【摘要】：膀胱灌注是通過導尿管將各種化學藥物注入膀胱內的給藥方式。膀胱灌注給藥具有可使膀胱內保持高藥物濃度同時基本無全身吸收的優(yōu)點,但是藥物在膀胱內保留通常不超過兩個小時就會隨灌注后的第一次排尿而被清除出體外,而膀胱灌注的療效很大程度上取決于藥物在膀胱內的滯留時間,因此采用控釋給藥來延長藥物滯留時間就顯得尤為必要。最新研究是采用溫度敏感凝膠貼附于膀胱壁上作為藥物儲存器用于膀胱灌注給藥。由于凝膠的粘性,它可以貼附在膀胱壁上避免隨著排尿而被排出體外,因此它所載的藥物在膀胱內的滯留時間就得到了延長。然而,由于凝膠的高粘度,凝膠載藥用于膀胱灌注最主要的問題就是很容易引起尿路堵塞,凝膠很容易堵塞膀胱內兩側細小的輸尿管口或尿道。由于凝膠粘附于膀胱壁,另一個問題就是很可能引起嚴重的膀胱刺激征。因此,盡管凝膠載藥用于膀胱灌注在延長藥物膀胱滯留時間方面優(yōu)勢明顯,但是鑒于上述的兩個缺點,很大程度上降低了凝膠載藥用于膀胱灌注的可行性。為了克服凝膠載藥用于膀胱灌注的缺陷,我們制備了一個可以用于膀胱灌注的漂浮凝膠載藥體系。漂浮凝膠載藥體系由泊洛沙姆407(Poloxamer407, P407)與碳酸氫銨(NH4HCO3)組成,在較低溫度下該體系為流動的溶液狀態(tài),而在37℃左右的體溫下則迅速轉變?yōu)椴涣鲃拥哪z狀態(tài),同時凝膠內的NH4HCO3在37℃時分解為二氧化碳、氨氣及水,凝膠內的氣體使凝膠內充滿氣泡,凝膠的密度降低,凝膠因此能夠漂浮于膀胱內的尿液中而不引起尿路堵塞。本實驗研究中,我們篩選出了45%P407與6% NH4HC03的混合溶液作為漂浮凝膠載藥體系的最佳配方。體外實驗中,我們證實了該混合溶液在37℃體溫下可以由溶液迅速轉變?yōu)槟z并產(chǎn)生氣泡,該載藥體系可穩(wěn)定漂浮于液體中并緩慢釋放出所載的抗腫瘤藥物阿霉素。在體內實驗中,當載藥體系溶液被灌注入兔子膀胱后,在兔子膀胱內迅速成膠并漂浮于膀胱內,漂浮凝膠對膀胱刺激性降低并持續(xù)緩慢釋放出所載的阿霉素。體內外的實驗結果表明漂浮凝膠載藥體系可顯著延長所載藥物阿霉素在膀胱內的滯留時間以提高藥效。我們的研究成果顯示,漂浮凝膠是膀胱灌注可用的載藥體系,并有望應用于膀胱癌的膀胱灌注化療載藥。
[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.
【學位授予單位】：南京大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R737.14

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5 張明s，

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