Enhanced Dissolution and Oral Bioavailability of Tegoprazan Using D-α-Tocopheryl Polyethylene Glycol 1000 Succinate-Based Melt Granulation System
Abstract
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…
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