Studies On Paeonol Loaded Poly(Lactide-Co-Glycolide) Nanoparticles For Oral Administration

Objective:Paeonol,an active ingredient derived from the extract of the dried root bark of the peony plant.Studies have confirmed that paeonol has variety of pharmacological activities including anti-inflammatory,anti-allergic,anti-tumor,anti-arrhythmia,etc.However,the clinical application of Paeonol is also greatly limited due to its poor water solubility,oxidization,and low oral bioavailability.Oral nanoparticles have the advantages of improving drug stability and oral bioavailability,sustained release,and targeted release of drugs,which have been favored by researchers in recent years.Among them,the biodegradable polymer material Poly Lactic-co-Gly-colic Acid（PLGA）has become the hottest carrier materials due to its excellent biocompatibility and biodegradability.In this study,PLGA-NPs were used as the carrier to deliver Paeonol orally,so as to improve its stability and oral bioavailability.Method:In this study,Paeonol PLGA nanoparticles were prepared by nano-precipitation using poloxamer 188 as emulsifier.The Paeonol PLGA nanoparticles prescription was optimized using single factor and orthogonal design method.Its appearance,morphology,particle size,PDI,zeta potential,encapsulation efficiency,and stability were evaluated respectively.The in vitro drug release behavior of Paeonol PLGA nanoparticles were studied in the simulated gastric fluid（SGF）and simulated intestinal fluid（SIF）by dynamic dialysis method.The in vivo pharmacokinetic studies were investigated in rats.The absorption characteristics of paeonol PLGA nanoparticles and paeonol solution in the intestine were investigated by in situ single-pass intestinal perfusion model in rats.Results:The optimal prescription of paeonol PLGA nanoparticles prepared by nano-precipitation method was as follows:the concentration of PLGA was 30 mg·m L^-1,the concentration of F68 was 0.8%（w/v）,and the volume ratio of oil to water was 1:3.The optimized paeonol PLGA nanoparticles were spherical with the particle size,PDI and Zeta potential were（237.7±4.92）nm,0.110±0.01,and（-25.33±1.37）m V,respectively.The encapsulation efficiency and drug loading were 86.26%±1.12,and12.74%±0.37,respectively.The prepared paeonol PLGA nanoparticles were stable when stored at 4°C.The results of in vitro release showed that paeonol PLGA nanoparticles had sustained release characteristics in the simulated gastric fluid and simulated intestinal fluid,which accorded with the first-order kinetic equation.In vivo pharmacokinetic studies indicated that the AUC_（0-t）,C_max,MRT_（0-t）and T_1/2zof paeonol PLGA nanoparticles were 3.79 times,1.89 times,1.40 times and 1.49 times than those of the suspension group,respectively.The results of in situ single-pass intestinal perfusion in rats displayed that the Ka values of paeonol PLGA nanoparticles in the duodenum,jejunum,ileum and colon were 1.12 times,1.40 times,1.52 times and 2.21times than that of paeonol solution,respectively,The Papp values of the ileum and colon were 1.27 times and 1.31 times that of the solution group,respectively.Conclusion:In this study,the formulation and preparation method of paeonol PLGA nanoparticles is feasible and has a certain sustained release effect.Besides,the paeonol PLGA nanoparticles can significantly improve the oral bioavailability and intestinal absorption characteristics,which provide experimental basis for the study of new oral preparation of paeonol.