Microneedle-enhanced codrug delivery for smoking cessation and appetite suppressi

描述（由申请人提供）：烟草成瘾是一个多因素的过程，受烟草烟雾暴露的许多药理和生理效应的调节。除了众所周知的烟草衍生尼古丁对大脑多巴胺能系统的影响外，其他次级强化因素，如体重调节，也与强迫性烟草使用有关。众所周知，吸烟会降低食欲，增加细胞新陈代谢的速度，导致体重稳定或减少。由于各种个性化的原因，目前的戒烟治疗在高达70%的病例中失败。再犯的主要原因之一，尤其是女性，是潜在的体重增加。戒烟期间体重增加的问题是有据可查的，研究一致建议将体重管理策略纳入患者管理计划。拟议的研究将使用一种新的微针增强经皮联合给药方法来测试一种新的药理学方法，我们假设这种方法将增强戒烟的努力。安非他酮被认为是戒烟的一线治疗方法，但这种药物的疗效相对较低。羟基安非他酮（BUPOH）是安非他酮的一种活性代谢物，可能比安非他酮具有显著的药物传递和治疗效果优势，包括更好的化学稳定性、更低的代谢药物相互作用潜力，以及在相关药物靶点上具有同等或更高的效力。BUPOH本身不具备允许治疗剂量的药物穿过人体皮肤屏障的基本物理化学特性。微针增强透皮给药是一种有效的无痛方法，可以增加许多药物的皮肤渗透。本研究将测试BUPOH共药的化学修饰优化是否会增强其微针辅助皮肤渗透，使其适合经皮给药。羟基安非他酮将与芬特明（phentmine，一种广泛使用的食欲抑制剂）化学结合。如果通过透皮给药以恒定速率给药，PHEN应该具有更可容忍的副作用。我们假设PHEN与戒烟药物BUPOH结合的经皮共药（相互前药或混合药）将成为一种有效的微针增强的戒烟和减肥透皮药物治疗。该项目的具体目标是：1 -合成一系列PHEN和BUPOH共药，旨在阐明微针增强透皮通量和随后的生物转化率的定量结构-渗透性关系（QSPR）。2 -测定药物在体外微针作用下在皮肤中的渗透和同步生物转化；3 -表征药物在豚鼠体内微针作用下的药代动力学。我们的体外数据与体内模型的相关性将有助于建立可靠的QSPR

DESCRIPTION (provided by applicant): Tobacco addiction is a multi-factorial process, regulated by a number of pharmacological and physiological effects of tobacco smoke exposure. In addition to the well-known effects of tobacco derived nicotine on brain dopaminergic systems, other secondary reinforcers such as body mass regulation are also involved with the compulsive tobacco use. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism, leading to body mass stabilization or reduction. Current smoking cessation treatments fail in up to 70% of cases, for a variety of individualized reasons. One of the main reasons for recidivism, especially in females, is the potential for weight gain. The problem of weight gain during smoking cessation is well documented, and studies consistently recommend incorporation of body weight management strategies to patient management plans. The proposed studies will use a novel microneedle-enhanced transdermal codrug delivery approach to test a new pharmacological approach that we hypothesize will enhance smoking cessation efforts. Bupropion is considered a first-line treatment for smoking cessation, but the efficacy of this drug is relatively low. Hydroxybupropion (BUPOH) is an active metabolite of bupropion that may have significant drug delivery and therapeutic effect advantages over bupropion, including better chemical stability, reduced metabolic drug interaction potential, and an equal or higher potency at relevant drug targets. BUPOH itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. Microneedle-enhanced transdermal delivery is an efficient and painless method for increasing the skin permeation of many drugs. The proposed studies will test whether chemical modification optimization of the BUPOH codrug will enhance its microneedle-assisted skin permeation making it suitable for transdermal delivery. Hydroxybupropion will be chemically combined with phentermine (PHEN), a widely used appetite suppressant. PHEN should have a more tolerable side-effect profile if delivered at a constant rate through transdermal delivery. We hypothesize that a transdermal codrug (mutual prodrug or hybrid drug) of PHEN linked to the smoking cessation drug, BUPOH, will make an effective microneedle-enhanced transdermal pharmacotherapy for smoking cessation and weight loss. The specific aims of this project are to: 1 - synthesize a series of PHEN and BUPOH codrugs designed to elucidate quantitative structure-permeability relationships (QSPR) for microneedle-enhanced transdermal flux and subsequent bioconversion rates. 2 - to measure the drugs' penetration and concurrent bioconversion in skin in vitro with microneedle use, and 3 - to characterize the pharmacokinetics of the drugs in guinea pigs in vivo with microneedle use. Correlation of our in vitro data with the in vivo model will aid in the creation of a reliable QSPR database for transdermal codrugs with microneedle use, as well as help to identify the most promising codrug/microneedle system for eventual human use.