Thermosensitive hydrogels based on chitosan are of great interests for injectable implant drug delivery. The poly(ethylene glycol)-grafted-chitosan (PEG-g-CS) hydrogel was reported as a potential thermosensitive system. The objective of the present study is to evaluate the cytotoxicity, in vivo degradation and drug release of PEG-g-CS hydrogel. Cytotoxicity was evaluated using L929 murine fibrosarcoma cell line. Degradation and drug release in vivo were investigated by subcutaneous injection of the hydrogel into Sprague-Dawley rats. PEG-g-CS polymer exhibits no significant cytotoxicity when its concentration is less than 3 mg mL(-1). After being implanted, PEG-g-CS hydrogel maintains its integrity for two weeks and collapses, merging into the tissue, in the third week. It causes moderate inflammatory response but no fibrous encapsulation around the hydrogel is found. The hydrogel presents a three-week sustained release of cyclosporine A with no significant burst release in vitro and produces the effective drug concentration in blood for more than five weeks in vivo, performing almost the same bioavailability to chitosan/glycerophosphate hydrogel. Further modifications of PEG-g-CS hydrogel might be necessary to modulate the degradation and to mitigate the fluctuations in blood drug concentration.
ABSTRACT:The aim of this study was to prepare and investigate the physical properties of a thermosensitive crosslinked chitosan pregel solution, and evaluate the in vitro release profiles of macromolecules from this sol-gel transition system. Chitosan and poly (vinyl alcohol) were used to form an interpenetrating polymeric network with glutaraldehyde as the crosslinker, and glycerophosphate (GP) was added to transform the pH-dependent solutions into thermosensitive pH-dependent solutions. Rheological study showed that the gelation was dependent on the crosslink degree and GP concentration of the solution. The crosslinked gel had excellent mechanic properties and no apparent "pores" and formed an integrated hydrogel texture according to scanning electronic micrograph. Gas chromatography test guaranteed the medication safety with no detection of glutaraldehyde remnants in the hydrogels. In vitro release study showed that the gelation does not significantly affect the macromolecules diffusion but the crosslinking degree does. These results indicated that the hydrogel formed an intensified three-dimensional hybrid network with interpenetrating molecules, which effectively buffered or delayed the macromolecules diffusion. The hydrogels sustained the drug release over 30 days and could be potentially used as in situ gelling implants.
In vitro drug release and degradation mechanism of Poly (dl-lactide-co-glycolic acid)-methoxypoly (ethyleneglycol) (PLGA-mPEG) microparticles were investigated under different pH conditions. Methotrexate(MTX), an antirheumatic drug, was employed as the model drug. In polyester-based microparticle system, two main issues involved in degradation were water uptake and the carboxylic groups produced by chain scission. Polymer composition was identified to be responsible for the odd degradation behavior in different releasing media. Because of the exposure of mPEG chains at the particle surface, microparticle degradation showed apparent different mechanism under the investigated releasing conditions. At pH 10.08, microparticles exhibited rapid weight loss but slower molecular weight decrease, and the degradation pattern was close to surface degradation. At pH 7.4, microparticles underwent heterogeneous bulk degradation. However, at pH 1.2, it showed fastest molecular weight decrease while slowest weight loss, and homogeneous degradation was observed. Particle agglomeration was also seen in acidic environment. Fourier transform infrared (FTIR) spectrum results indicated the crystallization of drugs under the low pH condition. Drug release was dependent on transport paths and drug property. These two factors were highly controlled by the polymer degradation and drug solubility in the releasing media as well as drug crystallinity.
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