School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Acta Biomater. 2016 May;36:152-63. doi: 10.1016/j.actbio.2016.02.041. Epub 2016 Mar 3.
To improve the ocular bioavailability of the model drug of pirenoxine sodium (PRN), organic-inorganic hybrid nanocomposites including layered double hydroxides (LDH) and chitosan derivatives (chitosan-glutathione (CG), chitosan-glutathione-valine (CG-V) and chitosan-glutathione-valine-valine (CG-VV)) were designed and characterized. In vivo precorneal retention study on rabbits showed that mean residence time (MRT) and area under the curve (AUC0-6h) of CG-PRN-LDH nanocomposite eye drop was up to 2.1-fold and 6.3-fold higher than those of commercial product, respectively. In vitro corneal penetration on rabbits demonstrated that the cumulative permeation of CG-VV-PRN-LDH nanocomposite dispersion was increased by 5.2 folds compared to that of commercial product, which may be due to the active transport effect of the nanocomposites by peptide transporter-1 (PepT-1). In addition, the ex vivo fluorescence imaging showed that fluorescent intensity of crystalline lens in rabbits was increased after the administration of PRN-LDH, CG-PRN-LDH, CG-V-PRN-LDH and CG-VV-PRN-LDH (in increasing order) nanocomposite eye drop. Finally, in vivo distribution evaluation in ocular tissues of rabbits revealed that AUC0-8h and MRT in crystalline lens exhibited 14.7-fold and 2.2-fold increase in CG-VV-PRN-LDH nanocomposite eye drop group than those of commercial group, respectively. In summary, the organic-inorganic hybrid nanocomposites with multifunctional properties may be a promising ocular drug delivery system to achieve prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability.
Due to several structural and physiological intraocular barriers, drug delivery to the ocular mid-posterior segments still faces great challenges. In this manuscript, organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides (LDH) were designed and constructed. Multifunctional properties of these hybrid nanocomposites were due to the possible active targeting to the peptide transporter-1 on the corneal epithelial cells, the bioadhesive ability and permeation enhancement of chitosan derivatives, and the electrostatic adsorption of LDH. Prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability of the model drug pirenoxine sodium were observed. Chitosan derivatives-LDH hybrid nanocomposites may be a promising ophthalmic drug system for the treatment of ocular diseases of mid-posterior segments.
为提高模型药物吡诺克辛钠（PRN）的眼部生物利用度，设计并制备了包含层状双氢氧化物（LDH）和壳聚糖衍生物（壳聚糖-谷胱甘肽（CG）、壳聚糖-谷胱甘肽-缬氨酸（CG-V）和壳聚糖-谷胱甘肽-缬氨酸-缬氨酸（CG-VV））的有机-无机杂化纳米复合材料。对兔的预角膜滞留研究表明，CG-PRN-LDH 纳米复合滴眼剂的平均驻留时间（MRT）和 AUC0-6h 分别提高至商品化制剂的 2.1 倍和 6.3 倍。对兔角膜渗透的体外研究表明，CG-VV-PRN-LDH 纳米复合分散体的累积渗透量增加了 5.2 倍，这可能归因于纳米复合材料通过肽转运蛋白-1（PepT-1）的主动转运作用。此外，离体荧光成像显示，PRN-LDH、CG-PRN-LDH、CG-V-PRN-LDH 和 CG-VV-PRN-LDH（依次递增）纳米复合滴眼剂给药后兔晶状体的荧光强度增加。最后，兔眼组织的体内分布评价显示，CG-VV-PRN-LDH 纳米复合滴眼剂组在晶状体中的 AUC0-8h 和 MRT 分别比商品化制剂组增加了 14.7 倍和 2.2 倍。综上所述，具有多功能特性的有机-无机杂化纳米复合材料可能是一种有前途的眼部药物传递系统，可实现延长预角膜滞留时间、提高角膜通透性和增强眼部生物利用度。
由于多种结构和生理眼内屏障的存在，药物输送至眼部中后部仍面临巨大挑战。在本研究中，设计并构建了基于壳聚糖衍生物和层状双氢氧化物（LDH）的有机-无机杂化纳米复合材料。这些杂化纳米复合材料的多功能特性归因于对角膜上皮细胞上肽转运蛋白-1 的可能主动靶向作用、壳聚糖衍生物的生物黏附能力和渗透增强作用以及 LDH 的静电吸附作用。观察到模型药物吡诺克辛钠的延长预角膜滞留时间、提高角膜通透性和增强眼部生物利用度。壳聚糖衍生物-LDH 杂化纳米复合材料可能是一种有前途的眼科药物系统，可用于治疗中后部眼部疾病。
