Lavender Oil-Infused Mirtazapine Nanoemulsion for Direct Nose- to-Brain Targeting

Lavender Oil-Infused Mirtazapine Nanoemulsion for Direct Nose- to-Brain Targeting | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lavender Oil-Infused Mirtazapine Nanoemulsion for Direct Nose- to-Brain Targeting Muhammad Ahsan Waqar, Maha Khalid, Rabeel Khan, Ansa Ashfaq, Shabab Zahra, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7282569/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Feb, 2026 Read the published version in BioNanoScience → Version 1 posted 7 You are reading this latest preprint version Abstract Neurological disorders, such as depression, are difficult to manage owing to limited brain drug delivery and suboptimal therapies. This study developed and evaluated lavender oil-based mirtazapine-loaded nanoemulsions for direct nose-to-brain targeting to enhance therapeutic efficiency and reduce systemic side effects. Nanoemulsions were prepared using homogenization-sonication, incorporating lavender oil, Tween-80, Span-80, ethanol, and distilled water. They exhibited spherical, uniformly distributed nanosized globules with nasal pH compatibility (6.14–6.19). Among the formulations, F4 showed optimal results with a zeta potential of –10.4 ± 0.9, ideal viscosity, high drug entrapment, and excellent in-vitro (92.78%) and ex-vivo (93.28%) mucosal penetration. Molecular docking confirmed the stable binding of mirtazapine to the dopamine receptor (PDB ID: 6CM4) via multiple hydrophobic and π-interactions. All formulations demonstrated stability under centrifugation and freeze-thaw conditions. Overall, this study supports mirtazapine nanoemulsions as a promising, non-invasive strategy for central nervous system drug delivery, improving bioavailability while minimizing systemic toxicity. Nanoemulsion Mirtazapine Depression Behavior Intranasal Delivery Brain Targeting Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 1. Introduction Pervasive and persistent poor states of mind, interest, and motivation, as well as potentially suicidal thoughts, are hallmarks of depression, a common and chronic mental illness [ 1 , 2 ] . It has a substantial socioeconomic impact, which includes higher medical expenses [ 3 , 4 ] . Although there are many theories about its pathophysiology, the exact cause remains unknown, and there are insufficiently precise diagnostic and therapeutic approaches [ 5 – 7 ] . The safety and tolerability of antidepressants are crucial factors that should be considered. The three most common types of antidepressants in clinical treatment are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin–norepinephrine reuptake inhibitors (SNRIs). These medications are associated with several adverse effects, including cardiovascular side effects such as orthostatic hypotension, tachycardia, and arrhythmias [ 7 , 8 ] gastrointestinal disturbances such as nausea, vomiting, diarrhea, and constipation [ 9 , 10 ] ; hepatotoxicity, particularly with certain TCAs and SNRIs, leading to elevated liver enzymes or, in rare cases, liver failure [ 11 , 12 ] ; and anorgasmia, delayed ejaculation, and diminished libido, which are examples of sexual dysfunction. [ 13 , 14 ] . Mirtazapine is a tetracyclic antidepressant primarily prescribed for the treatment of major depressive disorder [ 15 ] . Norepinephrine and serotonin release is increased by core presynaptic alpha-2 adrenal inhibiting autoreceptors and heteroreceptors. [ 16 , 17 ] . Additionally, it blocks the serotonin receptors 5-HT2 and 5-HT3, which contribute to its anxiolytic and antiemetic properties, making it a unique antidepressant with a broad therapeutic profile [ 18 ] . Despite its efficacy, oral administration of mirtazapine is often associated with extensive first-pass metabolism and delayed onset of action owing to poor penetration through the blood-brain barrier [ 19 , 20 ] . These limitations make it a suitable candidate for nose-to-brain delivery systems that can bypass hepatic metabolism and ensure faster and more targeted actions in the central nervous system [ 21 , 22 ] . Formulating Mirtazapine as a nanoemulsion for intranasal administration may significantly enhance its therapeutic outcomes by improving its bioavailability and onset of action while reducing systemic side effects [ 23 , 24 ] . Nanoemulsions, also known as mini-, submicron-, or ultrafine emulsions, are kinetically stable systems composed of one immiscible liquid dispersed in another, with droplet sizes ranging from 20 to 500 nm. These nanosized emulsions incorporate surfactants to reduce surface tension and prevent coalescence, thereby enhancing the solubility and stability of the incorporated drug particles [ 25 , 26 ] . Their small droplet size gives them a clear or hazy appearance and provides superior kinetic and thermodynamic stability compared to microemulsions, despite their similar size ranges. Nanoemulsions can be formulated into various dosage forms and administered through multiple routes, offering improved physical stability by resisting sedimentation, creaming, and coalescence owing to dominant Brownian motion [ 27 , 28 ] . They also enhance drug bioavailability, sometimes bypassing first-pass metabolism through lymphatic absorption [ 22 ] . However, despite their advantages, the commercial availability of nanoemulsions remains limited due to complex manufacturing processes, expensive equipment, and insufficient understanding of instability mechanisms, such as Ostwald ripening [ 29 , 30 ] . The primary aim of this study was to develop and evaluate a stable nanoemulsion formulation of mirtazapine for direct nose-to-brain delivery to enhance its bioavailability and therapeutic efficacy in the treatment of neurological disorders, particularly depression [ 31 ] . The objectives included the formulation of a mirtazapine-loaded nanoemulsion using lavender oil, tween-80, and span-80; characterization of the nanoemulsion in terms of its drug content, ionic potential, viscosity, pH, and droplet size; and assessment of its ex vivo penetration via the nasal mucosa and in vitro drug release [ 32 ] . This study also aimed to assess the stability of the formulation under different storage conditions to perform molecular docking [ 33 ] . This study aimed to establish the potential of nanoemulsion-based intranasal drug delivery as an efficient and noninvasive method for targeting the central nervous system [ 34 ] . 2. Materials and Methods 2.1 Materials We bought Mirtazapine from StandPharm in Pakistan. We bought lavender oil from Flav Chemicals Royal, China. Span-80 and Tween-80 were purchased from Daejung, China. Distilled water and ethanol were purchased from Merck KGaA (Darmstadt, Germany). All the chemicals and solvents used in this experiment were of analytical grade. 2.2 Method Four drug formulations (F1, F2, F3, and F4) were prepared for the study, as shown in Fig. 2 . The composition details of these formulations are presented in Table 1 . The drug solution was prepared by mixing 10 mg of the active ingredient in 2 ml ethanol with magnetic stirring. To prepare the oil phase, a lavender oil and a cosurfactant, Span 80. The drug solution was added dropwise to the oil phase through magnetic stirring. The aqueous phase was prepared by mixing Tween 80 with distilled water. This aqueous phase was homogenized for 30–45 minutes, and the oil phase was added dropwise to the aqueous solution during homogenization. A drop of the colored solution was added to the formulation during homogenization. Distilled water was then added to make the volume up to 10 ml. The formulation was sonicated for 10–15 minutes to remove any bubbles, as illustrated in Fig. 1 . Table 1 Composition of Mirtazapine-Loaded Nanoemulsions with varying percentages of Lavender Oil. This table presents the formulation details for four samples (F1–F4) with a constant oil-to-water phase ratio (1:4) and increasing percentages of lavender oil ranging from 20–80%. Formulation Oil Phase (mL) Water Phase (mL) Lavender Oil (%) F1 1.0 4.0 20 F2 1.0 4.0 40 F3 1.0 4.0 60 F4 1.0 4.0 80 3. Characterization of Nanoemulsion 3.1 pH Test, Refractive Index, Viscosity Measurement The stability of nanoparticle formulations, their drug release profiles, and their interactions with the nasal mucosa are all affected by pH [ 35 ] . To enhance drug absorption, the pH should be adjusted to match the nasal environment. Nasal pH generally ranges from 4.5 to 6.5 [ 36 ] . Chitosan-based nanoparticles possess pH-dependent properties that increase mucoadhesion and drug release, thereby enhancing therapeutic outcomes. pH-sensitive polymers have been used to achieve controlled drug release in response to pH changes. pH was measured using a pH meter [ 37 ] . The refractive index is related to the optical properties of the nanoparticles. This shows how light is transferred from the nanoemulsion medium and its transparency. The refractive index influences how nanoparticles interact with biological tissues; consequently, it affects their ability to penetrate the nasal mucosa and deliver drugs directly to the brain. The refractive index can be determined using an Abbes-type refractometer by pouring a droplet of nanoemulsion on a disk [ 38 ] . In the Viscosity Measurement, the flow properties and stability of the mirtazapine-loaded nanoemulsion were assessed using a viscometer [ 31 ] . The viscosity was measured under controlled conditions, typically at a standard temperature of 25°C [ 39 ] . Measurements were taken at varying spindle speeds to observe how viscosity changed with different shear rates. These data are crucial for understanding the rheological behavior of nanoemulsion, which affects their formulation and application potential [ 40 ] . 3.2 Scanning Electron Microscopy (SEM) Scanning Electron Microscopy was used to evaluate the superficial morphology of the nanoemulsions.The, and the three-dimensional structure of globules was observed using SEM [ 41 ] . A drop of sample was taken, dried in an oven, and then placed on an SEM stub. Then, SEM was employed to acquire digital photos at an accelerating voltage of 15 kV. [ 42 ] 3.3 Globule Size, Polydispersity Index (PDI) and Zeta Potential Analysis Droplet size and Polydispersity Index (PDI) are key in characterizing nanoemulsions because they increase the stability of the drug and its bioavailability [ 43 ] . The nanoemulsion droplet size usually ranges from 10 to 200 nanometers and is an essential parameter affecting the stability of nanoemulsions and the efficiency of drug delivery via the nasal route [ 44 ] . Dynamic light scattering (DLS), often known as photon correlation spectroscopy (PCS), is a commonly used technique for the measurement of tiny nanoemulsions. PCS involves shining a laser beam within the nanoemulsion and then analyzing the light scattering, which is produced by the Brownian motion of the tiny particles of the nanoemulsion [ 45 ] . As the tiny droplets pass faster, rapid fluctuations are produced in that light and are detected in PCS devices, such as the Malvern Zeta sizer. Based on these fluctuations, this device was used to calculate the average droplet size [ 46 ] . PDI is used to measure droplet size uniformity through a nanoemulsion, whose size ranges from 0 to 1 nanometer [ 47 ] . The zeta potential was used to determine the charge present on the surface of the particles when they were submerged in the liquid. The zeta potential was measured using a specialized instrument called the Malvern Zetasizer [ 48 ] . First, we dilute the nanoemulsion, and there will be some mobility of oil droplets, which gives the estimated value and allows us to determine the zeta potential [ 49 ] . 3.4 Dilution Test The dilution test was performed by adding a higher concentration of the continuous phase into the nanoemulsion; thus, 1 ml of the sample was taken and 4 ml of distilled water was added [ 50 ] . 3.5 Dye Soluble Test A water-soluble dye is emulsified in the aqueous phase of the w/o globule, but miscible in the o/w globule. [ 50 ] . To illustrate this, 1 mL of the nanoemulsion together with a few hydrophilic color droplets, safranine, was pipetted onto a glass slide and mixed well. The efficiency of the formulation was assessed under a microscope. 3.6 Fourier Transform Infrared Spectrophotometer (FTIR) FTIR was used to determine the compatibility and identify the functional groups [ 51 ] . It also provides the fingerprint and the mode of attachment of the molecule. The sample was first prepared using the appropriate method, after which scanning of the sample was performed at the specified scanning speed. 3.7 Differential Scanning Calorimetry (DSC) Physical characterization of the formulations was performed using DSC [ 52 ] . The sample formulations were dried and placed in a hermetically sealed aluminum pan. Nitrogen gas was introduced at 50 ml/min of flow rate in the system and then heated at 10°C/min [ 53 ] . 3.8 Stability Studies 3.8.1 Centrifugation Centrifugation of the formulations was performed at 3500 rpm for 30 min and observed for phase separation [ 54 ] . 