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辛伐他汀通过高强度鼻内阳离子自乳化药物递送系统(SMEDDS)和纳米乳剂被输送到大脑。

Simvastatin is delivered to the brain by high-strength intranasal cationic SMEDDS and nanoemulsions.

作者信息

Gama Francisco, Meirinho Sara, Pires Patrícia C, Tinoco Johann, Martins Gaspar Maria Carolina, Baltazar Graça, Alves Gilberto, Santos Adriana O

机构信息

Faculty of Health Sciences (FCS), University of Beira Interior, Av. Infante D. Henrique, Covilhã, 6200-506, Portugal.

Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Av. Infante D. Henrique, Covilhã, 6200-506, Portugal.

出版信息

Drug Deliv Transl Res. 2025 Jan 2. doi: 10.1007/s13346-024-01769-6.

Abstract

The repurposing of statins as neuroprotective agents and/or anti-brain tumor drugs is limited by challenges in brain bioavailability and systemic off-target effects. Therefore, improved and targeted delivery of statins to the brain is necessary. This study aimed to develop a high-strength liquid formulation of the poorly soluble prodrug simvastatin for intranasal administration, as a strategy to achieve high brain concentrations of the prodrug and/or its active form, tenivastatin. Cationic simvastatin nanoemulsions (c-NE) and self-microemulsifying drug delivery systems (c-SMEDDS) were screened for composition, extensively characterized, and the viscosity of the nanoemulsion was further optimized. The optimized c-NE and c-SMEDDS formulations achieved high drug strengths, approximately 5.5% and 9% (w/w), respectively. They formed highly homogeneous aqueous dispersions (polydispersity index < 0.1) with small droplet sizes (< 120 nm and ~ 25 nm, respectively) and remained stable for at least four months under refrigeration. Neither the c-NE nor the c-SMEDDS induced hemolysis up to concentrations of 40 µg/mL and 450 µg/mL of simvastatin, respectively. The zero-shear viscosity of the c-NE was increased to 186 mPa·s by incorporating 0.25% (w/w) polyvinylpyrrolidone, which approached the viscosity of the c-SMEDDS (~ 126 mPa·s). Following intranasal administration of the optimized formulations to Wistar rats at a dose of 10 mg/kg, simvastatin levels in the brain reached 50 to 150 ng/g between 15 and 60 min post-administration. These findings indicate that the developed c-NE and c-SMEDDS formulations hold promise for simvastatin intranasal delivery and brain targeting, potentially paving the way for the realization of simvastatin's neuroprotective potential.

摘要

他汀类药物重新用作神经保护剂和/或抗脑肿瘤药物受到脑生物利用度和全身非靶向效应方面挑战的限制。因此,有必要改进他汀类药物向脑内的靶向递送。本研究旨在开发一种用于鼻腔给药的难溶性前药辛伐他汀的高强度液体制剂,作为实现前药及其活性形式替尼伐他汀在脑内高浓度的策略。对阳离子辛伐他汀纳米乳(c-NE)和自微乳化药物递送系统(c-SMEDDS)进行了组成筛选、广泛表征,并进一步优化了纳米乳的粘度。优化后的c-NE和c-SMEDDS制剂实现了高药物强度,分别约为5.5%和9%(w/w)。它们形成了高度均匀的水性分散体(多分散指数<0.1),液滴尺寸较小(分别<120nm和25nm),在冷藏条件下至少稳定四个月。c-NE和c-SMEDDS在辛伐他汀浓度分别高达40μg/mL和450μg/mL时均未诱导溶血。通过加入0.25%(w/w)的聚乙烯吡咯烷酮,c-NE的零剪切粘度增加到186mPa·s,接近c-SMEDDS的粘度(126mPa·s)。以10mg/kg的剂量将优化后的制剂经鼻腔给予Wistar大鼠后,给药后15至60分钟内脑内辛伐他汀水平达到50至150ng/g。这些发现表明,所开发的c-NE和c-SMEDDS制剂在辛伐他汀鼻腔递送和脑靶向方面具有前景,可能为实现辛伐他汀的神经保护潜力铺平道路。

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