Improving Drug Entrapment Efficiency and Eliminating Free, Unloaded Drug Residues: A Review of Two Challenges with Liposomal Drug Delivery Systems

After several decades of research and development, liposomes have found many interesting applications in different disciplines of science, from biology to colloid science, tissue engineering, and regenerative medicine, and, more importantly, drug delivery, i.e., one of the most exciting fields of application and innovation where Ehrlich’s concept of a “magic bullet” has remained viable. This focus on liposomal drug delivery systems can be attributed in part to the phospholipid bilayer structure of these vesicles, which resembles the architecture of the eukaryotic cell membrane. Many liposomal drug carriers are being developed, and some of them, such as DOXIL, have also been commercialized. Drug-loaded liposomes can be prepared using various methods, depending on the drug's physicochemical properties and the desired characteristics of the final formulation. However, these products face two significant challenges: the presence of free, nonencapsulated drug molecules, which must often be removed, and limited drug-loading efficiency. Currently, no universal method exists to address either issue fully. This review aims to provide a comprehensive overview of strategies to enhance drug entrapment and remove free, non-encapsulated drug from liposomal formulations, to compare the advantages and limitations of current methods, and to identify remaining knowledge gaps to guide future research and formulation design. To this end, the first section describes drug loading methods, followed by purification techniques, with an emphasis on recently developed approaches and their specific benefits and drawbacks.