Chem. Pharm. Bull. 55(3) 368—371 (2007)

barrier to the permeation of most drugs, and especially as a hydrophobic barrier against hydrophilic drugs and ionized drugs. One possible means of facilitating the transdermal delivery of ionic drugs is through ion-pair formation. Oppositely charged ions can interact to form new species known as ion-pairs. This association reduces or neutralizes electrostatic charges and consequently reduces the electrical conductivity in a non-polar milieu. In our previous study, an increase in skin permeation of salicylate in isopropyl myristate (IPM) was found in the presence of counter ions (alkylamines and benzylamine); the increased permeation was attributed to the lipophilization of salicylate via an ion-pair. Diclofenac, which is a therapeutically important nonsteroidal anti-inflammatory drug, is extensively metabolized in the liver. Because of its short biological half-life, the drug needs to be administered quite frequently. Transdermal delivery of diclofenac may provide better patient compliance over oral administration. However, diclofenac is not easily absorbed on transdermal application. In this study we first examined the effects of amines, model cationic counter ions, on the in vitro percutaneous penetration of diclofenac through excised guinea pig dorsal skin. Guinea pig dorsal skin has been reported to be a good model for human skin. We furthermore examined the effects of combined use of ion-pair formation and microemulsions. Microemulsions, characterized as thermodynamically stable and clear isotropic systems with droplet sizes in the sub-micron range, have also been studied in pharmaceutical applications. They typically consist of an aqueous phase, an organic phase, and a surfactant/cosurfactant component. They may act as penetration enhancers, depending on the oil/surfactant constituents. Currently they are recognized as good vehicles for the percutaneous absorption of drugs such as tyrosine, bblockers, sucrose, ketoprofen and estradiol. Formulations based on microemulsions have several advantages over conventional formulations, namely: thermodynamic stability, enhanced drug solubilization and ease of manufacturing. Although ion-pair formation is a promising means of facilitating the transdermal delivery of ionic drugs, the solubility of ion-pairs in both aqueous and non-aqueous vehicles is still limited to obtain sufficient absorption rates. Therefore, in this study, microemulsions containing diclofenac ion-pairs were also used to further improve the solubility and skin permeability of the ion-pairs. We used microemulsions consisting of PBS, IPM, polyoxyethylene sorbitan monooleate (Tween 80) and ethanol, which are the aqueous phase, oil phase, surfactant and cosurfactant, respectively, as model microemulsions. The microemulsions of these constituents have been revealed to be useful as a permeation enhancing system for hydrophobic drugs such as free-base lidocaine and estradiol, as well as hydrophilic drugs such as lidocaine hydrochloride salts and diltiazem.