Epilepsy is a widespread, life-threatening neurological disorder affecting more than 70 million people in the world [1]. It greatly affects the quality of life and imposes socioeconomic burdens on patients and healthcare systems. It is characterized by recurrent unpredictable seizures that may involve a specific part of the body or the entire body (partial and generalized epilepsy). It is also characterized by loss of consciousness.

Management of epilepsy involves treatment with antiepileptic medications. In some cases, surgical intervention is advised. Carbamazepine (CBZ) is a major antiepileptic drug that is commonly prescribed to treat various forms of seizures [2]. It is a centrally acting medication used for the management of epilepsy, trigeminal neuralgia, and manic-depressive illness due to its structural similarity with tricyclic antidepressants [3]. It acts mainly by inhibiting sodium channels in the nerve, thereby reducing neuronal action potentials in the brain. It exerts an overall inhibitory effect on the nervous system. Also, it has been shown to stimulate GABA (gamma-aminobutyric acid, an inhibitory neurotransmitter) receptors [4,5], and inhibit Glutamate receptors leading to a sedative effect [6]. It was first discovered in Switzerland by chemist Walter Schindler in 1953 and was first marketed as a drug in 1962 [6].

CBZ has a narrow therapeutic range (4–12 μg/mL) with challenging pharmacokinetic properties. The drug's high lipophilicity limits its solubility in the gastrointestinal tract (GIT) and impairs its absorption. As a result, the drug shows an irregular plasma concentration profile with frequent fluctuation. It worsens the risk of side effects due to its narrow therapeutic window. It is metabolized in the liver by the CYP3A4 microsomal enzyme. So, it suffers from first-pass metabolism, which further reduces its bioavailability. Moreover, CBZ stimulates hepatic enzymes, thereby inducing self-metabolism. Furthermore, it is highly bound to plasma proteins (approximately 70–80 %) [7,8].

Consequently, CBZ is a suitable candidate for a targeted drug delivery system designed to overcome these pharmacokinetic problems. However, effective delivery to the brain remains a significant challenge, as it is the most protected organ in the body due to the presence of the blood brain barrier (BBB). The BBB employs multiple defense mechanisms (tight junctions, efflux transporters, and metabolic enzymes) to restrict the entry of various molecules into the central nervous system (CNS) [9].

Intranasal drug delivery (IDD) has emerged as a promising and efficient strategy for the treatment of CNS disorders. IDD bypasses the BBB and targets the drug directly to the brain tissues and cerebrospinal fluid through the olfactory and trigeminal neural pathways [10]. Also, it is a non-invasive and efficient route that enhances patient compliance and reduces systemic side effects. The potential of this route has been recognized by regulatory authorities. Notably, in 2019, the U.S Food and Drug Administration (FDA) approved the intranasal administration of esketamine, a fast-acting antidepressant, for resistant depression [11].

Furthermore, the latest research proved the success of nose to brain delivery in the treatment of various CNS disorders, involving schizophrenia [12], Alzheimer's disease [13], and even brain tumors [14]. However, there are major constraints in nasal delivery, including the restricted surface area in the nasal cavity, rapid mucociliary clearance with approximately half-life clearance of 15–20 min, and unsatisfactory mucosal permeability [15,16]. As a result, current efforts in intranasal brain-targeted drug delivery focus on the development of mucoadhesive nasal formulation. This approach enhanced permeation properties, aiming to prolong the residence time in the nasal cavity and improve the drug uptake across the nasal mucosa [[17], [18], [19]]. Among the various approaches to enhance nasal drug delivery to the brain are vesicular systems. They have gained considerable attention in recent years due to their ability to encapsulate hydrophilic and lipophilic drugs and facilitate their transport across biological barriers. Examples include niosomes [20], liposomes [18], cubosomes [15], transferosomes [16,21], and bilosomes [22].

