Effects of RM-?-CD on sublingual bioavailability of ?9-tetrahydrocannabinol in rabbits

Effects of RM-?-CD on sublingual bioavailability of ?9-tetrahydrocannabinol in rabbits
Received 31 January 2005; revised 15 April 2005; accepted 27 April 2005. Available online 13 June 2005.
Janne Mannilaa, , , Tomi J?rvinena, Kristiina J?rvinenb, Maarit Tarvainenb and Pekka Jarhoa
European Journal of Pharmaceutical Sciences
ScienceDirect
aDepartment of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland
bDepartment of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland
Abstract
The purpose of the present study was to develop novel cyclodextrin-containing sublingual formulations of cannabinoids.
Complexation of model cannabinoids, ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with randomly methylated ?-cyclodextrin (RM-?-CD) and hydroxypropyl-?-cyclodextrin (HP-?-CD), were studied by the phase-solubility method. Due to better complexation efficiency, RM-?-CD was selected for further studies. Solid THC/RM-?-CD and CBD/RM-?-CD complexes were prepared by freeze-drying. The dissolutions of both THC and CBD in the presence and absence of RM-?-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-?-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-?-CD and RM-?-CD, respectively. Dissolution rates of THC/RM-?-CD and CBD/RM-?-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-?-CD solution (F = 12.1 ? 1.4%; mean ? S.D.; n = 4) > oral THC/RM-?-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-?-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-?-CD complex substantially increases the bioavailability of THC in rabbits.
Keywords: Cannabinoids; Cyclodextrins; Delta(9)-tetrahydrocannabinol

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