Ocular Disposition of the Hemiglutarate Ester Prodrug of ∆9-Tetrahydrocannabinol from Various Ophthalmic Formulations

Abstract

Purpose The overall goal of this project is to enhance ocular delivery of ∆9-Tetrahydrocannabinol (THC) through the topical route. Methods Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. Results Aqueous solubility and stability and in vitro transcorneal permeability of THCHG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. Conclusion In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.

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.…”

“…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). …”

Δ9-Tetrahydrocannabinol Derivative-Loaded Nanoformulation Lowers Intraocular Pressure in Normotensive Rabbits

“…The tissue concentrations obtained were extremely low, namely, about 1 ng of 14 C-labeled THC/mg of wet tissue weighed 4 hours after dosing in the cornea and IC. Hingorani et al52 observed that the amount of THC permeating into the ocular tissues was below levels of detection in rabbit AH, VH, RC, and IC, 1 hour postadministration of THC in light mineral oil (0.1% w/v), emulsion (0.37% w/v), or micellar solutions (0.125% w/v THC, 0.5% w/v Cremophor RH 40) in NZW rabbits, with detectable levels only in the cornea and sclera. Such findings suggest that the lipophilic nature of THC prevents its partitioning from the oily vehicle into the tear film, in turn affecting its overall ocular bioavailability.…”

“…To improve the intrinsic solubility of THC, a prodrug strategy was used by Hingorani et al52,55 by using a hemiglutarate (dicarboxylic acid) ester (THC-HG), which, being ionized at physiological pH, would have better aqueous solubility (19 μg/mL). One hour postinstillation of 50 μL of THC-HG, formulated in 0.5% w/v Cremophor RH 40, 35.6 ± 12.5 ng of THC/50 mg of tissue was observed in the IC and 32.1 ± 12.6 ng of THC/100 μL was detected in AH of NZW rabbits, whereas the THC tissue concentrations obtained postdosing of 50 μL THC formulated in 0.5% w/v Cremophor RH 40 were below detection levels.…”

“…One hour postinstillation of 50 μL of THC-HG, formulated in 0.5% w/v Cremophor RH 40, 35.6 ± 12.5 ng of THC/50 mg of tissue was observed in the IC and 32.1 ± 12.6 ng of THC/100 μL was detected in AH of NZW rabbits, whereas the THC tissue concentrations obtained postdosing of 50 μL THC formulated in 0.5% w/v Cremophor RH 40 were below detection levels. This finding suggested that hydrophilic prodrug derivatization is an efficient method to improve the ocular bioavailability of THC 52. However, in terms of chemical stability, THC-HG was extremely unstable and underwent rapid degradation at acidic and alkaline pH conditions, as well as at physiological pH 55,56…”