Dermal Delivery of Diclofenac Sodium—In Vitro and In Vivo Studies

Abstract

Previously, we reported the use of confocal Raman spectroscopy (CRS) as a novel non-invasive approach to determine drug disposition in the skin in vivo. Results obtained by CRS were found to correlate with data from the well-established in vitro permeation test (IVPT) model using human epidermis. However, these studies used simple vehicles comprising single solvents and binary or ternary solvent mixtures; to date, the utility of CRS for monitoring dermal absorption following application of complex marketed formulations has not been examined. In the present work, skin delivery of diclofenac sodium (DFNa) from two topical dermatological drug products, namely Diclac® Lipogel 10 mg/g and Primofenac® Emulsion gel 1%, was determined by IVPT and in vivo by both CRS and tape stripping (TS) methodologies under similar experimental conditions. The in vivo data were evaluated against the in vitro findings, and a direct comparison between CRS and TS was performed. Results from all methodologies showed that Diclac promoted significantly greater DFNa delivery to the skin (p < 0.05). The cumulative amounts of DFNa which permeated at 24 h in vitro for Diclac (86.5 ± 9.4 µg/cm2) were 3.6-fold greater than the corresponding amounts found for Primofenac (24.4 ± 2.7 µg/cm2). Additionally, total skin uptake of DFNa in vivo, estimated by the area under the depth profiles curves (AUC), or the signal intensity of the drug detected in the upper stratum corneum (SC) (4 µm) ranged from 3.5 to 3.6-fold greater for Diclac than for Primofenac. The shape of the distribution profiles and the depth of DFNa penetration to the SC estimated by CRS and TS were similar for the two methods. However, TS data indicated a 4.7-fold greater efficacy of Diclac relative to Primofenac, with corresponding total amounts of drug penetrated, 94.1 ± 22.6 µg and 20.2 ± 7.0 µg. The findings demonstrate that CRS is a methodology that is capable of distinguishing skin delivery of DFNa from different formulations. The results support the use of this approach for non-invasive evaluation of topical products in vivo. Future studies will examine additional formulations with more complex compositions and will use a wider range of drugs with different physicochemical properties. The non-invasive nature of CRS coupled with the ability to monitor drug permeation in real time offer significant advantages for testing and development of topical dermatological products.

Confocal Raman Spectroscopy for Assessing Bioequivalence of Topical Formulations

“…The total amount of drug in the SC measured by CRS has been previously found to correlate with the cumulative amount of drug permeated measured with IVPT studies [19,20]. In the present study, the two products resulted in comparable amounts of IBU permeation in vitro With regards to the total amount of IBU that penetrated the SC, the area under the depth profiles curves (AUC) was used as a measure of drug uptake for each formulation, as reported previously [18,[38][39][40]. The AUC values measured after a 1 h application were 36.9 ± 17.4 and 47.4 ± 18.6 AU for Ibuleve and Nurofen, respectively.…”

“…Additionally, further studies using a wide range of drug substances and drug products are required to support the capability of CRS to assess the efficacy of products other than those tested in the present study. However, the present findings together with recent in vitro-in vivo correlation studies [17,19,20,38] demonstrate the capability of CRS to evaluate the BE of commercial formulations in vivo. The standardization of the procedure as well as the inclusion of appropriate power simulation analysis for an a priori determination of the time intervals and number of donors required is currently under development.…”

“…The average SC thickness of the volunteers was 18.0 ± 0.8 µm, estimated as reported in previous studies [14]. This value was used to normalise the distance to the skin surface [16,38]. The IBU depth profiles across the volar forearm skin of the volunteers for the two formulations are shown below in Figure 4.…”

“…With regards to the total amount of IBU that penetrated the SC, the area under the depth profiles curves (AUC) was used as a measure of drug uptake for each formulation, as reported previously [18,[38][39][40]. The AUC values measured after a 1 h application were 36.9 ± 17.4 and 47.4 ± 18.6 AU for Ibuleve and Nurofen, respectively.…”

Development and Characterisation of a Topical Methyl Salicylate Patch: Effect of Solvents on Adhesion and Skin Permeation

“…In vitro permeation experiments were performed using Franz-type diffusion cells with a diffusion area of about 0.79 cm 2 [46,47]. A full thickness of porcine ear skin was placed between the donor and receptor compartments by having the SC facing the donor compartment.…”