药学学报, 2018, 53(10): 1726-1735
引用本文:
黄传利, 吴永秋, 黄蓓, 杨健峰, 万君晗, 张彩凤, 龙晓英. 促进雷洛昔芬口服吸收的纳米乳处方设计、吸收机制及生物利用度研究[J]. 药学学报, 2018, 53(10): 1726-1735.
HUANG Chuan-li, WU Yong-qiu, HUANG Bei, YANG Jian-feng, WAN Jun-han, ZHANG Cai-feng, LONG Xiao-ying. Formulation design, absorption mechanism and bioavailability of nanoemulsions for enhancing oral absorption of raloxifene[J]. Acta Pharmaceutica Sinica, 2018, 53(10): 1726-1735.

促进雷洛昔芬口服吸收的纳米乳处方设计、吸收机制及生物利用度研究
黄传利1, 吴永秋2, 黄蓓2, 杨健峰2, 万君晗1, 张彩凤1, 龙晓英2,3
1. 广东药科大学药学院, 广东 广州 510006;
2. 广东药科大学中药学院, 广东 广州 510006;
3. 广东药科大学广东省局部精准药物递药制剂工程技术研究中心, 广东 广州 510006
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15 mg·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。
关键词:    雷洛昔芬      纳米乳      处方设计      细胞转运      生物利用度     
Formulation design, absorption mechanism and bioavailability of nanoemulsions for enhancing oral absorption of raloxifene
HUANG Chuan-li1, WU Yong-qiu2, HUANG Bei2, YANG Jian-feng2, WAN Jun-han1, ZHANG Cai-feng1, LONG Xiao-ying2,3
1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China;
2. School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China;
3. Guangdong Engineering and Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, China
Abstract:
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 andentrapment 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.
Key words:    raloxifene    nanoemulsion    formulation design    transcellular cell migration    bioavailability    
收稿日期: 2018-06-01
DOI: 10.16438/j.0513-4870.2018-0514
基金项目: 国家自然科学基金资助项目(81573353).
通讯作者: 龙晓英,Tel:86-20-39352168,Fax:86-20-39352174,E-mail:longxy3156@163.com
Email: longxy3156@163.com
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