The effects of pH and chemical enhancers on the percutaneous absorption of indomethacin

Abstract

The absorption of indomethacin through excised hairless mouse skin from aqueous solution was determined at different pH values. We found that the rate of its absorption increased with decreasing pH. Its distribution coefficient in octanol-phosphate buffer was also pH dependent. Furthermore, the change of permeability coefficient with pH correlated well with the distribution coefficient by a two-degree polynominal equation. The individual incorporation of five chemical enhancers into a polymeric patch at optimal pH resulted in an increase or decrease in the in vitro absorption rate and in the amount absorbed during the first 24 hours depending on the enhancer and its concentration used. Both sodium cholate at 4 and 6 %, and sodium lauryl sulfate at 4 % increased the absorption rate about four to seven times compared to the control. The in vivo absorption using rabbits from patch containing 6% sodium cholate also showed an increase in rate and the AUC compared to that from the control; however, the extent of the increase was much less compared to that obtained from the in vitro study. The stability of this drug in aqueous solution was also studied as a function of pH. It was confirmed that indomethacin was more stable at lower pH values. The pH-rate constant profile also indicated a specific base catalysis for its degradation at pH above 6.5. Due to its small solubilities at lower pHs, an optimal pH near 5 was suggested for the preparation of a transdermal delivery system for indomethacin.