3.8.2 Freeze-Thaw Method The formulations were observed during heating and cooling cycles. formulations were first exposed to 4°C and 45°C and were then observed for phase separation [ 55 ] . 3.9 In-vitro drug release studies Drug release from the formulations was investigated using dialysis membranes. Formulations were assessed using a rotating paddle dissolution apparatus. The formulations sealed in the dialysis membrane were immersed in a phosphate buffer solution. The samples were taken out at 5, 30, 60, 90, 120, 150, and 180 min intervals, and the drug concentration was measured using a UV-visible spectrophotometer at 309 nm wavelength [ 4 ] . 3.10 In-vitro Permeation Studies A Franz diffusion cell (Variomag Telesystem, H + P Labortechnik, Oberschleißheim, Germany) was used to perform the permeation studies. In the recipient compartment, 7mL of buffer was added, and 1mL of the sample was then added to the donor compartment. A cellophane membrane was placed between donor and recipient compartments. Medication was permitted to pass through the cellophane barrier. Before UV analysis, samples, each with a volume of 1 mL, were collected at different times and adequately diluted [ 56 ] . 3.11 Ex-vivo Permeation Studies We decided to use goat nasal mucosa for the ex vivo permeation investigations. On the initial day of the experiment, the goat head, acquired from a nearby slaughterhouse, was detached from the mucosal layer of the nasal cavity. Surgical scissors were used to split the nasal membrane. Saline solution was used to keep the mucosal layer hydrated during isolation. The receptor compartment (7 ml) of the Franz cell was filled with phosphate buffer (pH 6.8). With the mucosal side facing the donor and a diffusion area of 0.63 cm2, the mucosal layer was positioned between the donor and receptor compartments. At 37 ± 0.5°C, The median temperature was maintained. The donor compartment was filled with 1 mL of the studied material. Following five, ten, twenty, thirty, and sixty minutes, samples were removed from the receptor compartment. An equivalent volume of fresh buffer medium was used instead of receptor compartment volume. The extracted samples were appropriately diluted before examination using a UV spectrophotometer to determine the percentage of drug release. 3.12 Docking Studies Molecular docking analyses were performed using AutoDock Vina (version 1.5.7) [ 57 ] . Prior to docking, the three-dimensional structure of the dopamine receptor (PDB ID: 6CM4) was prepared by removing all co-crystallized ligands and water molecules. The receptor was further refined and analyzed using BIOVIA Discovery Studio 2021 to identify the possible binding site for the antidepressant drug mirtazapine. Subsequently, the protein and ligand structures were optimized and subjected to docking simulations, producing nine distinct binding poses of mirtazapine, along with their respective binding affinity scores. The most favorable conformation was selected by evaluating key molecular interactions within the binding pocket of the receptor using BIOVIA Discovery Studio 2021. 4. Results and Discussion 4.1 pH Test The pH of each formulation was measured. It was 6.19 and 6.14 for F2 and F3, which was in the range for nanoemulsions for nasal administration [ 58 ] . 4.2 Scanning Electron Microscopy (SEM) The exterior morphology of the nanoparticles in the formulations was assessed by SEM. The results shown in Fig. 3 indicated spherical nanosized globules. In addition, the nanoparticles were well separated, indicating stable formulations. These nanosized spherical globules were similar to the nanosized globules of mirtazipine-loaded nanocarriers prepared in a previous study [ 50 ] . 4.3 Polydispersity index (PDI) and Zeta potential analysis When creating nanoemulsions, the polydispersity index, zeta potential, and particle size distribution are important factors [ 43 ] . According to the given Fig. 4 , the zeta potential of sample F-4 is about − 10.4mV, which is closer to the neutral value of ± 30mV, which means that the formulation is more likely to be stable, and the negative sign helps to avoid aggregation of particles. The size distribution also indicates that the formulation is stable, as the smaller particles form a stable formulation with a larger rate and degree of medication absorption, in contrast to particles of a larger size. PDI is also an important parameter in the formulation of nanoemulsion, which shows that the droplet size in the procedure is consistent [ 59 ] . The PDI of sample F-4 was 0.800 according to the Table 2 , which is a broad size distribution indicating variations in droplet size that can cause instability in a formulation. Table 2 Globule size (Z-Average), intensity-weighted distribution (Dv), volume-weighted distribution (Dz), polydispersity index (PDI), zeta potential, and drug load analysis of nanoemulsion formulations (n = 3). The globule size of all formulations is below 200 nm, ensuring efficient nasal absorption. Although the negative zeta values may show superior colloidal stability, reducing particle aggregation, the low PDI values verify a uniform particle size distribution. Formulation Z-Average (nm) Dv (nm) Dz (nm) Polydispersity Index (PDI) Zeta Potential (mV) Surface Charge (mV) Drug Load (% w/w) F1 92.36 ± 1.5 106 ± 1.0 94 ± 1.0 0.550 ± 0.3 -12.5 ± 0.8 -12.5 ± 0.8 5.2 ± 0.2 F2 100.69 ± 1.8 126 ± 1.0 120 ± 1.0 0.637 ± 0.2 -15.6 ± 1.2 -15.6 ± 1.2 5.2 ± 0.2 F3 122.14 ± 0.9 136 ± 1.0 130 ± 1.0 0.794 ± 0.1 -17.0 ± 1.1 -17.0 ± 1.1 5.6 ± 0.3 F4 116.2 ± 1.2 134 ± 1.0 127 ± 1.0 0.800 ± 0.3 -10.4 ± 0.9 -10.4 ± 0.9 5.5 ± 0.3 PDI typically falls between 0 and 1, where 1 denotes a polydisperse particle dispersion, and 0 denotes a monodisperse system [ 60 ] . The constant particle diameter throughout the formulation was demonstrated by the low polydispersity values of the formulations. The measurement of the formulations' zeta potential values, which ranged from − 10.4 to -17.0 mV, showed that a stable nanoemulsion was formed. Figure 4 shows the nanoemulsion's zeta potential of (F2). 4.4 Dilution Test The formulations were subjected to dilution tests to evaluate their stability. The results of the dilution tests for formulations F2 and F3 are shown in Fig. 5 . 4.5 Dye Solubility Test Dye solubility tests were performed to assess the continuous phase of the nanoemulsions formulated. Because the safranine dye was dispersed uniformly, all of the formulations constituted oil-in-water nanoemulsions. 4.6 Fourier transform infrared spectroscopy (FTIR) FTIR was conducted to determine the molecular structure of mirtazapine in a nanoemulsion carrier system. The spectra in the above Fig. 6 show the characteristic absorption peaks of the four formulations labeled as F1, F2, F3, and F4 of Mirtazapine, with a wavenumber plotted on the x-axis representing the frequency of infrared light absorbed and transmittance on the y-axis indicating the amount of light passing through the drug. The infrared spectra of the formulations revealed several key peaks indicative of the functional groups of mirtazapine. The broad peak at 3300 cm–1, likely due to O-H or N-H stretching, suggests the presence of a hydroxyl or amine group. This peak exhibited slight shifts in the F3 and F4 formulations, which may be attributed to minor differences in hydrogen bonding or moisture content. The peaks observed in the 1600–1700 cm–1 region, corresponding to C = O, indicated the presence of aromatic rings or a carbonyl group in mirtazapine. This peak was consistent across all formulations, suggesting that the aromatic structure of mirtazapine remained unchanged. The sharp peak between 2900–3000 cm–1 is attributed to C-H stretching, which indicates the presence of alkyl chains in the sample. This peak was more pronounced in F2 and F4, possibly because of interactions between excipients and mirtazapine. Smaller peaks observed below 1000 cm–1 may indicate out-of-plane bending of the aromatic system in mirtazapine. F1 and F3 formulations showed slight variations in this region, potentially owing to the presence of different polymorphs of mirtazapine in these respective formulations. Therefore, we might interpret from the above observations that the presence of characteristic functional groups such as N-H and C-H confirmed the structure of mirtazapine. There are slight variations in the peaks, which might be due to excipient interactions, moisture content, polymorphism, or amorphous content. 4.7 Differential Scanning Calorimetry (DSC) Less intense peaks were observed from the formulation, indicating entrapment of the drug as nanoparticles in the formulation. The melting point of mirtazapine was 117°C. Our results for both formulations show the amorphous nature of the product. Mirtazapine's DSC revealed a distinct peak of endothermic activity at 117°C, which is consistent with data that have been published. This suggested that the medication was highly pure and crystalline. Mirtazapine's melting point vanished for the nanoemulsions, which is a clear sign that the medication changed from a crystalline state to an amorphous state, as illustrated in Fig. 7 . 4.8 Stability Studies 4.8.1 Centrifugation Centrifugation is used for the analysis of nanoemulsions to separate or assess their stability. A centrifugation test was performed on the formulations labeled F1, F2, F3, and F4 to evaluate their stability. Two milliliters of each formulation was added into centrifuge tubes, which were then placed into a centrifuge machine and spun at high speed (4000 RPM) for 30 min. After 30 min, the tubes were removed and observed. We did not notice any significant changes in F1, F2, and F3, indicating that the Nanoemulsions remained stable. No phase separation was observed for F1, F2, or F3. In the F4 formulation, phase separation was observed, indicating instability. This result is important for ensuring the stability of nanoemulsions, as illustrated in Fig. 8. 4.8.2 Freeze-Thaw Method The freeze-thaw test was performed on the nanoemulsion formulations labeled F1, F2,F3, and F4 to evaluate their stability at different temperatures. First, approximately 3 mL of each emulsion was added to the test tube and frozen at -21⁰C for one day. After freezing, the formulations were kept at room temperature for some time to defrost. These formulations were thawed at a slightly high temperature of 40⁰C for 60 min. We observed no noticeable changes in the texture, color, or consistency of the nanoemulsions. This test showed that the formulation remained stable and effective despite extreme temperature shifts. No sign of phase separation or degradation was observed in the formulations. This result is important to ensure the long-term stability of nanoemulsions during fluctuations in storage or environmental conditions. 4.9 In Vitro Drug Release Studies For drug release studies, a USP rotating paddle dissolution apparatus and cellophane membrane were used. At intervals of 5, 30, 60, 90, 120, 150, and 180 min, the samples were withdrawn, and the absorbance of each sample was recorded at a wavelength of 309 nm using a UV spectrophotometer. The formulation's % medication release versus time is shown in Fig. 9 . F4 showed the highest percentage of drug release (92.28%), whereas F1 exhibited the lowest medication release percentage (64.21%). 4.10 In-vitro Permeation Studies Samples were extracted 5, 10, 20, 30, and 60 min after the beginning of the procedure, and the absorbance was measured at 590 nm. The concentration was plotted against absorbance. The proportion of drug penetration of the formulation through the membrane is shown in Fig. 10 . Of all the formulations, F4 showed maximum drug penetration (92.78%). 4.11 Ex Vivo Permeation Studies After 5, 10, 20, 30, and 60 min, the samples were examined at 590 nm, and the percentage of drug release for each formulation was determined. The percentage of medication release through the nasal mucosa of the formulations is shown in Fig. 11 . Of all formulations, F4 exhibited the highest drug penetration (93.28%). 