Water-triggered in-situ gelling phospholipid oil enema for enhanced budesonide delivery and mucosal healing in ulcerative colitis
Budesonide (BUD) enema therapy for ulcerative colitis (UC) is limited by poor solubility, inadequate bio-adhesion, and rapid clearance due to intestinal peristalsis. To address the limitations of conventional budesonide enemas, we designed a water-triggered in situ phase-transition phospholipid formulation (termed PG oil). This system comprises soybean phosphatidylcholine (PC-98), glyceryl dioleate (GDO), propylene glycol, and anhydrous ethanol, and achieves markedly enhanced BUD solubilization (35 mg/mL), in contrast to its negligible aqueous solubility (0.021 mg/mL). Upon contact with colonic fluid, PG oil rapidly underwent sol-gel transition, forming a bio-adhesive lamellar liquid crystalline gel that serves as both a physical mucosal barrier and a sustained-release drug depot. In a dextran sulfate sodium (DSS)-induced colitis mouse model, rectal administration of BUD-PG oil (0.3 mg/kg) significantly outperformed free BUD suspension, as evidenced by restored body weight, reduced disease activity index, normalized colon length, and decreased spleen index. Immunohistochemistry revealed marked suppression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, MCP-1) in colonic tissue. Histological analysis demonstrated that BUD-PG promoted favorable mucosal repair characterized by reduced collagen deposition (Masson's trichrome: from 48.5% to 16.7%) while restoring gut barrier integrity through replenishment of goblet cells and upregulation of tight junction proteins (ZO-1, Occludin-1, Claudin-5, β-catenin). Collectively, this water-responsive in situ gelling phospholipid oil platform addresses critical limitations of conventional BUD enemas by combining sustained local drug delivery with physical mucosal protection, offering a promising therapeutic strategy for comprehensive mucosal healing in UC.