CN113952300A - 尼群地平自胶束化非晶态固体分散体的制备及效果分析 - Google Patents
尼群地平自胶束化非晶态固体分散体的制备及效果分析 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种抗高血压非晶态药物制剂领域,具体是尼群地平自胶束化非晶态固 体分散体的制备及效果分析。
背景技术
尼群地平黄色结晶性粉末,熔点为157~161℃,无臭,无味,遇光易变质。在丙酮或三氯甲烷中易溶,在甲醇或乙醇中略溶,在水中几乎不溶,为二氢吡啶类钙通道阻滞 剂。抑制血管平滑肌和心肌的跨膜钙离子内流,但以血管作用为主,故其血管选择性较 强。可引起冠状动脉、肾小动脉等全身血管的扩张,产生降压作用。化学名为1,4-二氢- 2,6-二甲基-4-(3-硝基苯)-3,5-吡啶二羧酸乙基甲酯。但其水中低溶解性导致了口服吸收 差,生物利用度低。
聚合物(聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物)为一种两亲 性非离子型共聚物载体材料,有增溶、抑晶、空间稳定、助悬、热敏、成膜等作用,具有双重功能,即通过水中形成胶束可作为固溶体的基质聚合物和活性溶剂, 其亲水性和非离子型溶解度不会随胃肠道pH而改变,以提高难溶性药物的溶解度和生物 利用度。同时,也可作为聚合物胶束释药系统的载体及一种能量屏障剂通过抑制晶体聚 集和生长从而发挥稳定纳米颗粒的作用。弥补了现有一些载体材料的不足,具有很好的 应用前景。
固体分散体(Solid dispersions,SD)指药物尤其是难溶性固体药物以分子、胶态或 无定型状态高度分散在适宜的载体材料中形成的固态分散体系,固体分散体技术是将晶 体药物转为无定型并提高难溶性药物溶出速率的常用方法之一。SD最大的特点为药物高 度分散于载体中,通过增大其溶出表面积来提高难溶性药物的溶出速率。非晶态固体分散体中,药物以非晶态存在于体系中,可以具有更强的改善难溶性药物功效的作用。
发明内容
本发明的目的在于提供尼群平自胶束化非晶态固体分散体的制备方法及效果分析, 以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
尼群地平/固体分散体的制备方法及效果分析,分别采用熔融-淬冷法、共 沉淀法、热熔挤出法制备尼群地平自胶束化非晶态固体分散体,以物理混合物作为对照,并分别测定不同方法得到药物的融合程度、稳定性、体外溶出度、溶解度及抑晶效 果,方法为:
b.共沉淀法制备固体分散体:称取过筛后的尼群地平原料药细粉30mg,辅 料120mg,混匀后置于茄形瓶中,加入适量甲醇溶解至药物完全溶解成澄清溶液;在旋转蒸发仪上蒸去有机溶剂后放入烘箱干燥24h,取出瓶中干燥物,研磨成细粉,过80目 筛,取过筛后细粉于自封袋中,密封避光保存;
c.熔融-淬冷法制备固体分散体:称取过筛后尼群地平细粉30mg,辅料120mg,混匀后至于坩埚中,盖上锅盖,置于微波炉中加热至完全熔融状态,取出迅速液 氮淬冷,冷却后药物成黄色透明固体,取出研磨成细粉,过80目筛,装入自封袋中,密 封避光保存;
d.热融挤出法制备固体分散体:热融仪器参数设定为温度为121℃,并逐渐加温直至药物与辅料混合后成熔融状态,然后设定双螺杆挤出机的挤出温度为121℃,温度升高到达设定值后启动螺杆,螺杆转速为70rpm,将制得的熔融混合物加到挤出机中,经过熔 融挤压,得到以条带状挤出物,条带状挤出物冷却后药物成黄色透明固体,取出研磨成 细粉,过80目筛,装入自封袋中,密封避光保存。
分析评价的方法包括:
e.通过SEM电子扫描显微镜来检测方法a-d得到的药物结构特征;
f.X-射线衍射实验检测方法a-d得到药物的稳定性:将尼群地平原料药,物理混合物,共沉淀固体分散体,微波-淬冷固体分散体,热熔挤出固体分散体,放置在条件为温 度25℃,相对湿度50%下一个月,测定其稳定性;
g.体外溶出和溶解度检测:以PBS(pH4.5)为溶出介质、以PBS(pH6.8)为溶出介质、以PBS(pH7.4)为溶出介质、以0.1mol/L HCl为溶出介质、以纯净水为溶出介质,检测方 法a-d得到药物的溶出度和溶解度;
与现有技术相比,本发明的有益效果是:
