N-三甲基壳聚糖对胰岛素液体栓剂直肠吸收的促进作用研究

 目的研究不同季铵化程度及其不同浓度的N-三甲基壳聚糖(N-trimethyl chitosan,TMC)对胰岛素液体栓剂药物直肠吸收的影响。方法以壳聚糖及碘甲烷为主要原料合成两种季铵化程度的TMC,即TMC40和TMC60。以泊洛沙姆407(P407)和泊洛沙姆188(P188)(15%∶20%)为基质,分别以浓度为0,0.1%和0.5%的TMC40或TMC60作为黏膜吸收促进剂制备胰岛素液体栓剂。以2 g·kg^-1(相当于胰岛素200 U·kg^-1)给药剂量直肠给糖尿病小鼠不同的胰岛素液体栓剂,用血糖试纸测定给药后糖尿病小鼠不同时间点的血糖值,计算出各制剂的AUC_0→4,进行比较。结果未加TMC的胰岛素液体栓剂没有降血糖的作用;加入了TMC的液体栓剂均能显著降低糖尿病小鼠的血糖水平,且随着TMC浓度的增加,促进作用增强,而当浓度相同时,TMC60的作用大于TMC40,其中含有0.5%TMC60的胰岛素液体栓剂降血糖的作用最好,在1.5 h时血糖降至最低,为初始水平的(19.6±6.5)%,其AUC_0→4为(108.2±4.6)。结论TMC可以促进胰岛素的直肠吸收,且随着其季铵化程度的增加,其促吸收作用增强。

Effect of N-Trimethyl Chitosan on Rectal Absorption of Insulin Liquid Suppositories

OBJECTIVE To study the effect of degree of quaternization and concentration of N-trimethyl chitosan on the rectal absorption of insulin liquid suppositories.METHODS Two kinds of TMC with different degree of quaternization,i.e.TMC40 and TMC60,were synthesized by a two-step method using chitosan and methyl-iodide.P407 and P188(15/20%) were used as the base to prepare insulin liquid suppository with TMC40 or TMC60 at different concentration(0%,0.1%,0.5%) as the absorption enhancer.Liquid suppositories were rectally administered to diabetic mice with a dose of 2 g·kg^-1(equals to insulin 200 U·kg^-1),and then the blood glucose level in different time were determined by blood glucose test strip and calculated the AUC_0→4.RESULTS The liquid suppository without TMC had no hypoglycemic effect.All the liquid suppositories with TMC had significant hypoglycemic effect(P<0.05).With the increase of the TMC concentration,the enhancing effect decreased.At the same concentration,TMC60 had better hypoglycemic effect than TMC40.The liquid suppository with 0.5% TMC60 had the best hypoglycemic effect.At 1.5 h,the blood glucose level was at nadir with(19.6±6.5)% of the original blood glucose level.The AUC_0→4 was(108.2±4.6).CONCLUSION TMC could enhance the rectal absorption of insulin.The degree of quaternization and concentration of TMC could significantly influence on the rectal absorption of insulin.