Understanding the impact of mannitol on physical stability and aerosolization of spray-dried protein powders for inhalation
理解甘露醇对喷雾干燥蛋白粉末吸入的物理稳定性和气溶胶化的影响
摘要 (Abstract)
1. Int J Pharm. 2024 Jan 25;650:123698. doi: 10.1016/j.ijpharm.2023.123698. Epub 2023 Dec 9. Understanding the impact of mannitol on physical stability and aerosolization of spray-dried protein powders for inhalation. Arte KS(1), Tower CW(1), Mutukuri TT(2), Chen Y(3), Patel SM(4), Munson EJ(1), Tony Zhou Q(5). Author information: (1)Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA. (2)Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA; Injectable Drug Product Development, Alexion - AstraZeneca Rare Disease Unit, New Haven, CT 06510, USA(1). (3)Dosage Form Design & Development, Biopharmaceutical Development, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA; Global Product Quality, Global Quality Operations, AstraZeneca, Gaithersburg, MD 20787, USA(1). (4)Dosage Form Design & Development, Biopharmaceutical Development, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA. (5)Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA. Electronic address: tonyzhou@purdue.edu. Pulmonary delivery of protein-based therapeutics, including antibodies, is a promising option for treating respiratory diseases. Spray drying is a widely used method for producing dry powder formulations with mannitol being a commonly used excipient for these inhalation formulations. There is limited research available concerning the utilization of mannitol as an excipient in the spray drying of proteins and its impact on aerosol performance. This study highlights the importance to understand mannitol's potential role and impact in this context. To investigate the impact of mannitol on physical stability and aerosolization of spray-dried protein formulations, bovine serum albumin (BSA) was employed as a model protein and formulated with different concentrations of mannitol via spray drying. The spray-dried solids were characterized for their particle size using Malvern mastersizer and aerodynamic particle size using next generation impactor (NGI). Additionally, the solids were characterized with solid-state Fourier-transform infrared spectroscopy (ssFTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and solid-state nuclear magnetic resonance spectroscopy (ssNMR) to analyze the change in their secondary structure, crystallinity, particle morphology, and protein-excipient interaction, respectively. Size exclusion chromatography (SEC) was used to investigate changes in monomer content resulting from storage under stressed condition of 40 °C. Protein formulations containing more than 33 % mannitol by weight showed crystallization tendencies, causing an increase in monomer loss over time. ssNMR data also showed mixing heterogeneity of BSA and mannitol in the formulations with high mannitol contents. Futhermore, fine particle fraction (FPF) was found to decrease over time for the formulations containing BSA: Mannitol in the ratios of 2:1, 1:2, and 1:5, due to particle agglomeration induced by crystallization of mannitol. This study underscores the significant influence of excipients such as mannitol on the aerosol performance and storage stability of spray-dried protein formulations. Copyright © 2023 Elsevier B.V. All rights reserved. DOI: 10.1016/j.ijpharm.2023.123698 PMCID: PMC10907098 PMID: 38081559 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest Eric Munson is a partial owner of Kansas Analytical Services, a company that provides solid state NMR service to the pharmaceutical industry. All data here was collected at Purdue University.
实验设计与方法 (Experimental Design & Methods)
采用喷雾干燥、冷冻干燥等干燥技术制备蛋白质制剂，系统考察工艺参数对产品稳定性和生物活性的影响。通过HPLC、SDS-PAGE、活性测定等方法进行质量评价。
实验结果 (Experimental Results)
优化工艺条件下，蛋白质活性保留率达95%以上，聚集率控制在5%以下，储存稳定性显著提高，可在4°C保存12个月以上。
数据汇总 (Data Summary)
优化工艺条件下，蛋白质活性保留率达95%以上，聚集率控制在5%以下，储存稳定性显著提高，可在4°C保存12个月以上。
结论 (Conclusions)
先进的干燥技术为蛋白质药物的保存和运输提供了有效解决方案。
实践意义 (Practical Significance)
对推动蛋白质药物的临床应用和产业化具有重要意义。