Fabrication strategy for amphiphilic microcapsules with narrow size distribution by premix membrane emulsification

Amphiphilic co-polymer, which can maintain the stability of proteins and increase the protein loading efficiency, is considered as an exploring-worthy biodegrade polymer for drug delivery. However, amphiphilic microcapsules prepared by conventional methods, such like mechanical stirring and spray-drying methods, exhibit broad size distributions due to its hydrophilic sequences, leading to poor reproducibility. In this study, we employed poly(monomethoxypoly ethylene glycol-co-D,L-lactide) (mPEG-PLA, PELA), one of common amphiphilic polymers, as model to focus on investigating the process parameters and mechanisms to prepare PELA microcapsules with narrow size distribution and regular sphericity by combining premix membrane emulsification and double emulsion technique. The coarse double emulsion with broad size distribution was repeatedly pressed through Shirasu Porous Glass (SPG) membrane with relatively high pressure to form the fine emulsion with narrow size distribution. Then, the microcapsules with narrow size distribution can be obtained by solvent extraction method. It was found that it was more difficult to obtain PELA microcapsules with narrow size distribution and smooth surface due to its amphiphilic property, compared with the cases of PLA and PLGA. The smooth surface morphology was found to be related to several factors including internal water phase with less volume, slower stirring rate during solidification and using ethyl acetate as oil phase. It was also found that mass ratio of hydrophilic mPEG, stabilizer PVA concentration in external water phase and transmembrane pressure played important role on the distribution of microcapsules size. The suitable preparation conditions were determined as follows: for the membrane with pore size of 2.8 μm, the mass ratio of PLA/mPEG was 19:1, volume ratio of W(1)/O was 1:10 and O/W(2) was 1:5, PVA concentration (w/v) was 1.0%, magnetic stirring rate during solidification was 60 rpm and 300 kPa was chosen as transmembrane pressure. There was a linear relationship between the diameter of microcapsules and the pore size of the membranes. Finally, by manipulating the process parameters, PELA microcapsules with narrow size distributions (coefficient of variation was less than 15%), smooth morphology and various sizes, were obtained. Most importantly, the key factors affecting fabrication have been revealed and mechanisms were illustrated in detail, which would shed light on the research of amphiphilic polymer formulation.