Study On Temperature/Glucose/pH Triple-sensitive Intelligent Drug Delivery System Loaded Glipizide

Objective Glipizide was selected as model drug first time,using chitosan (CS), sodium tripolyphosphate (TPP) andβ-sodium glycerophosphate ((3-GP) as main intelligent carriers, a novel temperature/glucose/pH triple sensitive intelligent drug delivery system loaded glipizide was studied.Methods A novel pH sensitive CS-TPP hydrogel beads and the pH sensitive CS-TPP microgels with smaller particle size were prepared by the ionic gelation method and emulsion-crosslinking method respectively. The optimum preparation technique of the hydrogel beads and microgels was investigated by single factor design and orthogonal test, the physical and chemical characterization of the hydrogel beads and microgels were performed by SEM and FTIR respectively, and the loading efficiency, encapsulation efficiency, swelling behavior and cumulative release properties of glipizide from hydrogel beads and microgels at various pH were investigated, the release mechanism in vitro was researched too. In addition, the temperature sensitive CS/β-GP hydrogel was prepared as carrier of injected implants. On this basis, the pH sensitive CS-TPP microgels and glucose oxidase were assembled into the the temperature sensitive CS/β-GP hydrogel, and the temperature/glucose/pH triple-sensitive intelligent hydrogel was carried out. Also, the characteristics gelation and release property of the temperature/ glucose/pH triple-sensitive hydrogel system at different glucose concentrations were investigated.Results The research results of the CS-TPP hydrogel beads:the results showed that the CS-TPP hydrogel beads were white, and the surface morphology of the hydrogel beads at the optimum preparation technique was spherical and regular before dried, there are folds on the surface after drying. The swelling behavior of the hydrogel beads at different pH media presented pH sensitivity, and the swelling ratio gradually increased with pH decreasing. In vitro release behavior of the hydrogel beads showed pH sensitivity too, within 3 h, the amount of glipizide released from the hydrogel beads was relatively high (46% %) at pH 1.5 acidic medium, while at the same time that released amount at pH2.5, pH5.0 and pH 6.8 were 38%,20% and 18% respectively, within 16 h, glipizide released amount was 87% at pH 1.5,80% at pH2.5,38% at pH5.0 and 37% at pH 6.8. The release mechanism of glipizide from the CS-TPP hydrogel beads at different pH was analyzed by a semi-empirical equation, and the results were found that glipizide release from hydrogel beads was controlled by Fickian Diffusion at pH1.5-pH5.0, and was controlled by Anomalous Transport at pH6.8-pH8.0. The research results of the CS-TPP microgels: the CS-TPP microgels at the optimum preparation technique had round shape and smooth surface, and average particle size was 55μm. The released amount of the CS-TPP microgels at pH1.5, pH5.0 and pH 6.8 were 90%,44% and 36% within 15 h respectively, after 48h, the released amount was 67% and 52% at pH5.0 and pH 6.8 respectively, drug release result showed that the CS-TPP microgels was pH sensitivity, and the drug released amount increased with pH decreasing. The research results of release mechanism illustrated that glipizide release from the CS-TPP microgels was controlled by Fickian Diffusion at pH1.5, and was controlled by Anomalous Transport at pH5.0 and pH6.8. The research results of the temperature/glucose/pH triple-sensitive hydrogels system:this hydrogel system was liquid at room temperature, and it occurred phase transition to become light yellow semi-solid state at the physiological temperature, the time of gel formation was 0.83min. Within 24h, the drug released amount of the hydrogel system at 0M,0.1M and 0.2M glucose concentration was 35%,59% and 93% respectively, this result indicated that this hydrogel system has significant glucose sensitivity, with the increase of the glucose concentration in the media, drug release from the temperature/glucose/pH triple-sensitive hydrogel system increased.Conclusion The glipizide loaded temperature/glucose/pH triple-sensitive hydrogel could be further developed for a intelligent drug delivery system suitable for subcutaneous injection, this intelligent delivery system can consciously feel the changes in blood sugar, when blood sugar increased, glucose molecules diffused into intelligent delivery system, glucose molecules reacted with glucose oxidase to generate gluconic acid, gluconic acid caused the decrease of pH of microenvironment within the hydrogel system, and the CS-TPP microgels feel this pH changes to controlled drug release, drug release increased with glucose concentration increasing. This intelligent drug delivery system can effectively reduce the number of taking medicine and improve the drug bioavailability and stability, and avoid side effects when administered orally.