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Purpose <p>Tizanidine hydrochloride, a centrally acting skeletal muscle relaxant, exhibits poor aqueous solubility, extensive first-pass metabolism, and a short half-life (2.5&#xa0;h), resulting in only ~ 21% oral bioavailability. The present study aimed to enhance systemic bioavailability and sustain the therapeutic effect of Tizanidine hydrochloride by developing Nanostructured Lipid Carriers (NLCs) incorporated into a transdermal patch delivery system.</p> Methods <p>Tizanidine hydrochloride-loaded Nanostructured Lipid Carriers were prepared by the nanoprecipitation method. Preliminary trials were conducted using a one-variable-at-a-time (OVAT) approach, followed by optimization using a Box–Behnken design. The optimized NLCs were characterized for particle size, polydispersity index (PDI), zeta potential, X-ray diffraction (XRD), and transmission electron microscopy (TEM). Nanostructured Lipid Carriers were incorporated into solvent-cast transdermal patches and evaluated for thickness uniformity, mechanical strength, and moisture content. In-vitro drug release studies were performed using a Franz diffusion cell to assess the release behaviour. Ex-vivo permeation studies were conducted across excised Wistar rat abdominal skin to determine drug flux and permeation parameters. Pharmacokinetic studies were performed in Wistar rats, and stability was assessed for 60 days under refrigerated and room-temperature conditions.</p> Results <p>The optimized Nanostructured Lipid Carriers (NLCs) displayed a mean particle size of 118.23 ± 3.45&#xa0;nm, zeta potential of − 26.8 ± 0.25 mV, and PDI of 0.252 ± 0.019, confirming nanoscale uniformity and colloidal stability. The NLCs exhibited a high entrapment efficiency of 84.8 ± 1.25%. The formulated transdermal patches demonstrated good flexibility, uniformity, and low moisture uptake. Ex-vivo permeation studies revealed a significantly enhanced steady-state flux of 1.7511&#xa0;µg/cm²/h for the NLCs-loaded patch compared to the conventional drug-loaded patch, resulting in an enhancement ratio of 3.89, indicating nearly four-fold improvement in transdermal delivery. In-vivo pharmacokinetic evaluation showed a markedly increased AUC₀–∞ of 33,247 ng·h/mL, representing an 8.79-fold enhancement over the marketed suspension (3,779 ng·h/mL). Stability studies demonstrated minimal variation in physical characteristics and entrapment efficiency, confirming the robustness of the developed QbD-optimized NLCs-based transdermal system.</p> Conclusion <p>The optimized NLCs-based transdermal patch provided sustained drug release for 24&#xa0;h and produced an 8.79-fold increase in systemic bioavailability (AUC₀–∞: 33,247 ng·h/mL) compared with the drug suspension, demonstrating its potential as a patient-friendly and clinically translatable alternative to conventional oral therapy for muscle spasticity.</p>

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Development and Optimization of Tizanidine HCl-Loaded NLCs-Based Transdermal Patch for Enhanced Bioavailability: A Quality by Design Approach

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Maulik Parmar,
  • Yash Bhimani,
  • Vishwa Patel,
  • Hemal Tandel

摘要

Purpose

Tizanidine hydrochloride, a centrally acting skeletal muscle relaxant, exhibits poor aqueous solubility, extensive first-pass metabolism, and a short half-life (2.5 h), resulting in only ~ 21% oral bioavailability. The present study aimed to enhance systemic bioavailability and sustain the therapeutic effect of Tizanidine hydrochloride by developing Nanostructured Lipid Carriers (NLCs) incorporated into a transdermal patch delivery system.

Methods

Tizanidine hydrochloride-loaded Nanostructured Lipid Carriers were prepared by the nanoprecipitation method. Preliminary trials were conducted using a one-variable-at-a-time (OVAT) approach, followed by optimization using a Box–Behnken design. The optimized NLCs were characterized for particle size, polydispersity index (PDI), zeta potential, X-ray diffraction (XRD), and transmission electron microscopy (TEM). Nanostructured Lipid Carriers were incorporated into solvent-cast transdermal patches and evaluated for thickness uniformity, mechanical strength, and moisture content. In-vitro drug release studies were performed using a Franz diffusion cell to assess the release behaviour. Ex-vivo permeation studies were conducted across excised Wistar rat abdominal skin to determine drug flux and permeation parameters. Pharmacokinetic studies were performed in Wistar rats, and stability was assessed for 60 days under refrigerated and room-temperature conditions.

Results

The optimized Nanostructured Lipid Carriers (NLCs) displayed a mean particle size of 118.23 ± 3.45 nm, zeta potential of − 26.8 ± 0.25 mV, and PDI of 0.252 ± 0.019, confirming nanoscale uniformity and colloidal stability. The NLCs exhibited a high entrapment efficiency of 84.8 ± 1.25%. The formulated transdermal patches demonstrated good flexibility, uniformity, and low moisture uptake. Ex-vivo permeation studies revealed a significantly enhanced steady-state flux of 1.7511 µg/cm²/h for the NLCs-loaded patch compared to the conventional drug-loaded patch, resulting in an enhancement ratio of 3.89, indicating nearly four-fold improvement in transdermal delivery. In-vivo pharmacokinetic evaluation showed a markedly increased AUC₀–∞ of 33,247 ng·h/mL, representing an 8.79-fold enhancement over the marketed suspension (3,779 ng·h/mL). Stability studies demonstrated minimal variation in physical characteristics and entrapment efficiency, confirming the robustness of the developed QbD-optimized NLCs-based transdermal system.

Conclusion

The optimized NLCs-based transdermal patch provided sustained drug release for 24 h and produced an 8.79-fold increase in systemic bioavailability (AUC₀–∞: 33,247 ng·h/mL) compared with the drug suspension, demonstrating its potential as a patient-friendly and clinically translatable alternative to conventional oral therapy for muscle spasticity.