Ganciclovir release rates in vitreous from different formulations of 1-O-hexadecylpropanediol-3-phospho-ganciclovir

Purpose: To determine the optimal formulation of lipid prodrug, 1-O-hexadecyl-oxypropyl-phospho-ganciclovir (HDP-P-GCV), for intravitreal delivery. Methods: Equal concentrations of crystalline or liposomal HDP-P-GCV were exposed to rabbit whole vitreous, core vitreous, peripheral vitreous, human plasma, and heat inactivated rabbit vitreous, and the samples were incubated at 37°C for one week. Aliquots were taken at day 1, 2, 3, and 7 and subjected to HPLC analysis for conversion to GCV. Results: The resultant concentration of GCV from crystalline HDP-P-GCV in vitreous was 198 ± 49 μM (n = 3) at day 1 and 1253 ± 248 μM (n = 3) at day 7. The resultant concentration of GCV from the liposomal formulation of HDP-P-GCV in vitreous was much lower, yielding a concentration of 66 ± 7 μM (n = 3) at day 1 and 243 ± 39 μM (n = 3) at day 7 (P < 0.001, t Test). When the crystalline HDP-P-GCV was incubated with heat-inactivated vitreous, the detectable GCV concentrations were low (22 μM) and did not increase over time. The concentration of GCV detected from the crystalline HDP-P-GCV in the core vitreous was 19.69 ± 3.84 μM (n = 3) at day 1 and 1537.36 ± 177.14 μM (n = 3) at day 7. The concentration of GCV released from crystalline HDP-P-GCV in peripheral vitreous was 32.86 ± 5.07 μM (n = 3) at day 1 and 1805.78 ± 327.94 μM (n = 3) at day 7. Detectable GCV concentration from both core and peripheral vitreous samples increased over time, however, the magnitude of GCV release from peripheral vitreous samples was higher (P < 0.05, t Test). Conclusion: In vitreous, HP-P-GCV as a crystalline formulation was converted to GCV more rapidly than liposomal formulation of HDP-P-GCV. Vitreous cells may play an important role in the metabolism of either formulation of HDP-P-GCV delivered into vitreous.