Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
J Control Release. 2011 Jan 5;149(1):81-8. doi: 10.1016/j.jconrel.2010.02.001. Epub 2010 Feb 6.
The feasibility of combining safe permeation enhancers in a mucoadhesive particulate system for the oral delivery of peptide drugs was investigated in this study. Polyelectrolyte complex nanoparticles (NPs) were prepared by ionic interaction of spermine (SPM) with polyacrylic acid (PAA) polymer. Cytotoxicity studies in Caco-2 monolayers revealed the safety of the delivery system in the concentration range used for permeation enhancement. The cellular transport of fluorescein isothiocyanate dextran (FD4) showed higher permeation enhancing profiles of SPM-PAA NPs, as compared to SPM solution or PAA NPs prepared by ionic gelation with MgCl(2) (Mg-PAA NPs). These permeation enhancing effects were associated with a reversible decrease in TEER values, suggesting a paracellular permeation pathway by reversible opening of the tight junctions. Furthermore, confocal microscopy results revealed strong association of the NPs prepared using fluorescence labeled PAA to Caco-2 cells. The permeation enhancing properties of SPM-PAA NPs were further evaluated in vivo after oral administration to rats, using FD4 and calcitonin as models of poorly permeating drugs. Confocal microscopy images of rats' small intestine confirmed previous findings in Caco-2 cells and revealed a strong and prolonged penetration of FD4 from the mucosal to the basolateral side of the intestinal wall. In addition, the proposed NPs were efficient in improving the oral absorption of calcitonin, as evidenced by the significant and prolonged reduction of the blood calcemia in rats.
本研究旨在探讨将安全渗透增强剂与黏膜黏附性微粒系统相结合，以实现肽类药物经口服递药的可行性。采用静电相互作用制备了聚阳离子（精胺，SPM）与聚阴离子（聚丙烯酸，PAA）聚合物的纳米粒（NPs）。在 Caco-2 单层细胞中的细胞毒性研究显示，在用于增强渗透的浓度范围内，该递药系统是安全的。荧光素异硫氰酸酯标记的葡聚糖（FD4）的细胞转运实验表明，与 SPM 溶液或用 MgCl2（Mg-PAA NPs）进行离子凝胶化制备的 PAA NPs 相比，SPM-PAA NPs 具有更高的渗透增强特性。这些渗透增强作用与 TEER 值的可逆降低有关，提示通过紧密连接的可逆开放存在经细胞旁途径的渗透。此外，共聚焦显微镜结果表明，用荧光标记的 PAA 制备的 NPs 与 Caco-2 细胞强烈结合。通过将 FD4 和降钙素作为渗透较差药物的模型，在大鼠口服给予 SPM-PAA NPs 后，进一步评估了其渗透增强特性。大鼠小肠的共聚焦显微镜图像证实了 Caco-2 细胞中的先前发现，并显示出 FD4 从黏膜侧至肠壁基底外侧侧的强烈和持续渗透。此外，所提出的 NPs 能够有效地提高降钙素的口服吸收，这可从大鼠血液钙降低的显著和持续时间延长得到证明。
