Epilepsy is a neurological condition marked by irregular electrical activity in the brain [1]. It disrupts central nervous system (CNS), leading to increased electrical impulses in either a specific area or throughout the brain, resulting in partial or generalized seizures [2]. Although epilepsy can occur at any age, it is more prevalent among the young and elderly [3]. As reported by the world health organization (WHO), an estimated 50 million people globally are affected by epilepsy, having 80 % residing in low and middle-income countries [4]. Individuals with epilepsy frequently face additional health challenges, including Alzheimer's, anxiety, depression and dementia [5] and studies show that most patients experience at least one comorbid condition [6].

Seizures that originate in specific regions of the brain are known as focal, commonly referred to as partial seizure, are restricted to specific regions of the brain, while generalized seizure affect both hemispheres of the brain simultaneously. These abnormal activities can be caused by structural, infectious or metabolic disruption [7]. In the mature mammalian central nervous system (CNS), γ-aminobutyric acid (GABA) acts as the primary inhibitory neurotransmitter and glutamate as excitatory one. An imbalance between these neurotransmitters has been associated with abnormal neuronal activity, contributing to the development of CNS disorders, including epilepsy. Medications that enhance GABAergic inhibition or decrease glutamatergic excitation have demonstrated antiseizure effects in animal models of epilepsy [8,9]. The main approach for treating epilepsy is symptomatic, focusing on preventing seizures through the prolong use of one or more antiepileptic drugs (AEDs). However, many patients face difficulties in achieving seizure control as a result of medication resistance or discontinuation of treatment. Around 30 % of patients experience refractory epilepsy, where seizures persist despite the use of two appropriately selected and well-tolerated AEDs [10].

Carbamazepine (CBZ) is a commonly prescribed anti-epileptic drug (AEDs) used to manage epilepsy in both children and adults. In addition to epilepsy treatment, it is also a mood stabilizer and is often prescribed for bipolar disorder [11]. It is an FDA-approved first-line therapy for trigeminal neuralgia. CBZ belongs to BCS class-II with low solubility and high permeability. Conventionally, it is taken orally, but its low water solubility (approximately 170 mg/L at 24 °C) leads to slow and inconsistent absorption in the gastrointestinal tract [12]. After oral administration, it is metabolized in the liver by cytochrome P450, reducing its half-life and requiring frequent dosing, which may affect compliance. A transdermal drug delivery system could bypass first-pass metabolism and provide sustained drug release [13]. Therefore, alternative dosage forms and delivery routes are required to improve the effectiveness of epilepsy treatment.

Nanotechnology offers significant potential for progress and application in the pharmaceutical sector. Transfersomes, a type of first-generation ultra-deformable vesicles were developed by Cevc and Blume in 1990 [14]. This technology is trademarked by the German company IDEA AG. Transfersomes consist of amphipathic agents, usually phospholipids, combined with one or more edge activators (EAs). Phospholipids are responsible for forming lipid vesicles, while surfactants (EAs) reduce transition temperature and disrupt the lipid bilayer, leading to highly flexible, self-optimizing and self-regulating properties. Transfersomes can entrape both hydrophilic and lipophilic drugs and are recognized for their high permeability, which enables them to deliver medications through the skin while maintaining their structural integrity [15]. Therefore, transfersomes can squeeze through narrow skin pores or constrictions significantly smaller than their size, while still maintaining their structural integrity [16]. The transdermal route is one of the promising methods for systemic drug delivery. It offers several benefits over conventional drug delivery, including bypassing first-pass metabolism, minimizing side effects, and avoiding significant fluctuations in plasma drug levels [13].

The goal of this research work was to formulate transfersomes based hydrogel for the sustained transdermal delivery of carbamazepine to manage epilepsy. Nanoformulation was developed with multiple objectives, including reducing dosing frequency, improving physicochemical properties and bioavailability by bypassing first-pass metabolism, and minimizing drug side effects. Additionally, CBZ nanoformulation is reported to decrease its conversion to 10–11 epoxide, which is associated with toxic effects [17]. The physicochemical properties of CBZ-TRFs were thoroughly explored through an array of cutting-edge in vitro, ex vivo and behavioral experiments, offering a comprehensive understanding of its performance and potential.