Study On The Preparation Process Of 5-aminosalicylic Acid Solid Lipid Nanoparticle Suppositories

Objective: Using 5-ASA as a model drug,5-ASA solid lipid nanoparticles(5-ASA-SLN)were prepared,combined with the concept of quality by design(Qb D)for experimental design,and the optimal preparation process was optimized.The 5-ASA-SLN and its freeze-dried powder prepared by the optimal process were characterized,and the drug release mechanism in vitro was explored.The 5-ASA-SLN suppository was finally prepared to achieve direct administration at the lesion site,which solved the problem of poor solubility of5-ASA and improved the curative effect.Methods: High performance liquid chromatography(HPLC)was used to establish a5-ASA in vitro analysis method.The microemulsion method was used to prepare 5-ASA-SLN.Using fish bone analysis method to investigate the index of encapsulation rate and turbidity,to screen the important factors that affect the preparation process of 5-ASA-SLN.The Plackett-Burman design was used to screen out the key process parameters from the six influencing factors of emulsification temperature,emulsification time,stirring speed,emulsifier to co-emulsifier ratio,mixed emulsifier to lipid ratio,and drug-fat ratio,combined with Box-Behnken design optimized the key process parameters,selected the optimal preparation process and examines the freeze-drying process,and selected the best freeze-drying process.Using transmission electron microscopy,laser particle size analyzer,Fourier transform infrared spectrometer,and differential scanning calorimeter(DSC)to characterize 5-ASA-SLN,verified the formation of 5-ASA-SLN.Measured the saturated solubility of the obtained 5-ASA-SLN and 5-ASA,and explored their in vitro release mechanism;Taking 5-ASA-SLN suppository appearance,melting time limit,weight difference,and stickiness as evaluation indicators,the optimal preparation process of5-ASA-SLN suppository was optimized.Results: The in vitro analysis method of 5-ASA was established and the method was stable and feasible.The preparation process of 5-ASA-SLN was analyzed by fish bone analysis method.Through single factor test,PBD test and BBD test,the optimal preparation process was glyceryl monostearate as lipid,polyoxyethylene hydrogenated castor oil as emulsifier,absolute ethanol as co-emulsifier,emulsification temperature was 65 ℃,emulsification time was 10 min,the stirring speed was 900 rpm,the ratio of emulsifier to co-emulsifier was 4.32:1,the ratio of mixed emulsifier to lipid was 6.38:1,the drug-to-lipid ratio was 1:15.6,and the amount of internal water phase was 20 ml.The amount of the dispersed phase was 50 ml,the dispersion method was a syringe drip under magnetic stirring,the curing temperature was 0℃-2℃,and the curing time was 30 min.After the verification test,the deviation between the measured value and the predicted value of 5-ASA-SLN encapsulation rate was 2.19%,and the was not easy to store,it was made into a freeze-dried powder,using sucrose as a freeze-dried protective agent,the amount of the protective agent was 3%,and the freeze-drying time was 30 hours.Finally,a white,plump,smooth and compact 5-ASA-SLN freeze-dried powder was obtained.The accelerated stability test showed that 5-ASA-SLN freeze-dried powder had better stability.It was observed by transmission electron microscope that 5-ASA-SLN was spherical.The infrared spectrum scanning and DSC analysis verified the formation of 5-ASA-SLN;The average particle size of 5-ASA-SLN was measured as(124.7±2.62)nm,PDI was 0.32±0.02 and the Zeta potential was(-15.0±0.8)m V,indicating that 5-ASA-SLN had a small particle size,uniform distribution and good stability.The saturated solubility of 5-ASA-SLN in distilled water was 33.12 times that of5-ASA.The in vitro release test results showed that 5-ASA-SLN had a certain slow-release effect,and the release model fit in accordance with the Higuchi equation.The 5-ASA-SLN freeze-dried powder was prepared into suppositories by hot-melt method,and finally prepared5-ASA-SLN plug waas milky white,uniform in color,smooth in surface,and intact bullet-shaped plug.Conclusion: Through process optimization,the prepared 5-ASA-SLN and its plug have a simple process,stable and feasible,and effectively solve the problem of poor solubility of5-ASA.