Skin permeability and pharmacokinetics of diclofenac epolamine administered by dermal patch in Yorkshire-Landrace pigs

Abstract

Susanna Tse,1 Kendall D Powell,2 Stephen MacLennan,3 Allan R Moorman,4 Craig Paterson,5 Rosonald R Bell11Pfizer Inc, Groton, CT, USA; 2Tandem Labs, Durham, NC, USA; 3BioCryst Pharmaceuticals Inc, Durham, NC, USA; 4Alta Vetta Pharmaceutical Consulting LLC, Durham, NC, USA; 5Salix Pharmaceuticals Inc, Raleigh, NC, USAPurpose: This study compared the pharmacokinetic profile, and systemic and local absorption of diclofenac, following dermal patch application and oral administration in Yorkshire- Landrace pigs.Patients and methods: Twelve anesthetized, female, Yorkshire-Landrace pigs were randomized to receive either the dermal patch (FLECTOR® patch, 10 × 14 cm; Alpharma Pharmaceuticals, a subsidiary of Pfizer Inc, New York, NY) or 50 mg oral diclofenac (Voltaren®; Novartis, East Hanover, NJ). Tissue (skin area of 2 × 2 cm and underlying muscles approximately 2–3 cm in depth) and blood (10 mL) samples were collected at timed intervals up to 11.5 hours after initial patch application or oral administration. The concentrations of diclofenac in plasma, skin, and muscle samples were analyzed using validated ultra performance liquid chromatography tandem mass spectrometric methods.Results: Peak systemic exposure of diclofenac was very low by dermal application compared with oral administration (maximum concentration [Cmax] values of 3.5 vs 9640 ng/mL, respectively). Absorption of diclofenac into underlying muscles beneath the dermal patch was sustained, and followed apparently zero-order kinetics, with the skin serving as a depot with elevated concentrations of diclofenac. Concentrations of diclofenac in muscles beneath the patch application site were similar to corresponding tissues after oral administration (Cmax values of 879 and 1160 ng/mL, respectively). In contrast to the wide tissue distribution of diclofenac after oral administration, dermal patch application resulted in high concentrations of diclofenac only on the treated skin and immediate tissue underneath the patch. Low concentrations of diclofenac were observed in the skin and muscles collected from untreated areas contralateral to the site of dermal patch application.Conclusion: Dermal patch application resulted in low systemic absorption and high tissue penetration of diclofenac compared with oral administration.Keywords: NSAIDs, systemic absorption, topical patch, tissue distribution