Kranz H, Bodmeier R
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
Eur J Pharm Sci. 2008 Jul 3;34(2-3):164-72. doi: 10.1016/j.ejps.2008.03.004. Epub 2008 Apr 8.
The objective of the study was to investigate key formulation variables affecting the release of bupivacaine hydrochloride, a local anesthetic, from different in situ forming biodegradable drug delivery devices. The formulations included ISM systems [in situ microparticles, a poly(lactide)-solvent phase dispersed into an external oil phase] and poly(lactide) solutions (in situ implant systems). The solubility of the biodegradable polymer poly(d,l-lactide) (PLA) in various organic solvents was determined using the Hansen multicomponent solubility parameter concept. The solvent release from ISM and polymer solutions into phosphate buffer which influences the polymer precipitation rate was investigated as a function of the type of solvent, polymer concentration and polymer:oil phase ratio by using a HPLC assay. Scanning electron microscopy (SEM) was performed in order to relate the drug release to the surface properties of the precipitated implants or microparticles. Suitable solvents for the preparation of the in situ forming drug delivery systems, such as N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and 2-pyrrolidone were found using the Hansen multicomponent solubility parameter concept. The injection of the polymer solutions (in situ implants) into the aqueous medium led to a rapid solvent/non-solvent exchange. The resulting in situ implants were porous, thus explaining the rapid initial drug release. Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles as shown by SEM measurements. Due to the presence of an external oil phase the solvent release into the buffer medium from ISM was significantly slower compared to the polymer solutions. The solvent release of the ISM systems into the phosphate buffer decreased with increasing polymer concentration and decreasing polymer:oil phase ratio. The type of solvent used also affected the solvent release. A slower solvent release into the aqueous medium resulted in less porous microparticles, thus explaining the reduced initial drug release from ISM systems compared to the polymer solutions.
该研究的目的是调查影响局部麻醉剂盐酸布比卡因从不同原位形成的可生物降解药物递送装置中释放的关键制剂变量。这些制剂包括ISM系统[原位微粒，即分散在外部油相中的聚（丙交酯）-溶剂相]和聚（丙交酯）溶液（原位植入系统）。使用汉森多组分溶解度参数概念测定了可生物降解聚合物聚（d，l-丙交酯）（PLA）在各种有机溶剂中的溶解度。通过HPLC测定法，研究了ISM和聚合物溶液向磷酸盐缓冲液中的溶剂释放，该释放影响聚合物沉淀速率，作为溶剂类型、聚合物浓度和聚合物：油相比的函数。进行扫描电子显微镜（SEM）以将药物释放与沉淀的植入物或微粒的表面性质相关联。使用汉森多组分溶解度参数概念发现了适用于制备原位形成药物递送系统的溶剂，如N-甲基-2-吡咯烷酮（NMP）、二甲基亚砜（DMSO）和2-吡咯烷酮。将聚合物溶液（原位植入物）注入水介质中导致快速的溶剂/非溶剂交换。所得的原位植入物是多孔的，因此解释了药物的快速初始释放。如SEM测量所示，与释放介质接触后，ISM系统的内部聚合物相固化并形成微粒。由于存在外部油相，与聚合物溶液相比，ISM向缓冲介质中的溶剂释放明显更慢。ISM系统向磷酸盐缓冲液中的溶剂释放随着聚合物浓度的增加和聚合物：油相比的降低而降低。所用溶剂的类型也影响溶剂释放。向水介质中较慢的溶剂释放导致微粒的孔隙率降低，因此解释了与聚合物溶液相比，ISM系统中初始药物释放的减少。
