INFLUENCE OF ALPHA-CYCLODEXTRIN AND HYDROXYALKYLATED BETA-CYCLODEXTRIN DERIVATIVES ON THE IN-VITRO CORNEAL UPTAKE AND PERMEATION OF AQUEOUSPILOCARPINE-HCL SOLUTIONS

Interactions in aqueous solution between pilocarpine hydrochloride (P- HCl), a rather hydrophilic drug with good water solubility, and variou s cyclodextrins (CDs) were described recently. To assess the influence of CDs on the diffusion behavior of pilocarpine, in vitro studies wer e performed using porcine or bovine corneas as diffusion barriers. The affinity of P-HCl for porcine cornea in the presence of alpha-cyclode xtrin (alpha-CD) and (hydroxyethyl)-beta-cyclodextrin (HE-beta-CD) was determined by drug uptake experiments. Additionally, in vitro permeat ion experiments through bovine corneas were conducted with a modified diffusion device optimized for corneal perfusion studies. The results obtained from the corneal uptake studies indicate that the addition of alpha-CD led to increased tissue drug levels. The increase in permeab ility of pilocarpine in the presence of alpha-CD was similar to 10-fol d (log P-app = -4.87 +/- 0.03) in comparison with plain P-HCl solution (log P-app = -5.89 +/- 0.06). Permeation studies with corneas pretrea ted with alpha-CD solution revealed enhanced corneal permeability of p ilocarpine due to alpha-CD-induced membrane effects. The hydroxyalkyla ted beta-CD derivatives HE-beta-CD (log P-app = -6.27 +/- 0.09) and (h ydroxypropyl)-beta-cyclodextrin (HP-beta-CD; log P-app = -6.40 +/- 0.0 3), however, seemed to cause slightly decreased permeation rates, supp orting the concept of an interaction between pilocarpine and the hydro xyalkylated-beta-CD derivatives. Considering physiological compatibili ty, the addition of CDs seems to be an effective tool to modify and op timize the ocular availability of pilocarpine.