Formulation factors affecting follicular (pilosebaceous route) drug delivery as evaluated with the hamster ear model.

Abstract

The objective of this study was to explore the pilosebaceous unit (PSU) route as a target for topical delivery and to determine the effect of formulation on drug delivery to PSU and other skin strata. A variety of in vitro and in vivo deposition studies as well as pharmacodynamic antiandrogenic sebaceous gland bioassays were carried out. Male Syrian hamster ear, as the model skin, was used and techniques to assess deposition of hydrophilic drugs into pilosebaceous units was developed. The major conclusions are: (1) The scraping technique, a procedure developed in our laboratory whereby follicularly deposited substances could be physically removed and analyzed, was found to be a viable method to assay follicularly deposited substances. This technique correlated well with quantitative fluorescence microscopy. (2) Multilamellar phospholipid liposomes enhanced follicular deposition of a fluorescent marker, carboxyfluorescein, over other conventional penetrant-type topical formulations. Deposition was not affected by whether or not the marker was fully entrapped within the liposome. (3) The data obtained from the in vitro and in vivo deposition and the bioassay studies using an antiandrogenic drug, cimetidine, suggested a complex variety of factors that influence how the formulation influences both the degrees of drug deposition and its pharmacological activity in the pilosebaceous unit. For in vitro studies, when cimetidine was formulated at pH values where it was in a predominately unionized form, the thermodynamic driving force effect was more important than surfactant wetting, solvent enhancer and liposomal bilayer deposition effect in influencing the extent of drug deposition into the PSU. (4) Although the phospholipid-based liposomal formulation was the most efficient of all those tested in depositing cimetidine into the pilosebaceous units, this formulation was the only one that yielded no significant antiandrogenic action, possibly due to the formation of an inactive complex formed between the negatively charged phospholipid bilayers and positively charged cimetidine. This further points out that deposition studies may not yield information as to the state of the drug at the receptor site, i.e., free or bound. Finally, the data for cimetidine in 50% alcohol solution shows that one can maintain local effects while reducing systemic activity by manipulating drug concentration.