Study On Novel Poly (Ether-anhydride) Gel Nanoparticles For Delivery Of Poorly Water-soluble Drugs

For some poorly water-soluble drugs, their low dissolution rate in theenvironmental lumen limits their bioavailability via absorption into thegastrointestinaltract.Nowadays,severalformulationapproachesincludinginhibitingcrystallization to form amorphous particles by solid dispersion, decreasing thediffusion layer through improved wettability by, e.g., addition of surfactants, andcomplexation et al. have been used to increase the drug dissolution rate and therebyoral absorption and bioavailabilitywith various advantages and disadvantages. In thisthesis, the crosslinkable PEG-based macromer and starting materials-methacrylicanhydride and PEG disuccinate were successfully synthesized and characterized byvarious methods and FT-IR, 1H-NMR et al. The gel nanoparticles which werespherical or elliptoid in shape with nano-sized range, were formulated by in situphotocrosslinking of the two synthesized PEG-based macromers with differentmolecular weight in the oil/water microemulsion. The degradation and swellingperformance were investigated. The results inidicated that the prepared particlesexhibited various swelling capabilities in water and in vitro degradation rates underthe experimental conditions, depending on crosslinking density (molecular weight ofmacromer)andthehydrophilicsusceptibility(containingornotadditive).Improve the capability of particles, the gel nanoparticles with core-shell structurewerepreparedbycopolymerizingmethacrylatedstearicacidandPEG-basedmacro-mer in the emulsion droplet, whose structure was characterzed by TEM andphosphotungsticaciddying.Indomethacin and paclitaxel as two poorly water-soluble drugs were respectivelyembedded in the gel nanoparticles and the nanogel with core-shell structure and theentrapment efficiency was determined by HPLC method. The physical state ofindomethacin in the gel nanoparticles was detected by X-ray and DSC analysis. Thein vitro dissolution behavior of indomethacin from the gel particles was studied bydialysis method and water solubility determination. It was found that the drug wasstable in the fabrication process and high drug entrapment efficiencycan be achievedforthecore-shellnanogel,above92%forindomethacinand85%forpaclitaxel.X-rayand DSC analysis showed that indomethacin was amorphously or molecularlydistributed in the gel particles and no recrystallization of indomethacin at room temperaturewas observedintherepresentative gel particles overa period ofat least 8months. The in vitro dissolution experiment indicated that the dissolution rate ofindomethacin from gel nanopartilces was obviously improved and the solubility ofindomethacin and paclitaxel were respectively enhanced by5-fold and 47-fold by thecore-shellnanogel.