摘要
系统进行口服纳米乳(nanoemulsions,NE)处方设计,并研究其对雷洛昔芬(raloxifene,RAL)口服吸收的影响及吸收机制。考察RAL水溶解度及NE各种辅料成分中的饱和溶解度、油水分配系数[oil-water partition coefficient, P(O/W)],并通过乳化能力确定NE的乳化剂与油的最佳配伍;由伪三元相图确定NE各成分比例,并由载药量确定最终RAL-NE处方;通过测定NE粒径、zeta电位、形态和RAL-NE在模拟胃肠液中的稳定性及包封率等评价其质量。采用MDCK细胞模型对RAL-NE体外跨膜转运及机制进行研究;最后测定RAL-NE的大鼠口服生物利用度。根据其溶解度及P(O/W),RAL可归为BCSII,RAL-NE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=1.67∶3.33∶3∶2,预纳米乳的载药量为15mg·g^(-1);RAL-NE包封率为(79.4±0.4)%,在模拟胃肠液中的粒径、zeta电位及药物含量基本保持不变;RAL在MDCK细胞水平的转运机制为网格蛋白介导内吞;RAL-NE相对于RAL混悬剂的口服生物利用度为171.9%,吸收显著提高(P<0.05)。体内外研究证明,经过系统研究的RAL-NE最佳处方能显著提高RAL的口服吸收。本文为口服NE研究与产品开发提供参考。
Oral formulations of nanoemulsions（NE） were systematically designed, and then their effects on oral absorption of raloxifene（RAL）, including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient [P（O/W）] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSII based on the solubility and P（O/W）. The best formulation of RAL-NE was composed of linoleic acid（LOA）∶isopropyl palmitate（IPP）∶cremophor RH40（RH40）∶alcohol as 1.67∶3.33∶3∶2. Drug loading in pre-nanoemulsion was 15 mg·g^（-1） and entrapment efficiency of RAL in NE was（79.4 ± 0.4） %. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations（P〈0.05）. This paper provides references for oral NE research and development.
作者
黄传利
吴永秋
黄蓓
杨健峰
万君晗
张彩凤
龙晓英
HUANG Chuan-li;WU Yong-qiu;HUANG Bei;YANG Jian-feng;WAN Jun-han;ZHANG Cai-feng;LONG Xiao-ying(School of Pharmacy;School of Traditional Chinese Medicine;Guangdong Engineering and Technology Research Center of Topical Precise Drug Delivery System,Guangdong Pharmaceutical University,Guangzhou 510006,China)
出处
《药学学报》
CAS
CSCD
北大核心
2018年第10期1726-1735,共10页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81573353)
关键词
雷洛昔芬
纳米乳
处方设计
细胞转运
生物利用度
raloxifene
nanoemulsion
formulation design
transcellular cell migration
bioavailability
