(T1530-08-52) Development of a Gastro-Retentive Bimodal Release Bilayer Tablet to Enable Once-Daily Dosing, Fast Onset and Blunted C_max for an NCE with Short Half-Life

Purpose: A short half-life (6-hour) cardiovascular drug requires frequent dosing (three-times-daily, TID) with immediate-release (IR) tablets to maintain therapeutic plasma concentrations, but this regimen leads to high C_max-related adverse effect and suboptimal patient compliance. To address these challenges, this study aimes to develop a once-daily (QD) formulation with bimodal release to achieve rapid therapeutic onset, sustain therapeutic efficacy, and reduce C_max-related adverse effects.

Methods: Bilayer tablets (BLT) were designed to achieve a bimodal drug release profile: an IR layer coupled with an extended-release (ER) layer. The gastro-retentive drug delivery system (GRDDS) formulation was selected for the ER layer based on the regional absorption results from the dog PK study showing that the drug molecule is mainly absorbed at the upper GI tract. The dose ratio between the IR and ER layers was modeled with GastroPlus^® to fine tune the desired bimodal release profile. The IR layer was fixed at 20 mg across all strengths, and the ER layer was titrated with 20, 40, and 60 mg potencies. The formulation was manufactured by blending, roller compaction, compression and film coating. Compaction simulation was implemented throughout the whole BLT development process. Three rounds of PK studies in beagle dogs (n=6) were employed to compare: (1) IR tablets: 60 mg, (2)  conventional BLT: IR 20 mg + ER 40 mg, (3) GRDDS BLT with three different dose strengths: low (IR 20 mg + ER 20 mg), mid (IR 20 mg + ER 40 mg) and high (IR 20 mg + ER 60 mg). Plasma concentrations were quantified via validated LC-MS/MS, with PK parameters (C_max, T_max, AUC_0-24h) analyzed through non-compartmental methods (WinNonlin).

Results: The GRDDS BLT formulation demonstrated a bimodal release profile that addressed all three design objectives. The IR layer achieved rapid absorption (T_max = 2 hours). The ER layer obtained sustained plasma concentrations above the therapeutic threshold (C_trough ≥10 ng/mL) for over 16 hours, enabling QD dosing. Critically, the GRDDS BLT reduced C_max by 44% (70 vs. 125 ng/mL for IR tablets) while maintaining comparable total drug exposure (AUC_0-24h). In contrast, IR tablets failed to sustain therapeutic concentrations beyond 8 hours, and conventional BLT showed erratic absorption. The GRDDS BLT formulations have consistent and reproducible PK profiles across all three different dosage strengths, with C_max values ranging from 48 to 70 ng/mL and therapeutic plasma concentrations maintained for 12–18 hours. The GRDDS BLT was successfully manufactured and released to support a biocomparison human PK study, which is expected to have outcome by end of 2025.

Conclusion: The GRDDS BLT formulation successfully resolved the competing demands of rapid onset, sustained efficacy, and C_max mitigation for a short half-life drug. By combining an IR layer with a gastro-retentive ER layer, the new formulation achieved rapid therapeutic onset, reduced dosing frequency from TID to QD and blunted peak plasma concentrations. This approach minimizes adverse effects associated with IR tablets while improving patient compliance through simplified dosing.

PK results of different formulations in beagle dogs (N=6)

PK results of GRDDS BLT with different dose combinations in beagle dogs (N=6)