Effects of RM-β-CD on sublingual bioavailability of Δ9-tetrahydrocannabinol in rabbits

Abstract: The purpose of the present study was to develop novel cyclodextrin-containing sublingual formulations of cannabinoids. Complexation of model cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with randomly methylated β-cyclodextrin (RM-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD), were studied by the phase-solubility method. Due to better complexation efficiency, RM-β-CD was selected for further studies. Solid THC/RM-β-CD and CBD/RM-β-CD complexes were prepared by freeze-drying. The dissolutions of both THC and CBD in the presence and absence of RM-β-CD were determined. THC was selected for in vivo studies: the pharmacokinetics of THC after both sublingual and oral administrations of ethanolic THC and THC/RM-β-CD complex solutions were studied in rabbits. The aqueous solubility of CBD and THC increased as a function of CD concentration, showing AL- and AP-type diagrams for HP-β-CD and RM-β-CD, respectively. Dissolution rates of THC/RM-β-CD and CBD/RM-β-CD complexes were significantly (p <0.05) higher than those of plain THC and plain CBD, respectively. The absolute bioavailability (F) of THC decreased in the following order: sublingual THC/RM-β-CD solution (F =12.1±1.4%; mean±S.D.; n =4)>oral THC/RM-β-CD solution (F =4.0±6.0%)≥sublingual ethanolic THC solution (F =3.8±2.8%)>oral ethanolic THC solution (F =1.3±1.4%). These results demonstrate that RM-β-CD increases both the aqueous solubility and dissolution rate of these cannabinoids, making the development of novel sublingual formulation possible. These results also suggest that the sublingual administration of a THC/RM-β-CD complex substantially increases the bioavailability of THC in rabbits. [Copyright &y& Elsevier]