CN105816425A - 一种制备纳米混悬液的前处理方法 - Google Patents
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Abstract
本发明公开了纳米混悬的一种前处理方法,属于药物制剂领域。具体方法如下:(1)制备含有稳定剂的水相A,超声脱气;(2)将药物加入到水相A所在容器中,密闭容器,降低容器内压力以除去药物颗粒间、孔隙内的空气;(3)在上述负压条件下,经高速剪切或快速搅拌,使药物混悬于水相A,再将容器与大气连通,使体系压力恢复常压,得混悬液B。本发明解决了药物、稳定剂在分散过程中易起沫的问题;所得的药物混悬液可通过高压均质、研磨、微射流等破碎方式对其进行纳米化,且在纳米化的过程中,混悬液性状稳定,无起沫的现象。提高了药物纳米混悬的制备效率和产率;且方法简单,易于实现,耗能少,可应用于工业化生产。
Description
技术领域
本发明涉及一种以药物、稳定剂为原料制备药物纳米混悬液的前处理方法,以便于制备纳米混悬液,属于药物制剂领域。
背景技术
纳米混悬液是以表面活性剂或(和)高分子聚合物为稳定剂,将药物颗粒分散在水中,通过自组装技术或者破碎技术制备的一种亚微胶体分散系。与其他的纳米制剂相比,纳米混悬制剂不需要任何载体材料,仅需要少量稳定剂即可实现大量药物纳米化,具有载药量高、粒径小、比表面积大、对生物膜粘附性强、不易被清除、能够提高难溶性药物的生物利用度等优势。
纳米混悬液常用的制备方法有多种,其中,以将药物颗粒由大到小的破碎技术(如研磨、高压均质、微射流等)最为常用。在破碎前,一般先将药物、稳定剂分散/溶解于水相,即对药物和稳定剂进行前处理。然而,分散过程中强烈的搅拌、剪切作用会使一些药物、稳定剂产生大量的泡沫,且泡沫会在破碎过程(研磨、高压均质、微射流等)中增多,进而阻碍破碎过程的进行,例如:在高压均质过程中,泡沫会吸附大量药物,阻碍其进入高压均质机进行破碎;在介质研磨过程中,漂浮的泡沫使药物与研磨珠碰撞的概率降低,且泡沫中的空气也会减弱药物与药物间、药物与研磨介质间的碰撞作用;在微射流过程中,泡沫会减弱两束高压液体束间的撞击力。综上,前处理过程产生的泡沫会阻碍破碎过程的进行、降低药物纳米混悬液的产率,因此,有必要采用一定的策略改善药物和稳定剂的前处理过程,减少甚至避免泡沫的出现,以便于破碎过程顺利进行。
发明内容
针对分散过程中的搅拌、剪切作用会使一些药物、稳定剂产生大量泡沫,进而阻碍破碎过程进行的实际问题,本发明提供了一种制备纳米混悬液的前处理方法,解决了药物、稳定剂在分散过程中易起沫的问题,大大提高了药物纳米混悬液的制备效率和产率。
本发明是通过如下技术方案实现的:
将药物加入到含有稳定剂的水相中,密闭容器,负压下经剪切或搅拌,使药物混悬于水相,再将容器与大气连通,得到药物混悬液。
药物混悬液可进一步运用高压均质、微射流、研磨等方式进行纳米化破碎。
具体操作步骤如下:
(1)制备含有0.01~30%(w/v)稳定剂的水相A,超声脱气;
(2)将0.01~300%(w/v)药物加入到水相A所在容器中,将容器密闭,并降低容器内压力以除去药物颗粒间、孔隙内的空气;
(3)在上述负压条件下,经高速剪切或快速搅拌,将药物混悬于水相A,再将容器与大气连通,使体系压力恢复正常,得混悬液B。
上述的稳定剂选自阿拉伯胶、黄原胶、透明质酸钠、海藻酸钠、卡波姆、聚乙烯醇、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、吐温类表面活性剂、司盘类表面活性剂、苄泽类表面活性剂、卖泽类表面活性剂、泊洛沙姆类表面活性剂、聚氧乙烯型非离子表面活性剂、聚乙二醇类表面活性剂、脱氧胆酸钠、十二烷基硫酸钠、卡波普中的一种或多种。
作为优选,本发明的稳定剂选自阿拉伯胶、黄原胶、透明质酸钠、海藻酸钠、卡波姆、聚乙烯醇、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮中的一种或几种。
稳定剂的用量为水体积的0.01~30%(w/v),作为优选,当稳定剂的用量为水体积的0.01~3%(w/v)时,不仅解决了纳米混悬在制备过程中易起沫的问题,同时具有较好的制备效率和产率。
上述的药物为难溶性药物,包括二氢吡啶类钙通道阻滞剂、紫杉烷类抗癌药物、喜树碱类抗癌药、帕利哌酮棕榈酸酯、伊曲康唑、他克莫司、布洛芬、阿奇霉素、非诺贝特、兰索拉唑、氯雷他定、格列美脲、格列本脲、西罗莫司、阿瑞匹坦、醋酸甲地孕酮、替尼泊苷、依托泊苷、地塞米松、螺内酯、双氯芬酸、甲硝唑、克霉唑、奥硝唑、两性霉素B等。
