Objective: The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) relates not only to the individual NSAID used but also to differences in formulation design. The aim of this study was to investigate the fundamental differences in ibuprofen and diclofenac drug delivery vehicles, specifically gels and plasters, compared to a recently launched 200 mg ibuprofen medicated plaster and characterize the resulting dermatologic-pharmacokinetic profiles into and through ex vivo human skin layers. Methods: In vitro skin permeation testing over 24 h and sacrificial timepoint penetration experiments (at 1, 4, 8, 12, and 24 h) were conducted using an automated flow-through diffusion cell system. The amount of drug delivered to the epidermis, dermis, and receptor solution (representing deeper tissue) was determined by liquid chromatography-tandem mass spectrometry. Skin protein binding of ibuprofen and diclofenac was investigated by spiking skin homogenate with increasing concentrations of each drug and determining the fraction unbound. Results: Differences were observed in the amount of drug recovered at sacrificial timepoints and rate at which drug was delivered to the target site between plaster and gel formulations of ibuprofen and diclofenac and between plaster formulations of the same drug (ibuprofen). While the amount of drug quantified at sacrificial timepoints did not necessarily determine in vivo flux rates, differences in drug distribution within the skin layers indicated where drug reservoirs were formed. Conclusions: These findings highlight the importance of intelligent formulation design in determining NSAID delivery through skin layers. Further work is required to quantify drug delivery into deeper tissues and the resultant local anti-inflammatory effects.

The mild epoxidation of strained alkenes using (DMPO) 2 MnCl catalyst (DMPO = 1,2-dimethyl-4(1H)-pyridinone-3-olate) in the presence of various oxidants was studied. Hydrogen peroxide and monopersulfate were found to be the best oxidants when used with imidazole in acetonitrile at 4 o C, with up to 94% conversion. Dismutation of hydrogen peroxide was also observed when used as an oxidant. The epoxidation using hydrogen peroxide or monoperoxysulfate appears to be mild and very selective for strained alkenes. A mechanism is proposed where imidazole is required for activation of the oxidant and where a detected Mn V =O species is proposed as the active species. Competitive reaction between H 2 O 2 and the substrate for the active species is proposed and homolytic vs heterolytic scissions of the O-O bond of the oxidant are discussed.