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)已成功应用于艾滋病毒感染者，显著减缓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，加剧了耐药性的发展。因此，对新的和改进的抗逆转录病毒药物的持续需求存在。目前的抗逆转录病毒药物针对HIV复制的五个步骤，包括抑制病毒进入(CCR5拮抗和融合抑制)和抑制病毒特异性酶逆转录酶、整合酶和蛋白酶。尽管这些现有药物中新一代抑制剂的疗效和毒性不断提高，但考虑开发针对艾滋病毒复制所需额外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药耐药病毒保持完全有效的作用，因此可能是现有HAART方案的高效补充，或者是未能接受长疗程RT和蛋白酶抑制剂治疗的患者抢救治疗方案的组成部分。显然，继续开发效力更强、毒性更低、抗药性遗传屏障更大的新药物，以及针对其他艾滋病毒复制步骤，是艾滋病毒治疗持续有效的关键需要。ImQuest制药公司正在开发IQP-0410，这是一种高效的艾滋病毒-1非核苷嘧啶二酮(PYD)抑制剂，分子量为352g/摩尔。在重复的抗病毒试验中，该化合物的治疗指数约为100万至400万，表明它对HIV-1的活性比奈韦拉平和早期的NNRTIs高几个数量级，与Sustiva的效力相似。但如果没有苏斯提瓦的重大毒副作用..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RT抑制剂(NNRTI)，但该化合物也在纳摩尔浓度下抑制病毒入侵。这种双重作用机制为IQP-0410耐药病毒的筛选提供了很高的遗传障碍，体外试验表明IQP-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。由于药物的低溶解性和通过粘膜对靶作用部位的穿透性差，嘧啶二酮类药物的治疗面临着巨大的障碍。因此，战略给药设计对于嘧啶二酮类药物作为可行的HAART产品的发展至关重要。通过常规给药，如注射或口服，PYD会受到肝脏的广泛首过代谢，限制了其疗效。我们提出了透皮膜，一种创新的药物传递策略，以提高PYD的治疗效果和通过聚合物制剂传递。具体地说，透皮膜给药比传统给药有许多优点，如改善患者长期治疗的依从性，绕过首过代谢，持续给药，避免药物在血浆中的峰和谷剂量，最大限度地减少患者间和患者内的变异性，并允许终止治疗。我们建议这个项目将确定一种透皮薄膜配方，将提高疗效，并允许长期治疗提供IQP-0410。 公共卫生意义：ImQuest制药公司正在开发一种治疗药物IQP-0410，这是一种高效的HIV-1非核苷嘧啶二酮抑制剂。ImQuest生物科学公司将利用他们在艾滋病毒药物开发和配方方面的专业知识，开发一种新型的给药系统透皮膜。这一输送载体将以固体剂型提供恒定的艾滋病毒治疗药物，其优势在于提高了患者在长期治疗中的依从性，绕过了首过代谢，持续给药，避免了药物在血浆中的峰谷剂量，最大限度地减少了患者之间和患者内部的变异性，并允许终止治疗。将要进行的研究将包括透皮膜的开发和对其长期输送治疗量IQP-0410的能力的评估。

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.