h h m where D, h, and gm are the diffusion coefficient, thickness, and activity coefficient in the stratum corneum, respectively, and the superscripts (* and °) denote with and without the enhancer, respectively. In the case of significant cotransport of an enhancer along with the principal permeant (drug), both the diffusion and activity coefficients of the drug are no longer constant but rather position-dependent within the membrane. A novel theoretical model greatly simplifies solving the problem by mathematically slicing the membrane into n thin elements, each sandwiched with slightly different enhancer concentrations.80

Modulation of skin reactions. Skin reactions, including irritation and sensitization, are indeed the Achilles heel of transdermal medication.81,82 Irritation may be defined as a local, reversible inflammatory response of the skin to the application of an agent without the involvement of an immunological mechanism. A large fraction of all drugs, depending on their concentrations, may have potential to cause skin irritation, although the "hidden" redness in the GI tract with oral administration sometimes is more severe than the "visual" one on skin. Sensitization results from an immune response to an antigen, which may lead to an exaggerated response on repeated exposure to the antigen. Irritation or sensitization may occur in response to either the drug or a component of the transdermal system. Careful testing of both active and placebo patches is needed.

The concentration-response relationships are important in optimizing drug or enhancer concentration to balance drug permeability versus skin tolerability. More sophisticated strategies involve modulation of the dermal immune system by coapplication of different polymeric formulations, excipients, enhancers, and drugs as "anti-irritants" or "countersensitizers." pH is suggested as the major contributing factor in the irritative response. A pH-controlled aqueous isopropanol counterion composition increases the skin permeation rate and improves the skin irritation profile for a weak-base amine drug.83 However, much work has been done in trial-and-error approaches and remains to be completed through understanding of the inflammatory processes, the agents responsible for irritation of the arachi-donic cascade, and the cellular network and signaling cascade as it pertains to the development of irritation and sensitization. Metabolic modulators, ion channel modulators, and mast cell degranulators are the latest contribution to understanding the mechanisms involved in these

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