Barreiro-Iglesias Rafael, Bromberg Lev, Temchenko Marina, Hatton T Alan, Concheiro Angel, Alvarez-Lorenzo Carmen
Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela 15872, Spain.
J Control Release. 2004 Jul 7;97(3):537-49. doi: 10.1016/j.jconrel.2004.04.007.
The capability of a family of copolymers comprising Pluronic (PEO-PPO-PEO) surfactants covalently conjugated with poly(acrylic acid) (Pluronic-PAA) to enhance the aqueous solubility and stability of the lactone form of camptothecin (CPT) was studied. The unprotected lactone form of CPT, which possesses cytotoxic activity, is rapidly converted to the ring-opened carboxylate form under physiological conditions. Firstly, surfactant properties such as critical micellization concentration (CMC) of Pluronic-PAA copolymers were characterized. Then, the equilibrium solubility partitioning and hydrolysis of the lactone form of CPT in the presence of Pluronic-PAA in water and in human serum were analyzed. CPT solubility in polymer micellar solutions was ca. 3- to 4-fold higher than that in water at pH 5. The amount of CPT solubilized per PPO was considerably greater in the Pluronic-PAA solutions than in the parent Pluronic solution, which suggests that the drug is not only solubilized by the hydrophobic cores and also by the hydrophilic POE-PAA shells of the micelles. The equilibrium partition coefficient of the CPT lactone between Pluronic-PAA solutions and water exceeded (2-3) x 10(3). The complete solubilization of CPT and the absence of chemical interactions between CPT and Pluronic-PAA were confirmed by modulated temperature differential scanning calorimetry (MTDSC), infrared spectroscopy, and X-ray diffraction of films. The loading of CPT into the Pluronic-PAA micelles was able to prevent the hydrolysis of the lactone group of the drug for 2 h at pH 8 in water. When compared to the unprotected CPT, the kinetics of the CPT hydrolysis in human serum was about 10-fold slower in the Pluronic-PAA formulations.
研究了一类由与聚丙烯酸共价共轭的普朗尼克（PEO-PPO-PEO）表面活性剂组成的共聚物（普朗尼克-PAA）增强喜树碱（CPT）内酯形式在水中的溶解度和稳定性的能力。具有细胞毒性活性的未保护CPT内酯形式在生理条件下会迅速转化为开环羧酸盐形式。首先，对普朗尼克-PAA共聚物的临界胶束浓度（CMC）等表面活性剂性质进行了表征。然后，分析了在水中和人血清中存在普朗尼克-PAA时CPT内酯形式的平衡溶解度分配和水解情况。在pH 5时，CPT在聚合物胶束溶液中的溶解度比在水中高约3至4倍。在普朗尼克-PAA溶液中，每PPO溶解的CPT量比在母体普朗尼克溶液中要大得多，这表明药物不仅被胶束的疏水核心溶解，还被胶束的亲水POE-PAA壳层溶解。CPT内酯在普朗尼克-PAA溶液和水之间的平衡分配系数超过（2-3）×10³。通过调制温度差示扫描量热法（MTDSC）、红外光谱和薄膜X射线衍射证实了CPT的完全溶解以及CPT与普朗尼克-PAA之间不存在化学相互作用。在水中pH 8时，将CPT负载到普朗尼克-PAA胶束中能够防止药物内酯基团水解2小时。与未保护的CPT相比，在普朗尼克-PAA制剂中CPT在人血清中的水解动力学慢约10倍。
