Box-Behnken结合响应面法优化制备氟尿嘧啶长循环热敏脂质体
|
摘要
目的:优化制备氟尿嘧啶长循环热敏脂质体.方法:运用Box-Behnken试验设计结合响应面法(BBD-RSM)以包封率为评价指标优化FU-LCTSLs的处方和制备工艺.考察按最优处方制备的FU-LCTSLs的理化性质,包括外观、粒径分布、Zeta电位、pH值和体外热敏释放实验,并对FU-LCTSLs进行稳定性研究.结果:经优化得到最优处方为脂质体膜材与氟尿嘧啶的质量比9.2∶1,水化液中氟尿嘧啶的浓度10mg/mL,有机相与水相的体积比7∶1.按此处方工艺制备的脂质体包封率40.85%,粒径113.7±8.7 nm,PDI=0.538±0.072,Zeta电位-15.34±4.26 mV,pH值7.35±0.04,温度敏感性良好,37℃下30 min累积释药率小于10%,42℃下8 min累积释药率大于95%.稳定性良好,0.22 um微孔滤膜过滤、注射用水或5%葡萄糖稀释对FU-LCTSLs包封率影响不大,4℃保存6个月渗漏率仅2.86%.
OBJECTIVE To prepare fluorouracil loaded long-circulating thermo-sensitive liposomes. METHODS Entrapment efficiency was used as an index to evaluate preparing methods and formulas by Box-Behnken design and responsed surface method. The physicochemical properties of FU-LCTSLs,including appearance,particle size distribution,zeta potential,pH,in vitro thermo-sensitive release behavior were investigated. FU-LCTSLs stability studies were also conducted. RESULTS The best entrapment efficiency was obtained when mass ratio of phospholipid to fluorouracil was9.2∶1,the concentration of fluorouracil rehydration solution was 10 mg/mL and the organic phase and the aqueous phase volume ratio was 7∶1. The entrapment efficiency of optimal formulation was40.85%,Particle size was 113.7±8.7 nm,PDI was 0.538±0.072,Zeta potential was-15.34±4.26 mV,pH value maintained at 7.35±0.04. Excellent temperature sensitivity was observed,cumulative release rate of FU-LCTSLs was less than 10% after 30 min 37 ℃ water bath,however,the value was more than 95% after 8 min 42 ℃ water bath. The optimal FU-LCTSLs exhibited good stability. Passing through 0.22 um filter membrane,dilutting by water for injection or 5% glucose solution generated little effect on the encapsulation efficiency of FU-LCTSLs. FU-LCTSLs maintained more stable when preserved under 4 ℃,the leakage after 6 months preservation was 2.86%.
OBJECTIVE To prepare fluorouracil loaded long-circulating thermo-sensitive liposomes. METHODS Entrapment efficiency was used as an index to evaluate preparing methods and formulas by Box-Behnken design and responsed surface method. The physicochemical properties of FU-LCTSLs,including appearance,particle size distribution,zeta potential,pH,in vitro thermo-sensitive release behavior were investigated. FU-LCTSLs stability studies were also conducted. RESULTS The best entrapment efficiency was obtained when mass ratio of phospholipid to fluorouracil was9.2∶1,the concentration of fluorouracil rehydration solution was 10 mg/mL and the organic phase and the aqueous phase volume ratio was 7∶1. The entrapment efficiency of optimal formulation was40.85%,Particle size was 113.7±8.7 nm,PDI was 0.538±0.072,Zeta potential was-15.34±4.26 mV,pH value maintained at 7.35±0.04. Excellent temperature sensitivity was observed,cumulative release rate of FU-LCTSLs was less than 10% after 30 min 37 ℃ water bath,however,the value was more than 95% after 8 min 42 ℃ water bath. The optimal FU-LCTSLs exhibited good stability. Passing through 0.22 um filter membrane,dilutting by water for injection or 5% glucose solution generated little effect on the encapsulation efficiency of FU-LCTSLs. FU-LCTSLs maintained more stable when preserved under 4 ℃,the leakage after 6 months preservation was 2.86%.
引文
[1]Yan J,Yang J,Ren W,etal.Induction Chemotherapy with Paclitaxel Liposome,Nedaplatin,and Fluorouracil in Patients with Locally Advanced Nasopharyngeal Carcinoma:A Phase II Study[J].International Journal of Radiation Oncology,Biology,Physics,2018,102(3).
[2]李允武,顾芳,沃雁,等.5-氟尿嘧啶乙醇脂质体和变形脂质体的制备及其体外透瘢痕研究[J].中国医药工业杂志,2013,44(5):479-482.
[3]周雪苹,艾又生.5-氟尿嘧啶热敏长循环脂质体的制备和评价[J].中国医院药学杂志,2013,33(15):1236-1240.
[4]杨庆良,夏永华,何岩,等.LHRHa与八聚精氨酸共修饰载氟尿嘧啶靶向脂质体的构建及其抗前列腺癌作用[J].医药导报,2015,34(1):30-34.
[5]张丹,廖芳,周洁,等.Box-Behnken Design-响应面优化法优化芍药总苷脂质体的制备工艺及体外释放研究[J].中草药,2015,46(3):359-364.
[6]冯玲玲,李楠,谭裕君.Box-Behnken优化黄芩苷脂质体的制备工艺及体外释放模型拟合的研究[J].中药材,2017,40(12):2902-2907.
[7]陆媛媛,符旭东,邓艾平,等.K237修饰的紫杉醇热敏脂质体的制备、处方优化和体外释放度研究[J].中国医院药学杂志,2017,37(8):722-726.
[8]张晓宏,赵秀峰,张九龙,等.Box-Behnken效应面法优化制备氯诺昔康柔性脂质体[J].沈阳药科大学学报,2016,33(4):264-270.
[9]周金幸,顾开龙,胡海洋,等.Box-Behnken效应面法优化制备主动载药盐酸小檗碱脂质体[J].沈阳药科大学学报,2014,31(11):856-861+866.
[2]李允武,顾芳,沃雁,等.5-氟尿嘧啶乙醇脂质体和变形脂质体的制备及其体外透瘢痕研究[J].中国医药工业杂志,2013,44(5):479-482.
[3]周雪苹,艾又生.5-氟尿嘧啶热敏长循环脂质体的制备和评价[J].中国医院药学杂志,2013,33(15):1236-1240.
[4]杨庆良,夏永华,何岩,等.LHRHa与八聚精氨酸共修饰载氟尿嘧啶靶向脂质体的构建及其抗前列腺癌作用[J].医药导报,2015,34(1):30-34.
[5]张丹,廖芳,周洁,等.Box-Behnken Design-响应面优化法优化芍药总苷脂质体的制备工艺及体外释放研究[J].中草药,2015,46(3):359-364.
[6]冯玲玲,李楠,谭裕君.Box-Behnken优化黄芩苷脂质体的制备工艺及体外释放模型拟合的研究[J].中药材,2017,40(12):2902-2907.
[7]陆媛媛,符旭东,邓艾平,等.K237修饰的紫杉醇热敏脂质体的制备、处方优化和体外释放度研究[J].中国医院药学杂志,2017,37(8):722-726.
[8]张晓宏,赵秀峰,张九龙,等.Box-Behnken效应面法优化制备氯诺昔康柔性脂质体[J].沈阳药科大学学报,2016,33(4):264-270.
[9]周金幸,顾开龙,胡海洋,等.Box-Behnken效应面法优化制备主动载药盐酸小檗碱脂质体[J].沈阳药科大学学报,2014,31(11):856-861+866.