目的 制备柚皮素(NRG)固体脂质纳米粒冻干粉,考察其理化性质及经大鼠肺部给药后的体内药动学行为。方法 采用乳化蒸发-低温固化法,以包封率、粒径为考察指标,正交试验优化其处方并考察其粒径、形态、电位及体外释放。以外观、色泽、再分散性为考察指标筛选最佳冻干保护剂,采用差式扫描量热(DSC)分析药物在纳米粒中的存在状态。通过肺部给药考察NRG固体脂质纳米粒和NRG原料药溶液在大鼠体内的药动学行为。结果 NRG固体脂质纳米粒外观呈球形,分布均匀,平均粒径为(97.69±2.84)nm,多分散系数(PDI)为0.207±0.010,Zeta电位为(-26.20±0.45)mV,包封率为(81.09±1.37)%,载药量为(8.30±0.04)%(n=3),5%甘露醇为冻干保护剂最好,药物以无定形状态分散在脂质载体中,体外溶出实验表明NRG固体脂质纳米粒与原料药相比具有明显的缓释作用。NRG原料药和纳米粒的C_max分别为(163.00±23.05)、(269.00±35.34)ng/mL,t_1/2分别为(5.13±0.23)、(18.93±7.90)h,AUC0-t分别为(929.32±190.28)、(3390.23±533.68)ng·h/mL,MRT分别为(7.19±0.44)、(23.29±9.27)h。结论 乳化蒸发-低温固化法制得的NRG固体脂质纳米粒,粒径小,包封率高,稳定性好,工艺简单。NRG固体脂质纳米粒肺部给药后有明显的缓释作用,能提高药物的生物利用度。

Objective To prepare naringenin-loaded solid lipid nanoparticles (NRG-SLN) lyophilized powder, and investigate its physicochemical properties and release characteristics, then to investigate the pharmacokinetic characteristics in rats after pulmonary delivery. Methods NRG-SLN were prepared by solvent emulsification-evaporation method, the formulation was optimized by orthogonal design, with encapsulation efficiency as reference, and the measurements of particle size, morphology, Zeta potential, the polydispersity index (PDI) and in vitro drug release behavior were performed. To screen the best lyoprotectants in appearance, color, and redispersibility as indexes the differential scanning calorimetry (DSC) was used to analyze its material phase of the drug in nanoparticles. The study on pulmonary pharmacokinetics in rats was carried out by pulmonary instillation. Results The NRG-SLN assumed a spherical shape with an even distribution of diameter and particle size of (97.69±2.84) nm, the PDI was 0.207±0.010, Zeta potential was (-26.20±0.45) mV, entrapment efficiency was (81.09±1.37)%, and drug loading was (8.30±0.04)% (n=3). Mannitol (5%) was the best protective agent for lyophilized powder of NRG-SLNs. The characterization indicated that the drug to amorphous state dispersed in a lipid. In vitro dissolution experiments showed NRG-SLN compared with pure drugs had obviously sustained release. After pulmonary administration to rats, the pharmacokinetic parameters of NRG-SLN and solution were as follows: C_max (163.00±23.05) and (269.00±35.34) ng/mL, AUC0-t (929.32±190.28) and (3 390.23±533.68) ng·h/mL, t_1/2 (5.13±0.23) and (18.93±7.90) h, MRT (7.19±0.44) and (23.29±9.27) h. Conclusion The technique of preparing NRG-SLN by solvent emulsification-evaporation has small particle size, high entrapment efficiency, and good stability, and the process is simple. Compared with the naringenin solution, the SLN show the sustained-release characteristics and can significantly improve the bioavailability after pulmonary administration.

辽宁医学院校长基金-奥鸿博泽基金-医药创新专项(XZJJ20130104-02)