Fabrication of self-emulsifying lipid microstructure by stiffness-tunable mold for drug delivery applications

Amphiphilic lipid formulations, such as self-emulsifying drug delivery systems, offer advantages for enhancing drug release control and expanding their applicability across various administration routes. By integrating microfabrication techniques with these lipid-based systems, additional functionalities such as controlled drug release can be introduced. This can broaden lipid's potential for advanced biomedical and pharmaceutical applications. However, lipids face major fabrication challenges due to their thermolability, solvent incompatibility, and poor mechanical properties. Here, we present a novel microfabrication route for self-emulsifying lipid drug delivery systems based on thermal imprinting of a stiffness-tunable mold, which stays inflexible during the thermal imprinting step and softens upon swelling for the demolding step. The stiffness tuning process is reversible to some extent through a simple drying process, allowing reuse of the mold. The presented method resolves the issues of mechanical stress and lipid dissolution during the demolding process, enabling the scalable and cost-efficient fabrication of lipid microstructures down to 20 µm resolution and a 5:1 aspect ratio. As a proof-of-concept, we fabricated honeycomb-shaped self-emulsifying drug delivery lipid microstructures on a mucoadhesive film. Lipid microstructure increases the mechanical robustness and accelerates lipid dissolution for sublingual administration of poorly water-soluble drugs. In vivo testing in mouse models confirmed efficient mucosal penetration and submucosal drug accumulation, showing potential as sublingual drug delivery devices.