THE EFFECT OF A MODIFIED BETA-CYCLODEXTRIN, SBE4-BETA-CD, ON THE AQUEOUS STABILITY AND OCULAR ABSORPTION OF PILOCARPINE

In the present study, the effects of a novel, modified beta-cyclodextrin derivative (SBE4-beta-CD; a variably substituted sulfobutyl ether of beta-cyclodextrin with an average degree of substitution of four) on the aqueous stability of pilocarpine and on its ocular absorption in albino rabbits were studied. For stability reasons, commercial pilocarpine eyedrops are formulated at pH 4-5, a pH range where pilocarpine (pK(a) approximate to 7) is almost completely ionized. As shown in the present and past studies, increasing the pH of the pilocarpine solution from 4.5 to 7.0 increases the ocular absorption of pilocarpine. SBE4-beta-CD increased the aqueous stability of pilocarpine (0.36 mM) at pH 7.0 (4 degrees C, projected values from Arrhenius data at 25 degrees C, 37 degrees C and 50 degrees C); in the absence of SBE4-beta-CD, t(90%) was 236 days. In the presence of 1 mM and 25 mM of SBE4-beta-CD, t(90%) was 382 days and 2054 days, respectively, suggesting that indeed, pilocarpine does interact with SBE4-beta-CD. SBE4-beta-CD did not damage the conceal epithelium in vitro and was well-tolerated by the rabbit eye in vivo. Coadministered SBE4-beta-CD did not significantly affect the miotic response of pilocarpine solutions at pH values of 4.5 or 7.0 when the molar ratio of SBE4-beta-CD to pilocarpine was between 0.2:1-7:1. The effect of the coadministered SBE4-beta-CD on the miotic response of pilocarpine solutions was also compared to that of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) which has recently been suggested to increase ocular bioavailability of pilocarpine in rabbits. Our studies could not confirm the earlier observations.