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Cyclosporine Copolymer Micelles And In Rats In Vivo Pharmacokinetic Studies

Posted on:2010-06-09Degree:MasterType:Thesis
Country:ChinaCandidate:D G YaoFull Text:PDF
GTID:2204360302958709Subject:Medicinal chemistry
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Polymeric micelles have been widely used to increase the solubility of some water-insoluble drugs in recent years. Cyclosporine A (CyA), a water-insoluble peptide, was chosen as the model drug for the study of solubilization capacity of polymeric micelles. The freeze-drying technology, in vitro release behavior and stability of CyA-loaded mPEG-PLGA polymeric micelles were also investigated. Pharmacokinetic behaviors of polymeric micelles in rats were studied compared with Sandimmune, a commonly used injection formulation. This study was done in order to find whether polymeric micelles can become a suitable carrier for insoluble drugs when prepared for intravenous injection.In this thesis, the block copolymers of mPEG-PLGA were prepared from D, L-LA, GA and mPEG (Mw 2000). The compositions of the copolymers were characterized by IR and 1HNMR. Molecular weight and polydispersity index, thermal properties and critical micelle concentration (CMC) were determined by GPC, DSC and fluorescence spectrophotometer. The results showed that the structure and molecular weight of obtained copolymers were basically in accord with pre-design. The obtained copolymers were satisfied the needed of present experiment.Blank micelles and CyA-loaded mPEG-PLGA micelles were prepared by co-solvent evaporation method. Entrapment efficiency and particle sizes as index, single factor experiments were carried out to evaluate the type of organic solvent, the ratio of organic to water and the initial concentration of CyA. The results show that micelles prepared here present core-shell structure and nano-scale. The obtained optimum experimental conditions are: a polymer type of mPEG-PLGA75/25(2) copolymer, a organic solvent of acetone, a ratio of organic to water of 1/5, a initial concentration of 5mg/ml. The entrapment efficiency increasing with the PLGA chain segment molecular weight enlarged, and the particle sizes present the same trend. The law of the particle size significantly increased as the ratio of LA to GA in PLGA segment enhanced was found for the first time.The freeze-drying conditions, release behavior and stability of CyA-loaded mPEG-PLGA micelles were separately investigated. Freeze-drying experimental results revealed that stereo protective agent (PEG4000, PEG6000, et al.) showed better protective effect. The particle size and entrapment efficiency remained basically unchanged after freeze-drying. The mPEG-PLGA micelles showed sustained release behavior and release lasted more than 10 days. The release behavior related to the ratio of LA to GA in PLGA segment and the higher the ratio of LA to GA the slower the drug release. While the molecular weight of PLGA segment increase, the drug remain capacity of the CyA-loaded mPEG-PLGA micelles enhanced. The mPEG-PLGA micellar preparation showed high stability under low temperature.Pharmacokinetic behaviors of polymeric micelles in rabbits after intravenous injection were studied compared with Sandimmune. Results showed that AUC and t1/2 of polymeric micelles and Sandimmune were 39.62(μg/ml)·h and 16.86 (μg/ml)·h, 11.12h and 7.21h, respectively. The results showed that administrated same dose of Sandimmune and micellar preparation, the micellar preparation showed the half-life prolonged and better sustained behavior...
Keywords/Search Tags:mPEG-PLGA copolymer, micelle, Cyclosporine A, critical micelle concentration, freeze-drying, in vitro release, stability, pharmacokinetics
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