1.本发明采用尼群地平作为模型药物,以自胶束化材料(聚乙烯己内酰胺- 聚乙酸乙烯酯-聚乙二醇接枝共聚物)作为载体材料来制备非晶态固体分散体,探讨尼群地 平自胶束化非晶态固体分散体的制备工艺、及其聚合物浓度对超饱和状态下尼群地平的 溶出效果的影响,来对其进行分析评价,最终分析得到采用热融挤出法所制备的尼群地 平自胶束化非晶态固体分散体,能更好的提高尼群地平的溶出及溶解度,并在超饱和实验中显示随聚合物浓度增大而抑制析晶效果越明显。
2.通过本发明的研究发现,热熔挤出法所制备的固体分散体增溶性较好,溶出度好,稳定性更高,相对于其他几种制备工艺,热熔挤出法更适用于投入实际生产过程中 使用,达到更好使用效果,为尼群地平自胶束化非晶态固体分散体生产降低研发成本和 技术保障。
附图说明
图1为通过SEM电子扫描显微镜来观察不同制备方法得到的尼群地平自胶束化非晶态 固体分散体及其对照组的微观状态图;
图2为方法a-d得到的不同药物一个月稳定性X射线衍射图;
图3为方法a-d得到的不同药物在PBS(pH4.5)介质中的溶出曲线、溶出速率图;
图4为方法a-d得到的不同药物在PBS(pH6.8)介质中的溶出曲线、溶出速率图;
图5为方法a-d得到的不同药物在PBS(pH7.4)中的溶出曲线、溶出速率图;
图6为方法a-d得到的不同药物在0.1mol/L HCl中的溶出曲线、溶出速率图;
图7为方法a-d得到的不同药物在纯净水中的溶出曲线、溶出速率图;
图8为方法a-d得到的不同药物在介质PBS(pH4.5)中的24h、48h溶解度图;
图9为方法a-d得到的不同药物在介质PBS(pH6.8)中的24h、48h溶解度图;
图10为方法a-d得到的不同药物在介质PBS(pH7.4)中的24h、48h溶解度图;
图11为方法a-d得到的不同药物在介质0.1mol/L HCl中的24h、48h溶解度图;
图12为方法a-d得到的不同药物在介质纯净水中的24h、48h溶解度图;
图13方法a-d得到的不同药物在介质PBS(pH6.8)中spring and parachute溶出曲线;
图14为超饱和抑晶实验4h结晶速率柱状图;
具体实施方式
以下的实施例便于更好的理解本发明,但并不限定本发明。下述实施例中的实验方 法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均 为自常规生化试剂商店购买得到的。以下实施例中的定量试验,均设置三次重复试验, 结果取平均值。
尼群地平自胶束化非晶态固体分散体的制备及效果分析,分别采用熔融-淬冷法、共 沉淀法、热熔挤出法制备尼群地平自胶束化非晶态固体分散体,以物理混合物作为对照,并分别测定不同方法得到药物的外观形貌、稳定性、体外溶出度、溶解度及抑晶效 果,方法为:
b.共沉淀法制备固体分散体:称取过筛后的尼群地平原料药细粉30mg,辅 料120mg,混匀后置于茄形瓶中,加入适量甲醇溶解至药物完全溶解成澄清溶液;在旋转蒸发仪上蒸去有机溶剂后放入烘箱干燥24h,取出瓶中干燥物,研磨成细粉,过80目 筛,取过筛后细粉于自封袋中,得到共沉淀固体分散体,密封避光保存;
c.微波-淬冷法制备固体分散体:称取过筛后尼群地平细粉30mg,辅料120mg,混匀后至于坩埚中,盖上锅盖,置于微波炉中加热至完全熔融状态,取出迅速液 氮淬冷,冷却后药物成黄色透明固体,取出研磨成细粉,过80目筛,装入自封袋中,得 到微波-淬冷固体分散体,密封避光保存;
d.热融挤出法制备固体分散体:
单个药物无定型的制备(MQ):称取过筛后的尼群地平原料药细粉200mg,置于坩埚中盖上锅盖,在油浴180℃的条件下加热至完全熔融状态,取出迅速加入液氮淬冷。冷却 后的无定型药物为黄色透明固体,将药物取出,研磨成细粉,过80目筛,取过筛后细粉 装于自封袋中,得到单个无定型药物,密封避光保存。
热融挤出的尼群地平自胶束化非晶态固体分散体的制备(MQ-SD):热融仪器参数设 定为温度为121℃,并逐渐加温直至药物与辅料混合后成熔融状态,然后设定双螺杆挤出 机的挤出温度为121℃,温度升到达设定值后启动螺杆,螺杆转速为70rpm,将制得的熔融混合物加到挤出机中,经过熔融挤压,得到以条带状挤出物,条带状挤出物冷却后药 物成黄色透明固体,取出研磨成细粉,过80目筛,得到热融挤出固体分散体,装入自封 袋中,密封避光保存。
分析评价的方法包括:
