新型眼用硝酸毛果芸香碱六角液晶凝胶的制备和评价  

Preparation and Evaluation of Pilocarpine Nitrate-Loaded Hexagonal Liquid Crystal Gel as a Novel Ocular Formulation

作　　者：王邢琦 王婷 许金红[1] 陆杨 李永霞[1] WANG Xing-qi;WANG Ting;XU Jin-hong;LU-Yang;LI Yong-xia(Department of Pharmacy,The PLA Navy Anqing Hospital,Anqing246000,China;School of Pharmacy,Anhui University of Chinese Medicine,Hefei230012,China)

机构地区：[1]中国人民解放军海军安庆医院药剂科,安徽安庆246000 [2]安徽中医药大学药学院,合肥230012

出　　处：《中国药学杂志》2022年第4期284-294,共11页Chinese Pharmaceutical Journal

基　　金：安庆市2018年第二批自筹经费科技计划项目资助(2018Z2025)。

摘　　要：目的本研究以硝酸毛果芸香碱(PN)为模型药,以植烷三醇(PHYT)/三辛酸甘油酯(TAG)/水三元系统制备六角相液晶(H_(II))凝胶,通过眼部给药提高PN的眼用生物利用度。方法采用偏光显微镜(CPLM)、小角X射线散射仪(SAXS)和流变学对H_(II)凝胶的内部结构进行表征;通过体外释放和离体角膜渗透对H_(II)凝胶的体外行为进行考察;采用荧光标记技术考察H_(II)凝胶的眼部保留时间,通过组织学考察H_(II)凝胶对眼组织的生物安全性,通过房水药动学初步考察H_(II)凝胶的局部药动学;以眼内压为指标初步研究其药效学。结果H_(II)凝胶的最优处方为PHYT⁃TAG⁃水⁃PN质量比(70.15∶3.85∶26∶2)。CPLM显示,H_(II)凝胶为清晰的光学双折射扇形纹理;SAXS结果显示,H_(II)凝胶布拉格峰相对位置散射矢量比为1∶√3∶√4;流变学结果显示,H_(II)凝胶表现出一种剪切变稀的假塑性非牛顿流体行为,流变性能良好;体外研究表明,H_(II)凝胶缓释效果良好,角膜穿渗透力强;体内结果表明,H_(II)凝胶眼部保留时间超过6 h,且安全无刺激。与滴眼液相比,H_(II)凝胶AUC_(0⁃12 h)值提高了6.03倍,降眼压效果好且持久。结论本研究表明,载药H_(II)凝胶可明显提高PN的眼用生物利用度,降低PN滴眼液的副作用,是非常具有潜力的眼用新剂型。OBJECTIVE To prepare a pilocarpine nitrate(PN)loaded inverse heagonal liquid crystal(H_(II))gel by using phytant⁃riol(PHYT)/triglyceride(TAG)/water ternary system and improve theeye bioavailability of PN by ocular administration.METHODS The inner structure of H_(II)gel were characterized by crossed polarized light microscopy(CPLM),small⁃angle X⁃ray scattering(SAXS)and rheology.And,thein vitrodrug release behavior andex vivocorneal permeation of H_(II)gel were evaluated.In addition,the preocular residence time,biosafety and local pharmacokinetics of H_(II)gel were investigated by fluorescein⁃tagged technology,histol⁃ogy and aqueous humor pharmacokinetics,respectively.Finally,the preliminary pharmacodynamics of the gels were studied with in⁃traocular pressure as an indicator.RESULTS The optimal proportion of the gel composed of PHYT/TAG/water/PN(70.15∶3.85∶26∶2,m/m/m/m).H_(II)mesophases were deemed to be the microstructure of the gels according to the typical spacing ratio 1∶√3∶√4.The gel exhibited a shear thinning pseudoplastic non⁃Newtonian fluid behavior with good rheological properties.In vitrostudies dis⁃played that H_(II)gel had a fine sustained⁃release effect and strong corneal penetration.In vivoresults revealed that H_(II)gel had a long resi⁃dence time on the eyeballs surface even more than 6 h,and it was safe and non⁃irritating.Compared with traditional eye drops,the AUC_(0⁃12 h)value of the gel was increased by 6.03⁃folds,and the effect of lowering intraocular pressure was excellent and lasting.CON⁃CLUSION These research findings hint that the drug⁃loaded H_(II)gel can significantly improve the eye bioavailability of PN and reduce the side effects of PN eye drops.It would be a promising dosage form for ocular drug delivery.

关 键 词：液晶凝胶 六角相 眼部给药 青光眼 硝酸毛果芸香碱 

分 类 号：R944[医药卫生—药剂学]