Construction Of Paeonol-mesoporous Silica System And Study On Its Drug Loading Performance

Objective:Paeonol（Pae）has anti-inflammatory and analgesic effects.Pae is a small-molecule phenolic drug,which has some shortcomings such as low melting point,volatilization,poor water solubility and photodecomposition,so its clinical application is limited.Therefore,this study prepared mesoporous silica（MSNs）nanocarriers and loaded Pae into the pores of MSNs nanocarriers to form a paeonol mesoporous silica system（Pae-MSNs）,aiming to improve the solubility and stability of Pae,improve its low melting point and volatile nature,and enhance its anti-inflammatory and analgesic effects.Methods:MSNs nanocarriers were prepared by sol-gel method.Fourier infrared spectroscopy（FT-IR）was used to analyze the removal of surfactants from solvent extraction and high-temperature calcination.The morphology of MSNs nanocarriers prepared by two methods of removing surfactants was observed by transmission electron microscopy（TEM）.The product yield of two surfactant removal methods was investigated in order to select the suitable surfactant removal method.The MSNs nanocarriers were characterized by X-ray diffraction（XRD）and differential thermal scanning（DSC）.Paeonol-mesoporous silica system was constructed by molecular simulation method.A method for the in vitro analysis of Pae was established by high performance liquid chromatography.The equilibrium solubility of Pae was determined by oscillating method.The preparation method of Pae MSNs was studied based on the loading rate,and the preparation process was optimized using single factor method and Box-Behnken response surface design（BBD）.The Pae-MSNs were characterized by infrared spectroscopy,differential scanning calorimetry,and X-ray diffraction.The equilibrium solubility,strong light and high temperature stability of Pae and Pae MSNs,and dissolution in different dissolution media were determined.XRD was used to detect the long-term storage stability of Pae-MSNs samples.The anti-inflammatory and analgesic effects of Pae-MSNs in vivo were evaluated using carrageene-induced foot swelling model and glacial acetic acid induced body twisting model.Results:Both high temperature calcination and solvent extraction can basically remove the surface active agent of MSNs nanocarriers.The shape of MSNs nanocarriers prepared by high-temperature calcination is spherical,about 200 nm,without collapse.The product yield of MSNs nanocarriers prepared by high temperature calcination is higher than that by solvent extraction.Therefore,high temperature calcination was selected as a suitable method to remove surfactants.The results of XRD and DSC showed that MSNs nanocarriers were prepared successfully.Paeonol-mesoporous silica drug delivery system was successfully constructed by molecular simulation.The in vitro analytical method of Pae-MSNs was established by high performance liquid chromatography and could be used for the determination of Pae content.The solubility of Pae in water was 484.79±0.68μg·m L^-1,indicating poor water solubility.Pae-MSNs was prepared by constant temperature magnetic stirring method,and the best preparation process was as follows:The loading concentration was 85.021 mg·m L-1,the feeding ratio was 2.228:1,the loading time was 35.908 h,the rotation speed was 450 r·min-1,and the ultrasonic time was 0.5 h.The loading rate of the three batches was（18.09±0.46）%.The results of DSC,XRD and FI-IR show that Pae has been successfully loaded on MSNs nanocarriers to form Pae-MSNs,the formation mechanism is physical adsorption,and the molecular simulation can successfully construct Paeonol-mesoporous silica system.Compared with Pae raw materials,the solubility of Pae in Pae-MSNs in water was increased by 4.02 times,the stability in strong light and high temperature was improved,and the cumulative dissolution percentage of Pae in different dissolution media was increased,and the dissolution mechanism was close to Weibull equation.The long-term storage results of Pae-MSNs for three months show that there is no Pae crystallization and the stability is good.In vivo anti-inflammatory and analgesic results showed that Pae-MSNs could effectively inhibit the foot swelling induced by carrageenan（P<0.01）,significantly reduce the thymus index and spleen index of rats（P<0.01）,significantly increase the activity of SOD in serum（P<0.05）and reduce the content of MDA.The expression levels of IL-1βand TNF-αwere significantly decreased（P<0.05）,and the writhing frequency caused by glacial acetic acid was effectively inhibited（P<0.01）.The anti-inflammatory and analgesic effect of PAe-ms Ns was stronger than that of Pae.Conclusion:In this study,MSNs nanocarriers were successfully prepared,and Pae was successfully loaded into MSNs nanocarriers to form Pae-MSNs.Pae-MSNs effectively improved the solubility,dissolution,strong light stability and high temperature stability of Pae API,enhanced the anti-inflammatory and analgesic effect of Pae API,and provided reference for the clinical treatment of Pae in the future.