Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada.
School of Chemistry, University of Bristol, Bristol, United Kingdom.
J Control Release. 2021 Aug 10;336:522-536. doi: 10.1016/j.jconrel.2021.06.045. Epub 2021 Jul 3.
The formation of trileucine-containing spray-dried microparticles intended for pulmonary delivery was studied in depth. A single-particle method was employed to study the shell formation characteristics of trileucine in the presence of trehalose as a glass former, and an empirical correlation was proposed to predict the instance of shell formation. A droplet chain instrument was used to produce and collect monodisperse particles to examine morphology and calculate particle density for different levels of trileucine. It was observed that the addition of only 0.5 mg/mL (10% w/w) trileucine to a trehalose system could lower dried particle densities by approximately 1 g/cm. In addition, a laboratory-scale spray dryer was used to produce batches of trileucine/trehalose powders in the respirable range. Raman spectroscopy demonstrated that both components were completely amorphous. Scanning electron microscopy and time-of-flight secondary ion mass spectrometry were used to study the particle morphologies and surface compositions. For all cases with trileucine, highly rugose particles with trileucine coverages of more than 60% by mass were observed with trileucine feed fractions of as little as 2% w/w. Moreover, it was seen that at lower trileucine content, smaller and larger particles of a polydisperse powder had slightly different surface compositions. The surface activity of trileucine was also modeled via a modified form of the diffusion equation inside an evaporating droplet that took into account initial surface adsorption and eventual surface desorption due to droplet shrinkage. Finally, using the Flory-Huggins theory, it was estimated that at room temperature, liquid-liquid phase separation would start when the trileucine reached an aqueous concentration of about 18 mg/mL. Besides the surface activity of trileucine, this low concentration was assumed to explain the substantial effect of trileucine on the morphology of spray-dried particles due to early phase separation. The methodology proposed in this study can be used in the rational design of trileucine-containing microparticles.
深入研究了用于肺部递药的含三亮氨酸喷雾干燥微球的形成。采用单颗粒法研究了在海藻糖作为玻璃形成剂的存在下三亮氨酸的壳形成特性，并提出了一个经验相关性来预测壳形成的情况。使用液滴链仪器产生和收集单分散颗粒，以检查不同水平三亮氨酸的形态并计算颗粒密度。观察到，仅向海藻糖系统中添加 0.5mg/mL（10%w/w）的三亮氨酸就可以将干燥颗粒密度降低约 1g/cm³。此外，还使用实验室规模的喷雾干燥器在可吸入范围内生产三亮氨酸/海藻糖粉末的批次。拉曼光谱表明两种成分均完全无定形。扫描电子显微镜和飞行时间二次离子质谱用于研究颗粒形态和表面成分。对于所有含三亮氨酸的情况，都观察到具有高达 60%以上三亮氨酸覆盖率的高度粗糙颗粒，而三亮氨酸进料分数低至 2%w/w。此外，还发现，在三亮氨酸含量较低的情况下，具有较小和较大粒径的多分散粉末的表面成分略有不同。还通过在蒸发液滴内考虑初始表面吸附和由于液滴收缩最终表面解吸的改进形式的扩散方程来模拟三亮氨酸的表面活性。最后，根据 Flory-Huggins 理论，估计在室温下，当三亮氨酸达到约 18mg/mL 的水相浓度时，将开始发生液-液相分离。除了三亮氨酸的表面活性外，还假设这个低浓度可以解释三亮氨酸对喷雾干燥颗粒形态产生显著影响的原因，这是由于早期的相分离。本研究提出的方法可用于含有三亮氨酸的微球的合理设计。
