吸入用pH敏感型尼达尼布脂质体的制备与优化

Preparation and Optimization of pH-Sensitive Nintedanib Liposomes for Inhalation

目的设计pH敏感的尼达尼布脂质体(Nb-Lips),使其靶向肺纤维化的酸性微环境。通过处方工艺优化Nb-Lips包封率(EE%)。方法采用薄膜水化法制备Nb-Lips,以EE%为指标通过单因素考察、响应面法对脂质体处方进行优化。通过动态光散射技术和微柱离心法考察其粒径、分散系数(PDI)、Zeta电位、EE%;采用透析法分别考察Nb-Lips在pH值为7.4、5.3的人工肺液中的体外释放行为;使用压缩空气式雾化器雾化Nb-Lips,并考察其雾化稳定性及空气动力学粒径。结果Nb-Lips粒径为(100.651±7.315)nm,PDI为(0.328±0.026),Zeta电位为(21.633±2.004)mV,优化后的EE%>80%。与在pH值为7.4的人工肺液中比较,Nb-Lips在pH值为5.3的人工肺液中总释放量高60.78%,且释放时间达48 h,远高于尼达尼布溶液。Nb-Lips雾化前后粒径、电位、PDI无显著差异,EE%下降4.25%,雾化后液滴微细粒子分数为37.49%。结论响应面法优化处方工艺有效地提高Nb-Lips EE%,成功制备酸性环境敏感的、可吸入、可缓慢释放的Nb-Lips。

Objective To design a pH-sensitive nintedanib liposomes(Nb-Lips)which targeted the acidic microenvironment of pulmonary fibrosis.The entrapment efficiency(EE%)was optimized by the formulation process.Methods Nintedanib liposomes were prepared by membrane hydration method,and the formulation of nintedanib liposomes were optimized by single factor experiments and response surface method(RSM).The particle size,polymer dispersity index(PDI),Zeta potential and encapsulation rate was investigated by dynamic light scattering technique and microcolumn centrifugation method.The release behavior of nintedanib liposomes in artificial lung fluid with pH 7.4 and artificial lung fluid with pH 5.3 was investigated by dialysis method.Nintedanib liposomes were atomized with a compressed air atomizer and its atomization stability and aerodynamic particle size were investigated.Results The particle size of nintedanib liposomes was(100.651±7.315)nm,the PDI was(0.328±0.026),the zeta potential was(21.633±2.004)mV,and the encapsulation rate was higher than 80%.Compared with nintedanib solution at pH 7.4,the total release of nintedanib liposomes in pH 5.3 artificial lung solution was 60.78%higher,and the release of nintedanib liposomes in pH 5.3 artificial lung solution was 48h delayed,which was much higher than that of nintedanib solution.The data reveals no significant differences in particle size,potential and PDI before and after atomization of nintedanib liposomes,and the encapsulation rate decreased 4.25%.The fine particle fraction of the atomized droplets was 37.49%.Conclusion The response surface method can effectively improve the encapsulation rate of nintedanib liposomes,and successfully prepare nintedanib liposomes that are sensitive to acidic environment,and can be inhaled and released slowly.