Division of Molecular Pharmaceutics and Drug Delivery, The University of Texas in Austin, 2409 University Avenue, Austin, Texas, 78712, USA.
Amgen Inc., Thousand Oaks, California, USA.
AAPS PharmSciTech. 2018 Oct;19(7):2755-2766. doi: 10.1208/s12249-018-0980-9. Epub 2018 Feb 27.
With the growing interest in developing biologics for pulmonary delivery, systematic fast screening methods are needed for rapid development of formulations. Due to the labile nature of macromolecules, the development of stable, biologically active formulations with desired aerosol performance imposes several challenges both from a formulation and processing perspective. In this study, spray-freeze-drying was used to develop respirable protein powders. In order to systematically map the selected design space, lysozyme aqueous pre-formulations were prepared based on a constrained mixture design of experiment. The physicochemical properties of the resulting powders were characterized and the effects of formulation factors on aerosol performance and protein stability were systematically screened using a logic flow chart. Our results elucidated several relevant formulation attributes (density, total solid content, protein:sugars ratio) required to achieve a stable lysozyme powder with desirable characteristics for pulmonary delivery. A similar logical fast screening strategy could be used to delineate the appropriate design space for different types of proteins and guide the development of powders with pre-determined aerodynamic properties.
随着人们对开发用于肺部给药的生物制剂的兴趣日益浓厚，需要系统的快速筛选方法来快速开发制剂。由于大分子的不稳定性，从制剂和加工的角度来看，开发具有所需气溶胶性能的稳定、具有生物活性的制剂都带来了一些挑战。在这项研究中，喷雾冷冻干燥被用于开发可吸入性蛋白质粉末。为了系统地绘制所选设计空间，根据受限混合实验设计方案制备了溶菌酶水前体配方。对所得粉末的物理化学性质进行了表征，并使用逻辑流程图系统筛选了制剂因素对气溶胶性能和蛋白质稳定性的影响。我们的结果阐明了实现具有用于肺部给药的理想特性的稳定溶菌酶粉末所需的几个相关制剂属性（密度、总固体含量、蛋白质：糖比）。类似的逻辑快速筛选策略可用于描绘不同类型蛋白质的适当设计空间，并指导开发具有预定空气动力学特性的粉末。