4.12 Docking Studies In the molecular docking studies of mirtazapine against the dopamine receptor (PDB ID: 6CM4), AutoDock Vina version 1.5.7 was employed [ 61 ] . Docking was performed three times for each formulation. Among the docking poses generated, the top-binding conformation showed interactions with various amino acid residues in the active site. The ligand formed carbon-hydrogen bonds with Tyr1088, while Asp1072 contributed to π-anion interactions. Ala1097, Ala1093, Ile1003, Val1071, and Lys221 engaged in π-alkyl interactions, while Arg220 formed a π-sigma interaction, stabilizing the ligand within the binding pocket. The binding pose was further supported by the hydrophobic interactions of the surrounding residues. These interactions, as visualized in the 3D binding site representation, confirmed the appropriate accommodation of mirtazapine within the hydrophobic pocket of the receptor (as illustrated in Fig. 12 ) and are summarized in Table 3 . Thus, the binding conformation was stabilized through a combination of π-anion, π-alkyl, π-sigma, and carbon-hydrogen bonding interactions. Table 3 The table summarizes the key non-covalent interactions contributing to the binding of Mirtazapine within the Dopamine receptor active site, with an estimated binding energy of -7.2 kcal/mol. The interaction profile includes carbon hydrogen bonding, π– sigma contact, π–anion interaction, and multiple π–alkyl associations. These binding forces play a pivotal role in stabilizing the ligand–receptor complex and may underlie the pharmacological efficacy of mirtazapine through enhanced receptor engagement and affinity. Type of Bond Amino Acid Residue Distance (Å) Carbon Hydrogen Bond TYR A:1088 3.36 Pi-Sigma ARG A:220 3.95 Pi-Anion ASP A:1072 4.25 Pi-Alkyl VAL A:1071 4.85 Pi-Alkyl ALA A:1093 5.14 Pi-Alkyl ALA A:1097 4.91 Pi-Alkyl ILE A:1003 5.3 Pi-Alkyl LYS A:221 4.42 5 Discussion This study highlights the significance of mirtazapine-loaded nanoemulsion in the treatment of neurological disorders, particularly in addressing the challenges posed by the blood-brain barrier (BBB) [ 62 ] . As research in this domain advances, it becomes increasingly necessary to develop more effective, stable, and sustainable solutions to enhance central nervous system (CNS) bioavailability [ 63 ] . Traditional methods of drug delivery, such as oral or intravenous routes, face significant issues, such as poor BBB penetration, systemic toxicity, and limited CNS bioavailability [ 64 ] . This research is valuable because it offers potential solutions to persistent obstacles, such as insufficient CNS drug concentration and high systemic exposure, which remain major challenges in the pharmaceutical industry [ 65 ] . Enhancing direct nose-to-brain drug delivery is crucial for improving the efficacy and longevity of treatments targeting the brain [ 42 ] . Despite progress in this field, current strategies for intranasal drug delivery still face substantial limitations [ 66 ] . Conventional methods are hindered by poor bioavailability, systemic toxicity, and extensive first-pass metabolism [ 67 ] . Although these methods have been commonly used, they do not effectively address the issues of direct brain targeting [ 68 ] . This gap highlights the need to explore alternative approaches, such as nanoemulsion formulations, which can provide superior performance and greater reliability [ 69 ] . The shortcomings of traditional methods emphasize the need for innovative solutions that leverage nanoemulsion technology to enhance drug delivery effectiveness and formulation stability [ 52 ] . To address these challenges, this study explored the use of a mirtazapine-loaded nanoemulsion for intranasal administration, a method that bypasses the BBB [ 70 ] . The basis for this approach lies in the potential of nanoemulsions to improve drug solubility, facilitate better CNS penetration, and provide sustained drug release [ 71 ] . This study aims to offer valuable insights into the viability of this innovative strategy, potentially providing a more reliable and sustainable solution for treating neurological conditions, such as depression [ 72 ] . The results of this investigation are in line with earlier studies showing the effectiveness of nanoemulsion devices for medication delivery [ 73 ] . For instance, Zhang et al. (2018) showed that nanoemulsions improve drug absorption and enhance targeting [ 74 ] . However, the present study distinguishes itself by employing a novel method involving high-energy emulsification through ultrasonication, resulting in a smaller and more uniform globule size [ 75 ] . This new approach provides important advancements in the understanding of intranasal drug delivery and contributes to the development of more effective delivery systems [ 76 ] . A key strength of this study is its methodology, which offers several distinct advantages [ 77 ] . The use of ultrasonication improves the reduction in globule size and increases the drug encapsulation efficiency. This formulation achieved high drug encapsulation and formulation consistency. This is crucial because it ensures the stability and ability of the formulation to offer controlled release over an extended period [ 42 ] . The improved performance observed in this study is attributed to the reduced particle size, electrostatic stability, and low viscosity, which together facilitate easy administration and enhance absorption by the nasal mucosa [ 78 ] . Additionally, the amount of lavender oil in the formulations boosted medication penetration [ 79 ] . Among the different formulations, F1 had the lowest concentration of lavender oil, followed by F2 and F3, with F4 having the highest concentration [ 80 ] . This gradient directly influenced the performance metrics, as the in situ release of drugs, in vitro penetration, and ex vivo permeability were greatest in F4 [ 81 ] . Previous studies have also supported the role of lavender oil in enhancing drug permeation, likely because of its ability to disrupt the lipid structure of biological membranes, thereby increasing drug diffusion [ 82 ] . In comparison with previous studies, our results highlight significant improvements in bioavailability and stability. For example, in a recent study, similar benefits were observed using nanoemulsion-based systems for CNS-targeted delivery, demonstrating that nanoemulsions have the potential to be viable substitutes for conventional medication delivery methods [ 28 ] .While the results of this study align with the existing literature in many respects, it also introduces new perspectives by demonstrating a higher drug release and exceptional formulation stability under accelerated conditions. These differences may be attributed to the improved emulsification method, particularly the use of ultrasonication for particle size reduction [ 10 ] . The findings of this study are in line with those of other studies. The nanoemulsion droplet sizes measured here fall within the nanometer range, similar to the values observed by Đorđević et al. for risperidone nanoemulsions and other studies on curcumin nanoemulsions [ 81 ] .Additionally, although slightly higher, the PDI values reflected comparable trends in droplet size distribution and uniformity. This alignment with prior studies supports the reliability of the formulation and characterization methods used, indicating that the developed nanoemulsions possess physicochemical properties that are suitable for effective drug delivery. Although the results are promising, this study had some limitations. One major constraint is the lack of in vivo validation, as the study primarily focused on in vitro evaluation [ 83 ] . Additionally, although the stability of the formulation was assessed under accelerated conditions, further long-term studies are needed to confirm its long-term stability and effectiveness in clinical settings. To increase the applicability of the findings, it is crucial to address these limitations in future studies [ 14 ] . The implications of this research extend beyond the theoretical findings, offering practical applications that could significantly impact the treatment of neurological disorders. By refining and optimizing intranasal nanoemulsion formulations, this study provides a foundation for future advancements in drug delivery to the CNS. Future studies should focus on in vivo testing, clinical trials, and large-scale production to fully exploit the benefits of this approach. If successfully translated into clinical practice, these findings could play a pivotal role in the pharmaceutical industry, particularly for developing non-invasive therapies for neurological disorders such as depression, schizophrenia, and epilepsy, thereby improving treatment outcomes and minimizing systemic side effects [ 12 ] . 6 Conclusion This study successfully formulated and evaluated mirtazapine-loaded nanoemulsions for potential nose-to-brain delivery, demonstrating significant advantages over conventional oral delivery. Among the formulations, F4 exhibited the highest drug release (92.28%), whereas F1 had the lowest (64.21%), highlighting the impact of formulation composition on drug release profiles. Stability assessments confirmed that F1, F2,F3, and F4 were stable under freeze-thaw and centrifugation tests, while F4 showed instability in the latter. SEM revealed spherical, well-separated nanoparticles, and DSC confirmed the transformation of mirtazapine into an amorphous form, which enhanced its solubility. FTIR analysis maintained the structural integrity of the drug, with slight variations due to excipient interactions. The zeta potential and PDI values indicated good stability and size distribution for most of the formulations. Notably, nose-to-brain delivery offers distinct advantages over oral delivery, including bypassing the blood-brain barrier, faster drug action, reduced systemic side effects, and improved bioavailability, making it a promising approach for treating central nervous system disorders. Declarations ETHICAL STATEMENT Ethics Approval and Consent to Participate N.A. Consent for Publication All authors agree to publish the article. Availability of Data and Materials All the data is available in the article file Competing Interests Authors declare no competing interests Funding N.A. Author’s Contributions M.A.W. supervised the project, contributed to the methodology, and was involved in the project administration. M.K. conceptualized the study, performed the formal analysis, and contributed to writing, reviewing, and editing the manuscript. R.K. contributed to conceptualization and participated in writing, reviewing, and editing the manuscript. A.A. curated the data and conducted formal analysis. S.Z. assisted with validation and contributed to data curation. A.S.A. contributed to validation and participated in methodology development. B.A.contributed to the conceptualization and conducted formal analysis. Acknowledgements N.A. Data Availability Statement All the data has been mentioned in the article file References König, H.; König, H.-H.; Konnopka, A., The excess costs of depression: a systematic review and meta-analysis. Epidemiology and psychiatric sciences 2020, 29 , e30. Ibrahim, M. M.; Basalious, E. B.; El-Nabarawi, M. A.; Makhlouf, A. I.; Sayyed, M. E.; Ibrahim, I. T. J. D. D.; Research, T., Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study. 2024, 14 (9), 2539-2557. Jin, Y.; Cui, R.; Zhao, L.; Fan, J.; Li, B., Mechanisms of Panax ginseng action as an antidepressant. Cell proliferation 2019, 52 (6), e12696. Alaayedi, M. H.; Maraie, N. K., Lomustine’s nanoemulsion as nose-to-brain drug delivery system for CNS tumor treatment. Saudi Pharmaceutical Journal 2023, 31 (8), 101692. Mago, R.; Tripathi, N.; Andrade, C., Cardiovascular adverse effects of newer antidepressants. Expert review of neurotherapeutics 2014, 14 (5), 539-551. Beach, S. R.; Kostis, W. J.; Celano, C. M.; Januzzi, J. L.; Ruskin, J. N.; Noseworthy, P. A.; Huffman, J. C., Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. The Journal of clinical psychiatry 2014, 75 (5), 11731. Misra, S. K.; Pathak, K. J. C.; Interfaces, Nose-to-brain targeting via nanoemulsion: significance and evidence. 2023, 7 (1), 23. Spindelegger, C. J.; Papageorgiou, K.; Grohmann, R.; Engel, R.; Greil, W.; Konstantinidis, A.; Agelink, M. W.; Bleich, S.; Ruether, E.; Toto, S., Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010. International journal of neuropsychopharmacology 2015, 18 (4), pyu080. Brambilla, P.; Cipriani, A.; Hotopf, M.; Barbui, C., Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry 2005, 38 (02), 69-77. El Sisi, A. M.; Eissa, E. M.; Hassan, A. H.; Bekhet, M. A.; El-Ela, F. I. A.; Roh, E. J.; Kharshoum, R. M.; Ali, A. A. J. P., Nose-to-Brain Delivery of Chitosan-Grafted Leciplexes for Promoting the Bioavailability and Antidepressant Efficacy of Mirtazapine: In Vitro Assessment and Animal Studies. 2025, 18 (1), 46. Voican, C. S.; Corruble, E.; Naveau, S.; Perlemuter, G., Antidepressant-induced liver injury: a review for clinicians. American Journal of Psychiatry 2014, 171 (4), 404-415. Salam, A.-M. S. T. Nose to Brain Delivery of Antiepileptic Drugs Using Nanoemulsions. University of Toledo, 2015. Atmaca, M., Selective serotonin reuptake inhibitor-induced sexual dysfunction: current management perspectives. Neuropsychiatric disease and treatment 2020 , 1043-1050. Pires, P. C.; Paiva-Santos, A. C.; Veiga, F. J. P., Nano and microemulsions for the treatment of depressive and anxiety disorders: An efficient approach to improve solubility, brain bioavailability and therapeutic efficacy. 2022, 14 (12), 2825. Vitorino, C.; Silva, S.; Bicker, J.; Falcão, A.; Fortuna, A. J. D. D. T., Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges. 2019, 24 (9), 1911-1923. Hassanein, E. H.; Althagafy, H. S.; Baraka, M. A.; Abd-Alhameed, E. K.; Ibrahim, I. M. J. N.