A Bubble-Driven Drug Delivery System Enhances Oral Absorption and Antipyretic Efficacy of Poorly Water-Soluble Andrographolide

Purpose While bubble-carrier systems hold great promise for enhancing the oral bioavailability of poorly water-soluble drugs, a deeper understanding of their underlying absorption mechanisms is still required. This study aimed to address this gap by developing a bubble-driven delivery system (BDDS) using the poorly water-soluble andrographolide (AG) as a model drug, and systematically evaluating its solubilization capacity and intestinal permeability.Methods The BDDS was optimized through the screening of effervescent formulations (citric acid: Na2CO3 = 6:5) and bile salts (sodium deoxycholate, SDC). Its performance was comprehensively assessed via in vitro dissolution tests, an everted intestinal sac assay, Caco-2 cell monolayer experiments, pharmacokinetic studies, and yeast-induced fever rat models.Results The BDDS achieved 75.0%–88.7% dissolution in gastrointestinal pH media, which was markedly superior to that of commercial dripping pills (DP; 30.5–50.2%). Its apparent permeability coefficient was 7.7-fold and 3.6-fold higher than that of free AG and DP, respectively. Transport studies indicated that SDC enhanced AG permeability primarily via the apical sodium-dependent bile acid transporter (ASBT)-mediated pathway, a mechanism further confirmed by inhibition with linerixibat. The relative oral bioavailability of BDDS versus DP reached 257.1%. BDDS demonstrated enhanced efficacy by significantly inhibiting key pro-inflammatory cytokines and thermoregulatory mediators in yeast-induced fever rats.Discussion The BDDS effectively overcomes AG’s low solubility (by SDC solubilization and CO2 bubbles) and permeability (via ASBT transport), outperforming conventional formulations in terms of preparation simplicity and storage stability.Conclusion BDDS is a promising strategy to improve oral absorption and therapeutic efficacy of BCS Class IV drugs like AG, with ASBT-mediated transport as a key mechanism.