CN106727415A - 一种含有胞磷胆碱钠的胶囊组合物及其制备方法 - Google Patents
一种含有胞磷胆碱钠的胶囊组合物及其制备方法 Download PDFInfo
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Abstract
本发明公开了一种含有胞磷胆碱钠的胶囊组合物及其制备方法，所述的含有胞磷胆碱钠的胶囊组合物包括胞磷胆碱钠、乳糖、微晶纤维素Avicel PH102、微粉硅胶和硬脂酸镁，所述胞磷胆碱钠与乳糖的质量比为1：0.1‑5，所述胞磷胆碱钠与微晶纤维素Avicel PH102的质量比为1：0.1‑3，所述胞磷胆碱钠与微粉硅胶的质量比为5‑50：1，所述胞磷胆碱钠与硬脂酸镁的质量比为10‑100：1。本发明提供的胞磷胆碱钠胶囊组合物采用干粉混合的工艺，直接灌装胶囊，选用PVC/PVDC40涂层铝塑包装，能确保良好防潮功能和崩解时限，在长期24个月稳定性考察中，水分无明显增加，胶囊壳无变脆现象，产品稳定、储藏时间长。
Description
技术领域
本发明属于医药制备领域，具体涉及一种含有胞磷胆碱钠的胶囊组合物及其制备方法。
背景技术
胞磷胆碱钠(Citicoline Sodium)，为胆碱胞嘧啶核苷二磷酸酯的单钠盐，是核苷衍生物，干燥品中胞磷胆碱钠不少于98％。胞磷胆碱钠可以通过降低脑血管阻力，增加脑血流来促进脑物质代谢，改善脑循环。也可增强脑干上行网状激活系统的机能，增强椎体系统的功能，改善运动麻痹，故对促进大脑功能的恢复和促进苏醒有一定作用。注入胞磷胆碱钠注射液后可迅速进入血液，有部分通过血脑屏障进入脑组织，胆碱部分在体内成为良好的甲基化供体，可对多种化合物有转甲基化作用，约1％的胆碱从尿排出。胞磷胆碱钠主要用于急性颅脑外伤和脑手术后意识障碍，对脑中风所致的偏瘫可逐渐恢复四肢的功能，也可用于其他中枢神经系统急性损伤引起的功能和意识障碍，也用于缺血性脑血管病和血管性痴呆。
胞磷胆碱钠易吸湿，在胞磷胆碱钠胶囊填充过程中过度暴露于空气中容易吸潮，造成粘冲或影响填充；并且胶囊剂在放置过程中，胶囊壳中的水分容易被囊壳内的胞磷胆碱颗粒吸收，导致胶囊壳变脆；经包装后，如采用铝塑包装，颗粒容易吸湿，导致水分增加，并且，本发明需要解决如下两个问题：
1、稳定性与市售产品一致：根据本专利制备的样品0天样品有关物质低于市售制剂产品，质量更优；长期24月和加速6月条件下稳定性未发生改变；其余检测指标亦合格，未出现显著变化；
2、生产成本：为解决胞磷胆碱钠吸湿性强导致吸收胶囊壳水分，使得胶囊壳变脆的问题，本专利选择常规的干粉混合直灌胶囊，选择双层铝塑材料进行包装。
而CN102525997B专利时通过挤出滚圆工艺制备胞磷胆碱钠微丸或者颗粒，再对微丸或者颗粒进行包衣达到防潮的目的。两个防潮目的一致，但是本专利优点是工艺简单，生产周期短，成本低于CN102525997B专利；CN102525997B专利公布的工艺需额外采用特殊设备挤出滚圆设备和流化床，本专利设备无需专用设备。
发明内容
发明目的：本发明提供一种含有胞磷胆碱钠的胶囊组合物及其制备方法。
技术方案：一种含有胞磷胆碱钠的胶囊组合物，所述的含有胞磷胆碱钠的胶囊组合物包括胞磷胆碱钠、乳糖、微晶纤维素Avicel PH102、微粉硅胶和硬脂酸镁，所述胞磷胆碱钠与乳糖的质量比为1：0.1-5，所述胞磷胆碱钠与微晶纤维素Avicel PH102的质量比为1：0.1-3，所述胞磷胆碱钠与微粉硅胶的质量比为5-50：1，所述胞磷胆碱钠与硬脂酸镁的质量比为10-100：1。
