Compartmental modeling of transdermal iontophoretic transport:: I.: In vitro model derivation and application

Purpose. The objective of this study was to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vitro. Methods. Two structurally different compartmental models describing the in vitro transport during iontophoresis and one compartmental model describing the in vitro transport in post-iontophoretic period are proposed. These models are based on the mass transfer from the donor compartment to the acceptor compartment via the skin as an intermediate compartment. In these models, transdermal iontophoretic transport is characterized by 5 parameters: 1) kinetic lag time (t(L)), 2) steady-state flux during iontophoresis (J(ss)), 3) skin release rate constant (KR), 4) the first-order rate constant of the iontophoretic driving force f(r)om the skin to the acceptor compartment (I-1), and 5) passive flux in the post-iontophoretic period (J(pas)). The developed models were applied to data on the iontophoretic transport in human stratum corneum in vitro of R-apomorphine after pretreatment with phosphate buffered saline pH 7.4 (PBS) and after pretreatment with surfactant (SFC), as well as the iontophoretic transport of 0.5 mg ml(-1) rotigotine at pH 5 (RTG). Results. All of the proposed models could be fitted to the transport data of PBS, SFC, and RTG groups both during the iontophoresis and in the post-iontophoretic period. The incorporation of parameter I-1 failed to improve the fitting performance of the model. This might indicate a negligible contribution of iontophoretic driving force to the mass transfer in the direction from the skin to the acceptor compartment, although it plays an important role in loading the skin with the drug. The estimated values of J(ss) of PBS, SFC, and RTG were identical (p>0.05) to the values obtained with the diffusion lag time method. Moreover, time required to achieve steady-state flux can be estimated based on the parameter t(L) and the reciprocal value of parameter K-R. In addition, accumulation of drug molecules in the skin is reflected in a reduction of the value of the K-R parameter. Conclusions. The developed in vitro models demonstrated their strength and consistency to describe the drug transport during and post-iontophoresis.