Optimization of microfluidic parameters for efficient production of liposomes and LNPs

Lindsay, Sarah Victoria

Thesis

Optimization of microfluidic parameters for efficient production of liposomes and LNPs

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Creator

Lindsay, Sarah Victoria

Rights statement

Strathclyde Thesis Copyright

Awarding institution

University of Strathclyde

Date of award

2024

Thesis identifier

T17054

Person Identifier (Local)

202086578

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Strathclyde Institute of Pharmacy and Biomedical Sciences

Abstract

The application of liposomes and lipid nanoparticles as drug delivery vehicles has increased in recent years since the development of the first liposomal drug, Doxil®, to, more recently, the SARS-CoV2 mRNA-LNP vaccines. Liposomes provide a novel and versatile approach to drug delivery with limited off target side effects and increased delivery to the target site. The development of microfluidics has facilitated the simplification and accelerated translation of nanoparticles, including liposomes and lipid nanoparticles, from bench to bedside. Microfluidics as a production method allows for in-process, fine-tuning control of particle physicochemical properties through the altering of the total flow rate (TFR) and flow rate ratio (FRR). Therefore, the aim of this work was to investigate the impact of the parameters on liposome and lipid nanoparticle characteristics and their application in a biological systems to consider the impact of manufacturing and formulation on potency. To achieve this, microfluidic process parameters and analytical tools were initially developed to support the knowledge space used to underpin subsequent studies. Design of experiments was then used to identify the complex interactions involved in liposome formation and build a predictive model for liposomal critical quality attributes manufactured by microfluidics. From these studies, it was shown flow rate ratio (FRR), lipid concentration and production temperature are critical for the determination of particle size, with higher order interactions present for other factors involved in microfluidic production, such as total flow rate (TFR) and solvent. To further investigate application of microfluidics for the production of liposomes, in vitro and in vivo studies of these liposomal formulations were conducted. These studies demonstrated that the choice of solvent used within microfluidic manufacturing impacted on both in vitro release and in vivo biodistribution. Finally, microfluidic manufacturing was applied to the manufacture of LNPs. These studies showed that a range of LNPs could be produced via microfluidics and that the choice of ionisable lipid impacted on their efficacy in vitro and in vivo; however, these studies demonstrated minimal correlation between in vitro and in vivo data. Overall, the work presented in this thesis demonstrates the versatility of microfluidic production for the manufacturing of lipid-based nanoparticles such that their attributes can be in-process controlled, thereby reducing the processing steps required. When manufacturing these systems, it is important to consider all factors involved in lipid composition and production processes, as both are critical for the final product critical quality attributes.

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