CN116172954A - 帕博西尼纳米混悬剂与帕博西尼纳米冻干粉及制备方法 - Google Patents
帕博西尼纳米混悬剂与帕博西尼纳米冻干粉及制备方法 Download PDFInfo
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Abstract
本发明公开了一种帕博西尼纳米混悬剂与帕博西尼纳米冻干粉及制备方法,包括帕博西尼、稳定剂、柠檬酸和碳酸氢钠,其中稳定剂为卵磷脂和SDS的组合,帕博西尼:卵磷脂:SDS的质量比为1:1~5:1~5,帕博西尼:柠檬酸:碳酸氢钠的摩尔比为1:1~4:1~4。本发明采用上述方法,制备帕博西尼纳米混悬剂,增加帕博西尼的溶出度;同时制备帕博西尼纳米混悬剂的冻干粉,进一步增加混悬剂的物理稳定性,解决了帕博西尼生物利用度低的问题。
Description
技术领域
本发明涉及医药技术领域,特别是涉及帕博西尼纳米混悬剂与帕博西尼纳米冻干粉及制备方法。
背景技术
纳米混悬剂(nanosuspensions)是难溶性药物纳米颗粒的亚微细粒胶态分散体,以表面活性剂为稳定剂,通过均质,湿磨等方法制备。将难溶性药物制成纳米混悬剂可以提高溶解度,提高药物的溶出度,进而提高药物的生物利用度。但由于纳米晶体在溶液中具有热力学特性和相对于体积状态的能量不利性,其稳定性仅能保持几天甚至几个小时,不利于储存,为了保持药物纳米结晶的稳定性,通常将纳米混悬剂转化成固体形式。
帕博西尼(Palbociclib)是由美国辉瑞研发的一种抗肿瘤药物,又称帕布昔利布。帕博西尼是全球首个细胞周期素依赖性激酶(CDK4/6)的抑制药物,通过抑制细胞DNA的合成,可用于治疗转移性乳腺癌。临床试验研究发现,该药没有传统化疗的副作用,肠道反应轻微,目前帕博西尼作为一线疗法用于先前未接受过系统治疗的雌激素受体阳性(ER+)、HER2阴性晚期乳腺癌绝经后女性。
帕博西尼在水溶液中的溶解度呈现明显的pH依赖性,帕博西尼易溶于pH低于4.0的介质中,当pH值高于pH4.0时,帕博西尼溶解度显著降低。人体消化道pH在由胃内到肠道的阶段逐渐升高,导致药物服用后在胃内溶解,胃排空后进入肠道内,因肠道环境pH较高,溶解的药物产生沉淀析出,故而降低了其生物利用度。为解决上述问题,本发明利用纳米混悬剂技术结合冷冻干燥固化纳米混悬液,制备纳米冻干粉。
发明内容
本发明的目的是提供帕博西尼纳米混悬剂与帕博西尼纳米冻干粉及制备方法,制备帕博西尼纳米混悬剂,增加帕博西尼的溶出度;同时制备帕博西尼纳米混悬剂的冻干粉,进一步增加混悬剂的物理稳定性,解决了帕博西尼生物利用度低的问题。
为实现上述目的,本发明提供了一种帕博西尼纳米混悬剂,其特征在于:包括帕博西尼、稳定剂、柠檬酸和碳酸氢钠,其中稳定剂为卵磷脂和SDS的组合,帕博西尼:卵磷脂:SDS的质量比为1:1~5:1~5,帕博西尼:柠檬酸:碳酸氢钠的摩尔比为1:1~4:1~4。
优选的,帕博西尼:卵磷脂:SDS的质量比为1:1~3:1~3。
更优选的,帕博西尼:卵磷脂:SDS的质量比为1:3:3。
优选的,帕博西尼:柠檬酸:碳酸氢钠的摩尔比为1:1~2:1~4。
更优选的,帕博西尼:柠檬酸:碳酸氢钠的摩尔比为1:2:2.4。
优选的,纳米混悬剂中帕博西尼纳米粒平均粒径为100~500nm。
帕博西尼纳米混悬剂的制备方法,包括以下步骤:
(1)将柠檬酸溶于四氢呋喃中,然后再加入帕博西尼原料药得到有机相;
(2)将稳定剂和碳酸氢钠溶于蒸馏水中,得水相;
(3)将有机相在水浴和搅拌的条件下缓慢滴入水相中,使帕博西尼均匀分散在水溶液中,旋转蒸发除去四氢呋喃,得到粗混悬液;
(4)将粗混悬液进行高压均质处理,得帕博西尼纳米混悬液。
优选的,步骤(1)中,每10mg帕博西尼四氢呋喃用量为1~5mL。
更优选的,步骤(1)中,每10mg帕博西尼四氢呋喃用量为5mL。
优选的,步骤(3)中,水浴的温度范围为0~50℃。
更优选的,步骤(3)中,水浴的温度范围为0℃。
