Development And In Vitro-in Vivo Evaluation Of A Microemulsion Formulation For The Oral Delivery Of Oxaprozin

Objective:The purpose of this research is to develop a new formulation that can enhance the oral absorption of oxaprozin.The advantage of microemulsion is that it can improve the solubility of poorly soluble drugs and avoid adverse reactions of the drugs themselves.This study includes the preparation and characterization of oxaprozin microemulsion,the in vitro release and in vivo pharmacokinetic evaluation of the selected microemulsion formulations,which provide a research basis for subsequent clinical trials.Methods:In the preparation of drug-loaded microemulsions,the oil phase,surfactants,and co-surfactants to be screened by drug solubility.After selecting the appropriate phases,the water titration method was used to titrate the different proportions of the oil phase and different proportions of surfactant and co-surfactant mixtures(S_mix),and established the pseudo-ternary phase diagram to select the formulation with larger microemulsion area for maximum drug load determination.Characterization experiments were performed on the selected microemulsion formulations,including particle size,zeta potential,p H,conductivity,microscopic morphology and stability,etc.,and the in vitro release experiment was performed on these formulations.The formulation with the best in vitro release effect was subjected to in vivo pharmacokinetic experiments in rats,and UPLC-MS/MS was used to determine the blood drug concentration,and finally its pharmacokinetic parameters were evaluated.Results:In the solubility experiment,the oil phase（Labrafil）,surfactants（Tween 20,Lanbrasol）and co-surfactants（Ethanol,Isopropanol,1,2-Propanediol）with greater solubility were screened out.Three different formulas（ME1,ME2,ME3）were screened out through pseudo-ternary phase diagram and maximum drug loading experiment.It was found from the dilution stability experiment that ME2 and ME3performed better,so the two formulations were characterized.The particle size of the blank microemulsion is 150.4 nm-181.8 nm,the particle size of the drug-loaded microemulsion is 222.2 nm-223.6 nm,and the Zeta potential of all formulations is between-38.38 m V and-38.44 m V.The pH value,polydispersity,percent transparency and conductivity of the selected formulation meet the requirements.Differential scanning calorimetry results show that the internal structure of the selected formulation is stable.Under the transmission electron microscope,it can be seen that the microemulsion droplets are spherical and uniformly distributed.The drug-loaded ME2 and ME3（the drug-loaded amounts are 7.24±0.06 mg/m L and7.47±0.06 mg/m L,respectively）were used in the in vitro release test.The results showed that the release percentage of drug-loaded ME3 could reach 99%within 24hours,while The medicated ME2 can also reach 80%.Finally,the in vitro release curve of drug-loaded ME3 was fitted with a release model,the results showed that the release curve was more in line with the first-order equation（the fitting correlation coefficient was the largest,0.99）,indicating that the drug-loaded ME3 had a certain sustained release effect.The in vivo pharmacokinetic experiment of the drug-loaded ME3 in rats showed that the microemulsion formulation significantly delayed the peak time of the plasma concentration and at the same time delayed the elimination half-life of the drug,which is very meaningful for clinical trials.Conclusion:The optimal formulation was 15%Labrafil,35%Tween 20/Isopropanol（K_m=2）and 50%distilled water,the drug-loaded amounts is 7.47±0.06 mg/m L.In vitro release of the oxaprozin-loaded microemulsion was best fit with the first-order model,meanwhile the microemulsion preparation has a certain sustained release effect.In vivo pharmacokinetic experiment indicated that the microemulsion formulation significantly delayed the peak time of blood concentration and at the same time pushed back the half-life of drug elimination,which is very meaningful for clinical trials.