Clinical Evaluation of Novel Methods for Extending Microneedle Pore Lifetime

描述（由申请人提供）：题为“延长微针孔隙寿命的新方法的临床评价”的拟议研究项目的长期目标是通过延长将微针插入皮肤中产生的孔隙的寿命来改善目前的经皮给药方法。经皮给药技术的改进（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全身给药方式，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类药物成瘾治疗方法产生重大影响，因为该提案研究了微针插入后纳洛酮（一种用于治疗阿片类药物和酒精滥用的阿片拮抗剂）的递送。有效的透皮给药将是目前纳洛酮口服和胃肠外制剂的极好替代品。该提案的具体目的包括1）抑制环加氧酶（考克斯）途径作为抑制孔闭合的手段，2）纳曲酮的药代动力学分析以表征考克斯抑制后的孔寿命，以及3）采用小干扰RNA（siRNA）方法抑制孔闭合。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。该提案中描述的许多方法涉及市售产品的新应用，或开发创新手段，以使用微针改善经皮给药。研究这些化合物和递送方法使得在人类概念验证研究中进行转化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.