CN101129338A - 超临界流体新技术微细化抗癌药物紫杉醇 - Google Patents
超临界流体新技术微细化抗癌药物紫杉醇 Download PDFInfo
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Abstract
紫杉醇具有广谱抗肿瘤活性，可用于治疗卵巢癌、乳腺癌，疗效显著，被公认为非常有发展前途的抗癌新药。但由于紫杉醇药物粉末粒径较大，口服几乎不吸收，生物利用度低，极大地限制了紫杉醇的临床应用。本发明采用超临界流体新技术微细化紫杉醇。实验中采用超临界CO2为抗溶剂，以超临界流体强制分散溶液技术方法微细化紫杉醇，考察了压力、温度、溶液浓度、溶液流速等参数对微细化紫杉醇的形态、粒径及其分布的影响。结果表明，改变工艺参数，可在一定范围内调控紫杉醇纳米粒粒径，所制纳米粒表面光滑，球形度好，平均粒径为670nm－940nm。溶液浓度及其流速是主要影响因素。
Description
技术领域
本发明属于药物物理特征及药物剂型改变的制备新方法和应用技术领域，特别是涉及采用新方法新技术微细化药物。
背景技术
紫杉醇具有广谱抗肿瘤活性，可用于治疗卵巢癌、乳腺癌、非小细胞肺癌、恶性黑色实体瘤及其它一些实体瘤，特别对治疗转移性卵巢癌、乳腺癌疗效显著，被公认为非常有发展前途的抗癌新药。目前已有50多个国家已批准销售合成紫杉醇。据美国国家癌症研究所(NCI)预测，在今后10-15年内紫杉醇将成为抗癌首选药物之一。
由于紫杉醇药物粉末粒径较大，口服几乎不吸收，生物利用度低，极大地限制了紫杉醇的临床应用。药物超细化后可以大大加快被吸收的速率，提高疗效，减少剂量。通过控制药物微粒的粒径和粒径分布，可以控制药物释放速率，从而控制药物在体内的浓度。常被用作微细化药物的方法有喷雾干燥法、乳化挥发法、研磨等。然而这些方法不是温度过高，就是存在大量有机溶剂残留，而且很难控制药物粒径大小和小的粒径分布。近年来，超临界流体抗溶剂技术已成功应用于制备聚合物颗粒，该技术在聚合物载体领域中的应用受到研究者普遍关注，其基本原理是利用超临界流体作为抗溶剂，吸收溶液中的有机溶剂，降低有机溶剂对溶质的溶解能力，使溶质过饱和而沉积析出形成颗粒。在SAS基础上发展起来的超临界流体强制分散溶液技术(Solution-enhanced dispersion by supercritical fluids，SEDS)，将同轴二流式喷嘴应用于SAS过程以使溶液充分雾化，增加传质效果，从而获得更高的溶液过饱和速率与结晶沉淀速率以制备更为细小的颗粒。
本实验在自行设计的超临界CO2制粒装置上，采用超临界CO2抗溶剂法首次微细化抗癌药物紫杉醇，并在前期研究基础之上考察了有重要影响的工艺参数对微球形貌、尺寸及其分布的影响。
发明内容
本发明的目的在于提供一种新的微细化药物的方法，解决传统方法不能制备药物领域所需要的药物粒径、形貌特征、物理特性。
本发明的目的是通过下述技术方案实现的：
具体方法的步骤如下：
连续式抗溶剂过程可描述如下：钢瓶中的CO2经制冷系统液化，由高压柱塞泵加压，管路中的恒温水浴升温后，泵入高压釜中，待釜内达到要求的压力，维持CO2泵入速率，开启放气阀以一定速率放气，以保持釜内压力恒定；达到实验温度后，药物溶液由高效液相色谱(HPLC)泵经釜顶喷嘴泵入高压釜，调节高压釜外部干燥箱及管路水浴温度，控制釜内温度，调节放气阀，维持釜内压力。结束泵样后，维持压力及温度不变，继续用CO2干燥一定时间后，缓慢卸压，待釜内压力降为常压时，取出样品。
本发明的用途：本发明主要用于微细化抗癌药物，提高药物的溶解度，改善紫杉醇的生物利用度，提高药物治疗癌症的疗效。
本发明的方法所制备的产品纯度高，分散性好，对环境无污染，且大大降低了其他传统方法所制备的药物微粒存在的有机残留量。
采用本发明的方法得到的紫杉醇纳米粒，如附图2所示。
本发明微细化药物的方法简单易行，易于推广应用。
附图说明
图1.原始的紫杉醇药物颗粒；
图2.SEDS法制备的超细紫杉醇药物颗粒；
图3.SEDS法制备的超细紫杉醇微粒粒径大小及分布。
具体实施方式
实施例1
(1).抗癌药物紫杉醇有机溶液
在反应瓶中加200-300mg紫杉醇，加入定量的有机溶剂，于室温下溶解。
(2).系统工艺参数的调制
达到实验要求的温度和压力后，超临界CO2由高压柱塞泵通过高压釜顶部同轴二流式喷嘴外侧通道，有机溶液由高效液相色谱(HPLC)泵通过喷嘴内侧通道，同时泵入高压釜，超临界CO2作为分散介质将有机溶液强制分散，同时也作为抗溶剂，吸收溶解溶液中的有机溶剂。
实施例2
(1).聚合物有机溶液
在反应瓶中加200-300mg聚合物，改变有机溶剂量，调整紫杉醇药物浓度，于室温下溶解。
(2).系统工艺参数的调制
改变实验要求的温度和压力后，超临界CO2由高压柱塞泵通过高压釜顶部同轴二流式喷嘴外侧通道，有机溶液由高效液相色谱(HPLC)泵通过喷嘴内侧通道，同时泵入高压釜，超临界CO2作为分散介质将有机溶液强制分散，同时也作为抗溶剂，吸收溶解溶液中的有机溶剂。
Claims (4)
1.一种用于微细化药物的新方法，其特征在于，在自行设计的超临界CO2装置上，采用超临界CO2抗溶剂法微细化抗癌药物紫杉醇，并考察了溶液浓度、溶液流速对微细化的紫杉醇药物纳米粒形貌、尺寸及其分布的影响。
2.根据权利1所述的微细化紫杉醇的新方法，其特征在于药物的浓度在0.25％wt/v-0.5％wt/v，HPLC的流速在0.25-0.5ml/min。
3.根据权利1所述的微细化紫杉醇的新方法，其特征在于CO2的流速在16-32NL/h，温度在32-40℃，压强在10-16MPa。
4.根据权利1所述的微细化紫杉醇的新方法，其特征在于同轴喷嘴的设计。
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