Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Nagar, Punjab, 160062, India.
Department of Pharmaceutical Engineering and Technology, Indian Institutes of Technology, Banaras Hindu University, Varanasi, UP, 221005, India.
AAPS PharmSciTech. 2019 Feb 27;20(3):131. doi: 10.1208/s12249-019-1330-2.
In the present study, stable chitosan nanoparticles (Ch-NPs) were developed using the ionotropic gelation method, where poly(sodium 4-styrenesulfonate) (PSS) was used as a cross-linking agent while polyglutamic acid (PGA) for functionalization to improve the oral uptake through calcium-sensing receptors and amino acid transporters present in intestinal epithelium. Formulation was optimized by the design of experiments (DoE) approach using a three-level central composite design and characterized for in vitro parameters such as morphology, particle size, polydispersity index (PDI), entrapment efficiency and zeta potential. Morphological analysis demonstrated the formation of spherical NPs with particle size, zeta potential, and entrapment efficiency in the range of 210 nm ± 2.8 nm, 18.1 mV ± 0.14 mV, and 85.9% ± 0.28%, respectively. The developed NPs exhibited sustained release at different pH conditions and almost threefold higher uptake in comparison with non-functionalized NPs in Caco-2 cell uptake studies. In vivo studies in diabetic animals demonstrated low levels of plasma glucose for almost 24 h. Pharmacological availability (PA) of insulin administered through Ch-PSS-PGA NPs (17.28 ± 0.9) was significantly higher as compared to that of insulin administered through control NPs, i.e., Ch-PGA NPs (10.9 ± 1.5) and Ch-PSS NPs (12.9 ± 1.8). Data on hand suggest the ability of the developed NPs in overcoming the poor stability and, thus, poor therapeutic efficacy following oral administration.
在本研究中，采用离子凝胶法制备了稳定的壳聚糖纳米粒子（Ch-NPs），其中使用聚（4-苯乙烯磺酸钠）（PSS）作为交联剂，聚谷氨酸（PGA）作为功能化剂，以通过肠道上皮细胞中存在的钙敏感受体和氨基酸转运体来提高口服摄取率。通过使用三水平中心复合设计的实验设计（DoE）方法对制剂进行了优化，并对体外参数（如形态、粒径、多分散指数（PDI）、包封效率和 Zeta 电位）进行了表征。形态分析表明，形成了粒径、Zeta 电位和包封效率在 210nm±2.8nm、18.1mV±0.14mV 和 85.9%±0.28%范围内的球形 NPs。在不同 pH 条件下，所开发的 NPs 表现出持续释放，并且在 Caco-2 细胞摄取研究中与未功能化的 NPs 相比，摄取量增加了近三倍。在糖尿病动物体内研究中，发现 Ch-PSS-PGA NPs 给药后几乎 24 小时内血糖水平较低。通过 Ch-PSS-PGA NPs 给药的胰岛素的药物利用度（PA）（17.28±0.9）明显高于通过对照 NPs，即 Ch-PGA NPs（10.9±1.5）和 Ch-PSS NPs（12.9±1.8）给药的胰岛素。现有数据表明，所开发的 NPs 能够克服口服给药后稳定性差的问题，从而提高治疗效果。
