王浩,温梦,鄂义峰,蔡东,崔银
WANG Hao,WEN Meng,E Yi-feng,CAI Dong,CUI Yin

• 1:锦州医科大学药学院
• 2:辽宁省药物作用与质量评价工程技术研究中心
• 3:锦州医科大学公共基础学院

摘要(Abstract)：

目的以大豆油为药物载体及乳滴基本成分,大豆磷脂为乳化剂,制备苯丁酸氮芥钠亚微乳,考察水相pH,油酸,吐温-80等因素对药物包封率、粒径稳定性的影响,并考察药物的释放行为。方法采用高速剪切法制备粗乳,磷酸调节粗乳外水相pH值,高压均质法制备亚微乳,密封高温高压灭菌得最终产品。激光动态光散射法测定乳滴粒径,酸度计测定乳剂的pH,考察两个时间段的储存期后的乳滴粒径、ζ电位和乳剂pH的变化。低温高速离心分离油水两相,高效液相色谱-紫外分光光度法测定水相及全乳的药物含量并得到包封率,正渗透膜透析法考察乳剂中苯丁酸氮芥钠在pH7.4的磷酸缓冲盐中的释放行为并对释放曲线进行拟合。结果粗乳pH值越低,苯丁酸氮芥钠在最终产品乳滴中的包封率越高,油酸和Tween-80有助于包封率和ζ电位绝对值的提高。所得乳剂在储存30、60 d后,均出现pH降低的现象。油酸防止了粒径的增长和ζ电位绝对值的降低,Tween-80未有此作用。药物有明显的突释相,突释相过后呈现缓释相,包封率越低突释率越高。药物的释放符合Freundlich方程。结论调节合适的pH,选用合适的助乳化剂,有助于得到包封率较高、稳定性较好、呈现特定缓释行为的苯丁酸氮芥钠乳剂。
Objective To prepare chlorambucil sodium submicroemulsion by using soybean oil as a drug carrier and basic ingredient of oil droplet, soybean phospholipid as a emulsifier,and to investigate the effect of aqueous phase pH,oleic acid and Tween-80 on drug encapsulation,particle size stability and the drug release behavior. Methods The coarse emulsion was prepared by high-speed shearing,and the pH of outer phase of coarse emulsion was adjusted by phosphoric acid. Then the sub-micro-emulsion was prepared by high-pressure homogenization. The final product was obtained after sterilizing by high-temperature after sealing. Laser dynamic light scattering was used to determine the particle size and ζ-potential of emulsions,and pH meter was used to determine the pH of emulsions. The particle size,ζ-potential and pH of the emulsions after a period of time storage were also investigated. The oil and aqueous phase of the emulsion were separated by low temperature-high speed centrifugation and the drug content in aqueous phase and total emulsion was determined by high performance liquid chromatography-ultra violet spectrometry method. The release behavior of chlorambucil sodium in pH 7. 4 phosphate buffered saline was investigated by osmotic membranes and the release curves was fitted. Results The lower pH of the coarse emulsions were adjusted,the higher entrapment efficiency of chlorambucil sodium in submicroemulsion. Oleic acid and Tween-80 facilitated the entrapment efficiency and increased the absolute value of ζ-potential. The pH of all emulsions became lower after 30 d and 60 d storage. And oleic acid prevented the increasing of particle sizes and the absolute value of ζ-potential while Tween-80 had no influence on particle size and ζ-potential. The drug has obvious burst release phase,and the sustained release phase after the burst release phase, the lower theencapsulation efficiency is, the higher the rate of release. The release of the drug is consistent with the Freundlich equation. Conclusions As the pH is adjusted to appropriate value,and a proper co-emulsifier is chosen,chlorambucil sodium emulsion can be obtained with higher entrapment efficiency,better stability and sustained release behavior.

关键词(KeyWords)： 亚微乳;苯丁酸氮芥钠;高压均质法;包封率;稳定性;Freundlich方程
submicroemulsion;chlorambucil sodium;high pressure homogenization;entrapment efficiency;stability;Freundlich equation

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金资助项目(511021178);; 辽宁省科技厅资助项目(2014022041);; 中国博士后基金资助项目(2014M561187)

作者(Author): 王浩,温梦,鄂义峰,蔡东,崔银
WANG Hao,WEN Meng,E Yi-feng,CAI Dong,CUI Yin

DOI: 10.14066/j.cnki.cn21-1349/r.2017.011.002

参考文献(References)：

• [1]DIGHIERO G,MALOUM K,DESABLENS B,et al.Chlorambucil in indolent chronic lymphocytic leukemia[J].New England Journal of Medicine,1998,338:1506-1514.
• [2]潘启超.抗癌药物的不良反应[J].新医学,1982,13(2):106-108.
• [3]RIECH K.抗癌药物对人体的不良反应[J].药学情报通讯,1987,5(1):23-29.
• [4]罗兰,潘金火.微粒作为靶向制剂载体的研究进展[J].中国医药工业杂志,1998,29(9):424-428.
• [5]宋宏林.苯丁酸氮芥脂质纳米载体注射给药系统[D].沈阳:沈阳药科大学,2011.
• [6]谷福根,吴春芝,刘红在.我国药用静脉注射乳剂的研究进展[J].中国新药杂志,2010,19(16):1415-1421.
• [7]方亮.药剂学[M].第八版.北京:人民卫生出版社,2016:66-69.
• [8]DRISCOLL D F,GIAMPIETRO K,WICHELHAUS D P,et al.Physicochemical stability assessments of lipid emulsion of varying oil composition[J].Clinical Nutrition,2001,20(2):151-157.
• [9]孙晓译.纳米给药系统的胞内转运研究[D].杭州:浙江大学,2010.
• [10]NORDEN T P,SIEKMANN B,LUNDQUIST S,et al.Physicochemical characterization of a drug-containing phospholipid-stabilized O/W emulsion for intravenous administration[J].European Journal of Pharmaceutical Science,2001,13(4):393-401.
• [11]董南,王秀林,盘金品,等.七、八元瓜环对抗癌药物苯丁酸氮芥稳定性和溶解度的影响研究[J].化学学报,2011,69(12):1431-1437.
• [12]王立新,何海冰,唐星,等.去甲基斑蝥酸钠脂质微球体内外评价[J].药学学报,2006,41(8):784-788.
• [13]王思玲,孙长山,苏德森,等.激光散射法分析异丙酚纳米乳剂的粒径大小与分布[J].沈阳药科大学学报,2003,20(5):336-359.
• [14]LEVY M Y,SCHUTZE W,FUHRER C,et al.Characerization of diazepam submicro emulsion interface:role of oleic acid[J].Journal of Microencapsulation,1994,11(1):79-92.
• [15]张小娟,李竹雯,李树,等.脂肪乳剂理化性质和稳定性的影响因素浅析[J].现代生物医学进展,2010,10(18):3581-3584.
• [16]董泽民.乳剂给药系统药物的靶向输送与释放[J].中国医药工业杂志,1995,26(12):558-563.
• [17]MUHANNAD J,MULLER B W.The effect of oil components and homogenization conditions on the physicochemical properties and stability of parenteral fat emulsions[J].International Journal of Pharmaceutics,1998,163(1/2):81-89.
• [18]FORMIGA F R,FONSECA I A A,SOUZA K B.Influence of a lipophilic drug on the stability of emulsions:An important approach on the development of lipidic carriers[J].International Journal of Pharmaceutics,2007,344(1/2):158-160.