药物的质量为水体积的0.01~300%(w/v),优选为4~15%(w/v)。
上述降低容器内压力后,容器内的绝对压力为1~101.325Kpa。
上述步骤所得的药物混悬液可运用高压均质、微射流、研磨等方式进行纳米化破碎,所得的药物纳米混悬液平均粒径范围为100~1000nm,且在破碎过程中,药物混悬液性状稳定,无起沫的现象,纳米混悬液的制备效率和产率明显提高。与常规技术相比,本发明具有以下优势:
(1)本发明的分散药物的方法,在分散药物时,分别运用超声、抽负压的方式除去水以及药物中所含有的空气,解决了药物、稳定剂在分散过程中易起沫的问题。有效避免了药物、稳定剂在分散、破碎过程中起沫的现象,并大大提高了药物纳米混悬液的制备效率和产率。
(2)本发明分散药物的方法简单,易于实现,且对于仪器要求较低,仪器的磨损少,耗能少,可应用于工业化生产。
附图说明
图1为本发明前处理操作流程示意图
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将发明限制在所述的实施例范围之中。
实施例1:一种紫杉醇纳米混悬液的制备
首先,制备含有0.01%(w/v)的HPMCE5、0.1%(w/v)的SDS的水相,超声除去水相中空气,将7%(w/v)的紫杉醇加入到上述水相所在容器中,密闭容器,降低容器内压力至5Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,将混悬液转移至球磨罐中,运用球磨机对其进行研磨,得到紫杉醇纳米混悬液,测得平均粒径为864.3nm。
实施例2:一种格列本脲纳米混悬液的制备
首先,制备含有0.5%(w/v)的PVPK30的水相,超声除去水相中空气,将6%(w/v)的格列本脲加入到上述水相所在容器中,密闭容器,降低容器内压力至10Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,将混悬液加入到高压均质机中进行纳米化,得到格列本脲纳米混悬液,测得其平均粒径为334.6nm。
实施例3:一种尼索地平纳米混悬液的制备
首先,制备含有0.1%(w/v)的HPMCE50、0.3%(w/v)的Tween20的水相,超声除去水相中空气,将5%(w/v)的尼索地平加入到上述水相所在容器中,密闭容器,降低容器内压力至3Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,将混悬液加入到高压均质机中进行纳米化,得到尼索地平纳米混悬液,测得其平均粒径为624.6nm。
实施例4:一种阿奇霉素纳米混悬液的制备
首先,制备含有0.5%(w/v)的HPC、0.3%(w/v)的脱氧胆酸钠的水相,超声除去水相中空气,将15%(w/v)的阿奇霉素加入到上述水相所在容器中,密闭容器,降低容器内压力至20Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,将混悬液加入到高压均质机中进行纳米化,得到阿奇霉素纳米混悬液,测得其平均粒径为651.6nm。
实施例5:一种两性霉素B纳米混悬液的制备
首先,制备含有2%(w/v)的EC的水相,超声除去水相中空气,将6%(w/v)的两性霉素B加入到上述水相所在容器中,密闭容器,降低容器内压力至50Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,将混悬液转移至球磨罐中,运用球磨机对其进行研磨,得到两性霉素B纳米混悬液,测得其平均粒径为437.6nm。
实施例6:一种非诺贝特纳米混悬液的制备
首先,制备含有0.5%(w/v)的HPMCE5、0.1%(w/v)的F68的水相,超声除去水相中空气,将6%(w/v)的非诺贝特加入到上述水相所在容器中,密闭容器,降低容器内压力至15Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于上述水相,之后,将容器与大气连通,待其恢复常压后,将混悬液转移至球磨罐中,运用球磨机对其进行研磨,得到非诺贝特纳米混悬液,测得其平均粒径为515.3nm。
实施例7:一种氯雷他定纳米混悬液的制备
