Department of Chemical Engineering, McMaster University, Hamilton, ON, L8S 4L7, Canada.
McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L7, Canada.
Pharm Res. 2022 Sep;39(9):2315-2328. doi: 10.1007/s11095-022-03341-8. Epub 2022 Jul 19.
Thermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to effectively encapsulate and protect labile biologics. This study investigates the impact of dextran mass ratio and molecular weight on activity retention, thermal stability and aerosol behaviour of a labile adenoviral vector (AdHu5) encapsulated within a spray dried mannitol-dextran blend.
Comparing formulations using 40 kDa or 500 kDa dextran at mass ratios of 1:3 and 3:1 mannitol to dextran, in vitro quantification of activity losses and powder flowability was used to assess suitability for inhalation.
Incorporating mannitol in a 1:3 ratio with 500 kDa dextran reduced viral titre processing losses below 0.5 log and displayed strong thermal stability under accelerated aging conditions. Moisture absorption and agglomeration was higher in dextran-rich formulations, but under low humidity the 1:3 ratio with 500 kDa dextran powder had the lowest mass median aerodynamic diameter (4.4 µm) and 84% emitted dose from an intratracheal dosator, indicating strong aerosol performance.
Overall, dextran-rich formulations increased viscosity during drying which slowed self-diffusion and favorably hindered viral partitioning at the particle surface. Reducing mannitol content also minimized AdHu5 exclusion from crystalline regions that can force the vector to air-solid interfaces where deactivation occurs. Although increased dextran molecular weight improved activity retention at the 1:3 ratio, it was less influential than the ratio parameter. Improving encapsulation ultimately allows inhalable vaccines to be prepared at higher potency, requiring less powder mass per inhaled dose and higher delivery efficiency.
针对呼吸道疾病的热稳定、喷雾干燥疫苗是肺部给药的有前途的候选物，需要仔细的赋形剂配方来有效包裹和保护不稳定的生物制剂。本研究考察了在喷雾干燥甘露醇-葡聚糖混合物中包裹的不稳定腺病毒载体（AdHu5）中葡聚糖的质量比和分子量对其活性保留、热稳定性和空气动力学行为的影响。
通过比较使用 40 kDa 或 500 kDa 葡聚糖的配方，在质量比为 1:3 和 3:1 的甘露醇与葡聚糖的情况下，评估对吸入的适用性，包括体外评估活性损失和粉末流动性。
在 500 kDa 葡聚糖的 1:3 比例中加入甘露醇，可将病毒滴度加工损失降低至 0.5 对数以下，并在加速老化条件下显示出很强的热稳定性。富含葡聚糖的配方中水分吸收和团聚更高，但在低湿度下，500 kDa 葡聚糖的 1:3 比例粉末的质量中值空气动力学直径（4.4 µm）最低，气管内给药器的 84%发射剂量，表明具有很强的空气动力学性能。
总体而言，富含葡聚糖的配方在干燥过程中增加了粘度，从而减缓了自扩散并有利地阻碍了病毒在颗粒表面的分配。降低甘露醇含量还最大限度地减少了 AdHu5 从结晶区的排除，结晶区可以迫使载体到达空气-固界面，在那里发生失活。尽管增加葡聚糖分子量在 1:3 比例时提高了活性保留，但它的影响不如比例参数大。改善封装最终可以制备更高效价的可吸入疫苗，需要每吸入剂量的粉末质量更少，输送效率更高。