e.通过SEM电子扫描显微镜来检测方法a-d得到的药物结构特征;X-射线衍射实验检测方法a-d得到药物的稳定性:将尼群地平原料药,物理混合物,共沉淀固体分散体, 微波-淬冷固体分散体,热熔挤出固体分散体,放置在条件为温度25℃,相对湿度50%下 一个月,测定其稳定性;体外溶出和溶解度检测:以PBS(pH4.5)为溶出介质、以PBS (pH6.8)为溶出介质、以PBS(pH7.4)为溶出介质、以0.1mol/L HCl为溶出介质、以纯净水 为溶出介质,检测方法a-d得到药物的溶出度和溶解度;超饱和抑晶实验:设定溶出仪参 数:T=37℃,转速100r/min,t=4h,以预溶有不同量浓度的PBS(pH6.8)为介 质,在紫外测定波长350nm处测定方法a-d得到药物的吸光度。结果如图1-图13所示。
超饱和抑晶实验:设定溶出仪参数:T=37℃,转速100r/min,t=4h,以预溶有不同量 浓度的PBS(pH6.8)为介质,在紫外测定波长350nm处测定方法a-d得到药物的吸光度。结果如图14-15所示。
实施例一
通过SEM电子扫描显微镜来观察权利要求1中S1-S4得到的药物结构特征,观察外观形貌;以尼群地平原料药和为对照组,检测物理混合固体分散体、微波-淬冷 固体分散体、共沉淀固体分散体和热熔挤出固体分散体在微观状态下的显微电镜扫描结 构。结果如图1所示:图(1)为尼群地平原料药在微观状态下的显微电镜扫描图,从图 中可看出其形态分布均匀,有明显片层结构;图(2)为辅料微观形态图,从图 中也可看出其分布均匀,并呈不规则圆球状;图(3)为物理混合物的微观状态图,可见 部分原料药与辅料融合在一起,呈无规则的形态;图(4)为单个无定型有药物的微观状 态图,单个药物通过熔融-淬冷后形态从原料药的片层结构变成了完全无规则状态;图 (5)为微波-淬冷固体分散体的微观状态图,由图看出原料药与辅料混合熔融后二者结合 在一起呈无规则状态分布,说明在熔融过程中二者产生了相互作用;图(6)(7)出现 与原料药相比明显大型片状结构,且分布均匀,说明在制备固体分散体过程中,药物与 辅料高度融合形成薄膜状分布。
实施例二
X-射线衍射实验检测方法a-d得到药物的稳定性:将尼群地平原料药,物理混合物, 共沉淀固体分散体,微波-淬冷固体分散体,热融挤出固体分散体,放置在条件为温度25℃,相对湿度50%下一个月,测定其稳定性;结果如图2所示:在ND结果中,相对 于一个月前,尼群地平出现了在16.8°,20.76°处出现了结晶衍射峰,说明在一个月内 其稳定性出现改变;MQ结果显示单个药物无定型中出现了与一个月前原料药相同的衍射 峰和19.6°处的结晶衍射峰,所以在以无定型晶体状态下长时间保存时稳定性会发生改 变析出结晶;而非洛地平自胶束化非晶态固体分散体如MQ-SD,C-SD,HME-SD的结果 显示,由不同工艺制备的各固体分散体相对于一个月前并无结晶衍射峰的出现,说明以 自胶束化固体分散体方式存在的非晶体状态可明显提高药物的稳定性,并以稳定的形式 存在。
实施例三
体外溶出度检测:
以PBS(pH4.5)为溶出介质:设定溶出仪参数:T=37℃,转速100r/min,t=2h。分别称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定 型药物30mg,及各固体分散体150mg,分别放入装有900ml PBS(pH4.5)溶出杯内,分别 在5min,10min,15min,30min,60min,90min,120min时取样5ml并同时补充相同体 积新鲜介质,并以0.45微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度,相同条 件重复3次,得尼群地平各样品在PBS(pH4.5)介质中的溶出速率,如图3所示:ND溶出 量一直处于最低,PM虽然加入了但通过物理混合的方式依旧没有显著提高原料 药的溶出效果,MQ在溶出0~90min内与物理混合物溶出量相差不大,在120min时达到 最大浓度为1.06mg/ml,高于PM,但从溶出速率来看速率并没明显提高;各固体分散体 在刚开始其溶出量与溶出速率明显提高,120min时各自溶出量与溶出速率明显高于 ND,PM,MQ;在0~15min内三种固体分散体溶出速率与溶出量相差不大,但在60~ 120min热熔挤出固体分散体溶出速率明显增大,高于另外两种固体分散体。
