Yin Lifang, Wang Yong, Wang Cuifeng, Feng Min
Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou, 510006, People's Republic of China.
AAPS PharmSciTech. 2017 Aug;18(6):2329-2335. doi: 10.1208/s12249-016-0709-6. Epub 2017 Jan 23.
Most therapeutic proteins are classified as class III drugs according to the Biopharmaceutical Classification System means that the low permeability across the intestinal epithelium is the rate-limited step for their oral absorption. Cationic chitosan nanoparticles have been found to open the tight junctions between epithelial cells. On the other hand, bioadhesive delivery devices could prolong the gastrointestinal residence time. In the present study, we developed a novel nano-reservoir bioadhesive tablets that combining the advantages of cationic nanoparticles and bioadhesive delivery devices anticipated achieving effective transport of sufficient protein drugs across the intestinal epithelium. The nano-reservoir in bioadhesive tablets was composed of chitosan nanoparticles (CS-NPs) loading a model protein drug bovine serum albumin (BSA). The formula of bioadhesive tablets was optimized by using rotatable central composite design and response surface methodology. The nano-reservoir, BSA-loaded CS-NPs, had an average particle diameter of 312.5 ± 12.89 nm and zeta-potential value of 26.76 ± 3.56 mV. Carboxymethyl chitosan added to the formula significantly ameliorated the tight junction damage of the Caco-2 cell monolayer induced by CS-NPs, meanwhile maintained the high transport efficiency of BSA. Permeability study exhibited that these nano-reservoir bioadhesive tablets combining the advantages of cationic nanoparticles and bioadhesive tablets significantly enhanced BSA transport through rabbit small intestine in comparison with either conventional bioadhesive tablets or CS-NPs. Therefore, these nano-reservoir bioadhesive tablets provided a great potential dosage form design for the oral delivery of protein drugs.
根据生物药剂学分类系统，大多数治疗性蛋白质被归类为III类药物，这意味着其跨肠上皮的低渗透性是口服吸收的限速步骤。已发现阳离子壳聚糖纳米颗粒可打开上皮细胞之间的紧密连接。另一方面，生物黏附递送装置可延长胃肠道停留时间。在本研究中，我们开发了一种新型的纳米储库生物黏附片，它结合了阳离子纳米颗粒和生物黏附递送装置的优点，预期可实现足够量的蛋白质药物有效穿过肠上皮的转运。生物黏附片中的纳米储库由负载模型蛋白质药物牛血清白蛋白（BSA）的壳聚糖纳米颗粒（CS-NPs）组成。采用旋转中心复合设计和响应面方法对生物黏附片的配方进行了优化。纳米储库，即负载BSA的CS-NPs，平均粒径为312.5±12.89 nm，ζ电位值为26.76±3.56 mV。添加到配方中的羧甲基壳聚糖显著改善了CS-NPs诱导的Caco-2细胞单层紧密连接损伤，同时保持了BSA的高转运效率。渗透性研究表明，与传统生物黏附片或CS-NPs相比，这些结合了阳离子纳米颗粒和生物黏附片优点的纳米储库生物黏附片显著增强了BSA通过兔小肠的转运。因此，这些纳米储库生物黏附片为蛋白质药物的口服递送提供了一种极具潜力的剂型设计。
