Gated Carbon Nanotube Membrane Transdermal Drug Delivery

门控碳纳米管膜透皮给药

• 批准号: 7652486
• 负责人: BRUCE Jackson HINDS
• 金额: $ 29.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652486
• 关键词: Affinity; Alkanes; Alkanesulfonates; Binding; Caliber; Carbon; Carbon Nanotubes; Cavia; Characteristics; Charge; Cigarette; Clonidine; Development; Devices; Dose; Drug Delivery Systems; Drug Kinetics; Electronics; Family suidae; Fentanyl; Film; Human; In Vitro; Incidence; Ionic Strengths; Iontophoresis; Ligands; Longitudinal Studies; Marketing; Membrane; Methods; Molecular; Nanotubes; Nicotine; Opiates; Patient-Controlled Analgesia; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Polymers; Polystyrenes; Production; Reaction Time; Research Personnel; Role; Safety; Security; Skin; Smoker; Solutions; Solvents; System; Therapeutic; Transdermal substance administration; Treatment Protocols; Withdrawal; aqueous; base; biomaterial compatibility; carboxylate; chronic pain; cost; craving; dosage; flexibility; improved; in vivo; irritation; programs; prototype; skin irritation; smoking cessation; success; voltage

DESCRIPTION (provided by applicant): Nicotine, fentanyl, and clonidine are established transdermal drug therapies that could be substantially improved using programmable variable drug delivery rates. With the development of a membrane that can be turned on or off with applied electrical bias, simple electronics can be employed to provide a well controlled dosing regimen, and create a security/safety feature for patch activation only when the electronic device is present. Transdermal nicotine therapy could be enhanced by creating nicotine plasma levels more similar to smokers' plasma levels, with a decreased incidence of cigarette craving. Clonidine therapy could be programmed for a slow dosage rate increase and then a slow dosage rate decrease, compatible with opiate withdrawal treatment. Transdermal fentanyl therapy could be improved by allowing a flexible dosage regimen for noninvasive patient controlled analgesia with added safety and security features. Recently we have developed a method to form a permeable membrane based on the hollow cores of carbon-nanotubes (CNT) passing perpendicularly through a polymer film. These inner-cores are 7.5-nm in diameter with carboxylate groups only at the ends of the CNTs. Since the CNT is electrically conductive while polystyrene film is insulating, it would be possible to draw a charged molecule into the CNT core with an applied bias. By chemically functionalizing the tip of the CNT cores with sulfonated terminated ligands that will block/open the core with an applied bias, dynamic delivery rates can be utilized for transdermal delivery. An electrically gated membrane could have broad applications in numerous drug delivery systems with production costs for membranes anticipated to be about $0.20/sq.ft. This membrane would also be expected to have minimal skin irritation potential as compared to iontophoresis, the current non-invasive programmable drug delivery method that could eventually compete with this system on the market. We hypothesize that three non-invasive programmable transdermal drug delivery systems can be successfully developed using CNT membranes combined with an applied electrical bias. The following specific aims should result in the development of three prototype drug delivery systems with improved therapeutic characteristics for smoking cessation, opiate withdrawal, and chronic pain treatment. Specific Aim 1: to quantify the nicotine, fentanyl, and clonidine flux rates through the CNT membranes as a function of size, polarity and binding affinity of the molecular gate keeper at the entrance to each CNT pore. Specific Aim 2: to prove the ability to open and close the pore entrance with applied bias to charged long-chained molecules- bonded to CNT tips. Specific Aim 3: to study the transdermal delivery rates in human skin in vitro for constant rates and voltage gated delivery rate changes, including the quantification of the dynamic response time to gated release. Specific Aim 4: to characterize the pharmacokinetics of the drugs in hairless guinea pigs and Yucatan miniature pigs in order to evaluate the in vivo success of constant rate and gated delivery.

描述（由申请人提供）：尼古丁，芬太尼和可乐定是建立的透皮药物疗法，可以使用可编程可变的药物输送速率大大改善。随着可以使用应用的电偏置打开或关闭膜的开发，可以使用简单的电子设备来提供良好的剂量方案，并仅在存在电子设备时才为贴剂激活创建安全/安全功能。通过创建与吸烟者的血浆水平更相似的尼古丁血浆水平，可以增强透皮尼古丁疗法，而香烟渴望的发生率降低。可乐定疗法可以通过缓慢的剂量升高，然后缓慢的剂量降低，与鸦片戒断治疗兼容。可以通过增加安全性和安全特征的非侵入性患者控制镇痛药，可通过允许灵活的剂量剂量来改善芬太尼治疗。最近，我们开发了一种基于垂直于聚合物膜的碳 - 纳米管（CNT）的空心核心形成可渗透膜的方法。这些核心直径为7.5 nm，仅在CNT的末端，羧酸盐基团。由于CNT是在聚苯乙烯膜进行绝缘的同时具有导电性的，因此有可能将带电的分子吸收到具有施加偏置的CNT芯中。通过化学功能化CNT核的尖端，用磺化的终止配体将其阻塞/打开构成偏置的核心，可以将动态递送速率用于透皮递送。电通膜的膜可能在众多药物输送系统中具有广泛的应用，其生产成本预计约为0.20美元/平方英尺。与离子电池相比，该膜也有望具有最小的皮肤刺激潜力，这是当前的非侵入性可编程药物输送方法，最终可以在市场上与该系统竞争。我们假设可以使用CNT膜和应用的电偏置成功开发了三种非侵入性的可编程透皮药物输送系统。以下特定目标应导致三种原型药物输送系统的发展，并具有改善的戒烟，鸦片戒断和慢性疼痛治疗的治疗特征。具体目标1：量化通过CNT膜的尼古丁，芬太尼和可乐定通量速率，这是每个CNT孔入口处分子栅极饲养者的大小，极性和结合亲和力的函数。具体目标2：证明能够用偏置偏置与CNT尖端键合的带电的长链分子的偏置打开和关闭孔入口的能力。特定目的3：研究人类皮肤的透皮递送率在体外的恒定速率和电压门控递送速率变化，包括对封闭式释放的动态响应时间进行定量。特定目的4：表征无毛豚鼠和尤卡坦微型猪中药物的药代动力学，以评估恒定速率和门控递送的体内成功。