CN107375225B - 一种琥珀酸呋罗曲坦缓释制剂及其制备方法 - Google Patents
一种琥珀酸呋罗曲坦缓释制剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种琥珀酸呋罗曲坦缓释制剂，其由琥珀酸呋罗曲坦、聚乙二醇、羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s和泊洛沙姆制成。本发明将固体分散技术与缓释亲水凝胶骨架技术相结合，按照先速释后缓释的“双释药”原理，制备琥珀酸呋罗曲坦缓释制剂，其显著提高了琥珀酸呋罗曲坦的溶解度，实现了先快速起效，再平稳缓慢释药的效果。
Description
技术领域
本发明涉及一种琥珀酸呋罗曲坦缓释制剂及其制备方法。
背景技术
琥珀酸呋罗曲坦，也称琥珀酸夫罗曲坦，中文化学名(R)-3-(甲基胺基)-2,3,4,9-四氢-1H-咔唑-6-甲酰胺琥珀酸。
夫罗曲坦(frovatriptan)一种新型抗偏头痛药，属于选择性5HT1B/1D受体激动药。它克服了第一代5HT1B/1D受体激动药舒马曲坦口服生物利用度低、半衰期短、复发率高的缺点，是成人中度、重度偏头痛发作的有效治疗药物。该由ElanPharmacuticalInc.研制开发，于2001年11月由美国FDA批准以其琥珀酸盐形式上市，用于有或无先兆偏头痛的急性治疗。
目前我国市场上主要有琥珀酸呋罗曲坦片剂以及注射液，常规片剂虽然服用方便，但受到崩解、药物释放等因素的影响，吸收效果不理想，且在治疗偏头痛时往往需要多次服药。注射液虽然疗效快，但携带、使用都不方便，并且琥珀酸呋罗曲坦在水溶液中并不稳定。
缓/控释制剂(sustained/controlled release preparations)具有降低血浓峰谷现象，减少用药次数和毒副作用，提高病人顺应性等优点，临床应用日益广泛。制备缓/控释制剂通常需要先将药物溶解，再加入缓/控释辅料，采用适当的工艺制成缓/控释制剂。水溶性药物因水中易溶解，易于制成缓/控释制剂，目前上市的品种较多。对于水难溶性药物，若利用常规的缓/控释技术制备缓释制剂，因药物溶解度小，溶出少，体内药物浓度低，难以维持治疗浓度，通常需要先采用增溶技术增加药物的溶解度，再以增溶后的物料为原料，制备缓/控释制剂，即先增溶再缓释。
固体分散技术(solid dispersion,SD)是提高难溶性药物溶解度及生物利用度的有效方法，以其制备缓/控释制剂的显著优点在于：既可直接制备，又可以先制成速释型固体分散体，再以速释型固体分散体为原料，选用缓/控释材料制备缓/控释制剂。
本发明尝试将固体分散技术与缓释亲水凝胶骨架技术相结合，提供一种在服用初期迅速释放而产生药效，后期缓慢平稳释放，长时间维持药效而不产生毒副反应的珀酸呋罗曲坦缓释制剂。
发明内容
本发明选用水溶性载体材料聚乙二醇制备琥珀酸呋罗曲坦速释固体分散体，利用固体分散体技术改善药物琥珀酸呋罗曲坦在常温下溶解度差问题；再以琥珀酸呋罗曲坦固体分散体为原料，选择具有缓释作用的骨架型材料羟丙甲纤维素(HPMC)，采用干法或湿法制粒压片制备水凝胶骨架型缓释制剂。
本发明基于先速释后缓释的“双释药”机理，提供了一种释药平稳、生物利用度高、给药次数少、患者顺应性好、稳定性好的琥珀酸呋罗曲坦缓释制剂。
具体的，本申请提供了一种琥珀酸呋罗曲坦缓释制剂，其由琥珀酸呋罗曲坦、聚乙二醇、羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s和泊洛沙姆制成。
优选的，该制剂中，聚乙二醇为PEG4000、PEG6000和PEG10000的混合物，更优选的，三者的比例为1：10：1。
更优选的，上述的琥珀酸呋罗曲坦缓释制剂，缓释骨架材料可以加入羟丙甲纤维素4000mPa.s与羟丙甲纤维素15000mPa.s的比例为5：1-1：5。
一种制备琥珀酸呋罗曲坦缓释制剂的方法，其包括如下步骤：步骤1.按上述配方准确称取琥珀酸呋罗曲坦、聚乙二醇、泊洛沙姆188，用无水乙醇溶解后，于60℃水浴，90rmp旋转蒸发至近干，于70℃水浴完全挥去溶剂，然后，放置于60℃真空干燥箱中12h，粉碎，过80目筛，得固体分散体，备用；步骤2.取步骤1所得固体分散体与羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s加入合适的辅料干法或湿法制备缓释片。
一种制备琥珀酸呋罗曲坦缓释制剂的方法，其包括如下步骤：步骤1.按上述配方准确称取琥珀酸呋罗曲坦、聚乙二醇、泊洛沙姆188，用无水乙醇溶解后，采用冷冻干燥或喷雾干燥法制备固体分散体，备用；步骤2.取步骤1所得固体分散体与羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s加入合适的辅料干法或湿法制备缓释片。