以PBS(pH6.8)为溶出介质:设定溶出仪参数:T=37℃,转速100r/min,t=2h,分别称取尼群地平原料药30mg物理混合物(尼群地平120mg),单个无定型 药物30mg,及各固体分散体150mg,分别放入装有900ml PBS(pH6.8)溶出杯内,分别在 5min,10min,15min,30min,60min,90min,120min时取样5ml并同时补充相同体积 新鲜介质,以0.45微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度,相同条件重 复3次,得尼群地平各样品在PBS(pH6.8)介质中溶出曲线与溶出速率,如图4所示:在 0~30min内ND,PM,MQ溶出量相差不大但明显低于其他三种固体分散体,在30min 时热熔挤出固体分散体的溶出度为0.37mg/ml与共沉淀固体分散体的溶出度0.35mg/ml相 近,而微波-淬冷固体分散体略低为0.22mg/ml,在30~120min内热熔挤出固体分散体溶 出速率最快;由此说明固体分散体可明显提高药物的溶出度,而不同工艺所制备的固体 分散体其溶出效果也有差异,在介质PBS(pH6.8)中热熔挤出法所制备的固体分散体增溶 效果最好。
以PBS(pH7.4)为溶出介质:设定溶出仪参数:T=37℃,转速100r/min,t=2h。分别称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定 型药物30mg,各固体分散体150mg,分别放入装有900ml PBS(pH7.4)溶出杯内,分别在 5min,10min,15min,30min,60min,90min,120min时取样5ml并同时补充相同体积 新鲜介质,以0.45微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度,相同条件重 复3次,得尼群地平各样品在PBS(pH7.4)介质中溶出曲线与溶出速率,如图5所示:原 料药ND一直处于最低溶出量,60~120min内MQ溶出速率逐渐提高,PM也有所提 高,热熔挤出固体分散体的溶出速率最高,所以在此介质中由不同工艺所制备的固体分 散体增溶效果更好,其中热熔挤出工艺最佳。
以0.1mol/L HCl为溶出介质:设定溶出仪参数:T=37℃,转速100r/min,t=2h。分别称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无 定型药物30mg,及各固体分散体150mg,分别放入装有900ml 0.1mol/L溶出杯内,分别 在5min,10min,15min,30min,60min,90min,120min时取样5ml并同时补充相同体 积新鲜介质,以0.45微米微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度,相同 条件重复3次,得尼群地平各样品在0.1mol/LHCl介质中溶出速率,如图6所示:原料药 ND溶出量最低,由不同工艺所制备的固体分散体溶出量高,在整个溶出过程中溶出速率 很快,以热熔挤出固体分散体效果最好,此结果可看出在pH值较小的酸性介质中,可提 高各样品溶出度,甚至对于原料药也有显著影响。
以纯净水为溶出介质:设定溶出仪参数:T=37℃,转速100r/min,t=2h,分别称取尼 群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,分别放入装有900ml纯净水溶出杯内,分别在5min, 10min,15min,30min,60min,90min,120min时取样5ml并同时补充相同体积新鲜介 质,以0.45微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度,相同条件重复3 次,结果如图7所示:在0~120min内原料药ND与PM溶出量相差不大,而MQ溶出 量均高于二者,在三个固体分散体中以共沉淀固体分散体(C-SD)的溶出量最低,以热 融挤出固体分散体的溶出量最高,溶出速率最快,其最大浓度为8.58mg/ml。由此推断, 在此介质纯净水中,其辅料对其原料药通过物理混合的方法无增溶效果,而单 个药物无定型及不同共艺所制备的固体分散体有明显增溶效果,其中以热融挤出工艺最 佳。
