大学毕业论文__论质量源于设计(qbd)在制剂处方筛选中的应用以长春新碱脂质体为例.docVIP

摘 要 研究背景：长春新碱是一种广谱抗癌药，广泛应用于肿瘤联合化疗，但由于严重的神经毒性和组织刺激性等不良反应，其临床应用受到限制。众所周知，脂质体是一种靶向给药制剂，具有类细胞结构，进入体内主要被网状内皮系统吞噬而活化机体的自身免疫功能，并改变被包封药物的体内分布，从而提高药物的治疗指数、减少药物的治疗剂量和降低药物的毒性。 研究目的：本研究拟将长春新碱开发成长循环脂质体制剂，以减小其严重的毒副反应。本论文主要论述长循环长春新碱脂质处方的开发，着重探讨QbD在制剂处方筛选中的应用。 研究方法：根据QbD的理念，首先明确长循环长春新碱脂质体的目标产品质量概况，结合以往脂质体处方开发的经验和风险评估的手段确定药品的关键质量属性。然后以药品的关键质量属性和目标产品质量为出发点，从内相缓冲液的种类、培化磷脂酰乙醇铵（PEG-DSPE）的用量和药物的装载比例等因素进行系统筛选，以找出高包封率和可接受的体外药物释放度的处方。然后将这些长春新碱脂质体和游离药物进行药代动力学、毒性和抗肿瘤效果对比，最终筛选出既有最佳的抗肿瘤效果又表现出最低毒性的处方，同时对该处方进行初步稳定性考察。结果表明筛选出的处方在冷藏条件下稳定，不易渗漏，包封率高，粒径分布均匀， 其质量属性符合预先设定的目标。 研究结论：本研究应用QbD的方法进行产品开发，对影响产品的关键质量属性进行了科学系统的研究，找出了影响产品质量的与处方和工艺相关的因素， 从而制定合理的控制战略， 使研发出的产品能够顺利转移到生产部门， 最终实现商业化生产。 关键词：质量源于设计，QbD；处方筛选；脂质体；关键质量属性；风险评估；稳定性；药物动力学 The application of QbD in Formulation Development for Vincristine Liposome Injection Abstract Background: Vincristine has been widely used in treatment of various cancers, especially in combined chemotherapy. However, clinical use of vincristine may cause severe neurotoxicity and tissues irritation, which limits its clinical application. It is well-known that liposome formulation is a targeted drug delivery system, which has structure similar to cells. There are many advantages to use liposome formulation in clinics. Liposomes could stimulate immune system once engulfed by reticuloendothelial system (RES). In-vivo distribution of a drug entrapped into liposomes could be changed, leading to decrease of therapeutical doses and thus adverse effects. Research Purposes: formulating vincristine into long-circulating liposomes may significantly reduce its severe adverse effects, so the clinical outcome could be further improved. The purpose of this thesis is to develop PEGylated vincristine liposome formulations using current Quality-by-Design (QbD) approach. Research Methods: Using QbD approach in formulation development, the quality target product profile (QTPP) of long-circulating vincristine liposome was first established and critical quality attributes (CQA) were i