优选的,步骤(4)中,高压均质处理的均质压力为800~1800bar,均质次数为3~20次。
更优选的,高压均质处理的均质压力为1600bar,均质次数为10次。
一种帕博西尼纳米冻干粉,其原料包括权利要求1~4任一项所述的帕博西尼纳米混悬剂和冻干保护剂,其中每1mL帕博西尼纳米混悬液中冻干保护剂的加入质量为5~10%(W/V)。
优选的,冻干保护剂选自甘露醇、乳糖、海藻糖中的一种。
更优选的,冻干保护剂为海藻糖,冻干保护剂的用量为10%(W/V)。
帕博西尼纳米冻干粉的制备方法,包括如下步骤:将帕博西尼纳米混悬剂分散均匀后加入冻干保护剂,摇匀后于冰箱中冷冻,冷冻后转移至冷冻干燥机中冷冻干燥,即得帕博西尼纳米冻干粉。
优选的,其特征在于,冷冻干燥的条件为:冰箱冷冻的时间为10h,冷冻干燥机的温度为-80℃,冷冻干燥的时间为24h。
本发明的有益效果:
1、本发明提供的帕博西尼纳米混悬剂,以纳米颗粒的形式进行储存并作为配料应用,帕博西尼纳米混悬剂的平均粒径在500nm以下,药物粒径大小降低到纳米级别,增大药物粒子的表面积,显著提升了作为水不溶性物质帕博西尼的溶出度,进而提高药物在体内的生物利用度。
2、本发明提供的帕博西尼纳米混悬剂,利用酸碱中和沉淀法-高压均质法制得,利用柠檬酸增加了帕博西尼在溶剂中的溶解性,同时利用柠檬酸与碳酸氢钠反应生成大量二氧化碳气泡,提高物理分散性,控制粒径范围,且反应生成的柠檬酸钠无毒无害。
3、本发明提供的帕博西尼纳米混悬剂的制备方法,原料天然,制备条件温和,制备过程绿色环保、无毒、无有害物质释放。
4、本发明制备的帕博西尼纳米冻干粉,外观光滑完整,复溶状态好,粒径增长较小,并且提高了药物的物理稳定性,方便运输和储存。
下面通过附图和实施例,对本发明的技术方案做进一步的详细描述。
附图说明
图1是本发明实施例15的帕博西尼纳米冻干粉复溶的透射电镜图;
图2是本发明实施例15的帕博西尼液相色谱图;
图3是本发明实施例15的帕博西尼原料药与帕博西尼纳米冻干粉体外累计释放曲线图。
具体实施方式
为了便于理解本发明,下面将参照实施例对本发明进行更全面的描述。实施例中给出了本发明的较佳实施方式。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施方式。相反地,提供这些实施方式的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施方式的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
实施例1
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂1份,加入蒸馏水,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径764.6±7.8nm(PDI=0.571±0.031),室温放置40min后絮凝。
实施例2
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂1份,SDS 1份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径587±6.8nm(PDI=0.511±0.043),室温放置40min后絮凝。
实施例3
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂2份,SDS 1份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径543±6.3nm(PDI=0.456±0.031),室温放置40min后絮凝。
实施例4