实施例四
体外溶解度检测
以PBS(pH4.5)为溶出介质:称取尼群地平原料药30mg,物理混合物(尼群地平30mg+Soluplus120mg),单个无定型药物30mg,及各固体分散体150mg,置与50ml比 色管中,以介质PBS(pH4.5)定容至刻度线,放入恒温摇床内设定参数:温度37℃,转速 100r/min,分别于24h,48h是吸取5ml并同时补充新鲜介质,通过0.45微米微孔滤膜过 滤,在紫外测定波长350nm处测定其吸光度,相同条件下重复三次,结果如图8所示: 在24h时原料药ND浓度为0.47mg/ml,PM 1.29mg/ml,MQ 10.04mg/ml,微波-淬冷SD 30.38mg/ml,共沉淀SD 23.21mg/ml,HME-SD 64.92mg/ml,由此看出固体分散体的增溶 效果更为明显,在不同工艺所制备的固体分散体中,以热融挤出工艺增溶效果最好;48h 后热熔挤出最大浓度为92.19mg/ml。
以PBS(pH6.8)为溶出介质:称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,置与50ml比 色管中,以介质PBS(pH6.8)定容至刻度线,放入恒温摇床内设定参数:温度37℃,转速 100r/min,分别与24h,48h吸取5ml并同时补充新鲜介质,通过0.45微米微孔滤膜过滤, 在紫外测定波长350nm处测定其吸光度,相同条件下重复三次,结果如图9所示:24h 内和48h的检测显示各样品溶解量均增大,但整体以HME-SD最好,浓度为 40.90mg/ml。所以在此介质中固体分散体对与尼群地平有显著增溶效果,以热融挤出所制 备的固体分散体效果最好。
以PBS(pH7.4)为溶出介质:称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,置与50ml比 色管中,以介质PBS(pH7.4)定容至刻度线,放入恒温摇床内设定参数:温度37℃,转速 100r/min,分别与24h,48h吸取5ml并同时补充新鲜介质,通过0.45微米微孔滤膜过滤, 在紫外测定波长350nm处测定其吸光度,相同条件下重复三次,结果如图10所示:各固 体分散体溶解度增大,其中HME-SD效果最好,说明固体分散体有明显增溶效果。
以0.1mol/L HCl为溶出介质:称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,置与50ml比 色管中,以介质0.1mol/L HCl定容至刻度线,放入恒温摇床内设定参数:温度37℃,转 速100r/min,分别与24h,48h吸取5ml并同时补充新鲜介质,通过0.45微孔滤膜过滤,在 紫外测定波长350nm处测定其吸光度,相同条件下重复三次,结果如图11所示:24h 内ND溶出浓度为0.55mg/ml,PM为1.16mg/ml,MQ为3.91mg/ml,MQ-SD为 11.20mg/ml,C-SD为7.11mg/ml,HME-SD为28.7mg/ml,可看出固体分散体增溶效果明 显;48h时,HME-SD效果最佳达到最大浓度为43.99mg/ml,而微波-淬冷固体分散体在 酸性介质中增溶效果受到影响。
以纯净水为溶出介质:称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,置与50ml比 色管中,以介质纯净水定容至刻度线,放入恒温摇床内设定参数:温度37℃,转速 100r/min,分别与24h,48h吸取5ml并同时补充新鲜介质,通过0.45微米微孔滤膜过滤, 在紫外测定波长350nm处测定其吸光度,相同条件下重复三次,结果如图12所示:在 24h时溶解度最低为尼群地平原料药浓度为0.52mg/ml,热融挤出SD为溶解度最大浓度 为61.81mg/ml,对于MQ,C-SD,MQ-SD其溶解度都大于ND与PM,说明在纯净水中 通过物理混合,制备单个药物无定型,固体分散体依旧可以对原料药产生增溶效果,其 中在48h时各样品溶解度依旧增大,说明在长时间溶出阶段其溶出及溶解度依旧可以保 持良好增溶效果。
实施例五
