N-三甲基壳聚糖对尼美舒利脂质体凝胶大鼠体内药动学的影响

目的：研究N-三甲基壳聚糖（TMC）对尼关舒利（NIM）脂质体凝胶大鼠皮肤局部给药的药动学影响。方法：以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。以泊洛沙姆407为基质制备5份NIM脂质体凝胶，1份不加TMC为NIM组，另4份凝胶分别用TMC40和TMC60（1．0％）作为包衣和混合材料，分别为TMC40C组，TMC40B组及TMC60C组，TMC60B组。经皮给药后采用RP—HPLC法测定大鼠皮肤和血浆中的药物浓度，计算药动学参数，并进行比较。结果：TMC40、TMC60季铵化程度分别为38％和59％。皮肤中的AUC0→t;NIM组〉TMC60C组〉TMC40C组〉TMC60B组〉TMC40B组（P〈0．05）；皮肤中的Cmax;NIM组、TMC60C组和TMC40C组均明显大于TMC60B组和TMC40B组（P〈0．05）；血浆中的AUC0→t;TMC60C组〉TMC60B组〉TMC40C组〉TMC40B组〉NIM组（P〈0．05）；血浆中的Cmax：TMC60C组〉TMC60B组〉TMC40C组〉TMC40B组和NIM组（P〈0．05）（其中C代表包衣组，B代表混合组）。结论：TMC的季铵化程度和不同作用方式对NIM脂质体的透皮吸收有较显著的影响，可通过合理选择，达到不同的制剂目的。

Study on Pharmacokinetic of Nimesulide Lipogel Affected by N-trimethyl Chitosan in Rats

Objective： To study the pharmacokinetic of nimesulide lipogel affected by N-trimethyl chitosan （TMC） in rats. Method ： Two kinds of TMC with different degree of quaternization, i. e. TMC40 and TMC60, were synthesized by a two-step method using ehitosan and methyl-iodide. Five kinds of lipogels were prepared with poloxamer407 as base. One of the lipogels was the NIM group without TMC ,and the others were with TMC40 （ 1.0% ） and TMC60 （ 1.0% ） respectively as coating or blending materials i. e. TMC40C group ,TMC40B group ,TMC60C group and TMC60B group, respectively. The plasma concentrations of nimesulide were determined using RP-HPLC method, and the pharmacokinetic parameters were calculated to estimate the influence of TMC. Result： The degree of quaternization of TMC40 and TMC60 was 38% and 59% , respectively. The main pharmacokinetie parameters of AUC0→t, and Cmax were compared, and significant differences were found. The order of AUC0→t of skin was NIM group 〉 TMC60C group 〉 TMC40C group 〉 TMC60B group 〉 TMC40B group （ P 〈 0. 05 ）. Cmax of skin was that NIM group, TMC60C group, TMC40C group all had significant differences with TMC60B group and TMC40B group （ P 〈 0.05 ）. The order of AUC0→t of plasma was TMC60C group 〉 TMC60B group 〉 TMC40C group 〉 TMC40B group 〉 NIM group （ P 〈 0. 05 ） ; and the order of Cmax in plasma was TMC60C group 〉 TMC60B group 〉 TMC40C group 〉 TMC40B and NIM groups （P 〈0. 05）. Conclusion： The NIM lipogels could be affected by the degree of quatemization of TMCs and their effect ways significantly.