本发明的有益效果是：
1.本发明将固体分散技术与缓释亲水凝胶骨架技术相结合，按照先速释后缓释的“双释药”原理，制备琥珀酸呋罗曲坦缓释制剂，其显著优点是提高了琥珀酸呋罗曲坦的溶解度，实现了缓释制剂口服先快速起效，再平稳缓慢释药。
2.本发明在制备固体分散体时，加入了泊洛沙姆，可以使琥珀酸呋罗曲坦有较好的溶出速率和生物利用度。3.PEG4000和PEG6000是本领域在制备固体分散体时常用的载体材料。PEG400流动性最差，制备的分散体分散性差，药物的溶解和吸收较差；PEG6000松脆、片状易于粉碎的固体，但PEG 6000作载体则固体分散体较软，特别是温度较高时存在析出结晶的情况，而采用两种载体的混合物制备固体分散体时，虽然该固体分散体能够获得较好的分散状态，但固体分散体的硬度和稳定性较差，研究发现在上述两种载体的混合物中加入少量PEG 10000可以改善固体分散体的硬度和稳定性。当PEG4000、PEG6000和PEG10000的比例为1：10：1时，所制备的固体分散体在分散度、硬度和稳定性上效果最好。
附图说明
图1实施例1处方1固体分散体的释放度曲线；
图2实施例1处方2固体分散体的释放度曲线；
图3实施例1处方3固体分散体的释放度曲线；
图4实施例1处方4固体分散体的释放度曲线；
图5实施例1处方5固体分散体的释放度曲线；
图6实施例1处方6固体分散体的释放度曲线；
图7实施例2缓释片的释放度曲线。
具体实施方式
实施例1
按下述配方准确称取琥珀酸呋罗曲坦、聚乙二醇、泊洛沙姆188，用无水乙醇溶解后，采用喷雾干燥法制备固体分散体。
采用药典方法测定体外溶出试验，结果显示：与琥珀酸呋罗曲坦原料相比，含药固体分散体溶解度有所提高，其中：PEG4000和PEG6000的组合，或PEG4000、PEG6000和PEG10000混合物作为载体材料时，固体分散体的溶解度最优，但PEG4000和PEG6000的组合作为载体制备的固体分散体硬度和稳定性较差。而PEG4000、PEG6000和PEG10000混合物作为载体时，其比例为1：10：1时效果最优，因此，选择上述比例的PEG混合物制备缓释片。
实施例2
称取实施例1处方6制备的固体分散体2g与羟丙甲纤维素4000mPa.s 2g、羟丙甲纤维素15000mPa.s 1g、微晶纤维素2g混匀后，加入70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘箱中烘30分钟后取出后，过16目筛整粒，压片分装。所得缓释片在模拟体内介质中释放速率恒定，体外释药符合Higuchi’s动力学方程，24h累积释药量达99％以上，具有明显的缓释特征。体内给药Beagle犬后，其血药浓度经时曲线与参比制剂相比具有明显缓释特征。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。
Claims (2)
1.一种琥珀酸呋罗曲坦缓释制剂，其特征在于：该制剂由琥珀酸呋罗曲坦、聚乙二醇、羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s和泊洛沙姆、微晶纤维素制成，聚乙二醇为PEG4000、PEG6000和PEG10000的混合物，
所述缓释制剂的制备方法为：
步骤1.称取琥珀酸呋罗曲坦2g、聚乙二醇6g、泊洛沙姆188 0.1g，用无水乙醇溶解后，于60℃水浴，90rmp旋转蒸发至近干，于70℃水浴完全挥去溶剂，然后，放置于60℃真空干燥箱中12h，粉碎，过80目筛，得固体分散体，备用；
步骤2.取步骤1所得固体分散体2g与羟丙甲纤维素4000mPa.s 2g、羟丙甲纤维素15000mPa.s 1g、微晶纤维素2g混匀后，加入70％的糖浆制备软材，过16目筛得到湿颗粒，于60℃烘箱中烘30分钟后取出后，过16目筛整粒，压片分装。
2.根据权利要求1所述缓释制剂的制备方法，其步骤包括：
步骤1. 按上述配方准确称取琥珀酸呋罗曲坦、聚乙二醇、泊洛沙姆188，用无水乙醇溶解后，于60℃水浴，90rmp旋转蒸发至近干，于70℃水浴完全挥去溶剂，然后，放置于60℃真空干燥箱中12h，粉碎，过80目筛，得固体分散体，备用；
步骤2.取步骤1所得固体分散体与羟丙甲纤维素4000mPa.s、羟丙甲纤维素15000mPa.s加入合适的辅料制备缓释片。
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