Development of a novel nanoparticle pyrimidinedione vaginal polymeric film as an

描述(申请人提供)：嘧啶二酮类(PYD)是高效的小分子抑制剂，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化合物在体外表现出作为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的进入抑制物的纳摩尔水平的活性。然而，随着杀微生物剂化合物的开发，作为该化合物配方一部分的交付问题已经滞后，导致产品开发的严重延误。由于嘧啶二酮类化合物的溶解度低，不易通过粘膜进入作用靶点，因此在作为杀菌剂时面临着巨大的障碍。战略给药设计对于嘧啶二酮类化合物作为可行的杀微生物剂产品的发展至关重要。我们提出了一系列创新的药物输送策略，通过聚合物生物化学配方来增强PYD抗艾滋病毒的疗效。具体地说，纳米颗粒包裹已经被用来克服使用疏水药物分子时的许多挑战；然而，它作为阴道给药系统的用途还没有被研究过。在该项目的R21阶段，我们建议开发纳米颗粒包裹的PYD作为一种新的药物递送方法，通过增加药物的长期释放，防止酶降解，增强粘膜下组织穿透和细胞定位来提高抑制HIV活性的效力。此外，我们还建议将纳米PYD制剂进一步配制成经阴道给药的聚合物薄膜剂型。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给药系统(凝胶、乳膏、阴道内环)中观察到的几个可接受性和依从性问题。我们的纳米颗粒PYD薄膜给药方法在杀微生物剂开发中提供了多项创新优势，包括无需重新配制有效药物成分(API)即可增强表观活性，通过受控药物释放实现长时间的艾滋病毒保护，使此类杀菌剂具有两性独立，以及引入一种通过阴道薄膜给药的新方法，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估，以确认PYD纳米颗粒在生物相关条件下的功效。将在专门设计的体外试验中对可生物降解的纳米颗粒中的PYD进行表征和评估，以确定药物的靶向和释放。此外，纳米颗粒PYD的抗HIV效果将在体外生物学相关测试中与未配制的PYD进行比较，以确定最佳配方。最后，将该制剂引入固体阴道膜剂中，以评价其预防艾滋病毒的生物学特性。

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.