DOP066 Temperature-triggered in situ forming lipidic gel for local treatment of ulcerative colitis
Authors: Aleandri S , Carone M , Spalinger M , Gaultney R A , Mezzenga R , Hlavačková K , Mookhoek A , Krebs P , Rogler G , Luciani P 
Published: January 2025

Abstract

Background
All treatments recommended by the European Crohn’s and Colitis Organization for Ulcerative Colitis (UC) have dose-dependent adverse effects. Therefore, the drug’s side effects must be weighed against potential benefits for UC treatment in patient management while the specific localization of the disease to the colon encourages the use of rectal therapy aims at having a high dose only at the inflammation site. However, the efficacy of conventional enema-based formulations is limited by their insufficient retention in the colon and faecal urgency. Therefore, exploring alternative delivery avenues, such as local applications via lipidic-based gel helps to develop more efficacious and safer therapies, overcoming the drawbacks associated with available rectal dosage forms.

Methods
Lipidic-based treatments with controlled release of embedded drugs (Tofacitinib and Tacrolimus) to the inflamed intestinal mucosal upon rectal administration were fully characterized in vitro and their efficacy was tested in vivo. Specifically, the efficacy of the formulations was evaluated on dextran sulfate sodium (DSS)-induced acute colitis and on T-cell transfer colitis models.

Results
To decrease the drugs’ adverse effects and to improve either the performance of the topical formulation or the therapeutic outcome of the drugs, we designed and developed a gel formulation based on the concept that at 25 °C, a low viscous formulation easier to administer and more able to treat remote tissue areas, are achieved. Once applied to the rectum, the precursor gel gradually absorbs heat from the body and rapidly converts it into a highly viscous gel, contributing to the formation of a depot in situ. The temperature-triggered in situ forming lipid gel (TIF-Gel) is versatile and can host and release drugs of different polarities, e.g., tofacitinib and tacrolimus, in a sustained manner. Further, it adheres to the colonic wall for at least 6 hours, thus preventing leakage and improving drug bioavailability. Mice treated with this regimen of TIF-Gel displayed decreased weight loss and disease severity when compared to mice treated with empty TIF-Gel or free drugs (administered as liquid solutions). Signs of systemic inflammation (determined by cellularity and local pro-inflammatory cytokine levels) were alleviated by drug-loaded TIF-Gel. Furthermore, local inflammation was also mitigated by the TIF-Gel as determined by a reduction in colon shortening and pathology.

Conclusion
TIF-Gel provides a valuable approach to effectively administer drugs locally to the colonic mucosa resulting in sustained drug release. TIF-Gel enhances the localized activity of these anti-inflammatory drugs while potentially reducing the risk of side effects.

References
Carone, M., Spalinger, M.R., Gaultney, R.A. et al. Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis. Nat Commun 14, 3489 (2023).