The enhancement effect of surfactants on the penetration of lorazepam through rat skin

Lorazepam is an anxiolytic, antidepressant agent, having suitable feature for transdermal delivery. The percutaneous permeation of lorazepam was investigated in rat skin after application of a water:propylene glycol (50:50% v/v). The enhancing effects of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on the permeation of lorazepam were evaluated using Franz diffusion cells fitted with rat skins. Flux, K-p, lag time and enhancement ratios (ERs) of lorazepam were measured over 24 h and compared with control sample. Furthermore, lorazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of lorazepam. The permeation profile of lorazepam in presence of the cationic surfactant, CTAB, reveals that an increase in the concentration of CTAB results in an increase in the flux of lorazepam in comparison with the control. But an increase in concentration of CTAB or benzalkounium chloride from 0.5 to 1% w/w or from 1 to 2.5% w/w resulted in a reduction in ER, respectively. Benzalkonium chloride which possessed the highest lipophilicity (log P = 1.9) among cationic surfactants provided the greatest enhancement for lorazepam flux (7.66-fold over control) at 1% w/w of the surfactant. CTAB (log P < 1) and sodium lauryl sulphate at a concentration of 5% w/w (the highest concentration) exhibited the greatest increase in flux of lorazepam compared with control (9.82 and 11.30-fold, respectively, over control). This is attributed to the damaging effect of the cationic and anionic surfactants on the skin at higher concentration. The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant molecules to form micelles and is normally observed only if interaction between micelle and the drug occurs. (C) 2002 Elsevier Science B.V. All rights reserved.