时佳,宋艳志,李宣,陈杰鹏,段丽丽,邓意辉
SHI Jia,SONG Yan-zhi,LI Xuan,CHEN Jie-peng,DUAN Li-li,DENG Yi-hui

• 1:沈阳药科大学药学院
• 2:苏州科伦药物研究院
• 3:广东双骏生物科技有限公司

摘要(Abstract)：

目的借助星点设计效应面法确定维生素K_2口服亚微乳的最优处方。方法采用微射流法制备维生素K_2口服亚微乳;采用星点设计效应面法,以乳剂的平均粒径(mean diameter,MD)、变异系数(coefficient of variation,CV)、离心稳定性常数(centrifugal stability contant,K_E)和冻融稳定性常数(freeze-thawing stability constant,K′_F)为评价指标,考察处方中聚氧乙烯40氢化蓖麻油、大豆卵磷脂及中链甘油三酸酯的用量对制剂的影响,预测最优处方。结果优选的最优处方为m(聚氧乙烯40氢化蓖麻油):m(大豆卵磷脂):m(中链甘油三酸酯)=2.0∶0.5∶5.0。采用最优处方制得的维生素K_2口服亚微乳平均粒径为(104.7±2.4)nm,变异系数为0.441±0.090,离心稳定性常数为3.20±0.43,冻融稳定性常数为2.05±0.21,实验结果与预测值相比偏差较小。结论星点设计效应面法所建立的模型能较好地用于维生素K_2口服亚微乳的处方优化。
Objective To optimize the preparation of vitamin K_2 oral submicron emulsion using the central composite design response surface methodolody(RSM-CDD).Methods The Vitamin K_2 oral submicron emulsion was prepared by microfluidics.In the RSM-CCD,mean diameter,coefficient of variation,centrifugal stability contant and constant of freeze-thaw stability were selected as response variables,RH_(40),SPC,MCT were employed as independent variables.The optimal formulation was predicted by the RSM-CCD.Results The mean diameter,coefficient of variation,centrifugal stability contant and freeze-thaw stability of the optimal preparation respectively were(104.7±2.4)nm,(0.441±0.090),(3.20±0.43)and(2.05±0.21).The deviations between measured values and predicted values were not considerable.Conclusions The model established by the RSM-CCD method can be rational for optimization of the preparation of vitamin K_2 oral submicron emulsion

关键词(KeyWords)： 维生素K2;口服亚微乳;星点设计效应面法;稳定性常数
vitamin K2;oral submicron emulsion;central composite design-response surface methodology;constant stability

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 时佳,宋艳志,李宣,陈杰鹏,段丽丽,邓意辉
SHI Jia,SONG Yan-zhi,LI Xuan,CHEN Jie-peng,DUAN Li-li,DENG Yi-hui

DOI: 10.14066/j.cnki.cn21-1349/r.2017.06.001

参考文献(References)：

• [1]邹志强,符诗聪,刘忠厚.维生素K2的研究进展[J].中国骨质疏松杂志,2006,11(3):389-392.
• [2]SUTOR A H,VON KRIES R,CORNELISSEN E M,et al.Vitamin K deficiency bleeding(VKDB)in infancy[J].Thrombosis and Haemostasis Publishe,1999,81:456-461.
• [3]IWAMOTO J,SATO Y.Menatetrenone for the treatment of osteoporosis[J].Expert Opinion on Pharmacotherapy,2013,14(4):449-458.
• [4]ABDEL-RAHMAN M S,ALKADY E A,AHMED S.Menaquinone-7as a novel pharmacological therapy in the treatment of rheumatoid arthritis:a clinical study[J].European Journal of Pharmacology,2015,761:273-278.
• [5]MOE S M,CHEN N X.Pathophysiology of vascular calcification in chronic kidney disease[J].Circulation Research,2004,95(6):560-567.
• [6]THEUWISSEN E,SMIT E,VERMEER C.The role of vitamin K in soft-tissue calcification[J].Advances in Nutrition:An International Review Journal,2012,3(2):166-173.
• [7]GOLDING J,GREENWOOD R,BIRMINGHAM K,et al.Childhood cancer,intramuscular vitamin K,and pethidine given during labour[J].British Medical Journal,1992,305(6849):341-346.
• [8]AMEMIYA T,MIZUNO S,HAYASHI Y,et al.Absorption of vitamin K2 by dogs after oral administration of a soft gelatin capsule formulation containing a new emulsion-type vehicle[J].Journal of pharmacy and Pharmacology,1999,51(12):1375-1380.
• [9]CRAUSTE-MANCIET S,BROSSARD D,DECROIX M-O,et al.Cefpodoxime-proxetil protection from intestinal lumen hydrolysis by oil-in-water submicron emulsions[J].International Journal of Pharmaceutics,1998,165(1):97-106.
• [10]ARAYA H,TOMITA M,HAYASHI M.The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds[J].International Journal of Pharmaceutics,2005,305(1):61-74.
• [11]吴伟,崔光华.星点设计-效应面优化法及其在药学中的应用[J].国外医学:药学分册,2000,27(5):292-298.
• [12]程晓波,王春玲,余振南,等.星点设计-效应面法优化葫芦素口服脂质纳米乳剂的处方[J].沈阳药科大学学报,2012,29(7):497-503.
• [13]伍勇,贺福元,曹燕,等.星点设计-效应面优化法对四物汤醇沉工艺的研究[J].中国医药导报,2009,6(3):17-19.
• [14]孙磊,王玉蓉.星点设计-效应面法优选远志的提取工艺[J].中成药,2006,28(3):328-331.
• [15]张文忠,韩保萍,胡红杰,等.药物乳剂的乳化原理及乳化技术[J].山东医药工业,2000,19(4):29-31.
• [16]宁黎丽,李雪梅.指导原则解读系列专题(二十一)化学药物稳定性研究的试验方法和设计[J].中国新药杂志,2010,19(12):1013-1016.
• [17]邱颖,朱玲,孙晓英.星点设计-效应面优化法与正交设计和均匀设计的比较及其在药剂研究中的应用[J].海峡药学,2011,23(2):18-20.
• [18]刘艳杰,项荣武.星点设计-效应面法在药学试验设计中的应用[J].中国现代应用药学,2007,24(6):455-457.
• [19]程骥,戴林东,朱家壁.星点设计-效应面法优化双嘧达莫肺靶向脂质体[J].中国药学杂志,2006,41(10):762-765.
• [20]何军,奉建芳,庞家忠,等.星点设计-效应面法优化水飞蓟素固体脂质纳米粒的制备[J].中国医药工业杂志,2005,36(1):18-21.
• [21]何艳,李高,吴笑春,等.星点设计-效应面法优化盐酸巴尼地平自微乳化释药系统[J].中国药师,2010,13(1):11-13.
• [22]GHOSH S,COUPLAND J N.Factors affecting the freeze-thaw stability of emulsions[J].Food Hydrocolloids,2008,22(1):105-111.
• [23]SAITO H,KAWAGISHI A,TANAKA M,et al.Coalescence of lipid emulsions in floating and freezethawing processes:examination of the coalescence transition state theory[J].Journal of Colloid and Interface Science,1999,219(1):129-134.