Design of immediate release combination preparation containing alkalizer and lansoprazole for mechanistic understanding of enhanced gastric stability, pharmacokinetics, and intragastric pH variability in healthy human subjects.

Abstract

We investigated the microenvironmental pH (pH_M)-modulating mechanism and intermolecular interaction of alkalizers and their impact on the aqueous stability, release profiles of drugs and alkalizers, pharmacokinetics, and intragastric pH variability in 46 healthy human subjects of lansoprazole (LAN), an acid-labile model drug. Preliminary screening of five alkalizers (CaCO₃, MgO, NaHCO₃, meglumine, and L-arginine) in LAN-loaded wet granules under simulated gastric fluid demonstrated that calcium carbonate (CaCO₃) appeared to be the best stabilizing agent for LAN in a dose-dependent manner according to solution pH changes and drug contents. Immediate-release fixed-dose combination tablets (IFT) containing LAN and CaCO₃ were prepared via a dual granulation process using a fluidized bed dryer (FBD) and/or a high shear mixer (HSM). Unlike the commercial enteric-coated granule-loaded Lanston® capsule, IFT released LAN and CaCO₃ simultaneously, achieving over 90% drug release within 30 min while maintaining its aqueous stability in pH 1.2 gastric fluid via the acid-neutralizing capacity of simultaneously released CaCO₃. The increased modulation of pH_M and the intermolecular complex of LAN with calcium ions are crucial for stabilizing LAN under low pH conditions. The optimal IFT formulation demonstrated long-term stability for 3 years, maintaining drug content and dissolution rates while liberating impurities (<0.2%) within regulatory guidelines. IFT demonstrated bioequivalence with the commercial enteric-coated Lanston® capsule with decreased "time to reach the maximum plasma concentration" and displayed superior intragastric pH control, maintaining pH above 4 for a longer duration over 24 h in a cross-over design in 46 healthy human subjects. The current novel IFT containing acid-labile LAN and CaCO₃ can be used to substitute current enteric-coated LAN tablets for the immediate release and rapid onset of LAN without chemical degradation in the gastric fluid.