Department of Mechanical Engineering, University of Alberta, Alberta, Canada.
Inhalation Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, South San Francisco, CA, USA.
Eur J Pharm Biopharm. 2022 Aug;177:308-322. doi: 10.1016/j.ejpb.2022.07.013. Epub 2022 Jul 26.
Administration of biologics such as proteins, vaccines, and phages via the respiratory route is becoming increasingly popular. Inhalable powder formulations for the successful delivery of biologics must first ensure both powder dispersibility and physicochemical stability. A lipid-based inhalable microparticle platform combining the stability advantages offered by dry powder formulations and high dispersibility afforded by a rugose morphology was spray dried and tested. A new simplified spray drying method requiring no organic solvents or complicated feedstock preparation processes was introduced for the manufacture of the microparticles. Trehalose was selected to form the amorphous particle core, because of its well-known ability to stabilize biologics, and also because of its ability to serve as a surrogate for small molecule actives. Phospholipid distearoyl phosphatidylcholine (DSPC), the lipid component in this formulation, was used as a shell former to improve powder dispersibility. Effectiveness of the lipid excipient in modifying trehalose particle morphology and enhancing powder dispersibility was evaluated at different lipid mass fractions (5%, 10%, 25%, 50%) and compared with that of several previously published shell-forming excipients at their effective mass fractions, i.e., 5% trileucine, 20% leucine, and 40% pullulan. A strong dependence of particle morphology on the lipid mass fraction was observed. Particles transitioned from typical smooth spherical trehalose particles without lipid to highly rugose microparticles at higher lipid mass fractions (>5%). In vitro aerosol performance testing demonstrated a significant improvement of powder dispersibility even at lipid mass fractions as low as 5%. Powder formulations with excellent aerosol performance comparable to those modified with leucine and trileucine were achieved at higher lipid mass fractions (>25%). A model biologic-containing formulation with 35% myoglobin, 35% glass stabilizer (trehalose), and 30% lipid shell former was shown to produce highly rugose particle structure as designed and excellent aerosol performance for efficient pulmonary delivery. A short-term stability at 40 °C proved that this protein-containing formulation had good thermal stability as designed. The results demonstrated great potential for the new lipid microparticle as a platform for the delivery of both small-molecule APIs and large-molecule biologics to the lung.
通过呼吸道给予蛋白质、疫苗和噬菌体等生物制剂的方法正变得越来越流行。为了成功地输送生物制剂，可吸入粉末制剂首先必须确保粉末的分散性和物理化学稳定性。本研究结合干粉制剂稳定性优势和粗糙形态带来的高分散性，开发了一种基于脂质的可吸入微颗粒平台，并对其进行喷雾干燥和测试。本研究引入了一种新的简化喷雾干燥方法，该方法无需有机溶剂或复杂的原料制备过程，用于制造微颗粒。海藻糖因其稳定生物制剂的能力而被选择形成无定形颗粒核心，也因为它可以作为小分子活性剂的替代品。在该制剂中，脂质成分二硬脂酰磷脂酰胆碱（DSPC）被用作壳形成剂，以提高粉末的分散性。在不同的脂质质量分数（5%、10%、25%、50%）下，评估了脂质赋形剂对海藻糖颗粒形态和增强粉末分散性的修饰效果，并与先前发表的几种壳形成赋形剂的有效质量分数（5%三亮氨酸、20%亮氨酸和 40%普鲁兰）进行了比较。观察到颗粒形态强烈依赖于脂质质量分数。颗粒从典型的无脂质光滑球形海藻糖颗粒转变为高粗糙的微颗粒，随着脂质质量分数的增加（>5%）。体外气溶胶性能测试表明，即使在脂质质量分数低至 5%的情况下，粉末的分散性也得到了显著改善。在较高的脂质质量分数（>25%）下，可实现具有优异气溶胶性能的粉末制剂，其性能可与用亮氨酸和三亮氨酸修饰的制剂相媲美。含有 35%肌红蛋白、35%玻璃稳定剂（海藻糖）和 30%脂质壳形成剂的模型生物制剂配方被证明产生了设计所需的高度粗糙颗粒结构和高效肺部输送的优异气溶胶性能。在 40°C 的短期稳定性表明，该含有蛋白质的配方具有良好的热稳定性。结果表明，这种新型脂质微颗粒具有作为小分子 API 和大分子生物制剂递送至肺部的平台的巨大潜力。
