Pharmacokinetics of angiotensin‐receptor blocker in cyclodextrin nanoparticle eye drops in rabbits

Purpose Cyclodextrin nanoparticles form water‐soluble complexes with lipophilic and poorly water‐soluble drugs and thus can greatly improve drug transport from the ocular surface to the posterior eye segment. The aim of the current study was to evaluate the ocular pharmacokinetics and biodistribution of two newly developed □‐cyclodextrin based angiotensin receptor antagonist formulations for topical administration: cyclodextrin‐Irbesartan 1.5% and cyclodextrin‐Candesartan 0.15%. Methods 59 rabbits were included in the study to receive one of the two study drugs. For each drug group, single and multiple dose pharmacokinetics were performed in a randomized fashion: Single dose rabbits were euthanized 0.5, 1.5, 3 or 6 hours post eye drop administration, whereas multiple dose animals were dosed for 5 days twice daily. Pharmacokinetic parameters including maximal drug concentration (Cmax) and time of maximal drug concentrations (Tmax) for single dosing and mean concentrations for multiple dosing were calculated for aqueous humor (AH) and retina/choroid (RT). Analysis was done using LC‐MS/MS. Results Topical administration of the study drugs was well tolerated. Single dose Irbesartan eye drop administration led to a RT Cmax of 251 ng/g ± 143 ng/g at 0.5 hours whereas in the AH a Cmax of 121 ng/g ± 69 ng/g was reached at 3 hours post instillation. For single dose Candesartan eye drops, RT Cmax was 63 ng/g ± 39 ng/g at 0.5 hours after application. AH reached a Cmax of 30 ng/g ± 14 ng/g at the 3 hours time point. For multiple dosing mean RT concentration reached 338 ng/g ± 124 ng/g for Irbesartan and 36 ng/g ± 10 ng/g for Candesartan, whereas mean AH concentrations were 231 ng/g ± 68 ng/g and 70 ng/g ± 22 ng/g, respectively. Conclusions The present data confirm that cyclodextrin based Candesartan and Irbesartan eye drops deliver drugs to the posterior pole of the eye in biologically relevant concentrations.