-s. s. A. o. P., Pharmacological update of mirtazapine: a narrative literature review. 2024, 397 (5), 2603-2619. Sharma, A.; Alam, M. A.; Kaur, A.; Sharma, S.; Yadav, S. J. C. P. R.; Reviews, R. F. C. P., Psychopharmacological Treatment of Depression and Anxiety and their Different Drug Delivery Targets. 2024, 20 (4), 297-322. Sachan, N.; Bahadur, S.; Sharma, P. K. J. D. D. L., Recent advances and novel approaches for nose to brain drug delivery for treatment of migraine. 2019, 9 (3), 182-198. Jilani, T.; Gibbons, J.; Faizy, R.; Saadabadi, A. J. S., Mirtazapine. 2024 . Mujtaba, M. A.; Rashid, M. A.; Godbole, M. D.; Alhamhoom, Y.; Shende, D. S.; Alshehri, S.; Akbar, M. J.; Kaleem, M.; Mahajan, U. N.; Shahzad, N. J. F. i. P., Escitalopram oxalate-loaded chitosan nanoparticle in situ gel formulation intended for direct nose-to-brain delivery: in vitro, ex vivo, and in vivo pharmacokinetic evaluation. 2025, 16 , 1577331. Alberto, M.; Paiva-Santos, A. C.; Veiga, F.; Pires, P. C. J. P., Lipid and polymeric nanoparticles: Successful strategies for nose-to-brain drug delivery in the treatment of depression and anxiety disorders. 2022, 14 (12), 2742. Shah, B.; Khunt, D.; Misra, M. J. F. J. o. P. S., Comparative evaluation of intranasally delivered quetiapine loaded mucoadhesive microemulsion and polymeric nanoparticles for brain targeting: Pharmacokinetic and gamma scintigraphy studies. 2021, 7 , 1-12. Naji, L.; Dennis, B.; Rosic, T.; Wiercioch, W.; Paul, J.; Worster, A.; Thabane, L.; Samaan, Z. J. D.; Dependence, A., Mirtazapine for the treatment of amphetamine and methamphetamine use disorder: A systematic review and meta-analysis. 2022, 232 , 109295. Shah, B. J. J. o. P. I., Microemulsion as a promising carrier for nose to brain delivery: Journey since last decade. 2021 , 1-24. Karami, Z.; Zanjani, M. R. S.; Hamidi, M. J. D. d. t., Nanoemulsions in CNS drug delivery: recent developments, impacts and challenges. 2019, 24 (5), 1104-1115. Susa, F.; Arpicco, S.; Pirri, C. F.; Limongi, T. J. P., An Overview on the Physiopathology of the Blood–Brain Barrier and the Lipid-Based Nanocarriers for Central Nervous System Delivery. 2024, 16 (7), 849. Gupta, A.; Eral, H. B.; Hatton, T. A.; Doyle, P. S. J. S. m., Nanoemulsions: formation, properties and applications. 2016, 12 (11), 2826-2841. Singh, Y.; Meher, J. G.; Raval, K.; Khan, F. A.; Chaurasia, M.; Jain, N. K.; Chourasia, M. K. J. J. o. c. r., Nanoemulsion: Concepts, development and applications in drug delivery. 2017, 252 , 28-49. Pavoni, L.; Perinelli, D. R.; Bonacucina, G.; Cespi, M.; Palmieri, G. F. J. N., An overview of micro-and nanoemulsions as vehicles for essential oils: Formulation, preparation and stability. 2020, 10 (1), 135. Grosso, C.; Silva, A.; Delerue-Matos, C.; Barroso, M. F. J. P., Single and multitarget systems for drug delivery and detection: up-to-date strategies for brain disorders. 2023, 16 (12), 1721. Eissa, E. M.; El Sisi, A. M.; Bekhet, M. A.; El-Ela, F. I. A.; Kharshoum, R. M.; Ali, A. A.; Alrobaian, M.; Ali, A. M. A., pH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy. Pharmaceuticals 2024, 17 (8), 978. Pailla, S. R.; Talluri, S.; Rangaraj, N.; Ramavath, R.; Challa, V. S.; Doijad, N.; Sampathi, S. J. D. J. o. P. S., Intranasal Zotepine Nanosuspension: Intended for improved brain distribution in rats. 2019, 27 , 541-556. Albaqshi, L.; Singh, A.; Khan, S.; Kumar, M.; Kour, J.; Pottathil, S.; Aldhubiab, B.; Tiwari, A.; Nair, A. B. J. I. J. P. E. R., Formulation and optimization of aripiprazole-loaded nanostructured lipid carriers for nose-to-brain delivery. 2024, 58 (2), 579-588. Kakkar, V.; Modgill, N.; Kumar, M. J. H. M. i. D. T. M. t. I. D. D., Novel drug delivery systems for herbal antidepressants. 2016 , 529-556. Clementino, A. R.; Pellegrini, G.; Banella, S.; Colombo, G.; Cantù, L.; Sonvico, F.; Del Favero, E., Structure and fate of nanoparticles designed for the nasal delivery of poorly soluble drugs. Molecular Pharmaceutics 2021, 18 (8), 3132-3146. Kenneth, E. M.; Xaveir, S. N.; John, M. C.; Patience, O. O.; Krause, R., Evaluation of Accelerated Stability Testing of a Mirtazapine-loaded Nanoemulsion as per International Conference on Harmonization (ich) Protocols. American Journal of Nanoscience and Nanotechnology Research 2018, 6 (1), 8-17. Mohammed, M. A.; Syeda, J. T.; Wasan, K. M.; Wasan, E. K., An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics 2017, 9 (4), 53. Abdulbaqi, M. R.; Albadri, A. A.; Abdulelah, F. M., Nanoemulsion Preparation, Identification and Evaluation Review. Journal of Global Pharma Technology 2019, 11 (07), 198-206. Okoturo, O.; VanderNoot, T., Temperature dependence of viscosity for room temperature ionic liquids. Journal of Electroanalytical Chemistry 2004, 568 , 167-181. Kenneth, E. M.; Xavier, S. N.; John, M. C.; Patience, O. O.; Krause, R., Evaluation of accelerated stability testing of a mirtazapine-loaded nanoemulsion as per. Am J Nanosci Nanotechnol Res 2018, 6 , 1-10. Bhatt, P.; Bhatt, T.; Jain, V.; Jain, R.; Bigoniya, P., Nanoemulsion through cold emulsification: An advanced cold manufacturing process for a stable and advanced drug delivery system. Journal of Applied Pharmaceutical Science 2024, 14 (5), 012-021. Kakad, S. P.; Gangurde, T. D.; Kshirsagar, S. J.; Mundhe, V. G., Nose to brain delivery of nanosuspensions with first line antiviral agents is alternative treatment option to Neuro-AIDS treatment. Heliyon 2022, 8 (7). Algahtani, M. S.; Ahmad, M. Z.; Ahmad, J., Investigation of factors influencing formation of nanoemulsion by spontaneous emulsification: impact on droplet size, polydispersity index, and stability. Bioengineering 2022, 9 (8), 384. Preeti; Sambhakar, S.; Malik, R.; Bhatia, S.; Al Harrasi, A.; Rani, C.; Saharan, R.; Kumar, S.; Geeta; Sehrawat, R., Nanoemulsion: An Emerging Novel Technology for Improving the Bioavailability of Drugs. Scientifica (Cairo) 2023, 2023 , 6640103. Verma, N. K.; Yadav, A.; Yadav, V., Recent Advances In Nanoemulsion Based Drug Delivery System: A Review. 2022 . Tscharnuter, W., Photon Correlation Spectroscopy in Particle Sizing. 2006. Eid, A.; Elmarzugi, N.; El Enshasy, H., Preparation and evaluation of olive oil nanoemulsion using sucrose monoester. International Journal of Pharmacy and Pharmaceutical Sciences 2013, 5 , 434-440. Kamble, S.; Agrawal, S.; Cherumukkil, S.; Sharma, V.; Jasra, R. V.; Munshi, P., Revisiting zeta potential, the key feature of interfacial phenomena, with applications and recent advancements. ChemistrySelect 2022, 7 (1), e202103084. Gurpreet, K.; Singh, S., Review of nanoemulsion formulation and characterization techniques. Indian Journal of Pharmaceutical Sciences 2018, 80 (5). Waqar, M. A.; Zaman, M.; Hameed, H.; Jamshaid, M.; Irfan, A.; Shazly, G. A.; Paiva-Santos, A. C.; Bin Jardan, Y. A., Formulation, characterization, and evaluation of β-Cyclodextrin functionalized hypericin loaded nanocarriers. ACS omega 2023, 8 (41), 38191-38203. Dutta, A., Fourier transform infrared spectroscopy. Spectroscopic methods for nanomaterials characterization 2017 , 73-93. Abdelbary, G. A.; Tadros, M. I., Brain targeting of olanzapine via intranasal delivery of core–shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies. International journal of pharmaceutics 2013, 452 (1-2), 300-310. Pu, X.; Sun, J.; Han, J.; Lian, H.; Zhang, P.; Yan, Z.; He, Z., Nanosuspensions of 10-hydroxycamptothecin that can maintain high and extended supersaturation to enhance oral absorption: preparation, characterization and in vitro/in vivo evaluation. Journal of nanoparticle research 2013, 15 , 1-13. Azeem, A.; Rizwan, M.; Ahmad, F. J.; Iqbal, Z.; Khar, R. K.; Aqil, M.; Talegaonkar, S., Nanoemulsion components screening and selection: a technical note. Aaps Pharmscitech 2009, 10 , 69-76. Nemade, S.; Kakad, S.; Kshirsagar, S.; Padole, T., Development of nanoemulsion of antiviral drug for brain targeting in the treatment of neuro-AIDS. Beni-Suef University Journal of Basic and Applied Sciences 2022, 11 (1), 138. Zaman, M.; Hanif, M., In vitro and ex vivo assessment of hydrophilic polymer- and plasticizer-based thin buccal films designed by using central composite rotatable design for the delivery of meloxicam. Advances in Polymer Technology 2018, 37 (6), 1823-1836. Zahra, S.; Zaib, S.; Khan, I. J. I. J. o. B. M., Identification of isobenzofuranone derivatives as promising antidiabetic agents: Synthesis, in vitro and in vivo inhibition of α-glucosidase and α-amylase, computational docking analysis and molecular dynamics simulations. 2024, 259 , 129241. Pires, P. C.; Santos, A. O., Nanosystems in nose-to-brain drug delivery: A review of non-clinical brain targeting studies. Journal of controlled release 2018, 270 , 89-100. Affandi, M.; Julianto, T.; Majeed, A., Development and stability evaluation of astaxanthin nanoemulsion. Asian J Pharm Clin Res 2011, 4 (1), 142-148. Baboota, S.; Shakeel, F.; Ahuja, A.; Ali, J.; Shafiq, S. J. A. p., Design, development and evaluation of novel nanoemulsion formulations for transdermal potential of celecoxib. 2007, 57 (3), 315. Trott, O.; Olson, A. J. J. J. o. c. c., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. 2010, 31 (2), 455-461. Vitorino, C.; Silva, S.; Gouveia, F.; Bicker, J.; Falcão, A.; Fortuna, A. J. E. j. o. p.; biopharmaceutics, QbD-driven development of intranasal lipid nanoparticles for depression treatment. 2020, 153 , 106-120. Tawfik, M. A.; Eltaweel, M. M.; Fatouh, A. M.; Shamsel-Din, H. A.; Ibrahim, A. B. J. D. D.; Research, T., Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique. 2023, 13 (12), 3059-3076. Nigam, K.; Kaur, A.; Tyagi, A.; Nematullah, M.; Khan, F.; Gabrani, R.; Dang, S. J. D. d.; research, t., Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. 2019, 9 , 879-890. Sharma, D.; Sharma, R. K.; Sharma, N.; Gabrani, R.; Sharma, S. K.; Ali, J.; Dang, S. J. A. p., Nose-to-brain delivery of PLGA-diazepam nanoparticles. 2015, 16 , 1108-1121. Jena, D.; Srivastava, N.; Yasir, M.; Dan, D. J. C. N., Intranasal delivery of lipid nanoparticles: A ground-breaking approach for brain targeting. 2024, 9 (3), 209-223. Komane, P. P.; Kumar, P.; Choonara, Y. E., Nanoparticles and treatment of depression. In Natural Molecules in Neuroprotection and Neurotoxicity , Elsevier: 2024; pp 1959-1987. Văruț, R. M.; Popescu, A. I. S.; Gaman, S.; Niculescu, C. E.; Niculescu, A. Ș.; Dop, D.; Stepan, M. D.; Ionovici, N.; Singer, C. E.; Popescu, C. J. P., Cyclodextrin-Based Drug Delivery Systems for Depression: Improving Antidepressant Bioavailability and Targeted Central Nervous System Delivery. 2025, 17 (3), 355. Virmani, R.; Virmani, T.; Pathak, K., Nanovesicles for delivery of central nervous system drugs. In Applications of Nanovesicular Drug Delivery , Elsevier: 2022; pp 315-339. Sharma, S.; Dang, S. J. C. p. d., Neuropsychological disorders and their nanocarriers. 2020, 26 (19), 2247-2256. IBRAHIM, M.; BASALIOUS, E.; El-NABARAWI, M.; MAKHLOUF, A. J. J. o. R. i. P., Lipid nanocapsules: A Novel Strategy for Brain Targeting via Nasal Administration. 2024, 28 (2). Ghazwani, M.; Vasudevan, R.; Kandasamy, G.; Manusri, N.; Devanandan, P.; Puvvada, R. C.; Veeramani, V. P.; Paulsamy, P.; Venkatesan, K.; Chidmabaram, K. J. G., Formulation of intranasal mucoadhesive thermotriggered in situ gel containing mirtazapine as an antidepressant drug. 2023, 9 (6), 457. Patel, M. S.; Mandal, S. D.; Mandal, S.; Faldu, S.; Patel, J. J. T. J. o. P. S., Nasotransmucosal Delivery of Curcumin-Loaded Mucoadhesive Microemulsions for Treating Inflammation-Related CNS Disorders. 2022, 19 (5), 560. Chavda, V. P.; Balar, P. C.; Bezbaruah, R.; Vaghela, D. A.; Rynjah, D.; Bhattacharjee, B.; Sugandhi, V. V.; Paiva-Santos, A. C. J. N., Nanoemulsions: summary of a decade of research and recent advances. 2024, 19 (6), 519-536. Mandal, S.; Mandal, S. D.; Chuttani, K.; Dharamsi, A.; bhushan Subudhi, B. J. J. o. D. D. S.; Technology, Transnasomucosal mucoadhesive microemulsion of zaltoprofen: A comparative brain distribution study. 2017, 39 , 237-246. Thakkar, H.; Patel, A.; Chauhan, N. J. C. o. Y. S., Formulation and optimization of mucoadhesive microemulsion containing mirtazapine for intranasal delivery. 2014, 5 (1), 25-25. Gadhave, D.; Choudhury, H.; Kokare, C. J. A. N., Neutropenia and leukopenia protective intranasal olanzapine-loaded lipid-based nanocarriers engineered for brain delivery. 2019, 9 , 151-168. Jain, A. S.; Bavaskar, K. R.; Rokade, P. B.; Rane, B. R.; Morani, D. O. J. J. o. P. S.; Research, Fabrication and Evaluation of Amitriptyline HC1 Loaded Nanostructured Lipid Carriers and In-Vitro Characterization. 2025, 17 (1), 1-8. Patel, D.; Thakkar, H. J. T. d., Formulation considerations for improving intranasal delivery of CNS acting therapeutics. 2022, 13 (7), 371-381. Mandlik, S. K.; Ranpise, N. S.; Mohanty, B. S.; Chaudhari, P. R. J. D. D.; Research, T., A coupled bimodal SPECT-CT imaging and brain kinetics studies of zolmitriptan-encapsulated nanostructured polymeric carriers. 