一种根据所述的含有胞磷胆碱钠的胶囊组合物的制备方法，包括如下步骤：
(1)过筛：取胞磷胆碱钠过60目筛；取乳糖和微晶纤维素Avicel PH102分别过60目筛；
(2)一次混合：称取处方量50％的胞磷胆碱钠加入多维混合机内，投入经过处理的乳糖和微晶纤维素Avicel PH102，混合速度为15～20rpm，混合时间为5～10min；将剩余的胞磷胆碱钠加入多维混合机内，继续混合15～20min；
(3)二次混合：加入处方量微粉硅胶混合均匀，混合速度15～20rpm，混合时间15～20min；
(4)三次混合：加入处方量硬脂酸镁混合均匀，混合速度20rpm，混合时间15min；
(5)灌装：测定颗粒含量，胶囊灌装，PVC/PVDC40涂层铝塑包装。
有益效果：本发明提供的胞磷胆碱钠胶囊组合物采用干粉混合的工艺，直接灌装胶囊，选用PVC/PVDC40涂层铝塑包装，能确保良好防潮功能和崩解时限，在长期24个月稳定性考察中，水分无明显增加，胶囊壳无变脆现象，产品稳定、储藏时间长。
具体实施方式
下面结合具体实施例对本发明进行详细阐述。
综述如下：一种含有胞磷胆碱钠的胶囊组合物，所述的含有胞磷胆碱钠的胶囊组合物包括胞磷胆碱钠、乳糖、微晶纤维素Avicel PH102、微粉硅胶和硬脂酸镁，所述胞磷胆碱钠与乳糖的质量比为1：0.1-5，所述胞磷胆碱钠与微晶纤维素Avicel PH102的质量比为1：0.1-3，所述胞磷胆碱钠与微粉硅胶的质量比为5-50：1，所述胞磷胆碱钠与硬脂酸镁的质量比为10-100：1。
一种根据所述的含有胞磷胆碱钠的胶囊组合物的制备方法，包括如下步骤：
(1)过筛：取胞磷胆碱钠过60目筛；取乳糖和微晶纤维素Avicel PH102分别过60目筛；
(2)一次混合：称取处方量50％的胞磷胆碱钠加入多维混合机内，投入经过处理的乳糖和微晶纤维素Avicel PH102，混合速度为15～20rpm，混合时间为5～10min；将剩余的胞磷胆碱钠加入多维混合机内，继续混合15～20min；
(3)二次混合：加入处方量微粉硅胶混合均匀，混合速度15～20rpm，混合时间15～20min；
(4)三次混合：加入处方量硬脂酸镁混合均匀，混合速度20rpm，混合时间15min；
(5)灌装：测定颗粒含量，胶囊灌装，PVC/PVDC40涂层铝塑包装。
具体实施案例1：最佳
胞磷胆碱钠胶囊的制备处方(以1000片计)：
制备过程：
(1)取胞磷胆碱钠过60目筛；取乳糖和微晶纤维素Avicel PH102分别过60目筛。
(2)称取处方量50％的胞磷胆碱钠加入多维混合机内，投入经过处理的乳糖和微晶纤维素Avicel PH102，混合速度20rpm，混合时间5min；将剩余的胞磷胆碱钠加入多维混合机内，继续混合15min。
(3)加入处方量微粉硅胶混合均匀，混合速度20rpm，混合时间15min。
(4)加入处方量硬脂酸镁混合均匀，混合速度20rpm，混合时间15min。
(5)测定颗粒含量。胶囊灌装，PVC/PVDC40涂层铝塑包装。
具体实施案例2：包材选择不合适
胞磷胆碱钠胶囊的制备处方(以1000片计)：
制备过程：
(1)取胞磷胆碱钠过60目筛；取乳糖和微晶纤维素Avicel PH102分别过60目筛。
