**1. Introduction**

Intranasal delivery as a non-invasive drug delivery method has gained popularity in recent years. A wide range of medicinal chemicals may be delivered intranasally for topical, systemic, and central nervous system action since the nasal mucosa provides many advantages as a target tissue for drug delivery. It is currently acknowledged that intranasal drug delivery is a beneficial and trustworthy option compared to oral and parenteral routes. Without a doubt, intranasal medication administration has been utilized

**Citation:** Ghazwani, M.; Vasudevan, R.; Kandasamy, G.; Manusri, N.; Devanandan, P.; Puvvada, R.C.; Veeramani, V.P.; Paulsamy, P.; Venkatesan, K.; Chidmabaram, K.; et al. Formulation of Intranasal Mucoadhesive Thermotriggered In Situ Gel Containing Mirtazapine as an Antidepressant Drug. *Gels* **2023**, *9*, 457. https://doi.org/10.3390/ gels9060457

Academic Editor: Mario Grassi

Received: 6 April 2023 Revised: 25 May 2023 Accepted: 26 May 2023 Published: 2 June 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

extensively for a long time for the symptomatic alleviation, prevention, and treatment of topical nasal diseases [1,2] The nasal mucosa has, however, recently made a significant comeback as a therapeutically effective route for systemic drug administration. In general, pharmacologically active substances with limited stability in gastrointestinal fluids, poor intestinal absorption, and/or significant hepatic first-pass elimination, such as peptides, proteins, and polar medicines, are among the main targets for intranasal delivery. The intranasal delivery method appears to be an effective strategy to get over the blood-brain barrier (BBB) barriers, enabling direct medication delivery of central nervous system (CNS) active substances during their biophase [3,4].

A nanostructured drug delivery system known as a nanoemulsion (NE) is characterized by its small droplet size and kinetic stability, which prevents flocculation even when the substance is stored for extended periods of time. It is suitable for drug delivery because it has a number of benefits, such as ease of synthesis and optimization, high drug loading capacity, higher drug permeability across mucosal membranes, and increased bioavailability of drug molecules [5–8].

Antidepressant mirtazapine is used to treat moderate to severe depression. The Food and Drug Administration has approved it as the sole tetracyclic antidepressant to treat depression and anxiety. Being a powerful antagonist at postsynaptic 5-HT2 and 5-HT3 (serotonergic) and central noradrenergic receptors, it is also used to treat anxiety by boosting central noradrenergic and serotonergic (5-HT1) neurotransmission [9,10]. Although mirtazapine is quickly absorbed after oral administration, its absolute bioavailability is only 50% due to strong first-pass metabolism. These factors highlight the necessity for an alternate drug delivery technology that can target mirtazapine to the brain with precision. Intranasal administration methods may be predicted to decrease the extensive dispersion of medications to non-targeted areas such systemic/peripheral circulation since pharmaceuticals are preferentially transported to the brain. To ensure that the drug is quickly transported through the nasal mucosa and via the olfactory bulb, the delivery mechanism must be carefully constructed [11,12]. The preparation and characterization of a thermotriggered nanoemulsion loaded with mirtazapine for intranasal administration was the goal of this work. The research was done with the intention of delivering drugs to the brain for a faster onset of action than oral administration, minimizing adverse effects, maximizing therapeutic index, and lowering dosage and dosing frequency.

### **2. Result and Discussion**

### *2.1. Saturation Solubility Studies*

The saturation solubility studies of mirtazapine were carried out in different solvents. Oleic acid was selected as the oil phase from the solubility studies (Figure 1) based on the drug's solubility, and Tween 80 and ethanol were selected as the surfactant and cosurfactant, respectively. Tween 80 not only effectively dissolves drugs but also effectively forms emulsions.

### *2.2. Construction of Pseudo-Ternary Phase Diagrams*

Microemulsions were prepared using oleic acid as the oil phase, Tween 80 as the surfactant, and ethanol as the co-surfactant. Figure 2 represents the pseudo-ternary phase diagrams of oleic acid with various ratios of Tween 80 and ethanol. Based on the pseudoternary phase diagrams, a higher ratio of Smix than oil, i.e., 9:1 ratio of Smix:oil was selected. The optimized ratio mixture of surfactant to co-surfactant was 1:3.

*Gels* **2023**, *9*, x FOR PEER REVIEW 3 of 15

**Figure 1.** Saturation solubility studies of mirtazapine in different solvents and oils. **Figure 1.** Saturation solubility studies of mirtazapine in different solvents and oils. selected. The optimized ratio mixture of surfactant to co-surfactant was 1:3.

do-ternary phase diagrams, a higher ratio of Smix than oil, i.e., 9:1 ratio of Smix:oil was

**Figure 2.** Pseudoternary phase diagrams. **Figure 2.** Pseudoternary phase diagrams.

### *2.3. Development of Microemulsion Formulations*

Formulations were developed based on the highest microemulsion zone obtained from pseudo-ternary phase diagrams. A 1:3 ratio of Smix (Tween 80: ethanol) and a 9:1 ratio of oil and Smix was selected, and further various formulations like RD1, RD2, RD3 were formulated. Carbopol 934P was used as a mucoadhesive agent in the formulation, which helps the formulation to remain adhered to the mucosal membrane. A thermotriggered formulation was prepared by changing different concentrations of poloxamer 407, i.e.,15%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, and 20%. Poloxamer 407 of 18.5% concentration was selected based on gelling time and gelling temperature. The optimized formulation (RD1) gave a gelling time of 4 sec and a gelling temperature of 32 ◦C.

### *2.4. Characterization of Nanoemulsion*
