Effect of intraocular pressure (IOP) and choroidal circulation on controlled episcleral drug delivery to retina/vitreous ☆

Abstract Transscleral drug delivery may become a safe alternative to the intravitreal injection for chronic retinal diseases such as age-related macular degeneration or diabetic macular edema. However, the drug delivered onto the sclera subjects to vigorous clearance by episcleral and choroidal circulation; in addition, the penetration from episclera to retina needs to overcome counter-directional ocular fluid current driven by intraocular pressure (IOP) as well as unfavorable drug disposition exerted by drug transporters before the drug reach retina. It is imperative to understand these processes and quantitate their influence for efficient designing of a sustained formulation or device to achieve efficient transscleral drug delivery. The current study was focused on the effects of intraocular pressure (IOP) and choroidal circulation on transscleral drug delivery using triamcinolone acetonide (TA) as a model drug. Rabbit eye IOP was modulated through cannulation in ex vivo study or through cryopexy of ciliary body in vivo studies before subtenon TA injection or episcleral TA-film implantation. In a subgroup of the rabbit eyes, localized choroid atrophy was induced by cryopexy before TA-film implantation. Each condition had a concurrent control group. The vitreous TA concentration was quantitated by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS). The vitreous TA concentration was compared between the study and control groups for effect of IOP or choroid circulation. For ex vivo studies, higher IOP was a significant effect against TA penetration from episclera towards vitreous. TA was 8.5 ± 5 ng/mL in receptor chamber with a cross pressure of 50 mm Hg versus 15.9 ± 10 ng/mL with the cross pressure of 5 mm Hg; p  = 0.001, t -test. A multivariate regression demonstrated each mm Hg of IOP increase would result in 3 ng/mL lower concentration in the receptor chamber. Similar IOP effect was also identified in a 3-hour study using euthanized rabbit eyes whose IOP was controlled at 10 or 40 mm Hg by cannulation (3261 ± 1821 ng/mL vs. 755 ± 763 ng/mL; p  = 0.013, Wilcoxon test). However, the effect of IOP was not significant in alive animal with the same IOP setting. In vivo chronic study using low IOP (7.7 mm Hg) versus normal IOP (14.4 mm Hg), vitreous TA was not statistically significant (154 ± 200 ng/mL vs. 80 ± 130 ng/mL, p  = 0.17, Wilcoxon test). However, removing of choroidal circulation by local cryopexy significantly enhanced the TA penetration from episclera to vitreous (mean 163 ± 129.8 ng/mL for choroidal cryopexy vs. 81.8 ± 37.2 ng/mL for ciliary cryopexy or 75.5 ± 36 ng/mL for control group, p  = 0.007, regression analysis). In conclusion, the effect of IOP on transscleral drug delivery was not a significant effect in alive rabbit eyes; however, choroidal circulation seems to be a significant effect to affect TA penetration from episclera towards retina and vitreous.