Microfluidic Manufacture of Lipid-Based Nanomedicines

Abstract

Nanoparticulate technologies have revolutionized drug delivery allowing for passive and active targeting, altered biodistribution, controlled drug release (temporospatial or triggered), enhanced stability, improved solubilization capacity, and a reduction in dose and adverse effects. However, their manufacture remains immature, and challenges exist on an industrial scale due to high batch-to-batch variability hindering their clinical translation. Lipid-based nanomedicines remain the most widely approved nanomedicines, and their current manufacturing methods remain discontinuous and face several problems such as high batch-to-batch variability affecting the critical quality attributes (CQAs) of the product, laborious multistep processes, need for an expert workforce, and not being easily amenable to industrial scale-up involving typically a complex process control. Several techniques have emerged in recent years for nanomedicine manufacture, but a paradigm shift occurred when microfluidic strategies able to mix fluids in channels with dimensions of tens of micrometers and small volumes of liquid reagents in a highly controlled manner to form nanoparticles with tunable and reproducible structure were employed. In this review, we summarize the recent advancements in the manufacturing of lipid-based nanomedicines using microfluidics with particular emphasis on the parameters that govern the control of CQAs of final nanomedicines. The impact of microfluidic environments on formation dynamics of nanomaterials, and the application of microdevices as platforms for nanomaterial screening are also discussed.

3D Printing Technologies in Personalized Medicine, Nanomedicines, and Biopharmaceuticals

“…However, the use of 3D printing to fabricate microfluidic devices capable of high-throughput synthesis of nanomedicines with tuneable dimensions is feasible [ 163 , 164 , 165 , 166 , 167 , 168 ]. Utilising a high-resolution 3D printing process based on FDM or stereolithography, reliable patterning of channel features with dimensions of ~200 µm has been demonstrated, resulting in the production of nanomedicines (<100 nm at a production rate of 4 mg/min) [ 169 ].…”

“…3D printing microfluidic devices are capable of high-throughput synthesis of nanomedicines with tuneable dimensions, resulting in an enormous advantage compared with the conventional batch method [ 163 , 164 , 165 , 166 , 167 , 171 , 172 ]. Still, solvent and unencapsulated drug removal remain a challenge for continuous manufacturing using these devices.…”

Liposomes in Cancer Therapy: How Did We Start and Where Are We Now

“…In addition, it is a long and laborious process that involves several operations. Additional levels of complexity are usually related to the additional testing performed prior to, during, and after the manufacturing, storage, and clinical applications as well as the lack of well controlled good manufacturing practices (GMPs) [ 70 , 92 ]. Recently, the preparation of drug-loaded liposomes has been revolutionized by the state-of-the-art microfluidic systems [ 93 ].…”

“…The aqueous solvent will then replace the organic solvent and promote the self-assembly of liposomes. This technique has the advantage of producing uniformly sized unilamellar liposomes because of the ability to change the flow rate of the lipid solution in the organic solvent and aqueous phase [ 92 , 94 ]. Other techniques to determine nanoparticle size includes atomic force microscopy (AFM), nanoparticle tracking analysis (NTA), absorption spectroscopy, and analytical ultracentrifugation [ 95 , 96 , 97 , 98 ].…”

Combining 3D Printing and Microfluidic Techniques: A Powerful Synergy for Nanomedicine

“…However, these previously unseen discoveries are frequently hampered in their applicability due to a lack of appropriate techniques for their development. The area of NM, which is now more relevant than ever, provides constant insights into the extent to which the use of new formulations is hindered by the impossibility of safe, fast, large-scale production [ 121 ]. In terms of data reported in the literature, the last few years have seen an unprecedented surge in the fields of MF and AM [ 24 , 122 ].…”