Short-duration ocular iontophoresis of ionizable aciclovir prodrugs: A new approach to treat herpes simplex infections in the anterior and posterior segments of the eye

The objective was to investigate (trans) corneal and transscleral iontophoresis of biolabile amino acid ester prodrugs of aciclovir (ACV-X, X= Arg, Gly and Trp) as a means to increase ocular bioavailability of ACV. Prodrugs displayed tissue-dependent susceptibility to hydrolysis. Iontophoresis of ACV-Arg, ACV-Gly and ACVTrp (5 mM, 0.5 mA/cm(2)) for 5 min followed by 55 min passive diffusion resulted in appreciable corneal deposition (21.5 +/- 5.1, 14.1 +/- 2.0 and 5.3 +/- 0.6 nmol/cm(2), respectively) and transcorneal permeation (13.9 +/- 1.6, 10.9 +/- 1.8 and 5.7 +/- 0.5 nmol/cm(2), respectively) of ACV species. In contrast, passive delivery of ACV across porcine cornea after 1 h was < LOQ (i.e.< 0.125 nmol/cm(2)). Transscleral permeation of ACV-Arg, ACV-Gly and ACV-Trp (9 mM, 1.25 mA/cm(2)) after iontophoresis for 5 min was 20.4 +/- 3.8, 12.3 +/- 0.3 and 8.4 +/- 0.4 nmol/cm(2), respectively - far superior to passive delivery which was again < LOQ. Using intact porcine eye globes, 5 min transscleral iontophoresis of ACV-Gly at 3.75 mA/cm(2) resulted in considerable delivery of ACV species to the choroid/retina and vitreous humour (5.7 +/- 2.3 and 11.7 +/- 3.7 nmol/cm(2), respectively). Furthermore, the average concentration of ACV species in the whole eyeball (4.5 +/- 1.6 nmol/cm(3)) was significantly higher than the IC50 of ACV against HSV-1 (< 0.22 nmol/cm(3)), demonstrating the potential application for the treatment of ocular HSV infections.