2018, 8 , 797-805. Akilo, O. D. Exploration of an Electro-Magneto-Responsive Polymeric Drug Delivery System for Enhanced Nose-To-Brain Delivery. University of the Witwatersrand, Johannesburg (South Africa), 2016. Cui, J.; Li, M.; Wei, Y.; Li, H.; He, X.; Yang, Q.; Li, Z.; Duan, J.; Wu, Z.; Chen, Q. J. F. i. p., Inhalation aromatherapy via brain-targeted nasal delivery: Natural volatiles or essential oils on mood disorders. 2022, 13 , 860043. Ahmad, N.; Ahmad, R.; Al Qatifi, S.; Alessa, M.; Al Hajji, H.; Sarafroz, M. J. B. c., A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy. 2020, 14 , 1-15. Additional Declarations No competing interests reported. Supplementary Files GraphicalAbstract.png Graphical Abstract Cite Share Download PDF Status: Published Journal Publication published 26 Feb, 2026 Read the published version in BioNanoScience → Version 1 posted Editorial decision: Revision requested 15 Oct, 2025 Reviews received at journal 26 Sep, 2025 Reviewers agreed at journal 13 Sep, 2025 Reviewers invited by journal 10 Sep, 2025 Editor assigned by journal 12 Aug, 2025 Submission checks completed at journal 11 Aug, 2025 First submitted to journal 03 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7282569","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":514479296,"identity":"e162c411-2a3f-46d7-898b-5b26766c1c79","order_by":0,"name":"Muhammad Ahsan Waqar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACCQQz8UFCBZBiZm4gWstjgwdnQFoYidbC+EzyYRuYgV8L/+z2h58L2+xk+2cfTpNInFcbzd8O1PKjYhtuS+6cMZae2ZZsPONcWrJF4rbjuTMOMzYw9py5jduaGzkM0rzbmBMbzvAk3kjcdiy3AaiFmbENtxb5G+mPf/Nuq0+cf4b/g0TinGO58wlpMbiRYAa05XDihjMMSRKJDTW5GwhpMbyRY2bN+++48cYzDMkGCccO5G4EajmIzy9yQIfd5jlTLTvvDEPiwx81dbnzzh8++OBHBR7vQwEsLg6DyQME1SNpqSNG8SgYBaNgFIwwAABJc2N2OLVmnAAAAABJRU5ErkJggg==","orcid":"","institution":"Lahore University of Biological \u0026 Applied Sciences","correspondingAuthor":true,"prefix":"","firstName":"Muhammad","middleName":"Ahsan","lastName":"Waqar","suffix":""},{"id":514479297,"identity":"2d720bd4-4089-49da-a7ed-a8413f5c6677","order_by":1,"name":"Maha Khalid","email":"","orcid":"","institution":"Lahore University of Biological \u0026 Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Maha","middleName":"","lastName":"Khalid","suffix":""},{"id":514479298,"identity":"9e4e01c0-63ae-4858-a85e-98ada41a3799","order_by":2,"name":"Rabeel Khan","email":"","orcid":"","institution":"Lahore University of Biological \u0026 Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rabeel","middleName":"","lastName":"Khan","suffix":""},{"id":514479299,"identity":"ea81bb91-b53f-47b6-a577-8be7631b3f93","order_by":3,"name":"Ansa Ashfaq","email":"","orcid":"","institution":"The University of Lahore","correspondingAuthor":false,"prefix":"","firstName":"Ansa","middleName":"","lastName":"Ashfaq","suffix":""},{"id":514479300,"identity":"4a62b2f4-6973-4993-9d40-76ce3c4d8ddc","order_by":4,"name":"Shabab Zahra","email":"","orcid":"","institution":"University of Central Punjab","correspondingAuthor":false,"prefix":"","firstName":"Shabab","middleName":"","lastName":"Zahra","suffix":""},{"id":514479301,"identity":"4101672e-5c96-487c-a305-ccde474dd5ce","order_by":5,"name":"Aima Subia Alvi","email":"","orcid":"","institution":"Lahore University of Biological \u0026 Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Aima","middleName":"Subia","lastName":"Alvi","suffix":""},{"id":514479302,"identity":"756a4a0a-92ad-4608-8285-528fe732c162","order_by":6,"name":"Bisma Arshad","email":"","orcid":"","institution":"Lahore University of Biological \u0026 Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Bisma","middleName":"","lastName":"Arshad","suffix":""}],"badges":[],"createdAt":"2025-08-03 09:53:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7282569/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7282569/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12668-026-02443-6","type":"published","date":"2026-02-26T15:57:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91654481,"identity":"1ae4faec-6959-4803-90b7-510132ec6404","added_by":"auto","created_at":"2025-09-18 17:46:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":201298,"visible":true,"origin":"","legend":"\u003cp\u003eThe diagram shows the step-by-step preparation of Mirtazapine nanoemulsion. Mirtazapine is first dissolved in ethanol and mixed with the oil phase (lavender oil and Span-80). Separately, water and Tween-80 form the aqueous phase. The oil phase is slowly introduced to the aqueous portionunder high-speed stirring to form a coarse emulsion, which is then sonicated to produce a stable nanoemulsion.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/4c988b60a63b3df83e3c9ffa.png"},{"id":91653431,"identity":"06ab0499-e9bd-4b39-90d4-f7b0453229c8","added_by":"auto","created_at":"2025-09-18 17:38:43","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":56771,"visible":true,"origin":"","legend":"\u003cp\u003eFour drug formulations—F1, F2, F3, and F4—were prepared for the study.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/3c7bcb1a918997300e78352d.jpeg"},{"id":91653454,"identity":"795d8bf9-f718-461c-b587-c8fae0a7df0d","added_by":"auto","created_at":"2025-09-18 17:38:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":140648,"visible":true,"origin":"","legend":"\u003cp\u003eScanning Electron Microscopy, indicating a nanosized particle\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/0ab867cbec55b92a59bbed80.png"},{"id":91653440,"identity":"39cdee6d-052b-49a5-9255-80a87af26e13","added_by":"auto","created_at":"2025-09-18 17:38:43","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":119458,"visible":true,"origin":"","legend":"\u003cp\u003eThe graph shows the apparent zeta potential distribution of the sample, with a sharp peak centered near 0 mV, indicating a near-neutral surface charge. The high total counts at this narrow peak suggest a uniform particle population. Such a distribution typically implies low colloidal stability due to minimal electrostatic repulsion.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/8495dd833b6b112291f99260.jpeg"},{"id":91655710,"identity":"7abd28e0-8b93-4981-833f-1ba3bb072818","added_by":"auto","created_at":"2025-09-18 18:02:43","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":142149,"visible":true,"origin":"","legend":"\u003cp\u003eDilution of formulation F2 showing pink color (Figure A), and formulation F4 showing blue color (Figure B).\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/4d51fc7826b8095b4a593f2c.jpeg"},{"id":91654480,"identity":"1d1473cb-d493-4c5e-a926-e04976c73ec5","added_by":"auto","created_at":"2025-09-18 17:46:44","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":137057,"visible":true,"origin":"","legend":"\u003cp\u003eFTIR spectra of different mirtazapine formulations (F1–F4) showing characteristic absorption peaks across the range of 4000–500 cm⁻¹. The spectra indicate similarities in functional groups, with minor variations suggesting possible formulation-dependent interactions. Key peaks around 3300 cm⁻¹ (N-H stretching) and 1600–1000 cm⁻¹ (C-H bending) are observed.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/36100a5592e45b9bfc32af5e.png"},{"id":91653533,"identity":"01de067a-c6b6-4680-a7b4-83f2ed2e115a","added_by":"auto","created_at":"2025-09-18 17:38:44","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":210026,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDSC-TGA analysis of samples F1 and F2.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Thermogram of sample F1 and (B) thermogram of sample F2 illustrate weight loss and thermal transitions with increasing temperature. The green curves represent weight loss, while the blue curves indicate heat flow. Both samples exhibit characteristic thermal decomposition and phase transitions, reflecting their thermal stability and behavior under elevated temperatures. (n = 3)\u003c/p\u003e","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/44accb33393aea22d8a51d75.jpeg"},{"id":91654486,"identity":"293fb9dd-1d14-4797-b8e5-ebe2c66a5fd5","added_by":"auto","created_at":"2025-09-18 17:46:44","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":440239,"visible":true,"origin":"","legend":"\u003cp\u003eVisual assessment of formulations F1–F4 before and after centrifugation\u003c/p\u003e\n\u003cp\u003e(A) Formulations F1–F4 before centrifugation and (B) the same formulations after centrifugation\u003c/p\u003e","description":"","filename":"floatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/0bc6291b5ee071a14bdec5cb.png"},{"id":91653493,"identity":"f6a12952-8c25-4484-952b-726886e2b2ff","added_by":"auto","created_at":"2025-09-18 17:38:44","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":50963,"visible":true,"origin":"","legend":"\u003cp\u003eThe graph illustrates the release kinetics of mirtazapine over time, demonstrating that formulation F4 exhibited the highest drug release (92.28%) compared to other formulations. This indicates improved sol–gel transition properties and sustained drug release. One-way ANOVA was applied, and each bar represents mean ± SEM. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001. (n = 3)\u003c/p\u003e","description":"","filename":"floatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/256a22e8fc9f32b198a09543.png"},{"id":91653483,"identity":"b85514e8-5273-48e1-a0e9-60d856483f47","added_by":"auto","created_at":"2025-09-18 17:38:44","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":54477,"visible":true,"origin":"","legend":"\u003cp\u003eIn vitro drug permeation study across a synthetic dialysis membrane. The graph compares the permeation efficiency of various formulations, where F4 showed the highest permeation (92.78%). This suggests enhanced formulation permeability and drug diffusion potential of mirtazapine. One-way ANOVA was applied, and each bar represents mean ± SEM. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001. (n = 3)\u003c/p\u003e","description":"","filename":"floatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/60a677dd384201235223daa5.png"},{"id":91653517,"identity":"f70b4dd3-69b4-4524-872e-e9f2a4c35155","added_by":"auto","created_at":"2025-09-18 17:38:44","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":54808,"visible":true,"origin":"","legend":"\u003cp\u003eEx-vivo permeation profile across goat nasal mucosa. The cumulative percentage permeation of mirtazapine was assessed over time. F4 demonstrated the highest ex vivo permeation (93.28%), indicating superior mucosal penetration and potential for effective nasal brain targeting. One-way ANOVA was applied, and each bar represents mean ± SEM. *P \u0026lt; 0.05; **P \u0026lt; 0.01; ***P \u0026lt; 0.001. (n = 3)\u003c/p\u003e","description":"","filename":"floatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/a6aac7b87aeea6328ae1c073.png"},{"id":91654483,"identity":"11eeb0d8-eb4a-4d47-a34a-d222e5438ede","added_by":"auto","created_at":"2025-09-18 17:46:44","extension":"png","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":338454,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eMolecular docking study of Mirtazapine with the dopamine receptor.\u003c/em\u003e\u003cbr\u003e\n(A) Three-dimensional and (B) two-dimensional representations illustrate the key interactions between Mirtazapine and the active site of the receptor. The ligand is stabilized by carbon hydrogen bonding (Tyr1088), π-anion interaction (Asp1072), and multiple π-alkyl or π-sigma interactions with Ala1093, Ala1097, Val1071, Ile1003, Arg220, and Lys221. These interactions collectively support the drug Mirtazapine's strong binding affinity and potential pharmacological efficacy. \u003cem\u003e(n = 3)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/ec4eb319070a288c64d278c1.png"},{"id":103765596,"identity":"db6152f0-d55f-4a48-846d-037392a2c865","added_by":"auto","created_at":"2026-03-02 16:05:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3612958,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/d182ea04-f796-4ee4-8eb6-3a0bc5ddf3ad.pdf"},{"id":91653413,"identity":"5077f59b-fac2-45e2-ad0a-e8befaeb65b8","added_by":"auto","created_at":"2025-09-18 17:38:43","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":380417,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-7282569/v1/584fd379894bfa1edd370b64.