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Objective <p>The aim was to prepare and optimize dual drug-loaded nanostructured lipid carriers (NLCs) of quetiapine hemi-fumarate (QHF) and semi-sodium valproate (SVP) to improve delivery of these drugs in the treatment of schizophrenia by intranasal route.</p> Methods <p>Experimental design used was a four-factor, three-level Box-Behnken design that enabled assessment of the effect of formulation and processing variables, namely cholesterol level, oleic-acid level, homogenization-speed, and level of surfactant, on critical quality attributes like particle-size, zeta-potential, and entrapment-efficiency of both drugs simultaneously. The NLCs with optimized formulation were assessed for physicochemical characterization, FTIR, X-ray diffraction studies, in-vitro drug release, ex-vivo nasal permeation, and in-vivo pharmacodynamics in a rat model of ketamine-induced schizophrenia.</p> Results <p>Optimized formulation had a particle-size of 218 ± 2.8&#xa0;nm, zeta-potential of 24.6 ± 1.24mV, and entrapment efficiency of 72.5 ± 4.2% for QHF and 73.6 ± 2.5% for SVP with overall desirability of 0.8. Statistical analysis concluded cholesterol concentration and speed of homogenization as major factors influencing the formulation. FTIR analysis proved no interaction between drugs and excipients, whereas XRD pattern portrayed relative amorphosis of drugs in lipid matrix. Release studies proved sustained release of drugs, whereas ex-vivo permeation analyses proved higher permeation of drugs through nasal routes compared to suspensions. Behavioral, biochemical, and neuro-inflammatory analysis in-vivo proved enhanced therapeutic effects of QHF-SVP-loaded NLCs compared to prevailing treatments.</p> Conclusions <p>Dual drug-loaded NLCs showed improved nasal permeability, sustained release, and maximized efficacy in vivo. These results suggest that the new QHF-SVP-loaded NLC formulation is a highly effective formulation for the intranasal delivery of drugs for the treatment of schizophrenia.</p>

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Brain-Targeted Intranasal Co-Delivery of Quetiapine and Valproate via Optimized Nanostructured Lipid Carriers: Design, Characterization, and In Vivo Evaluation

  • 期刊论文

  • 发表日期：

    2026年4月17日

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  • Hitesh Kumar Dewangan,
  • Bharat Bhusan,
  • Mohammed F. Aldawsari,
  • Mohammad Muqtader Ahmed,
  • Md. Khalid Anwer

摘要

Objective

The aim was to prepare and optimize dual drug-loaded nanostructured lipid carriers (NLCs) of quetiapine hemi-fumarate (QHF) and semi-sodium valproate (SVP) to improve delivery of these drugs in the treatment of schizophrenia by intranasal route.

Methods

Experimental design used was a four-factor, three-level Box-Behnken design that enabled assessment of the effect of formulation and processing variables, namely cholesterol level, oleic-acid level, homogenization-speed, and level of surfactant, on critical quality attributes like particle-size, zeta-potential, and entrapment-efficiency of both drugs simultaneously. The NLCs with optimized formulation were assessed for physicochemical characterization, FTIR, X-ray diffraction studies, in-vitro drug release, ex-vivo nasal permeation, and in-vivo pharmacodynamics in a rat model of ketamine-induced schizophrenia.

Results

Optimized formulation had a particle-size of 218 ± 2.8 nm, zeta-potential of 24.6 ± 1.24mV, and entrapment efficiency of 72.5 ± 4.2% for QHF and 73.6 ± 2.5% for SVP with overall desirability of 0.8. Statistical analysis concluded cholesterol concentration and speed of homogenization as major factors influencing the formulation. FTIR analysis proved no interaction between drugs and excipients, whereas XRD pattern portrayed relative amorphosis of drugs in lipid matrix. Release studies proved sustained release of drugs, whereas ex-vivo permeation analyses proved higher permeation of drugs through nasal routes compared to suspensions. Behavioral, biochemical, and neuro-inflammatory analysis in-vivo proved enhanced therapeutic effects of QHF-SVP-loaded NLCs compared to prevailing treatments.

Conclusions

Dual drug-loaded NLCs showed improved nasal permeability, sustained release, and maximized efficacy in vivo. These results suggest that the new QHF-SVP-loaded NLC formulation is a highly effective formulation for the intranasal delivery of drugs for the treatment of schizophrenia.