Synthesis, Characterization, And Drug Delivery Behavior Of Amphiphilic Chitosan Derivatives

Interest in natural polymer matrices for pharmaceutical formulation continues to growspecially in drug sustained/controlled release system, allowing to targeting the release ofdrugs in specific conditions or site. Special attention is currently given to chitosan, anatural cational polymer of poly（aminosaccharide）, for its non-toxic, biodegradable andbiocompatible, which was widely used in medical, argicultural, food and chemistryindustries. However, chitosan is only soluble in a few dilute acid solutions which greatlylimits its wide applications. The mainly purpose of this paper was successfully synthesizeda series novel amphiphilic chitosan derivatives by incorporation of carboxymethyl group ashydrophilic moieties in the C2position-NH₂, and diethylaminoethyl group as hydrophobicgroups in the C6position-CH₂OH of structural unit of chitosan, which expanded thescopes of Chitosan’ applications.Amphiphilic chitosan derivatives2-N-carboxymethyl-6-0-diethylaminoethyl-chitosan（DEAE-CMC） were prepared by the technology of “Amino protection—Modified reaction—Amino deprotection and restoration”. The paper discussed the synthesis conditions onthe yield of the DEAE-CMC, and the preparation programs were optimized and tested withL9（34） orthogonal. The structure of DEAE-CMC was characterized by UV-VIS spectrum,IR spectrum,¹HNMR spectroscopy, thermal stability. The fundamental physical-chemicalproperties of the synthesized compounds had been made systematic and in-depth study.The DEAE-CMC/VB₁₂microspheres were prepared by “Emulsion—Crosslinking—Solidification” method with the mean diameter, loading content, entrapment efficiency asperformance indicators. The concentration of DEAE-CMC, the optimal molar ratio of DEAE-CMC to VB₁₂, the mixing speed at emulsion stage, the quantity of emulsifyingagent were discussed with orthogonal method. The orthogonal intuitive analysis andvariance analysis were also used in the optimal selection procedure. The structure andphysical-chemical properties of the DEAE-CMC/VB₁₂microspheres were analysized byIR spectrum, TG and DSC. The partical size, topography and microstructure of themicrospheres were analyzed by laser particle size analyzer and scanning electronmicroscopy （SEM）.The result showed that the optimum conditions for the preparation ofDEAE-CMC/VB₁₂microspheres were as follows: the concentration of DEAE-CMC was2%, optimal molar ratio of DEAE-CMC to VB₁₂was12:1, the mixing speed at emulsionatage was1000r/min; the quantity of emulsifying agents was2mL. Microstructureindicated that the whole size of the microspheres loaded VB₁₂was dispersed in0.2-50μm,and the mean particle size was4.53μm. The microspheres became smaller with gooddispersion, uniform size, less agglomeration sphere; the spherical was regular with roundedsurfaces. However, The SEM images showed that incorporation of drug into themicrospheres altered the surface morphology of DEAE-CMC microspheres; some of thedrugs were adsorped and filled in the cystoid structure of the microspheres.The drug release behavior of the DEAE-CMC/VB₁₂microspheres in pH7.4phosphate buffer solutions showed that: the release time can last about60h, the loadingcontent was12.47%, and the entrapment efficiency was33.70%. At the equilibrium, theaccumulated release ratio of the drug was56.30%.5kinds of common experience modelswere fitted with the drug release behaviors of microspheres in vitro, and the paper alsoestablished the models of the drug release kinetics equations. Considerating the degree offitting and parameters at complexities situation, we used the Akaike’s InformationCriterion （AIC） to evaluate the models and the results showed that: the second orderexponential decay kinetics model was more better reflect the actual drug release of themicrospheres.