Estimation and enhancement of in vitro corneal transport of S-1033, a novel antiglaucoma medication

To improve the in vitro corneal transport of S-1033, a novel prostaglandin-derivative antiglaucoma medication, the effects of several factors such as benzalkonium chloride (BAC), concentration of S-1033, and lipophilicity on the corneal permeability of S-1033 were investigated. The apparent permeability coefficient (P(app)) of S-1033 was 5.81 x 10^-7 cm/s on application of 0.1 mM solution. The addition of BAC (0.005%) enhanced by 2.5-fold the transport percent and P(app) of S-1033. Corneal transport tended to be improved by methyl esterification of S-1033 but not by the coexistence of BAC with S-1033 methyl ester. TLC analysis showed that S-1033 methyl ester was hydrolyzed to S-1033 during passage through the cornea. The therapeutic concentration of S-1033 (5.4 mM, the highest concentration in the experiments), greatly promoted its transport and increased P(app). However, there was little difference in the uptake percent, which showed the transcorneal percent and corneal accumulation percent at steady state, for these dosing conditions. The highest concentration gave the lowest corneal accumulation percent and the highest corneal clearance, indicating that the transport rate of S-1033 in the cornea to the receptor side was the largest, which may have been responsible for the marked improvement of the transcorneal transport of S-1033. Increases in corneal accumulation of S-1033 due to methyl esterification and BAC addition seem to be due to the increase of lipophilicity and ion pair formation, respectively. To investigate the relationship between corneal permeability and the partition coefficient (PC) with or without BAC, the permeabilities of prostaglandin F(2α) (PGF(2α)) and prostaglandin E₂ (PGE₂) were estimated. The larger the value of logPC in the range of - 0.67-3.89, the larger was the value of P(app) in the absence of BAC. However, in the presence of BAC, there was a parabolic relationship, which suggests that BAC can greatly affect the interaction between cornea and drugs.