10-96)%
崩解剂(2-35)%
矫味剂(1-40)%
包衣材料(0.2-2)%
泡腾剂(0-30)%
助流剂(0.01一5)%
润滑剂(0.3-3)%。
其中:
填充剂包括但不仅限于甘露醇(粒状或粉状)、木糖醇、山梨醇、麦芽糖、赤藓醇、微晶纤维素、硅烷化微晶纤维素(PROSOLVSMCC)、聚合糖(EMDEX)、偶合糖、葡萄糖、乳糖、蔗糖(糖粉)、糊精、预胶化淀粉、和淀粉等,可以单独使用,也可以组合应用。
粘合剂包括但不仅限于淀粉、预胶化淀粉、糊精、麦芽糖糊精、蔗糖、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮(PVP)、海藻酸及海藻酸盐、黄原胶、羟丙基纤维素和羟丙基甲基纤维素,可单独使用,也可组合使用。
崩解剂包括但不仅限于交联聚乙烯吡咯烷酮(PVPP)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基甲基纤维素(L-HPC)、交联羧甲基纤维素钠(CCNa)和大豆多糖(EMCOSOY)等,可单独使用,也可组合使用。
包衣材料包括但不仅限于明胶、阿拉伯胶、海藻酸盐、壳聚糖、羧甲基纤维素盐、醋酸纤维素酞酸酯、丙烯酸树脂类(国产丙烯酸树脂I、II、III、IV,Eudragit系列)、聚乙二醇(PEG)、聚乙烯醇(PVA)、聚乙酸乙烯酯、聚乙烯吡咯烷酮(PVP)、甲基纤维素(MC)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)和羟基甲基纤维素,可单独使用,也可组合使用。6
矫味剂包括但不仅限于甘露醇、木糖醇、甜菊甙、乳糖、果糖、蔗糖、蛋白糖、麦芽糖醇、甘草甜素、环己氨基磺酸钠、明胶、阿斯巴甜、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸等,可单独使用,也可组合使用。
助流剂包括但不仅限于微粉硅胶、滑石粉、Cab-O-sil、Aerosil、水合硅铝酸钠等,可单独使用,也可组合使用。
润滑剂包括但不仅限于硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸锌、单硬脂酸甘油脂、聚乙二醇、氢化植物油、硬脂富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁和滑石粉等,可单独使用,也可组合使用。权利要求6所述及的任何一种制备方法,其特征在于:根据情况还可加入辅料泡腾剂。
泡腾剂包括但不仅限于苹果酸、柠檬酸(枸橼酸)或酒石酸与碳酸氢钠或碳酸钠的混合物。
二、制备方法
本发明所述及的二氢麦角碱及其衍生物的口腔崩解片,其制备方法可选直接压片法或冷冻干燥法。由于主药的量很小,所以矫味和掩味是非必需的。直接压片法
具体制备方法如下:
第一步原料预处理:具体可采用的方法有①原料过筛后不作其它处理,②将过筛后的原料或混和其它辅料后进行粉末包衣,③将原料和适量辅料制粒;
第二步将填充剂、矫味剂、崩解剂和助流剂按量称取并混合均匀,再与上述所得之物料混合使均匀;
第三步加入润滑剂混匀备用;
第四步所得物料经中间体检测,确定片重后,送入压片机压片,用泡罩包装,即得。
冷冻干燥法具体制备方法如下:
第一步原料预处理:具体可采用的方法有①原料过筛后不作其它处理,②将过筛后的原料或混和其它辅料后进行粉末包衣,③将原料和适量辅料制粒;
第二步将前一步所制备的原料、包衣粉末或颗粒混悬于纤维素类高分子材料的溶液A中,然后将明胶、水溶性糖醇和矫味剂混合后溶解形成溶液B,再将适量纯水稀释并充分混匀后置模具中冷冻,再方法冻干机中冻干至物料完全干燥,压封,用泡罩包装。
有益效果
片剂是一种传统剂型,因其质量稳定、剂量准确、服用、携带方便、机械化程度高、生产成本低而成为目前最常用的剂型之一,但因片剂加压成型,崩解较慢、生物利用度较低,且部分患者吞服较为困难,因而片剂的推广使用在一定程度上受到限制。为此口服固体速释制剂成为近年新药研发的一个热点,特别是口腔崩解片,因其服用方便、起效快、生物利用度高、口感好而成为片剂开发的重点。
口腔崩解片是指不需用水或只需少量水,无需咀嚼,片剂置于舌面,遇唾液后迅速崩解,或借吞咽动力,药物即可入胃起效的片剂。口腔崩解片的特点是吸收快、生物利用度高,肠道残留少,副作用低,避免肝脏首过效应等。
据《口腔崩解片的剂型特点和质量控制会议纪要》的要求,口腔崩解片比滴丸和普通片的崩解速度有本质的飞跃,口腔崩解片的崩解一般在30秒以内,最多不超过1分钟。
具体实施例
通过以下的实施例来描述本发明所述二氢麦角碱及其衍生物口腔崩解片的制备方法;所举的实施例是为了更好地说明本发明,而不是对本发明进行限制。
实施例一.
