title: Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: potential in glaucoma therapy.
abstract: The aim of the present study was to evaluate and improve the in vitro transcorneal permeability characteristics of Δ(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 (HPβCD) or randomly methylated beta cyclodextrin (RMβCD), 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 HPβCD. THC-HS and THC-HG exhibited pH-dependent permeability. In the presence of HPβCD, 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. RMβCD, 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.
authors: Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
authors: Tushar
authors: T
authors: Hingorani
authors: Waseem
authors: W
authors: Gul
authors: Mahmoud
authors: M
authors: Elsohly
authors: Michael A
authors: MA
authors: Repka
authors: Soumyajit
authors: S
authors: Majumdar
mesh_terms: D000818:Animals; D003315:Cornea / Q000378:metabolism*; D013759:Dronabinol / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005901:Glaucoma / Q000188:drug therapy*; D066298:In Vitro Techniques; D010539:Permeability; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D012995:Solubility
chemical_list: D011355:Prodrugs; D013759:Dronabinol