Microneedle-enhanced codrug delivery for smoking cessation and appetite suppressi

微针增强联合药物输送用于戒烟和食欲抑制

• 批准号: 8303925
• 负责人: Audra L. Stinchcomb
• 金额: $ 20.36万
• 依托单位: ALLTRANZ, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303925
• 关键词: Adjuvant; Adverse effects; Appetite Depressants; Area; Body Weight; Body Weight decreased; Brain; Bupropion; Cancer Etiology; Cardiovascular system; Cavia; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Clinical; Comorbidity; Data; Databases; Desire for food; Dose; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Female; Heating; Human; Human Volunteers; Hybrids; Hydrogen Bonding; Hydrolysis; In Vitro; Kinetics; Link; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metabolic; Metabolism; Methods; Modification; Molecular; Naltrexone; Nicotine; Painless; Patients; Penetration; Permeability; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phentermine; Physiological; Process; Prodrugs; Property; Recommendation; Regulation; Route; Series; Skin; Smoking; Solubility; Solvents; Structure; Synthesis Chemistry; System; Testing; Therapeutic; Therapeutic Effect; Time; Tobacco; Tobacco Dependence; Tobacco smoke; Tobacco use; Toxicity Tests; Translating; United States; Weight Gain; Weight maintenance regimen; Weight-Loss Drugs; Withholding Treatment; Woman; chemical stability; cigarette smoking; cost effective; design; drug efficacy; improved; in vivo; in vivo Model; increased appetite; lipophilicity; malignant breast neoplasm; melting; naltrexol; novel; premature; recidivism; reinforcer; smoking cessation; water solubility

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.

描述（由申请方提供）：烟草成瘾是一个多因素过程，受烟草烟雾暴露的许多药理学和生理学效应的调节。除了众所周知的烟草衍生的尼古丁对大脑多巴胺能系统的影响外，其他次级代谢物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，增加细胞代谢率，导致体重稳定或减少。目前的戒烟治疗失败的情况下，高达70%，由于各种个性化的原因。累犯的主要原因之一，尤其是女性，是体重增加的可能性。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药物递送方法来测试一种新的药理学方法，我们假设这将增强戒烟的努力。安非他酮被认为是戒烟的一线治疗药物，但这种药物的疗效相对较低。羟基安非他酮（BUPOH）是安非他酮的活性代谢物，与安非他酮相比，其可能具有显著的药物递送和治疗效果优势，包括更好的化学稳定性、降低的代谢药物相互作用潜力以及在相关药物靶点处的相等或更高的效力。BUPOH本身不具有允许治疗剂量的药物穿过人体皮肤屏障的基本物理化学性质。针头增强透皮给药是一种有效、无痛的增加药物经皮渗透的方法。拟议的研究将测试BUPOH联合药物的化学修饰优化是否会增强其微针辅助皮肤渗透，使其适合透皮给药。羟基安非他酮将与广泛使用的食欲抑制剂芬特明（PHEN）化学结合。如果通过透皮给药以恒定速率给药，则PHEN应具有更可耐受的副作用概况。我们假设，与戒烟药物BUPOH相关的PHEN的经皮联合药物（相互前药或混合药物）将成为戒烟和减肥的有效微针增强经皮药物疗法。该项目的具体目标是：1 -合成一系列PHEN和BUPOH的共同药物，旨在阐明定量结构-渗透性关系（QSPR）的微针增强的透皮通量和随后的生物转化率。2 -使用微针在体外测量药物在皮肤中的渗透和同时的生物转化，和3 -使用微针在体内表征药物在豚鼠中的药代动力学。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 我们的数据库为微针使用的经皮联合药物提供了一个数据库，并有助于确定最有前途的联合药物/微针系统，以供最终人类使用。 公共卫生相关性：在美国，可预防死亡的主要原因是吸烟，每年有超过44万人过早死亡。众所周知，吸烟会降低食欲，增加细胞代谢率，导致体重稳定或减少。试图戒烟的人再犯的主要原因之一是体重增加的可能性，特别是在女性中。尽管许多关于戒烟和体重增加的研究结果各不相同，但主要建议是将减肥治疗与戒烟结合起来。流行的减肥药芬特明与戒烟药羟基安非他酮的经皮联合用药（相互前药或混合药物）可能是治疗合并症的理想药物。