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂2份,SDS 2份,加入蒸馏水中溶解,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径466±5.5nm(PDI=0.387±0.029),室温放置3小时后絮凝。
实施例5
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂3份,SDS 1份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径456±5.9nm(PDI=0.376±0.026),室温放置3小时后絮凝。
实施例6
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂3份,SDS 3份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径411±4.9nm(PDI=0.345±0.028),室温放置5小时后絮凝。
实施例7
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂3份,SDS 6份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径403±4.6nm(PDI=0.315±0.024),室温放置5小时后絮凝。
实施例8
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸氢钠加入蒸馏水中,再称取卵磷脂5份,SDS 5份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径409±5.2nm(PDI=0.343±0.031),室温放置5小时后絮凝。
实施例9
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取1份碳酸氢钠加入蒸馏水中,再称取卵磷脂3份,SDS 3份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径417±4.4nm(PDI=0.332±0.025),室温放置5小时后絮凝。
实施例10
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取4份碳酸氢钠加入蒸馏水中,再称取卵磷脂3份,SDS 3份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液,测得平均粒径408±4.5nm(PDI=0.331±0.024),室温放置5小时后絮凝。
将实施例1-10制得的帕博西尼纳米初混悬剂,进行筛选,具体处方筛选条件,见表1。
表1帕博西尼纳米初混悬剂筛选条件
根据以上实施例得到的帕博西尼纳米初混悬剂,从粒径、PDI和稳定性综合考虑,本发明优选处方实施例6,7,8、9、10为优选结果,从实例中也可发现当稳定剂与主药的质量比越大的时候,制得的初纳米混悬剂越稳定,卵磷脂单作为稳定剂效果较差,配合SDS效果较好。当稳定剂与帕博西尼质量比大于6:1时,制得的初混悬剂效果均较好,考虑成本及载药量等问题,辅料用量更小的处方;同时通过实施例也可以发现柠檬酸和碳酸氢钠的用量对帕博西尼初混悬剂的影响并不大,但是通过大量实验也发现柠檬酸量太小,会导致帕博西尼在溶剂中不能完全溶解,柠檬酸和碳酸氢钠用量比过大或者过小,会导致纳米混悬剂的PH过低或过高,因此选择帕博西尼:卵磷脂:SDS质量比=1:3:3,帕博西尼:柠檬酸:碳酸氢钠的摩尔比=1:2:2.4,即实施例6为最佳处方。
实施例11
考察均质压力对纳米混悬剂的影响。
将实施例6制备的初纳米混悬剂分别于800bar、1000bar、1200bar、1400bar、1600bar、1800bar压力下均质10次,测得不同压力下纳米混悬剂的粒径,结果见表2。
表2高压均质压力对纳米混悬剂粒径的影响
均值压力(bar) | 粒径 | PDI |
