Pharmacokinetics Of New Carriers For Dry Powder Inhalar Based On CD-MOF

Cyclodextrin-metal organic framework（CD-MOF,in this dissertation is specialized forγ-CD-MOF）emerge as a novel class of porous materials consisting of the cyclodextrin and metal ions through metal-ligand coordination bonds.In recent years,the innovation and application of new carriers are crucial for the pulmonary drug delivery.CD-MOF has more characteristics,such as controllable particle size,large cavity and specific surface area,of which the CD-MOF with the particle size of 1 to 5μm suitable for the aerodynamic size for drug delivery of pulmonary.The main contents are as follows:（1）The immediate release study of CD-MOF based on pharmacokinetics.CD-MOF was prepared by solvothermal method.In order to track the pharmacokinetics porperty of CD-MOF,Rhodamine B（RhoB）was used as a fluorescent reagent to prepare the CO-MOF-RhoB by co-crystallization method.Then,characterization methods like FTIR spectroscopy and thermogravimetric analysis were performed to confirm the RhoB exist in CD-MOF.The image-pro plus 6.0 software was used to count particles size of CD-MOF,and which were in the range of 1～5μm.The stability of CD-MOF was investigated in PBS7.4 solution and the results showed that CD-MOF disintegrated completely within 2 min after exposured.For the pharmacokinetic study,CO-MOF-RhoB powder was blown into the rat lungs by a DP-4 pulmonary device,meanwhile,the lung tissues were removed at different time points of each rat.The in vivo imaging system（IVIS）was used to observe the fluorescence intensity of the lungs after administration of CO-MOF-RhoB.The results showed that fluorescence intensity was maximum within 5 min and almost no fluorescence response after 2 h,indicating that CO-MOF-RhoB rapidly degraded in vivo after administration.RhoB was quantified by HPLC-FID in rat plasma to confirm that the reduction of fluorescence was the degradation of CO-MOF-RhoB rather than excretion through other channels.The results showed that the plasma concentration of RhoB was the highest at 5 min,indicating that RhoB was released after rapid degradation of CO-MOF-RhoB in the lung.Furthermore,CD-MOF had no toxicity in the A549 cells and lung tissue.In conclusion,CD-MOF could be used as a carrier of immediate release for dry powder inhalers.（2）Pharmacokinetics of crosslinked CD-MOF as a sustained release carrier for DPI.A crosslinked CD-MOF（CL-MOF）was prepared using diphenyl carbonate as a crosslinking agent.CL-MOF-RhoB was prepared by bonding with CL-MOF and RhoB.Then,the stability of CL-MOF in PBS 7.4 solution and rat lung homogenate were investigated and the results showed that 25.57%of CL-MOF was degraded in PBS7.4 solution within 7 days,however,21.34%of CL-MOF was degraded within 1 h in the tissue homogenate,which was faster than in PBS7.4 solution.It was indicated that CL-MOF could be affected by metabolic enzymes in the rat lung.The lung tissues were taken out at different time points after administration of CL-MOF-RhoB,which was the same process with the in vivo study of CD-MOF.The intensity of fluorescence in lungs was observed by IVIS,and the results showed that the fluorescence was attenuated at a slower rate and had a obvious fluorescence response at 24 h after administration,indicating that CL-MOF-RhoB was slowly degraded in the lung tissues.Meanwhile,the concentration of RhoB in rat plasma was measured and showed that the time of maxiture concentration(T_max)was delayed comparing with CO-MOF-RhoB,demonstrating that the sustained release of CL-MOF-RhoB was also confirmed.Furthermore,CL-MOF could not be phagocytosed by J774A.1 cells,revealing that it was degraded slowly without being cleared in the lung.CL-MOF had no toxicity of lung tissues and A549 cells in rats,indicating that CL-MOF had good biosafety and could be used as a sustained-release carrier for dry powder inhalers.（3）Pharmacokinetics of dry powder inhalation of budesonide using CD-MOF.Budesonide（BUD）was used as a model drug to prepare CD-MOF-BUD by incubation.A HPLC-MS/MS method was established and validated including specificity,linearity,precision,accuracy,recovery,lower limit of quantitation,stability,matrix effect to quantify the concentration of BUD in rat plasma.The pharmacokinetics was compared between CD-MOF-BUD and reference BUD products,and the results showed that the mean BUD concentration-time curve of the CD-MOF-BUD group was similar to that of the pulmicipamide.Furthermore,the T_maxwas about 30 min,and no significant difference in AUC between the CD-MOF-BUD group and pulmicipamide group,indicating that CD-MOF-BUD had a property of immediate release and carried BUD into the lungs effectively.In summary,CD-MOF and CL-MOF with controlled particle size,good biocompatibility,and biosafety have been evaluated and validated as potential immediate and sustained release carriers for dry powder inhalers.