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This study was aimed to enhance the percutaneous absorption of tizanidine hydrochloride (TZ) across Strat- MTM artificial membrane and excised hairless mouse skin using various vehicles and chemical permeation enhancers. Solubility studies were performed using hydrophilic and lipophilic vehicles. To initially evaluate vehicle effects on skin permeation, Strat-MTM membrane was adopted using Franz-type diffusion cells loaded with 0.4 mg donor dose. Effects of fatty acids on the permeation of TZ from PG and PGMC were compared, and the effects of various hydrophilic vehicles in the presence of linoleic acid were studied using excised hairless mouse skin specimens. The mean solubility (mg/ml) of TZ in hydrophilic vehicles was higher: water > PG > DMSO > ethanol > PEG 200 > NMP > PEG 300 > PEG 400 > DGME, and solubilities in lipophilic vehicles such as PGMC, PGMC, IPM, Captex 200 and Captex 300 were much less than 1.0 mg/ ml. Permeation rates through StratTM membrane from pure vehicles were in the rank order: PGMC ≥ LBF>DMSO≥ NMP ≥ PGML ≥ PG ≥ PEG 200 ≥ DGME ≥ EtOH. However, permeation rates of TZ through hairless mouse skin from pure vehicles were very low, although PG showed the highest flux (1.66±0.28 μg/cm2 · hr). Therefore, PG was selected in further studies. Addition of enhancers (3 v/v%) into PG markedly increased the flux (μg/cm2 · hr): oleyl alcohol (14.9±3.1) ≥ oleic acid (14.5±1.6) ≥ linoleic acid (13.7±1.3) > capric acid (4.4±0.6) > caprylic acid (2.1±0.4). Among hydrophilic vehicles with linoleic acid, PG and DMSO revealed relatively higher permeation for TZ. Increase of donor dose in PG resulted in dose-dependent permeation fluxes. These results suggest that permeation properties of TZ from nonaqueous solutions are markedly different between Strat-MTM membrane and excised hairless mouse skin, and transdermal delivery of TZ would be feasible with a combination of PG and enhancers.