Clinical Evaluation of Novel Methods for Extending Microneedle Pore Lifetime

描述(由申请人提供)：这项名为“延长微针毛孔寿命的新方法的临床评估”的拟议研究项目的长期目标是通过延长将微针插入皮肤产生的毛孔的寿命来改进目前的经皮给药方法。改进经皮给药技术(通过使用微针)将具有重要的临床意义，因为它提供了一种侵入性较小的系统给药方法，这将导致更大的患者安全性和依从性。这也可能对开发更好的酒精中毒和阿片成瘾治疗方法具有重要意义，因为这项提案审查了微针植入后纳曲酮(一种用于治疗阿片类药物和酒精滥用的阿片类拮抗剂)的输送情况。有效的经皮给药将是目前口服和注射用纳曲酮的极佳替代品。该提案的具体目的包括1)抑制环氧合酶(COX)途径作为抑制孔道关闭的手段，2)纳曲酮的药代动力学分析以表征COX抑制后的孔道寿命，以及3)使用小干扰RNA(SiRNA)方法抑制孔道关闭。研究方法将涉及使用体外和体内模型(细胞培养、qRT-PCR、ELISA)、动物模型(无毛豚鼠和尤卡坦小型猪)和人体研究。提案中描述的许多方法涉及商业上可获得的产品的新应用，或者开发利用微针改善经皮给药的创新手段。研究这些化合物和给药方法使在人类概念验证研究中进行翻译生物工程和生物制药培训研究成为可能。

DESCRIPTION (provided by applicant): The long-term objective of the proposed research project entitled "Clinical evaluation of novel methods for extending microneedle pore lifetime" is to improve current methods of transdermal drug delivery by increasing the lifetime of pores created from inserting microneedles into the skin. Improvement of transdermal drug delivery techniques (via the use of microneedles) would have important clinical implications by providing a less invasive means to deliver drugs systemically, which would lead to greater patient safety and compliance. This could also have strong implications in developing better treatments for alcoholism and opiate addiction, as this proposal examines the delivery of naltrexone (an opiate antagonist used for the treatment of opioid and alcohol abuse) following microneedle insertion. Effective transdermal delivery would be an excellent alternative to the current oral and parenteral formulations of naltrexone. The specific aims of the proposal include 1) inhibition of the cyclooxygenase (COX) pathway as a means to inhibit pore closure, 2) pharmacokinetic analysis of naltrexone to characterize pore lifetime following COX inhibition, and 3) employing small-interfering RNA (siRNA) methods to inhibit pore closure. The research methods will involve the use of in vitro and in vivo models (cell culture, qRT-PCR, ELISAs), animal models (hairless guinea pigs and Yucatan miniature pigs), and human studies. Many of the methods described in the proposal involve novel applications of commercially available products, or development of innovative means to improve transdermal drug delivery with the use of microneedles. Studying these compounds and delivery methods makes it feasible to do translational bioengineering and biopharmaceutical training research in human proof-of-concept studies.