G.K. Gulati, L. Berger, B. Jackson Hinds
University of Washington,
Keywords: carbon nanotube membrane, nicotine, smoking cessation, microdilaysis membrane probe, transdermal
Summary:Purpose: Transdermal nicotine patches and nicotine gums therapy along with psychological counseling support is most widely used therapy for smoking cessation, but has low success rate of 25% for 2 year without relapse. An ideal therapy would be a programmable device where smartphone program the device to high and low nicotine fluxes and coupled with a novel app for remote counseling. Variable delivery by switchable transdermal nicotine delivery device based on carbon nanotube (CNT) membrane can improve smoking cessation therapy due to low power usage (10 day battery life) and an ability to be switched by small applied bias. Described is a process to optimize and screen CNT membranes to reach target dose rates of 1.1 and 0.1-0.3 µmol/cm2/h corresponding to blood levels reached by nicotine gum and skin patches. Successful CNT membranes were then demonstrated in an ex-vivo study, where CNT membrane was placed on porcine skin, and transdermal fluxes were measured in microdialysis membrane probe placed beneath skin on flow-cell. A microdialysis probe was used to measure direct nicotine in animal- skin since in blood stream nicotine is rapidly converted to cotinine metabolite. In-vivo, a microdialysis membrane probe was implanted in skin of hairless guinea pig to show transdermal therapeutic nicotine fluxes with high temporal resolutions. Results: A 5-7 mm diameter and 5 µm thickness CNT membrane was functionalized to provide a anionic gatekeeper chemistry at carbon nanotubes tip entrances that modulate the electrophoretic and electroosmotic pumping of nicotine with electrical bias. Thus, these carbon nanotubes channels mimics biological voltage gated ion channels. The OFF (0 mV) and ON (-1.5V) fluxes through CNT membranes were 0.24-0.3 µmoles/cm2/h and 1.3-1.7 µmoles/cm2/h equivalent to transdermal patch and nicotine gum fluxes, respectively, and ON/OFF ratio of 9-12 suggest good switching potential of membrane. An ex-vivo, nicotine levels across porcine skin in microdilaysis were increased 6-8 times when the CNT membrane was turned from OFF to ON state. The ON phase nicotine level were~3 times than commercial nicotine patch control group. In an in-vivo study, CNT membrane was integrated into device with watch battery for bias. A 5-7 times increased in dialysate nicotine and and ~6 times increased in plasma cotinine were seen in animal when device was switched from OFF to ON state, demonstrating the switching potential of our device. A ~2-2.5 times dialysate nicotine levels and ~1.4 times plasma cotinine during ON state as compared to commercial nicotine patch control group, suggesting the therapeutic potential of our device. Conclusion: Device OFF and ON fluxes can mimic patch and gum therapy for smoking cessation. Ex-vivo, microdialysis membrane probe was successful to show switching between high and low nicotine fluxes through CNT membrane device across porcine skin. In-vivo, a better device-ON state flux for nicotine in dialysate and for cotinine in plasma than commercial nicotine patch suggest the therapeutic potential of our device. A blue-tooth enabled devices along with smart phone app based interventions with tools for behavioral support are highly promising for smoking cessation therapy. .