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Journal Article 
Enhanced Controlled Transdermal Delivery of Mexazolam Using Ethylene-vinyl Acetate 
Cho, CW; Shin, SC 
Iranian Journal of Pharmaceutical Research
ISSN: 1735-0328 
Repeated oral administration of mexazolam, an anti-anxiety agent, may cause adverse effects such as gastric disturbance, drowsiness, and ataxia due to transiently high blood levels. Transdermal administration would avoid the systemic side effects and gastric disorders after oral administration. We have developed a matrix using ethylene-vinyl acetate (EVA), a heat-processible and flexible material, for transdermal delivery of mexazolam. Drug solubility was highest at 40% PEG-400 volume fraction. The release and permeation profiles through the rat skin were determined for 24 h using a modified Keshary-Chien diffusion cell. The drug release was increased by increasing the concentration with a linear relationship between the release rate and the square root of loading dose. Increasing temperature increased drug release from the EVA matrix. The activation energy (E-a), which was measured from a slope of log P versus 1000/T plot, was 8.64 Kcal/mol for a 1.5% loading dose. To reduce the brittleness and increase the pore of the EVA matrix, diffrent plasticizers were used. Among the plasticizers, including the citrates or the phthalate groups, diethyl phthalate showed the highest effect on the release of mexazolam. To increase the skin permeation of mexazolam from the EVA matrix, enhancers such as the fatty acids, the pyrrolidones, the propylene glycol derivatives, the glycerides, and the non-ionic surfactants were added to the EVA matrix, respectively, and skin permeation was evaluated using a modified Keshary-Chien diffusion cell fitted with intact excised rat skin. Among the several enhancers used, N-methyl-2-pyrrolidone showed the best enhancement factor. In conclusion, enhanced transdermal delivery of mexazolam through an EVA matrix containing plasticizer and a permeation enhancer could be useful in the development of a transdermal drug delivery system. 
Mexazolam; EVA; Matrix; Plasticizer; Transdermal delivery; Penetration enhancer 
• Diethyl phthalate (DEP)
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