School of Pharmacy, The University of Auckland, Auckland, New Zealand.
School of Pharmacy, The University of Auckland, Auckland, New Zealand; School of Pharmacy and Chemistry, Kingston University, London, UK.
J Control Release. 2014 Jan 28;174:188-94. doi: 10.1016/j.jconrel.2013.11.022. Epub 2013 Dec 5.
Microemulsions (MEs) have been studied extensively as colloidal carriers for the delivery of both water-soluble and lipid-soluble drugs. Our previous study showed that addition of water to ME formulations resulted in phase transition to either liquid crystal (LC) or coarse emulsion (CE). The aim of this study was to investigate whether these MEs could be used as drug delivery vehicles for prolonged release through in-situ phase transition following extravascular injection. Three ME formulations from the same pseudo-ternary phase diagram were investigated with respect to their phase transition behavior, and in-vivo drug release; a coarse emulsion-forming ME (CE-ME), an oil rich LC-forming ME (LC-ME1), and an oil poor LC-forming ME (LC-ME2). CE-ME was a W/O ME and both LC-MEs were O/W type. The release profiles of (99m)Tc labeled MEs following subcutaneous (SC) injection in rabbits were investigated with gamma-scintigraphy. The CE-ME dispersed readily in water, forming a CE, whereas the LC-forming MEs formed 'depots' in water. Polarized microscopy revealed a LC boundary spontaneously formed at the water/ME interface for the LC-MEs with the LC-ME2 forming a substantially thicker LC layer. The CE resulting from the water-induced transition of the CE-forming ME had a higher viscosity than the MEs, but lower than the LCs resulted from LC-MEs. Compared to LC-ME1, LC-ME2 underwent more rapid phase transition and the resultant LC had significant higher viscosity. The LCs formed from both ME formulations exhibited pseudoplastic properties; increasing the shear rate decreased the apparent viscosity exponentially. Following SC injection into the animal thigh, the LC-MEs had more prolonged release of (99m)Tc in a first-order manner, than CE-ME. The oil poor LC-ME2 had the slowest release with a t1/2 of 77min, 2.3 times longer than the oil rich LC-ME1; consistent with the thickness of LC layer formation observed in-vitro and their relative viscosities. In conclusion, the present in-vivo study has demonstrated the application of MEs as extravascular injectable drug delivery systems for sustained release. The retention of the vehicles at the injection site and the release rate were determined predominantly by their phase transition rather than ME type or oil content.
微乳液 (MEs) 已被广泛研究作为水溶性和脂溶性药物的胶体载体。我们之前的研究表明，向 ME 制剂中加水会导致向液晶 (LC) 或粗乳液 (CE) 相转变。本研究旨在探讨这些 ME 是否可以作为通过血管外注射后原位相转变的延长释放的药物传递载体。根据其相转变行为和体内药物释放，研究了来自同一拟三元相图的三种 ME 制剂；一种粗乳液形成的 ME（CE-ME）、一种富含油的 LC 形成的 ME（LC-ME1）和一种贫油的 LC 形成的 ME（LC-ME2）。CE-ME 是一种 W/O ME，两种 LC-MEs 均为 O/W 型。用γ闪烁照相术研究了 (99m)Tc 标记 ME 经皮下 (SC) 注射后在兔子体内的释放曲线。CE-ME 易于在水中分散，形成 CE，而 LC 形成的 ME 在水中形成“储库”。偏光显微镜显示，对于 LC-MEs，在水/ME 界面处自发形成 LC 边界，其中 LC-ME2 形成的 LC 层厚得多。由 CE 形成的 ME 的水诱导转变产生的 CE 具有比 ME 更高的粘度，但比由 LC-MEs 产生的 LC 低。与 LC-ME1 相比，LC-ME2 经历了更快速的相转变，并且所得 LC 具有显著更高的粘度。两种 ME 制剂形成的 LC 均表现出假塑性；增加剪切速率会使表观粘度呈指数下降。SC 注射到动物大腿后，LC-ME 以一级方式更持久地释放 (99m)Tc，比 CE-ME 更持久。贫油 LC-ME2 的释放最慢，t1/2 为 77min，比富油 LC-ME1 长 2.3 倍；与体外观察到的 LC 层形成的厚度及其相对粘度一致。总之，本体内研究证明了 ME 作为血管外可注射药物传递系统用于持续释放的应用。载体在注射部位的保留和释放速率主要由其相转变而不是 ME 类型或油含量决定。
