Abstract
Background: Cubosomes are nanostructured lipid carriers with a bicontinuous cubic phase that can encapsulate both hydrophilic and lipophilic drugs, making them promising systems for transdermal delivery. Tizanidine (TZN), a centrally acting α2-adrenergic agonist, exhibits limited oral bioavailability due to extensive first-pass metabolism. TZN nanocubosomal gel (TNCUBs-gel) was developed and in vitro release, ex vivo skin permeation, and in vivo pharmacokinetics were evaluated in comparison with its oral solution.
Methods: TZN-loaded cubosomal dispersion was used as the base system and incorporated into Carbopol 934 gels (1, 1.5 and 2% w/w) to prepare TNCUBs (g1-g3). The formulations were screened for pH, viscosity, and texture, and the 1.5% formulation (TNCUBs-g2) was selected for further studies. In vitro release was evaluated over 24 h, ex vivo permeation across rat skin was investigated using Franz diffusion cells, and in vivo pharmacokinetic studies were conducted in adult male Wistar rats to compare the transdermal TNCUBs-gel with an oral TZN solution. Plasma TZN concentrations were quantified using a validated HPLC-UV method.
Results: TNCUBs-g2 released 59.7±1.9% of TZN over 24 h. Ex vivo, TNCUBs-g2 exhibited a fourfold higher flux (32.3 µg cm⁻² h⁻¹) than the plain solution. In vivo, the transdermal formulation achieved substantially greater systemic exposure with AUC₀–₂₄=1403.19±42.1 ng·h/mL versus 455.05±9.5 ng·h/mL for oral dosing (P<0.001), indicating sustained absorption and enhanced bioavailability.
Conclusion: The TNCUBs-gel represents a stable, controlled-release transdermal platform that markedly enhances skin permeation and systemic exposure compared with oral administration, supporting its therapeutic potential.