Transethosomes (TEs) are lipid vesicles composed of a mixture of lipid, ethanol, and edge activator. TEs are hybrids between transferosomes and ethosomes with better biocompatibility, vesicular elasticity, and higher encapsulation efficiency compared to transferosomes and ethosomes [23,24]. Rearrangement of lipid bilayers with ethanol and edge activator leads to improved vesicle elasticity and enhanced permeation properties. Many studies verified that TEs can enhance drug bioavailability, therapeutic efficacy, minimize drug side effects, and improve patient compliance [25]. TEs have demonstrated significant potential in delivering hydrophobic drugs (like CBZ) by enhancing solubility, stability, and mucosal penetration [[26], [27], [28]]. They were formulated and loaded with antifungal, antibacterial, and cardiovascular agents for transdermal drug delivery [29]. They were fabricated as transdermal patches to consider delivery of hormones [30]. Moreover, their ability to permeate skin layers favored their fabrication for topical drug delivery systems [31]. When taken intranasally, transethosomes can facilitate direct transport of CBZ to the brain, overcoming the limitations of conventional delivery methods.

Compared to other lipid-based carriers such as niosomes, cubosomes, and solid lipid nanoparticles, TEs demonstrate clear dominance in nasal delivery applications. Unlike niosomes and solid lipid nanoparticles, which often exhibit limited permeability and rigidity. TEs possess enhanced deformability and penetration due to their ethanol and surfactant-rich composition. While cubosomes offer structural stability, their complex internal structure can hinder rapid mucosal transport. In contrast, TEs efficiently traverse nasal barriers, achieve higher drug encapsulation, and facilitate more effective nose-to-brain delivery. These reasons make them more versatile and potent platform for intranasal therapeutic targeting [32]. Moreover, incorporating TEs into a mucoadhesive gel further enhances their performance by increasing nasal residence time, reducing mucociliary clearance, and promoting sustained drug release [[33], [34], [35], [36]].

In-vivo biodistribution studies using the radiolabeling technique could be used for the determination of the radio kinetic parameters. So, it would help in determining the targeting drug efficacy through the intranasal route. The radiolabeling technique could be performed using one of three approaches: (I) direct radiolabeling of the new formulation [37], (ii) radiolabeling the drug before its incorporation into a new optimized formulation (radioformulation) [38], or (iii) using a radiopharmaceutical indicator [39]. Radioformulation offers a promising new avenue in radio-imaging by enabling the development of nano radiopharmaceuticals. This can serve as innovative imaging probes for various organs, such as the brain or tumors. The uptake of radioactivity, which corresponds to drug concentration (drug uptake), can be accurately tracked in various body organs and fluids [38,40].

The objective of this study was to develop a transethosomal mucoadhesive intranasal gel for brain-targeted delivery of CBZ (TM-CBZ). This would avoid the drawbacks of conventional oral administration. The integration of transethosomal technology with mucoadhesive systems represents a significant advancement in intranasal drug delivery. That would offer a non-invasive and efficient approach to brain targeting. This system would have the potential to achieve rapid and effective seizure control while minimizing systemic side effects, by combining the deformability and permeability of TEs with the sustained release properties of a mucoadhesive gel. This study not only highlights the potential of intranasal delivery systems for treating neurological disorders but also provides a foundation for future research aimed at optimizing and translating such systems for clinical use. This research involved the formulation, optimization, and characterization of TEs and their incorporation into a mucoadhesive gel. A comprehensive evaluation of the system's potential for effective brain targeting was performed. Key evaluations include in-vitro studies to assess drug release kinetics and nasal mucosal permeation. In addition, in-vivo biodistribution studies utilizing radiolabeling techniques by [99mTc]. Intranasal administration of radiolabeled transethosomal mucoadhesive ([99mTc]Tc -TM-CBZ) would be compared with oral radiolabeled carbamazepine solution ([99mTc]Tc -CBZ), to quantify brain drug delivery. Additionally, the pharmacodynamic efficacy of the system was evaluated using pilocarpine-induced seizure models on albino rats to determine its anti-epileptic potential and overall therapeutic performance.