基于超临界流体强化溶液快速分散技术的冬凌草甲素脂质体口服制剂制备工艺研究

Preparation Technology Study on Oridonin A Oral Liposomes Based on Supercritical Fluid Solution-enhanced Dispersion

目的:优化超临界流体强化溶液快速分散技术(SEDS)制备冬凌草甲素脂质体口服制剂(ORI-LIP)的工艺,并探讨其与常规脂质体制备技术的优势。方法:以粒径为评价指标,采用正交试验考察压力、温度、进样流速对SEDS制备ORI-LIP的影响。同时,采用薄膜分散法和逆向蒸发法制备ORI脂质体,比较3种方法所制脂质体的粒径、包封率、载药量及稳定性(6个月加速试验),并比较ORI原料药与3种脂质体的体外溶出行为的差异。结果:优化后的ORI-LIP SEDS制备工艺条件为温度50℃,压力18MPa,进样流速1 m L/min;与薄膜分散法和逆向蒸发法比较,以SEDS技术制备的脂质体的粒径[(147.4±4.8)nm]更小,包封率(67.8%)、载药量(7.8%)及稳定性(粒径略有增加,包封率仅降低4.4%)都更高。体外溶出试验结果显示,与原料药比较,各脂质体的释药速率缓慢且持久,且累积释放度更高;其中,SEDS技术制备的ORI-LIP在24 h时达到溶出平衡,且累积溶出度最高,达到67.2%。结论:SEDS制备的ORI-LIP粒径小,包封率、载药量较高,稳定性较好,能显著提高药物的体外溶出度;该技术与常规脂质体制备技术相比有一定的优势。

OBJECTIVE:To optimize the preparation technology of Oridonin A oral liposomes(ORI-LIP)by using supercritical fluidsolution-enhanced dispersion(SEDS)technology,and to investigate its advantage with routine liposome preparation technologies.METHODS:Using particle size as evaluation index,orthogonal design was employed to investigate the influence of pressure,temperature and flow rate on the preparation technology of ORI-LIP by SEDS.At the same time,thin film dispersion and reverse evaporation method were used to prepare ORI liposomes.The particle size,encapsulation efficiency,drug loading amount and stability(accelerated test for 6 months)were compared among 3 methods.Moreover,the difference in dissolution behavior in vitro of ORI crude drug and 3 kinds of liposomes was evaluated.RESULTS:The optimized preparation condition of ORI liposomes by SEDS included temperature of 50℃,pressure of 18 MPa,flow rate of 1 mL/min.Compared with thin film dispersion and reverse evaporation method,the liposomes prepared by the SEDS method exhibited smaller particle size([147.4±4.8)nm],better encapsulation efficiency(67.8% ),drug-loading amount(7.8% )and stability(particle size increased slightly,encapsulation efficiency decreased only by 4.4% ).Results of in vitro dissolution test showed that compared with crude drug,release rate of each liposome was slow and persistent,and the cumulative release rate was higher.The accumulative release rate of ORI-LIP prepared by SEDS could achieve to 67.2% ,and reached to dissolution equilibrium at 24 h.CONCLUSIONS:ORI-LIP prepared by SEDS has smaller particle size,higher encapsulation efficiency,drug loading amount and stability,which can improve the in vitro release of ORI.Compared with conventional methods,SEDS technology has certain advantages.