Preparation And Characterization Of PH-Sensitive Mesoporous Zirconium Diphosphonates For Controllable Colon-targeted Delivery

Mesoporous organophosphonates materials is a novel organic-inorganic hybrid materials. It has found wide applications as adsorption, catalysis, separation, biological medicine materials due to their tunable pore structure, high specific surface area, large pore volume and various chemical surface properties. It has aroused broad interest by researchers in material science.Here, pH-sensitive mesoporous zirconium diphosphonates have been prepared through a one-pot co-condensation method with large and tunable mesopores. The pH-sensitive mesoporous zirconium diphosphonates as smart drug carriers for pH-controllable release were investigated to develop an oral colon-targeted drug delivery system.The main results of research in this dissertation were as follows:1. pH-Sensitive mesoporous zirconium diphosphonates have been successfully synthesized through the surfactant-assisted procedure using the organophosphonate derivative of piperazine, 1,4-bis (phosphomethyl) piperazine (BPMP), and ZrCl4 as the metal precursor. These materials were characterized by N2 adsorption–desorption isotherms, scanning electron microscopy (SEM), 31P MAS NMR spectrum, 13C MAS NMR spectrum and element analysis.2. The adsorption behaviors of mesoporous zirconium diphosphonates for PDS were investigated in details. Firstly, the surface areas of pH-sensitive mesoporous zirconium diphosphonates affected the adsorptive capacities of PDS. High surface areas benefited the higher adsorptive capacity. The maximum adsorptive capacity of PDS can reach as high as near 300 mg g-1. Secondly, the pore size of pH-sensitive mesoporous zirconium diphosphonates determined their adsorptive model for PDS. With small mesopores'were prone to single adsorption model, while with large mesopore's was inclined to multiple adsorption model. Thirdly, mesoporous zirconium diphosphonates exhibited rapid adsorptive rate for PDS, they can reach equilibrium within 2 h from the kinetics of adsorption for PDS. The adsorption of PDS onto mesoporous zirconium diphosphonates were well represented by pseudo-second-order kinetics. The adsorption mechanism depended on both adsorbents and adsorbate, and the rate-limiting step may be physisorption through the strong electrostatic interaction between cationic mesoporous zirconium diphosphonates and anionic PDS. Fourthly, the recycle ability of mesoporous zirconium diphosphonates is tested and the regeneration efficiency can remain 87.5 % after one cycle compared to the fresh sample, and can still reaches 76.3 % even after six cycles.3. The release behaviors of PDS-loaded mesoporous zirconium diphosphonates under different pH values were studied in details. Extremely little PDS release from mesoporous zirconium diphosphonates was observed under the simulated acidic environment of the stomach (pH = 1.2) within 48 h. When PDS-loaded Mesoporous zirconium diphosphonates was placed in the simulated environmental pH value of the intestine (pH = 7.5), mesoporous zirconium diphosphonates released PDS in a slow release rate within 4 h (only 30% of the loaded amount of PDS), and released loaded PDS completely within the followed 44 h. According to the transport time of gastrointestinal tract, it can be considered that the mesoporous zirconium diphosphonates as vehicles can carry PDS passing through the stomach without PDS release and released loaded PDS completely in the colon, followed by a minimal PDS release in the small intestine.4. The release behaviors of diclofenac sodium loaded mesoporous zirconium diphosphonates coated by lag-time films were studied in the simulated gastrointestinal solutions. Lag-time of 6 h can be controlled through adjusting the thickness of film. Diclofenac sodium loaded mesoporous zirconium diphosphonates coated by lag-time films released no diclofenac sodium in the simulated gastric solution, released diclofenac sodium less than 10 % (percent of released amount of diclofenac sodium) in the simulated small intestinal solution and slowly released diclofenac sodium controlled by pH-sensitivity of mesoporous zirconium diphosphonates in the simulated colonic solution. Thus, diclofenac sodium can be colon-specificlly released in such a time and pH value controlled colon-targeted drug release system.