Preparation Of Nasal Zolmitriptan Liposome In Situ Gel And Evaluation Of Its Brain-Targeting And Pharmacokinetics

Objective:Migraine is a very common neurovascular disease,the etiology is complex,the mechanism has not been fully elucidated.Triptans,which work by targeting serotonin receptors(5-HT1B and 5-HT1D),are commonly used in the clinical treatment of migraine.However,the bioavailability of these drugs is low,and the lipid solubility is low,so it is difficult to cross the blood-brain barrier,which affects the clinical efficacy.This study intends to use the liposome drug delivery system to prepare the zolmitriptan liposome,and further prepare the nasal in-situ gel preparation,and study its safety,efficacy,pharmacokinetics and brain targeting characteristics.Methods:Zolmitriptan liposomes were prepared by thin film ultrasonic dispersion method and characterized by HPLC.The in-situ gel preparation of zolmitriptan liposome was prepared by using deacetylated gellan gum as gel matrix,and its stability,dissolution rate and in vitro release were studied.The toxicity test of toad maxillary mucosa cilia in vivo and the histopathological examination of rat nasal cavity were used to investigate the safety of the preparation.Nitroglycerin induced migraine rat model was used to evaluate the efficacy of the preparation on migraine.The pharmacokinetic characteristics and brain targeting of zolmitriptan liposome in situ gel preparation were investigated with zolmitriptan solution given via caudal vein as control.Results:1.The particle size of the prepared zolmitriptan liposome was less than 200 nm,the distribution was relatively uniform,and the encapsulation rate was more than 80%.2.When the in-situ gel preparation prepared by mixing deacetylated gellan gum(concentration 0.5%)with zolmitriptan liposome solution was stored at 4℃ for 28 days,the encapsulation efficiency did not decrease significantly,and the pH value and appearance did not change significantly.In vitro drug release test showed that the cumulative release rate was less than 50.0%for 2 h and 73.7%for 8 h.3.Zolmitriptan liposome in-situ gel preparation treatment had no significant effect on the continuous swinging time of toad maxillary mucosal cilia;Zolmitriptan liposome in-situ gel preparation was used in the nasal cavity of rats for 7 consecutive days,and no nasal mucosal damage was found by pathological examination.4.Intranasal administration of zolmitriptan liposome in-situ gel significantly improved the migraine symptoms of nitroglycerin-induced migraine rats,significantly reduced the contents of CGRP in plasma and brain,and significantly increased the content of 5-HT in migraine rats.5.Compared with the intravenous administration of zolmitriptan solution,the elimination half-life of zolmitriptan in plasma and brain was 1.60 and 2.32 times longer after intranasal administration of zolmitriptan solution,and the brain targeting index reached 10.53.Conclusion:In this study,the preparation of Zolmitriptan liposome in-situ gel for nasal use has the characteristics of safety,high efficiency,long-term effect and significant brain targeting.