CN112545999A - 一种阿法骨化醇制剂及其制备方法 - Google Patents
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Abstract
本发明提供了一种阿法骨化醇颗粒,属医药技术领域。本发明利用包合技术将不溶于水的阿法骨化醇包合,再加入适量的辅料制粒,工艺简单,药物稳定,溶出迅速,吸收快,生物利用度高,服用方便。
Description
技术领域
本发明提供了一种阿法骨化醇颗粒,属医药技术领域。本发明利用包合技术将不溶于水的阿法骨化醇包合,再加入适量的辅料制备颗粒,工艺简单,药物稳定,溶出迅速,吸收快,生物利用度高,服用方便。
背景技术
阿法骨化醇化学名为9,10-开环胆甾-5Z, 7E, 10(19)-三烯-1α,3β-二醇,最早由美国骨保健国际公司研制,并先后在以色列(1979年)、德国(1979年)、日本(1982年)、意大利(1985年)获得批准上市。阿法骨化醇多用于因维生素D代谢障碍而引起的钙代谢紊乱,临床用于治疗骨质疏松、慢性肾功能不全、甲状腺功能减退症、抗维生素D佝偻病、骨软化症等。现世界各国销量较大的是丹麦Leo制药公司生产的阿法骨化醇产品,我国从1997年开始有国产产品上市,目前国内市场上主要有阿法骨化醇的片剂和胶丸,剂型单调、普通,受到崩解、药物释放等因素的影响,给药时间间隔短,有效血药浓度波动大,吸收、治疗效果不理想。
目前,阿法骨化醇的主要制剂形式是软胶囊剂和胶丸;剂型比较单调,并且阿法骨化醇对光和空气敏感,对于普通有机溶剂溶解度较低,软胶囊剂和胶丸的稳定性不好,崩解时间较长,起效慢,生物利用度低。阿法骨化醇由于性质特殊,难溶于水等溶剂,因此难以制成颗粒剂。
发明内容
本发明为了解决现有阿法骨化醇制剂起效慢、生物利用度低的缺点,发明了阿法骨化醇颗粒,采用特定的包合材料对难溶于水的阿法骨化醇进行包合,包合后后可溶于水,易于制备颗粒,并崩解迅速,起效快。
本发明提供一种阿法骨化醇颗粒,其特征在于:按重量计,处方为:阿法骨化醇包合物0.2%,崩解剂8-28%,粘合剂16-30%,润滑剂10-15%,湿润剂5%,填充剂适量。
进一步优化的,按重量计,处方为:阿法骨化醇包合物0.2%,崩解剂18%,粘合剂20%,润滑剂16%,湿润剂5%,填充剂适量。
本发明所述阿法骨化醇颗粒,其特征在于包合物材料为β-环糊精与葡萄糖基-β-环糊精的混合物,且二者比例为4:1。
本发明所述阿法骨化醇颗粒,其特征在于崩解剂为交联羧甲基纤维素钠、微晶纤维素、枸橼酸中的一种或几种;粘合剂为聚维酮、羟丙基纤维素中的一种或两种;填充剂为淀粉、甘露醇中的一种或两种;润滑剂为硬脂酸镁、微粉硅胶中的一种或两种。
进一步优化的,其特征在于崩解剂中枸橼酸按重量计为2%;粘合剂为聚维酮和羟丙基纤维素,且二者比例为1:4。
本发明所述阿法骨化醇颗粒的制备方法,其特征在于,该方法包括如下步骤:
A、阿法骨化醇包合物制备:阿法骨化醇与包合材料以2:1的摩尔比例制备阿法骨化醇包合物;
B、制备颗粒:粘合剂加入蒸馏水,制成粘合剂溶液;称取处方量的阿法骨化醇包合物与填充剂、崩解剂,用等量递加法将其混合均匀,每次混合30min,加入粘合剂溶液制成软材,30目筛制粒,干燥后过20目筛整粒,加入润滑剂混匀后即得。
本发明在试验过程中意外的发现,在生产中加入2%的枸橼酸做为崩解剂,崩解效果得到了极大提高;另外包合物材料为包合物材料为β-环糊精与葡萄糖基-β-环糊精的混合物,且二者比例为4:1,阿法骨化醇包合的效果最好,能够显著提高阿法骨化醇在水中的溶解度。
本发明阿法骨化醇颗粒采用特定的包合材料及比例对难溶于水的阿法骨化醇进行包合,并筛选改良崩解剂,试验所得颗粒剂相对现有的软胶囊剂或胶囊剂,具有崩解快、药物稳定的特点,可缩短口服给药的达峰时间和提高峰浓度;本发明阿法骨化醇颗粒服用方便。