Spring and Parachute实验:设定溶出仪参数:T=37℃,转速100r/min,t=36h,分别 称取尼群地平原料药30mg,物理混合物(尼群地平120mg),单个无定型药物30mg,及各固体分散体150mg,分别放入装有900ml PBS(pH6.8)溶出杯内,每隔30min取样5ml并同时补充相同体积新鲜介质,以0.45微米微孔滤膜过滤,在紫外测定 波长350nm处测定其吸光度,在PBS(pH6.8)介质中36h溶出曲线,结果如图13所示: 在整体溶出阶段热熔挤出固体分散体增溶效果最好,说明利用热熔挤出这种工艺所制备 的固体分散体可更好提高辅料与原料药的相互作用,从而达到最好的增溶效果。
实施例六
超饱和抑晶实验:设定溶出仪参数:T=37℃,转速100r/min,t=4h。称取尼群地平原 料药30mg,以最少量甲醇使其溶解达到超饱和状态,放入装有900ml以PBS(pH6.8) (预溶有不同量的使其浓度为0mg/ml,0.05mg/ml,0.1mg/ml,0.15mg/ml, 0.35mg/ml)为介质的溶出杯内,分别在15min,30min,60min,90min,120min, 150min,180min,210min,240min时取样5ml并同时补充相同体积新鲜介质,以0.45微 米微孔滤膜过滤,在紫外测定波长350nm处测定其吸光度。相同条件重复3次,结果如 图14、图15所示:0~15min内各组浓度迅速下降,而空白组未放入辅料为浓 度下降最多,在15min时浓度为19.13mg/ml,在之后处于一直下降趋势,在4h后仅为最 低浓度为4.25mg/ml,说明在4h内药物产生结晶,从而在介质PBS(pH6.8)中药物浓度下 降,而其它各组,随着聚合物浓度的增大其浓度下降越少,在4h后0.35mg/ml组为 11.8mg/ml,0.15mg/ml组为10.04mg/ml,0.1mg/ml组为8.69mg/ml,0.05mg/mll组为 6.47mg/ml,说明在尼群地平超饱和溶液中其聚合物浓度大小可对药物溶出产生 影响,其随聚合物浓度增大抑制析晶效果越明显,从而达到增溶效果。
Claims (2)
1.尼群地平自胶束化非晶态固体分散体的制备及效果分析,其特征在于,分别采用熔融-淬冷法、共沉淀法、热熔挤出法制备尼群地平自胶束化非晶态固体分散体,并分别测定不同方法得到药物的融合程度、稳定性、体外溶出度、溶解度及抑晶效果,方法为:
b.共沉淀法制备固体分散体:称取过筛后的尼群地平原料药细粉30mg,自胶束化聚合物辅料120mg,混匀后置于茄形瓶中,加入适量甲醇溶解至药物完全溶解成澄清溶液;在旋转蒸发仪上蒸去有机溶剂后放入烘箱干燥24h,取出瓶中干燥物,研磨成细粉,过80目筛,取过筛后细粉于自封袋中,密封避光保存;
c.熔融-淬冷法制备固体分散体:称取过筛后尼群地平细粉30mg,自胶束化聚合物辅料120mg,混匀后至于坩埚中,盖上锅盖,置于微波炉中加热至完全熔融状态,取出迅速液氮淬冷,冷却后药物成黄色透明固体,取出研磨成细粉,过80目筛,装入自封袋中,密封避光保存;
d.热熔挤出法制备固体分散体:热融仪器参数设定为温度为121℃,并逐渐加温直至药物与辅料混合后成熔融状态,然后设定双螺杆挤出机的挤出温度为121℃,温度升高到达设定值后启动螺杆,螺杆转速为70rpm,将制得的熔融混合物加到挤出机中,经过熔融挤压,得到以条带状挤出物,条带状挤出物冷却后药物成黄色透明固体,取出研磨成细粉,过80目筛,装入自封袋中,密封避光保存;
2.根据权利要求1所述的尼群地平自胶束化非晶态固体分散体的制备及效果分析,其特征在于,分析评价的方法包括:
e.通过SEM电子扫描显微镜来观察权利要求1中方法a-d得到的药物结构特征;
f.X-射线衍射实验检测权利要求1中方法a-d得到药物的稳定性:将尼群地平原料药,物理混合物,共沉淀固体分散体,微波-淬冷固体分散体,热熔挤出固体分散体,放置在条件为温度25℃,相对湿度50%下一个月,测定其稳定性;
g.体外溶出和溶解度检测:以PBS(pH4.5)为溶出介质、以PBS(pH6.8)为溶出介质、以PBS(pH7.4)为溶出介质、以0.1mol/L HCl为溶出介质、以纯净水为溶出介质,检测权利要求1中方法a-d得到药物的溶出度和溶解度;
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