| The objectives of this study were to evaluate peripheral H1-antihistamine efficacy, and systemic absorption after application of liposome formulations containing hydroxyzine or cetirizine to the skin of a rabbit model and to evaluate the physicochemical stability of these liposome formulations containing hydroxyzine or cetirizine. Using L-alpha-phosphatidylcholine (PC), L-alpha-phosphatidylserine (PS), and L-alpha-phosphatidylcholine hydrogenated (HPC) and hydrating buffers pH 5.0--7.0, small unilamellar (SUV), HPC-SUV and multilamellar (MLV) vesicles containing hydroxyzine or cetirizine were produced by ethanol injection, extrusion, and thinlipid film hydration methods, respectively. PC-MLV were subjected to hydration times of 1h, 24h, and 48h as well as five cycles of freeze-thawing. Liposomes freshly prepared and stored for up to 24 months at 10 +/- 2°C, 25 +/- 3°C, 37 +/- 0.1°C were evaluated by determining percent entrapment of hydroxyzine (PETH) or cetirizine (PEC), by checking the physical appearance, by determining particle size, and by taking transmission electron micrographs (TEM) and optical micrographs (MOM). For in vivo evaluation each liposome formulation and Glaxal Base (GB), the control, containing 10 mg of hydroxyzine or cetirizine was applied to the shaved backs of rabbits (3.08 +/- 0.05 kg) then intradermal tests with 0.05 ml histamine phosphate (1mg/ml), and blood sampling were performed before application, and at pre-selected times for 24 h. Wheal suppression was calculated and hydroxyzine and cetirizine plasma concentrations were measured. Based on the percent entrapment of 90%, physical appearance and TEM, HPC-SUV, and HPC-MLV at pH 6.5, were the most stable liposomal formulations. Hydroxyzine or cetirizine SUV and MLV for in vivo testing were prepared at pH 6.5 using PC and HPC. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. The areas under the plasma hydroxyzine concentration versus time curve (AUC) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng.h/mL, respectively, were lower than that from GB; 492 +/- 141 ng.h/mL, P ≤ .05, over 24 hours, while concentrations of cetirizine from hydroxyzine in all formulations were similar. After 24h, only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin. (Abstract shortened by UMI.)... |