一、处方
原辅料名称 用量(g)
甲磺酸二氢麦角碱 10.00
羟丙基甲基纤维素 10.00
甘露醇(粉) 600.00
甘露醇(颗粒) 210.00
微晶纤维素 50.00
阿斯巴甜 5.00
薄荷香精 15.00
交联聚乙烯吡咯烷酮 50.00
低取代羟丙基纤维素 30.00
微粉硅胶 10.00
硬脂酸镁 10.00
蒸馏水 适量
共压成10,000片,共计1000.00
二.制备方法
1)取羟丙基甲基纤维素,用适量的蒸馏水溶解,再加入处方量的甲磺酸二氢麦角碱和阿斯巴甜,搅拌均匀,备用;
2)将甘露醇(粉)置流化床(一步制粒机)中流化,然后喷入上述物料制粒;
3)制粒完毕后进行干燥,水分控制在1%~3%,备用;
4)将其余的辅料混合均匀,备用;
5)将步骤3)和步骤4)的物料混匀,测定含量,确定片重、压片,包装即得。
实施例二
一.处方
原辅料名称 用量(g)
甲磺酸二氢麦角碱 10.00
甘露醇(粉) 90.00
EudragitE100 16.00
EudragitNE30D(干重) 4.00
甘露醇(颗粒) 400.00
聚合糖 358.00
阿斯巴甜 5.00
香橙香精 15.00
交联羧甲基纤维素钠 50.00
羧甲基淀粉钠 30.00
微粉硅胶 12.00
硬脂酸镁 10.00
95%乙醇溶液 适量
共压成10,000片,共计1000.00。
二.制备方法
1)取EudragitE100和EudragitNE30D用适量的95%7醇溶液溶解,备用;
2)取处方量的甲磺酸二氢麦角碱和甘露醇粉混合均匀后置流化床中流化;
3)将步骤1)的溶液喷入步骤2)中进行粉末包衣;
4)将阿斯巴甜、香橙香精、交联羧甲基纤维素钠、羧甲基淀粉钠、微粉硅胶和硬脂酸镁混合均匀,备用;
5)将步骤3)和步骤4)的物料混合均匀,备用;
6)再递加甘露醇和聚合糖,混合均匀,备用;
7)进行中间体检测后,确定片重,压片,片子硬度控制在15~55牛顿,包装,即得。
实施例三
一.处方
原辅料名称 用量(g)
甲磺酸二氢麦角碱 10.00
枸橼酸 100.00
碳酸氢钠 100.00
羟丙基甲基纤维素 5.00
甘露醇(粉) 200.00
甘露醇(颗粒) 410.00
硅烷化微晶纤维素 50.00
甜菊甙 10.00
人参香精 15.00
交联聚乙烯吡咯烷酮 50.00
羧甲基淀粉钠 30.00
微粉硅胶 10.00
硬脂酰富马酸钠 10.00
蒸馏水 适量
共压成10,000片,共计1000.00。
二.制备方法
1)将羟丙基甲基纤维素用适量蒸馏水溶解,作为粘合剂溶液,备用;
2)将枸橼酸和碳酸氢钠分别用适量的1)溶液制粒,干燥,备用;
3)将甲磺酸二氢麦角碱和甘露醇粉混合均匀后用适量的1)溶液制粒,干燥,备用;
4)将其余的辅料混合均匀,备用;
5)将步骤2)、3)和4)的物料混合均匀,进行中间体检测后,确定片重,压片,片子硬度控制在15~55牛顿,包装,即得。
实施例四
一、处方
原辅料名称 用量(g)
甲磺酸二氢麦角碱 10.00
甘露醇 810.00
甲基纤维素 80.00
明胶 80.00
甜菊甙 20.00
共压成10,000片,共计1000.00
二、制备方法
a)将甲基纤维素用适量水溶解后将甲磺酸二氢麦角碱溶于其中;
