依托泊苷过饱和自微乳化释药系统的制备工艺及质量评价研究

Preparation technology of supersaturatable self-microemulsifying drug delivery system of etoposide and quality evaluation

目的制备依托泊苷(etoposide,VP-16)过饱和自微乳化释药系统(supersaturatable self-microemulsifying drug delivery system,S-SMEDDS),增加难溶性药物VP-16的溶解度,并对其进行质量评价,为提高其生物利用度提供科学依据。方法对VP-16 S-SMEDDS的处方及制备工艺进行研究,从不同油相、表面活性剂的配伍情况以及不同助表面活性剂伪三元相图中微乳区域的大小,确定自微乳化浓缩液的基本处方组成;以VP-16的溶解度和析晶情况为考察指标进行处方优化,筛选适宜的促过饱和物质和最佳处方载药量;进行VP-16 S-SMEDDS的制备工艺研究,以自微乳化速率为指标,考察制备工艺对过饱和自微乳液自乳化能力的影响,并对VP-16 S-SMEDDS进行理化性质、溶出度、稳定性的考察。结果确定最优处方为聚氧乙烯氢化蓖麻油(RH40)-聚乙二醇400(PEG 400)-辛酸葵酸三甘油酯(GTCC)-聚乙烯吡咯烷酮K30(PVP K30)(20∶20∶10∶1),其中药物用量为2%。最佳工艺条件为37℃,20 r/min磁力搅拌20 min。VP-16 S-SMEDDS的平均粒径为(82.7±3.3)nm,粒径分布较集中,3批VP-16 S-SMEDDS中VP-16的平均质量分数为19.98 mg/g;溶出实验结果表明,在60 min时累积溶出率接近100%。稳定性研究的结果表明,高温与光照均影响VP-16 S-SMEDDS的稳定性与自微乳化能力,而冷热循环对其无影响,初步稳定性实验结果显示VP-16 S-SMEDDS的稳定性良好。结论优化处方的VP-16 S-SMEDDS能显著增加VP-16的溶解度,且质量稳定,可进一步提高VP-16的生物利用度。

Objective To prepare supersaturatable self-microemulsifying drug delivery system （S-SMEDDS） of etoposide （VP-16） for increasing the solubility of difficult soluble drug of etoposide, which will provide a scientific basis for improving its bioavailability. Methods To study the prescription and preparation technology of S-SMEDDS of VP-16, according to different oil phases, compatibility of surfactants, and the microemulsion area size in the pseudo ternary phase diagram of different cosurfactants, to determine the basic prescription of self-microemulsifying concentrate, optimize the prescription of VP-16 based on its solubility and crystallization conditions, with filtrating appropriate precipitation inhibitor and the best prescription drug loading. The rate of self-microemulsifying was taken as index to study the preparation technology of VP-16 S-SMEDDS for investigating the influence on the ability of selfmicroemulsifying. Results The optimal prescription is： RH40-PEG 400-GTCC-PVP K30 （20 ： 20 ： 10 ： 1）, 2% drug content of the mass fraction. The optimum technological conditions are 37 ℃, 20 r/min, and 20 min by magnetic stirring. The average particle size of VP- 16 S-SMEDDS is （82.7 ± 3.3） nm and the size distribution of VP- 16 S-SMEDDS is relatively concentrated.The average content of VP-16 in three batches of S-SMEDDS is 19.98 mg/g. Results of dissolut!on test showed that at 60 min the cumulative dissolution is close to 100%. Stability study results show that the high temperature and light could influence the drug stability and micro emulsification ability ofVP-16 S-SMEDDS, while the psychro-thermal cycles test has no influence to it. After the preliminary stability test, the results show that the stability ofVP-16 S-SMEDDS is good. Conclusion The optimized prescription of VP-16 S-SMEDDS can significantly increase the solubility of VP-16, and it＇s quality is stable, which could improve its bioavailability further. The research method is scientific, reliable, and feasible.