N-三甲基壳聚糖对苯甲酸利扎曲普坦鼻腔吸收的促进作用及安全性评价

Absorption Enhancement and Safety Evaluation of N-Trimethyl Chitosan for Rizatriptan Benzoate Nasal Determination

目的:对N-三甲基壳聚糖(TMC)作为鼻腔给药系统吸收促进剂的作用及安全性进行评价。方法:以苯甲酸利扎曲普坦(RB)为模型药物,采用大鼠在体鼻腔循环法,以RB药液为阴性对照,以含0.5%羧甲基壳聚糖(CMCS)RB药液为阳性对照,对含同用量、不同季铵化程度TMC(TMC20、TMC40、TMC60)的RB药液进行鼻腔吸收实验,筛选出最佳的TMC季铵化程度,同时对筛选出的最佳TMC进行最佳用量的优选,并以生理盐水为阴性对照,1%去氧胆酸钠为阳性对照,对其大鼠鼻黏膜刺激性及对蟾蜍纤毛的影响进行考察。结果:与RB药液相比,0.5%CMCS及3种TMC均对RB鼻腔吸收有明显的吸收促进作用,与CMCS相比,TMC20促进作用较弱(P<0.05),TMC40及TMC60均呈现更大的吸收促进作用(P<0.05),且TMC60作用强于TMC40(P<0.05)。随着TMC60用量的增加,促进吸收作用越大,但1.0%与1.5%TMC60之间差异无统计学意义(P>0.05)。与生理盐水及RB药液相比,1.0%TMC60对大鼠鼻粘膜及蟾蜍纤毛运动均无明显影响(P>0.05)。结论:TMCs具有较好的RB鼻腔吸收促进作用,且以1.0%TMC60最佳,同时安全性较好,值得进一步研究。

Objective:To explore the nasal absorption enhancement and safety of N-trimethyl chitosan(TMC).Methods:Rizatriptan benzoate(RB)was used as the model drug.Nasal circulatory test in rats was carried out with RB solution as the negative control and 0.5%carboxymethyl chitosan(CMCS)RB solution as the positive control,and the absorption enhancement of TMCs(TMC20,TMC40 and TMC60)with various quaternization degrees at the same amount was studied to screen out the optimal TMC.Meanwhile,the optimal amount of the best TMC was investigated.The influences of the best TMC at the optimal amount on the nasal mucosa of rats and the movement of toad palate cilia were also explored with saline as the negative control and 1%sodium deoxycholate as the positive control.Results:Compared with RB solution,0.5%CMCS and the three TMCs all showed significant RB nasal absorption enhancement.Compared with that of CMCS,RB nasal absorption enhancement of TMC20 was weaker(P<0.05),while that of TMC40 and TMC60 was stronger(P<0.05),and that of TMC60 was the best(P<0.05).With the increase of TMC60 amount,the enhancement was stronger,while there was no notable difference between 1.0%TMC60 and 1.5%TMC60(P>0.05).Compared with saline and RB solution,1.0%TMC60 showed no significant influences on the nasal mucosa of rats and the movement of toad palate cilia(P>0.05).Conclusion:TMCs show promising RB nasal absorption enhancement and 1.0%TMC60 is the best with good safety,which is valuable to be studied further.