Preparation And Pharmacokinetic Evaluation Of Phillygenin Self-microemulsion

Phillygenin(PG)is a bisepoxylignan compound.Phillygenin is almost insoluble in water,but it has good solubility in organic solvent.Modern pharmacological research has shown that phillygenin has strong anti-inflammatory,liver protection,inhibition of tyrosinase activity and other pharmacological effects.Although phillygenin has a wide range of pharmacological activities,the further development and utilization of phillygenin are limited due to its poor water solubility and incomplete oral absorption.Therefore,it is of great significance to improve the bioavailability of phillygenin by pharmaceutical technology.As a thermodynamically stable lipid preparation,the self-microemulsifying drug delivery system(SMEDDS)has attracted widespread attention in improving the bioavailability of drug.After oral administration,SMEDDS can spontaneously form an oil-in-water microemulsion with a droplet size less than 100 nm under the gastrointestinal motility.The formed microemulsion is beneficial to improve the solubility of the drug,and the smaller droplet size can provide a larger surface area to promote the absorption of the drug.Therefore,SMEDDS has a good application prospect as an excellent carrier for low solubility and poor absorption drug.In recent years,the research on phillygenin has been mainly focused on the pharmacological activity,and there were few reports about its formulation.Therefore,this subject aimed to develop a stable,safe and efficient drug delivery system,so as to effectively solve the problems of poor water solubility and low bioavailability of phillygenin.In the experiment,by studying the solubility of phillygenin in various excipients and combining the pseudo-ternary phase diagram,the prescription components of PG-SMEDDS were screened.Furthermore,the optimization of the prescription was carried out through the response surface method,and the best prescription wasdetermined.According to the best prescription proportion,PG-SMEDDS was prepared and its in vitro quality and dissolution were evaluated.Finally,the absorption effect of PG-SMEDDS in rats was studied,and the pharmacokinetic differences between PG-SMEDDS and phillygenin suspension were compared.The main research contents of this paper are summarized as follows:1.Before the prescription study,the HPLC method was established for the determination of phillygenin in vitro and its methodology was verified.The results showed that the established HPLC method has strong specificity,high precision and it could meet the methodological requirements of analysis method.The established HPLC method could be used for the determination of phillygenin in vitro.2.Taking solubility and emulsification effect as indicators,the solubility of PG in various excipients and the compatibility between oil and surfactant were studied.It was preliminarily determined that Labrafil M1944 CS was selected as oil phase,and EL-35 was used as surfactant.Furthermore,the co-surfactants and the range of the amount of each component was studied by drawing the pseudo-ternary phase diagram.The experiment has determined that PEG-400 was used as a co-surfactant,the use range of Km with 0.5~3,and the amount of oil phase was 10%~60%.Based on this result,the prescription was further optimized by using the response surface method,and the best proportion of each component in the prescription was determined.The best prescription of PG-SMEDDS consisted of 27.8% Labrafil M1944 CS,33.6% Cremophor EL,38.6%PEG-400 and 10.2 mg/g phillygenin.3.Using morphology,particle size,and PDI as evaluation indicators,the in vitro quality of PG-SMEDDS was studied.The results showed that the microemulsion droplets was observed to be spherical shape and had uniform distribution,with an average droplet size of 40.11 nm and PDI of 0.151.The self-emulsifying efficiency of the PG-SMEDDS was evaluated by visualobservation,and its emulsification time was 42.03 s.The results showed that PG-SMEDDS had higher emulsification efficiency.By studying the stability of PG-SMEDDS under different conditions,the results showed that PG-SMEDDS had good stability.In addition,the dissolution behavior of PG-SMEDDS and free PG in different dissolution media was investigated.It was found that the cumulative dissolution of PG-SMEDDS could reach more than 90% at about 60 min,and the drug was almost completely dissolved.However,the maximum dissolution of the free PG was only 60%.The results showed that the in vitro dissolution of PG-SMEDDS was significantly better than that of free PG,and the dissolution of PG-SMEDDS was basically independent of p H.4.A method for determining the content of phillygenin in rat plasma was established by UPLC and its methodology was investigated.The method validation results showed that the established method could meet the requirements of biological sample analysis and it can be used for detecting the plasma concentration of phillygenin.Subsequently,pharmacokinetic studies were performed by single-dose intragastric administration,and the pharmacokinetic parameters of PG-SMEDDS and PG suspension were calculated by the non-compartmental model.The pharmacokinetic results showed that SMEDDS could increase the plasma concentration of phillygenin in rats and improve its oral bioavailability.