Dallal Bashi Yahya H, Zhao Xinyu, McCoy Clare F, Kumar Narender, Teleshova Natalia, Lamb Dolores J, Fernández Romero José A, Meyer Abigail, Barnable Patrick, Aravantinou Meropi, Asowata Osaretin E, White Melissa A, Travis Alexander J, Haddad Lisa B, Shen Xin, Young Vicky-Leigh, Boyd Peter, Malcolm R Karl
College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL, UK.
Int J Pharm. 2025 Nov 10;684:126120. doi: 10.1016/j.ijpharm.2025.126120. Epub 2025 Aug 26.
Lactic acid is the most abundant organic weak acid in the healthy human vagina and plays a pivotal role in maintaining an acidic vaginal environment protective against exogenous bacteria and viruses. However, in dysbiotic or non-optimal vaginal environments, significantly decreased concentrations of lactobacilli result in reduced lactic acid production, increased vaginal pH, and enhanced risk of sexually transmitted infections (including human immunodeficiency virus), and bacterial vaginosis. Various gel-based products are marketed to administer lactic acid vaginally for the treatment of bacterial vaginosis and non-hormonal contraception, and there is interest in developing vaginal ring products for sustained/controlled release of lactic acid. However, lactic acid is not compatible with the most common addition-cure type of silicone elastomer used to manufacture vaginal rings; the carboxylic acid group inhibits the hydrosilylation reaction used to cure the elastomer system. Here, we report that DL-lactide-a racemic mixture of (R,R)-D-lactide and (S,S)-L-lactide, in which the dilactide molecules are cyclic lactones derived from esterification of two molecules of lactic acid-can be successfully incorporated into and released from addition-cure medical grade silicone elastomer vaginal rings. Following release of lactide from the rings into an aqueous medium, the lactide molecule rapidly hydrolyses to produce only lactic acid. We demonstrate that lactic acid (i) is formed f release of lactide from the rings; (ii) inhibits sperm motility, (iii) inhibits replication of HIV-1 and HSV-2, and (iv) is active against Gardnerella vaginalis (one of the causative organisms responsible for bacterial vaginosis) but not lactobacillus (associated with optimal human vaginal health). The results support the inclusion of lactide as a lactic acid prodrug in next-generation multipurpose contraceptive silicone elastomer vaginal rings.
乳酸是健康人类阴道中含量最丰富的有机弱酸，在维持阴道酸性环境以抵御外源细菌和病毒方面发挥着关键作用。然而，在阴道生态失调或非最佳阴道环境中，乳酸杆菌浓度显著降低会导致乳酸生成减少、阴道pH值升高，以及性传播感染（包括人类免疫缺陷病毒）和细菌性阴道病的风险增加。各种基于凝胶的产品被推向市场，用于阴道给药乳酸以治疗细菌性阴道病和非激素避孕，并且人们对开发用于乳酸持续/控释的阴道环产品也很感兴趣。然而，乳酸与用于制造阴道环的最常见的加成固化型硅氧烷弹性体不相容；羧酸基团会抑制用于固化弹性体体系的硅氢化反应。在此，我们报告（R,R）-D-丙交酯和（S,S）-L-丙交酯的外消旋混合物DL-丙交酯（其中二丙交酯分子是由两分子乳酸酯化形成的环状内酯）可以成功地掺入加成固化医用级硅氧烷弹性体阴道环并从其中释放出来。丙交酯从环中释放到水性介质后，丙交酯分子迅速水解，仅产生乳酸。我们证明乳酸（i）由环中丙交酯的释放形成；（ii）抑制精子活力；（iii）抑制HIV-1和HSV-2的复制；（iv）对阴道加德纳菌（细菌性阴道病的致病生物之一）有活性，但对乳酸杆菌（与最佳人类阴道健康相关）无活性。这些结果支持将丙交酯作为乳酸前药纳入下一代多功能避孕硅氧烷弹性体阴道环中。
