Tegoprazan (TPZ) is a promising potassium-competitive acid blocker, but its pH-dependent low solubility often leads to erratic oral absorption. Although several hydrophilic polymer-based amorphous solid dispersions have been attempted to enhance dissolution, they often suffer from thermodynamic instability or rely on complex, solvent-mediated manufacturing processes. Herein, to enhance dissolution and oral absorption, a crystalline drug-loaded melt granulation (MG) system using D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was fabricated while maintaining stable physicochemical properties. MGs were prepared via a solvent-free, hot-melt process by optimizing the type of solid surfactant carrier, the ratio of drug to solid surfactant, and the type and ratio of flow-enhancing excipients. The optimized composition was TPZ:TPGS:microcrystalline cellulose = 1:2:4 (w/w/w). Solid-state analyses revealed that TPZ was uniformly dispersed within the granules while retaining its crystalline form. Compared to the raw drug, the MG showed remarkably faster and higher dissolution across both acidic and neutral media. Under long-term (25 °C/60% RH) and accelerated storage conditions (40 °C/75% RH) for 24 weeks, MG exhibited robust physicochemical stability, showing no drug degradation, changes in dissolution behavior, or crystalline alterations. Moreover, in a pharmacokinetic evaluation in Sprague–Dawley rats, MG provided marked absorption enhancement, yielding over 1.8-fold increases in exposure compared to the raw material. Consequently, the crystalline drug-loaded TPGS-based MG represents a promising strategy for improving the oral delivery of TPZ.

Background/Objectives: The aim of this study was to design a nanosuspension (NS) of tegoprazan (TPZ), a novel potassium-competitive acid blocker (P-CAB), to overcome its low aqueous solubility and improve oral absorption. Methods: TPZ NSs were prepared using a lab-scale bead-milling technique. Subsequently, their physicochemical properties, in vitro dissolution profiles, storage stability, and in vivo pharmacokinetic profiles were evaluated. Results: Among various screened stabilizers, polyvinyl alcohol was selected as the suspending agent due to its favorable physicochemical stability. The optimized NS exhibited a mean particle size of approximately 270 nm and a zeta potential of −12.1 mV, preserving the crystalline state of TPZ. In vitro dissolution studies revealed that the NS and its freeze-dried form (NS-FD) markedly enhanced drug dissolution across all tested dissolution media (pH 1.2, 4.0, 6.8, and distilled water) compared to the raw drug material. Furthermore, the NS formulations remained physically and chemically stable for up to 12 weeks under long-term and accelerated storage conditions (25 °C/60% relative humidity (RH) and 40 °C/75% RH). In vivo pharmacokinetic studies in male Sprague–Dawley rats revealed that the oral TPZ NS resulted in approximately a 2.1-fold increase in systemic exposure compared to the raw material and microsuspension. Conclusions: These findings suggest that TPZ NS is a promising strategy to enhance the oral absorption of P-CAB, using a simple, organic-solvent-free fabrication process.