RESUMO
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 diameterâ¯=â¯108.9⯱â¯41.7â¯nm, zeta potentialâ¯=â¯-21.70⯱â¯3.78â¯mV, drug loadingâ¯=â¯7%, and entrapment efficiencyâ¯=â¯46.4%. Of the total PS delivered topically to the eye, >95% was retained in the anterior segment, predominantly in the cornea (Cmaxâ¯=â¯101.3⯵M; Tmaxâ¯=â¯1â¯h; T1/2â¯=â¯2.6â¯h; area AUC0-16hâ¯=â¯164.4⯵M·h) and conjunctiva (Cmaxâ¯=â¯89.4⯵M; Tmaxâ¯=â¯0.25â¯h; T1/2â¯=â¯3.1â¯h; AUC0-16hâ¯=â¯63.5⯵M·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.