Optimal control of heat-assisted transdermal drug-delivery systems

Process modeling techniques and optimal control theories were implemented to facilitate the development of efficient heat-assisted transdermal drug-delivery systems. The dermal route offers several advantages over conventional methods, such as oral formulations. Entry into the general circulation through the skin circumvents firstpass metabolism, the process by which an orally-administered drug is chemically altered before reaching the target organ. In addition, the technology fosters greater patient compliance and provides a continuous dosing regimen. Drawbacks, such as a delay observed after an initial transdermal fentanyl patch application, led to the use of chemical enhancers (e.g. oleic acid, acetone) and physical techniques, including iontophoresis, electroporation and thermal energy. A heat-enhanced transdermal system provides a viable alternative for the treatment of cancer-related breakthrough pain. The method decreases the time it takes the active pharmaceutical ingredient (API) to reach a steady-state concentration in the blood. However, in spite of these activities, a modeling and control structure, that can help understand and assess the effects of heat on transdermal transport, is lacking in the literature. This contribution provides such a framework and applies modern control theories to optimize treatment strategies. Clinicians may have the ability to combine a reduced number of clinical trials and simulation data to recommend drug-dosage regimens that keep the API in the targeted tissue at a prescribed level. Optimal temperature profiles of an electric heating pad were computed to maintain the normalized flux around a desired value of 0.0125 cm/hr in one simulation study. Another investigation showed that the temperature could be pre-programmed to prevent the delivery rate to fall below a critical value.