The ocular pharmacokinetics and biodistribution of phospho-sulindac (OXT-328) formulated in nanoparticles: Enhanced and targeted tissue drug delivery.

We studied the pharmacokinetics, biodistribution and metabolism of phospho-sulindac (PS), a novel agent efficacious in the treatment of dry eye, formulated in nanoparticles (PS-NPs) following its topical administration to the eye of New Zealand White rabbits. The nanoparticles were spherical with effective diameter = 108.9 ± 41.7 nm, zeta potential = -21.70 ± 3.78 mV, drug loading = 7%, and entrapment efficiency = 46.4%. Of the total PS delivered topically to the eye, >95% was retained in the anterior segment, predominantly in the cornea (Cmax = 101.3 μM; Tmax = 1 h; T1/2 = 2.6 h; area AUC0-16h = 164.4 µM·h) and conjunctiva (Cmax = 89.4 μM; Tmax = 0.25 h; T1/2 = 3.1 h; AUC0-16h = 63.5 µM·h), the tissues most affected by dry eye disease. No PS or its metabolites were detected in the systemic circulation. PS was metabolized to PS sulfide and PS sulfone; all three molecules were hydrolyzed to sulindac, which was converted to sulindac sulfide and sulindac sulfone. A solution formulation of PS provided lower PS levels in ocular tissues but higher levels of PS metabolites, compared to PS-NPs. Therefore, NPs represent an effective formulation for the topical ocular administration of PS for anterior segment diseases, such as dry eye disease.