Pre-exposure prophylaxis (PrEP) has emerged as a prominent approach for the prevention of HIV infections. While the latest advances have resulted in effective oral and injectable product options, there are still gaps in on-demand, event-driven, topical products for HIV prevention that are safe and effective. Here we describe the formulation development of a dual-compartment topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) that may be administered when needed, vaginally or rectally, pre- or post-coitus, for flexible HIV prophylaxis. Specifically, we describe the lab-scale formulation development, preclinical mucosal safety and pharmacokinetics (PK) testing in rabbits, long-term stability, and scale-up clinical manufacturing of the lead TAF/EVG (20 mg/16 mg) inserts, which are currently in clinical stages of development. As designed, the inserts are small, discreet and portable, offering a number of promising attributes, such as simple and robust direct-compression manufacturing, fast initial disintegration/dissolution, and suitable mechanical strengths showing low hardness (<8 kg), friability (<1 %), and moisture content (<1 %). The inserts initiated disintegration quickly (∼ ≤ 15 min) providing full in vitro release (>90 %) of TAF and EVG within 60 min of dissolution. The lead insert was selected from formulation prototypes that met the evaluation criteria for manufacturability and characterization, along with a dose-ranging PK study in non-human primates. Successful technology transfer for clinical development of the lead TAF/EVG (20 mg/16 mg) insert was confirmed under current Good Manufacturing Practices (cGMP) conditions. Based on the 12 months (lab-scale) and 24 months (clinical batch) stability data, the TAF/EVG inserts are projected to have a long shelf life of over 2 years, if stored at or below 30 °C/65 % RH. Overall, these newly designed topical inserts have formulation properties that enable stable storage and fast release of the antiretroviral payload from a small, portable and discreet dosage form. They are safe and effective when applied vaginally or rectally, before or after coitus, providing the basis for a new method of flexible on-demand HIV prevention for cisgender and transgender women and men. The TAF/EVG inserts are currently the most clinically advanced on-demand topical product, as attested by their completed and ongoing clinical trials.

中文翻译：

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结合替诺福韦艾拉酚胺和艾替拉韦的双室局部插入剂的配方开发，用于灵活的按需 HIV 预防


暴露前预防 （PrEP） 已成为预防 HIV 感染的重要方法。虽然最新进展带来了有效的口服和注射产品选择，但在安全有效的按需、事件驱动、用于 HIV 预防的局部产品方面仍然存在差距。在这里，我们描述了含有富马酸替诺福韦艾拉酚胺 （TAF） 和艾替拉韦 （EVG） 的双室局部插入物的配方开发，可以在需要时通过阴道或直肠、前或后给药，用于灵活的 HIV 预防。具体来说，我们描述了实验室规模的制剂开发、兔子临床前粘膜安全性和药代动力学 （PK） 测试、长期稳定性以及先导 TAF/EVG （20 mg/16 mg） 插入物的放大临床生产，目前处于临床开发阶段。按照设计，嵌件体积小、隐蔽且便于携带，具有许多有前途的特性，例如简单而坚固的直接压缩制造、快速的初始崩解/溶解以及显示低硬度 （<8 kg）、脆性 （<1 %） 和水分含量 （<1 %） 的适当机械强度。插入片段在溶解后 60 分钟内（∼ ≤ 15 分钟）开始崩解，在体外完全释放 （>90 %） 的 TAF 和 EVG。先导插入物是从符合可制造性和表征评估标准的配方原型中选出的，以及在非人灵长类动物中进行的剂量范围的 PK 研究。在当前的良好生产规范 （cGMP） 条件下，已确认用于先导 TAF/EVG （20 mg/16 mg） 插入物临床开发的成功技术转让。 根据 12 个月（实验室规模）和 24 个月（临床批次）稳定性数据，如果在 30 °C/65 % RH 或以下储存，TAF/EVG 插件的保质期预计超过 2 年。总体而言，这些新设计的外用插入物具有配方特性，能够从小型、便携和隐蔽的剂型中稳定储存和快速释放抗逆转录病毒有效载荷。它们在阴道或直肠、之前或之后使用时是安全有效的，为顺性别和跨性别女性和男性灵活的按需 HIV 预防新方法提供了基础。TAF/EVG 插入物是目前临床上最先进的按需外用产品，其已完成和正在进行的临床试验证明了这一点。