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<p>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 &lt; 0.1) with small droplet sizes (&lt; 120&#xa0;nm and ~ 25&#xa0;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&#xa0;µg/mL and 450&#xa0;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&#xa0;mg/kg, simvastatin levels in the brain reached 50 to 150 ng/g between 15 and 60&#xa0;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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年1月2日

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

摘要

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.

Graphical Abstract