Etomidate-loaded Pluronic F108 Polymeric Micelles:preparation And In Vivo/Vitro Evaluation

ObjectA novel etomidate micelle solution was prepared using Pluronic F108 amphiphilic polymer as carrier and containing the model drug etomidate.The evaluation of its in vitro and in vivo properties,in vivo efficacy and safety in vivo was also studied.Method?1?Etomidate-loaded Pluronicc Micelles?Eto-SOPM?were prepared by using the thin-film hydration method.?2?The preparation of drug-loaded micelles Eto-SOPM,through orthogonal experiment with the encapsulation efficiency as the evaluation index,optimize the preparation process and formulation.?3?The morphological size,particle size distribution,zeta potential,drug entrapment efficiency,drug loading,and micellar morphology and structure of the micelles were evaluated by means of transmission electron microscopy,dynamic light scattering,and ultraviolet spectrophotometry.The drug release in vitro of ETO-SOPM in pH=7.3 environment was investigated.?4?The median effective dose(ED₅₀)and median lethal dose(LD₅₀)of Eto-SOPM were measured sequentially and the therapeutic index(TI=LD₅₀/ED₅₀)was calculated to evaluate the efficacy and safety of Eto-SOPM.To observe the sedative and hypnotic effects and safety of rats after intravenous injection of Eto-SOPM.?5?The acute toxicity and subacute toxicity of rats after administration were observed.The effects of continuous infusion of Eto-SOPM and etomidate emulsion Injection on adrenal cortex function in rats were observed.Results?1?The average entrapment efficiency of Eto-SOPM prepared at the best place was?87.01±0.70?%,and the average drug loading was?6.73±0.05?%.The results of TEM and DLS showed that the synthesis of Eto-SOPM was successful.?2?The transmission electron microscopy?TEM?showed that Eto-SOPM was well-formed,spherical or spheroid-like,uniformly distributed,with an average particle size of?109.23±0.81?nm,uniform size,PDI?0.296±0.049?,and average zeta potential??1.909±1.029?mV,negatively charged.?3?In vitro drug release experiments showed that the release rate of etomidate in Eto-SOPM micelle was faster,and the average cumulative release after 4 hours was close to 80%,which was significantly higher than the cumulative release of etomidate emulsion injection..Released rapidly under PH=7.3 environment,and the cumulative release increased,and the release basically accorded with the Weibull equation.?4?The ED₅₀0 and LD₅₀0 of Eto-SOPM was measured by up-and-down method in rats.The ED₅₀[95%CI]of intravenous injection of Eto-SOPM was 0.68[0.59⁰.77]mg/kg,the LD₅₀[95%CI]was 20.24[18.20²2.28]mg/kg,and the TI was 29.76,not statistically significant compared with etomidate emulsion?P>0.05?.?5?Both Eto-SOPM and etomilace emulsion were able to work quickly after intravenous injection,but the sedative and hypnotic maintenance time of rats in the Eto-SOPM group was?514.35±27.23?s,and they recovered from righting reflexes to standing time was?86.95±20.93?s.Compared with etomidate emulsion injection,the anesthesia maintenance and recovery time of rats were significantly shortened?P<0.05?.?6?Pathological results showed no abnormalities in the brain,kidney,and adrenal gland tissues of the rats administered with acute toxicity test in both groups.Compared with the normal control group,single intravenous injection of LD₅₀0 Eto-SOPM and etomidate emulsion have different degrees of cardiotoxicity,liver toxicity and lung injury.Pathological results in the subacute toxicity test showed that there were cardiotoxicity and pulmonary interstitial fibrosis in both groups of rats,and no abnormalities were found in other organs.?7?The two groups of rats were continuously infused with Eto-SOPM and etomidate emulsion injection for 3 hours.There was no difference in cortisol and adrenocorticotropic hormone concentrations between the two groups at each time point.However,the concentration of cortisol in the two groups of rats was significantly lower than that of the infusion before continuous infusion for 3 hours?P<0.05?,but both of them basically recovered to the previous level at 24 hours after the administration.ConclusionThe Eto-SOPM micelles have been successfully prepared in this study.The preparation process is simple and feasible and Eto-SOPM is spherical or spheroidal with small and uniform particle size.Eto-SOPM micelles can rapidly release the drug while effectively solubilizing etomidate,and have a rapid anesthetic effect and a short recovery time after anesthesia,which is consistent with the requirements of general anesthetics.Eto-SOPM has good safety and little toxic side effects.These results show that Eto-SOPM is a promising agent for short-acting general anesthesia with etomidate and is worthy of further study in the future.