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Lavender Oil-Infused Mirtazapine Nanoemulsion for Direct Nose- to-Brain Targeting","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePervasive and persistent poor states of mind, interest, and motivation, as well as potentially suicidal thoughts, are hallmarks of depression, a common and chronic mental illness \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. It has a substantial socioeconomic impact, which includes higher medical expenses\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Although there are many theories about its pathophysiology, the exact cause remains unknown, and there are insufficiently precise diagnostic and therapeutic approaches\u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. The safety and tolerability of antidepressants are crucial factors that should be considered. The three most common types of antidepressants in clinical treatment are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin\u0026ndash;norepinephrine reuptake inhibitors (SNRIs). These medications are associated with several adverse effects, including cardiovascular side effects such as orthostatic hypotension, tachycardia, and arrhythmias \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e gastrointestinal disturbances such as nausea, vomiting, diarrhea, and constipation\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e; hepatotoxicity, particularly with certain TCAs and SNRIs, leading to elevated liver enzymes or, in rare cases, liver failure \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e; and anorgasmia, delayed ejaculation, and diminished libido, which are examples of sexual dysfunction. \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMirtazapine is a tetracyclic antidepressant primarily prescribed for the treatment of major depressive disorder\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Norepinephrine and serotonin release is increased by core presynaptic alpha-2 adrenal inhibiting autoreceptors and heteroreceptors.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Additionally, it blocks the serotonin receptors 5-HT2 and 5-HT3, which contribute to its anxiolytic and antiemetic properties, making it a unique antidepressant with a broad therapeutic profile\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Despite its efficacy, oral administration of mirtazapine is often associated with extensive first-pass metabolism and delayed onset of action owing to poor penetration through the blood-brain barrier\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. These limitations make it a suitable candidate for nose-to-brain delivery systems that can bypass hepatic metabolism and ensure faster and more targeted actions in the central nervous system\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Formulating Mirtazapine as a nanoemulsion for intranasal administration may significantly enhance its therapeutic outcomes by improving its bioavailability and onset of action while reducing systemic side effects\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eNanoemulsions, also known as mini-, submicron-, or ultrafine emulsions, are kinetically stable systems composed of one immiscible liquid dispersed in another, with droplet sizes ranging from 20 to 500 nm. These nanosized emulsions incorporate surfactants to reduce surface tension and prevent coalescence, thereby enhancing the solubility and stability of the incorporated drug particles\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Their small droplet size gives them a clear or hazy appearance and provides superior kinetic and thermodynamic stability compared to microemulsions, despite their similar size ranges. Nanoemulsions can be formulated into various dosage forms and administered through multiple routes, offering improved physical stability by resisting sedimentation, creaming, and coalescence owing to dominant Brownian motion\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. They also enhance drug bioavailability, sometimes bypassing first-pass metabolism through lymphatic absorption\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. However, despite their advantages, the commercial availability of nanoemulsions remains limited due to complex manufacturing processes, expensive equipment, and insufficient understanding of instability mechanisms, such as Ostwald ripening\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe primary aim of this study was to develop and evaluate a stable nanoemulsion formulation of mirtazapine for direct nose-to-brain delivery to enhance its bioavailability and therapeutic efficacy in the treatment of neurological disorders, particularly depression\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The objectives included the formulation of a mirtazapine-loaded nanoemulsion using lavender oil, tween-80, and span-80; characterization of the nanoemulsion in terms of its drug content, ionic potential, viscosity, pH, and droplet size; and assessment of its ex vivo penetration via the nasal mucosa and in vitro drug release\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. This study also aimed to assess the stability of the formulation under different storage conditions to perform molecular docking\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. This study aimed to establish the potential of nanoemulsion-based intranasal drug delivery as an efficient and noninvasive method for targeting the central nervous system\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Materials\u003c/h2\u003e\u003cp\u003eWe bought Mirtazapine from StandPharm in Pakistan. We bought lavender oil from Flav Chemicals Royal, China. Span-80 and Tween-80 were purchased from Daejung, China. Distilled water and ethanol were purchased from Merck KGaA (Darmstadt, Germany). All the chemicals and solvents used in this experiment were of analytical grade.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Method\u003c/h2\u003e\u003cp\u003eFour drug formulations (F1, F2, F3, and F4) were prepared for the study, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The composition details of these formulations are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The drug solution was prepared by mixing 10 mg of the active ingredient in 2 ml ethanol with magnetic stirring. To prepare the oil phase, a lavender oil and a cosurfactant, Span 80. The drug solution was added dropwise to the oil phase through magnetic stirring. The aqueous phase was prepared by mixing Tween 80 with distilled water. This aqueous phase was homogenized for 30\u0026ndash;45 minutes, and the oil phase was added dropwise to the aqueous solution during homogenization. A drop of the colored solution was added to the formulation during homogenization. Distilled water was then added to make the volume up to 10 ml. The formulation was sonicated for 10\u0026ndash;15 minutes to remove any bubbles, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComposition of Mirtazapine-Loaded Nanoemulsions with varying percentages of Lavender Oil. This table presents the formulation details for four samples (F1\u0026ndash;F4) with a constant oil-to-water phase ratio (1:4) and increasing percentages of lavender oil ranging from 20\u0026ndash;80%.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFormulation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOil Phase (mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWater Phase (mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLavender Oil (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Characterization of Nanoemulsion","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e3.1 pH Test, Refractive Index, Viscosity Measurement\u003c/h2\u003e\u003cp\u003eThe stability of nanoparticle formulations, their drug release profiles, and their interactions with the nasal mucosa are all affected by pH\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. To enhance drug absorption, the pH should be adjusted to match the nasal environment. Nasal pH generally ranges from 4.5 to 6.5 \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Chitosan-based nanoparticles possess pH-dependent properties that increase mucoadhesion and drug release, thereby enhancing therapeutic outcomes. pH-sensitive polymers have been used to achieve controlled drug release in response to pH changes. pH was measured using a pH meter\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe refractive index is related to the optical properties of the nanoparticles. This shows how light is transferred from the nanoemulsion medium and its transparency. The refractive index influences how nanoparticles interact with biological tissues; consequently, it affects their ability to penetrate the nasal mucosa and deliver drugs directly to the brain. The refractive index can be determined using an Abbes-type refractometer by pouring a droplet of nanoemulsion on a disk\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the Viscosity Measurement, the flow properties and stability of the mirtazapine-loaded nanoemulsion were assessed using a viscometer\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The viscosity was measured under controlled conditions, typically at a standard temperature of 25\u0026deg;C\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. Measurements were taken at varying spindle speeds to observe how viscosity changed with different shear rates. These data are crucial for understanding the rheological behavior of nanoemulsion, which affects their formulation and application potential\u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Scanning Electron Microscopy (SEM)\u003c/h2\u003e\u003cp\u003eScanning Electron Microscopy was used to evaluate the superficial morphology of the nanoemulsions.The, and the three-dimensional structure of globules was observed using SEM\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. A drop of sample was taken, dried in an oven, and then placed on an SEM stub. Then, SEM was employed to acquire digital photos at an accelerating voltage of 15 kV.\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Globule Size, Polydispersity Index (PDI) and Zeta Potential Analysis\u003c/h2\u003e\u003cp\u003eDroplet size and Polydispersity Index (PDI) are key in characterizing nanoemulsions because they increase the stability of the drug and its bioavailability\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. The nanoemulsion droplet size usually ranges from 10 to 200 nanometers and is an essential parameter affecting the stability of nanoemulsions and the efficiency of drug delivery via the nasal route \u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e. Dynamic light scattering (DLS), often known as photon correlation spectroscopy (PCS), is a commonly used technique for the measurement of tiny nanoemulsions. PCS involves shining a laser beam within the nanoemulsion and then analyzing the light scattering, which is produced by the Brownian motion of the tiny particles of the nanoemulsion\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e. As the tiny droplets pass faster, rapid fluctuations are produced in that light and are detected in PCS devices, such as the Malvern Zeta sizer. Based on these fluctuations, this device was used to calculate the average droplet size \u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e. PDI is used to measure droplet size uniformity through a nanoemulsion, whose size ranges from 0 to 1 nanometer \u003csup\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe zeta potential was used to determine the charge present on the surface of the particles when they were submerged in the liquid. The zeta potential was measured using a specialized instrument called the Malvern Zetasizer \u003csup\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/sup\u003e. First, we dilute the nanoemulsion, and there will be some mobility of oil droplets, which gives the estimated value and allows us to determine the zeta potential\u003csup\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Dilution Test\u003c/h2\u003e\u003cp\u003eThe dilution test was performed by adding a higher concentration of the continuous phase into the nanoemulsion; thus, 1 ml of the sample was taken and 4 ml of distilled water was added \u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Dye Soluble Test\u003c/h2\u003e\u003cp\u003eA water-soluble dye is emulsified in the aqueous phase of the w/o globule, but miscible in the o/w globule.\u003csup\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e. To illustrate this, 1 mL of the nanoemulsion together with a few hydrophilic color droplets, safranine, was pipetted onto a glass slide and mixed well. The efficiency of the formulation was assessed under a microscope.