Synthesis Of Non-spherical Dexamethasone Microcrystalline Sustained-release Formulation And Its Local Delivery In The Inner Ear

Sudden sensorineural hearing loss now appears to affect populations that are young,professional and social,and seriously influence their life quality and professional performances.However,the clinical administration routes,drug types and therapeutic efficacy are restricted by the blood-labyrinth barrier and common diseases such as hypertension and diabetes.In order to reduce the side effects of hormones and cross the inner ear barrier reasonably,based on the clinical practice,we synthesized dexamethasone(DEX)diamond-shaped microcrystals using precipitation method followed by alternate deposition of poly(L-lysine)(PLL)and silk fibroin(SF)via LbL assembly,the physicochemical properties including the shape,crystal form,dispersity,dissolution or sustained release,of DEX MCs and DEX-(PLL/SF)3 were investigated.The distribution of DEX on the RWM,in vivo pharmacokinetics and tissue histology were evaluated using guinea pigs as well.The main research in this dissertation is as following:1.The diamond-shaped DEX MCs were synthesized by precipitation method.We investigated the effect of parameters on the shape and size of DEX MCs including PVA concentrations,stirring speed,solvent volume ratio and temperature and solvent type.Finally,the optimized diamond-shaped DEX MCs were obtained with a size of about 7.68 μm and a thickness of about 750 nm.And the DEX polymorphic transformation occurred from crystal form A to B during the process of precipitation.DEX-(PLL/SF)3 was prepared followed by alternate deposition of PLL and SF via electrostatic force-driven LbL assembly on the DEX MCs.Compared to raw DEX,DEX MCs and DEX-(PLL/SF)3 could be uniformly dispersed,DEX MCs had faster dissolution rate and DEX-(PLL/SF)3 formulation was completely released within 2 days.2.In vivo animals’ experiments,after IT administration of DEX-(PLL/SF)3 in guinea pigs,the distribution of DEX-(PLL/SF)3 was uniform on the RWM.The pharmacokinetics profiles of DEX-(PLL/SF)3 in vivo showed that the water-insoluble DEX suspension could delivery DEX sustainably into inner ear.And increased concentration of DEX treatment resulted in higher perilymph DEX levels and prolonged duration of exposure.3.The biocompatibility of DEX-(PLL/SF)3 after IT administration was good.Compared to the control group,the tight junction and microvilli on the RWM and stria vascular(SV)of DEX-(PLL/SF)3 group had no morphology change.The cochlear hair cells were well maintained and the stereociliary bundles were regularly arranged and had no pathological changes-Besides,the histological results verified that cochlear tissues had no inflammatory responses.