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 (pHM)-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 pHM 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…
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