Major Depressive Disorder (MDD) is one of the neuro-psychiatric illnesses having the largest frequency among young and middle age group individuals. It is now widely accepted that depression frequently manifests during adolescence and gets worse over time. MDD may appear at any age, with onset typically occurring in the middle of the 20s. Currently, the incidence rate of the newly diagnosed depression is more in 25–35 years old patients [1]. An individual's emotions, beliefs, sense of self, behavioral patterns, interpersonal interactions, cardiorespiratory fitness, biological processes, degree of productivity and job satisfaction, and general happiness are all considerably affected by this widespread multifactorial condition [2,3].

Escitalopram (ESC) is a selective serotonin reuptake inhibitor (SSRI) and regarded as one of the optimal candidates among all SSRIs for the treatment of MDD due to its high tolerability and selectivity [4]. It specifically binds to serotonin transporter and inhibits serotonin (5-HT) reuptake and as a result, the level of serotonin is augmented in synaptic clefts. The main issue with ESC is that it undergoes significant amount of hepatic metabolism, primarily via CYP2C19, CYP3A4 and to a lesser extent CYP2D6 enzymes, producing metabolites such as S-di-demethylcitalopram and S-demethylcitalopram (S-DCT) [5]. Furthermore, it belongs to BCS class II drugs with poor aqueous solubility. Both of these factors synergistically facilitate towards its lower systemic as well as brain bioavailability. The most feasible alternative to these issues is to deliver targeted dose of ESC. One such strategy could be nose-to-brain delivery of the drugs by utilizing lipid nano-carriers, which are suitable and relatively safe means of central nervous system (CNS) targeting [6].

Nose to brain delivery is the simpler and direct way for brain targeting, which avoids bloodstream clearance. Nose to brain delivery provides several advantages over other routes of drug administration, including fast onset of action, avoidance of the intestinal and hepatic pre systemic disposition, reduction of systemic exposure and side effects, direct delivery and targeting to the brain and cerebral spinal fluid (CSF), ease of administration and better patient compliance. Additionally, avoiding the blood brain barrier (BBB) could significantly increases the concentration of the active pharmaceutical agent in the CNS [7]. In comparison to other routes of administration, intranasal administration is non-invasive, avoids the first-pass metabolism and may also enhance the amount of drug that reaches the brain [8]. Previously, several studies have been reported with improved brain bioavailability of the drugs including high first pass metabolism through oral route of administration [9]. Among the various lipid nano-carriers i.e., liposomes, solid lipid nanoparticles (SLNs) and nanostructured lipid nanocarriers (NLCs), the later were opted because of their extensive stability profile and higher drug entrapment in contrast to the formers [10]. The NLCs have the capability of acting as an effective delivery carriers for both hydrophilic and hydrophobic drugs entity [11,12]. NLCs have become suitable carrier system for the researchers to incorporate variety of drugs delivered via oral, parenteral, topical, intranasal, and intraocular routes [13]. Moreover, it is thought to be the recent trend to utilize NLCs for targeted drug delivery to the brain, transport of anti-cancer medications, gene based targeted drug delivery and non-pharmaceutical based delivery of other essential chemicals. However, it is difficult to administer NLCs for nose to brain delivery and a system is needed to retain the NLCs in nose and to control the drug release over extended period of time.

In situ gelling systems offer ease of administration when in liquid form at room temperature followed by rapid gelling at body temperature that results in longer duration of residence and possibility of sustained release of drug. These systems have resulted in several benefits including enhanced permeation and absorption across nasal membrane, improved bioavailability, and/or prolonged delivery [14]. An in-situ gelling system will provide a dual advantage of longer residence time in the nasal cavity while with an easy administration of the formulation due to its liquid state [15].

Although, previously NLCs have been developed for the combination therapy of escitalopram (ESC) and paroxetine for the intransal delivery [16]. However, it did not provide the data on single therapy of ESC to evaluate its therapeutic efficiency in brain diseases. Thus, this study was aimed to evaluate solely the therapeutic profile of ESC enclosed within NLCs. Herein, ESC-NLCs were prepared, statistically optimized and characterized for particle properties and drug entrapment. Solid state characterization of the prepared ESC-NLCs were performed to investigate the potential properties and the compatibility of drug and excipients. The optimized ESC-NLCs were incorporated in thermosensitive poloxamer gel to develop ESC-NLCs gel followed by its physical evaluation. In vitro drug release and ex vivo permeation studies of the ESC-NLCs gel were carried out and compared with ESC suspension. The bioavailability of the ESC in brain was determined in Sprague-Dawley rats, followed by the investigation of behavioral analysis and neuro inflammation in LPS induced depression model.