【摘要】：研究目的：建立載紫杉醇脂質(zhì)體體外含量以及包封率測定方法；制備載紫杉醇陽離子脂質(zhì)體,通過單因素考察篩選最優(yōu)處方；制備透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體,對其理化性質(zhì)、體外釋放、體內(nèi)藥效學及藥物動力學進行初步評價。 研究方法：采用HPLC法建立載紫杉醇脂質(zhì)體體外紫杉醇含量測定方法和包封率的測定方法,并進行方法學考察；采用薄膜分散法進行載紫杉醇陽離子脂質(zhì)體的制備,并對影響脂質(zhì)體成形的因素進行單因素考察,獲得最優(yōu)處方；負電性透明質(zhì)酸包裹到荷正電的載紫杉醇陽離子脂質(zhì)體上,透射電鏡觀察其形態(tài),激光粒度分析儀測定粒徑,電勢分析儀測定Zeta電位值；采用動態(tài)膜透析法對透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體進行體外釋放行為的考察；采用小鼠進行藥物動力學評價,荷瘤小鼠進行體內(nèi)藥效學評價。 研究結(jié)果：成功建立載紫杉醇脂質(zhì)體體外含量以及包封率測定方法,方法學考察符合要求。成功制備載紫杉醇陽離子脂質(zhì)體,通過單因素考察進行處方優(yōu)化,獲得最優(yōu)處方,最優(yōu)處方的粒徑、電位、包封率和載藥量分別為(162.1±4.59)nm、(27.04±5.88)mV、(97.63±1.47)%、(4.05±0.08)%成功制備透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體,最優(yōu)處方的粒徑、電位、包封率和載藥量分別為(237.87±6.63) nm、(-29.99±0.61) mV、(89.44±3.80)%、(3.60±0.15)%；體外釋放結(jié)果顯示泰素(?)組的釋放行為擬合的數(shù)學方程為lnln(1/(1-Q/100))=0.96321nt-2.3540(r=0.9970),符合韋伯方程；透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體組的釋放行為擬合的數(shù)學方程為100-Q=45.9567e-0.2010t+54.8828e-0.0026t,符合Bioexponential數(shù)學模型；體內(nèi)藥物動力學試驗結(jié)果發(fā)現(xiàn)透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體組血藥濃度迅速降低,30min后血藥濃度均低于泰素(?)組；藥物動力學參數(shù)計算結(jié)果顯示,透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體K10為2.163±0.20732h-1,顯著低于泰素(?)組(P0.001)；體內(nèi)藥效學結(jié)果顯示載紫杉醇陽離子脂質(zhì)體組小鼠的瘤體積變化與泰素(?)組相似,而透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體組小鼠瘤體積顯著小于泰素(?)組(P0.001)。 結(jié)論：經(jīng)透明質(zhì)酸修飾的載紫杉醇脂質(zhì)體是一種制備工藝簡單,理化性質(zhì)穩(wěn)定,抑瘤效果明顯,并具有一定緩釋作用的制劑。
[Abstract]:Objective: to establish a method for the determination of paclitaxel-loaded liposomes in vitro and entrapment efficiency, to prepare Taxol-loaded cationic liposomes, and to screen the optimal prescription by single factor investigation. The physicochemical properties, in vitro release, pharmacokinetics and pharmacokinetics of hyaluronic acid modified paclitaxel liposomes were evaluated. Methods: the determination method of paclitaxel content in vitro and the entrapment efficiency of paclitaxel-loaded liposomes were established by HPLC method, and the methodology was investigated. The preparation of Taxus alcohol cationic liposomes was carried out by thin film dispersion method, and the factors affecting the formation of liposomes were investigated by single factor, and the optimal prescription was obtained. The negative hyaluronic acid was wrapped on the positively charged Taxus alcohol cationic liposomes, the morphology was observed by transmission electron microscope, the particle size was measured by laser particle size analyzer, and the potential value of Zeta was measured by potential analyzer. The release behavior of hyaluronic acid modified paclitaxel liposomes in vitro was investigated by dynamic membrane dialysis, and the pharmacokinetics of paclitaxel liposomes modified by hyaluronic acid was evaluated by pharmacokinetics in mice and in vivo by tumor bearing mice. Results: a method for the determination of paclitaxel-loaded liposomes in vitro and entrapment efficiency was successfully established, and the methodological investigation met the requirements. Taxol cationic liposomes were successfully prepared and optimized by single factor investigation. The optimal prescription was obtained. The particle size, potential, entrapment efficiency and drug loading of the optimal prescription were (162.1 鹵4.59) nm, (27.04 鹵5.88) mV, respectively. Paclitaxel liposomes modified by hyaluronic acid were successfully prepared by (9763 鹵1.47)% and (4.05 鹵0.008)% hyaluronic acid modified paclitaxel liposomes. The optimal prescription particle size, potential, entrapment efficiency and drug loading were (237.87 鹵6.63) nm, (- 29.99 鹵0.61) mV, respectively. (89.44 鹵3.80)%, (3.60 鹵0.15)%; The results of in vitro release showed that Taxol (?) The mathematical equation of the release behavior of the group was lnln (1 / (1-Q/100) = 0.96321nt-2.3540 (r 鈮，

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