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.

Introduction

Proton pump inhibitors (PPIs) are widely prescribed acid-suppressing medications that irreversibly inhibit H+/K+-ATPase in gastric parietal cells (Bruno et al., 2019). Although highly effective in reducing acid secretion by over 95% when adequately dosed, their therapeutic utility is often limited by formulation challenges owing to their pH-dependent solubility and stability (Srebro et al., 2022). Among PPIs, LAN has emerged as a particularly effective agent, demonstrating rapid symptom relief in gastroesophageal reflux disease (GERD) and duodenal ulcers compared to other medications (Tolman et al., 2000). However, similar to other PPIs, LAN displays pH-dependent stability that is highly sensitive to acidic environments, leading to formulation challenges such as the use of alkalizers or enteric coating to enhance its gastric stability while maintaining its bioavailability and therapeutic efficacy (Kuroda et al., 2006).

Most commercial formulations utilize enteric coating or pelletization technologies to protect drugs from gastric acid degradation (Maderuelo et al., 2019). For example, Kang et al. demonstrated that the incorporation of alkalizers into hydroxypropyl methylcellulose-based matrix systems effectively modulated the microenvironmental pH (pHM) and enabled dual release while minimizing gastrointestinal irritation in vivo (Kang et al., 2017). Although effective, these approaches cause delayed absorption and onset of action, limiting immediate relief of acid-related symptoms (Tonini et al., 2003). Comparable findings have been reported for weakly basic drugs, in which the inclusion of acidifiers in solid dispersions effectively sustained an acidic microenvironment through controlled acidifier release, pHM stabilization, and maintenance of the amorphous structure, thereby causing markedly enhanced dissolution and minimal recrystallization (Tran et al., 2010b). The incorporation of alkalizers into amorphous solid dispersion–based orodispersible tablets markedly improved the dissolution and stability of acid-labile drugs under gastric conditions, demonstrating the current advancements in pH-modulated formulations beyond conventional enteric-coated systems (Alhamhoom et al., 2024). Although they are simple to manufacture, enteric-coated formulations fail to address the critical clinical need for rapid symptom control, particularly in patients with severe acid reflux or nocturnal acid breakthroughs (Hunt et al., 2007).

Among various alkalizers, CaCO3 was identified as the most effective pHM modulator on the basis of acid-neutralizing capacity, gastric stability of LAN, and an acceptable safety/regulatory profile, consistent with its long-standing use as a pharmaceutical excipient in oral solid dosage forms (Al Omari et al., 2016). CaCO3 also exhibits rapid acid-neutralizing properties through chemical reactions with gastric acid (Feng et al., 2024; Voropaiev and Nock, 2021). Upon ionization to Ca2+ and CO32-, it provides more efficient acid neutralization than sodium bicarbonate at lower doses based on ion stoichiometry (Feng et al., 2024). Conceptual evidences for employing alkalizers to regulate pHM in solid dosage systems was well established by Tran et al., who systematically explained the synergistic roles of pHM modulation, structural amorphization, and molecular interactions in enhancing the dissolution and stability of ionizable drugs (Tran et al., 2010a). This enhanced efficiency was attributed to the divalent nature of calcium ions and the dual neutralizing capacity of carbonate ions (Feng et al., 2024). For instance, 600 mg of CaCO3 can effectively modulate gastric pH to create a protective microenvironment (Voropaiev and Nock, 2021). The particle size, surface area, and crystalline structure of CaCO3 contribute to its rapid neutralizing action and sustained pH-modulating effects (Jimoh et al., 2017; Som et al., 2016). This unique combination of properties presents an opportunity to develop an innovative nonenteric formulation approach. Similarly, Nguyen et al. demonstrated that the incorporation of divalent metal alkalizers, particularly magnesium oxide, into solid dispersions established strong molecular interactions with benzimidazole derivatives and significantly enhanced the gastric stability via pHM modulation (Van Nguyen et al., 2017).

We investigated the effects of different alkalizers (CaCO3, MgO, NaHCO3, meglumine, and L-arginine) on gastric stability, solution pH, pHM, and intermolecular interactions using instrumental analysis. The pHM was determined potentiometrically using a pH meter equipped with a surface pH electrode. Detailed intermolecular interactions between LAN and the alkalizer in the granules were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT-IR). Furthermore, surface morphologies were visualized using field-emission scanning electron microscopy (FE-SEM).

In the present study, we hypothesized that a systematically selected low-dose divalent alkalizer, dispersed in a well-designed dual-granulation matrix, can modulate the pHM and form a transient intermolecular complex with LAN sufficient to protect the drug during gastric residence, thereby enabling immediate drug release without an enteric coating. To test this hypothesis, five alkalizers (CaCO3, MgO, NaHCO3, meglumine, L-arginine) were screened; CaCO3 was identified as the most effective and was formulated into an immediate-release fixed-dose combination tablet (IFT, T7) via a two-step granulation process using a fluidized bed dryer and a high-shear mixer. The resulting IFT achieved rapid and complete release of both CaCO3 and LAN, maintained long-term stability for 36 months, and demonstrated bioequivalence to the commercial enteric-coated Lanston® capsule in 46 healthy human subjects, with a shorter Tmax and superior 24-h intragastric pH control. To the best of our knowledge, this is the first study to (i) systematically compare five alkalizers for pHM modulation of LAN-loaded granules and tablets with depth-resolved pH measurement, (ii) mechanistically characterize the intermolecular complex between LAN and CaCO3 using DSC, PXRD, and FT-IR, and (iii) demonstrate bioequivalence and superior pharmacodynamic pH control of a non-enteric, CaCO3-based IFT versus the enteric-coated reference product in a large cross-over clinical study, thus providing a clinically meaningful alternative to conventional enteric coating for acid-labile PPIs.

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Materials

LAN was obtained from Hetero Drugs Ltd. (Hyderabad, India). The CaCO3 was supplied by Bioka Funka Kogyo Co. (Tokyo, Japan). MgO, sodium bicarbonate, and L-arginine were purchased from Sigma-Aldrich (St. Louis, MO, USA). Meglumine was purchased from Merck KGaA (Darmstadt, Germany). Povidone K30 and K90 were supplied by BASF SE (Ludwigshafen, Germany). Croscarmellose sodium (CCS; Vivasol®) and microcrystalline cellulose (MCC; Vivapur® 101) were obtained from JRS Pharma GmbH & Co. KG (Rosenberg, Germany). Sodium stearyl fumarate (SSF) was provided by JRS Pharma GmbH Co. KG (Rosenberg, Germany). Ethanol was purchased from Duksan Pure Chemicals Co., Ltd. (Ansan, Korea). Crospovidone (Kollidon® CL) was supplied by BASF SE (Ludwigshafen, Germany). All other chemicals and reagents were of analytical grade. Purified water was prepared using a Milli-Q water purification system (Millipore, Billerica, MA, USA).

Il-Ki Hong, Dinh Hoai Nam, Youngju Jeong, Jun-Bom Park, Chulhun Park, Beom-Jin Lee, 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, International Journal of Pharmaceutics: X, Volume 11, 2026, 100579, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100579.