Long Acting Film Technology for Contraception and HIV Prevention (LATCH)

项目摘要 几项研究(ASPIRE，VOICE)表明，坚持对艾滋病毒预防的成功至关重要 方法在女性中使用。通过替代药物递送技术为女性提供选择可以 影响依从性。一个令人信服的策略包括联合使用抗艾滋病毒药物和避孕药来 防止怀孕。该提案计划开发下一代多用途预防技术(MPT)。 月经阴道给药4‘-乙炔-2-氟-2’-脱氧腺苷(EFdA) 前药(EFdA-P)和孕激素(左旋诺孕酮(LNG)或雌孕酮(ENG))以实现以下双重目标 预防艾滋病毒感染和怀孕。EFdA-P显示生物利用度和组织通透性增加 与母体EFdA相比，EFdA是一种高效、令人兴奋的新型抗病毒药物。这款多功能的延长版MPT 电影平台旨在为艾滋病毒高危女性提供一种离散、低成本和方便的替代方案 感染和意外怀孕。 我们实验室的最新数据显示，薄膜可以在阴道内释放抗艾滋病毒药物长达1个月，即使在 月经和性交的背景。利用这些知识和我们的专业知识来开发 阴道内薄膜，这项提议将开发一个联合递送黄体酮(许可避孕药)的薄膜平台 药剂)和EFdA-P在预定的速率下至少1个月。含有EFdA的MPT薄膜也将 生成以供比较。这一里程碑驱动的建议书的R61阶段将产生关键的预先制定 EFdA/EFdA-P和LNG/ENG药物组合的数据，并优化MPT薄膜配方，以实现一 两种药物均可在一个月内交付，短期稳定性良好。这一阶段还将建立与 用阴道组织和微生物菌群的体外膜原型，随后对非阴道滞留进行研究 人类灵长类(NHP)模型。R61阶段将展示MPT薄膜原型达到 两种药物在体内的期望释放曲线(NHP模型)。使用明确定义的进行/不进行标准，销售线索 MPT薄膜将转变为R33相。R33阶段将涉及支持IND的活动，包括药物- 药物相互作用，体外转运和代谢研究，生产放大和建立长期 铅MPT薄膜的稳定性。它还将证明铅的安全性(大鼠、兔和NHP)和有效性 MPT膜在NHP模型中抗SHV感染的实验研究它还将确认电影在上下文中发挥作用的能力 在NHP模型中，性行为及其提供避孕水平孕激素的能力。成功者 拟建工作的完成将产生一种新的延长释放的MPT电影平台，可以应用于 其他药物组合。

PROJECT ABSTRACT Several studies (ASPIRE, VOICE) have shown that adherence is paramount to the success of HIV prevention methods in women. Providing women with options through alternative drug delivery technologies can positively impact adherence. A compelling strategy includes co-delivery of an anti-HIV agent with a contraceptive agent to prevent pregnancy. This proposal plans to develop a next generation multipurpose prevention technology (MPT) film platform for once a month intravaginal administration of the 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) prodrug (EFdA-P) and a progestin (levonorgestrel (LNG) or etonogestrel (ENG)) to achieve the dual goal of preventing HIV infection and pregnancy. EFdA-P showed increased bioavailability and tissue permeability compared to the parent EFdA, a highly potent exciting new antiviral drug. This versatile extended release MPT film platform is intended to provide a discrete, low cost and convenient alternative to women at high risk of HIV infection and unintended pregnancy. Recent data from our lab shows that films can deliver an anti-HIV agent in the vagina for up to 1 month even in the context of menses and sexual intercourse. Using this knowledge and our expertise in the development of intravaginal films, this proposal will develop a film platform for co-delivery of a progestin (licensed contraceptive agent) and EFdA-P at a predetermined rate for at least 1 month. MPT films containing EFdA will also be generated for comparison. The R61 phase of this milestone driven proposal will generate critical preformulation data for EFdA/EFdA-P and LNG/ENG drug combinations and optimize the MPT film formulation to achieve one- month delivery of both drugs with desired short-term stability. This phase will also establish the compatibility of film prototype with vaginal tissue and microbial flora in vitro followed by vaginal retention studies in the non- human primate (NHP) model. The R61 phase will demonstrate the ability of the MPT film prototype to attain desired release profiles of both drugs in vivo (NHP model). Using a clearly defined go / no go criteria, a lead MPT film will be transitioned to the R33 phase. The R33 phase will involve IND-enabling activities including drug- drug interaction, in vitro transporter and metabolism studies, manufacturing scale up and establishing long-term stability of the lead MPT film. It will also demonstrate the safety (rat, rabbit, and NHP) and efficacy of the lead MPT film against SHIV infection in NHP model. It will also confirm the ability of the film to function in the context of sexual activity and its ability to deliver contraceptive levels of progestin in the NHP model. The successful completion of proposed work will generate a novel extended release MPT film platform that can be applied to other drug combinations.