A Thermoresponsive In Situ Salified Self-Nanoemulsifying Drug Delivery System of Olmesartan Medoxomil: Overcoming Leakage and Drug Trapping Limitations.

Background/Objectives: Solid self-nanoemulsifying drug delivery systems (SNEDDS) prepared by adsorption onto porous carriers are widely used to improve the oral delivery of poorly water-soluble drugs. However, this approach is limited by increased dosing volume and incomplete drug release. This study aims to develop a thermoresponsive in situ salified SNEDDS (T-IS-SNEDDS) that simultaneously prevents formulation leakage and overcomes the release limitations of conventional adsorption-based solidification. Methods: Excipients were selected by solubility screening of oils and surfactants. Sodium and calcium carbonate were evaluated for in situ salt formation. Adsorption-based solid SNEDDS and thermoresponsive formulations containing poloxamer 188 with propylene glycol or polyethylene glycol 400 were prepared. Droplet size was measured after aqueous dilution. Solid-state characterization used scanning electron microscopy, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. In vitro dissolution performance was evaluated against the raw drug and adsorption-based formulations. Results: Imwitor 308 and Tween 80 exhibited the highest solubilization capacities. Sodium carbonate (10 mg/g) markedly increased the solubility of olmesartan medoxomil from 4.11 ± 0.11 to 46.01 ± 1.92 mg/g. Although liquid in situ salified SNEDDS achieved rapid dissolution (94.2 ± 1.8% at 10 min), adsorption-based solidification required four capsules and yielded incomplete drug release (67.76 ± 3.18%). Both thermoresponsive formulations accommodated the therapeutic dose in a single capsule and released ≈95% of the drug within 60 min. Conclusions: The combined in situ salified drug loading and thermoresponsive matrix strategy successfully enables single capsule administration while overcoming the incomplete release of adsorption-based solid SNEDDS.