Drug Delivery
Microfluidic LNP formulation. Nucleic acids in buffer (left) and LNP precursors in solvent (right) are injected into the two inlets of a microfluidic cartridge, where they are
mixed in a controlled fashion. LNPs of different sizes can be produced by varying the
relative and total flow rates (far right)
drug delivery vehicles is that their properties are almost completely independent of the API they are being used to transport; they can be made to a range of sizes or magnitudes of charge, and used with hydrophobic or hydrophilic payloads, helping to overcome the solubility issues associated with the former.
At scales relevant to clinical and commercial production, liposomes are generally formed by nanoprecipitation, followed by multiple extrusion or homogenisation steps to refine size. With nano- precipitation, lipid components are dissolved in a water-miscible solvent, then mixed with an aque- ous buffer. The resulting changes in the polarity cause the nanoparticle components to self-assem- ble. This turbulent mixing approach is difficult to control and challenging to reproduce precisely, as a wide range of parameters – including the mixing mechanism, temperature, pH, nanoparticle compo- sition and shear forces – affect the self-assembly process. Further processing steps, such as sonica- tion, homogenisation or membrane extrusion, are therefore required to ensure consistent sizing across the particle population. These additional processing steps are labour-intensive, suffer from poor batch-to-batch reproducibility and are diffi- cult to scale. This not only affects the efficacy of liposomes as drug delivery vehicles – particle size has a significant impact on biodistribution – but it also makes it difficult to compare results, establish trends or apply rational design principles during development. Researchers developing liposomal drug delivery vehicles therefore all face the same challenges: developing a potent formulation, meet-
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ing the reproducibility criteria of regulatory authorities and achieving reliable scale-up for fur- ther testing.
Along comes microfluidics
These issues have significantly impeded progress in this promising area of drug formulation, as many pharmaceutical developers are tentative in their nanomedicine approaches due to a lack of in-house expertise, a poor track record of success and a per- ceived risk en route to market. This has created a clear demand for rapid, flexible and controlled mixing processes, enabling consistent nano- medicine production that meets the joint pressures of short development timelines and ever-increasing regulatory considerations.
Laminar flow microfluidics is now emerging as the potential solution to these challenges. Under laminar flow, two fluid streams entering a microfluidic channel appear as separate adjacent streams, despite being miscible, before slowly dif- fusing together. This process is both reproducible and well-controlled, however, rapid mixing is cru- cial to achieving small, uniform particles. There are two microfluidic designs in particular that promote rapid mixing and are already commonly used in nanomedicine formulation: hydrodynamic flow focusing and chaotic advection. Flow focus- ing has been used predominantly to formulate polymeric nanoparticles by entrapping hydropho- bic small molecules, although there have also been some examples of its use with nucleic acid formulations. In contrast, chaotic advection has been broadly adopted, largely because it can
Drug Discovery World Fall 2017
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