Study On Synthesis, Characterization And Properties Of Chitosan-based Sustained Releasing Drug Deliveries

Three series of chitosan-based drug deliveries were designed and synthesized with lactose acid modified chitosan as guiding group and their structures were characterized in this thesis. The drug sustained releasing systems were constructed with 5-fluorouracil as model drug and their releasing behavior in vitro was studied. The main contents of this thesis include following:(1) Three series of novel chitosan-based drug deliveries were designed and synthesized. They were: i) chitosan-based drug deliveries modified with dipeptide, ii) chitosan-based drug deliveries modified with carboxyethyl, iii) chitosan-based drug deliveries modified with lysine. A total of eight new compounds were obtained and their structures were characterized by IR, UV-Vis, LC/MS or 1_H NMR.(2) Microspheres of dendritic chitosan -5 - fluorouracil (6) were prepared by the use of dialysis method based on principle of self-assembly. The diameter of microspheres was determined by laser diffraction and the configuration of microspheres was scanned using SEM. The results were the average diameter of microspheres of 4μm and regular spheres with good distribution.(3) Some synthetic conditions were optimized. i) Optimum conditions of bromoacetyl phenylalanine(1) were pH value of 10~11, temperature of -4℃and reaction time of 1.5h. ii) N,N-dicarboxyethyl chitosan was synthesized by microwave heating. Optimum conditions with fixed power of 550W were heating time of 50 min, reaction rate of 260 times as conventional heating and the DS of N,N-dicarboxyethyl chitosan of 1.13. iii) Synthesis conditions of dendritic chitosan-5-fluorouracil(6) were resaerched and the mechanism of crosslinking side reactions was explored and the optimum reaction time was 24h under room temperature.(4) The drug loading(w/w) and releasing properties in vitro of drug sustained releasing systems were determined with UV-Vis. i) Dendritic chitosan-5- fluorour- acil (6) was drug loading of 10.60%. In alkaline media (PBS solution, pH 7.4) and acid media (HCl/KCl solution, pH 1.2), its zero-order releasing time were 42h, 34h respectively and cumulative releasing percentage were 57.40%, 77.86% respectively in 182h. ii) Microspheres of dendritic chitosan -5 - fluorouracil were drug loading of 13.21% and encapsulation efficiency of 26.1%. In alkaline and acid media its slight burst release phenomenon appeared at the beginning of 10h and 6h respectively, cumulative releasing percentage of burst release were 19.93%, 23.82% respectively and cumulative releasing percentage were 58.89%, 79.33% respectively in 182h. iii) Dendritic galactosylated chitosan-5-fluorouracil (7) was drug loading of 7.48%. In alkaline and acid media, its zero-order releasing time were 34h, 28h respectively and cumulative releasing percentage were 65.45%, 87.51% respectively in 182h. iv) Dendritic chitosan lysyl-5-fluorouracil (10) was drug loading of 9.17%. v) Dendritic four-galactosylated chitosan-5 - fluorouracil (13) was drug loading of 1.63%. In alkaline and acid media, its zero-order releasing time were 64h, 24h respectively and cumulative releasing percentage were 71.97%, 82.34% respectively in 184h.