School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK,
Drug Deliv Transl Res. 2015 Feb;5(1):27-37. doi: 10.1007/s13346-015-0216-4.
This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.
本研究描述了一种基质型硅酮弹性体阴道环装置的临床前开发，该装置旨在提供 UC781 的控制释放，UC781 是非核苷类逆转录酶抑制剂。在体外释放模型中，对人和猕猴大小的环进行水槽条件测试，结果表明 UC781 持续释放，释放量足以将阴道液浓度维持在高于体外 IC50（2.0 至 10.4 nM）82-860 倍的水平，从而有可能预防 HIV 经粘膜传播。100 毫克 UC781 环在长尾猕猴中耐受性良好，通过细胞因子分析确定未引起局部炎症，并在 28 天研究过程中维持阴道液中 UC781 的中位数浓度在 0.27 至 5.18 mM 之间。完成体外释放和猕猴药代动力学研究后，对环中残留 UC781 含量的分析表明，分别释放了 57 和 5 毫克 UC781。对长尾猕猴中 100 毫克 UC781 阴道环的药代动力学分析显示体内-体外相关性较差，这归因于 UC781 在阴道液中的溶解度非常差，导致溶解控制的药物释放机制，而不是预期的扩散控制机制。
