Novel rate-controlled nanoparticles of 17ß-estradiolfor cerebral ischemia therapy

• Main Authors: Chun-Jen Cheng, 鄭鈞任
• Other Authors: 蔡東榮
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/70728951775338046546

碩士 === 高雄醫學大學 === 藥學研究所碩士班 === 94 === Cerebral ischemia leaded to brain damage caused by damaging and endogenous protective mechanism included excitotoxicity, inflammation, overproduction of free radicals and nerve cell apoptosis. Recently, 17ß-estradiol, a sex hormone, has been demonstrated the neuroprotective and neuroregenerative effect for cerebral ischemia. Base on its lipophilic character, it can penetrate the blood-brain barrier and achieve high central levels after peripheral administration. However, estradiol is poorly retained within the brain. According to recent study, the protective effects of estradiol were dose-dependent. Moreover, estradiol has short half-life (1hr) and the time of therapeutic window for ischemia therapy was 4hr. From these viewpoints, the time of remedy and drug dosage were the obstacles for cerebral ischemia therapy. The purpose of this study was to improve these disadvantages by the nanoparticles with sustained release character. In our researsh, bovine serum albumin was chosen as the carrier of the nanoparticles and particles were prepared by the oil-in-water emulsion technique and chemical cross-linking with glutaraldehyde. To obtain the optimum formulation, statistical experimental design was applied to evaluate the influence of some formulation variables and a two-factor five-level central composite design of response surface methodology was chosen as the model. The independent variables were the pH value of aqueous phase and the amount of glutaraldehyde. The dependent variables were drug content, particle sizes, polydispersity index, particle zeta potential, drug encapsulation efficiency, initial burst percentage, cumulative release percentage within the time of therapeutic window, cumulative release percentage of the first 12hr, time of 50% drug release and time 75% drug release . The optimum formulation (when pH value of aqueous phase was 9.98; 5% glutaraldehyde was added to 1611.89 µl. ) was developed from those response equation of each fitted model. The release profiles reveal that 71.17±0.24% drug was released within the time of therapeutic window and then follow therelationship of zero-order release model (from the 4hr to 24hr). The results demonstrated that the little differences between predicated and actual result of optimum formulation revealed high correlation and the application of two-factor five-level response surface methodology design resulted a useful tool for the optimization of 17ß-estradiol nanoparticles. Besides, the brain microdialysis study demonstrated that 17ß-estradiol nanoparticles with the ability to penetrate blood-brain barrier and obviously increased and maintained drug concentration in the brain over 12hr.