Release kinetics of liposome-encapsulated ganciclovir after intravitreal injection in rabbits

Abstract

This study was undertaken to establish experimentally whether the intravitreal application of liposomally-entrapped ganciclovir could prolong intraocular therapeutic levels when it is compared to the intravitreal injection of a simple solution of the drug. New Zealand white rabbits were given an intravitreal injection of the drug solution and of liposome-encapsulated ganciclovir. The intravitreal clearance of ganciclovir was determined after a single injection of either the drug solution (200 micrograms/0.1 mL) or the liposomally-entrapped (with 41% load; 82 micrograms drug load and 118 micrograms free) ganciclovir. The ganciclovir vitreal concentrations were measured at various time intervals for a period up to 43 days using an HPLC method. The results of this study clearly demonstrated that prolonged intravitreal drug levels (above the mean inhibitory dose of cytomegalovirus of 1 microgram/mL) after administration of the liposome-entrapped ganciclovir and estimated to continue beyond 30-43 days. The injection of the 200 micrograms/0.1 mL of drug solution showed a mean vitreous concentration which was higher than the ID50 only for 55 h. The disappearance rate constant for the liposome-encapsulated injections was approximately 22 x slower than simple drug solution injections (controls). No evidence of retinal toxicity was found by clinical or light microscopy examination of the treated eyes.

Liposome-Nanogel Structures for Future Pharmaceutical Applications

“…Different liposomal administration routes to deliver drugs (oral [40], intranasal [41], ocular [42][43][44], topical instillation [45][46][47], intravitreal and subconjunctival [48,49], topical [50], aerosol [51], epidural) have been extensively investigated to provide more effective therapy through direct targeting to the site of action, extending level of drug, prolonging drug activity at the targeted site.…”

Intravitreal Pharmacokinetics of Plain and Liposome-Entrapped Fluconazole in Rabbit Eyes

“…The elimination rate constant from the vitreous for the liposome-encapsulated fluconazole was approximately 7 times slower than the plain fluconazole injection. The delayed elimination of drag from the vitreous was also documented in liposomeentrapped ganciclovir (14). Drag transport within the vitreous space of the normal phakic eyes should be slow because of collagenous matrix present in the vitreous cavity.…”

Albumin Nanoparticles for the Intravitreal Delivery of Anticytomegaloviral Drugs

“…In order to overcome these drawbacks and to improve patient comfort by reducing the frequency of dosing, many drug delivery systems able to provide therapeutic ganciclovir concentrations for prolonged periods of time have been proposed, including implantable devices [32,33], liposomes [34] and microparticles [35]. Ganciclovir intravitreal implants continuously release drug for 6 to 8 months into the vitreous at levels substantially higher than those achieved with intravenous therapy [36,37].…”

“…These new pharmaceutical dosage forms appear to preserve the visual acuity and quality of life of patients; although it has been described that an intravitreal injection of particulate or vesicle dispersions requires submicronic size ranges to avoid interference with vision [39]. On the one hand, liposomal formulations can provide effective intravitreal concentrations of ganciclovir for 30 days with no sign of ocular toxicity [34]. On the other hand, microparticles containing ganciclovir did not show any retinal or adjacent tissue toxicity following either electroretinography or histological studies [35].…”