CN1947721B - 表阿霉素缓释制剂的制备方法 - Google Patents
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Abstract
表阿霉素缓释制剂的制备方法，涉及一种载药高分子微球，尤其是涉及一种载表阿霉素聚乳酸缓释制剂的制备方法。提供一种避免使用表面活性剂，所得载药微球大小均一，表面圆滑，包封率和载药率较高，具有良好的缓释功效的表阿霉素缓释制剂的制备方法。其步骤为：将表阿霉素盐酸盐溶于DMF中，得溶液A，再加入三乙胺得溶液B，再加入聚乳酸得溶液C，再加入水得混浊液，将混浊液转移至透析袋中，并置于水中透析，搅拌，隔1～3h换水，透析后将得到的产物离心，超声，水洗，除去未包埋的表阿霉素，取沉淀物冷冻干燥，得表阿霉素聚乳酸缓释制剂。
Description
技术领域
本发明涉及一种载药高分子微球，尤其是涉及一种载表阿霉素聚乳酸缓释制剂的制备方法。
背景技术
聚乳酸(PLA)因具有良好的生物相容性及生物可降解性，被广泛应用于药物缓释，已成为生物降解医用材料中最受重视的材料之一。目前，聚乳酸载药微球的制备方法主要有相分离法、乳化溶剂挥发法、喷雾法等。其中乳化溶剂挥发法的应用最为广泛。乳化一溶剂挥发法是将聚合物溶解在有机溶剂中，然后，在搅拌下于水溶液中乳化，随着溶剂的挥发，聚合物微球慢慢形成。此类方法在乳化过程中要用到大量表面活性剂，如聚乙烯醇，而此类表面活性剂通常会粘附在微球表面，导致微球的生物降解性能，体内分布、药物释放特性及生物相容性等的改变。(参见文献：1、Lee，S.C，Oh，J.T，Jang，M.H，Chung，S.I.J.Control.Release，1999，59，123；2、Sjostrom，B，Bergenstahl，B，Kronberg，B.J.Pharm.Sci.，1993，82，584；3、Witschi，C，Doelker，E.Eur.J.Pharm.Biopharm，1997，43，215.)。
表阿霉素是抗肿瘤常用化疗药物，其主要作用是直接嵌入DNA碱基对之间，干扰转录过程，阻止mRNA的形成，从而抑制肿瘤细胞的生长，具有一定的抗肿瘤活性，但其对人体也有较强的骨髓抑止及心脏毒性，另外，表阿霉素在高温高湿度下不稳定，药物溶解后在室温下只能保存24h。
发明内容
本发明的目的旨在针对现有的制备表阿霉素缓释制剂的方法中的不足，提供一种避免使用表面活性剂，所得载药微球大小均一，表面圆滑，包封率和载药率较高，具有良好的缓释功效的表阿霉素缓释制剂的制备方法。
本发明的技术方案是采用透析法制备PLA载表阿霉素缓释微球。
本发明的具体步骤如下：
1)将表阿霉素盐酸盐溶于N-N二甲基甲酰胺(DMF)中，得表阿霉素盐酸盐溶液，记为溶液A；
2)在溶液A中加入三乙胺，得溶液B；
3)在溶液B中加入聚乳酸，得溶液C；
4)在溶液C中加入水，得混浊液；
5)将混浊液转移至透析袋中，并将透析袋置于水中透析，同时搅拌，隔1～3h换水；
6)透析4～48h后将步骤5得到的产物离心，超声，水洗，除去未包埋的表阿霉素，取沉淀物冷冻干燥，得表阿霉素聚乳酸缓释制剂。
按质量比N-N二甲基甲酰胺∶水∶表阿霉素盐酸盐∶聚乳酸∶三乙胺＝3000∶(160～12000)∶(0.5～8)∶(5～80)∶(2～4)。聚乳酸的相对分子量最好为(0.5～5)万。透析袋的截留分子量(MWCO)最好为8000～14000。
本发明采用透析法成功制备了粒径分布窄，表面圆滑，表阿霉素在微球内分布均匀，包封率高，且有良好缓释功效的聚乳酸载表阿霉素微球。将表阿霉素制成微球，降低了表阿霉素的心脏毒性以及骨髓抑制等毒性，对肿瘤的治疗有重要意义。制备微球时将表阿霉素与一定量的三乙胺混合，可以显著延长表阿霉素在高湿高温条件下的稳定性，从而保证了载药聚乳酸微球缓释时药物的药效。因没有表面活性剂的参与，微球的生物降解性能，体内分布、药物释放特性及生物相容性等均可得到明显的改善。另外此法操作工艺简单、实施条件温和，易重复。通过改变透析所用溶剂、聚乳酸浓度、表阿霉素浓度和初始加入的水的体积可以调控微球粒径大小、粒径分布，包封率和载药率。
附图说明
图1为本发明实施例1所得微球的SEM图片。
图2为本发明实施例1所得微球的体外释放曲线。在图2中，横坐标为时间(d)，纵坐标为累积释药量(％)。
图3为本发明实施例2所得微球的SEM图片。
图4为本发明实施例3所得微球的SEM图片。
图5为本发明实施例4所得微球的激光共聚焦显微镜断层扫描图。
图6为本发明实施例4所得微球的SEM图片。
图7为本发明实施例5所得微球的SEM图片。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1：
