Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Int J Pharm. 2012 Nov 15;438(1-2):217-24. doi: 10.1016/j.ijpharm.2012.08.045. Epub 2012 Aug 31.
The study was aimed to prepare a series of poly(acrylic acid)-cysteine-2-mercaptonicotinic acid conjugates (preactivated thiomers) and to evaluate the influence of molecular mass or degree of preactivation with 2-mercaptonicotinic acid (2MNA) on their permeation enhancing properties. Preactivated thiomers with different molecular mass and different degree of preactivation were synthesized and categorized on the basis of their molecular mass and degree of preactivation as PAA(100)-Cys-2MNA (h), PAA(250)-Cys-2MNA (h), PAA(450)-Cys-2MNA (h), PAA(450)-Cys-2MNA (m) and PAA(450)-Cys-2MNA (l). In vitro permeation studies, the permeation enhancement ability for preactivated thiomers was ranked as PAA(450)-Cys-2MNA (h)>PAA(250)-Cys-2MNA (h)>PAA(100)-Cys-2MNA (h) on both Caco-2 cell monolayers and rat intestinal mucosa. Comparing the influence of degree of preactivation with 2MNA on permeation enhancement, the following order PAA(450)-Cys-2MNA (h)>PAA(450)-Cys-2MNA (m)≈PAA(450)-Cys-2MNA (l) on Caco-2 cell monolayers and PAA(450)-Cys-2MNA (m)>PAA(450)-Cys-2MNA (h)>PAA(450)-Cys-2MNA (l) on intestinal mucosa was observed. The P(app) of sodium fluorescein was 5.08-fold improved on Caco-2 cell monolayers for PAA(450)-Cys-2MNA (h) and 2.46-fold improved on intestinal mucosa for PAA(450)-Cys-2MNA (m), respectively, in comparison to sodium fluorescein in buffer only. These results indicated that preactivated thiomers could be considered as a promising macromolecular permeation enhancing polymer for non-invasive drug administration.
本研究旨在制备一系列聚（丙烯酸）-半胱氨酸-2-巯基烟酸缀合物（预激活硫醇），并评价分子质量或与 2-巯基烟酸（2MNA）预激活程度对其渗透增强性能的影响。根据分子质量和预激活程度，合成了不同分子质量和不同预激活程度的预激活硫醇，并将其分为 PAA(100)-Cys-2MNA(h)、PAA(250)-Cys-2MNA(h)、PAA(450)-Cys-2MNA(h)、PAA(450)-Cys-2MNA(m)和 PAA(450)-Cys-2MNA(l)。体外渗透研究结果表明，在 Caco-2 细胞单层和大鼠肠黏膜上，预激活硫醇的渗透增强能力依次为 PAA(450)-Cys-2MNA(h)>PAA(250)-Cys-2MNA(h)>PAA(100)-Cys-2MNA(h)。比较 2MNA 预激活程度对渗透增强的影响，在 Caco-2 细胞单层上，其顺序为 PAA(450)-Cys-2MNA(h)>PAA(450)-Cys-2MNA(m)≈PAA(450)-Cys-2MNA(l)，在肠黏膜上，其顺序为 PAA(450)-Cys-2MNA(m)>PAA(450)-Cys-2MNA(h)>PAA(450)-Cys-2MNA(l)。与缓冲液中的荧光素钠相比，PAA(450)-Cys-2MNA(h)使荧光素钠在 Caco-2 细胞单层上的 P(app)提高了 5.08 倍，PAA(450)-Cys-2MNA(m)使荧光素钠在肠黏膜上的 P(app)提高了 2.46 倍。这些结果表明，预激活硫醇可以被认为是一种有前途的非侵入性药物给药的高分子渗透增强聚合物。
