目的 研究雷洛昔芬纳米乳的处方设计。方法 考察雷洛昔芬在纳米乳辅料中的溶解度;在此基础上,通过乳化能力筛选出适合的乳化剂与油;助乳化剂与油、乳化剂三者之间的组合及最佳比例由伪三元相图确定;通过载药量考察雷洛昔芬对纳米乳处方的影响;采用壳聚糖、羧化壳聚糖调节纳米乳Zeta电位;通过测定粒径评价载药纳米乳在不同稀释倍数及不同pH缓冲盐中的稳定性。 结果 雷洛昔芬纳米乳最佳处方为亚油酸(LOA)-棕榈酸异丙酯(IPP)-聚氧乙烯氢化蓖麻油(RH40)-乙醇(0.167 g∶0.333 g∶0.3 g∶0.2 g),载药量为15 mg;壳聚糖及羧化壳聚糖可分别使纳米乳的Zeta电位从原来的-0.95 mV变为20 mV及-13 mV左右;不同pH及稀释倍数对3种纳米乳的稳定性影响不大。结论 通过系统研究,获得了Zeta电位分别为正值、负值及接近零的3个雷洛昔芬纳米乳处方,为后期雷洛昔芬纳米乳吸收机制的研究奠定了基础。
Abstract
OBJECTIVE To study formulation design of raloxifene nanoemulsion. METHODS The solubilities of raloxifene in excipients of nanoemulsion were investigated. On the basis, emulsifier and oil were selected by the emulsifying ability. The combination and optimum proportion among co-emulsifier, oil and emulsifier were determined by the pseudo-ternary phase diagram. The effect of raloxifene on nanoemulsion prescription was studied by drug loading. Finally chitosan and carboxylated chitosan were used to regulate the Zeta potential of raloxifene nanoemulsions. RESULTS The optimum formulation ratio of LOA, IPP, RH40 and ethanol for loading 15 mg raloxifene is 0.167 g∶0.333 g∶0.3 g∶0.2 g, respectively. The Zeta potentials of the nanoemulsions can be changed by chitosan and carboxylated chitosan from -0.954 mV to 20 mV and -13 mV or so,respectively. The effect of different pH and dilution times on stability of formulations were slight. CONCLUSION The formulations of raloxifene nanoemulsion including positive, negative and near zero Zeta potential were obtained, which have laid a foundation for absorption mechanism study of the raloxifene nanoemulsion.
关键词
雷洛昔芬 /
纳米乳 /
溶解度 /
处方设计 /
Zeta电位
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Key words
raloxifene /
nanoemulsion /
solubility /
formulation design /
Zeta potential
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中图分类号：
R944
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参考文献
[1] SHAFIQ S, SHAKEEL F, TALEGAONKAR S, et al. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm, 2007, 66(2): 227-243.
[2] VYAS T K, SHAHIWALA A, AMIJI M M. Improved oral bioavailability and brain transport of saquinavir upon administration in novel nanoemulsion formulations. Int J Pharm, 2008, 347(1): 93-101.
[3] YU H, HUANG Q. Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions. J Agricul Food Chem, 2012, 60(21): 5373-5379.
[4] YAN J H,RUI W, JUN L S. Effect of raloxifene on postmenopausal osteoporosis. Pract Prevent Med (实用预防医学), 2010, 17(3): 551-552.
[5] BARRETT-CONNOR E, MOSCA L, COLLINS P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. New Engl J Med, 2006, 355(2): 125-137.
[6] CAULEY J A, NORTON L, LIPPMAN M E, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treatment, 2001, 65(2): 125-134.
[7] STRICKLER R, STOVALL D W, MERRITT D, et al. Raloxifene and estrogen effects on quality of life in healthy postmenopausal women: a placebo-controlled randomized trial. Obste Gynecol, 2000, 96(3): 359-365.
[8] TRAN T H, POUDEL B K, MARASINI N, et al. Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent. Int J Pharm, 2013, 443(1): 50-57.
[9] JEONG E J, LIU Y, LIN H M, et al. Species-and disposition model-dependent metabolismof raloxifene in gut and liver: role of UGT1A10. Drug Metabol Dispos, 2005,33(6): 785-794.
[10] RAVI P R, ADITYA N, KATHURAL H, et al. Lipid nanoparticles for oral delivery of raloxifene: optimization, stability, in vivo evaluation and uptake mechanism. Eur J Pharm Biopharm, 2014, 87(1): 114-124.
[11] Ch.P(2015)VolⅡ(中国药典2015年版.四部). 2015:370.
[12] RAO J,MCCLEMENTS D J. Formation of flavor oil microemulsions, nanoemulsions and emulsions: influence of composition and preparation method. J Agric Food Chem, 2011, 59 (9):5026-5035.
[13] ANTON N,VANDAMME T F. Nanoemulsions and microemulsions: clarifications of the critical differences. Pharm Res, 2011, 28 (5):978-985.
[14] LIU B. New Drug Formulation and New Technology(药物新剂型与新技术). Beijing:People ′s Health Publishing House, 1998:59-60.
[15] SHEPHERD J, PACKARD C J, PATSCH J R, et al. Effects of dietary polyunsaturated and saturated fat on the properties of high density lipoproteins and the metabolism of apolipoprotein AI. J Clin Invest, 1978, 61(6): 1582.
[16] ROWE R C, SHESKEY P J, WELLER P J, et al. Handbook of Pharmaceutical Ingredients (4th ed)(药用辅料手册 第四版). Beijing:Chemical Industry Press, 2004.
[17] GELDERBLOM, J. VERWEIJ, K. NOOTER, A. Sparreboom.Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer, 2001(37):1590-1598.
[18] JAIN V, PRASAD V, JADHAV P, et al. Preparation and performance evaluation of saquinavir laden cationic submicron emulsions. Drug Deliv, 2009, 16(1): 37-44.
[19] MENG J, HU L. Positively-charged microemulsion for improving the oral bioavailability of alendronate: in-vitro and in-vivo assessment. J Pharm Pharmacol, 2011, 63(3):400-408.
[20] MUTALIK S, ANJU P, MANOJ K, et al. Enhancement of dissolution rate and bioavailability of aceclofenac: a chitosan-based solvent change approach. Int J Pharm, 2008, 350(1):279-290.
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脚注
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基金
国家自然科学基金项目资助(81573353)
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