Permeation of WIN 55,212-2, a potent cannabinoid receptor agonist, across human tracheo-bronchial tissue in vitro and rat nasal epithelium in vivo

Abstract

The aim of this study was to investigate the intranasal absorption of R-(+)-WIN 55,212-2 mesylate in vivo and in vitro. Permeation experiments of R-(+)-WIN 55,212-2 formulations with 2% dimethyl-beta-cyclodextrin (DMbetaCD), 2% trimethyl-beta-cyclodextrin (TMbetaCD) or 2% randomly methylated-beta-cyclodextrin (RAMbetaCD) in 1:1 propylene glycol/saline and 1.5% propylene glycol +3% Tween 80 in saline were conducted using EpiAirway tissue and an anesthetized rat nasal absorption model, respectively. Samples were analysed by liquid chromatography-mass spectrometry. Mucosal tolerance was screened using paracellular marker permeation and tissue viability as indices. Nasal absorption of WIN 55,212-2 was rapid, with a t(max) (time of peak concentration) of 0.17 to 0.35 h in vivo. Relative to 1.5% propylene glycol +3% Tween 80 (control), 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD resulted in 24-, 20-, 17- and 10-fold WIN 55,212-2 permeation increases in vitro, respectively. The in vivo absolute bioavailabilities were also increased with 1:1 propylene glycol/saline, RAMbetaCD, DMbetaCD and TMbetaCD compared to 1.5% propylene glycol +3% Tween 80 (0.15 vs. 0.66-0.77). The viability of the EpiAirway tissues was significantly reduced by DMbetaCD and TMbetaCD formulations. This study showed that WIN 55,212-2 mesylate can be delivered via the nasal route. Absorption of R-(+)-WIN 55,212-2 was rapid and bioavailability was significantly improved using methylated cyclodextrins and propylene glycol-based cosolvent.

Aerodynamical, Immunological and Pharmacological Properties of the Anticancer Antibody Cetuximab Following Nebulization

“…Anticancer antibodies, whether they are naked or conjugated (with the exception of trastuzumab (Herceptin \ ) and gemtuzumab ozogamycin (Mylotarg \ )), are generally supplied as liquids, but spraydrying of pure proteins in aqueous solutions often produces aggregates and/or loss of activity. Although the addition of disaccharides or surfactant in the medium can stabilize immunoglobulin during spray-drying, novel drug formulation must be established and evaluated (19)(20)(21)34).…”

“…However, it is not responsible for the aggregation formation since no insoluble particles were observed after incubation of native cetuximab in the same conditions in a water bath. Previous studies showed that recirculation of the aerosol droplets into the reservoir exerts high shear stress on the drugs, leading to protein denaturation and aggregation (34,36). In contrast to the AeronebPro \ , both the jet and the ultrasonic nebulizers have a recirculation system that might explain aggregate formation.…”

Nose-to-brain transport of melatonin from polymer gel suspensions: a microdialysis study in rats

“…These tissues were well utilized as permeation barriers of nasal membranes as reported in earlier investigations (Agu et al, 2004, Agu et al, 2006, Babu et al, 2008). The tissues grown on the deep snap wells along with the modified 6-well plates provided a secure donor and receiver compartments.…”

Prevalidation of an Acute Inhalation Toxicity Test Using the EpiAirwayIn VitroHuman Airway Model

“…It has been successfully utilized by numerous research laboratories worldwide in applications including toxicology, drug delivery, pharmacology, and infectious disease research. 17–28 A complete bibliography of additional peer-reviewed research articles that include EpiAirway data is available from MatTek ( ).…”