Mao Shirui, Bakowsky Udo, Jintapattanakit Anchalee, Kissel Thomas
Department of Pharmaceutics and Biopharmacy, Philipps-University of Marburg, Ketzerbach 63, D-35032 Marburg, Germany.
J Pharm Sci. 2006 May;95(5):1035-48. doi: 10.1002/jps.20520.
Polyelectrolyte complexes (PEC) formed from chitosan derivatives and insulin was prepared and parameters influencing complex formation were characterized. Turbidimetric titration, in combination with dynamic light scattering (DLS) and laser doppler anemometry (LDA), were used to study the complexation process. The morphology of the PECs was determined using atomic force microscopy (AFM). PEC formation was predominantly pH-dependent. Complexation with insulin occurred only above critical pH value (pHc) of 6.0 for all the chitosan derivatives investigated. Soluble PECs in the size range of 200-500 nm with spherical or subspherical morphology and smooth surface structure were obtained at optimized polymer/insulin charge ratios. Optimal conditions were obtained when the pH of PECs was in the range of 6.5-8.0, depending on polymer structure. The stability of PECs was influenced by polymer chain length. Only when the MW of the polymers was > or =25-kDa PEC precipitation could be avoided. An increase in the ionic strength of the medium accelerated complex dissociation. Chitosan methylation and PEGylation significantly improved the stability of insulin in the PECs. Moreover, the PEC could protect insulin from degradation even at 50 degrees C for at least 6 h. All complexes could be lyophilized without influencing the particle size, complex concentration, and stability of insulin. On the basis of our results, we suggest that interactions involved in PEC formation were predominantly electrostatic in nature, involving the positively charged amino groups of chitosan and the negatively charged insulin above its isoelectric point. Intranasal absorption of the polyelectrolyte nanocomplexes will be studied in vivo.
制备了由壳聚糖衍生物和胰岛素形成的聚电解质复合物（PEC），并对影响复合物形成的参数进行了表征。采用比浊滴定法，结合动态光散射（DLS）和激光多普勒测速仪（LDA）研究了复合过程。使用原子力显微镜（AFM）测定了PEC的形态。PEC的形成主要取决于pH值。对于所有研究的壳聚糖衍生物，与胰岛素的复合仅在临界pH值（pHc）6.0以上发生。在优化的聚合物/胰岛素电荷比下，获得了尺寸范围为200-500 nm、具有球形或亚球形形态且表面结构光滑的可溶性PEC。根据聚合物结构，当PEC的pH值在6.5-8.0范围内时可获得最佳条件。PEC的稳定性受聚合物链长度的影响。只有当聚合物的分子量≥25 kDa时，才能避免PEC沉淀。介质离子强度的增加加速了复合物的解离。壳聚糖甲基化和聚乙二醇化显著提高了胰岛素在PEC中的稳定性。此外，即使在50℃下至少6小时，PEC也能保护胰岛素不被降解。所有复合物都可以冻干，而不影响颗粒大小、复合物浓度和胰岛素的稳定性。根据我们的结果，我们认为PEC形成过程中涉及的相互作用主要是静电性质的，涉及壳聚糖带正电荷的氨基和高于其等电点带负电荷的胰岛素。将在体内研究聚电解质纳米复合物的鼻内吸收。