具体实施方式
实施例1-6(处方为按重量计):
实施例7-12(处方为按重量计):
试验例1 阿法骨化醇包合物的优选试验
1、包合剂种类的优选试验
a包合物的制备
将包和物α-环糊精,β-环糊精,羟基β-环糊精,2-羟丙基β-环糊精与葡萄糖基-β-环糊精分别配成饱和溶液,分别加入阿法骨化醇;其中包和物与阿法骨化醇的摩尔比例均为1:1;混合45分钟,形成包含物,将包合物分离出来。将析出的包合物滤过,洗净、干燥即得。测定所制备的包合物的溶解度;
b溶解度测定方法
将阿法骨化醇和包合物分别置于10 ml量瓶中,加水配成过饱和溶液,于37℃恒温水浴中静置,过滤取滤液,以50%乙醇作溶剂,稀释定容,摇匀,于波长264nm处测其吸收度,代入回归方程,计算阿法骨化醇包合物中药物在水中的溶解度。
c试验结果
试验结果见表1。
表1 不同种类的包和物在水中的溶解度
从表1的实验数据可见,采用β-环糊精和葡萄糖基-β-环糊精制备得到阿法骨化醇包和物的溶解性能最好,与其它包和物相比有显著性差异。
按包合物的制备方法,考察不同比例的β-环糊精和葡萄糖基-β-环糊精制备所得包合物的溶解性,进一步筛选包合材料的最优配比。
表2 不同比例的包和物在水中的溶解度
从表2的实验数据可见,β-环糊精和葡萄糖基-β-环糊精比例为4:1时,包合物的溶解性最好,具有显著差异。
2、包合剂用量的筛选试验
将阿法骨化醇与β-环糊精、葡萄糖基-β-环糊精按照表3所述的摩尔比例进行包合,包和方法同1a,溶解度的测定方法见1b,试验结果见表3。
表3 不同包合剂用量的溶解度
从表3的实验数据可见,将阿法骨化醇与复合包合材料按照2:1的摩尔比例进行包和时,阿法骨化醇的溶解度最好,可显著提高阿法骨化醇溶解度。
试验例2 阿法骨化醇颗粒的崩解时限试验
按照崩解时限测定方法(参照中国药典2015版)测定实施例1-12所制备的阿法骨化醇颗粒的崩解时限。试验结果见表4。
表4 崩解时限
从试验结果可见,崩解剂中添加2%枸橼酸可明显提高崩解速度;当粘合剂为聚维酮和羟丙基纤维素,且二者比例为1:4时,能够显著提高崩解时限,药物的溶出速度最快,制剂的稳定性也最为优异。
Claims (7)
1.一种阿法骨化醇颗粒,其特征在于阿法骨化醇为包合物。
2.如权利要求1所述的阿法骨化醇颗粒,其特征在于:按重量计,处方为:阿法骨化醇包合物0.2%,崩解剂8-28%,粘合剂16-30%,润滑剂10-15%,湿润剂5%,填充剂适量。
3.如权利要求1-2所述的阿法骨化醇颗粒,其特征在于:按重量计,处方为:阿法骨化醇包合物0.2%,崩解剂18%,粘合剂20%,润滑剂16%,湿润剂5%,填充剂适量。
4.如权利要求1所述的阿法骨化醇颗粒,其特征在于包合物材料为β-环糊精与葡萄糖基-β-环糊精的混合物,且二者比例为4:1。
5.如权利要求2所述的阿法骨化醇颗粒,其特征在于崩解剂为交联羧甲基纤维素钠、微晶纤维素、枸橼酸中的一种或几种;粘合剂为聚维酮、羟丙基纤维素中的一种或两种;填充剂为淀粉、甘露醇中的一种或两种;润滑剂为硬脂酸镁、微粉硅胶中的一种或两种。
6.如权利要求1-4所述的阿法骨化醇颗粒,其特征在于崩解剂中枸橼酸按重量计为2%;粘合剂为聚维酮和羟丙基纤维素,且二者比例为1:4。
7.如权利要求1-6所述的阿法骨化醇颗粒的制备方法,其特征在于,该方法包括如下步骤:
A、阿法骨化醇包合物制备:阿法骨化醇与包合材料以2:1的摩尔比例制备阿法骨化醇包合物;
B、制备颗粒:粘合剂加入蒸馏水,制成粘合剂溶液;称取处方量的阿法骨化醇包合物与填充剂、崩解剂,用等量递加法将其混合均匀,每次混合30min,加入粘合剂溶液制成软材,30目筛制粒,干燥后过20目筛整粒,加入润滑剂混匀后即得。
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