Development of a novel nanoparticle pyrimidinedione vaginal polymeric film as an

性状（由申请方提供）：嘧啶二酮（PYD）是一种高效小分子抑制剂，具有双重抗HIV作用机制：病毒进入抑制和非核苷逆转录酶抑制（NNRTI）。PYD化合物在体外显示出作为NNRTI的亚纳摩尔水平的活性和作为趋化因子受体结合和融合之前发生的进入抑制剂的纳摩尔水平的活性。然而，随着杀微生物剂化合物的开发，作为化合物配方一部分的递送问题已经落后，导致产品开发严重延迟。由于低溶解度和通过粘膜至作用靶位点的渗透性差，嘧啶二酮作为杀微生物剂面临显著障碍。战略性药物递送设计对于嘧啶二酮作为可行的杀微生物剂产品的发展至关重要。我们提出了一个创新的药物输送策略的组合，以提高PYD抗艾滋病毒的疗效，通过聚合物生物化学制剂。具体而言，纳米颗粒包封已被用于克服使用疏水性药物分子时存在的许多挑战;然而，尚未研究其作为阴道药物递送系统的用途。在该项目的R21阶段，我们建议开发PYD的纳米颗粒包封作为一种新的药物递送方法，通过增加长期药物释放，防止酶降解，增强粘膜下组织渗透和细胞定位来提高HIV抑制活性的效力。此外，我们提出进一步将纳米颗粒PYD制剂配制成阴道递送聚合物膜剂型。这种“速溶”固体剂型最近被提出作为一种创新的替代方案，以解决在更传统的阴道递送系统（凝胶、乳膏、阴道内环）中观察到的几个可接受性和顺应性问题。我们的纳米颗粒PYD膜递送方法在杀微生物剂开发中提供了几个创新优势，通过提出增强的表观活性而无需活性药物成分（API）重新配制，通过受控药物释放在长时间内赋予HIV保护，使这种杀微生物剂不依赖于交配，以及引入一种通过阴道膜的新型药物递送方法，该方法解决了凝胶和其他半固体剂型的许多可接受性问题。 将进行生物学表征和评价，以确认PYD纳米颗粒在生物学相关条件下的疗效。将PYD包封到可生物降解的纳米颗粒中将在专门设计的体外测定中进行表征和评估，以确定药物靶向和释放。此外，将在生物相关的体外试验中将纳米颗粒PYD的抗HIV功效与未配制的PYD进行比较，以确定最佳配方。最后，该制剂将被引入固体阴道膜剂型中，以评价其在HIV预防中的生物学特性。

DESCRIPTION (provided by applicant): Pyrimidinediones (PYD) are highly potent small molecule inhibitors that have a dual anti-HIV mechanism of action: viral entry inhibition and non-nucleoside reverse transcriptase inhibition (NNRTI). The PYD compounds have shown in vitro subnanomolar levels of activity as an NNRTI and nanomolar levels of activity as inhibitors of entry occurring prior to chemokine receptor binding and fusion. However, as microbicides compounds are being developed, delivery issues that are part of the formulation of the compound have lagged behind causing a critical delay in product development. Due to low solubility and poor penetration through the mucosa to the target site of action, Pyrimidinediones face significant obstacles as microbicides. Strategic drug delivery design is essential for Pyrimidinediones to advance as viable microbicide products. We propose a combination of innovative drug delivery strategies to enhance PYD anti-HIV efficacy through polymer biochemistry formulations. Specifically, nanoparticle encapsulation has been used to overcome many of the challenges presented when using hydrophobic drug molecules; however, its use as a vaginal drug delivery system has not been investigated. In the R21 phase of this project, we propose to develop nanoparticle encapsulation of PYD as a novel drug delivery method to improve the potency of HIV inhibition activity by increasing long term drug release, protecting against enzymatic degradation, enhancing submucosal tissue penetration and cell localization. Additionally, we propose to further formulate the nanoparticle PYD formulation into a vaginally delivery polymer film dosage form. Such "quick dissolving" solid dosage forms have recently been proposed as a innovative alternative to address several acceptability and compliance issues observed in more traditional vaginal delivery systems (gels, creams, intra-vaginal rings). Our nanoparticle PYD film delivery approach offers several innovative advantages in microbicide development by suggesting enhanced apparent activity without active pharmaceutical ingredient (API) reformulation, conferring HIV protection over long periods of time through controlled drug release, making such a microbicide coitally-independent, and introducing a novel drug delivery method through vaginal films that addresses many of the acceptability issues with gels and other semi-solid dosage forms. Biological characterization and evaluation will be preformed to confirm the efficacy of PYD nanoparticles in biologically relevant conditions. The encapsulation of PYD into biodegradable nanoparticles will be characterized and evaluated in specifically designed in vitro assays to determine drug targeting and release. Additionally, the anti-HIV efficacy of the nanoparticle PYD will be compared to unformulated PYD in biologically relevant in vitro assays to determine the optimal formulation. Finally, the formulation will be introduced into a solid vaginal film dosage form to evaluate its biological properties in HIV prevention.