Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery
Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery
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DOI：
10.1208/s12249-014-0244-2
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发表时间：
2015-06-01
影响因子：
3.3
通讯作者：
Mitra, Ashim K.
中科院分区：
文献类型：
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作者：
Cholkar, Kishore;Gunda, Sriram;Mitra, Ashim K.
本研究的目的是开发一种透明的、含水的雷帕霉素混合纳米束制剂（MNFs），用于眼后给药。以维生素E生育酚聚乙二醇琥珀酸酯（TPGS） （Vit E TPGS）和八苯醇醚-40 （Oc-40）为聚合物基质制备雷帕霉素MNF（0.2%）。用粒径、电荷、形状和粘度等参数对MNF进行表征。利用质子核磁共振（H-1 NMR）鉴定了MNF中未包裹的雷帕霉素。对人视网膜色素上皮细胞（D407）和兔原代角膜上皮细胞（rPCECs）进行细胞毒性评价。对雄性新西兰大白兔进行了体内后眼雷帕霉素分布研究。优化后的MNF具有良好的雷帕霉素包埋和负载效率。空白MNF和雷帕霉素MNF的平均粒径分别为10.98 +/- 0.089 nm和10.84 +/- 0.11 nm。透射电镜分析表明，纳米胶束呈球形。通过H-1 NMR研究证实了MNF中游离雷帕霉素的缺失。安慰剂和负载雷帕霉素的MNF均未对D407和rpecs产生细胞毒性，表明制剂是可耐受的。体内研究表明，雷帕霉素在视网膜脉络膜中的浓度非常高（362.35 +/- 56.17 ng/g）。在玻璃体中没有发现药物表明雷帕霉素在脂质视网膜组织中被隔离。综上所述，我们成功地开发了一种透明的、含水的由Vit E TPGS和Oc-40组成的MNF，并装载了雷帕霉素。眼后组织分布研究表明，在视网膜脉络膜（药物作用的地方）有非常高的雷帕霉素水平，而药物在玻璃体中的分配可以忽略不计。
The objective of this study was to develop a clear, aqueous rapamycin-loaded mixed nanomicellar formulations (MNFs) for the back-of-the-eye delivery. MNF of rapamycin (0.2%) was prepared with vitamin E tocopherol polyethylene glycol succinate (TPGS) (Vit E TPGS) and octoxynol-40 (Oc-40) as polymeric matrix. MNF was characterized by various parameters such as size, charge, shape, and viscosity. Proton nuclear magnetic resonance (H-1 NMR) was used to identify unentrapped rapamycin in MNF. Cytotoxicity was evaluated in human retinal pigment epithelial (D407) and rabbit primary corneal epithelial cells (rPCECs). In vivo posterior ocular rapamycin distribution studies were conducted in male New Zealand white rabbits. The optimized MNF has excellent rapamycin entrapment and loading efficiency. The average size of MNF was 10.98 +/- 0.089 and 10.84 +/- 0.11 nm for blank and rapamycin-loaded MNF, respectively. TEM analysis revealed that nanomicelles are spherical in shape. Absence of free rapamycin in the MNF was confirmed by H-1 NMR studies. Neither placebo nor rapamycin-loaded MNF produced cytotoxicity on D407 and rPCECs indicating formulations are tolerable. In vivo studies demonstrated a very high rapamycin concentration in retina-choroid (362.35 +/- 56.17 ng/g tissue). No drug was identified in the vitreous humor indicating the sequestration of rapamycin in lipoidal retinal tissues. In summary, a clear, aqueous MNF comprising of Vit E TPGS and Oc-40 loaded with rapamycin was successfully developed. Back-of-the-eye tissue distribution studies demonstrated a very high rapamycin levels in retina-choroid (place of drug action) with a negligible drug partitioning into vitreous humor.