Poly (acrylic acid)-Grafted Gellan Gum as a Matrix for Gastro-RetentiveControlled Release of Antidiabetic Drug and Physiologically BasedPharmacokinetic Modelling Using PK-Sim Software

Introduction: Gastro-retentive systems can improve the bioavailability of drugs with a narrow absorption window, such as Metformin Hydrochloride (MH). Gellan gum, a biocompatible matrix polymer, requires modification to achieve effective controlled-release properties. This study investigates poly(acrylic acid)-grafted gellan gum (PAA-g-GG) as a controlled-release matrix- forming agent. Methods: Grafting was performed by microwave-assisted polymerization technique with ceric ammonium nitrate. A 2² factorial design was used to optimize the grafting parameters in this project. The grafted copolymers were characterized by DSC in addition to FT-IR, and then incorporated into MH matrix tablets. The wet granulation method was used for preparing the tablets. Tablets were evaluated for physical properties, in vitro drug release, release kinetics, and PBPK behavior using PKSim®. results: Optimal grafting (85%) was achieved with a 10:1 AA:GG ratio and 400 mg initiator (i.e. G1). DSC study confirmed thermal compatibility. The F2 formulation showed uniform physical properties as well as sustained drug release (i.e. 36.75% over 240 min), outperforming both ungrafted and synthetic polymer-based tablets. Release followed Higuchi kinetics (R² > 0.98), and PBPK modelingconfirmed reduced Cmaxwith prolonged absorption. Results: Optimal grafting (85%) was achieved with a 10:1 AA: GG ratio and 400 mg initiator (i.e., G1). DSC study confirmed thermal compatibility. The F2 formulation showed uniform physical properties as well as sustained drug release (i.e., 36.75% over 240 min), outperforming both ungrafted and synthetic polymer-based tablets. Release followed Higuchi kinetics (R² = 0.9855–0.9963), and PBPK modelling confirmed reduced Cmax with prolonged absorption. Discussion: The sustained release behavior of the grafted gum performed better than both the ungrafted gellan gum and synthetic polymers such as HPMC and Carbopol, representing its superior matrix-forming ability. PBPK modelling confirmed reduced Cmax with prolonged absorption, indicating the potential clinical relevance of the formulation. Conclusion: PAA-g-GG is a promising grafted natural polymer for gastro-retentive controlledrelease tablets of MH, presenting an efficient and biocompatible alternative to synthetic matrices; however, further in vivo studies are required to fully establish its clinical applicability.