A novel approach to pure cochleate preparation via electrostatic charge modulation

Abstract

Cochleates are spiral structures formed from self-assembly between phospholipids and cations. They are promising drug delivery vehicles offering significant advantages such as drug protection, sustained release, and enhanced therapeutic efficacy. However, current preparation methods often produce cochleates along with undesired multiple intermediate structures, thus complicating their formulation to effective dosage forms. This study reports a novel approach to preparing cochleates with unprecedented purity using mixed anionic (DOPS/DMPS)˗cationic (DOTAP) liposomes in 9:1 ratio. Unlike anionic DOPS or DMPS liposomes, mixed cationic-anionic DOPS:DOTAP or DMPS:DOTAP liposomes show reduced electrostatic repulsion and lower stability, allowing efficient interaction with calcium. This interaction facilitates optimal self-assembly to less stable intermediate structures and a rapid transition to pure cochleates. Cationic DOTAP, in conjunction with Ca²⁺, facilitates lipid bilayer fusion by overcoming repulsive forces and reducing energy barriers through interaction with negatively charged DOPS/DMPS. Zeta potential, PDI and FESEM studies show the purity of cochleates is primarily determined by the electrostatic charges and stability properties of the liposomes and the intermediate structures. Pure cochleates produced from mixed anionic-cationic phospholipids using the reported process have immense potential as drug delivery vehicles in the (bio)pharmaceutical industry.