Polnok A, Borchard G, Verhoef J C, Sarisuta N, Junginger H E
Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Eur J Pharm Biopharm. 2004 Jan;57(1):77-83. doi: 10.1016/s0939-6411(03)00151-6.
N-Trimethyl chitosan chloride (TMC) is a soluble chitosan derivative that shows effective enhancing properties for peptide and protein drug transport across mucosal membranes. TMC was synthesized by reductive methylation of chitosan in an alkaline environment at elevated temperature. The number of methylation process steps and the base used in the process was demonstrated to affect the degree of quaternization of the primary amino group and methylation of 3- and 6-hydroxyl groups. 1H-Nuclear magnetic resonance spectra showed that the degree of quaternization of TMC was higher when using sodium hydroxide as the base compared to using dimethyl amino pyridine. The degrees of quaternization as well as O-methylation of TMC increased with the number of reaction steps. O-Methylation resulted in decreased solubility of TMC. The high degree of quaternization of TMC with a low degree of O-methylation was prepared by employing one reaction step with two subsequent addition steps and a controlled alkaline environment of the mixture reaction.
N-三甲基壳聚糖氯化物（TMC）是一种可溶性壳聚糖衍生物，对肽和蛋白质药物跨粘膜转运具有有效的增强作用。TMC是通过壳聚糖在碱性环境中高温下的还原甲基化反应合成的。甲基化过程步骤的数量以及该过程中使用的碱被证明会影响伯氨基的季铵化程度以及3-和6-羟基的甲基化程度。1H-核磁共振光谱表明，与使用二甲基氨基吡啶相比，使用氢氧化钠作为碱时TMC的季铵化程度更高。TMC的季铵化程度以及O-甲基化程度随着反应步骤的数量而增加。O-甲基化导致TMC的溶解度降低。通过采用一个反应步骤、两个后续添加步骤以及对混合反应进行可控的碱性环境，制备了具有低O-甲基化程度的高季铵化程度的TMC。
