Development of Transdermal Films for the the Delivery of HIV Therapeutics

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）已成功用于hiv感染者，可显著减少疾病进展并改善感染者的预后。然而，HAART疗法的副作用、毒性和药物-药物相互作用导致患者对药物方案的依从性降低，助长了耐药性的发展。因此，持续需要新的和改进的抗逆转录病毒药物。目前的arv靶向HIV复制的五个步骤，包括抑制病毒进入（CCR5拮抗和融合抑制）以及抑制病毒特异性酶逆转录酶、整合酶和蛋白酶。尽管在这些现有药物类别中，新一代抑制剂的功效和毒性不断得到改善，但考虑开发针对艾滋病毒复制所需的其他步骤的新药物也很重要。这些新药物有望对现有的耐药和多重耐药病毒保持充分的活性，因此可能是现有HAART方案的高效补充，或在长期RT和蛋白酶抑制剂治疗失败的患者中作为挽救治疗方案的组成部分。很明显，继续开发具有增强效力、降低毒性、更大的耐药遗传屏障以及靶向其他HIV复制步骤的新药物，是HIV治疗持续有效性的关键需求。ImQuest Pharmaceuticals正在开发IQP-0410，一种高效的非核苷嘧啶二酮（PYD） HIV-1抑制剂，分子量为352 g/mol。在重复抗病毒试验中，该化合物显示出大约100万到400万的治疗指数，表明它对HIV-1的活性比奈韦拉平和早期nnrti高几个数量级，与Sustiva的效力相似。但没有Sustiva报道的明显毒性虽然IQP-0410的主要作用机制是抑制病毒逆转录酶（RT），在亚纳摩尔浓度下作为典型的第三代非核苷类RT抑制剂（NNRTI），但该化合物也在纳摩尔浓度下抑制病毒进入。这种双重作用机制为选择iip -0410耐药病毒提供了高度的遗传屏障，体外实验表明，iip -0410对临床相关的耐药病毒株和对蛋白酶抑制剂耐药的多重耐药病毒株具有显著的活性。由于其溶解度低，难以通过粘膜到达作用靶点，嘧啶二酮作为一种治疗药物面临着很大的障碍。因此，战略性给药设计对于嘧啶二酮作为可行的HAART产品推进至关重要。通过常规给药，如注射或口服，PYD将受到肝脏广泛的首过代谢限制其有效性。我们提出透皮膜是一种创新的药物递送策略，通过聚合物配方提高PYD的治疗效果和递送。具体来说，经皮膜给药比传统给药有许多优点，如提高患者对长期治疗的依从性，绕过首过代谢，持续给药，避免血浆中给药峰谷，最大限度地减少患者间和患者内部的变异性，并允许治疗终止。我们建议该项目将确定一种透皮膜配方，以提高功效并允许长期治疗iip -0410。

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has been successfully utilized in HIV-infected individuals to significantly reduce disease progression and improve the prognosis of infected individuals. However, the side-effects, toxicity, and drug-drug interactions of HAART therapies have resulted in reduced patient adherence to the drug regimens, fueling the development of drug resistance. Thus, a continuing need for new and improved antiretroviral agents exists. Current ARVs target five steps in HIV replication, and include inhibition of virus entry (CCR5 antagonism and fusion inhibition) and inhibition of the virus-specific enzymes reverse transcriptase, integrase and protease. Although improvements in the efficacy and toxicity of new generation inhibitors in these existing classes of drugs continues to occur, it is also important to consider the development of new and novel drugs targeting additional required steps in HIV replication. These new agents would be expected to remain fully active against existing drugresistant and multi-drug resistant viruses and thus might be highly effective supplements to existing HAART regimens or constituents of salvage therapy regimens in patients failing long courses of RT and protease inhibitor therapies. It is clear that the continued development of new agents with enhanced potency, reduced toxicity, and a greater genetic barrier to resistance, as well as targeting other HIV replication steps, is a critical need for the continued effectiveness of HIV therapy ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione (PYD) inhibitor of HIV-1 with a molecular weight of 352 g/mole. The compound exhibited a therapeutic index of approximately one to four million in replicate antiviral assays, indicating that it was several orders of magnitude more active against HIV-1 than nevirapine and the early NNRTIs and of similar potency to Sustiva. but without the significant toxicities reported for Sustiva.. Although the primary mechanism of action of IQP-0410 is inhibition of the viral reverse transcriptase (RT), acting as a typical third generation nonnucleoside RT inhibitor (NNRTI) at sub-nanomolar concentrations, this compound also inhibits viral entry at nanomolar concentrations. The dual mechanism of action confers a high genetic barrier to the selection of IQP-0410-resistant viruses and in vitro assays have shown significant activity of IQP-0410 against clinically relevant drug resistant virus strains and against multi-drug resistant virus strains with resistance to protease inhibitors. Due to low solubility and poor penetration through the mucosa to the target site of action, pyrimidinediones face significant obstacles as a therapeutic. Therefore, strategic drug delivery designs are essential for pyrimidinediones to advance as viable HAART products. Through conventional administration, such as injections or oral, PYD would be subjected to extensive first pass metabolism by the liver limiting its effectiveness. We propose transdermal films an innovative drug delivery strategy to enhance PYD therapeutic efficacy and delivery through polymeric formulations. Specifically, transdermal films delivery has many advantages over conventional administration such as improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. We propose that this project will identify a transdermal film formulation that will enhance efficacy and allow long term therapeutic delivery of IQP-0410. PUBLIC HEALTH RELEVANCE: ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione inhibitor of HIV-1, as a therapeutic drug. ImQuest Biosciences will utilize their expertise in HIV drug development and formulation to develop a novel delivery system transdermal films. This delivery vehicle will provide constant HIV therapeutics in a solid dosage form that has the advantage of improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. The research to be performed will include development of the transdermal film and the evaluation of its ability to deliver a therapeutic amount of IQP-0410 over long periods of time.