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，受烟草烟雾暴露的一些药理和生理效应调节。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，其他次级增强剂，如体重调节，也参与了烟草的强迫使用。众所周知，吸烟会降低食欲，增加细胞新陈代谢的速度，导致身体质量稳定或减少。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。再次犯罪的主要原因之一，特别是在女性中，是体重增加的可能性。戒烟期间体重增加的问题已经有了很好的记录，研究一直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的经皮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加强戒烟努力。安非他酮被认为是戒烟的一线药物，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，与安非他酮相比具有显著的药物释放和疗效优势，包括更好的化学稳定性，降低的代谢药物相互作用势，以及在相关药物靶点上具有同等或更高的效力。BUPOH本身并不具有允许治疗性剂量的药物通过人体皮肤屏障的基本物理化学性质。微针强化透皮给药是一种有效且无痛的方法，可增加多种药物的皮肤渗透性。拟议的研究将测试BUPOH辅药的化学修饰优化是否会增强其微针辅助的皮肤渗透，使其适合经皮给药。羟基安非他酮将与广泛使用的食欲抑制药苯丙酮(Phen)进行化学结合。如果通过经皮给药以恒定的速率给药，苯酚应该有更易耐受的副作用。我们假设，与戒烟药物BUPOH相连的Phen透皮辅药(相互前药或混合药物)将成为一种有效的微针增强型经皮戒烟和减肥药物。本项目的具体目标是：1-合成一系列Phen和BUPOH辅助药物，旨在阐明微针增强的透皮通量和随后的生物转化率的定量结构-通透性关系(QSPR)。2-用微针测定药物的体外透皮吸收和并行生物转化；3-用微针测定药物在豚鼠体内的药代动力学。我们的体外数据与体内模型的关联将有助于创建可靠的QSPR 使用微针的透皮辅药数据库，以及帮助确定最终供人类使用的最有前景的辅药/微针系统。 与公共健康相关：在美国，吸烟是可预防死亡的主要原因，每年有超过44万人过早死亡。众所周知，吸烟会降低食欲，增加细胞新陈代谢的速度，导致身体质量稳定或减少。试图戒烟的人再次犯罪的主要原因之一是体重可能增加，特别是在女性身上。尽管许多关于戒烟和体重增加的研究结果各不相同，但主要的建议是将减肥治疗与戒烟结合起来。广受欢迎的减肥药苯丙氨酸与戒烟药物羟基安非他酮联用的透皮辅药(相互前药或混合药物)可能是治疗这种共病的理想药物。

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. PUBLIC HEALTH RELEVANCE: The leading cause of preventable deaths in the United States is cigarette smoking, with over 440,000 premature deaths occurring each year. Cigarette smoking is known to reduce appetite and increase the rate of cellular metabolism, leading to body mass stabilization or reduction. One of the main reasons for recidivism in persons trying to quit smoking is the potential for weight gain, especially in women. Regardless of the varied findings of the many studies on smoking cessation and weight gain, the primary recommendation has been to incorporate weight loss treatment with smoking cessation. A transdermal codrug (mutual prodrug or hybrid drug) of the popular weight-loss drug phentermine linked to a smoking cessation drug, hydroxybupropion, could be the ideal pharmacotherapy for the comorbidity.