Effect of Ion Pairing on In Vitro Transcorneal Permeability of a Δ9-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 Δ9-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 random 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 to 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 (7-fold and 3-fold greater permeability compared to 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.

Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability

“…21 A significant improvement in aqueous solubility was observed as a result of the ionization of the molecules at physiological pH. Transcorneal permeability, however, remained low at a physiological pH.…”

Ocular Disposition of ∆8-Tetrahydrocannabinol from Various Topical Ophthalmic Formulations

“…Another setback in these studies was the mineral oil solution, which had poor penetrating properties and therefore could not get past the corneal membrane (33). Previous reports have shown the ability of the relatively hydrophilic prodrug of Δ 9 -THC to reach into the iris-ciliary bodies, though no drug was seen to reach the retina-choroid (15, 16). The micellar solutions of the parent Δ 9 -THC on the other hand could not penetrate the surface tissues such as the cornea and sclera, highlighting the innate inability of the highly lipophilic molecule to permeate across the surface layers.…”

“…A previously published bio-analytical method (16) using fluorescence detection was modified and used for analyzing THC content in the ocular tissues. HPLC system comprised of a Waters 600 pump, Waters 717 plus refrigerated autosampler and Waters 2475 fluorescence detector, set at an excitation wavelength of 220 nm and Δ 8 -THC was detected at emission wavelength of 305 nm.…”

“…Previous reports from our group have demonstrated the physicochemical characteristics and permeability and in vivo disposition of Δ 9 -THC and it’s relatively water soluble prodrugs in the eye. The effects of ion pairing and micellar solutions on the disposition of Δ 9 -THC in the eye were studied in these previous reports (15, 16). …”

Corneal endothelial changes in long-term cannabinoid users

“…In the anterior segment of the eye, CB1 cannabinoid receptors are located in the corneal epithelium, corneal endothelium, trabecular meshwork, Schlemm's canal, ciliary body and sphincter papillae (5). Cannabinoids have been reported to reduce intraocular pressure by increasing aqueous outflow (6). Both cannabinoids obtained from plants and synthetic cannabinoids have been shown to potentially have a neuroprotective effect in glaucoma treatment (7).…”