Formulation, optimization, and preclinical assessment of a QbD-engineered transethosomal pregabalin patch for...

Neuropathic pain is a major clinical challenge since it has complex pathophysiology and multifactorial etiology. Pregabalin is an anticonvulsant drug that binds with the α2δ subunit of voltage-gated calcium channels, decreases their influx, and eventually lowers the release of excitatory neurotransmitters. The conventional oral Pregabalin exhibits lower therapeutic efficacy because of its variable absorption, CNS side effects, and frequent dosing. This present study suggests a new transdermal formulation containing transethosomes loaded with pregabalin to provide sustained drug release, enhanced drug penetration into the skin, and subsequently reduced systemic side effects. Transethosomes were formulated by thin-film hydration method, and their optimization was done through Box Behnken design, which recorded optimal particle size of 124.4 ± 2.54 nm, zeta potential of -20.5 ± 0.35 mV, and entrapment efficiency of 83.4 ± 0.8%. Formulation was then added to a transdermal patch containing eucalyptus oil and checked for in vitro release, which revealed that PGB-TES-P + EO showed more sustained drug release. Enhanced transdermal penetration of PGB-TES-P + EO was proved by ex vivo permeation and through fluorescence microscopy. In vivo assessment in the streptozotocin-induced diabetic neuropathic pain model demonstrated significant improvement in locomotor activity and pain responses, as well as a decline in the proinflammatory markers such as TNF-α and COX-2, which post-treatment values of 120.5 ± 6.57 and 119.1 ± 2.82, respectively. The final formulation showed no irritation to the skin and was found to be stable according to the ICH guidelines. Altogether, this system presents a potential alternative for non-invasive delivery for Pregabalin with improved drug permeation in neuropathic pain management.