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Fourier Transform Infrared Spectrophotometer (FTIR)\u003c/h2\u003e\u003cp\u003eFTIR was used to determine the compatibility and identify the functional groups\u003csup\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/sup\u003e. It also provides the fingerprint and the mode of attachment of the molecule. The sample was first prepared using the appropriate method, after which scanning of the sample was performed at the specified scanning speed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.7 Differential Scanning Calorimetry (DSC)\u003c/h2\u003e\u003cp\u003ePhysical characterization of the formulations was performed using DSC\u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e. The sample formulations were dried and placed in a hermetically sealed aluminum pan. Nitrogen gas was introduced at 50 ml/min of flow rate in the system and then heated at 10\u0026deg;C/min \u003csup\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.8 Stability Studies\u003c/h2\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.8.1 Centrifugation\u003c/h2\u003e\u003cp\u003eCentrifugation of the formulations was performed at 3500 rpm for 30 min and observed for phase separation\u003csup\u003e[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.8.2 Freeze-Thaw Method\u003c/h2\u003e\u003cp\u003eThe formulations were observed during heating and cooling cycles. formulations were first exposed to 4\u0026deg;C and 45\u0026deg;C and were then observed for phase separation\u003csup\u003e[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.9 \u003cem\u003eIn-vitro\u003c/em\u003e drug release studies\u003c/h2\u003e\u003cp\u003eDrug release from the formulations was investigated using dialysis membranes. Formulations were assessed using a rotating paddle dissolution apparatus. The formulations sealed in the dialysis membrane were immersed in a phosphate buffer solution. The samples were taken out at 5, 30, 60, 90, 120, 150, and 180 min intervals, and the drug concentration was measured using a UV-visible spectrophotometer at 309 nm wavelength\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e3.10 \u003cem\u003eIn-vitro\u003c/em\u003e Permeation Studies\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eA Franz diffusion cell (Variomag Telesystem, H\u0026thinsp;+\u0026thinsp;P Labortechnik, Oberschlei\u0026szlig;heim, Germany) was used to perform the permeation studies. In the recipient compartment, 7mL of buffer was added, and 1mL of the sample was then added to the donor compartment. A cellophane membrane was placed between donor and recipient compartments. Medication was permitted to pass through the cellophane barrier. Before UV analysis, samples, each with a volume of 1 mL, were collected at different times and adequately diluted\u003csup\u003e[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e3.11 \u003cem\u003eEx-vivo\u003c/em\u003e Permeation Studies\u003c/h2\u003e\u003cp\u003eWe decided to use goat nasal mucosa for the ex vivo permeation investigations. On the initial day of the experiment, the goat head, acquired from a nearby slaughterhouse, was detached from the mucosal layer of the nasal cavity. Surgical scissors were used to split the nasal membrane. Saline solution was used to keep the mucosal layer hydrated during isolation. The receptor compartment (7 ml) of the Franz cell was filled with phosphate buffer (pH 6.8). With the mucosal side facing the donor and a diffusion area of 0.63 cm2, the mucosal layer was positioned between the donor and receptor compartments. At 37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u0026deg;C, The median temperature was maintained. The donor compartment was filled with 1 mL of the studied material. Following five, ten, twenty, thirty, and sixty minutes, samples were removed from the receptor compartment. An equivalent volume of fresh buffer medium was used instead of receptor compartment volume. The extracted samples were appropriately diluted before examination using a UV spectrophotometer to determine the percentage of drug release.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e3.12 Docking Studies\u003c/h2\u003e\u003cp\u003eMolecular docking analyses were performed using AutoDock Vina (version 1.5.7)\u003csup\u003e[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/sup\u003e. Prior to docking, the three-dimensional structure of the dopamine receptor (PDB ID: 6CM4) was prepared by removing all co-crystallized ligands and water molecules. The receptor was further refined and analyzed using BIOVIA Discovery Studio 2021 to identify the possible binding site for the antidepressant drug mirtazapine. Subsequently, the protein and ligand structures were optimized and subjected to docking simulations, producing nine distinct binding poses of mirtazapine, along with their respective binding affinity scores. The most favorable conformation was selected by evaluating key molecular interactions within the binding pocket of the receptor using BIOVIA Discovery Studio 2021.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Results and Discussion","content":"\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1 pH Test\u003c/h2\u003e\n \u003cp\u003eThe pH of each formulation was measured. It was 6.19 and 6.14 for F2 and F3, which was in the range for nanoemulsions for nasal administration\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2 Scanning Electron Microscopy (SEM)\u003c/h2\u003e\n \u003cp\u003eThe exterior morphology of the nanoparticles in the formulations was assessed by SEM. The results shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e indicated spherical nanosized globules. In addition, the nanoparticles were well separated, indicating stable formulations. These nanosized spherical globules were similar to the nanosized globules of mirtazipine-loaded nanocarriers prepared in a previous study\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e\n \u003ch2\u003e4.3 Polydispersity index (PDI) and Zeta potential analysis\u003c/h2\u003e\n \u003cp\u003eWhen creating nanoemulsions, the polydispersity index, zeta potential, and particle size distribution are important factors\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. According to the given Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, the zeta potential of sample F-4 is about \u0026minus;\u0026thinsp;10.4mV, which is closer to the neutral value of \u0026plusmn;\u0026thinsp;30mV, which means that the formulation is more likely to be stable, and the negative sign helps to avoid aggregation of particles. The size distribution also indicates that the formulation is stable, as the smaller particles form a stable formulation with a larger rate and degree of medication absorption, in contrast to particles of a larger size. PDI is also an important parameter in the formulation of nanoemulsion, which shows that the droplet size in the procedure is consistent\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e]\u003c/sup\u003e. The PDI of sample F-4 was 0.800 according to the Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, which is a broad size distribution indicating variations in droplet size that can cause instability in a formulation.\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGlobule size (Z-Average), intensity-weighted distribution (Dv), volume-weighted distribution (Dz), polydispersity index (PDI), zeta potential, and drug load analysis of nanoemulsion formulations (n\u0026thinsp;=\u0026thinsp;3). The globule size of all formulations is below 200 nm, ensuring efficient nasal absorption. Although the negative zeta values may show superior colloidal stability, reducing particle aggregation, the low PDI values verify a uniform particle size distribution.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFormulation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZ-Average (nm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDv (nm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDz (nm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePolydispersity Index (PDI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZeta Potential (mV)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSurface Charge (mV)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDrug Load (% w/w)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e106\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.550\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e100.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e126\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e120\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.637\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e122.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e136\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e130\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.794\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e116.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e127\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.800\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003ePDI typically falls between 0 and 1, where 1 denotes a polydisperse particle dispersion, and 0 denotes a monodisperse system\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/sup\u003e. The constant particle diameter throughout the formulation was demonstrated by the low polydispersity values of the formulations. The measurement of the formulations\u0026apos; zeta potential values, which ranged from \u0026minus;\u0026thinsp;10.4 to -17.0 mV, showed that a stable nanoemulsion was formed. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e shows the nanoemulsion\u0026apos;s zeta potential of (F2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003e4.4 Dilution Test\u003c/h2\u003e\n \u003cp\u003eThe formulations were subjected to dilution tests to evaluate their stability. The results of the dilution tests for formulations F2 and F3 are shown in Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\n \u003ch2\u003e4.5 Dye Solubility Test\u003c/h2\u003e\n \u003cp\u003eDye solubility tests were performed to assess the continuous phase of the nanoemulsions formulated. Because the safranine dye was dispersed uniformly, all of the formulations constituted oil-in-water nanoemulsions.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e\n \u003ch2\u003e4.6 Fourier transform infrared spectroscopy (FTIR)\u003c/h2\u003e\n \u003cp\u003eFTIR was conducted to determine the molecular structure of mirtazapine in a nanoemulsion carrier system.\u003c/p\u003e\n \u003cp\u003eThe spectra in the above Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e show the characteristic absorption peaks of the four formulations labeled as F1, F2, F3, and F4 of Mirtazapine, with a wavenumber plotted on the x-axis representing the frequency of infrared light absorbed and transmittance on the y-axis indicating the amount of light passing through the drug.\u003c/p\u003e\n \u003cp\u003eThe infrared spectra of the formulations revealed several key peaks indicative of the functional groups of mirtazapine. The broad peak at 3300 cm\u0026ndash;1, likely due to O-H or N-H stretching, suggests the presence of a hydroxyl or amine group. This peak exhibited slight shifts in the F3 and F4 formulations, which may be attributed to minor differences in hydrogen bonding or moisture content. The peaks observed in the 1600\u0026ndash;1700 cm\u0026ndash;1 region, corresponding to C\u0026thinsp;=\u0026thinsp;O, indicated the presence of aromatic rings or a carbonyl group in mirtazapine. This peak was consistent across all formulations, suggesting that the aromatic structure of mirtazapine remained unchanged. The sharp peak between 2900\u0026ndash;3000 cm\u0026ndash;1 is attributed to C-H stretching, which indicates the presence of alkyl chains in the sample. This peak was more pronounced in F2 and F4, possibly because of interactions between excipients and mirtazapine. Smaller peaks observed below 1000 cm\u0026ndash;1 may indicate out-of-plane bending of the aromatic system in mirtazapine. F1 and F3 formulations showed slight variations in this region, potentially owing to the presence of different polymorphs of mirtazapine in these respective formulations.\u003c/p\u003e\n \u003cp\u003eTherefore, we might interpret from the above observations that the presence of characteristic functional groups such as N-H and C-H confirmed the structure of mirtazapine. There are slight variations in the peaks, which might be due to excipient interactions, moisture content, polymorphism, or amorphous content.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec27\" class=\"Section2\"\u003e\n \u003ch2\u003e4.7 Differential Scanning Calorimetry (DSC)\u003c/h2\u003e\n \u003cp\u003eLess intense peaks were observed from the formulation, indicating entrapment of the drug as nanoparticles in the formulation. The melting point of mirtazapine was 117\u0026deg;C. Our results for both formulations show the amorphous nature of the product. Mirtazapine\u0026apos;s DSC revealed a distinct peak of endothermic activity at 117\u0026deg;C, which is consistent with data that have been published. This suggested that the medication was highly pure and crystalline. Mirtazapine\u0026apos;s melting point vanished for the nanoemulsions, which is a clear sign that the medication changed from a crystalline state to an amorphous state, as illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec28\" class=\"Section2\"\u003e\n \u003ch2\u003e4.8 Stability Studies\u003c/h2\u003e\n \u003cdiv id=\"Sec29\" class=\"Section3\"\u003e\n \u003ch2\u003e4.8.1 Centrifugation\u003c/h2\u003e\n \u003cp\u003eCentrifugation is used for the analysis of nanoemulsions to separate or assess their stability. A centrifugation test was performed on the formulations labeled F1, F2, F3, and F4 to evaluate their stability. Two milliliters of each formulation was added into centrifuge tubes, which were then placed into a centrifuge machine and spun at high speed (4000 RPM) for 30 min. After 30 min, the tubes were removed and observed. We did not notice any significant changes in F1, F2, and F3, indicating that the Nanoemulsions remained stable. No phase separation was observed for F1, F2, or F3. In the F4 formulation, phase separation was observed, indicating instability. This result is important for ensuring the stability of nanoemulsions, as illustrated in Fig. 8.