National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, PR China.
Colloids Surf B Biointerfaces. 2011 Oct 15;87(2):399-408. doi: 10.1016/j.colsurfb.2011.05.051. Epub 2011 Jun 17.
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.
两亲共聚物可以维持蛋白质的稳定性并提高蛋白质载药量，被认为是一种有前途的可生物降解聚合物用于药物输送。然而，通过传统方法（例如机械搅拌和喷雾干燥方法）制备的两亲性微胶囊由于其亲水性序列而表现出较宽的粒径分布，导致重现性差。在这项研究中，我们使用聚（单甲氧基聚乙二醇-co-D,L-丙交酯）（mPEG-PLA，PELA），作为一种常见的两亲性聚合物的模型，通过结合预混膜乳化和双重乳液技术，重点研究制备具有较窄粒径分布和规则球形的 PELA 微胶囊的工艺参数和机制。通过相对较高的压力将粗的双乳液反复通过 Shirasu Porous Glass（SPG）膜，以形成具有较窄粒径分布的细乳液。然后，通过溶剂萃取法可以获得具有较窄粒径分布的微胶囊。结果发现，与 PLA 和 PLGA 的情况相比，由于其两亲性，获得具有较窄粒径分布和光滑表面的 PELA 微胶囊更加困难。发现光滑的表面形态与几个因素有关，包括体积较小的内水相、固化过程中较慢的搅拌速度以及使用乙酸乙酯作为油相。还发现亲水 mPEG 的质量比、外部水相中的稳定剂 PVA 浓度和跨膜压力对微胶囊粒径分布起着重要作用。确定的合适制备条件如下：对于孔径为 2.8μm 的膜，PLA/mPEG 的质量比为 19:1，W（1）/O 的体积比为 1:10，O/W（2）为 1:5，PVA 浓度（w/v）为 1.0%，固化过程中的磁力搅拌速度为 60rpm，选择 300kPa 作为跨膜压力。微胶囊的直径与膜的孔径之间存在线性关系。最后，通过控制工艺参数，获得了具有较窄粒径分布（变异系数小于 15%）、光滑形态和各种尺寸的 PELA 微胶囊。最重要的是，揭示了影响制备的关键因素，并详细说明了机制，这将为两亲性聚合物制剂的研究提供启示。
