Microfluidics based manufacture of liposomes simultaneously entrapping hydrophilic and lipophilic drugs

Abstract

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually, and in combination, using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ∼90 to 300nm. In terms of drug loading, microfluidics production promoted high loading within ∼100nm vesicles for both the water soluble drug (20-25% of initial amount added) and the bilayer embedded drug (40-42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug.

The Use of an Efficient Microfluidic Mixing System for Generating Stabilized Polymeric Nanoparticles for Controlled Drug Release

“…5B), consistent with several previous articles 27,28) but the opposite of that reported in another study. 26) We believe that an excessively high flow rate ratio, which dramatically reduces the proportion of organic solution and affects the solubility of the carrier (PLGA in our case and phospholipids in the other reports), may produce heterogeneous nanoparticles. Several researchers have investigated other parameters, such as the concentration of the carriers, buffers, and solvents, which might influence solubility and stability of the carrier and the characteristics of the nanoparticles.…”

“…Examples include lipid nanoparticles, 20) polymer nanoparticles, [21][22][23] non-ionic surfactant nanoparticles 24) and cochleate microparticles. 25) To date, most applications have focused on the preparation of liposomes [26][27][28] and there is little information regarding the generation of other types of nanoparticles using this approach. In this study, we focused on the preparation of PLGA nanoparticles and investigated the influence of various conditions on the PLGA nanoparticles.…”

“…For example, changing the flow rate ratio to above 1/1 (2/1, 28) 3/1 26,27) ) resulted in a remarkable decrease in the diameters of liposomes with several compositions. These results suggest that dilution of the organic solution into the aqueous solution is remarkably promoted by increasing the flow rate ratio.…”

“…Several researchers have investigated other parameters, such as the concentration of the carriers, buffers, and solvents, which might influence solubility and stability of the carrier and the characteristics of the nanoparticles. 24,26) Additionally, the viscosity is a possible key parameter. Although we did not investigate it, the concentration of PLGA and drug may affect the viscosity and affect the particle size and PDI.…”

A facile microfluidic method for production of amphotericin B lipid complex

“…Thus, microfluidic systems have been increasingly used for fabrication of drug carriers such as liposomes, polymer nanoparticles, emulsion etc. [6][7][8][9][10][11] . In microfluidic technology, continuous and multiphase fluidic systems are usually used for production of drug carrier 12 .…”