(1)将5mg的表阿霉素盐酸盐溶于30ml N-N二甲基甲酰胺(DMF)得溶液A；(2)取10μl三乙胺加入溶液A中得溶液B；(3)称量50mg的聚乳酸(相对分子量为5000)加入溶液B中，得溶液C；(4)在溶液C中加入1.6ml水，得混浊液；(5)将混浊液转移至透析袋中，并将透析袋置于蒸馏水中透析，同时搅拌，隔2h换水；(6)8h后将步骤5得到的产物离心，超声，水洗3次，除去未包埋的表阿霉素，取沉淀冷冻干燥所得样品。所得样品测得包封率为59.6％，载药率为6.8％，通过扫描电镜观察到微球表面圆滑，粒径分布在400nm～700nm，见图1。通过粒度分析测得微球粒径平均大小为589.5nm，多分散度(polydispersity)为0.095。体外释放实验得出这种微球有缓慢释放表阿霉素得功效，药物最终释放可达70％，见图2。
实施例2：
(1)将12mg的表阿霉素盐酸盐溶于18ml N-N二甲基甲酰胺(DMF)得溶液A；(2)取12μl三乙胺加入溶液A中得溶液B；(3)称量60mg的聚乳酸(相对分子量为5000)加入溶液B中，得溶液C；(4)在溶液C中加入2ml纯净水，得混浊液；(5)将混浊液转移至透析袋中(8000～14000)，并将透析袋置于蒸馏水中透析，同时搅拌，隔2h换水；(6)24h后将步骤5得到的产物离心，超声，水洗3次，除去未包埋的表阿霉素，取沉淀冷冻干燥所得样品。所得样品测得包封率为53.6％，载药率为7.4％，扫描电镜观察到微球表面圆滑，粒径分布在200nm～600nm，见图3。通过粒度分析测得微球平均粒径大小为389.7nm，多分散度(polydispersity)为0.086。
实施例3：
(1)将4mg的表阿霉素盐酸盐溶于3ml N-N二甲基甲酰胺(DMF)得溶液A；(2)取2μl三乙胺加入溶液A中得溶液B；(3)称量40mg的聚乳酸(相对分子量为1万)加入溶液B中，得溶液C；(4)在溶液C中加入0.75ml纯净水，得混浊液；(5)将混浊液转移至透析袋中(8000～14000)，并将透析袋置于蒸馏水中透析，同时搅拌，隔2h换水；(5)4h后将步骤5得到的产物离心，超声，水洗3次，除去未包埋的表阿霉素，取沉淀冷冻干燥所得样品。所得样品测得包封率为30.9％，载药率为4.9％，扫描电镜观察到微球表面圆滑，粒径分布在500nm～1200nm，见图4；通过粒度分析测得微球粒径平均大小为863.5nm，多分散度(polydispersity)为0.067。
实施例4：
(1)将8mg的表阿霉素盐酸盐溶于3ml N-N二甲基甲酰胺(DMF)得溶液A；(2)取2μl三乙胺加入溶液A中得溶液B；(3)称量80mg的聚乳酸(相对分子量为1万)加入溶液B中，得溶液C；(4)在溶液C中加入12ml纯净水，得混浊液；(5)将混浊液转移至透析袋中(8000～14000)，并将透析袋置于蒸馏水中透析，同时搅拌，隔2h换水；(5)4h后将步骤5得到的产物离心，超声，水洗3次，除去未包埋的表阿霉素，取沉淀冷冻干燥所得样品。所得样品测得包封率为24.6％，载药率为2.6％，通过激光共聚焦显微镜观察得出表阿霉素在微球内均匀分布，见图5；通过扫描电镜观察到微球大小均一，粒径分布在600nm～900nm，微球表面圆滑，见图6：通过粒度分析测得微球粒径平均大小为768.4nm，多分散度(polydispersity)为0.068。
实施例5：
(1)将12mg的表阿霉素盐酸盐溶于9ml N-N二甲基甲酰胺(DMF)得溶液A；(2)取12μl三乙胺加入溶液A中得溶液B；(3)称量60mg的聚乳酸(相对分子量为5000)加入溶液B中，得溶液C；(4)在溶液C中加入12ml纯净水，得混浊液；(5)将混浊液转移至透析袋中(8000～14000)，并将透析袋置于蒸馏水中透析，同时搅拌，隔2h换水；(5)48h后将步骤5得到的产物离心，超声，水洗3次，除去未包埋的表阿霉素，取沉淀冷冻干燥所得样品。所得样品测得包封率为24.6％，载药率为9.1％，通过扫描电镜观察到微球大小均一，表面圆滑，粒径分布在250nm～470nm，见图7；通过粒度分析测得微球粒径平均大小为313.6nm，多分散度(polydispersity)为0.059。
Claims (3)
1.表阿霉素缓释微球的制备方法，其特征在于其步骤为：
1)将表阿霉素盐酸盐溶于N-N二甲基甲酰胺中，得表阿霉素盐酸盐溶液，记为溶液A；
2)在溶液A中加入三乙胺，得溶液B；
3)在溶液B中加入聚乳酸，得溶液C；
4)在溶液C中加入水，得混浊液；
5)将混浊液转移至透析袋中，并将透析袋置于水中透析，搅拌，隔1～3h换水；
6)透析4～48h后将步骤5得到的产物离心，超声，水洗，除去未包埋的表阿霉素，取沉淀物冷冻干燥，得表阿霉素聚乳酸缓释制剂；
按质量比N-N二甲基甲酰胺∶水∶表阿霉素盐酸盐∶聚乳酸∶三乙胺＝3000∶160～12000∶0.5～8∶5～80∶2～4。
2.如权利要求1所述的表阿霉素缓释微球的制备方法，其特征在于聚乳酸的相对分子量为0.5万～5万。
3.如权利要求1所述的表阿霉素缓释微球的制备方法，其特征在于透析袋的截留分子量为8000～14000。
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