Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Int J Pharm. 2015 Mar 30;482(1-2):123-30. doi: 10.1016/j.ijpharm.2015.01.043. Epub 2015 Jan 27.
The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6-20 μm were prepared by a double emulsion (W1/O/W2) method using dichloromethane as volatile solvent. It was found that the microspheres were spherical with a non-porous surface; imatinib loading efficiency (LE) was highly dependent on the pH of the external water phase (W2). By increasing the pH of W2 phase above the highest pKa of imatinib (pKa 8.1), at which imatinib is mainly uncharged, the LE increased from 10% to 90% (pH 5.0 versus pH 9.0). Conversely, only 4% of its counter ion, mesylate, was retained in the microspheres at the same condition (pH 9.0). Since mesylate is highly water soluble, it is unlikely that it partitions into the organic phase. We demonstrated, using differential scanning calorimetry (DSC), that imatinib was molecularly dispersed in the polymeric matrix at loadings up to 8.0%. At higher drug loading, imatinib partially crystallized in the matrix. Imatinib microspheres released their cargo during three months by a combination of diffusion through the polymer matrix and polymer erosion. In conclusion, we have formulated imatinib microspheres with high LE and LC. Although we started with a double emulsion of imatinib mesylate, the obtained microspheres contained imatinib base which was mainly molecularly dispersed in the polymer matrix. These microspheres release imatinib over a 3-month period which is of interest for local treatment of cancer.
本研究的目的是开发载有伊马替尼的聚（D，L-丙交酯-共-乙交酯）（PLGA）微球，其具有高载药效率，能够在较长时间内持续释放伊马替尼。采用二氯甲烷作为挥发性溶剂的双乳液（W1/O/W2）法制备了粒径为 6-20μm 的甲磺酸伊马替尼载 PLGA 微球。结果发现，微球呈球形，表面无孔；伊马替尼载药效率（LE）高度依赖于外部水相（W2）的 pH 值。通过将 W2 相的 pH 值提高到高于伊马替尼的最高 pKa（pKa8.1），即伊马替尼主要带电荷时，LE 从 10%增加到 90%（pH5.0 与 pH9.0 相比）。相反，在相同条件下（pH9.0），其反离子甲磺酸盐仅保留在微球中 4%。由于甲磺酸盐高度水溶性，它不太可能分配到有机相中。我们使用差示扫描量热法（DSC）证明，在载药量高达 8.0%时，伊马替尼以分子形式分散在聚合物基质中。在更高的药物载药量下，伊马替尼在基质中部分结晶。伊马替尼微球通过扩散通过聚合物基质和聚合物侵蚀的组合在三个月内释放其货物。总之，我们已经制定了具有高 LE 和 LC 的伊马替尼微球。虽然我们从甲磺酸伊马替尼的双乳液开始，但得到的微球含有主要以分子形式分散在聚合物基质中的伊马替尼碱。这些微球在 3 个月内释放伊马替尼，这对于癌症的局部治疗很有意义。
