Preparation of Drug-Loaded Liposomes with Multi-Inlet Vortex Mixers

Abstract

The multi-inlet vortex mixer (MIVM) has emerged as a novel bottom-up technology for solid nanoparticle preparation. However, its performance in liposome preparation remains unknown. Here, two key process parameters (aqueous/organic flow rate ratio (FRR) and total flow rate (TFR)) of MIVM were investigated for liposome preparation. For this study, two model drugs (lysozyme and erythromycin) were chosen for liposome encapsulation as the representative hydrophilic and hydrophobic drugs, respectively. In addition, two modified MIVMs, one with herringbone-patterned straight inlets and one with zigzag inlets, were designed to further improve the mixing efficiency, aiming to achieve better drug encapsulation. Data showed that FRR played an important role in liposome size control, and a size of <200 nm was achieved by FRR higher than 3:1. Moreover, increasing TFR (from 1 to 100 mL/min) could further decrease the size at a given FRR. However, similar regularities in controlling the encapsulation efficiency (EE%) were only noted in erythromycin-loaded liposomes. Modified MIVMs improved the EE% of lysozyme-loaded liposomes by 2~3 times at TFR = 40 mL/min and FRR = 3:1, which was consistent with computational fluid dynamics simulations. In summary, the good performance of MIVM in the control of particle size and EE% makes it a promising tool for liposome preparation, especially for hydrophobic drug loading, at flexible production scales.

Controlling lamellarity and physicochemical properties of liposomes prepared using a microfluidic device

“…Notably, Zheng et al reported the same trend using erythromycin as the model compound for the hydrophobic drug. 30 The DL% showed a similar trend to that of the recovery% (Fig. 1(e)).…”

Microfluidic vortex focusing for high throughput synthesis of size-tunable liposomes

“…The process was highly repeatable, with minimal variation in mean diameter observed over 6 replicates for each liposome synthesis condition. The inverse relationship between FRR and vesicle size is consistent with liposome formation using both hydrodynamic flow focusing 29,39,41 and rapid micromixing [44][45][46][47]67 . However, the vortex focusing process was found to yield low polydispersity, with an average PDI value of 0.04 and nearly constant size variance over the full range of flow rate ratios (Fig.…”

“…In the cyclonic flow cell, stretching and folding of the fluid interface under the influence of the vortical flow field contributes to rapid mixing of the miscible aqueous and lipid streams 65 . This aspect of the mixing process is similar to other vortex mixers explored for liposome synthesis [66][67][68][69] , in which both lipid and buffer are injected tangentially into a mixing chamber to generate chaotic advection patterns in a manner similar to herringbone or toroidal micromixers. Compared with mixing by conventional ethanol injection 70 , vortex mixing can yield enhanced mixing rates and improved control over liposome size.…”

“…Compared with mixing by conventional ethanol injection 70 , vortex mixing can yield enhanced mixing rates and improved control over liposome size. However, as with microfluidic chaotic advection mixers [44][45][46][47] , liposome polydispersity tends to be high due to spatial variations across the mixing zone, with reported polydispersity index (PDI) values typically above 0.2 regardless of flow rate ratio 67,69 .…”

Erythromycin Formulations—A Journey to Advanced Drug Delivery

“…Recent investigations revealed the multi-inlet vortex mixer technology as a suitable method to reach liposomal ERY with sizes lower than 200 nm and an encapsulation efficiency around 35%. It was reported that this method allowed for a good control on liposome size and EE by simply tuning the aqueous/organic flow rate ratio and flow parameters [ 39 ].…”