Study On Intranasal Awakening Drug-loaded Hydrogels

Objective:In response to sleep deprivation,a first-generation wake-up drug caffeine temperature-sensitive gel and a second-generation wake-up drug armodafinil nanocrystalline hydrogel were prepared in this paper,which were administered through the nasal mucosa to investigate the nasal delivery effect on sleep deprivation rats' cognitive function,verify the targeting and high efficiency of nasal drug delivery in the treatment of central nervous system diseases.Methods:The caffeine was mixed with poloxamers 407 and 188 in different proportions to prepare caffeine temperature-sensitive gel,and its properties such as rheology,in vitro release,and nasal irritation were investigated.The orthogonal design was used to optimize the formulations.Armodafinil nanocrystalline hydrogels were prepared by the antisolvent precipitation and lyophilization process.Its particle size,potential,rheology,crystallography,in vitro nasal mucosa,nasal cavity retention time,and irritation of the nasal mucosa were investigated.A 72-hour sleep deprivation model was established using a sleep deprivation instrument.Caffeine temperature-sensitive gel and armodafinil nanocrystalline hydrogel were delivered nasally.In other behavioral experiments,observe the H.E.pathological sections of different hippocampal divisions,detect the expression of BDNF protein in the hippocampal tissue,and verify its pharmacodynamic effects against sleep deprivation and maintaining cognitive function.LC-MS/MS technology was used to compare the plasma and brain drug distribution in rats after oral and nasal administration of the same dose of armodafinil,and to verify the target of maintaining the cognitive function of rats by armodafinil nasal delivery orientation and efficiency.Results:The caffeine temperature-sensitive gel is temperature-sensitive at 35?of the nasal cavity,which release rate in vitro is relatively slow,and no irritation of the nasal mucosa.Armodafinil nanocrystals have a particle size of about 100 nm and a potential of about-35 m V.They have a certain viscoelasticity,are easily retained in the nasal cavity.Armodafinil nanocrystals have high gel dissolution,fast nasal mucosal penetration rate in vitro,no nasal mucosal irritation.The Morris water maze experiment showed that both the caffeine temperature-sensitive gel and the armodafinil nanocrystalline hydrogel can significantly reduce the sleep escape latency,increase the number of platform crossings,effectively improve the learning ability and cognitive levels of sleep deprived rats.Open field experiments show that both the caffeine temperature-sensitive gel and the armodafinil nanocrystalline hydrogel can increase the central movement distance and the number of uprights,effectively improve the spontaneous activity and exploration behavior of sleep deprived rats.However,the fecal index indicates that caffeine temperature-sensitive gels significantly increased anxiety behaviors in rats with sleep deprivation,while armodafinil had the opposite effect.Elevated plus maze and antisedation and hypnosis experiments show that caffeine temperature-sensitive gel can significantly improve the excitability of sleep deprivation rats.Observation of H.E.pathological sections in different regions of the hippocampus showed that both the caffeine temperature-sensitive gel and the armodafinil nanocrystalline hydrogel had certain protective effects on hippocampal neuron cells.The results of BDNF protein detection indicated that the protective effect of armodafinil nanocrystal hydrogel on hippocampal neurons may be related to the specific increase of BDNF expression.Pharmacokinetics and tissue distribution experiments prove that compared with oral administration,nasal delivery of armodafinil nanocrystalline hydrogels has a short peak time of the drug in the plasma,high peak concentration,and high brain tissue distribution,which fully proves that the efficient and targeted drug delivery.Conclusion:Nasal delivery of caffeine temperature-sensitive gel and armodafinil nanocrystalline hydrogel can effectively improve the cognitive level of sleep deprived rats,and has the advantages of high safety,high targeting,and high efficiency,expanding clinical applications new dosage form.