Beta-cyclodextrins enhance bioavailability of pilocarpine.

Cyclodextrins have been used to improve drug solubility, stability and absorption for oral and parenteral administration. However, their potential for improving ocular drug delivery has received little attention. To evaluate the ability of hydroxypropyl-beta-cyclodextrins to improve ophthalmic drug bioavailability following topical administration, the miotic effect of topical solutions of pilocarpine was studied in New Zealand White rabbits. Pilocarpine varying in dose from 5 to 500 micrograms in the presence or absence of 5% cyclodextrin was administered (50 microliters) topically and the change in pupil diameter determined. These results demonstrated that pilocarpine alone or in the presence of cyclodextrin produces a dose-related reduction in pupil diameter. The addition of cyclodextrins produced a significant left-shift in the dose response curve, with an ED50 of 64 micrograms and 19 micrograms for pilocarpine and pilocarpine/5% cyclodextrin solutions, respectively. Studies in which the concentration of cyclodextrin was varied revealed that a one-to-one molar ratio of pilocarpine to cyclodextrin was sufficient to provide maximum increase in pilocarpine bioavailability. Electrophysiology and scanning electron microscopic studies demonstrated that cyclodextrin does not disrupt the normal ion transport currents, barrier properties or surface features of the corneal epithelium. Viscosity measurements indicated that difference in the viscosity of pilocarpine and pilocarpine/cyclodextrin solutions cannot account for increased bioavailability of pilocarpine. These data support the idea that the addition of cyclodextrin significantly improves the ocular bioavailability of pilocarpine. This enhanced bioavailability of pilocarpine does not appear to be due to a mechanism destructive to the epithelium or to an increase in vehicle viscosity.