【正文】 EPR）效應(yīng)富集到腫瘤組織中， 以此提高對腫瘤細胞的殺傷力，增強藥物療效。聯(lián)合化療是連 續(xù) 用 藥 2 周為一周期。熔點為 218220?C。首先分析研究長春新堿的市售制劑 的 臨床用量、理化性質(zhì)、藥代動力學(xué)等參數(shù)。 此外也有 腹痛、便秘，麻痹性腸梗阻 的報道 。 癌癥是人類的大敵，在攻克癌癥堡壘中，目 前化療還是主要的手段，而提高化療效果的關(guān)鍵是如何提高藥物的靶向性和降低藥物的毒副作用。然后將這些長春新堿脂質(zhì)體和游離藥物 進行藥代動力學(xué)、毒性和抗腫瘤效果對比，最終篩選出 既 有最佳的抗腫瘤效果 又表現(xiàn)出 最低毒性的處方 ，同時 對該處方進行初步穩(wěn)定性考察 。 眾所周知， 脂質(zhì)體是一種靶向給藥制劑，具有類細胞結(jié)構(gòu)，進入體內(nèi)主要被網(wǎng)狀內(nèi)皮系統(tǒng)吞噬而活化機體的自身免疫功能，并改變被包封藥物的體內(nèi)分布，從而提高藥物的治療指數(shù)、減少藥物的治療劑量和降低藥物的毒性。 關(guān)鍵詞： 質(zhì)量源于設(shè)計， QbD； 處方篩選；脂質(zhì)體 ；關(guān)鍵質(zhì)量屬性；風(fēng)險評估；穩(wěn)定性；藥物動力學(xué) II 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 bined chemotherapy. However, clinical use of vincristine may cause severe neurotoxicity and tissues irritation, which limits its clinical application. It is wellknown 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). Invivo 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 longcirculating liposomes may significantly reduce its severe adverse effects, so the clinical oute could be further improved. The purpose of this thesis is to develop PEGylated vincristine liposome formulations using current QualitybyDesign (QbD) approach. Research Methods: Using QbD approach in formulation development, the quality target product profile (QTPP) of longcirculating vincristine liposome was first established and critical quality attributes (CQA) were identified using prior experience and risk assessment tool. Then, the type of intraliposomal trapping agents, the amount of PEGDSPE and the drugtoHSPC ratio (D/L) were investigated to obtain formulations with high encapsulation efficiency and acceptable invitro drug release profile. Moreover, invivo evaluation in animals was also conducted, including pharmacokiic studies, acute toxicity and antitumor efficacy. Finally， a PEGylated liposome formulation with improved therapeutic index and reduced toxicity was selected. The selected liposome vincristine formulation met the predefined QTPP with good physical and chemical stability, higher encapsulation efficiency, lower leaking rate, and acceptable particle size distribution. Research Conclusions: The thesis work followed the principle of QbD to systemically and scientifically evaluate the factors that have impact on product quality attributes and III identify critical quality attributes. Thus, source of variables in formulation and process can be understood and properly controlled. The vincristine liposome formulation developed from this study should be able to successfully transfer to production site in next step to achieve final mercial production. Keywords: Quality by design, QbD, formulation screen, liposome, critical quality attributes, risk assessment, stability, pharmacokiics IV 目 錄 第 1 章 前言 .......................................................................................................................1 第 2 章 長春新堿市售制劑分析 ...........................................................................................3 長春新堿理化性質(zhì) ..........................................................................................................3 長春新堿的市售制劑 .......................................................................................................3 長春新堿的臨床應(yīng)用 .......................................................................................................3 長春新堿的藥代動力學(xué) ...................................................................................................3 第 3 章 長循環(huán)長春新堿脂質(zhì)體的目標(biāo)產(chǎn)品質(zhì)量概況及關(guān)鍵質(zhì)量屬性 ...................................5 長循環(huán)長春新堿脂質(zhì)體的目標(biāo)產(chǎn)品質(zhì)量概況 ....................................................................5 長循環(huán)長春新堿脂質(zhì)體的關(guān)鍵質(zhì)量屬性 ...........................................................................6 pH............................................................................................................................6 粒徑 ........................................................................................................................6 包封率和體外釋放率 ................................................................................................7 降解產(chǎn)物 .................................................................................................................7 殘留溶劑 .................................................................................................................7 無菌和細菌內(nèi)毒素 ...................................................................................................7 第 4 章 處方篩選 .............................................................................................................. 10 處方變量的風(fēng)險評估 .................................................................................................... 10 內(nèi)相緩沖液的影響 ....................................................................................................... 12 脂質(zhì)體的制備方學(xué) ................................................................................................. 12 初步分析方法學(xué) ..................................................................................................... 13 硫酸銨梯度法 [1] ..................................................................................................... 14 磺丁基醚 β環(huán)糊精 三乙胺梯度法 [5]........................................................................ 14 試驗結(jié)果 ............................................................................................................... 15 培化磷脂酰乙醇銨（ PEGDSPE）密度的影響 ............................................................... 16 藥物 類脂比（ D/L）的影響 ...........................