Liposomes: the gold standard in drug delivery technology - innovative applications from academia to industry

Liposomes are spherical vesicles composed of one or more phospholipid bilayers enclosing an aqueous core, enabling the encapsulation of small molecules, peptides, proteins, and nucleic acids, irrespective of their hydrophilicity or hydrophobicity. First described by Bangham and colleagues in 1964, liposomes have emerged as one of the most successful nanocarrier systems in modern medicine due to their unique physicochemical properties, including biocompatibility, controlled release, and enhanced therapeutic efficacy. Their clinical and industrial success is exemplified by the FDA approval of Doxil® in 1995, followed by the expansion to 24 marketed formulations addressing critical needs in oncology, pain management, and vaccines. This thesis provides a comprehensive exploration of liposomal drug delivery technology, covering sustained-release applications, the development of advanced lipid-based delivery systems for novel compounds, and scalable production methodologies. While the first chapter provides a brief overview of the state of the art in liposome research, the subsequent chapters (Chapters 2–4) present three interconnected but independent research projects. Specifically, the second chapter of this thesis details work conducted during my visiting period in Professor Luciani’s laboratory at the University of Bern. This study focused on the development of a depot liposomal system for veterinary applications, specifically addressing the limitations of carprofen, a widely used nonsteroidal anti-inflammatory drug (NSAID). Due to its poor aqueous solubility and short in vivo half-life, a lipid-based depot formulation was designed to achieve a controlled release profile over 48 hours. Extensive formulation screening and in-depth characterization were conducted to optimize the system. Additionally, a novel agarose gel matrix-based setup was developed to simulate the subcutaneous environment, providing a robust in vitro model for evaluating the performance of sustained-release liposomal formulations administered via subcutaneous injection. Finally, a preliminary scale-up of the formulation was successfully achieved, demonstrating its potential for industrial translation. The third chapter leveraged the interdisciplinary expertise of our research group in pharmaceutical chemistry and nanotechnology to develop innovative lipid-based drug delivery systems for neurodegenerative disease treatment. A promising human monoamine oxidase B (hMAO-B) inhibitor was selected and formulated into two highly PEGylated lipid-based carriers. A Design of Experiments (DoE) approach was employed to systematically screen, characterize, and optimize critical process parameters (CPPs) using a microfluidic platform, ensuring the development of formulations with well-defined critical quality attributes (CQAs). This study highlights the potential of combining rational drug design with tailored nanocarrier systems to address specific therapeutic challenges. By integrating medicinal chemistry with advanced formulation strategies, this work demonstrates how interdisciplinary approaches can overcome the limitations of isolated fields, paving the way for more effective neurodegenerative disease treatments and establishing a framework for future innovations in nanomedicine. The final chapter, reflecting the hybrid nature of this industrial PhD, details the research conducted during my 12-month placement in the Development laboratory at BSP Pharmaceuticals. This project focused on developing a directly scalable microfluidic platform designed to support high-throughput screening for liposomal product optimization, as well as the full-scale production of previously optimized systems. The microfluidic setup employed in the previous chapter was utilized to characterize and replicate two commercial-like formulations, one based on Doxil® and the other on Marqibo®, demonstrating its versatility across different liposomal compositions. Through different levels of DoE, the platform enabled the production of highly monodisperse and regulatory-compliant liposomal formulations. Finally, with minor modifications to the microfluidic setup and implementation of optimized process parameters, a successful scale-up was achieved, producing up to 1 L of liposomal product in under 20 minutes. By refining critical process parameters and ensuring robustness, this work bridges the gap between laboratory-scale research and industrial pharmaceutical manufacturing, validating the feasibility of large-scale liposome production. Collectively, through three interconnected yet independent research projects, this thesis explores novel approaches to liposome formulation and application as drug carriers while establishing advanced methodologies for their screening, optimization, and scale-up. By integrating rational design principles, microfluidic technologies, and rigorous experimental frameworks, these studies contribute to the evolution of liposomal nanomedicine from bench to bedside, furtherly enhancing its status as the gold standard in drug delivery technology.