Transdermal Delivery of Dideoxynucleoside-Type Anti-HIV Drugs. 2. The Effect of Vehicle and Enhancer on Skin Permeation

Abstract

The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 °C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 °C, an in vitroskin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic systemic level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.