首先,制备含有1.0%(w/v)的阿拉伯胶、0.5%(w/v)的HPC的水相,超声除去水相中空气,将7.5%(w/v)的氯雷他定加入到上述水相所在容器中,密闭容器,降低容器内压力至1Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于上述水相,之后,将容器与大气连通,待其恢复常压后,将混悬液转移至球磨罐中,运用球磨机对其进行研磨,得到氯雷他定纳米混悬液,测得其平均粒径为329.3nm。
实施例8:一种螺内酯纳米混悬液的制备
首先,制备含有0.5%(w/v)的PVA、0.1%(w/v)的F127的水相,超声除去水相中空气,将6.5%(w/v)的螺内酯加入到上述水相所在容器中,密闭容器,降低容器内压力至80Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,运用微射流技术对药物进行纳米化,得到螺内酯纳米混悬液,测得其平均粒径为831.5nm。
实施例9:一种尼莫地平纳米混悬液的制备
首先,制备含有0.5%(w/v)的HPMC的水相,超声除去水相中空气,将7%(w/v)的尼莫地平加入到上述水相所在容器中,密闭容器,降低容器内压力至5Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,运用微射流技术对药物进行纳米化,得到尼莫地平纳米混悬液,测得其平均粒径为431.5nm。
实施例10:一种兰索拉唑纳米混悬液的制备
首先,制备含有3%(w/v)的PVPK30的水相,超声除去水相中空气,将15%(w/v)的兰索拉唑加入到上述水相所在容器中,密闭容器,降低容器内压力至30Kpa以除去药物颗粒间、孔隙内的空气,开启搅拌使药物混悬于水相,之后,将容器与大气连通,待其恢复常压后,运用微射流技术对药物进行纳米化去,得到兰索拉唑纳米混悬液,测得其平均粒径为524.5nm。
Claims (9)
1.一种制备纳米混悬液的前处理方法,其特征在于:将药物加入到含有稳定剂的水相中,密闭容器,负压下剪切或搅拌后,将药物混悬于水相,再将容器与大气连通,得到药物混悬液。
2.如权利要求1所述的制备纳米混悬液的前处理方法,其特征在于:所得药物混悬液可进一步运用高压均质、微射流、研磨方式进行纳米化破碎。
3.如权利要求1或2所述的制备纳米混悬液的前处理方法,其特征在于步骤如下:
(1)制备含有稳定剂的水相A,超声脱气;
(2)将药物加入到水相A所在容器中,将容器密闭,并降低容器内压力以除去药物颗粒间、孔隙内的空气;
(3)在上述负压条件下,经高速剪切或快速搅拌,将药物混悬于水相A,再将容器与大气连通,使体系压力恢复正常,得混悬液B。
4.根据权利要求1-3任何一项所述的纳米混悬液的前处理方法,其特征在于:所述的稳定剂质量为水体积的0.01~30%(w/v),优选为0.01~3%(w/v)。
5.根据权利要求1-4任何一项所述的纳米混悬液的前处理方法,其特征在于,所述稳定剂选自阿拉伯胶、黄原胶、透明质酸钠、海藻酸钠、卡波姆、聚乙烯醇、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、吐温类表面活性剂、司盘类表面活性剂、苄泽类表面活性剂、卖泽类表面活性剂、泊洛沙姆类表面活性剂、聚氧乙烯型非离子表面活性剂、聚乙二醇类表面活性剂、脱氧胆酸钠、十二烷基硫酸钠、卡波普中的一种或多种;
作为优选,稳定剂选自阿拉伯胶、黄原胶、透明质酸钠、海藻酸钠、卡波姆、聚乙烯醇、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮中的一种或几种。
6.根据权利要求1-5任何一项所述的纳米混悬液的前处理方法,其特征在于,所述的药物为难溶性药物,包括二氢吡啶类钙通道阻滞剂、紫杉烷类抗癌药物、喜树碱类抗癌药、帕利哌酮棕榈酸酯、伊曲康唑、他克莫司、布洛芬、阿奇霉素、非诺贝特、兰索拉唑、氯雷他定、格列美脲、格列本脲、西罗莫司、阿瑞匹坦、醋酸甲地孕酮、替尼泊苷、依托泊苷、地塞米松、螺内酯、双氯芬酸、甲硝唑、克霉唑、奥硝唑、两性霉素B。
7.根据权利要求6所述的纳米混悬液的前处理方法,其特征在于,所述药物的质量为水体积的0.01~300%(w/v),优选为:4~15%(w/v)。
8.根据权利要求1-3任何一项所述的纳米混悬液的前处理方法,其特征在于,降低容器内压力后,容器内的绝对压力为1~101.325Kpa。
9.根据权利要求1-8任何一项所述的纳米混悬液的前处理方法,其特征在于,制备的纳米混悬液的粒径范围为100~1000nm。
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