CN112546005A - 一种骨化三醇片及其制备方法 - Google Patents
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Abstract
本发明提供了一种骨化三醇片,属医药技术领域。本发明利用包合技术将不溶于水的骨化三醇包合,再加入适量的辅料压片,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
本发明提供了一种骨化三醇片,属医药技术领域。本发明利用包合技术将不溶于水的骨化三醇包合,再加入适量的辅料压片,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
骨化三醇(Calcitriol)为白色结晶粉末,对光和空气敏感。微溶于甲醇、乙醇、乙酸乙酯。Tm为111-115℃。它是人体内维生素D3最重要的代谢活性产物之一,具有促使小肠吸收钙并调节骨质中无机盐转运等作用;主要用于骨质疏松症;慢性肾功能衰竭病人的肾性骨营养不良,特别是需要长期血液透析的病人;手术后自发性及假性甲状旁腺机减退;维生素D3依赖性佝偻病以及血磷酸盐过少维生素D抗性佝偻病;银屑病等皮肤病;以及其他维生素D缺乏症。骨化三醇的口服吸收快,3~6小时达高峰,t1/2约3~6小时,经7小时后尿钙浓度增加,单次口服剂量可持续药理活性3~5日。
目前,骨化三醇的主要制剂形式是软胶囊剂和胶丸;剂型比较单调,并且骨化三醇对光和空气敏感,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。骨化三醇由于性质特殊,难溶于水等溶剂,因此难以制成片剂。
发明内容
本发明为了解决现有骨化三醇制剂起效慢、生物利用度低的缺点,发明了骨化三醇片,采用特定的包合材料对难溶于水的骨化三醇进行包合,包合后可溶于水,易于压片,并崩解迅速,起效快。
本发明提供一种骨化三醇片,其特征在于由骨化三醇包合物、崩解剂、粘合剂、填充剂、润滑剂组成。包合物材料为β-环糊精、2-羟丙基-β-环糊精的混合物,且二者比例为2-5:1-3。
更进一步的,其特征在于包合物材料β-环糊精与2-羟丙基-β-环糊精比例为3:2。
本发明的骨化三醇片,其特征在于崩解剂为低取代纤维素、羧甲基淀粉钠、聚乙烯吡咯烷酮中的一种或几种;粘合剂为淀粉浆、聚维酮、聚乙二醇中的一种或几种;填充剂为淀粉、乳糖、糊精中的一种或几种;润滑剂为硬脂酸镁、微粉硅胶中的一种或几种。
更进一步的,其特征在于崩解剂为低取代纤维素和聚乙烯吡咯烷酮,且二者比例为1:3;粘合剂为聚维酮和聚乙二醇,且二者比例为4:1。
本发明所述骨化三醇片,其特征在于骨化三醇片的处方为(按重量计):骨化三醇包合物0.1 %,崩解剂10-25%,粘合剂15-30%,润滑剂12-20%,填充剂适量。
更优选的骨化三醇片,其特征在于骨化三醇片的处方为(按重量计):骨化三醇包合物0.1 %,崩解剂20%,粘合剂25%,润滑剂18%,填充剂适量。
本发明所述骨化三醇片的制备方法,其特征在于,该方法包括如下步骤:
A、骨化三醇包合物制备:骨化三醇与包合材料以1:3的摩尔比例制备骨化三醇包合物;
B、压片:粘合剂加入蒸馏水,制成粘合剂溶液;称取处方量的原辅料,分别过80目筛备用;按处方量取骨化三醇包合物与填充剂、崩解剂混合均匀,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,加入润滑剂混匀后压片即得。
本发明在试验过程中意外的发现,包合物材料为β-环糊精、2-羟丙基-β-环糊精的混合物,且二者比例为2-5:1-3时,骨化三醇包合的效果较好,能够显著提高骨化三醇在水中的溶解度,其中β-环糊精与2-羟丙基-β-环糊精比例为3:2时,骨化三醇包合的效果最好,相比其他包合物和比例有显著性差异。
本发明骨化三醇片采用特定的包合材料及比例对难溶于水的骨化三醇进行包合,包合后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;本发明骨化三醇片服用方便。
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 骨化三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-环糊精分别配成饱和溶液,分别加入骨化三醇;其中包和物与骨化三醇的摩尔比例均为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
将骨化三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,计算骨化三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2-羟丙基β-环糊精制备得到骨化三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2-羟丙基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2-羟丙基β-环糊精比例为2-5:1-3时,包合物的溶解性较好,而二者比例为3:2时,包合物溶解性最好,具有显著差异。
2、包合剂用量的筛选试验
将骨化三醇与β-环糊精、2-羟丙基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,将骨化三醇与复合包合材料按照1:3的摩尔比例进行包和时,骨化三醇的溶解度最好,可显著提高骨化三醇溶解度。
试验例2 骨化三醇片的崩解时限试验
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所制备的骨化三醇片的崩解时限。试验结果见表4。
表4 崩解时限
从试验结果可见,崩解剂为低取代纤维素和聚乙烯吡咯烷酮,且二者比例为1:3、粘合剂为聚维酮和聚乙二醇,且二者比例为4:1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 (9)
1.一种骨化三醇片,其特征在于骨化三醇为包合物。
2.如权利要求1所述的骨化三醇片,其特征在于由骨化三醇包合物、崩解剂、粘合剂、填充剂、润滑剂组成。
3.如权利要求2所述的骨化三醇片,其特征在于包合物材料为β-环糊精、2-羟丙基-β-环糊精的混合物,且二者比例为2-5:1-3。
4.如权利要求3所述的骨化三醇片,其特征在于包合物材料β-环糊精与2-羟丙基-β-环糊精比例为3:2。
5.如权利要求2所述的骨化三醇片,其特征在于崩解剂为低取代纤维素、羧甲基淀粉钠、聚乙烯吡咯烷酮中的一种或几种;粘合剂为淀粉浆、聚维酮、聚乙二醇中的一种或几种;填充剂为淀粉、乳糖、糊精中的一种或几种;润滑剂为硬脂酸镁、微粉硅胶中的一种或几种。
6.如权利要求4所述的骨化三醇片,其特征在于崩解剂为低取代纤维素和聚乙烯吡咯烷酮,且二者比例为1:3;粘合剂为聚维酮和聚乙二醇,且二者比例为4:1。
7.如权利要求1-5任一项所述的骨化三醇片,其特征在于骨化三醇片的处方为(按重量计):骨化三醇包合物0.1 %,崩解剂10-25%,粘合剂15-30%,润滑剂12-20%,填充剂适量。
8.如权利要求1-6任一项所述的骨化三醇片,其特征在于骨化三醇片的处方为(按重量计):骨化三醇包合物0.1 %,崩解剂20%,粘合剂25%,润滑剂18%,填充剂适量。
9.如权利要求1-7所述的骨化三醇片的制备方法,其特征在于,该方法包括如下步骤:
A、骨化三醇包合物制备:骨化三醇与包合材料以1:3的摩尔比例制备骨化三醇包合物;
B、压片:粘合剂加入蒸馏水,制成粘合剂溶液;称取处方量的原辅料,分别过80目筛备用;按处方量取骨化三醇包合物与填充剂、崩解剂混合均匀,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,加入润滑剂混匀后压片即得。
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