Two-tier strategy: Oral **exenatide** lipid formulation with enteric capsules enhances stability and permeability

Oral delivery of therapeutic peptides like glucagon-like peptide-1 (GLP-1) analogs faces significant hurdles, primarily enzymatic degradation in the gastrointestinal tract and poor intestinal permeability. Current injectable GLP-1 therapies are highly effective for Type 2 Diabetes Mellitus and obesity, but patient adherence can be limited. Developing an effective oral formulation could revolutionize treatment, addressing the need for improved bioavailability and convenience by protecting the peptide from harsh gastric conditions and enhancing its absorption.

Researchers designed a lipid-based formulation (LBF) for the model GLP-1 analog exenatide (EXE), specifically its hydrophobic ion-paired (HIP) form, prepared with sodium docusate (1:4 molar ratio). The optimized LBF consisted of 85% Labrafac™ MC60, 10% Kolliphor® RH40, and 5% propylene glycol. This formulation was loaded with 6 mg/g solubilized EXE (HIP form) and 20 mg/g of sodium caprate as a permeation enhancer. The team then engineered customized gelatin/HPMC-AS enteric capsules to provide a second layer of protection, evaluating the formulation's stability against α-chymotrypsin degradation and its physicochemical properties.

The hydrophobic ion-pairing of exenatide (EXE-HIP) with sodium docusate successfully increased its lipophilicity, shifting the log P from -2.9 ± 0.3 for native EXE to 0.9 ± 0.2. This modification significantly improved solubility in lipid excipients, particularly in Labrafac™ MC60. The optimized LBF achieved a final particle size of 106 nm. The formulation demonstrated substantial protection against α-chymotrypsin-mediated degradation, suggesting that the lipid droplets effectively sequestered EXE-HIP, limiting enzymatic access. Short-term stability studies, however, indicated higher impurity formation for solubilized EXE-HIP compared to suspended EXE acetate, especially at room temperature. The engineered enteric capsules provided crucial gastric protection. > The two-tier strategy, combining the LBF with enteric capsules, offered significant protection against enzymatic degradation and enhanced the peptide's physicochemical properties for improved oral delivery.