Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore.
Matralix Pte Ltd, 71 Ayer Rajah Crescent, #07-05, Singapore 139951, Singapore.
Int J Pharm. 2021 Mar 1;596:120230. doi: 10.1016/j.ijpharm.2021.120230. Epub 2021 Jan 21.
Lipids serve as excellent excipients for drug products. Solid lipid microparticles (SLMs) are relatively underexplored in drug delivery; these particles are conventionally prepared using processes yielding polydisperse size distributions, such as spray congealing or emulsification. In this paper, we demonstrate a microfluidics-enabled process for particle engineering of monodisperse solid lipid microparticles with size and content uniformity. To overcome low solubility, we use a volatile solvent to increase drug loading, making the drug-lipid solution a single phase, enabling identical drug loading across particles. We use microfluidic flow extrusion of the solution to generate uniform drug-loaded SLMs, substantially enhancing monodispersity. This method generalises across three drugs-ibuprofen, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), and naproxen, and two lipids-beeswax and hard fat (Suppocire NAI 25A), forming particles of various solid states: amorphous naproxen in crystalline lipids, crystalline ROY in crystalline lipids, and a eutectic mixture of ibuprofen-hard fat. In vitro dissolution studies on the ibuprofen-hard fat SLMs reveal gradual release, fitting the Higuchi model with 50-65% drug released over 72 h. This work expands the drug particle engineering toolbox to enable the formulation of SLMs with high precision in particle size and drug loading. Moreover, the diverse solid-state outcomes enabled by our method makes it applicable to various drugs having different formulation requirements (crystalline/amorphous).
脂质是药物产品的优良赋形剂。固体脂质微球 (SLM) 在药物传递中相对较少被探索；这些颗粒通常使用产生多分散粒径分布的工艺制备，例如喷雾凝固或乳化。在本文中，我们展示了一种基于微流控的方法，用于对单分散固体脂质微球进行颗粒工程改造，使其具有粒径和含量的均匀性。为了克服低溶解度的问题，我们使用挥发性溶剂来提高药物载药量，使药物-脂质溶液成为单相，从而实现颗粒间的相同药物载药量。我们使用溶液的微流控流延挤出法生成均匀的载药 SLM，从而大大提高了单分散性。这种方法适用于三种药物——布洛芬、5-甲基-2-[(2-硝基苯基)氨基]-3-噻吩甲腈 (ROY) 和萘普生，以及两种脂质——蜂蜡和硬脂 (Suppocire NAI 25A)，形成各种固态的颗粒：结晶脂质中的无定形萘普生、结晶脂质中的结晶 ROY 以及布洛芬-硬脂的共晶混合物。体外布洛芬-硬脂 SLM 的溶解研究表明其具有逐渐释放的特点，符合 Higuchi 模型，72 小时内释放 50-65%的药物。这项工作扩展了药物颗粒工程工具包，使能够以高精度控制粒径和药物载药量来制备 SLM。此外，我们的方法所实现的多样化固态结果使其适用于具有不同制剂要求（结晶/无定形）的各种药物。
