Formulation And Studies Of Resveratrol-SMEDDS

Objective:Resveratrol (Res) is a non-flavonoid poly-phenolic compound whichcontains the structure of stilbenes.It is abundant in peanuts, grapes and otherfoods that are universally consumed as part of human diet.Resveratrol hasattracted comparative interest for its beneficial potentials for human health,such as anti-in flamatory, anti-tumor,anti-oxidant and cardioprotectiveactivities. However, the characteristics of resveratrol are high metabolizationand elimination,which is a barrier to the development of clinical applications.In this context,the study aims at designing an approach of SMEDDS toovercome its poor solubility, limited stability and weak bioavailability.Methods:1The preparation of Res-SMEDDS formulations: The solubility of Resin various oils, surfactants, and cosolvents was studied, in order to select thesuitable compositions of SMEDDS. Through the Pseudo-ternary phasediagram study, the ratio of surfactant, cosolvent, and oil which gave thebroadest self-emμLsifying regions was selected. The combination of triacetin,Cremophor EL (2:1) and Cremophor RH40(1:1) with isopropanol was used todevelop the Res-SMEDDS. The selected oil and a mixture of surfactant andcosolvent were mixed by gentle stirring and vortex mixing until ahomogeneous mixture formed.Then Res was mixed with self-microemulsionby the technology of ultrasound wave.2The identifications of Res-SMEDDS: The formulations were analyzedfor droplet size and appearance. The particle size was measured by a MalvernInstruments Zetasizer Nano series. The particle appearance was analyzed by atransmission electron microscope.3Study on stability of Res-SMEDDS: established the method of HPLCfor the determination of Res content. To confirm the stability of the Res-SMEDDS formulations, Droplet size, appearance, and Res contents weredetermined at0day,5,10days,1,2, and3months for Res-SMEDDS byaccelerated testing and stress testing.4In vivo pharmacokinetic study in rats: established the method ofHPLC for the determination of Res content in plasma. Domestic suspension ofRes as reference, the study was carried out to study its pharmacokinetics andbioavailability.5The single-pass intestinal experiment in rats: established the methodof HPLC for the determination of Res content in perfusion fluid. Domesticsuspension of Res as reference, the study was carried out to study its Ka andPapp.Results:1Based on the consequences of the solubility in vehicles, the vehiclesselected for further investigation were MCT, triacetin, Cremophor EL,Cremophor RH40, PEG400and isopropanol. Pseudo-ternary phase diagramsof various oils, surfactants and cosurfactants were constructed. Consequently,the best formulation was triacetin, Cremophor EL, Cremophor RH40, andisopropanol (22：27：13.5：37.8).2The appearance of particle was circle and iso-seperated. The systemhad a particle size less than15nm which was measured by a MalvernInstruments Zetasizer Nano series.3Established the method of HPLC for the determination ofRes-SMEDDS with the detection wavelength of305nm, the study onmethodology showed that Absorbance and Res concentration had asatisfactory linear relationship in the concentration range of10μg/mL～200μg/mL, research on recovery, stability, and precision all met therequirements. The suitable model of regression was the Higuchi equation.The developed formulation was investigated for its stability at40℃, RH75±5%, and light test conditions. There were no changes in appearance of allformulations after storing at the tested light, temperature, and humidity. Thepercent of Res content in Res-SMEDDS formulation was stable at all conditions for the duration of the experiments, apart from the tested light.4The datas of Ka and Papp on Res-SMEDDS were1.352±0.05860(×10-2min-1),1.497±0.07827(×10-3cm/min). In addition, thedatas of Ka and Papp on Res-Suspension were0.659±0.08570(×10-2min-1),0.657±0.08991(×10-3cm/min). There wastremendous augmentation in the values of intestinal absorption as compared toRes-Suspension. Overall, the results indicated that the Res-SMEDDSformulation were remarkably superior to the suspension in absorption andpermeability.5The results of SD rats pharmacokinetics showed that the AUC0â†'∞ofRes-SMEDDS and Res-Suspension had the significant difference, Tmax andMRT prolonged, Cmax increased.Conclusions:The developed Res-SMEDDS formulation in this study was the newstrategy to overcome the poor water solubility and weak stability. The resultsare that Res-SMEDDS can improve the dissolution rate and drug intestinalabsorption and oral bioavailability of Res in rats. In addition, this study alsoindicates that SMEDDS formulation can be applied to enhance bioavailabilityof indissoluble drugs which contain many pharmacological effects.