Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA.
Dosage Form Design & Development, Biopharmaceutical Development, AstraZeneca, 1 MedImmune Way, Gaithersburg, MD 20878, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA; Institute of Materials Science, University of Connecticut, 97 North Eagleville Road, Storrs, CT 06269, USA.
含有高度浓缩蛋白质的冻干蛋白质制剂通常具有较长的重构时间。目标是了解配方在调节重构时间中的作用。研究了配方变量，例如总固体百分比、蛋白质浓度、蛋白质与糖的比例、不同的蛋白质和包含可结晶赋形剂对影响重构的滤饼特性的影响，即滤饼润湿性、重构液渗入滤饼、滤饼崩解和滤饼多孔结构。此外，还评估了几种粘度测量对重构时间的影响。重构时间主要受“浓缩制剂粘度”的影响，而来自总固体百分比和蛋白质浓度的贡献可以忽略不计。” 最终蛋糕中的部分结晶也加速了重构。润湿性、液体渗入滤饼、滤饼崩解趋势和滤饼多孔结构对于无定形滤饼是不变的，并且与重构时间无关。然而，这些特性对结晶度的存在很敏感，并导致至少部分结晶饼的重建速度更快。“浓缩配方粘度”与无定形滤饼的重构时间密切相关，提供了对无定形配方重构所涉及步骤的见解。最终蛋糕中的部分结晶也加速了重构。润湿性、液体渗入滤饼、滤饼崩解趋势和滤饼多孔结构对于无定形滤饼是不变的，并且与重构时间无关。然而，这些特性对结晶度的存在很敏感，并导致至少部分结晶饼的重建速度更快。“浓缩配方粘度”与无定形滤饼的重构时间密切相关，提供了对无定形配方重构所涉及步骤的见解。发现蛋糕崩解趋势和蛋糕多孔结构对于无定形蛋糕是不变的，并且与重构时间无关。然而，这些特性对结晶度的存在很敏感，并导致至少部分结晶饼的重建速度更快。“浓缩配方粘度”与无定形滤饼的重构时间密切相关，提供了对无定形配方重构所涉及步骤的见解。发现蛋糕崩解趋势和蛋糕多孔结构对于无定形蛋糕是不变的，并且与重构时间无关。然而，这些特性对结晶度的存在很敏感，并导致至少部分结晶饼的重建速度更快。“浓缩配方粘度”与无定形滤饼的重构时间密切相关，提供了对无定形配方重构所涉及步骤的见解。
Lyophilized protein formulations containing highly concentrated proteins often have long reconstitution times. The goal was to understand the role of formulation in mediating the reconstitution time. Formulation variables such as % total solids, protein concentration, protein-to-sugar ratio, different proteins and inclusion of a crystallizable excipient were investigated for their effect on cake properties influencing reconstitution namely, cake wettability, penetration of reconstitution fluid into the cake, cake disintegration and cake porous structure. Additionally, several measures of viscosity were also evaluated for their effect on reconstitution time. Reconstitution time was primarily influenced by the "concentrated formulation viscosity" with negligible contributions from % total solids and protein concentration. "Concentrated formulation viscosity" was sensitive to both protein-to-sugar ratio and the protein itself. Partial crystallinity in the final cake also expedited reconstitution. Wettability, liquid penetration into the cake, cake disintegration tendency and cake porous structure were found to be invariant for amorphous cakes and did not correlate with reconstitution time. However, these properties were sensitive to the presence of crystallinity and resulted in faster reconstitution at least of the partially crystalline cakes. "Concentrated formulation viscosity" strongly correlated with reconstitution times of amorphous cakes, providing insights on the steps involved in the reconstitution of amorphous formulations.
