Temperature-triggeredin situforming lipid mesophase gel for local treatment of ulcerative colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colonic mucosa. There is no cure for UC and its chronic relapsing/remitting nature strongly affects patient quality of life. Current treatment options frequently have significant side effects and remission rates are limited raising a demand for new treatment strategies. Novel therapeutic approaches that could maximize the drug concentration at the site of inflammation with minimal systemic exposure, like topical applications, would address this unmet clinical need. To date, few drug delivery systems (DDSs) have been designed to topically convey small molecules to the rectum and left-sided colon. Here, we developed and tested a drug delivery platform for topical treatment of UC based on a temperature-triggered in situ forming adhesive lipid gel (TIF-Gel). Due to its soft-gel consistency, its high encapsulation efficacy and its drug-controlled release, TIF-Gel suggests a more patient-friendly and effective application with respect to the rectal formulations currently available. Capitalizing on the biocompatible and biodegradable self-assembled structure of lipid mesophases (LMPs), we loaded TIF-Gel with tofacitinib (TOFA; an hydrophilic inhibitor of the enzymes Janus kinase 1 and 3) or TAC ( an hydrophobic immunosuppressive drug), both indicated in the treatment of UC. We designed and fully characterized our biocompatible lipid formulation in vitro and tested it in vivo using two different murine models of intestinal inflammation, in chemically-induced and T cell transfer-mediated models of colitis. Both approaches (TIF-Gel-TOFA and TIF-Gel-TAC) led to reduce either colitis disease severity or intestinal inflammation compared to vehicles, therefore showing therapeutic efficacy. Overall, our findings show that TIF-Gel can deliver drugs locally to the colonic mucosa to mitigate intestinal inflammatory disease in a pre-clinical model. They also suggest that, in a clinical setting, TIF-Gel might provide a patient-friendly approach to improve colitis while allowing a reduction of the adverse effects associated with a systemic therapy.

Artificial mucus layer formed in response to ROS for the oral treatment of inflammatory bowel disease

“…The formation of a mucus-like hydrogel barrier, which blocks excessive activation of the immune system by intestinal bacteria, is the key to the therapeutic efficacy of HASH 60% in IBD. Inspired by hydrogels acting as artificial mucosal barriers, researchers have developed several in situ hydrogels for the treatment of IBD (10,(44)(45)(46). Rectal injection or administration using an endoscope severely compromises patient compliance, although these hydrogels have shown excellent therapeutic efficacy.…”