Celator Pharmaceuticals Corp, 1779 W 75th Avenue, Vancouver, BC V6P 6P2, Canada.
Int J Pharm. 2010 May 31;391(1-2):248-59. doi: 10.1016/j.ijpharm.2010.02.014. Epub 2010 Feb 13.
The biophysical characterization of CPX-351, a liposomal formulation of cytarabine and daunorubicin encapsulated in a synergistic 5:1 molar ratio (respectively), is presented. CPX-351 is a promising drug candidate currently in two concurrent Phase 2 trials for treatment of acute myeloid leukemia. Its therapeutic activity is dependent on maintenance of the synergistic 5:1 drug:drug ratio in vivo. CPX-351 liposomes have a mean diameter of 107 nm, a single phase transition temperature of 55.3 degrees C, entrapped volume of 1.5 microL/micromol lipid and a zeta potential of -33 mV. Characterization of these physicochemical properties led to identification of an internal structure within the liposomes, later shown to be produced during the cytarabine loading procedure. Fluorescence labeling studies are presented that definitively show that the structure is composed of lipid and represents a second lamella. Extensive spectroscopic studies of the drug-excipient interactions within the liposome and in solution reveal that interactions of both cytarabine and daunorubicin with the copper(II) gluconate/triethanolamine-based buffer system play a role in maintenance of the 5:1 cytarabine:daunorubicin ratio within the formulation. These studies demonstrate the importance of extensive biophysical study of liposomal drug products to elucidate the key physicochemical properties that may impact their in vivo performance.
CPX-351 是一种脂质体药物，由阿糖胞苷和柔红霉素组成，两者的摩尔比为 5:1。CPX-351 是一种有前途的候选药物，目前正在进行两项针对急性髓系白血病的 2 期临床试验。其治疗活性依赖于体内维持协同的 5:1 药物-药物比值。CPX-351 脂质体的平均直径为 107nm，具有单一的相变温度 55.3°C，包封体积为 1.5µL/µmol 脂质，zeta 电位为-33mV。这些理化性质的表征导致鉴定出脂质体内部的结构，后来发现该结构是在阿糖胞苷加载过程中产生的。荧光标记研究明确表明，该结构由脂质组成，代表第二个脂双层。对脂质体和溶液中药物-赋形剂相互作用的广泛光谱研究表明，阿糖胞苷和柔红霉素与铜(II)葡萄糖酸盐/三乙醇胺基缓冲系统的相互作用在制剂中维持 5:1 的阿糖胞苷:柔红霉素比值中发挥作用。这些研究表明，对脂质体药物进行广泛的物理化学研究对于阐明可能影响其体内性能的关键物理化学性质非常重要。
