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<p>This study aimed to develop dothiepin HCl–loaded nanostructured lipid carriers (NLCs) incorporated into an in situ nasal gel. NLCs were chosen to overcome the drug’s poor solubility, extensive first-pass metabolism, and limited blood–brain barrier penetration, thereby enhancing brain-targeted delivery and antidepressant efficacy via the nasal route. DOTH.HCl suffers from poor solubility, extensive first-pass metabolism, and limited ability to cross the blood–brain barrier, which significantly restricts its therapeutic efficacy. Dothiepin HCl–loaded NLCs were prepared by melt emulsification and high-speed homogenization using glyceryl monostearate and oleic acid (65:35) with Tween 80 and PVA as surfactants. The nanoemulsion was freeze-thawed and lyophilized to obtain dry NLCs. Optimization was done via Box–Behnken design, and characterization included entrapment efficiency, particle size, and zeta potential measurements. The optimized NLC formulation showed high entrapment efficiency (90.59%), a zeta potential of − 28.8&#xa0;mV, and a particle size of 168.3&#xa0;nm, indicating good stability and nanoscale dispersion. The in situ gel exhibited suitable viscosity (150 ± 4.08&#xa0;kPa), pH (6.8 ± 0.12), and strong mucoadhesive strength (3328 ± 2.44 dyne/cm<sup>2</sup>), supporting prolonged nasal residence. Drug permeability from the NLC-based gel was significantly higher than that of pure DOTH.HCl solution and conventional oral administration, suggesting improved drug transport to the brain. In vivo studies confirmed enhanced antidepressant activity, with increased swimming and climbing times, reduced immobility, and higher brain serotonin (197.7 ± 5.78&#xa0;pg/mg) and norepinephrine levels (1.72 ± 0.02&#xa0;nM/mg). The developed NLC-based in situ nasal gel presents a promising non-invasive alternative to oral therapy, potentially improving patient compliance and therapeutic outcomes in depression management.</p>

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Development and optimization of dothiepin hydrochloride–loaded nanostructured lipid carrier incorporated in situ nasal gel for enhanced brain-targeted antidepressant delivery

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Divya Bhagat,
  • Varsha Balkrishna Mane,
  • Manoj Shinde,
  • Nagesh Aloorkar,
  • Sagar Pathade,
  • Sanuja Kadam,
  • Rushikesh Kshirsagar

摘要

This study aimed to develop dothiepin HCl–loaded nanostructured lipid carriers (NLCs) incorporated into an in situ nasal gel. NLCs were chosen to overcome the drug’s poor solubility, extensive first-pass metabolism, and limited blood–brain barrier penetration, thereby enhancing brain-targeted delivery and antidepressant efficacy via the nasal route. DOTH.HCl suffers from poor solubility, extensive first-pass metabolism, and limited ability to cross the blood–brain barrier, which significantly restricts its therapeutic efficacy. Dothiepin HCl–loaded NLCs were prepared by melt emulsification and high-speed homogenization using glyceryl monostearate and oleic acid (65:35) with Tween 80 and PVA as surfactants. The nanoemulsion was freeze-thawed and lyophilized to obtain dry NLCs. Optimization was done via Box–Behnken design, and characterization included entrapment efficiency, particle size, and zeta potential measurements. The optimized NLC formulation showed high entrapment efficiency (90.59%), a zeta potential of − 28.8 mV, and a particle size of 168.3 nm, indicating good stability and nanoscale dispersion. The in situ gel exhibited suitable viscosity (150 ± 4.08 kPa), pH (6.8 ± 0.12), and strong mucoadhesive strength (3328 ± 2.44 dyne/cm2), supporting prolonged nasal residence. Drug permeability from the NLC-based gel was significantly higher than that of pure DOTH.HCl solution and conventional oral administration, suggesting improved drug transport to the brain. In vivo studies confirmed enhanced antidepressant activity, with increased swimming and climbing times, reduced immobility, and higher brain serotonin (197.7 ± 5.78 pg/mg) and norepinephrine levels (1.72 ± 0.02 nM/mg). The developed NLC-based in situ nasal gel presents a promising non-invasive alternative to oral therapy, potentially improving patient compliance and therapeutic outcomes in depression management.