用于膀胱灌注的漂浮凝胶载药体系的建立及研究

发布时间：2019-03-26 09:34

【摘要】：膀胱灌注是通过导尿管将各种化学药物注入膀胱内的给药方式。膀胱灌注给药具有可使膀胱内保持高药物浓度同时基本无全身吸收的优点,但是药物在膀胱内保留通常不超过两个小时就会随灌注后的第一次排尿而被清除出体外,而膀胱灌注的疗效很大程度上取决于药物在膀胱内的滞留时间,因此采用控释给药来延长药物滞留时间就显得尤为必要。最新研究是采用温度敏感凝胶贴附于膀胱壁上作为药物储存器用于膀胱灌注给药。由于凝胶的粘性,它可以贴附在膀胱壁上避免随着排尿而被排出体外,因此它所载的药物在膀胱内的滞留时间就得到了延长。然而,由于凝胶的高粘度,凝胶载药用于膀胱灌注最主要的问题就是很容易引起尿路堵塞,凝胶很容易堵塞膀胱内两侧细小的输尿管口或尿道。由于凝胶粘附于膀胱壁,另一个问题就是很可能引起严重的膀胱刺激征。因此,尽管凝胶载药用于膀胱灌注在延长药物膀胱滞留时间方面优势明显,但是鉴于上述的两个缺点,很大程度上降低了凝胶载药用于膀胱灌注的可行性。为了克服凝胶载药用于膀胱灌注的缺陷,我们制备了一个可以用于膀胱灌注的漂浮凝胶载药体系。漂浮凝胶载药体系由泊洛沙姆407(Poloxamer407, P407)与碳酸氢铵(NH4HCO3)组成,在较低温度下该体系为流动的溶液状态,而在37℃左右的体温下则迅速转变为不流动的凝胶状态,同时凝胶内的NH4HCO3在37℃时分解为二氧化碳、氨气及水,凝胶内的气体使凝胶内充满气泡,凝胶的密度降低,凝胶因此能够漂浮于膀胱内的尿液中而不引起尿路堵塞。本实验研究中,我们筛选出了45%P407与6% NH4HC03的混合溶液作为漂浮凝胶载药体系的最佳配方。体外实验中,我们证实了该混合溶液在37℃体温下可以由溶液迅速转变为凝胶并产生气泡,该载药体系可稳定漂浮于液体中并缓慢释放出所载的抗肿瘤药物阿霉素。在体内实验中,当载药体系溶液被灌注入兔子膀胱后,在兔子膀胱内迅速成胶并漂浮于膀胱内,漂浮凝胶对膀胱刺激性降低并持续缓慢释放出所载的阿霉素。体内外的实验结果表明漂浮凝胶载药体系可显著延长所载药物阿霉素在膀胱内的滞留时间以提高药效。我们的研究成果显示,漂浮凝胶是膀胱灌注可用的载药体系,并有望应用于膀胱癌的膀胱灌注化疗载药。
[Abstract]:Bladder perfusion is a way of administration of various chemical drugs into the bladder through a urinary catheter. the administration of the bladder has the advantage that the high drug concentration in the bladder is substantially free of systemic absorption, but the retention of the drug in the bladder typically does not exceed two hours and is cleared out of the body with the first urination after perfusion, While the efficacy of the bladder perfusion is largely dependent on the retention time of the drug within the bladder, it is particularly necessary to use the controlled-release administration to extend the drug retention time. The most recent study was to apply a temperature sensitive gel to the bladder wall as a drug reservoir for the administration of the bladder. As a result of the viscosity of the gel, it can be attached to the bladder wall to avoid being expelled from the body as a result of urination, so that the retention time of the drug contained in it is prolonged in the bladder. However, due to the high viscosity of the gel, the most important problem of gel-loaded medicine in the filling of the bladder is that the urinary tract is easily blocked, and the gel is easy to block the fine ureters or the urethra on both sides of the bladder. Another problem is that the gel adheres to the bladder wall, and another problem is likely to cause a serious bladder irritation sign. Thus, although the advantages of the gel-loaded drug in the extension of the drug bladder retention time are significant, in view of the above two disadvantages, the feasibility of the gel-loaded drug for bladder perfusion is largely reduced. In order to overcome the defects of gel-loaded medicine in the bladder perfusion, a floating gel drug-carrying system which can be used for bladder perfusion is prepared. The floating gel drug-carrying system consists of poloxamer 407 (Poloxamer 407, P407) and potassium bicarbonate (NH4HCO3), the system is a flowing solution state at a lower temperature, and is rapidly converted into a non-flowing gel state at the body temperature of about 37 DEG C, and the NH4HCO3 in the gel is decomposed into carbon dioxide at the temperature of 37 DEG C, The gas and water in the gel are filled with air bubbles in the gel, the density of the gel is reduced, and the gel can therefore float in the urine in the bladder without causing a blockage of the urinary tract. In this experiment, we selected a mixed solution of 45% P407 and 6% NH4HC03 as the best formulation of the floating gel drug-loading system. In in vitro experiments, we confirm that the mixed solution can be rapidly converted into a gel by a solution at a body temperature of 37 DEG C and generate bubbles, and the drug-containing system can be stably floating in the liquid and slowly release the contained anti-tumor drug adriamycin. In that in vivo experiment, when the solution of the drug-carrying system is injected into the bladder of the rabbit, the glue is rapidly formed in the bladder of the rabbit and float in the bladder, and the floating gel reduces the irritation of the bladder and continuously releases the contained adriamycin. The results of in-vivo experiments show that the floating gel drug-loading system can significantly prolong the retention time of the drug-loaded adriamycin in the urinary bladder to improve the drug effect. Our research results show that the floating gel is a drug-loaded system that can be used for bladder perfusion and is expected to be applied to the bladder perfusion chemotherapy of bladder cancer.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.14

【共引文献】