Preparation And Pharmacokinetic Evaluation Of Ipriflavone Self-microemulsion

ObjectiveIpriflavone is a synthetic isoflavone derivative,suitable for improving the symptoms of primary osteoporosis,increasing bone density and reducing bone turnover rate,effective prevention and treatment of osteoporosis,but the dissolution of ipriflavone Low solubility and low oral bioavailability limit its clinical use.The self-microemulsion drug delivery system is a new type of oral drug delivery system containing oil phase,surfactant and co-surfactant.After oral administration,O/W type microemulsion（particle size≤100 nm）is formed through gastric peristalsis in the gastrointestinal tract.The formation of microemulsion not only promotes the dissolution of drugs,but also produces a larger surface area.This topic screens the oil phase,emulsifiers and co-emulsifiers and other auxiliary materials,prepares ipriflavone into self-microemulsion preparations,optimizes the ipriflavone self-microemulsion formulations,and effectively improve the absorption rate and bioavailability of ipriflavone,thereby improving the clinical efficacy of ipriflavone.MethodsBefore proceeding with the prescription study,establish an in vitro method for the determination of ipriflavone.To investigate the solubility of ipriflavone in different excipients,select oil phase,emulsifier and co-emulsifier with relatively large solubility.The prescription components were screened out through the compatibility test of oil phase,emulsifier and co-emulsifier.Further draw the pseudo ternary phase diagram,observe the milking area,and determine the Km value and oil phase range of the emulsifier and co-emulsifier.Taking oil phase and Km as the investigating factors,particle size,Zeta potential,and self-emulsification time as evaluation indicators,the star point design-response surface method is used to optimize the formulation.The quality of epriflavonoid self-microemulsion was investigated by the appearance,particle size distribution,Zeta potential,polydispersity index and drug loading of the microemulsion,and its stability,influencing factors,and dissolution rate were investigated.Establish an high-performance liquid chromatography method for determining the blood concentration of ipriflavone,using 6 healthy rabbits to carry out two preparations,two-period single-dose oral administration of self-made ipriflavone self-microemulsion capsules and commercially available ipriflavone tablets.At the time point of the blood drug concentration,draw the blood drug concentration-time curve,and calculate the relevant pharmacokinetic parameters through the non-chamber model.ResultsAccording to the investigation of the solubility of ipriflavone in various excipients,the drawing of pseudo-ternary phase diagrams and the star point design-response surface method to optimize the formulation,the optimal formulation of ipriflavone self-microemulsion is determined to be:Labrafac lipophile wl 1349,Labrasol,PEG-400 accounted for 21.20%,52.27%and26.53%respectively.The appearance of ipriflavone from the microemulsion is clear and colorless or slightly blue opalescent.The microemulsion has uniform particle size,uniform distribution and no adhesion under the transmission electron microscope.The average particle size of the ipriflavone self-microemulsion is measured as（34.08±1.26）nm,the Zeta potential is（-27.04±1.02）m V,the polydispersity index is 0.071±0.010,and the maximum drug loading of the self-microemulsion.It is（133.62±1.75）mg·m L^-1.The self-microemulsion preparation of ipriflavone has good stability,and the dissolution rate is significantly higher than that of ipriflavone tablets.The parameters of eproflavonoid self-microemulsion and eproflavonoid tablets were obtained through pharmacokinetic experiments,C_maxis（971.37±28.52）ng·m L^-1and（537.57±18.64）ng·m L^-1;T_maxis（0.54±0.10）h and（0.96±0.10）h;AUC_0¹6his（3385.44±191.59）ng·h·m L^-1and（1845.34±66.40）ng·h·m L^-1,relative bioavailability The degree is（184.10±6.49）%.ConclusionsThe preparation process of the ipriflavone self-microemulsion preparation is simple,the particle size of the best prescription is uniform,the distribution is uniform,the stability is good,and the in vitro dissolution rate is significantly increased.The results of pharmacokinetic experiments showed that the pharmacokinetic parameters T_max,C_max,and AUC_0¹6hof ipriflavone self-microemulsion preparations are significantly different from those of ipriflavone tablets.And AUC_0¹6hincreased significantly,and the relative bioavailability is（184.10±6.49）%of ipriflavone tablets.The results of pharmacokinetic experiments showed that it is preliminarily confirmed that the release time of ipriflavone from the microemulsion preparation is earlier,the blood concentration is significantly increased,the absorption effect in the body and the oral bioavailability were effectively improved,and the expected purpose of the experiment is achieved.