ABSTRACT
Introduction .................................................................................................................................... 272 Methods .......................................................................................................................................... 273 Animal Model.............................................................................................................................. 273 Transport Experiments ............................................................................................................... 273 Permeability Coefficient Determination................................................................................. 273 Reversibility Study................................................................................................................... 274 Model Description and Analysis of Experimental Data ........................................................ 275 Permeant Solubility Determination........................................................................................ 276 Determinations of Partition Coefficients in Bulk Organic Solvent/PBS Systems ................. 276
Partition Experiments ................................................................................................................. 276 n-Heptane Treatment and SC Preparation............................................................................. 276 HMS SC Delipidization ........................................................................................................... 276 Partition Experiments with Heptane-Treated and Delipidized HMS SC .............................. 277
Permeant Partitioning into the Transport Rate-Limiting Domain and Equilibrium Permeant Partitioning into the Stratum Corneum Intercellular Lipids ............. 278
Results and Discussion ................................................................................................................... 278 Isoenhancement Concentrations and Enhancer Effects ........................................................... 278 Effects of Alkyl Chain Length..................................................................................................... 279 Effects of Polar Head Functional Groups .................................................................................. 281 Effects of Hydrocarbon Chain Carbon-Carbon Double Bond ................................................. 281 Effects of Branched Alkyl Chain ................................................................................................ 283 Equilibrium Partition Enhancement of ES into SC Intercellular Lipids .................................... 286 Transport Rate-Limiting Domain and Equilibrium Partitioning Domain.................................. 286 Effects of Permeation Enhancement on Permeants of Different Molecular Sizes ................... 287 Permeation Enhancers in a Nonaqueous System in Transdermal Drug Delivery ................... 289
Conclusions .................................................................................................................................... 290 Acknowledgment ........................................................................................................................... 290 References....................................................................................................................................... 290
Most of the chemical permeation enhancer studies over the past decades have been aimed at gaining better insights into the relationship between the nature of the enhancers and their effectiveness in permeation enhancement. In typical in vitro studies of chemical permeation enhancers, the enhancer in question is usually applied with a drug in solution or suspension to one side of the membrane, and the effectiveness of the enhancer compared to a control is determined by the rate of transport of the drug. Under this approach, the different relationships among the enhancer molecular structures and their effects as permeation enhancers have been observed (e.g., reviewed in Lee et al., 1991; Smith and Maibach, 1995; Hadgraft, 2001).
