Abstract：
Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber\'s hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 μg/g of tissue), followed by the conjunctiva (0.74 ± 0.18 μg/g) and sclera (0.25 ± 0.06 μg/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues. Graphical abstract.
摘要：
罂粟碱,一种溶解性差的鸦片生物碱，最近已被证明可以减少视网膜炎症，因此它可能在Leber遗传性视神经病变的治疗中具有治疗性应用。在这项研究中,制备了基于中链甘油三酯的罂粟碱滴眼液，并使用离体猪眼模型评估了二乙基二醇单乙醚（DGME）对其眼部分布的影响。还通过使眼睛定向以仅使角膜或巩膜暴露于制剂来研究药物渗透的途径。此外，进行了体内研究以确认眼部耐受性并评估眼部药物分布.我们的结果表明，在存在DGME的情况下，角膜和巩膜中的罂粟碱浓度增加，但通过角膜途径给药时，视网膜脉络膜（RC）药物浓度略有降低，这表明DGME增强了药物在眼前组织中的积累，但对后给药的影响很小。在体内,含有DGME的罂粟碱滴眼液表现出良好的眼部耐受性，在角膜中观察到最高的药物浓度（1.53±0.28μg/g组织），其次是结膜（0.74±0.18μg/g）和巩膜（0.25±0.06μg/g），分别。然而,在RC中没有检测到药物，玻璃体或血浆。总的来说,这项研究强调DGME影响眼部分布和罂粟碱的积累。此外，结果表明，对于溶解在疏水性非水性载体中的疏水性药物，通过经腹途径的角膜渗透可能是药物渗透至眼后部组织的主要途径。图形抽象。
