Episcleral clearance of sodium fluorescein from a bioerodible sub-tenon's implant in the rat

Abstract

We quantified episcleral drug clearance of sodium fluorescein (NaFl) in rats to examine the hypothesis that there is rapid clearance of episcleral water soluble drugs, and that this rapid clearance may limit the amount of drug that is able to reach the posterior segment from an episcleral location. 2 mm implants containing either 12 or 22 ug of NaFl were manufactured and in vitro release rates were determined. Implants were placed in the sub-Tenon's space and the amount of drug remaining in the conjunctiva/sclera/choroid complex (CSCC) at various time points was quantified following tissue solubilization and fluorescence quantification using a spectrofluorometer. Kinetics of NaFl clearance was determined in live animals, following euthanasia and in animals in which choroidal non-perfusion had been achieved with indocyanine green-enhanced 810 nm diode laser thrombosis of the choroidal vasculature. Choroidal non-perfusion in these laser-treated rats was verified with Concavalin-A staining of choroidal flatmounts. In vitro, >99% of drug was released by 25 minutes for the low dose implants, and by 60 minutes for the high dose implants. In vivo, both implant doses were >99% cleared from the episcleral tissue by 3 hrs. By 7 hrs, an average of only 0.14 ± 0.131 ng of NaFl per mg of wet tissue weight (mean ± SD) remained in the CSCC with the low dose implant, and 0.29 ± 0.428 ng of NaFl per mg of wet tissue weight remained in animals with the high dose implant. By comparison, in euthanized animals at 7 hrs following sub-Tenon's implantation, 432.0 ± 181.40 ng of NaFl per mg of wet tissue weight was in the episcleral tissue of animals with the low dose implant, and of 787.8 ± 409.89 ng of NaFl per mg of wet tissue weight remained in the animals with the high dose implant. In live animals with selective thrombosis of the choroidal vasculature, the difference in the amount of drug remaining in the episcleral tissue as compared to control live animals was not significant at all time points for both implant doses. In conclusion, there is rapid clearance of episcleral NaFl delivered from a bioerodible subtenon's implant. The clearance mechanisms are dramatically reduced following euthanasia, suggesting that elimination is occurring via active physiologic mechanisms, rather than by passive diffusion clearance (CL(diff)) (Pfister et al. 2003). Interestingly, the choroid does not appear to play a prominent role as clearance of episcleral NaFl was not affected by elimination of choroidal blood flow. Further work is needed to delineate the pathways of episcleral drug clearance.

Drug Delivery to the Eye: What Benefits do Nanocarriers offer?

“…It was found that in enucleated eyes, substantial concentrations were detected compared with live eyes, pointing to a big role played by dynamic barriers and circulatory systems, in clearing the drug from the episcleral location. These results are further confirmed by studies performed by Chan et al which show a higher role of episcleral clearance than choroidal circulation for a drug delivered from a bioerodible subtenon implant in a rat model [42].…”

“…Liposomes are also extensively studied for intravitreal and subconjunctival sustained delivery by many research groups [26][27][28][29][30][31][32][33][34][35][36]. For delivery of therapeutic agents for longer periods in a more controlled manner, solid implants or polymeric films have demonstrated the ability for sustained delivery of agents to the posterior ocular segment [19,[37][38][39][40][41][42][43][44]. Another interesting sustained-release formulation is POT-4 (Potentia Pharma ceuticals, KY, USA), which is a synthetic peptide that reversibly binds complement factor C3 and functions as a complement inhibitor.…”

<p>Efficacy of Sub-Tenon Micro-Perfusion of Cyclophosphamide in Rabbits with Severe Ocular Inflammation</p>

“… 21 , 22 However, it is difficult to maintain the sustained drug concentrations at target tissue by single sub-Tenon administration due to the rapid clearance of drug by blood and lymphatic flow. 23 , 24 Thus, development of a sustained release platform using sub-Tenon administration may provide an approach to achieve stable drug concentrations and prolonged drug duration.…”

Studies on sustained release platforms for delivery of therapeutic agents to the posterior segment of the eye

“…Chan et al has shown that >99% of the implanted NaF was cleared by 3 hours, and by episcleral circulation. [118].When animals were euthanized immediately following the administration, the NaF was detectable, indicating that the elimination is occurring by means of the dynamic circulation.…”

“…For delivery of therapeutic agents for longer periods in a more controlled manner, solid implants or polymeric films have been studied. [112][113][114][115][116][117][118][119][120]. Intravitreal delivery of polymeric systems may cause clouding of vision, which is not the case for periocular administration.…”