Effect of ion pairing on in vitro transcorneal permeability of a [Delta]9-tetrahydrocannabinol prodrug: Potential in glaucoma therapy

The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of [Delta]9-tetrahydrocannabinol (THC) through prodrug derivatization and formulation approaches. In vitro corneal permeability of THC and its hemisuccinate (THC-HS) and hemiglutarate (THC-HG) ester prodrugs and WIN 55-212-2 (WIN), a synthetic cannabinoid, was determined using isolated rabbit cornea. The formulations studied included hydroxypropyl beta cyclodextrin (HP[beta]CD) or randomly methylated beta cyclodextrin (RM[beta]CD), as well as prodrug-ion-pair complexes with l-arginine or tromethamine. Corneal permeability of WIN was found to be two-fold higher than THC in the presence of HP[beta]CD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HP[beta]CD, at pH 5 (donor solution pH), both prodrugs exhibited six-fold higher permeability compared with THC. However, permeability of the prodrugs was about three-fold lower than that of THC at pH 7.4. RM[beta]CD, at pH 7.4, led to a significant improvement in permeability. Formation of ion-pair complexes markedly improved the solubility and permeability of THC-HG (sevenfold and threefold greater permeability compared with THC and WIN, respectively) at pH 7.4. The in vitro results demonstrate that the use of an ion-pair complex of THC-HG could be an effective strategy for topical delivery of THC. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:616-626, 2012 [PUBLICATION ABSTRACT]