(2)称取处方量50％的胞磷胆碱钠加入多维混合机内，投入经过处理的乳糖和微晶纤维素Avicel PH102，混合速度20rpm，混合时间5min；将剩余的胞磷胆碱钠加入多维混合机内，继续混合15min。
(3)加入处方量微粉硅胶混合均匀，混合速度20rpm，混合时间15min。
(4)加入处方量硬脂酸镁混合均匀，混合速度20rpm，混合时间15min。
(5)测定颗粒含量。胶囊灌装，PVC涂层铝塑包装。
具体实施案例3：湿法制粒工艺
胞磷胆碱钠胶囊的制备处方(以1000片计)：
制备过程：
(1)取胞磷胆碱钠粉碎过60目筛；取预胶化淀粉、微晶纤维素和羧甲基淀粉钠，分别过60目筛，备用。
(2)将处方量胞磷胆碱钠与预胶化淀粉、微晶纤维素和羧甲基淀粉钠置湿法制粒机中混匀，搅拌速率不低于40Hz，混合时间不低于5min；配制8％PVP K30水溶液用于湿法制粒，边加浆液边开启搅拌，搅拌速率30～35Hz，浆液在30秒内加入湿法制粒机锅内；同时开启制粒转子，调节制粒转速30Hz～32Hz，继续制粒220秒～250秒。用18目筛将湿颗粒整粒，95℃-105℃干燥将水分控制在5％以内。用20目筛将干颗粒整粒，根据干颗粒重量加入处方量折算后硬脂酸镁量，于二维混合机中混合均匀15min。
(3)测定颗粒含量。胶囊灌装，PVC/PVDC40涂层铝塑包装。
具体实施案例1各项性能表
具体实施案例2各项性能表
具体实施案例3各项性能表
通过上述3组具体实施案例各项性能表的对比，可得出如下结论：
1、具体实施案例1只有选对合理的赋形剂种类用量和包装材料，才能制备出质量可靠、成本低廉的产品供应患者。
2、具体实施案例2选择不合适的包材，导致长期放置过程中吸潮，水分增加，囊壳变脆，产品质量亦有所下降。
3、具体实施案例3中选用常规的湿法制粒，产品质量劣于具体实施案例1。
本发明不局限于上述最佳实施方式，任何人在本发明的启示下都可得出其他各种形式的产品，但不论在其形状或结构上作任何变化，凡是具有与本申请相同或相近似的技术方案，均落在本发明的保护范围之内。
Claims (2)
1.一种含有胞磷胆碱钠的胶囊组合物，其特征在于：所述的含有胞磷胆碱钠的胶囊组合物包括胞磷胆碱钠、乳糖、微晶纤维素Avicel PH102、微粉硅胶和硬脂酸镁，所述胞磷胆碱钠与乳糖的质量比为1：0.1-5，所述胞磷胆碱钠与微晶纤维素Avicel PH102的质量比为1：0.1-3，所述胞磷胆碱钠与微粉硅胶的质量比为5-50：1，所述胞磷胆碱钠与硬脂酸镁的质量比为10-100：1。
2.根据权利要求1所述的含有胞磷胆碱钠的胶囊组合物的制备方法，其特征在于：包括如下步骤：
(1)过筛：取胞磷胆碱钠过60目筛；取乳糖和微晶纤维素Avicel PH102分别过60目筛；
(2)一次混合：称取处方量50％的胞磷胆碱钠加入多维混合机内，投入经过处理的乳糖和微晶纤维素Avicel PH102，混合速度为15～20rpm，混合时间为5～10min；将剩余的胞磷胆碱钠加入多维混合机内，继续混合15～20min；
(3)二次混合：加入处方量微粉硅胶混合均匀，混合速度15～20rpm，混合时间15～20min；
(4)三次混合：加入处方量硬脂酸镁混合均匀，混合速度20rpm，混合时间15min；
(5)灌装：测定颗粒含量，胶囊灌装，PVC/PVDC40涂层铝塑包装。
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