A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Therapy with topical non‐steroidal anti‐inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. WHAT THIS STUDY ADDS • This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. AIMS To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid‐based delivery system under development (DCF100C). METHODS This was a single‐centre, open‐label, three‐period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren® Emulgel® gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. RESULTS All four DCF100C formulations demonstrated a three‐ to fivefold, dose‐dependent increase in systemic diclofenac availability compared with Voltaren® Emulgel® and were approximately 30–40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren® Emulgel® (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation. CONCLUSION DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.

Hydrogel increases diclofenac skin permeation and absorption

“…As illustrated in the present study, differences in the compositions of topical diclofenac formulations have been shown to be the primary determinants of differences in the rate of transdermal drug delivery (Brunner et al, ; Escribano et al, ; Folzer et al, ; Nivsarkar et al, ). For example, Escribano et al () compared the ex vivo human skin permeation of four distinct formulations of diclofenac sodium, including one microemulsion formulation.…”

“…Okuyama et al reported that adding diisopropyl adipate, which is a component of the present hydrogel formulation, to a diclofenac alcohol gel synergistically enhanced the in vivo absorption of diclofenac in guinea‐pigs as shown by plasma AUC and by underlying muscle concentrations (Okuyama et al, ). Others have reported that formulating diclofenac as an acid rather than as a salt may enhance the transdermal absorption compared with diclofenac emulsion gel (Brunner et al, ). In addition, small differences in ex vivo transdermal permeation rates have been reported for different salts of diclofenac when tested in simple solutions (Minghetti, et al, ), but whether these differences occur in complex transdermal formulations has not been described.…”

“…Factors that influence the transdermal permeation of topically applied NSAID formulations include chemical structure and properties of the drug (e.g. molecular weight, hydrophilic vs. hydrophobic properties, free‐acid or free‐base vs. salt form of the molecule), and the composition of the formulation, particularly the inclusion of excipients that enhance dermal penetration (Brunner et al, ; Escribano, et al, ; Folzer, et al, ; Lane, ; Marwah, et al, ; Nivsarkar, et al, ; Vitorino et al, ).…”

Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging

“…This was an observational study, and the sample size was determined based on previous pharmacological studies using CEUS or functional MRI for monitoring of renal perfusion as well as pharmacological studies on topical diclofenac application . In the mentioned work by Getzin et al ., a power calculation was performed for different scenarios with small pharmacological effects on renal perfusion.…”

“…Therefore, topical diclofenac administration is frequently discussed as an alternative for patients at risk of adverse drug events, since it might have less systemic side effects . Nonetheless, some preparations of topical diclofenac have been reported to reach measurable plasma concentrations after repeated application …”