Hamman J H, Kotzé A F
Department of Pharmaceutics, School of Pharmacy, Faculty of Health Sciences, Potchefstroom University for Christian Higher Education, South Africa.
Drug Dev Ind Pharm. 2001 May;27(5):373-80. doi: 10.1081/ddc-100104312.
N-Trimethyl chitosan chloride (TMC), a chemically modified derivative of chitosan, is the first chitosan derivative shown to be an effective absorption enhancer for peptide and protein drugs across mucosal epithelia. TMC is synthesized by reductive methylation with methyl iodide in the presence of a strong base such as sodium hydroxide. In this reaction, the primary amino group on the C-2 position of chitosan is changed to a quaternary amino group. The charge density, as determined by the degree of quaternization, and probably also the molecular weight of TMC are important factors that influence the absorption enhancement effect and toxicity of this polymer. The molecular weight of the starting polymer decreases during the synthesis procedure due to factors such as the strong alkaline environment and elevated experimental temperatures. This study investigated the effects of two different bases, sodium hydroxide and dimethyl amino pyridine, together with a varying number and duration of reaction steps, on the degradation and the degree of quaternization of TMC polymers. 1H-NMR (nuclear magnetic resonance) spectra showed a major increase in the degree of quaternization (21%-59%) of TMC with an increase in the number of reaction steps when sodium hydroxide was used as the base. Intrinsic viscosity values indicated that the use of dimethyl amino pyridine did not cause polymer degradation to the same extent as sodium hydroxide, but that the degree of quaternization of TMC stayed low (7.3%-9.6%) even when the number of reaction steps was increased. A combination of the two bases did not reduce polymer degradation, while the degree of quaternization was limited to relatively low values (12.5%-34.4%).
N-三甲基壳聚糖氯化物（TMC）是壳聚糖的一种化学修饰衍生物，是首个被证明可有效增强肽类和蛋白质药物跨黏膜上皮吸收的壳聚糖衍生物。TMC是在强碱（如氢氧化钠）存在下，通过与碘甲烷进行还原甲基化反应合成的。在该反应中，壳聚糖C-2位上的伯氨基转变为季铵基。由季铵化程度决定的电荷密度以及TMC的分子量可能也是影响该聚合物吸收增强效果和毒性的重要因素。由于强碱环境和实验温度升高等因素，起始聚合物的分子量在合成过程中会降低。本研究考察了两种不同的碱（氢氧化钠和二甲基氨基吡啶）以及不同反应步骤数和反应持续时间对TMC聚合物降解和季铵化程度的影响。1H-NMR（核磁共振）光谱显示，当使用氢氧化钠作为碱时，随着反应步骤数增加，TMC的季铵化程度大幅提高（21%-59%）。特性粘度值表明，使用二甲基氨基吡啶不会像氢氧化钠那样导致聚合物发生同等程度的降解，但即便增加反应步骤数，TMC的季铵化程度仍保持在较低水平（7.3%-9.6%）。两种碱联合使用并未降低聚合物降解程度，而季铵化程度则被限制在相对较低的值（12.5%-34.4%）。
