硝酸益康唑纳米粒在兔眼内的药代动力学研究

摘要

背景 硝酸益康唑因眼内的通透性差而影响其在眼部的抗真菌效果,通过改变硝酸益康唑的剂型增加其眼内通透性成为目前研究的热点. 目的 研究质量分数0.5％硝酸益康唑纳米粒溶液点眼后的眼部通透性及眼部药代动力学.方法 采用溶剂扩散法制备0.5％硝酸益康唑纳米粒,透射电子显微镜下观察纳米粒性状,激光散射法测定纳米粒的大小.收集27只新西兰大白兔双眼点0.5％硝酸益康唑纳米粒滴眼液后,分别于点眼后5、15、30、45、60、90、120、180、240 min抽取大白兔房水100μl,然后处死动物获取角膜组织,制备角膜组织匀浆.用反相高效液相色谱法( HPLC)定量测定房水和角膜样本中硝酸益康唑的质量浓度和质量分数,采用3 p97药代动力学软件进行计算机拟合求得0.5％硝酸益康唑纳米粒溶液点眼后眼部的药代动力学参数. 结果 所制备的硝酸益康唑纳米粒的平均粒径为50.1 nm,形状均匀圆整,包封率为96.0％.采用反相HPLC法可以将硝酸益康唑同其他杂质分离,最低定量质量浓度为0.1 mg/L,硝酸益康唑在角膜中的平均回收率为98.09％;在房水中平均回收率为99.66％.各时间点房水及角膜组织中均可检测出硝酸益康唑,其中角膜组织中和房水中均于点眼后5 min时质量分数和质量浓度达最高,分别为(40.620±7.756) μg/g和(0.504±0.153) mg/L,在角膜和房水中的消除半衰期(t1/2)分别为23.5 min和18.6 min.结论 0.5％硝酸益康唑纳米粒点眼可使药物在角膜和房水中达到有效的药物质量分数和质量浓度.%Background Econazole nitrate is not effective as an antifungal eyedrop because of its poor intraocular permeability,therefore changing the formulation of econazole nitrate to improve its intraocular permeability become a critical point in the treatment of intraocular fungal infection. Objective The present study was to observe the penetration of 0.5％ econazole nitrate nanoparticles in the corneas and aqueous humors following its topicaladministration. Methods Econazole nitrate nanoparticles were prepared by quasi-emulsion solvent diffusion.Characteristics and size of nanoparticles were examined with transmission electron microscope and laser scatteringmethod,respectively.Econazole nitrate nanoparticles drops (0.5％ )was topically administered in 27 New Zealandwhite rabbits bilaterally,and aqueous humor and corneas were obtained after the application of the eye drops for 5,15,30,45,60,90,120,180,240 minutes respectively to detect the concentration of econazole nitrate with highperformance liquid chromatography (HPLC). The pharmacokinetic parameters were calculated with 3 p97pharmacokinetic computer software.The use of the animals followed the Regulation for the Administration of AffairsConcerning Experimental Animals by State Science and Technology Commission. Results The diameter of thenanoparticles was 50 nm with the round shape and encapsulation efficiency was 96.0％.Econazole nitrate nanoparticlesat the concentration of 0.5％ could be rapidly separated with other elements by HPLC with a lowest quantitativeconcentration of 0.1 mg/L.The mean recovery rates of econazole nitrate nanoparticles were 98.09％ in cornea and 99.66％ in aqueous humor,respectively after topical administration.The peak levels of econazole nitrate nanoparticles in cornea and aqueous humor were achieved at 5 minutes after application ( cornea:40.620 μg/g± 7.756 μg/g;aqueous humor:0.504 mg/L±0.153 mg/L),and its half-life( t1/2 )in cornea and aqueous humor was 23.5 minutes and 18.6 minutes,respectively. Conclusions Econazole nitrate nanoparticles at 0.5％ concentration can remain a feasible bioavailability in ocular tissue and therapeutic level in cornea and aqueous humor.