800 | 374±4.1nm | 0.297±0.031 |
1000 | 344±4.0nm | 0.265±0.024 |
1200 | 316±3.8nm | 0.244±0.021 |
1400 | 277±3.5nm | 0.235±0.020 |
1600 | 228±3.0nm | 0.218±0.018 |
1800 | 221±3.2nm | 0.211±0.016 |
由表2,当均质压力大于1400bar时,粒径均较小,符合粒径相对均一的要求,考虑到仪器损耗,最终选择均质压力为1600bar。
实施例12
考察均质次数对纳米混悬剂的影响。
将实施例6制备的初纳米混悬剂分别于1600bar压力下均质3、10、15、20次,测得不同均质次数下纳米混悬剂的粒径,结果见表3。
表3高压均质次数对纳米混悬剂粒径的影响
均值次数 | 粒径 | PDI |
3 | 313±3.2nm | 0.257±0.024 |
10 | 228±3.0nm | 0.218±0.018 |
15 | 221±2.9nm | 0.216±0.020 |
20 | 218±3.1nm | 0.219±0.019 |
由表3可见,均质次数为10次时粒径较小,分布较均匀,且随着增加均质次数再增加粒径的程度变化不明显,为节约资源,故理想均质次数为10次。
实施例13
制备帕博西尼纳米混悬剂冻干粉。
选取实施例12均质次数为10次制得的帕博西尼纳米混悬剂,将冻干保护剂加入其中,摇匀后于冰箱冷冻10h,冷冻干燥机-80℃冷冻干燥24h,得到帕博西尼纳米冻干粉。
实施例14
选取实施例12均质次数为10次制得的帕博西尼纳米混悬剂,将不同种类和不同比例的冻干保护剂加入其中,摇匀后于冰箱冷冻10h,冷冻干燥机-80℃冷冻干燥24h,得到不同保护剂配比的帕博西尼纳米冻干粉。具体影响见表4。
表4不同冻干保护剂对帕博西尼纳米冻干粉的影响
如表4所示,通过比较,当添加海藻糖10%冻干后,冻干粉质地疏松、且均一,加入蒸馏水进行复溶,很快就可以分散均匀,测定复溶后粒径变化较小,稳定性也较好,因此选择加入海藻糖10%作为冻干保护剂制备冻干粉。
实施例15
称取柠檬酸2份,用四氢呋喃溶解,再加入帕博西尼1份,得到有机相;称取2.4份碳酸钠加入蒸馏水中,再称取卵磷脂3份,SDS 3份,加入蒸馏水中,溶胀5个小时,得到水相。约0℃水浴中将有机相缓慢滴入水相中,80rpm继续搅拌20秒,旋转蒸发除去四氢呋喃,即得帕博西尼粗混悬液。
将粗混悬液至于高压均质机中1600bar压力下,均质10次,即得帕博西尼纳米混悬剂。将帕博西尼纳米混悬剂,加入海藻糖10%,摇匀后于冰箱冷冻10h,冷冻干燥机-80℃冷冻干燥24h,得到帕博西尼纳米冻干粉。
性能测试
帕博西尼纳米冻干粉稳定性测试。
将实施例15制得的帕博西尼纳米冻干粉分装于1mL西林瓶中,于室温条件放置,分别于第0、2、4、6、8周取样,观察冻干粉的外观,复溶后测定粒径及多分散系数。结果见表5。
表5帕博西尼纳米冻干粉的稳定性
由表5可见,样品常温放置,能在较长时间内保持良好的体系稳定。
帕博西尼纳米混悬剂冻干粉粒径及形态。
将实施例15制得的帕博西尼纳米冻干粉进行扫描电镜观察,取少量样品溶于蒸馏水中,放置于玻璃板上,待自然挥发干燥后,喷金,电子显微镜扫描。如图1所示,制备的帕博西尼纳米粒子略呈球形,大小均一。
帕博西尼纳米冻干粉体外溶出度。
将帕博西尼原料药与实施例15制得的帕博西尼纳米冻干粉进行体外溶出度对比实验,不同时间点,样品经含量检测并计算累计释放百分率。
溶出度实验方法:利用透析袋释放法考察帕博西尼原料药、纳米冻干粉的体外溶出特性。溶出温度为(37±0.5)℃,转速为100r/min。称量适量帕博西尼原料药放入透析袋中,置于质量分数1%十二烷基磺酸钠的缓冲溶液(PH=7.4,20mL)中,另外称取相当于等量原料药的帕博西尼纳米冻干粉放入透析袋中,置于质量分数1%十二烷基磺酸钠的缓冲溶液(PH=7.4,20mL)中。于0、5、10、20、40、60、和90分钟处取样1mL,经0.22um微孔滤膜滤过。取样后立即补充1mL等温新鲜介质。
