Lorraine Wearley

Enhancement of the in Vitro Skin Permeability of Azidothymidine (AZT) via Iontophoresis and Chemical Enhancer

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C10MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C10MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C10MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.

Iontophoresis-facilitated transdermal delivery of verapamil I. In vitro evaluation and mechanistic studies

Abstract The feasibility of using iontophoresis to enhance the permeation rate of verapamil, in ionic form, was investigated in vitro using the skin of hairless mouse and hairless rat. A specially designed power source was used to deliver pulsed direct current. A number of physicochemical and electrochemical variables which might affect iontophoretic transport of the charged molecule were studied with an aim towards exploring the mechanisms involved. The permeation rate of verapamil ion (VH + ) was observed to increase with an increase in drug concentration, donor solution pH, as well as with current density. On the other hand, increasing the concentration of a competing ion, like Na + , in the donor was noted to first reduce the permeation rate of VH + and then cause some increase in drug flux. Using optimum iontophoresis conditions, the skin permeation rate of VH + can be enhanced substantially. This enhancement is due to both an increase in permeation rate and a decrease in lag time compared to passive diffusion.

Iontophoresis-facilitated transdermal delivery of verapamil. II: Factors affecting the reversibility of skin permeability

Abstract In this study the effects of current intensity and duration of application as well as the effect of donor concentration on reversibility of skin permeability were studied. The experimental findings demonstrate that the iontophoresis treatment increases the concentration of drug in the skin and this concentration varies with current intensity, donor solution concentration and duration (until steady state is reached). At low donor concentrations a return to passive diffusion was observed 8 to 10 h after treatment, when 50% of the drug had desorbed from the skin. At higher concentrations, 20 h was required for 50% desorption of the drug; in addition, there was a significant increase in the volume flow of water. The prolonged desorption time and increase in water flux serves to sustain the enhanced permeation rate, so that no return to passive permeation was observed.

Iontophoretic transdermal permeation of verapamil (III): Effect of binding and concentration gradient on reversibility of skin permeation rate

Abstract This study was undertaken to determine if the prolonged reversibility time (i.e., time required for the skin permeation rate to return to that of passive diffusion after an iontophoresis treatment) of verapamil HCl was related to an increased concentration gradient across the skin and binding of the drug in the skin. The concentration gradient across the stratum comeum, determined by stripping the skin, was significantly greater after an iontophoresis treatment than that obtained under passive diffusion; furthermore, the concentration of drug in the viable skin was also significantly greater with iontophoresis. Verapamil was found to bind with both the stratum comeum and the viable skin. The increased concentration gradient and binding of drug in the skin could be responsible for a prolongation of the enhanced permeation rate observed after iontophoresis treatment.

Relationship among physicochemical properties, skin permeability, and topical activity of the racemic compound and pure enantiomers of a new antifungal

The topical antifungal Sch-39304 is a racemic compound comprised of two enantiomers, Sch-42427 and Sch-42426, only one of which (Sch-42427) is pharmacologically active. The pure enantiomers have a lower melting point and, therefore, a higher solubility than the racemic compound. Because of these differences in physicochemical properties, the concentration of the pure enantiomers in vehicles and in the skin was predicted to be an order of magnitude higher than the racemic compound. It was hoped that the pharmacological activity would also be higher. By measuring the flux of the chiral forms through human cadaver skin, the expected differences in skin solubility were confirmed. However, only a minimal difference between racemate and active enantiomer was observed in the lesion scores using a guinea pig dermatophyte model. By fitting the data to the Emax pharmacodynamic model, it is demonstrated that the maximum effect occurs at a concentration lower than the saturated concentration of the less soluble racemic compound. The data illustrate that the efficacy of topically active compounds may not be linearly related to drug concentration in either the vehicle or the skin.