School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , CMU-Rue Michel Servet 1 , 1211 Geneva 4 , Switzerland.
Faculty of Biology and Medicine , University of Lausanne , Rue du Bugnon 21 , 1011 Lausanne , Switzerland.
Mol Pharm. 2020 Jan 6;17(1):59-69. doi: 10.1021/acs.molpharmaceut.9b00707. Epub 2019 Dec 5.
Sustained-release formulations for ocular delivery are of increasing interest given their potential to significantly improve treatment efficacy and patient adherence. The objectives of this study were (i) to develop a sustained-release formulation of spironolactone (SPL) using a biodegradable and injectable polymer, hexyl-substituted poly-lactic acid (hexPLA) and (ii) to investigate the ocular biodistribution and tolerability of SPL and its metabolites in rats in vivo over 1 month following a single intravitreal injection (IVT inj). The concentrations of SPL and its two principal active metabolites, 7α-thiomethylspironolactone and canrenone (CAN), in the different ocular compartments were determined at different time points (3, 7, and 31 days after IVT inj) using a validated ultra-high-performance liquid chromatography-mass spectrometry method. Systemic exposure following a single IVT inj of 5% SPL-hexPLA formulation was evaluated by quantifying SPL and its metabolites in the plasma. Ocular tolerability of the formulation was evaluated using in vivo retinal imaging and histology. In vitro release studies revealed a sustained release of SPL from 5% SPL-hexPLA for up to 65 days. In vivo studies showed that SPL and its metabolites were detected in all ocular tissues at 3 and 7 days post-IVT inj. At 31 days post-IVT inj, SPL and CAN were mainly detected in the retina. These results also highlighted the clearance pathway of SPL and its metabolite involving the anterior and posterior routes in the first week (days 3 and 7), then mainly the posterior segment in the last week (day 31). This study showed that a single IVT inj of 5% SPL-hexPLA in rats enabled sustained delivery of therapeutic amounts of SPL for up to 1 month to the retina without systemic exposure. This formulation may be of interest for the local treatment of diseases involving overactivation of the mineralocorticoid receptor in the chorioretina such as chronic central serous chorioretinopathy.
由于其潜在的显著提高治疗效果和患者依从性，眼部递药的缓释制剂越来越受到关注。本研究的目的是：（i）使用可生物降解和可注射的聚合物己基取代聚乳酸（hexPLA）来开发螺内酯（SPL）的缓释制剂；（ii）研究 SPL 及其两种主要活性代谢物 7α-硫甲基螺内酯和坎利酮（CAN）在大鼠单次玻璃体内注射（IVT inj）后 1 个月内的眼部分布和体内耐受性。采用经验证的超高效液相色谱-质谱法，在不同时间点（IVT inj 后 3、7 和 31 天）测定不同眼部隔室中 SPL 及其两种主要活性代谢物的浓度。通过定量分析血浆中 SPL 及其代谢物，评估单次 IVT inj 5% SPL-hexPLA 制剂后的系统暴露情况。采用体内视网膜成像和组织学评价制剂的眼部耐受性。体外释放研究表明，5% SPL-hexPLA 制剂可在长达 65 天内持续释放 SPL。体内研究表明，在 IVT inj 后 3 和 7 天，所有眼部组织均检测到 SPL 及其代谢物。在 IVT inj 后 31 天，SPL 和 CAN 主要在视网膜中检测到。这些结果还突出了 SPL 及其代谢物的清除途径，在前 7 天（第 3 和第 7 天）涉及前、后途径，然后在后 1 周（第 31 天）主要涉及后段。本研究表明，在大鼠中单次玻璃体内注射 5% SPL-hexPLA 可使 SPL 以治疗剂量持续释放长达 1 个月到达视网膜，而无系统暴露。该制剂可能对治疗涉及脉络膜视网膜中盐皮质激素受体过度激活的疾病（如慢性中心性浆液性脉络膜视网膜病变）有局部治疗作用。
