Abstract：
Glaucoma is known to be one of the principal causes of vision loss due to elevated intraocular pressure. Currently, latanoprost eye drops is used as first-line treatment for glaucoma; however, it possesses low bioavailability due to rapid precorneal clearance. A novel delivery system with a mucoadhesive property could overcome this problem. Therefore, we attempt to develop a combination of self-assembling latanoprost nanomicelles (Latcel) and a mucoadhesive polymer (N,O-carboxymethyl chitosan: N,O-CMC) to improve the corneal residence time. Latcel was developed using Poloxamer-407 by thin film hydration method, followed by the addition of N,O-CMC using simple solvation to obtain Latcel-CMC and characterized using various physicochemical characterization techniques. The particle size of Latcel-CMC was 94.07 ± 2.48 nm and a zeta potential of -16.03 ± 0.66 mV, with a sustained release for 24h whereas marketed latanoprost drops released 90 % of the drug within 1h. In vitro cytotoxicity studies, HET-CAM, and in vivo Draize test showed the biocompatibility of Latcel-CMC. Cellular uptake studies performed using fluorescein isothiocyanate (FITC) loaded nanomicelles in human corneal epithelial cells indicates the increased cellular uptake as compare to plain FITC solution. In vivo ocular residence time was evaluated in Wistar rats using Indocyanine green (ICG) loaded nanomicelles by an in vivo imaging system (IVIS), indicating Latcel-CMC (8h) has better residence time than plain ICG solution (2h). The Latcel-CMC showed improved corneal residence time and sustained release of latanoprost due to increased mucoadhesion. Thus, the developed N,O-Carboxymethyl chitosan based nanomicelles eye drop could be a better strategy than conventional eye drops for topical delivery of latanoprost to treat glaucoma.
摘要：
已知青光眼是由于眼内压升高引起的视力丧失的主要原因之一。目前,拉坦前列素滴眼液被用作青光眼的一线治疗;然而,由于快速的角膜前清除，它具有低生物利用度。具有粘膜粘附特性的新型递送系统可以克服该问题。因此,我们尝试开发自组装拉坦前列素纳米胶束（Latcel）和粘膜粘附聚合物（N，O-羧甲基壳聚糖:N,O-CMC)改善角膜停留时间。Latcel是使用泊洛沙姆-407通过薄膜水合方法开发的，然后加上N,O-CMC使用简单的溶剂化获得Latcel-CMC，并使用各种物理化学表征技术进行表征。Latcel-CMC的粒径为94.07±2.48nm，ζ电位为-16.03±0.66mV，持续释放24小时，而市售拉坦前列素滴剂在1小时内释放90％的药物。体外细胞毒性研究，HET-CAM,体内Draize试验显示了Latcel-CMC的生物相容性。在人角膜上皮细胞中使用负载异硫氰酸荧光素（FITC）的纳米胶束进行的细胞摄取研究表明，与普通的FITC溶液相比，细胞摄取增加。通过体内成像系统（IVIS）使用装载吲哚菁绿（ICG）的纳米胶束在Wistar大鼠中评估了体内眼停留时间，表明Latcel-CMC（8h）比普通ICG溶液（2h）具有更好的停留时间。由于粘膜粘附增加，Latcel-CMC显示出改善的角膜停留时间和拉坦前列素的持续释放。因此，发达的N，基于O-羧甲基壳聚糖的纳米胶束滴眼剂可能是比用于局部递送拉坦前列素以治疗青光眼的常规滴眼剂更好的策略。