用高效液相色谱仪于280nm处测定其吸收峰面积;流动相为0.1%甲酸水溶液:乙腈=80:20;色谱柱温度为30℃,进样流速为1mL/min,进样量为5uL;色谱柱为:Supfex JX-C184.6mm×250mm,5um。帕博西尼的液相色谱图见图2。
帕博西尼的标准曲线回归方程为:Y=11.2016X+2.6343(r=0.99997)。帕博西尼在20-300ug/mL范围内具有良好的线性关系。测定样品吸收峰面积,计算药物浓度。将不同时间测得的药物浓度对时间作图。结果如图3所示,本发明制备的帕博西尼纳米冻干粉释放速率明显高于原料药。
综上,本发明利用纳米混悬剂技术结合冷冻干燥固化纳米混悬液,制备纳米冻干粉,将药物粒径大小降低到纳米级别,增大药物粒子的表面积,提高药物的溶出度,进而提高药物在体内的生物利用度。
最后应说明的是:以上实施例仅用以说明本发明的技术方案而非对其进行限制,尽管参照较佳实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对本发明的技术方案进行修改或者等同替换,而这些修改或者等同替换亦不能使修改后的技术方案脱离本发明技术方案的精神和范围。
Claims (10)
1.一种帕博西尼纳米混悬剂,其特征在于:包括帕博西尼、稳定剂、柠檬酸和碳酸氢钠,其中稳定剂为卵磷脂和SDS的混合,帕博西尼:卵磷脂:SDS的质量比为1:1~5:1~5,帕博西尼:柠檬酸:碳酸氢钠的摩尔比为1:1~4:1~4。
2.根据权利要求1所述的帕博西尼纳米混悬剂,其特征在于:纳米混悬剂中帕博西尼纳米粒平均粒径为100~500nm。
3.一种如权利要求1~2任一项所述的帕博西尼纳米混悬剂的制备方法,其特征在于,包括以下步骤:
(1)将柠檬酸溶于四氢呋喃中,然后再加入帕博西尼原料药得到有机相;
(2)将稳定剂和碳酸氢钠溶于蒸馏水中,得水相;
(3)将有机相在水浴和搅拌的条件下缓慢滴入水相中,使帕博西尼均匀分散在水溶液中,旋转蒸发除去四氢呋喃,得到粗混悬液;
(4)将粗混悬液进行高压均质处理,得帕博西尼纳米混悬液。
4.根据权利要求3所述的帕博西尼纳米混悬剂的制备方法,其特征在于:步骤(1)中,每10mg帕博西尼四氢呋喃用量为1~5mL。
5.根据权利要求3所述的帕博西尼纳米混悬剂的制备方法,其特征在于:步骤(3)中,水浴的温度范围为0~50℃。
6.根据权利要求3所述的帕博西尼纳米混悬剂的制备方法,其特征在于:步骤(4)中,高压均质处理的均质压力为800~1800bar,均质次数为3~20次。
7.一种帕博西尼纳米冻干粉,其特征在于:其原料包括权利要求1~4任一项所述的帕博西尼纳米混悬剂和冻干保护剂,其中每1mL帕博西尼纳米混悬液中冻干保护剂的加入质量为5~10%(W/V)。
8.根据权利要求5所述的帕博西尼纳米冻干粉,其特征在于:冻干保护剂选自甘露醇、乳糖、海藻糖中的一种。
9.一种权利要求7~8任一项所述的帕博西尼纳米冻干粉的制备方法,其特征在于,包括如下步骤:将帕博西尼纳米混悬剂分散均匀后加入冻干保护剂,摇匀后于冰箱中冷冻,冷冻后转移至冷冻干燥机中冷冻干燥,即得帕博西尼纳米冻干粉。
10.根据权利要求9所述的帕博西尼纳米冻干粉的制备方法,其特征在于,冷冻干燥的条件为:冰箱冷冻的时间为10h,冷冻干燥机的温度为-80℃,冷冻干燥的时间为24h。
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CN110354075A (zh) * | 2019-04-26 | 2019-10-22 | 沈阳药科大学 | 一种氯雷他定纳米混悬剂及其制备方法 |
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