Synthesis, Characterization And Application In Drug Release Of PH-and Tempareture-sensitive Hydrogel Beads/microparticles

In this thesis, carboxymethyl chitosan and methacrylic acid are used as pH-sensitive functional monomers, and N,N-diethylacrylamide is used as temperature-sensitive functional monomer. Thermo-and pH-sensitive hydrogel beads/microgels with different sizes and spherical structure have been synthesized by using different preparation methods to adjust the polymer composition. The drug release experiment results show that these drug carriers have good pH-and temperature-sensitivity. They could be used as suitable candidate for drug site-specific carrier in intestine, which have no cytotoxicity. The results are summarized as following:1. A series of novel carboxymethyl chitosan grafted poly(N-vinylpyrrolidone) copolymers with different grafting percentages is synthesized. The hydrogel beads are prepared by an ionic crosslinked method. The swelling ratio experiment of the hydrogels shows that the hydrogel beads have good pH-sensitivity. From drug release experiments for these beads, it can be seen that the drug release rate decreased with increasing grafting percentage, crosslinker concentration and pH value. The preliminary results for releasing experiments of model drug show that CMCTS-g-PVP beads have better control ability than CMCTS beads. This system has a great application potentiality for the carrier and controlled-release in intestine.2. pH-and temperature-sensitive carboxymethyl chitosan-graft poly(N,N-diethylacrylamide) (CMCTS-g-PDEA) copolymers are obtained by using free radical copolymerization in water solution. The hydrogel beads are prepared based on Ca2+ ionic crosslinking in acidic solution, and the dual crosslinked network structure is formed. The result about swelling characteristics of hydrogel beads indicates that the beads have obvious pH-and temperature-sensitivity. In vitro release results of drug-loaded beads indicate that the dual crosslinked method can effectively control the drug release rate under gastrointestinal tract conditions which is superior to traditional single crosslinked beads. In addition, increasing the grafting percentage and temperature can decrease the release rate of VB2. The dual crosslinked hydrogel beads based on carboxymethyl chitosan-graft-poly(N,N-diethylacrylamide) can serve as suitable candidate for drug site-specific carrier in intestine.3. Temperature-and pH-responsive P(DEA-co-MAA) microspheres of nanometer size with core-shell structure have been prepared by surfactant-free emulsion polymerisation (SFEP) method. With the pH value increasing, the hydrodynamic diameter size (Dv) of the microgels significantly could increas. By increasing MAA content in the copolymers, their LCST increased, and the LCST can reach the body's physiological temperature. The in vitro release studies show that the drug release behavior of P(DEA-co-MAA) microspheres is better than the drug release behavior of PDEA microspheres. These P(DEA-co-MAA) microspheres can decrease release rate of BSA drug in gastric and accomplish purpose in controlled release for drug side-specific in intestine. The cytotoxicity of all prepared microgels is low, and they have no apparent cytotoxicity.4. Nanosized self-assembly of CMCTS-g-PDEA microgels is obtained by simple strategy. Morphology of the self-assemby microgel can be controlled by adjusting the grafting percentage, that is, microcapsules and microparticles. The in vitro release studies show that the drug release rate of microgel in the acidic environment is significantly lower than the release rate in alkaline environment, and for the microcapsules, release percentage decreases with increasing grafting percentage. Moreover, although the microparticles have a higher grafting percentage, the drug release rate of microparticles is faster than the microcapsules because of its smaller network crosslinking density. The qualitative cytotoxicity test of the microgels shows that they have no apparent cytotoxicity.5. The PHEMA-b-PDEA-b-PHEMA triblok copolymer is successfully synthesized by atom transfer radical polymerization method, and the copolymer can self-assemble into nanomicelles with uniform diameter in water solution. The micelles are thermodynamically stable in aqueous media with a low critical micelle concentration value. In vitro drug release from the drug-loaded micelles have a dramatically thermosensibility. To be used as drug carriers, they will accumulate at target sites and release drugs in a local hyperthemia method. The cytotoxicity of all prepared microgels is low, and they have no apparent cytotoxicity.