Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Dosage Form Design & Development, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD 20878, USA.
Eur J Pharm Biopharm. 2021 Aug;165:361-373. doi: 10.1016/j.ejpb.2021.05.005. Epub 2021 May 8.
Lyophilized protein formulations containing highly concentrated proteins often have long and variable reconstitution times. Reconstitution time is dependent on a number of factors in a complex manner. Furthermore, factors influencing the reconstitution of partially crystalline cakes are reportedly different from those of amorphous cakes. The objectives of this work were to identify the key factors governing reconstitution and understand the mechanisms involved in reconstitution of both amorphous and partially crystalline cakes. Partial crystallinity in the final cake, larger pores and low "concentrated formulation viscosity" (i.e., viscosity near the surface of the dissolving cake) were identified as desirable characteristics for expediting reconstitution. Crystallinity and larger pores dramatically improved wettability and liquid penetration into partially crystalline cakes, ultimately resulting in well dispersed small pieces of partially dissolved cake. The smaller disintegrated cake pieces dissolved faster because of the increased surface area. The amorphous cakes exhibited poorer wettability than partially crystalline cakes. Moreover, the ability of the reconstitution fluid to penetrate the pores, and the resulting cake disintegration was much lower than that observed for partially crystalline cakes. In fact, for some of the amorphous cakes, the reconstitution fluid did not penetrate the cake at all. As a result, the undissolved intact cake or a large cake chunk floated on the reconstitution fluid amidst foam or bubbles generated during reconstitution. Dissolution of the floating cake appeared to proceed via gradual surface erosion where reconstitution time was found to be highly correlated with the viscosity near the surface of the dissolving cake solids. A higher viscosity prolonged reconstitution. Thus, both formulation and processing conditions can be tailored to achieve faster reconstitution. Including a crystallizable excipient proved to be beneficial. Incorporating an annealing step to facilitate crystallization of the crystallizable excipient and to promote larger pores was also found to be advantageous. A viscosity lowering excipient in the formulation could potentially be helpful but needs to be explored further.
含有高浓度蛋白质的冻干蛋白制剂通常具有较长且可变的复溶时间。复溶时间取决于许多因素，且以复杂的方式相互影响。此外，据报道，影响部分结晶饼状物复溶的因素与无定形饼状物的不同。这项工作的目的是确定控制复溶的关键因素，并了解无定形和部分结晶饼状物复溶的相关机制。最终饼状物的部分结晶度、较大的孔和低“浓缩制剂粘度”（即在溶解饼状物的表面附近的粘度）被确定为加速复溶的理想特征。结晶度和较大的孔显著提高了部分结晶饼状物的润湿性和液体渗透能力，最终导致部分溶解的饼状物分散良好的小块。由于表面积增加，较小的崩解饼状物溶解得更快。无定形饼状物的润湿性比部分结晶饼状物差。此外，复溶液渗透孔的能力以及由此产生的饼状物崩解程度比观察到的部分结晶饼状物要低得多。事实上，对于一些无定形饼状物，复溶液根本没有渗透到饼状物中。因此，未溶解的完整饼状物或大的饼状物块漂浮在复溶液上，同时在复溶过程中会产生泡沫或气泡。漂浮饼状物的溶解似乎通过逐渐的表面侵蚀进行，在该过程中发现复溶时间与溶解饼状物固体表面附近的粘度高度相关。较高的粘度会延长复溶时间。因此，可以定制制剂和加工条件以实现更快的复溶。包含可结晶赋形剂被证明是有益的。加入退火步骤以促进可结晶赋形剂的结晶并促进更大的孔也是有利的。制剂中降低粘度的赋形剂可能会有所帮助，但需要进一步研究。
