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

Abstract

PurposeThis 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 methodsTwelve 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.ResultsPeak 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.ConclusionDermal patch application resulted in low systemic absorption and high tissue penetration of diclofenac compared with oral administration.

Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster

“…The systemic exposure to the DHEP medicated plaster at steady state, after 4 days of twicedaily application, was over 99% less than after a single oral dose of diclofenac 27 . This in accordance with the findings from a relevant animal model, which showed that penetration of diclofenac into the underlying muscle when applied as a medicated plaster was sustained and appeared to follow zero-order kinetics, while systemic bioavailability and distribution into other tissues was very limited 10 . Similar concentrations of diclofenac in the immediate tissue underlying the patch area were obtained with both topical and 50 mg oral administration of diclofenac 10 .…”

“…Topical NSAID formulations are designed to deliver effective analgesic activity when locally applied while limiting systemic exposure. A recent analysis of the Cochrane Database of Systematic Reviews concluded that topical NSAIDs are safe and effective in helping to reduce pain associated with acute sprains and strains and that topical NSAIDs, specifically diclofenac and ketoprofen, may provide useful levels of pain relief in osteoarthritis [8][9][10] . In acute musculoskeletal pain conditions such as strains and sprains, the number needed to treat (NNT) to achieve ≥50% pain relief when used for approximately 7 days was between 1.8 and 4.7 depending on the active substance and formulation 9,11 .…”

“…The safety and efficacy of the marketed DHEP medicated plaster have been demonstrated by data from clinical studies and postmarketing experience of the treatment of acute musculoskeletal pain associated with soft tissue injuries and inflammatory pathologies, including osteoarthritis and A c c e p t e d M a n u s c r i p t other rheumatological conditions 5,8,9,[21][22][23][24][25][26] . Results from a skin permeability and pharmacokinetic study 10 and a pharmacokinetic study in healthy volunteers 27 show that the systemic exposure of diclofenac is very low compared with oral administration when applied as the DHEP medicated plaster. The systemic exposure to the DHEP medicated plaster at steady state, after 4 days of twicedaily application, was over 99% less than after a single oral dose of diclofenac 27 .…”

Biodistribution of diclofenac following repeated topical applications of two diclofenac sodium formulations to minipigs

“…Outside the patch area, the skin and underlying muscle contained low concentrations of diclofenac. This study provided direct evidence that the topical application of diclofenac produced low systemic absorption while achieving high tissue penetration . In addition, other studies present results supporting the hypothesis that certain tissues serve as a depot, which allows for the continuous diffusion of the topically applied agent into surrounding tissues and systemic circulation .…”

Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels

“…Transdermal formulations of diclofenac sodium are used for the localized treatment of symptomatic joint pain in osteoarthritis (Heyneman et al, 2000;Tse et al, 2012).…”