K. Higaki et al., ESTIMATION AND ENHANCEMENT OF IN-VITRO CORNEAL TRANSPORT OF S-1033, ANOVEL ANTIGLAUCOMA MEDICATION, International journal of pharmaceutics, 132(1-2), 1996, pp. 165-173
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.