Preparation And Pharmacokinetics Of Febuxostat Solid Self-microemulsion

Objective Febuxostat is a xanthine oxidase inhibitor.Compared with other anti-gout drugs,its pharmacological activity is mainly through acting on the molybdopterin center of xanthine oxidase,thereby reducing the production of uric acid and achieving the treatment of hyperuric acid.The role of blood disease and gout.However,due to the low solubility of febuxostat in water,its oral bioavailability is low,and the clinical effect is not significant.This experiment intends to prepare it into a solid self-microemulsion preparation to improve the release rate and bioavailability of the drug.Methods Preliminarily screen the excipients with greater saturated solubility for Febuxostat by solubility experiment,draw a pseudo ternary phase diagram using appearance and emulsification time as metrics,determine the area of milk formation,and use emulsification time and average particle size as indicators.Response surface method formulation optimization,through the microemulsion particle size,Zeta potential,emulsification time,morphology to evaluate the quality of febuxostat self-microemulsion preparation and its stability,related substances and in vitro dissolution were investigated.Established HPLC to determine the blood concentration of febuxostat,using commercially available febuxostat tablets(specification: 40 mg)as the reference preparation,and self-made febuxostat self-microemulsion capsules(specification: 40 mg)as the test preparation.Twelve healthy rabbits were used for single-dose oral administration pharmacokinetic experiments,blood drug concentration was measured,blood drug concentration time curve was drawn,and related pharmacokinetic parameters were calculated.Results Through solubility experiment,pseudo-ternary phase diagram drawing and star point design-response surface method formulation optimization,the best formulation of febuxostat self-microemulsion was determined: ethyl oleate39.60%,Tween-80 45.54% and TRANSCUTOL HP 14.85%.After diluting 100 times with distilled water,the appearance is uniform and transparent.The emulsion droplets are uniform and spherical when observed under a transmission electron microscope.The zeta potential is(-25.20±0.60)m V,the average particle size is(35.40±0.30)nm,and the self-emulsification time It is(50.60±0.12)s.Febuxostat self-microemulsified preparations have good stability.Different dilution ratios and different media have little effect on the emulsification time and particle size of the microemulsion;temperature and rotation speed affect the particle size of the microemulsion Smaller,but with the increase of temperature and speed,the shorter the emulsification time,the faster the emulsification speed,and the content of related substances meets the requirements.The in vitro dissolution can reach more than 80% in different media within 10 minutes.The pharmacokinetic parameters of the reference preparation and the commercial preparation obtained through the pharmacokinetic experiment are: Cmax(1408.84±45.87)ng·m L-1,(890.43±32.54)ng·m L-1;Tmax(0.40±0.80)h,(1.00±0.28)h;AUC0~t(4542.59±85.81)ng·h·m L-1,(2423.93±82.30)ng·h·m L-1;AUC0~∞(5091.52±24.32)ng·h· m L-1,(2924.44±35.82)ng·h·m L-1,relative bioavailability is(187.71±8.58)%.Conclusions The preparation process of the solid self-microemulsion preparation of febuxostat is convenient.The microemulsion after dilution is observed under the transmission electron microscope with uniform morphology,small particle size,good stability,and the content of related substances meets the requirements.The prepared febuxostat The solid self-microemulsion has a high in vitro dissolution rate.The results of pharmacokinetic experiments show that the self-made microemulsion preparations have significant differences in pharmacokinetic parameters Tmax,Cmax,AUC0~t compared with those on the market.The Cmax of the febuxostat self-microemulsified preparation prepared in this experiment was significantly increased,and the bioavailability was 1.87 times that of the commercially available tablet.According to the pharmacokinetic results,it was preliminarily determined that the febuxostat self-microemulsified preparation was released in vivo.The fast drug speed and high blood concentration effectively improved the bioavailability of febuxostat and achieved the expected purpose of the experiment.