Study On The Fast-acting Nano-formulation Of Zopiclone For Intranasal Administration

There are many obstacles to the drug treatment of central nervous system(CNS)diseases.Among them,the slow onset and low actual utilization due to the Blood-Brain Barrier(BBB)is the biggest problem.The special anatomical structure of the nasal cavity in mammals forms a pathway from the olfactory mucosa to the brain through the olfactory nerve,making it possible for medicines to bypass the BBB,so as to take effect quickly and improve the bioavailability.Moreover,medicines can be absorbed through the abundant capillary system of the nasal mucosa and rapidly enter into the blood circulation,avoiding the first-pass effect.Therefore,for the treatment of CNS diseases,nasal administration is considered to be a highly potential brain-targeted drug delivery strategy.Drugs need to dissolve and penetrate through the nasal mucosa to enter the nasalto-brain pathway.There have certain limitations such as limited administration volume,removal of medicines by cilia,and low medicine absorption rate.In recent years,it has been found that nanocrystallization of insoluble drugs can provide a large specific surface area to improve their dispersibility in aqueous solutions.Taking zopiclone as a model,this thesis studied the preparation and nasal delivery of zopiclone nano-formulations to explore the feasibility of nanomedicine into the brain through the nose-to-brain pathway.The specific research contents were as follows:(1)Exploration of the preparation methods of zopiclone nano-formulations:Zopiclone liposomes with phospholipids and cholesterol as the main membrane materials were prepared by the combination of thin-film dispersion and ultrasound method.The membrane material ratio,the number of ultrasonic treatments,the hydration time,and the hydration medium were changed to investigate the effects of different preparation schemes on the size of liposomes.The membrane filter method was used to separate the unencapsulated free drug to determine the encapsulation efficiency and drug loading of liposomes.Zopiclone liposomes with a particle size of about 170 nm with a polydispersity index of 0.326 were obtained.The encapsulation efficiency of zopiclone exceeded 80%,which met the requirements of pharmacopeia.L929 cells were used for preliminary safety analysis of zopiclone liposomes.The results have shown that the liposomes did not have significant cytotoxicity.Zopiclone liposomes were administered nasally to mice.Compared with the blank group,the drugloaded liposomes have shown obvious sedative and hypnotic effects,indicating that zopiclone retained its drug activity.(2)Preparation of zopiclone nanosuspension by the ultrasonic spray-precipitation method: To increase the drug content as much as possible,considering the preparation of carrier-free drug nanoparticles.Zopiclone nanosuspensions were prepared by the ultrasonic spray-precipitation method.The nanosuspensions were freeze-dried into powder,which could be re-dispersed to meet the drug concentration requirements of different administration volumes.The effects of the concentration of dispersant in the anti-solvent,the intensity of ultrasound,and the speed of the liquid feed on the particle size,potential,and drug content of the nanosuspension were investigated.After comprehensive consideration,zopiclone nanosuspension with a particle size of 192 nm with a polydispersity index of less than 0.2,and potential of-14.5 m V was selected for subsequent experiments,and the drug content was greater than 35 %.UV-vis spectroscopy,FTIR,DSC,XRD,and other techniques were used to characterize and analyze the zopiclone nanosuspension.The results have shown that the preparation process did not cause damage to the chemical structure of zopiclone,ensuring the drug activity in the nanosuspension.The results of simulated release in vitro have shown that compared with the raw material of zopiclone,nanosuspension can significantly improve the dissolution rate of zopiclone.Cytotoxicity and animal behavior experiments have shown that the zopiclone nanosuspension has great biocompatibility and drug activity,and has certain application potential.The efficacy and pharmacology of zopiclone nanosuspension were investigated by intranasal administration in mice.Behavioral experiments have shown that zopiclone nanosuspension can not only shorten the sleep latency,but also prolong the sleep time of mice,and has sedative and hypnotic effects.What’s more,behavioral experiments and blood concentration experiments had shown that for zopiclone nanosuspension,nasal administration has a faster effect than oral administration.It has been preliminarily proved that nasal administration can achieve the purpose of rapid onset of drugs for the treatment of CNS diseases.