title: The effect of a modified beta-cyclodextrin, SBE4-beta-CD, on the aqueous stability and ocular absorption of pilocarpine.
abstract: 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 (pKa approximately 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, t90% was 236 days. In the presence of 1 mM and 25 mM of SBE4-beta-CD, t90% was 382 days and 2054 days, respectively suggesting that indeed, pilocarpine does interact with SBE4-beta-CD. SBE4-beta-CD did not damage the corneal 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
authors.forename: K
authors.initials: K
authors.lastname: Järvinen
authors.forename: T
authors.initials: T
authors.lastname: Järvinen
authors.forename: D O
authors.initials: DO
authors.lastname: Thompson
authors.forename: V J
authors.initials: VJ
authors.lastname: Stella
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000042:Absorption / Q000187:drug effects; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D002417:Cattle; D002463:Cell Membrane Permeability; D003315:Cornea / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology*; D004355:Drug Stability; D004361:Drug Tolerance; D004848:Epithelium / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D009883:Ophthalmic Solutions; D010862:Pilocarpine / Q000493:pharmacokinetics*; D011680:Pupil / Q000187:drug effects; D011817:Rabbits; D047392:beta-Cyclodextrins
chemical_list: D003505:Cyclodextrins; D009883:Ophthalmic Solutions; D047392:beta-Cyclodextrins; D010862:Pilocarpine; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin