(T1030-02-08) The Potential of In Vitro Dissolution Absorption System 2 (IDAS2) as a Bioequivalence Decision Tool

Purpose: The In Vitro Dissolution Absorption Systems 2 (IDAS2) has been developed to simultaneously assess the dissolution and permeation profiles of oral products in biorelevant conditions [1-4]. The purpose of this study is to examine the potential of IDAS2 as a bioequivalence (BE) decision tool. The three acetaminophen oral products, an immediate-release tablet (IR tablet, 325 mg), an immediate-release liquid-filled capsule (IR capsule, 325 mg), and an extended-release tablet (ER tablet, 650 mg), were selected as model formulations. The IR tablet and the IR capsule were used as the BE model formulations, and the ER tablet as the non-BE model formulation (vs IR formulations). In addition, the ER tablet has a bilayer structure; half is an immediate-release layer, and the other half is an extended-release layer. In this study, both dissolution and permeation profiles for the three acetaminophen formulations were compared using the IDAS2.

Methods: The IDAS2 is comprised of a dissolution vessel (500 mL, pH 6.5 FaSSIF) and two permeation chambers (2 × 8 mL, pH 7.4 4.5% BSA-HBSSg) mounted with Caco-2 cell monolayers. The paddle rotation speed was set at 50 rpm and the water bath was warmed at 37°C. In this system, the dose concentration is determined by two doses per 500 mL, which is equivalent to the Biopharmaceutics Classification System of standard, the dose per 250 mL. The single dose is 650 mg. Therefore, four IR tablets/capsules (4 × 325 mg) or two ER tablets (2 × 650 mg) were added to the dissolution vessel and the dissolution and permeation samples were collected for 2 hours. The dissolution samples were immediately filtered through a syringe filter and the filtrates were then diluted 40-fold using an HPLC mobile phase. The permeation samples were replaced by the same volume of fresh and pre-warmed receiver buffer. The drug concentration in the dissolution and permeation samples were quantified using an HPLC-UV and an LC/MS/MS, respectively. The % dissolved and the area under the dissolved concentration-time curve (AUC_dissolved) were calculated as dissolution parameters. The permeation rate (the slope of the time profile of the permeated amount) was calculated as a permeation parameter.

Results: The IR tablet exhibited the most rapid dissolution of acetaminophen; the % dissolved was 83% at 5 min and 100% at 10 min. In contrast, the IR capsule showed an initially slow-release profile due to the capsule disintegration when compared to the IR tablet. The % dissolved was 10% at 10 min and 94% at 30 min. After 30 min, the drug was completely dissolved. The ER tablet showed a sustained release profile over time due to its specific formulation. The % dissolved was 33% at 5 min and 79% at 120 min. The calculated AUC_dissolved values for the IR tablet, the IR capsule, and the ER tablet were 5.26 ± 0.08, 4.58 ± 0.08, and 3.28 ± 0.14 (mg・h/mL), respectively. Thus, a significantly low AUC_dissolved value for the ER tablet was observed when compared to the IR tablet/capsule. In contrast, the AUC_dissolved ratio for the IR capsule to the IR tablet was 0.87, while a significant difference was observed between these two formulations. The permeation rates for all three formulations had an r² value greater than 0.995, indicating that all the permeation rates were quantified as linear, although the IR capsule showed the initially slow dissolution profile. The IR tablet and IR capsule showed similar permeation rates (not significantly different), which were 475 ± 26.9 and 500 ± 18.9 (μg/h), respectively. In contrast, the ER tablet showed a significantly slower permeation rate than the IR tablet/capsule, resulting in a permeation rate of 315 ± 20.1 (μg/h). The ratios of the permeation rates for the ER tablet to the IR tablet and the IR capsule to the IR tablet were 0.66 and 1.05, respectively. These observed ratios were consistent with the criteria for qualifying BE/non-BE in humans, where the AUC_plasma and C_max for test formulations are within 80-125% of those for a reference-listed drug (RLD). Therefore, the findings obtained from this study indicate that IDAS2 can be used to determine the BE/non-BE for oral formulations.

Conclusion: In this study, the potential of using the IDAS2 as a BE decision tool was investigated. The significant differences between the IR tablet/capsule (BE model formulations) and the ER tablet (non-BE model formulation) were observed in both dissolution and permeation profiles. In contrast, there was no significant difference in the permeation rate between the IR tablet and the IR capsule. Therefore, the IDAS2 would help better predict the BE/non-BE in humans when developing oral generic products.

References: [1] J Pharm Sci. 108, 2334-2340 (2019).
[2] Eur J Pharm Sci. 143, 105164 (2020).
[3] J Pharm Innov. 15, 591-602 (2020).
[4] Eur J Pharm Biopharm. 165, 1-12 (2021).