Water-triggered in-situ gelling phospholipid oil enema for enhanced budesonide delivery and mucosal healing in ulcerative colitis

Abstract

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.