吡诺克辛钠-层状双氢氧化物纳米片及插层纳米粒复合物滴眼液的研究

Ophthalmic solution of pirenoxine sodium-layered double hydroxide nanosheets and intercalated nanoparticles

为考察新型药物载体层状双氢氧化物(LDH)纳米片在眼部给药系统的应用,采用LDH纳米片为载体,羧甲基纤维素钠(CMC)为稳定剂,吡诺克辛钠(PRN)为模型药物,制备CMC-PRN-LDH纳米片复合物;采用共沉淀法制备PRN-LDHs插层纳米粒复合物。通过X射线衍射、原子力显微镜、透射电镜、激光粒度仪等对LDH纳米片、CMC-LDH纳米片复合物及两种载药-LDH纳米复合物理化性质进行研究。通过体外稳定性、体外释放、家兔泪液滞留实验比较了两种载药-LDH纳米复合物的差异。结果显示,CMC-PRN-LDH纳米片复合物相对稳定,而PRN-LDHs插层纳米粒稳定性较差,二者12 h体外累积释放百分率分别为70.44%和44.21%。CMC-PRN-LDH纳米片复合物滴眼液的AUC0-6 h和MRT分别为市售滴眼液的4.18和1.79倍,而PRN-LDHs插层纳米粒复合物滴眼液眼部滞留结果差异较大。CMC-PRN-LDH纳米片复合物滴眼液对眼部无刺激性。上述结果表明,LDH纳米片可作为眼部给药载体,能显著提高药物在角膜前的滞留时间。

The aim of this study was to evaluate the potential application of layered double hydroxide（LDH） nanosheets for ocular drug delivery. Using LDH nanosheets as carriers, carboxymethyl cellulose（CMC） as a stabi- lizer and pirenoxine sodium（PRN） as the model drug, CMC-PRN-LDH nanosheets were prepared. PRN-LDHs nanoparticles were synthesized via co-precipitation method. X-ray diffraction, atomic force microscopy, transmis- sion electron microscopy and laser particle sizer were employed to characterize the physieochemical properties of LDH nanosheets, CMC-LDH nanosheets and PRN-LDH nanocomposites. Stability, accumulative release in vitro and preeorneal retention in vivo of both CMC-PRN-LDH nanosheets and PRN-LDHs nanoparticles were evalua- ted. It was found that CMC-PRN-LDH nanosheets were electrostatically stabilized by CMC absorbed on the surface of LDH nanosheets, but PRN-LDHs nanoparticles aggregated in phosphate buffered saline. 12-hr accumu- lative release percentage of PRN from CMC-PRN-LDH nanosheets and PRN-LDHs nanoparticles were 70. 44% and 44.21% in vitro, respectively. Compared with the commercial PRN eye drops, there existed 4. 18-foldincrease in AUC0.6 h and 1.79-fold in mean retention time of CMC-PRN-LDH nanoshects. Negligible levels of PRN-LDHs nanoparticles might be attributed to inter-groups difference. Draize test showed that CMC-PRN-LDH nanosheets were non-irritant to the rabbit eyes after single and repeated dosing. It suggest that this novel LDH nanosheet could be a promising carrier for ocular drug delivery with prolonged residence time.