A Novel Rectal Foam Formulation for the Treatment of Inflammatory Bowel Disease

In recent years, the incidence of inflammatory bowel disease (IBD), characterized by mucosal damage, chronic inflammation, and recurrent episodes, has been steadily rising, yet ideal therapeutic solutions remain elusive. Researchers have identified a 33-amino acid peptide called glucagon-like peptide 2 (GLP-2), which has been shown to stimulate intestinal growth, repair mucosal damage, and enhance epithelial integrity. However, GLP-2 has an extremely short half-life of only 7 minutes, significantly limiting its clinical application. To address this challenge, researchers developed a long-acting GLP-2 analog, Glepaglutide (GL), which employs amino acid substitutions to extend its half-life in vivo to 50 hours. Nevertheless, Glepaglutide requires subcutaneous injection, which can negatively impact patient compliance. This study aimed to develop a novel drug delivery system to administer Glepaglutide via a rectal foam formulation for IBD treatment, achieving a balance between local and systemic effects while improving patient convenience.

Source and Background of the Study

The study was led by Wunan Zhang, William Van den Bossche, Hafsa Yagoubi, and others, with authors affiliated with Belgium’s Université catholique de Louvain (UCLouvain) and Vrije Universiteit Brussel (VUB). It was published in the journal Advanced Healthcare Materials as a cutting-edge investigation into innovative drug delivery methods. The objective of the study was to load Glepaglutide into a CO2-enhanced rectal foam to explore its potential for combining the local and systemic anti-inflammatory effects in the treatment of IBD.

Research Process

This comprehensive, original research was systematically designed and can be divided into the following components:

1. Formulation Development and Characterization

The study developed a rectal foam formulation (Glepaglutide-loaded foam, GLF) based on Glepaglutide. The formulation was prepared by mixing acidic and basic solutions in a 1:1 ratio, generating foam through CO2 evolution. Key parameters, including foam expansion volume, kinetics, and stability, were measured in detail. Results showed no significant differences in foam characteristics between GLF and drug-free foam, confirming that adding Glepaglutide did not adversely affect the foam’s physical properties.

Structural stability of Glepaglutide during the formulation process was assessed via circular dichroism (CD) spectroscopy and intrinsic fluorescence. Despite significant changes to the secondary structure of Glepaglutide during foaming (α-helix content decreased from 36.9% to 14.4%), the preservation of critical structural regions, such as tryptophan residues, maintained its therapeutic activity.

2. Efficacy Evaluation in an Acute Colitis Mouse Model

Using a dextran sodium sulfate (DSS)-induced colitis mouse model, the therapeutic potential of GLF was validated. Five groups were included: healthy control, untreated DSS-induced control, subcutaneous injection of Glepaglutide (GLSC), rectal foam (GLF), and rectal Glepaglutide solution (GLS). Treatments were administered on days 2, 4, and 6, and outcomes were assessed through weight change, Murine Endoscopic Index of Colon Severity (MEICS), and histological analysis.

Compared with the DSS control group, GLF significantly alleviated colitis symptoms. MEICS scores indicated that GLF’s efficacy was comparable to that of subcutaneous GLSC. Histological analysis further confirmed that GLF significantly reduced mucosal damage, similar to GLSC’s reparative effects.

3. Anti-Inflammatory Effects and Systemic Efficacy

Levels of key pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, along with myeloperoxidase (MPO) activity, were measured to affirm the anti-inflammatory effects of GLF. Both local (GLF) and systemic (GLSC) administrations significantly inhibited the expression of these markers. Notably, GLF achieved a pronounced reduction in IL-6 and IL-1β levels (80% and 60%, respectively). Additionally, GLF exhibited excellent local anti-inflammatory effects and systemic therapeutic efficacy via enhanced colon absorption.

Plasma levels of citrulline, a mucosal healing marker secreted by intestinal epithelial cells, were also measured. Results indicated that GLF significantly elevated citrulline levels, matching those observed in the GLSC group. This suggests that GLF not only provides localized therapy but also induces systemic intestinal protection.

4. Validation of Drug Absorption Enhancement Mechanism

To explore the foam’s ability to enhance macromolecule absorption, fluorescein-labeled dextran (FD 4k) was employed as a model compound. Results showed that GLF could significantly increase FD 4k plasma concentrations within 15 minutes, and the enhanced permeability effect dissipated after 4 hours. This confirmed that CO2-enhanced formulations transiently open tight junctions, enhancing drug permeability in the colon.

Key Findings and Significance

This study introduced an innovative drug delivery method by utilizing a CO2-enhanced rectal foam to administer Glepaglutide for IBD treatment. The formulation demonstrated strong anti-inflammatory and mucosal healing effects in the acute colitis mouse model while achieving a balance between local and systemic therapeutic outcomes. Significantly, the foam extended drug retention time in the colon and temporarily increased colonic permeability, making it a promising platform for future macromolecule-based therapies.

Study Highlights

1. Innovative Rectal Foam Delivery System
   The GLF formulation, employing CO2 as a permeation enhancer, significantly improved macromolecule absorption in the colon and achieved outstanding anti-inflammatory efficacy.

2. Dual Local and Systemic Benefits
   GLF promoted local mucosal healing while providing systemic intestinal protection, addressing the insufficiencies of traditional local administration methods.

3. Increased Patient Compliance
   Compared to conventional subcutaneous injections, rectal foam formulations offer a non-invasive alternative, making them more acceptable for patients and enhancing clinical applicability.

4. Biomarker-Based Insights
   Increased citrulline levels highlighted the role of GLP-2 analogs in promoting intestinal healing, providing a new quantitative indicator for therapeutic evaluation.

Outlook and Limitations

While this study achieved promising results, stability optimization of macromolecules in foam formulations remains a future challenge. Furthermore, the translation of these results from mouse models to humans will require large-scale clinical trials. This innovative platform represents a significant advancement in rectal drug delivery systems and provides new opportunities for treating IBD and other conditions requiring localized drug retention and systemic absorption.