N-三甲基壳聚糖对睾酮凝胶在兔体内药动学的作用研究

 目的研究N-三甲基壳聚糖(N-trimethyl chitosan,TMC)对睾酮凝胶在兔体内药动学的作用,考察TMC的透皮吸收促进作用效果。方法用壳聚糖及碘甲烷为主要原料,合成季铵化程度分别为40%和60%的TMC,即TMC40和TMC60,通过¹H-NMR确定其季铵化程度。以泊洛沙姆P407为基质制备4份凝胶,以睾酮为模型药物,以月桂氮酮(2%)为阳性对照,以不加促渗剂为阴性对照,另两份凝胶分别含TMC40和TMC60各5%作为促渗剂。经皮给药后采用RP-HPLC测定兔血浆中的睾酮浓度,计算药动学参数,对4种凝胶进行比较,考察TMC40,TMC60的促渗效果。结果经1H-NMR确定合成得到的TMC40,TMC60季铵化程度分别为38.8%和67.2%。主要药动学参数t_max,ρ_max,K_a,AUC经方差分析及双单侧t检验后,TMC60较空白组及月桂氮酮组各参数均具有显著性差异(P<0.05),TMC40较空白组有明显促进作用(P<0.05),较月桂氮酮组除参数K_a外无显著性差异(P>0.05)。结论TMC60具有显著的促进睾酮凝胶透皮吸收作用,TMC40较空白组促进吸收作用明显,但效果与2%月桂氮酮相比无显著性差异。

Pharmacokinetic Study on Testosterone Gel Enhanced by N-Trimethyl Chitosan in Rabbits

OBJECTIVE To study the pharmacokinetics of testosterone gel enhanced by N-trimethyl chitosan(TMC) in rabbits and to estimate the penetration enhancement effect of TMC.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.The degree of quaternization of TMC was determined by 1H-NMR.Four kinds of gels were prepared using testoterone as model drug.Azone(2%) were used as penetration enhancer in the positive control group.No enhancer was used in the blank control.TMC40(5%) and TMC60(5%) was used as penetration enhancer respectively in the other two groups.Plasma concentrations of testosterone were determined using RP-HPLC method.Pharmacokinetic parameters were calculated to estimate the influence of TMC on penetration enhancement.RESULTS The degree of quaternization of TMC40 and TMC60 were 38.8% and 67.2%,respectively.The main pharmacokinetic parameters were compared by t test.The pharmacokinetic parameters of TMC60 showed significant differences compared with both Azone and the blank control(P<0.05),as well as TMC40 compared with the blank control (P<0.05).However,no significant difference was found between TMC40 and Azone group except the parameter K2a(P>0.05).CONCLUSION TMC60 has significant penetration enhancement on the transdermal delivery of testosterone gel.The penetration enhancement of TMC40 is stronger than that of the blank control significantly,however the difference is not significant compared with Azone(2%).