Abstract
Purpose::
To develop a depot formulation for drug delivery to the posterior segment of the eye.
Methods::
Fresh porcine eyes (<4 h post mortem) were obtained from a local slaughter-house, with the animals having been processed under standard UK regulations for animals for human consumption. Human eyes (<48 h post-mortem) were received from the East Anglian Eye Bank. Four thermally responsive formulations based on aqueous solutions of poloxamer F127 (P) and alginate (A) were developed and physically characterised using oscillatory rheology and texture analysis. The formulations were: T1 (14% P / 0.1 % A), T2 (17% P / 0.1 % A), T3 (14% P / 1.0% A) and T4 (14% P and 0.2% polycarbophil). Transport of a model drug, sodium fluorescein, over the sclera was studied in vitro using a novel modification of a dialysis chamber fitted with one of the following barriers: a polycarbonate membrane, porcine sclera or human sclera. Following sub-conjunctival injection into excised porcine eyes (n=6 per timepoint) and incubation at pig body temperature, the distribution of the tracer through the ocular tissues was monitored over 9 h.
Results::
Texture analysis indicated that T2 had much greater adhesion to excised porcine sclera tissue (14.70 ± 4.43 g.s) than the other formulations, eg 0.18 ± 0.02 g.s for T1. Oscillatory rheological measurements showed that all formulations were liquid at room temperature but gelled rapidly (< 1 minute) when exposed to body temperature and subsequently behaved in a visco-elastic fashion. Transport studies using the polycarbonate membrane (n=3) showed that the rate of movement decreased in the following order: T1 (90% migration at 2.5 h), T3 (90% at 3.75 h), T4 (35% at 24 h), T2 (0% even at 24 h). Using porcine (n=3) and human (n=2) sclera, the same general trends were observed, but the migration rate was slower, eg 90% at 70 h for T3 and human sclera. Analysis of the tracer location after sub-conjunctival injection indicated there was movement from the injection site through the sclera towards the choroid and the retina, eg T3 showed 1.90 ± 1.2 % retinal accumulation after 6 hours. The extent of tracer movement mirrored the in vitro data, with the exception of T2, which showed much higher movement in the ex vivo studies than was expected.
Conclusions::
The modified dialysis chamber is a simple technique, which allows rapid comparison of formulations and natural barriers such as sclera. Sub-conjunctival injections of thermo-setting formulations may provide a novel and relatively simple method of drug delivery to the posterior segments of the eye.
Keywords: sclera • drug toxicity/drug effects • retina