Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Dosage Form Design & Development, Biopharmaceutical Development, AstraZeneca, 1 Medimmune Way, Gaithersburg, MD 20878, USA.
Eur J Pharm Biopharm. 2021 Dec;169:256-267. doi: 10.1016/j.ejpb.2021.10.014. Epub 2021 Oct 31.
Freeze-drying is an effective approach to improve the long-term stability of nanomedicines. Lyoprotectants are generally considered as requisite excipients to ensure that the quality of nanoparticles is maintained throughout the freeze-drying process. However, depending on the type of nanoparticles, the needs for lyoprotectants or the challenges they face during freeze-drying may be different. In this study, we compared and identified the impact of freeze-drying on key characteristics of three types of nanoparticles: solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. Sucrose, trehalose, and mannitol were added to nanoparticle suspensions before freeze-drying. The same conservative freeze-drying conditions with controlled ice nucleation at -8 °C were employed for all formulations. The collapse temperatures of nanoparticle formulations were found to be the same as those of the lyoprotectant added, except PN formulation. Likely the poly(vinyl alcohol) (PVA) in the formulation induced a higher collapse temperature and retardation of drying of PNs. Freeze-drying of both SLNs and liposomes without lyoprotectants increased particle size and polydispersity, which was resolved by adding amorphous disaccharides. Regardless of the addition of lyoprotectants, freeze-drying did not alter the size of PNs possibly due to the protection from PVA. However, lyoprotectants were still necessary to shorten the reconstitution time and reduce the residual moisture. In conclusion, different types of nanoparticles face distinct challenges for freeze-drying, and lyoprotectants differentially affect various stability and quality attributes of freeze-dried nanoparticles.
冷冻干燥是提高纳米药物长期稳定性的有效方法。冷冻保护剂通常被认为是确保纳米颗粒质量在冷冻干燥过程中得以维持的必需辅料。然而，根据纳米颗粒的类型，对冷冻保护剂的需求或其在冷冻干燥过程中面临的挑战可能会有所不同。在本研究中，我们比较并确定了冷冻干燥对三种类型纳米颗粒（固体脂质纳米粒、聚合物纳米粒和脂质体）关键特性的影响。在冷冻干燥前，将蔗糖、海藻糖和甘露醇添加到纳米颗粒悬浮液中。所有配方均采用相同的保守冷冻干燥条件，控制在-8°C 时进行冰核形成。发现纳米颗粒制剂的塌陷温度与添加的冷冻保护剂的温度相同，除了聚合物纳米粒制剂。可能是制剂中的聚乙烯醇（PVA）引起了更高的塌陷温度和聚合物纳米粒干燥的延迟。没有添加冷冻保护剂的固体脂质纳米粒和脂质体的冷冻干燥会增加颗粒大小和多分散性，而添加无定形二糖则可以解决这个问题。无论是否添加冷冻保护剂，冷冻干燥都不会改变聚合物纳米粒的大小，这可能是由于 PVA 的保护作用。然而，冷冻保护剂仍然是必需的，以缩短复溶时间并减少残留水分。总之，不同类型的纳米颗粒在冷冻干燥方面面临着不同的挑战，冷冻保护剂对冷冻干燥纳米颗粒的各种稳定性和质量属性有不同的影响。
