聚乙二醇脂肪酸酯新型纳米囊泡系统经皮递运阿托伐他汀钙：在聚氧乙烯 407 诱导的高脂血症大鼠中无肝毒性的改善作用。
Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats.
机构信息
Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
出版信息
J Control Release. 2017 May 28;254:10-22. doi: 10.1016/j.jconrel.2017.03.039. Epub 2017 Mar 23.
CONTEXT
Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle.
OBJECTIVE
The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route.
METHODS
The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits.
RESULTS
The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186-583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity.
CONCLUSION
The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.
背景
阿托伐他汀钙（ATV）是一种降胆固醇药物，口服后全身利用率（14%）较低，此外还会对胃肠道、肝脏和肌肉产生其他副作用。
目的
本研究旨在通过开发一种新的纳米囊泡系统来包裹 ATV，使其通过透皮途径给药，以提高 ATV 的生物利用度并克服口服给药带来的并发症。
方法
通过将不同的聚乙二醇脂肪酸酯（如 Labrasol、Cremophor EL、Gelucire 44/14 和 Tween 80）作为边缘活性剂（EAs）掺入脂质双层中，制备囊泡系统。研究了磷脂酰胆碱（PC）：EA 摩尔比对囊泡理化性质的影响。在大鼠中评估了优化配方的药代动力学研究。在泊洛沙姆 407 诱导的高脂血症大鼠中测试了优化配方。使用市售试剂盒测量血浆脂质谱、肝酶活性和氧化应激参数。
结果
结果表明，ATV 的包封效率（EE%）高达 55.62%至 83.91%。含有 Labrasol 的制剂表现出最高的 EE%。囊泡的平均直径在 186-583nm 范围内。含有 Gelucire 44/14 的 T8 作为 EA，摩尔比为 15:1（PC:EA），粒径最小，透皮渗透参数最佳。药代动力学研究表明，与口服 ATV 混悬剂相比，经皮给药纳米转脂体 ATV 凝胶后，生物利用度提高了约三倍，具有统计学意义（p<0.05）。透皮囊泡系统可显著降低血浆总胆固醇、甘油三酯和 LDL 胆固醇，与口服 ATV 相当。此外，它还降低了血浆丙二醛水平，并消除了肝酶活性的升高。
结论
研究结果表明，所提出的透皮囊泡系统可作为 ATV 给药的一种有前途的替代方法。
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