Bernkop-Schnürch Andreas, Weithaler Andrea, Albrecht Karin, Greimel Alexander
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef-Möller-Haus, 6020 Innsbruck, Austria.
Int J Pharm. 2006 Jul 6;317(1):76-81. doi: 10.1016/j.ijpharm.2006.02.044. Epub 2006 Apr 3.
It was the aim of this study to develop a mucoadhesive nanoparticulate delivery system. Nanoparticles were generated by in situ gellation of the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) with tripolyphosphate (TPP) followed by stabilization via the formation of inter- and intrachain disulfide bonds by oxidation with H(2)O(2) in various concentrations. Afterwards TPP was removed by exhaustive dialysis at pH 1-2. Incorporation of the model compound fluorescein diacetate (FDA) was achieved by incubation of this fluorescence marker, dissolved in acetonitrile, with aqueous particle suspensions for 1h at room temperature. Mucoadhesion studies were performed on porcine intestinal mucosa. Results showed that the preparation method described above leads to nanoparticles of a mean diameter of 268+/-15 nm and a FDA load of 2%. Due to the removal of the anionic crosslinker TPP, the zeta potential of the nanoparticles was raised from 4+/-1 up to 19+/-2 mV without loosing stability of the nanoparticles. The more H(2)O(2) was added to the particles, the more inter- and intrachain disulfide bonds were formed. The more thiol groups were oxidized within the particles, however, the lower was the improvement in mucoadhesive properties. Nevertheless, even when 91% of all thiol groups on the nanoparticles were oxidized, their mucoadhesive properties were still twice as high as the mucoadhesive properties of unmodified nanoparticles. Thiolated chitosan nanoparticles show a two-fold higher zeta potential (I), improved stability (II) and more than doubled mucoadhesive properties (III) than corresponding unmodified chitosan nanoparticles. Therefore, they seem to be advantageous over ionically crosslinked chitosan nanoparticles.
本研究的目的是开发一种粘膜粘附纳米颗粒递送系统。通过硫醇化壳聚糖-4-硫代丁脒（壳聚糖-TBA）与三聚磷酸钠（TPP）原位凝胶化生成纳米颗粒，随后通过用不同浓度的H₂O₂氧化形成链间和链内二硫键来实现稳定化。之后，通过在pH 1-2下进行彻底透析去除TPP。通过将溶解在乙腈中的荧光标记物荧光素二乙酸酯（FDA）与水性颗粒悬浮液在室温下孵育1小时来实现模型化合物的包封。在猪肠粘膜上进行粘膜粘附研究。结果表明，上述制备方法可得到平均直径为268±15 nm且FDA负载量为2%的纳米颗粒。由于去除了阴离子交联剂TPP，纳米颗粒的ζ电位从4±1 mV提高到19±2 mV，而纳米颗粒的稳定性并未丧失。向颗粒中添加的H₂O₂越多，形成的链间和链内二硫键就越多。然而，颗粒内被氧化的巯基越多，粘膜粘附性能的改善就越低。尽管如此，即使纳米颗粒上91%的巯基被氧化，其粘膜粘附性能仍比未修饰的纳米颗粒高两倍。硫醇化壳聚糖纳米颗粒的ζ电位（I）比相应的未修饰壳聚糖纳米颗粒高两倍，稳定性（II）得到改善，粘膜粘附性能（III）增加了一倍多。因此，它们似乎比离子交联壳聚糖纳米颗粒更具优势。
