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目的:研究N-三甲基壳聚糖(TMC)对尼美舒利(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AUC_(0→1):NIM组>TMC60C组>TMC40C组>TMC60B组>TMC40B组(P<0.05);皮肤中的C_(max):NIM组、TMC60C组和TMC40C组均明显大于TMC60B组和TMC40B组(P<0.05);血浆中的AUC_(0→1):TMC60C组>TMC60B组>TMC40C组>TMC40B组>NIM组(P<0.05);血浆中的C_(max):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。
OBJECTIVE: To study the pharmacokinetics of N-trimethyl chitosan (TMC) on topical skin administration of nimesulide (NIM) liposome gel in rats. Methods: Chitosan and methyl iodide were used as main raw materials to synthesize TMC with quaternization degree of 40% and 60% respectively, namely TMC40 and TMC60. Five polydipsims NIM liposomes were prepared with Poloxamer 407 as substrate, one without TMC as NIM group and the other four with TMC40 and TMC60 (1.0%) as coating and mixing materials respectively TMC40C group, TMC40B group and TMC60C group, TMC60B group. The drug concentration in the skin and plasma of rats was determined by RP-HPLC after transdermal administration. The pharmacokinetic parameters were calculated and compared. Results: The quaternization degree of TMC40 and TMC60 were 38% and 59% respectively. The AUC_ (0 → 1) in the skin: NIM group> TMC60C group> TMC40C group> TMC60B group> TMC40B group (P <0.05); skin Cmax: the NIM group, TMC60C group and TMC40C group were significantly greater than TMC60B (0 → 1) in plasma: TMC60C group> TMC60B group> TMC40C group> TMC40B group> NIM group (P <0.05); plasma Cmax: TMC60C group > TMC60B group> TMC40C group> TMC40B group and NIM group (P <0.05) (where C represents a coating group and B represents a mixed group). Conclusion: The degree of quaternization and different modes of action of TMC have a significant impact on the transdermal absorption of NIM liposomes, which can be achieved through reasonable choice.