Trimaille Thomas, Gurny Robert, Möller Michael
Department of Pharmaceutics and Biopharmaceutics, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 30, Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland.
J Biomed Mater Res A. 2007 Jan;80(1):55-65. doi: 10.1002/jbm.a.30888.
Poly(hexyl-substituted lactides) (PHLA) as new hydrophobic polyesters with controlled molecular weights and narrow distributions were synthesized by ring-opening polymerization (ROP) using tin(II) 2-ethylhexanoate (Sn(Oct)(2)) and benzyl alcohol as catalyst and initiator. Glass transition temperatures (T(g)) and zero shear viscosities (eta(0)) at 25 degrees C could be modulated from T(g)= -42 degrees C to -10 degrees C and 40 to 4850 Pa s, respectively, by varying the polymer molecular weight and the number of hexyl groups along the polymer chain. Degradation studies were performed in terms of both mass and molecular weight loss in the course of time. The degradation mechanism is shown to be of the "bulk erosion" type, and comparable to standard poly(D,L-lactide) (PLA). Despite the increased steric hindrance in the poly(monohexyl-substituted lactide) (PmHLA) due to the hexyl side groups, its degradation rate at pH 7.4 and 37 degrees C was found to be slightly higher than observed for the analogue standard PLA. This could be attributed to the flexible rubbery state of the hexyl-substituted polymer (T(g) approximately -15 degrees C) at the physiological temperature, which is favoring the degradation in comparison to the rigid and glassy standard PLA (T(g) approximately 40 degrees C). In contrast, degradation studies performed at 60 degrees C, where both polymers are above their glass transition temperature, confirmed that the degradation rate is lower for the sterically more hindered PmHLA. The degradation products were analyzed by ESI-MS. Hydrolysis lead first to the corresponding oligo-ester fragments and finally to the nontoxic 2-hydroxyoctanoic acid and lactic acid. Tetracycline was tested as a model drug for release studies. This drug was found to be released faster and in higher amounts in its active form from the PHLA matrix than from standard PLA. The results presented in this work demonstrate the potential of these hydrophobic polylactide-based semisolid materials as an alternative to conventional PLA/PLGA for injectable drug delivery systems.
采用2-乙基己酸亚锡（Sn(Oct)(2)）和苄醇作为催化剂和引发剂，通过开环聚合（ROP）合成了具有可控分子量和窄分布的新型疏水性聚酯聚（己基取代丙交酯）（PHLA）。通过改变聚合物分子量和聚合物链上己基的数量，25℃下的玻璃化转变温度（T(g)）和零剪切粘度（η(0)）可分别从T(g)= -42℃调节至-10℃以及从40调节至4850 Pa·s。通过质量和分子量随时间的损失进行了降解研究。降解机制显示为“本体侵蚀”类型，与标准聚（D,L-丙交酯）（PLA）相当。尽管由于己基侧链，聚（单己基取代丙交酯）（PmHLA）中的空间位阻增加，但其在pH 7.4和37℃下的降解速率略高于类似的标准PLA。这可能归因于己基取代聚合物在生理温度下处于柔性橡胶态（T(g)约为-15℃），与刚性玻璃态的标准PLA（T(g)约为40℃）相比，更有利于降解。相反，在60℃下进行的降解研究中，两种聚合物均高于其玻璃化转变温度，证实空间位阻更大的PmHLA降解速率更低。通过电喷雾电离质谱（ESI-MS）分析了降解产物。水解首先产生相应的低聚酯片段，最终产生无毒的2-羟基辛酸和乳酸。测试了四环素作为释放研究的模型药物。发现该药物以活性形式从PHLA基质中释放的速度比从标准PLA中更快且量更大。这项工作中呈现的结果证明了这些疏水性聚丙交酯基半固体材料作为传统PLA/PLGA用于可注射药物递送系统的替代品的潜力。
