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.