Intracorneal iontophoretic delivery of triamcinolone acetonide prodrugs: Physicochemical parameters guiding electrotransport

Intracorneal delivery of ten amino acid (alanine, arginine, asparagine, glutamine, glycine, histidine, isoleucine, lysine, methionine and valine) ester prodrugs of triamcinolone acetonide (TA-AA) was investigated in vitro, using a corneal iontophoresis device (IONTOFOR-CXL; SOOFT Italia S.p.A.) approved for clinical use in the treatment of keratoconus. Short duration iontophoresis (1 mA for 5 min) was performed and intracorneal deposition of TA was quantified by HPLC-UV and UHPLC-MS/MS. The data evidenced the clear advantage of TA-AA prodrug iontophoresis compared to passive delivery and revealed unexpected and prodrug dependent deposition profiles. Despite their superior electrical mobility, intracorneal delivery of dications, TA-Arg and TA-Lys, did not outperform that of TA-Ala and TA-Gly. In silico investigations to relate the TA-AA prodrugs' physicochemical properties to their electrotransport confirmed that increased lipophilicity potential did not favour iontophoretic transport. For TA-Ala and TA-Gly, it was hypothesized that the greater charge distribution and decreased tendency to interact with the corneal tissue via electrostatic and H-bonds contributed to their successful iontophoretic delivery. Intracorneal biodistribution of TA confirmed that TA-Gly iontophoresis resulted in supratherapeutic concentrations in deep corneal stroma, exceeding TA IC50 by similar to 10(4)-fold. The results clearly demonstrated the successful combination of the clinically approved SOOFT iontophoretic device and the TA-AA prodrugs for targeted corneal iontophoretic delivery.