【摘要】：為得到制劑學特性優(yōu)良,且高穩(wěn)定性的鹽酸吉西他濱脂質(zhì)體,本論文以PEG修飾二硬脂酰磷脂酰乙醇胺(PEG2000-DSPE)、氫化大豆磷脂(HSPE)、膽固醇(Chol)為載體材料,采用改良薄膜法、凍融法制備PEG化鹽酸吉西他濱脂質(zhì)體。建立了鹽酸吉西他濱含量測定的HPLC法,并進行了方法學驗證。該方法專屬性強,重復性良好(RSD2%),準確度高,鹽酸吉西他濱在1~40μg/mL內(nèi)線性關(guān)系良好。采用葡聚糖凝膠色譜法分離脂質(zhì)體和游離藥物,準確度較好,回收率高。對脂質(zhì)體制備工藝進行了研究,通過對比薄膜分散法、乙醇注入法、逆相蒸發(fā)法、改良薄膜法、凍融法、硫酸銨梯度法以及PEG2000-DSPE摻入方式等制備方法對吉西他濱脂質(zhì)體包封率的影響,最終確定采用改良薄膜法與凍融法相結(jié)合,PEG2000-DSPE后加制備PEG化鹽酸吉西他濱脂質(zhì)體;并通過單因素試驗結(jié)合響應面分析法,對PEG化鹽酸吉西他濱脂質(zhì)體的處方和制備工藝進行優(yōu)化;優(yōu)化后的脂質(zhì)體平均包封率71.8%,在透射電鏡下呈球狀、均勻完整、分散性較好;平均粒徑為202.1±5.6 nm,多分散系數(shù)(PDI)為0.209±0.04,Zeta電位-17.9±0.73 m V。穩(wěn)定性試驗結(jié)果表明,在一定范圍內(nèi),PEG化脂質(zhì)體有一定的抗稀釋和抗氧化作用;在4℃條件下能穩(wěn)定存放30 d;在強酸、強堿、高溫條件下不穩(wěn)定。為達到長期保存目的,篩選了PEG化鹽酸吉西他濱脂質(zhì)體凍干粉針劑的處方和工藝。凍干后PEG化脂質(zhì)體的藥物保留率在90%以上,平均粒徑為227.4±6.4 nm,PDI為0.223±0.05,Zeta電位為-17.4±0.86 mV,在4℃條件下能穩(wěn)定存放3個月。體外釋放結(jié)果表明,PEG化脂質(zhì)體中藥物的釋放速率較游離藥物和普通脂質(zhì)體釋放速率小;PEG外加法比內(nèi)加法制備的脂質(zhì)體釋藥速率小,且均具有一定的緩釋作用。綜上所述,本文制備了PEG化鹽酸吉西他濱脂質(zhì)體及其凍干制劑,并對其制備工藝、制劑學性質(zhì)進行了研究,為以后深入研究鹽酸吉西他濱以及其它水溶性藥物脂質(zhì)體制劑打下了良好的基礎(chǔ)。
[Abstract]:In order to obtain gemcitabine hydrochloride liposomes with excellent properties and high stability, PEG modified distearyl phosphatidylethanolamine (PEG2000-DSPE) and hydrogenated soybean phospholipid (HSPE), cholesterol (Chol) were used as carrier materials. PEG gemcitabine hydrochloride liposomes were prepared by modified thin film method and freeze-thaw method. A HPLC method for the determination of gemcitabine hydrochloride was established and validated. The method has good specificity, good repeatability (RSD2%) and high accuracy. The calibration curve of gemcitabine hydrochloride is good in the range of 1 ~ 40 渭 g / mL. The separation of liposomes and free drugs by dextran gel chromatography showed good accuracy and high recovery. The preparation process of lipid system was studied by comparing film dispersion method, ethanol injection method, reverse phase evaporation method, modified thin film method, freeze-thaw method. The effects of ammonium sulfate gradient method and PEG2000-DSPE incorporation method on the entrapment efficiency of gemcitabine liposomes were studied. Finally, the modified thin film method combined with freeze-thaw method was used to prepare gemcitabine hydrochloride liposomes with PEG after PEG2000-DSPE. The formulation and preparation technology of PEG gemcitabine hydrochloride liposomes were optimized by single factor test and response surface analysis. The average entrapment efficiency of the liposomes was 71.8% and the average particle size was 202.1 鹵5.6mV, (PDI) was 0.209 鹵0.04, Zeta potential was-17.9 鹵0.73 MV, and the average diameter of the liposomes was 202.1 鹵5.6mmol / L, (PDI) was 0.209 鹵0.04mV. the average entrapment efficiency of the liposomes was 71.8%. The stability test results show that PEG liposomes have certain anti-dilution and anti-oxidation effects within a certain range, can be stored stably at 4 鈩，

本文編號：2446122