Enhanced solubility, stability, and transcorneal permeability of δ-8-tetrahydrocannabinol in the presence of cyclodextrins

Abstract

The purpose of this study was to investigate the effect of cyclodextrins (CDs) on aqueous solubility, stability, and in vitro corneal permeability of delta-8-tetrahydrocannabinol (Δ(8)-THC). Phase solubility of Δ(8)-THC was studied in the presence of 2-hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated-β-cyclodextrin (RMβCD) and sulfobutyl ether-β-cyclodextrin sodium salt (SβCD). Stability of Δ(8)-THC in 5% w/v aqueous CD solutions, as a function of pH, was studied following standard protocols. In vitro corneal permeation of Δ(8)-THC (with and without CDs) across excised rabbit cornea was also determined. Phase-solubility profile of Δ(8)-THC in the presence of both HPβCD and RMβCD was of the A(P) type, whereas, with SβCD an A(L) type was apparent. Aqueous solubility of Δ(8)-THC increased to 1.65, 2.4, and 0.64 mg/mL in the presence of 25% w/v HPβCD, RMβCD, and SβCD, respectively. Significant degradation of Δ(8)-THC was not observed within the study period at the pH values studied, except for at pH 1.2. Transcorneal permeation of Δ(8)-THC was dramatically improved in the presence of CDs. The results demonstrate that CDs significantly increase aqueous solubility, stability, and transcorneal permeation of Δ(8)-THC. Thus, topical ophthalmic formulations containing Δ(8)-THC and modified beta CDs may show markedly improved ocular bioavailability.

Fig. 1

Solubility of Δ⁸-THC in water and as a function of pH. The solubility studies were carried out at 25°C for a period of 24 h. Values are represented as mean ± SD (n = 3)

Fig. 2

Apparent first order degradation rate constant (k × 10² h⁻¹) of Δ⁸-THC at 25°C as a function of pH. Results are depicted as mean ± SD (n = 3)

Fig. 3

a Phase solubility of Δ⁸-THC in the presence of HPβCD at 25°C, following 24-h equilibration. Each point represents mean ± SD (n = 6). Insert represents that the phase solubility of Δ⁸-THC as A_L type up to a concentration of 80 mM HPβCD. The total diagram is classified as A_P type. b Phase solubility of Δ⁸-THC in the presence of RMβCD at 25°C, following 24-h equilibration. Each point represents mean ± SD (n = 6). The diagram is classified as A_P type. c Phase solubility of Δ⁸-THC in the presence of SβCD at 25°C, following 24-h equilibration. Each point represents mean ± SD (n = 6). The diagram is classified as A_L type

Fig. 4

Transcorneal permeation of Δ⁸-THC from Δ⁸-THC suspension and Δ⁸-THC in the presence of 5% w/v cyclodextrin formulation. Results are depicted as mean ± SD (n = 4). ND not detectable