pH-时间双依赖型载药复合物的制备及其释药行为

Preparation and Drug Release Behavior of pH-time Dual-dependent Drug Loaded Complex

关键词:  ZSM-5  微孔分子筛  浸渍离心法  肠道靶向递送系统

Key words:  ZSM-5  microporous molecular sieve  impregnation centrifugation  intestinal targeted delivery system

摘要:

目的 制备一种新型ZSM-5微孔分子筛基载药复合物，并考察其体外释药行为。方法 以ZSM-5微孔分子筛为载体，采用浸渍离心法将小分子抗肿瘤药物5-氟尿嘧啶(5-fluorouracil，5-FU)载入分子筛中，制备5-FU@ZSM-5初级药物组装体，再以提拉法于其表面利用天然有机高分子海藻酸钠(alginate，ALG)钙化覆膜，制备5-FU@ZSM-5@CaALG载药复合物。采用紫外分光光度法考察其载药率；利用X射线衍射、固体紫外-可见漫反射光谱、氮气等温吸脱附、扫描电镜、傅里叶变换红外光谱等手段对其结构和理化性质进行表征；通过体外释放度试验考察其释药性能。结果 紫外定量分析结果表明：载药复合物的载药率为11.7%。表征结果表明：小分子药物5-FU进入ZSM-5孔道，载药后未破坏ZSM-5的MFI拓扑结构。体外“时间-溶出介质变换”释放试验表明：与5-FU@ZSM-5组装体相比，5-FU@ZSM-5@CaALG载药复合物呈现出显著的pH-时间双依赖行为，其在人工胃液中2 h内累积释放率<10%，即>90%的药量能进入人工肠液，在人工胃肠液中48 h内累积释放率为85.2%。结论 微孔ZSM-5分子筛可以作为5-FU优良的载体材料，配合CaALG可同时实现肠道定位给药和长效作用。

Abstract:

OBJECTIVE To prepare a new ZSM-5 microporous molecular sieve based drug loaded composite and to investigate its drug release behavior in vitro. METHODS Using ZSM-5 microporous molecular sieve as carrier, a small molecule antitumor drug 5-fluorouracil(5-FU) was loaded into the molecular sieve by impregnation centrifugation and the primary drug assembly of 5-FU@ZSM-5 was prepared. Then, the surface of the primary drug assembly was coated with natural organic polymer sodium alginate(ALG) through calcification by lifting method, and the drug loaded complex of 5-FU@ZSM-5@ CaALG was finally obtained. The drug loading rate of the drug loaded complex was investigated by UV spectrophotometry. The structure and physicochemical properties were characterized by X-ray diffraction, solid UV-VIS diffuse reflectance spectroscopy, nitrogen isothermal adsorption and desorption, scanning electron microscopy and Fourier transform infrared spectroscopy. The drug release performance of 5-FU@ZSM-5@CaALG was investigated by in vitro release degree experiment. RESULTS The results of UV quantitative analysis showed that the drug loading rate of the drug loaded complex was 11.7%. The characterization results showed that the small molecule drug 5-FU entered the ZSM-5 channel and did not destroy the MFI topology of ZSM-5 after drug loading. In vitro “time-dissolution medium transformation” release experiment showed that, compared with the drug assembly of 5-FU@ZSM-5, the drug loaded complex of 5-FU@ZSM-5@CaALG showed significant pH-time dual-dependent behavior. The cumulative release rate of the drug in the artificial gastric juice within 2 h was less than 10%, that is, more than 90% of the drug could enter the artificial intestinal juice. The cumulative release rate was 85.2% in artificial gastrointestinal fluid within 48 h. CONCLUSION Microporous ZSM-5 molecular sieve can be used as an excellent carrier material for 5-FU. In combination with CaALG, it can simultaneously achieve intestinal targeted drug delivery and long-term effect.