Linxweiler Helen, Thiesen Judith, Krämer Irene
Department of Pharmacy, University Medical Centre of Johannes Gutenberg-University, Langenbeckstraße 1, 55131 Mainz, Germany.
Pharmaceutics. 2024 Oct 26;16(11):1372. doi: 10.3390/pharmaceutics16111372.
BACKGROUND/OBJECTIVES: The study objective was to determine the physicochemical stability of nab-paclitaxel (Pazenir) ready-to-use (RTU) dispersion for infusion in original glass vials and ready-to-administer (RTA) infusion dispersion in EVA infusion bags.
Triplicate test dispersions were prepared and stored light protected for a maximum of 28 days either in the original glass vials (RTU) at 2-8 °C or in EVA infusion bags (RTA) at 2-8 °C and at 25 °C. Directly after reconstitution and on days 1, 3, 5, 7, 14, 21, and 28 samples were withdrawn and paclitaxel concentrations assayed by a stability-indicating HPLC method. In parallel, pH and osmolality were measured. In a second series, test dispersions were stored over a 14-day period and inspected daily for visible particles and colour changes. Samples were taken daily for particle size analysis. Integrity and particle size distribution of the nanoparticles were determined by dynamic light scattering (DLS) and albumin monomers, dimers, oligomers, or polymers by size-exclusion-chromatography (SEC).
Non-redispersible particles were observed in test dispersions on day 5 (RTA 25 °C), day 7 (RTA 2-8 °C), and day 11 (RTU 2-8 °C). DLS analysis revealed out-of-specification results for the polydispersity index from day 7 (RTA 25 °C) and day 12 (RTU, RTA refrigerated). Paclitaxel concentrations remained >95% of the initial concentrations for 7 days (RTU 2-8 °C, RTA 25 °C) and for 14 days (RTA 2-8 °C). All test dispersions met the specifications regarding the oligomeric status of albumin, pH, and osmolality over the investigation periods.
Stability of nab-paclitaxel dispersions is limited by the release of water-insoluble paclitaxel from the nanoparticles and subsequent crystallisation and by formation of insoluble albumin aggregates. Based on our overall results, shelf life of refrigerated RTU and RTA nab-paclitaxel dispersions is limited to 7 days. Shelf life of RTA nab-paclitaxel dispersions stored at room temperature is limited to 4 days. Careful visual inspection of nab-paclitaxel dispersions after reconstitution and prior to administration is highly recommended to detect non-redispersible particles.
背景/目的：本研究的目的是确定在原始玻璃小瓶中即用型（RTU）纳米白蛋白结合紫杉醇（Pazenir）输注分散液以及在乙烯-醋酸乙烯酯（EVA）输液袋中即给药型（RTA）输注分散液的物理化学稳定性。
制备一式三份的测试分散液，并在2-8°C条件下于原始玻璃小瓶（RTU）中或在2-8°C和25°C条件下于EVA输液袋（RTA）中避光储存最多28天。复溶后以及在第1、3、5、7、14、21和28天直接取出样品，采用一种稳定性指示高效液相色谱法测定紫杉醇浓度。同时，测量pH值和渗透压。在第二个系列中，测试分散液储存14天，每天检查是否有可见颗粒和颜色变化。每天取样进行粒度分析。通过动态光散射（DLS）测定纳米颗粒的完整性和粒度分布，通过尺寸排阻色谱法（SEC）测定白蛋白单体、二聚体、寡聚体或聚合物。
在第5天（RTA 25°C）、第7天（RTA 2-8°C）和第11天（RTU 2-8°C）的测试分散液中观察到不可再分散颗粒。DLS分析显示，从第7天（RTA 25°C）和第12天（RTU、RTA冷藏）起，多分散指数超出规格。在7天内（RTU 2-8°C，RTA 25°C）和14天内（RTA 2-8°C），紫杉醇浓度保持在初始浓度的>95%。在整个研究期间，所有测试分散液在白蛋白的寡聚状态、pH值和渗透压方面均符合规格。
纳米白蛋白结合紫杉醇分散液的稳定性受到纳米颗粒中不溶性紫杉醇的释放及随后的结晶以及不溶性白蛋白聚集体形成的限制。基于我们的总体结果看，冷藏的RTU和RTA纳米白蛋白结合紫杉醇分散液的保质期限制为7天。室温储存的RTA纳米白蛋白结合紫杉醇分散液的保质期限制为4天。强烈建议在复溶后和给药前仔细目视检查纳米白蛋白结合紫杉醇分散液，以检测不可再分散颗粒。
