Effect of formulation factors on the trans-scleral iontophoretic and post-iontophoretic transports of a 40 kDa dextran in vitro.

The aim of the work was to study in vitro, across isolated porcine sclera and across the trilayer sclera-choroid-Bruch's membrane (SCB), the effect of iontophoresis on the permeation of a 40 kDa dextran (FD-40), chosen as model compound of high molecular weight neutral drugs. In particular, the effect of vehicle composition (in terms of buffering agent and ionic strength) and current intensity (from 0.3 to 4.2 mA, corresponding to 0.5-7 mA cm(-2)) was investigated. Additionally the post-iontophoretic transport of FD-40 through SCB was studied. The results obtained in the present paper confirm the importance of formulation parameters during transscleral iontophoresis of a neutral high molecular weight hydrophilic compound transported by electroosmosis. In particular, ionic strength seems to be the more relevant parameter, while the buffering agent (phosphate vs HEPES) is not relevant. The enhancement obtained increases--although in a stepwise way--with current intensity, after a threshold value of approximately 1.5 mA. However, the real variable to be considered is probably current density (threshold value 2.5 mA cm(-2)) more than intensity, in analogy with transdermal iontophoresis. The inclusion of further static barriers besides the sclera, such as choroid and Bruch's membrane, reduces, as expected, the permeation of FD-40, but iontophoresis is able to significantly promote FD-40 transport also through this more complex barrier, without altering its permeability. Finally, the study of the post-iontophoretic transport highlights the formation of a pronounced FD-40 reservoir inside the sclera. This reservoir permits to obtain in vitro a sustained transscleral flux up to 3 h after current stop. This result could be of interest in the case of a real application, prolonging the enhancement effect also after iontophoresis stop.