b)将甘露醇、明胶和甜菊甙溶于水中,然后和前述溶液液混合,然后置模具中冻干,压封,用泡罩包装,即得。
Claims (7)
1.一种二氢麦角碱及其药学上可接受盐口腔崩解片,其特征在于其重量组成为二氢麦角碱及其药学上可接受盐1~10%、包衣材料聚丙烯酸树脂0.2~2%、崩解剂交联羧甲基纤维素钠和羧甲基淀粉钠共计8~35%、填充剂10-84.8%、矫味剂2~40%、助流剂1.2~5%、润滑剂1~3%组成,其中填充剂选自甘露醇、微晶纤维素、糊精、乳糖、淀粉、麦芽糖糊精、聚合糖和预胶化淀粉中的一种或多种,矫味剂选自甘露醇、乳糖、甜菊甙、明胶、阿斯巴甜、甜蜜素、甘草甜素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸中的一种或多种,助流剂选自微粉硅胶、滑石粉、Cab-O-sil、Arosil、水合硅铝酸钠中的一种或多种,润滑剂选自硬脂酸镁、单硬脂酸甘油脂、十二烷基硫酸镁、滑石粉中、硬脂富马酸钠中的一种或多种;其中将二氢麦角碱及其药学上可接受盐用包衣材料进行粉末包衣后,所得颗粒与其它辅料一起压制成崩解片。
2.如权利要求1所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片,其中填充剂是甘露醇和/或聚合糖。
3.如权利要求1所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片,其中矫味剂是阿斯巴甜和/或香橙香精。
4.如权利要求1所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片,其中润滑剂是硬脂酸镁。
5.如权利要求1所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片,其中助流剂是微粉硅胶。
6.如权利要求1所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片,其特征在于其重量组成为:二氢麦角碱及其药学上可接受盐10份,聚丙烯酸树脂20份,甘露醇490份,阿斯巴甜5份,香橙香精15份,交联羧甲基纤维素钠50份,羧甲基淀粉钠30份,微粉硅胶12份,硬脂酸镁10份,聚合糖358份。
7..如权利要求1-6任意一项所述的一种二氢麦角碱及其药学上可接受盐口腔崩解片的制备方法,其特征在于由以下步骤组成:
第一步二氢麦角碱及其药学上可接受盐的预处理;取所选定的包衣材料,用与之相适应的溶媒溶解并稀释至适当浓度备用,再取二氢麦角碱及其药学上可接受盐置于流化床中使沸腾,然后以适当速度喷入上述溶液进行粉末包衣,得二氢麦角碱及其药学上可接受盐粉末包衣颗粒,干燥后过筛备用;
第二步将矫味剂与二氢麦角碱及其药学上可接受盐颗粒或经第一步掩味处理后的原料颗粒按量称取,并混合均匀备用;
第三步将填充剂、崩解剂、助流剂按量称取并混合均匀,再与经第二步所得之物料混合使均匀,加入润滑剂混匀,备用;
第四步所得物料经中间体检测,确定片重后,送入压片机压片即得。
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