Research On The Drug Loading Mechanism Of β-Cyclodextrin-Metal Organic Framework And Its Application

Objective:Cyclodextrin-Metal Organic Framework（CD-MOF）is a promising drug carrier,which has attracted extensive attention from researchers in the past years.However,current studies mainly focus on theγ-Cyclodextrin-Metal Organic Framework（γ-CD-MOF）as a carrier,and few studies have been conducted on theβ-Cyclodextrin-Metal Organic Framework（β-CD-MOF）,its drug loading mechanism and drug delivery applications.In this paper,Dimercaptosuccinic acid（DMSA）was used as the model drug to studyβ-CD-MOF and its drug loading mechanism and application.And Ursodeoxycholic acid was used as a model drug to continue to explore its application value to taste masking.This study provided the basis for the development of new preparations based onβ-CD-MOF.Methods:1.Establishment of quality evaluation methodsA stable method for the determination of DMSA by Ultraviolet Spectroscopy and High Performance Liquid Chromatography was established.2.Study on optimized process of drug loadingβ-CD-MOF was used as a carrier to load DMSA.The optimal loading process ofβ-CD-MOF/DMSA was optimized by investigating the effects of feeding molar ratio,incubation temperature,incubation time and its water solubility and stability of the composition were investigated.3.Characterization and mechanism research ofβ-CD-MOFβ-CD-MOF/DMSA was determined by Differential Scanning Calorimetry,X-ray Powder Diffraction analysis,Scanning Electron Microscopy and the interaction forces betweenβ-CD-MOF and DMSA were verified by Synchrotron Radiation Fourier Transform Infrared Spectroscopy,which could verify the change ofβ-CD-MOF after drug loading.The molecular simulation method was used to perform molecular docking of DMSA withβ-CD-MOF,and the calculation of crystal binding energy was used to provide theoretical basis for drug loading ofβ-CD-MOF.4.β-CD-MOF/DMSA application in drug loading.The hydrophilic matrix tablets ofβ-CD-MOF/DMSA was determined by investigating the species,proportion and lubricant types of hydroxypropyl methyl cellulose.The release behavior in different media was also investigated.Taking Ursodeoxycholic acid（UDCA）as the model drug,different drug loading processes were investigated withβ-CD-MOF to achieve taste masking of UDCA.Results:1.Establishment of quality evaluation methodsThe UV and HPLC determination method were established for DMSA andβ-CD-MOF/DMSA.2.Study on optimized process of drug loadingThe best process of loading DMSA inβ-CD-MOF was Determined:feeding molar ratio(n_DMSA:n_MOF)5:1,the temperature of 60℃,the incubation time for 2 h.The delivery process was stable andβ-CD-MOF/DMSA is stable in severe conditions.3.Characterization and mechanism research ofβ-CD-MOFβ-CD-MOF/DMSA was verified by Differential Scanning Calorimetry,X-ray Powder Diffraction analysis,Scanning Electron Microscopy and the interaction forces betweenβ-CD-MOF and DMSA were verified by Synchrotron radiation Fourier Transform Infrared Spectroscopy.DMSA could be stable inβ-CD-MOF in severe condition（high temperature,high humidity,strong lighting）.Molecular modeling was used to calculate the interaction betweenβ-CD-MOF and DMSA.When the concentration of DMSA was high,the binding energy ofβ-CD-MOF decreased and structural transformation occurred.4.β-CD-MOF/DMSA application in drug loadingThe hydrophilic matrix tablets were prepared byβ-CD-MOF/DMSA and the best process was 10%HPMC K4M,89%β-CD-MOF/DMSA,1%sodium stearate fumarate.Sustained-release tablet could release uniformly in water,and still achieve the sustained-release effect in the medium of PH 4.5 and PH 6.8.Ursodeoxycholic acid was carried byβ-CD-MOF.After different drug loading processes were investigated,theβ-CD-MOF was able to mask the taste of Ursodeoxycholic acid in maintaining high drug loading.Conclusion:In this study,UV and HPLC methods for the determination of Dimercaptosuccinic acid were established.The composition ofβ-CD-MOF/DMSA was obtained with optimizing the drug loading process.After drug loading,the structural transformation ofβ-CD-MOF was proved by various characterization methods and molecular modeling and calculation.Besides,DMSA was found to be stable in the reticular structure ofβ-CD-MOF.Preparation ofβ-CD-MOF/DMSA hydrophilic matrix sustained-release tablets,which can release uniformly in the medium to achieve sustained-release effect.By optimizing the process ofβ-CD-MOF/Ursodeoxycholic acid,the bitterness of Ursodeoxycholic acid can be concealed with maintaining the high drug loading.This research provided a reference for the drug delivery ofβ-CD-MOF in the future.