Division of Pharmaceutics, Freeze-Drying Focus Group, University of Erlangen Cauerstraße, 91058 Erlangen, Germany.
J Pharm Sci. 2012 Jan;101(1):354-62. doi: 10.1002/jps.22745. Epub 2011 Sep 8.
On the basis of a previously developed formulation and process guideline for lyophilized, highly concentrated drug nanosuspensions for parenteral use, it was the purpose of this study to demonstrate that the original nanoparticle size distribution can be preserved over a minimum period of 3 months, even if aggressive primary drying conditions are used. Critical factors were evaluated that were originally believed to affect storage stability of freeze-dried drug nanoparticles. It was found that the nature and concentration of the steric stabilizer, such as Poloxamer 338 and Cremophor EL, are the most important factors for long-term stability of such formulations, independent of the used drug compound. The rational choice of an adequate steric stabilizer, namely Poloxamer 338, in combination with various lyoprotectants seems crucial to prevent physical instabilities of the lyophilized drug nanoparticles during short-term stability experiments at ambient and accelerated conditions. A 200 mg/mL concentration of nanoparticles could successfully be stabilized over the investigated time interval. In the course of the present experiments, polyvinylpyrrolidone, type K15 was found superior to trehalose or sucrose in preserving the original particle size distribution, presumably based on its surface-active properties. Lastly, it was demonstrated that lower water contents are generally beneficial to stabilize such systems.
基于先前开发的用于注射用冻干高浓度药物纳米混悬剂的配方和工艺指南，本研究旨在证明即使使用强烈的初级干燥条件，原始纳米颗粒的粒径分布也可以在至少 3 个月的时间内保持不变。评估了被认为会影响冷冻干燥药物纳米颗粒储存稳定性的关键因素。结果发现，亲油性稳定剂（如泊洛沙姆 338 和 Cremophor EL）的性质和浓度是此类制剂长期稳定性的最重要因素，而与所用药物化合物无关。合理选择合适的亲油性稳定剂（如泊洛沙姆 338）与各种冻干保护剂相结合，对于防止冻干药物纳米颗粒在环境和加速条件下的短期稳定性实验中发生物理不稳定性至关重要。在研究的时间间隔内，可以成功稳定 200mg/mL 浓度的纳米颗粒。在本实验过程中，发现聚乙烯吡咯烷酮 K15 在保持原始粒径分布方面优于海藻糖或蔗糖，这可能基于其表面活性特性。最后，证明较低的水分含量通常有利于稳定此类体系。
