Dicko Awa, Frazier April A, Liboiron Barry D, Hinderliter Anne, Ellena Jeff F, Xie Xiaowei, Cho Connie, Weber Tom, Tardi Paul G, Cabral-Lilly Donna, Cafiso David S, Mayer Lawrence D
Celator Pharmaceuticals Corp., 1779 W 75th Avenue, Vancouver, British Columbia V6P6P2, Canada.
Pharm Res. 2008 Jul;25(7):1702-13. doi: 10.1007/s11095-008-9561-z. Epub 2008 Mar 5.
The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (copper gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio.
Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro-release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV-Vis were used to characterize the aggregation state of the drugs within the liposomes.
Coordinated release of the drugs from liposomes was disrupted by removing copper gluconate. Approximately 45% of the total irinotecan was detectable in the copper-containing CPX-1 formulation by NMR, which decreased to 19% without copper present in the liposomal interior. Formation of higher order, NMR-silent aggregates was associated with slower and uncoordinated irinotecan release relative to floxuridine and loss of the synergistic drug/drug ratio. Solution spectroscopy and calorimetry revealed that while all formulation components were required to achieve the highest solubility of irinotecan, direct drug-excipient binding interactions were absent.
Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.
阐明双药脂质体制剂CPX-1中药物（氟尿苷、伊立替康）与辅料（葡萄糖酸铜、三乙醇胺）之间的分子间/分子内相互作用，以确定能够使伊立替康和氟尿苷协同释放并将两种药物维持在固定的1:1摩尔协同比例的物理化学性质。
采用体外释放试验评估伊立替康和氟尿苷从脂质体中的释放情况。利用荧光、核磁共振光谱（NMR）和紫外可见光谱对脂质体内药物的聚集状态进行表征。
去除葡萄糖酸铜后，药物从脂质体中的协同释放受到破坏。通过核磁共振，在含铜的CPX-1制剂中可检测到约45%的总伊立替康，而脂质体内部不存在铜时，这一比例降至19%。相对于氟尿苷，形成更高阶的、核磁共振不可见的聚集体与伊立替康释放较慢且不协调以及协同药物/药物比例的丧失有关。溶液光谱和量热法表明，虽然所有制剂成分都是实现伊立替康最高溶解度所必需的，但不存在直接的药物-辅料结合相互作用。
伊立替康、氟尿苷与辅料之间的长程相互作用调节了伊立替康的聚集状态，使两种药物能够同时从脂质体中释放。
