The Preparation And Characterization Of Resveratrol Solid Lipid Nanoparticles And Nanostructured Lipid Carriers

Resveratrol?Res?,a non-flavonoid polyphenolic compound derived from plants,is mainly used for the treatment of skin cancer,cardiovascular disease,primary liver cancer,breast cancer,and hypertension.However,its self-oxidation,rapid metabolism,short half-life and other characteristics result in low bioavailability after administration,then it can not reach the ideal effective treatment level.It is necessary to formulate new drug delivery system to improve its stability and bioavailability.In this study,solid lipid nanoparticles?SLN?and nanostructured lipid carrier?NLC?were constructed for the administration of Res and the properties of Res-SLN and Res-NLC were evaluated.Firstly,preformulation studies of Res were conducted.The solubility in different solutions?including organic solvents,phosphate buffers,solid-liquid lipids,different surfactants?,oil-water partition coefficient,and stability were investigated.As result,the solubility of the drug in aqueous solution was only 0.03 mg/mL,but the solubility in ethanol and acetone was much higher.The solubility of Res in glyceryl monostearate?GMS?,glycerol monolaurate?GML?,caprylic acid glyceride?ODO?,triacetin?GT?and Tween 80 was much higher than the other ingredients screened.The oil-water partition coefficient of Res in the water and different pH phosphate buffer are about 1,there is no significant difference.It is stable in acidic solution and unstable in alkaline solution.The content of the drug substance under high temperature,high humidity and illumination conditions is reduced to an extent which indicates the stability of Res is poor.Secondly,Res-SLN and Res-NLC were prepared by high speed shear-ultrasonic method.According to the mean particle size,the shear rate was selected as 12000 r/min and the ultrasonic time was selected as 10 min.According to the determination of encapsulation efficiency,GMS was selected as solid lipid,ODO was liquid?solid-liquid ratio 1:1?and Tween 80 was surfactant.The optimal preparation of NLC was 22 mg Res,83.5 mg GMS,83.5 mg ODO,80 mg Tween 80 in the total volume of 5 mL by the response surface methodology-central composite design.Thirdly,SLN and NLC containing Res was characterized to understand the physical state of the drug in SLN and NLC and the interaction of between drug and carrier.Res-SLN and Res-NLC showed a uniform spherical shape in the nanometer size range under the observation of TEM,and the NLC particle size was lower than SLN.XRD and DSC results further demonstrated that the drug existed in amorphous form in SLN and NLC.As the liquid lipid increasing,the crystallinity of NLC decreased and the stability increased.The FTIR results showed no intermolecular interaction between Res and GMS.In vitro release behavior of SLN and NLC dispersions,lyophilized powders and Res suspensions in PBS at pH 7.4 was investigated.Res showed 91.56%in 13 hours.SLN and NLC drug release were composed of two stages,namely in the initially burst phase and the slowly sustained release phase,the dispersion release curve conformed to the Higuchil model,and the freeze-dried powder release was best fitted with the Korsmeyer-Peppas model with an index n>1.A preliminary study on the stability of SLN and NLC dispersions and lyophilized powders showed that the stability of NLC dispersions was higher than that of SLN,but visible flocs appeared after 30days,and the stability of the dispersion was poor,requiring low temperature storage.There was no significant change in the drug loading and particle size of SLN and NLC lyophilized powder after storage for 90 days at room temperature.The content was not significantly decreased under high temperature?40??,high humidity and illumination conditions,and the stability was good.Finally,the efficacy of Res-SLN and Res-NLC on cell proliferation in vitro were investigated.HepG2 hepatoma cells were used to investigate the inhibitory effect of Res-SLN and Res-NLC.The results of MTT assay showed that the cell growth inhibition rate increased significantly with the increase of concentration in the range of 5-80?g/mL?P<0.05?,and it showed a certain dose and time dependence;The IC₅₀ of Res-SLN and Res-NLC after 48 h was 20.19?g/mL and 12.74?g/mL,respectively.The research of this subject showed that Res-SLN and Res-NLC prepared by high-speed shear-ultrasound technology using GMS:ODO?1:1?as solid-liquid lipid,tween 80 as surfactant,it can effectively control drug release.and improve the stability of Res.In vitro cell experiments showed that SLN and NLC on HepG2 cell proliferation was effective than Res.The above research has a laid foundation for the application development of Res preparations.