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 女性的方法。通过替代药物输送技术为妇女提供选择， 影响粘附性。一个令人信服的战略包括共同提供抗艾滋病毒剂与避孕剂， 预防怀孕。该提案计划开发下一代多用途预防技术（MPT） 用于每月一次阴道内施用4 '-乙炔基-2-氟-2'-脱氧腺苷（EFdA）的薄膜平台 前药（EFdA-P）和孕激素（左炔诺孕酮（LNG）或依托孕烯（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渗透性增加 与母体EFdA相比，EFdA是一种非常有效的令人兴奋的新型抗病毒药物。这种多功能的延长释放MPT 一个电影平台的目的是提供一个离散的，低成本和方便的替代妇女在高风险的艾滋病毒 感染和意外怀孕。 我们实验室最近的数据表明，即使在阴道中，薄膜也可以在阴道中提供长达1个月的抗艾滋病毒药物。 月经和性交的背景。利用这些知识和我们的专业知识， 阴道内电影，这项建议将开发一个电影平台，共同提供一种避孕药（许可避孕药 试剂）和EFdA-P以预定速率施用至少1个月。含有EFdA的MPT膜也将在 生成用于比较。此里程碑驱动提案的R61阶段将生成关键的预制定 EFdA/EFdA-P和LNG/ENG药物组合的数据，并优化MPT膜制剂，以实现单- 两种药物的月递送具有所需的短期稳定性。此阶段还将确定以下内容的兼容性： 在体外用阴道组织和微生物植物群的薄膜原型，然后在非阴道内进行阴道滞留研究。 人灵长类动物（NHP）模型。R61阶段将展示MPT薄膜原型的能力， 两种药物在体内的期望释放曲线（NHP模型）。使用明确定义的go / no go标准， MPT膜将过渡到R33相。R33阶段将涉及IND使能活动，包括药物- 药物相互作用、体外转运蛋白和代谢研究、生产规模扩大和建立长期 铅MPT膜的稳定性。还将证明电极导线的安全性（大鼠、家兔和NHP）和有效性 MPT膜在NHP模型中抗SHIV感染。它也将证实电影在语境中发挥作用的能力 在NHP模型中，性活动和其提供避孕水平的孕激素的能力。成功 完成拟议的工作将产生一个新的延长释放MPT电影平台，可应用于 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.