A Mesalazine-Aloperine Co-Amorphous System for Simultaneous Dissolution Enhancement, Permeability Improvement, and...

Background/Objectives: Mesalazine (MSZ), the first-line therapy for ulcerative colitis (UC), is a BCS Class IV drug limited by poor aqueous solubility and low intestinal permeability, which together restrict colonic drug delivery and therapeutic efficacy. This study aimed to develop a co-amorphous (CAM) system of MSZ and aloperine (ALO) to enhance MSZ dissolution and permeation while achieving anti-UC synergy. Methods: The MSZ-ALO CAM system was prepared via solvent evaporation and characterized by PXRD, DSC, FTIR, and ¹H NMR. Equilibrium solubility, intrinsic dissolution rate (IDR), and in vitro permeability were assessed under biorelevant pH conditions. Physical stability was evaluated under long-term and accelerated conditions. Network pharmacology predicted potential therapeutic targets and synergistic mechanisms. Results: Solid-state characterization confirmed a homogeneous single-phase CAM system stabilized mainly by a carboxylate-ammonium ionic bond and hydrogen bonding. At pH 4.5, where MSZ solubility was lowest, equilibrium solubility and IDR increased up to 71.9-fold and 35.8-fold, respectively. In vitro permeability at pH 6.5 increased 2-fold. The system remained physically stable for eight months under dry conditions and withstood accelerated stresses without recrystallization. Network pharmacology identified 51 shared targets among MSZ, ALO, and UC, enriched in MAPK, HIF-1, and AMPK pathways; core hubs included HSP90AA1, SRC, CASP3, GSK3B, and ALB. Conclusions: This study presented the first MSZ-ALO CAM system that simultaneously addresses the dual solubility and permeability barriers of MSZ and provided a multi-target pharmacological basis for synergistic UC therapy, offering a promising pharmaceutical strategy for colon-targeted delivery.