ESTIMATION AND ENHANCEMENT OF IN-VITRO CORNEAL TRANSPORT OF S-1033, ANOVEL ANTIGLAUCOMA MEDICATION

To improve the in vitro corneal transport of S-1033, a novel prostagla ndin-derivative antiglaucoma medication, the effects of several factor s such as benzalkonium chloride (BAC), concentration of S-1033, and li pophilicity on the corneal permeability of S-1033 were investigated. T he 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. Corn eal transport tended to be improved by methyl esterification of S-1033 but not by the coexistence of BAC with S-1033 methyl ester. TLC analy sis showed that S-1033 methyl ester was hydrolyzed to S-1033 during pa ssage through the cornea. The therapeutic concentration of S-1033 (5.4 mM, the highest concentration in the experiments), greatly promoted i ts transport and increased P-app. However, there was little difference in the uptake percent, which showed the transcorneal percent and corn eal accumulation percent at steady state, for these dosing conditions. The highest concentration gave the lowest corneal accumulation percen t and the highest corneal clearance, indicating that the transport rat e of S-1033 in the cornea to the receptor side was the largest, which may have been responsible for the marked improvement of the transcorne al transport of S-1033. Increases in corneal accumulation of S-1033 du e to methyl esterification and BAC addition seem to be due to the incr ease of lipophilicity and ion pair formation, respectively. To investi gate the relationship between corneal permeability and the partition c oefficient (PC) with or without BAC, the permeabilities of prostagland in F-2 alpha (PGF(2 alpha)) and prostaglandin E(2) (PGE(2)) were estim ated. The larger the value of logPC in the range of -0.67-3.89, the la rger was the value of P-app in the absence of BAC. However, in the pre sence of BAC, there was a parabolic relationship, which suggests that BAC can greatly affect the interaction between cornea and drugs.