青蒿琥酯脂质体粉雾剂的制备及其治疗大鼠急性肺损伤的作用  

Preparation of liposomal artesunate dry powder inhalers and the effect on the acute lung injury of rats

作　　者：胡玉贞[1] 李淼[2] 张桐桐[1] 金义光[1,2] 

机构地区：[1]安徽医科大学,安徽合肥230032 [2]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《药学学报》2016年第12期1906-1912,共7页Acta Pharmaceutica Sinica

基　　金：国家科技重大专项资助项目(2012ZX09301003-001-009);北京市自然科学基金青年项目资助(7154230)

摘　　要：青蒿琥酯是青蒿素衍生物,具有抗炎和抗疟疾作用,但其难溶于水,口服吸收差。急性肺损伤(acute lung injury,ALI)是一种严重的弥漫性肺部疾病,具有进程快和死亡率高的特点。本文用薄膜分散法制备了青蒿琥酯脂质体,冻干后得到粉雾剂(dry powder inhalers,DPI),经肺吸入后用于治疗ALI。青蒿琥酯脂质体的包封率为71.4%,粒径为47.3 nm,zeta电位为-13.7 mV。粉雾剂的空气动力学粒径为4.2μm,体外肺部沉积率为34.5%。将脂多糖(lipopolysaccharide,LPS)经气管喷入大鼠肺中成功建立ALI大鼠模型。大鼠很快出现自主活动明显减少、精神萎靡、呼吸加快和腹泻等症状。1 h后,将青蒿琥酯脂质体粉雾剂(liposomal artesunate dry powder inhalers,LADPIs)经气管直接喷入ALI大鼠肺内。LADPIs治疗组与模型组比较,症状减轻。DPI组的炎症因子TNF-α和IL-6水平低于青蒿琥酯原料药组和阳性药地塞米松组(P<0.05),表明青蒿琥酯治疗ALI的主要机制为抗炎作用,并且脂质体粉雾剂剂型可增加药物肺内利用,提高疗效。LADPIs有望成为治疗ALI的有效制剂。Artesunate is one of artemisinin derivatives with anti-malarial and anti-inflammatory activities though its water solubility and bioavailability are low. Acute lung injury（ALI） is a seriously dispersive lung disease with a high mortality. In this study, artesunate liposomes were prepared with the film dispersion method, and then lyophilized to obtain the liposomal artesunate dry powder inhalers（LADPIs）. The LADPIs were pulmonary-delivered into the lung to treat ALI in rats. The artesunate liposomes had the capsulation efficiency of 71.4%, the particle size of 47.3 nm, and the zeta potential of-13.7 m V. The LADPIs had the aerodynamic particle size of 4.2 μm and the fine particle fraction（FPF） of 34.5%. ALI was established in rats by instilling lipopolysaccharide（LPS） into the lungs. The rats quickly showed a reduction in movement and acceleration in breath followed by diarrhea and so on. The LADPIs were directly administrated into the lungs of ALI rats through airways after 1 h of LPS challenge. The treatment induced a reduction in ALI syndromes. Two inflammatory factors, including TNF-α and IL-6, were significantly reduced by the artesunate powder in the LADPI group similarly to the reduction in the positive drug dexamethasone group（P〈0.05）. Therefore, the anti-inflammatory effect of LADPIs contributed to the anti-ALI activity. Furthermore, the liposomal formulation improved drug bioavailability in the lung and increased therapeutic efficiency. The LADPIs are promising medicines for therapy of ALI through local drug administration.

关 键 词：青蒿琥酯 急性肺损伤 脂质体 粉雾剂 

分 类 号：R943[医药卫生—药剂学]