Comparative in vivo bioequivalence and in vitro dissolution of two valproic acid sustained-release formulations

Abstract

Objective: A study was conducted to establish the bioequivalence between different sustained-release formulations of valproic acid (Depakene R and Selenica R), which were developed in Japan.

Materials and methods: The clinical investigation was designed in a randomized, crossover fashion with a single dose given to 12 healthy subjects. The subjects were administered a single 600 mg dose of valproic acid in one of two formulations. Serial venous blood samples were obtained over 72 hours after each administration to measure valproic acid in serum by enzyme immunoassay (EIA). In addition, a dissolution test was performed. Each sample was analyzed by an high-performance liquid chromatography to determine the dissolution rate of valproic acid.

Results: No difference in maximum concentration or area under the curve was found between the two formulations. The time to maximum concentration of the new formation was significantly delayed compared with the conventional formulation (10.8 +/- 1.7 versus 17.6 +/- 1.8 hours, p < 0.001). Apparent clearance or elimination half-life did not differ between the two formulations. An in vitro dissolution study showed that Depakene R was significantly more dissoluble than Selenica R.

Conclusion: Based on the results, the present study demonstrated a significant difference between the two sustained-release formulations in the absorption profile, and also demonstrated that the bioavailability of valproic acid in the two formulations was similar but absorption speed (lag time) was very different.

Keywords: Depakene R; Selenica R; bioequivalence; sustained-release; valproic acid.

Figure 1

Dissolution profiles of Depakene R and Selenica R. Error bars indicate standard errors. Open and solid circles are the data for Depakene R and Selenica R, respectively. Notes: *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 2

Tablet characteristics for the slow-release preparations of Depakene R and Selenica R.

Figure 3

Serum concentration-time curves of valproic acid after single oral doses of Depakene R and Selenica R. Error bars indicate standard errors. Open and solid circles are the data for Depakene R and Selenica R, respectively. Notes: *p < 0.05, **p < 0.01, ***p < 0.001.