Do interactions between protein and phospholipids influence the release behavior from lipid-based exenatide depot...

Area of Science:

• Biopharmaceutics
• Materials Science
• Drug Delivery Systems

Background:

• Protein and peptide release from vesicular phospholipid gels (VPGs) is complex, influenced by gel erosion, drug diffusion, lipid bilayer interactions, and formulation properties.
• Existing models struggle to directly correlate specific parameters with observed release kinetics.

Purpose of the Study:

• To investigate the contribution of drug-membrane interactions to exenatide release kinetics from VPGs composed of different phospholipids (POPC, POPG, and mixtures).
• To elucidate the primary mechanisms governing exenatide release from VPG formulations.

Main Methods:

• In vitro release studies of exenatide and phospholipids from VPGs.
• Determination of exenatide binding affinities to lipid membranes using microscale thermophoresis (MST).
• Evaluation of release kinetics across a range of pH conditions and VPG compositions.

Main Results:

• Exenatide release from anionic POPG-containing VPGs occurred with a half-life of approximately 5 days, primarily controlled by gel erosion, irrespective of pH-dependent binding.
• Exenatide release from zwitterionic POPC VPGs exhibited a significantly longer half-life (30-55 days), indicating slower diffusion due to membrane barrier properties rather than binding affinity.
• High affinity binding of exenatide to POPG membranes was observed at pH 4.5 (cationic exenatide), but not at pH 7.4 (anionic exenatide) or with POPC membranes.

Conclusions:

• Gel erosion and drug membrane permeability are the dominant factors controlling exenatide release from POPC-POPG VPGs.
• Drug binding to the lipid membranes plays a minimal role in the overall release mechanism of exenatide from these VPG formulations.