Evaluation of diclofenac diethylammonium gel by in vitro permeation and in vivo bioavailability studies

Abstract

Four topical diclofenac diethylammonium gel products, including three commercial preparations (products A, B, C) and one experimental formulation (D), were evaluated in this study for their in vitro release through cellulose acetate and polytetrafluoroethylene (PTFE) membranes and for their in vitro permeation through the shed snake skin of Elaphe obsolete. The in vitro data were then compared to the results from the in vivo permeation studies in humans using the skin stripping technique. Both the in vitro release rate and the cumulative amount of diclofenac diethylamminium released through the cellulose acetate membrane correlated well with the amount of drug remaining in the stratum corneum at time 0, 1 and 3 hours following in vivo skin stripping of the stratum corneum of human forearm. In addition, the rate and extent of drug release through this membrane was found to correlate significantly with the area under the amount of drug in the stratum corneum versus time curve during the 6 hr study (AUC 0-6) (r = 0.9731-0.9875 p<0.05). There were also similarities in the raking order among the four products with respect to the in vitro release and the in vivo skin stripping parameters. Furthermore, the in vivo results indicated that following the drug release, the four products were rapidly absorbed through the stratum corneum at about the same rate as judged from the percent drug permeated through the skin at various time (p>0.05). On the other hand, there was no correlation between the in vivo parameters and the in vitro permeation through the shed snake skin or the in vitro release through the poorly wetted polytetrafluoroethylene membrane. These results led to the suggestion that the release of diclofence from the gel base play a rate limiting role in the overall percutaneous absorption through the stratum corneum of human forearm. Relative topical bioavailabilities, as calculated from the retios of AUC 0-6 between the test and reference product (A), were found to be 27.63, 126.41 and 34.96% for product B, C and D, respectively. In conclusion, the in vivo skin stripping method appeared to be a rapid and simple technique to evaluate the topical bioavailability of diclofenac diethylammonium gel products as well as to elucidate of percutaneous absorption characteriatics.