Characterization of a Novel Intraocular Drug-Delivery System Using Crystalline Lipid Antiviral Prodrugs of Ganciclovir and Cyclic Cidofovir.

摘要

PURPOSE: In an earlier study, a novel intraocular drug-delivery system was reported in which hexadecyloxypropyl-phospho-ganciclovir (HDP-P-GCV) was used as a prototype. The hypothesis was that many biologically effective compounds could be modified to crystalline lipid prodrugs and could be delivered directly into the vitreous in a long-lasting, slow-release form. This study was undertaken to characterize this new drug-delivery system further, by using small particles of HDP-P-GCV and hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV). METHODS: HDP-P-GCV was microfluidized into 4.4-渭m (median) particles, injected into rabbit vitreous. The vitreous drug level was then measured at different time points. Crystalline HDP-cCDV was synthesized, suspended in 5% dextrose, and injected into the rabbit's vitreous at 10, 55, 100, 550, or 1000 渭g in 50 渭L vehicle per eye, to determine the highest nontoxic dose. The dose, 100 渭g, was injected into 24 rabbit eyes, to evaluate pharmacokinetics; into 14 rabbit eyes with established HSV retinitis, to evaluate its efficacy; and into 58 rabbit eyes before herpes simplex virus (HSV) infection to evaluate its intraocular antiviral duration. RESULTS: Microfluidized particles of HDP-P-GCV showed an increased drug release rate compared with the large-particle drug formulation, with area under concentration-time curve (AUC) of 219.8 +/- 114.1 (n = 3) versus 108.3 +/- 47.2 (n = 3) for unmodified HDP-P-GCV during the 12-week period after a 2.8-micromole intravitreal injection. There was a 103% increase of the drug released from the microfluidized formulation of HDP-P-GCV versus the unmodified formulation. Intravitreal injections of HDP-cCDV at doses of 100 渭g/eye or lower were not toxic. After the 100 渭g/eye injections, HPLC analysis showed a vitreous HDP-cCDV level of 0.05 渭M at week 5, which declined to 0.002 渭M at week 8. The concentration at week 8 (0.002 渭M) remained above the IC(50) for cytomegalovirus (0.0003 渭M). The pretreatment study demonstrated an antiviral effect that lasted 100 days after a single intravitreal injection. CONCLUSIONS: This crystalline lipid prodrug intravitreal delivery system is an effective approach to achieving sustained, therapeutic drug levels in the eye. Small microfluidized particles of HDP-P-GCV provide more rapid dissolution and higher vitreous drug levels.