\u003c/p\u003e\u003cspan\u003e\n \u003ch2\u003e\u003cstrong\u003e4.8.2 Freeze-Thaw Method\u003c/strong\u003e\u003c/h2\u003e\n \u003c/span\u003e\n \u003cp\u003eThe freeze-thaw test was performed on the nanoemulsion formulations labeled F1, F2,F3, and F4 to evaluate their stability at different temperatures. First, approximately 3 mL of each emulsion was added to the test tube and frozen at -21⁰C for one day. After freezing, the formulations were kept at room temperature for some time to defrost. These formulations were thawed at a slightly high temperature of 40⁰C for 60 min. We observed no noticeable changes in the texture, color, or consistency of the nanoemulsions. This test showed that the formulation remained stable and effective despite extreme temperature shifts. No sign of phase separation or degradation was observed in the formulations. This result is important to ensure the long-term stability of nanoemulsions during fluctuations in storage or environmental conditions.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec30\" class=\"Section2\"\u003e\n \u003ch2\u003e4.9 \u003cem\u003eIn Vitro\u003c/em\u003e Drug Release Studies\u003c/h2\u003e\n \u003cp\u003eFor drug release studies, a USP rotating paddle dissolution apparatus and cellophane membrane were used. At intervals of 5, 30, 60, 90, 120, 150, and 180 min, the samples were withdrawn, and the absorbance of each sample was recorded at a wavelength of 309 nm using a UV spectrophotometer. The formulation\u0026apos;s % medication release versus time is shown in Fig. \u003cspan class=\"InternalRef\"\u003e9\u003c/span\u003e. F4 showed the highest percentage of drug release (92.28%), whereas F1 exhibited the lowest medication release percentage (64.21%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\n \u003ch2\u003e4.10 \u003cem\u003eIn-vitro\u003c/em\u003e Permeation Studies\u003c/h2\u003e\n \u003cp\u003eSamples were extracted 5, 10, 20, 30, and 60 min after the beginning of the procedure, and the absorbance was measured at 590 nm. The concentration was plotted against absorbance. The proportion of drug penetration of the formulation through the membrane is shown in Fig. \u003cspan class=\"InternalRef\"\u003e10\u003c/span\u003e. Of all the formulations, F4 showed maximum drug penetration (92.78%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\n \u003ch2\u003e4.11 \u003cem\u003eEx Vivo\u003c/em\u003e Permeation Studies\u003c/h2\u003e\n \u003cp\u003eAfter 5, 10, 20, 30, and 60 min, the samples were examined at 590 nm, and the percentage of drug release for each formulation was determined. The percentage of medication release through the nasal mucosa of the formulations is shown in Fig. \u003cspan class=\"InternalRef\"\u003e11\u003c/span\u003e. Of all formulations, F4 exhibited the highest drug penetration (93.28%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec33\" class=\"Section2\"\u003e\n \u003ch2\u003e4.12 Docking Studies\u003c/h2\u003e\n \u003cp\u003eIn the molecular docking studies of mirtazapine against the dopamine receptor (PDB ID: 6CM4), AutoDock Vina version 1.5.7 was employed\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/sup\u003e. Docking was performed three times for each formulation. Among the docking poses generated, the top-binding conformation showed interactions with various amino acid residues in the active site.\u003c/p\u003e\n \u003cp\u003eThe ligand formed carbon-hydrogen bonds with Tyr1088, while Asp1072 contributed to \u0026pi;-anion interactions. Ala1097, Ala1093, Ile1003, Val1071, and Lys221 engaged in \u0026pi;-alkyl interactions, while Arg220 formed a \u0026pi;-sigma interaction, stabilizing the ligand within the binding pocket.\u003c/p\u003e\n \u003cp\u003eThe binding pose was further supported by the hydrophobic interactions of the surrounding residues. These interactions, as visualized in the 3D binding site representation, confirmed the appropriate accommodation of mirtazapine within the hydrophobic pocket of the receptor (as illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e12\u003c/span\u003e) and are summarized in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Thus, the binding conformation was stabilized through a combination of \u0026pi;-anion, \u0026pi;-alkyl, \u0026pi;-sigma, and carbon-hydrogen bonding interactions.\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe table summarizes the key non-covalent interactions contributing to the binding of Mirtazapine within the Dopamine receptor active site, with an estimated binding energy of -7.2 kcal/mol. The interaction profile includes carbon hydrogen bonding, \u0026pi;\u0026ndash; sigma contact, \u0026pi;\u0026ndash;anion interaction, and multiple \u0026pi;\u0026ndash;alkyl associations. These binding forces play a pivotal role in stabilizing the ligand\u0026ndash;receptor complex and may underlie the pharmacological efficacy of mirtazapine through enhanced receptor engagement and affinity.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eType of Bond\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAmino Acid Residue\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDistance (\u0026Aring;)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCarbon Hydrogen Bond\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTYR A:1088\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Sigma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eARG A:220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Anion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eASP A:1072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVAL A:1071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALA A:1093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALA A:1097\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eILE A:1003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePi-Alkyl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLYS A:221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"5 Discussion","content":"\u003cp\u003eThis study highlights the significance of mirtazapine-loaded nanoemulsion in the treatment of neurological disorders, particularly in addressing the challenges posed by the blood-brain barrier (BBB)\u003csup\u003e[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/sup\u003e. As research in this domain advances, it becomes increasingly necessary to develop more effective, stable, and sustainable solutions to enhance central nervous system (CNS) bioavailability\u003csup\u003e[\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]\u003c/sup\u003e. Traditional methods of drug delivery, such as oral or intravenous routes, face significant issues, such as poor BBB penetration, systemic toxicity, and limited CNS bioavailability\u003csup\u003e[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]\u003c/sup\u003e. This research is valuable because it offers potential solutions to persistent obstacles, such as insufficient CNS drug concentration and high systemic exposure, which remain major challenges in the pharmaceutical industry\u003csup\u003e[\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]\u003c/sup\u003e. Enhancing direct nose-to-brain drug delivery is crucial for improving the efficacy and longevity of treatments targeting the brain\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDespite progress in this field, current strategies for intranasal drug delivery still face substantial limitations\u003csup\u003e[\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]\u003c/sup\u003e. Conventional methods are hindered by poor bioavailability, systemic toxicity, and extensive first-pass metabolism\u003csup\u003e[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]\u003c/sup\u003e. Although these methods have been commonly used, they do not effectively address the issues of direct brain targeting\u003csup\u003e[\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]\u003c/sup\u003e. This gap highlights the need to explore alternative approaches, such as nanoemulsion formulations, which can provide superior performance and greater reliability\u003csup\u003e[\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]\u003c/sup\u003e. The shortcomings of traditional methods emphasize the need for innovative solutions that leverage nanoemulsion technology to enhance drug delivery effectiveness and formulation stability\u003csup\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTo address these challenges, this study explored the use of a mirtazapine-loaded nanoemulsion for intranasal administration, a method that bypasses the BBB\u003csup\u003e[\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]\u003c/sup\u003e. The basis for this approach lies in the potential of nanoemulsions to improve drug solubility, facilitate better CNS penetration, and provide sustained drug release\u003csup\u003e[\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]\u003c/sup\u003e. This study aims to offer valuable insights into the viability of this innovative strategy, potentially providing a more reliable and sustainable solution for treating neurological conditions, such as depression\u003csup\u003e[\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe results of this investigation are in line with earlier studies showing the effectiveness of nanoemulsion devices for medication delivery\u003csup\u003e[\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]\u003c/sup\u003e. For instance, Zhang et al. (2018) showed that nanoemulsions improve drug absorption and enhance targeting\u003csup\u003e[\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]\u003c/sup\u003e. However, the present study distinguishes itself by employing a novel method involving high-energy emulsification through ultrasonication, resulting in a smaller and more uniform globule size\u003csup\u003e[\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]\u003c/sup\u003e. This new approach provides important advancements in the understanding of intranasal drug delivery and contributes to the development of more effective delivery systems\u003csup\u003e[\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eA key strength of this study is its methodology, which offers several distinct advantages\u003csup\u003e[\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e]\u003c/sup\u003e. The use of ultrasonication improves the reduction in globule size and increases the drug encapsulation efficiency. This formulation achieved high drug encapsulation and formulation consistency. This is crucial because it ensures the stability and ability of the formulation to offer controlled release over an extended period\u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e. The improved performance observed in this study is attributed to the reduced particle size, electrostatic stability, and low viscosity, which together facilitate easy administration and enhance absorption by the nasal mucosa\u003csup\u003e[\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAdditionally, the amount of lavender oil in the formulations boosted medication penetration\u003csup\u003e[\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]\u003c/sup\u003e. Among the different formulations, F1 had the lowest concentration of lavender oil, followed by F2 and F3, with F4 having the highest concentration\u003csup\u003e[\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e]\u003c/sup\u003e. This gradient directly influenced the performance metrics, as the in situ release of drugs, in vitro penetration, and ex vivo permeability were greatest in F4\u003csup\u003e[\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]\u003c/sup\u003e. Previous studies have also supported the role of lavender oil in enhancing drug permeation, likely because of its ability to disrupt the lipid structure of biological membranes, thereby increasing drug diffusion\u003csup\u003e[\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn comparison with previous studies, our results highlight significant improvements in bioavailability and stability. For example, in a recent study, similar benefits were observed using nanoemulsion-based systems for CNS-targeted delivery, demonstrating that nanoemulsions have the potential to be viable substitutes for conventional medication delivery methods\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.While the results of this study align with the existing literature in many respects, it also introduces new perspectives by demonstrating a higher drug release and exceptional formulation stability under accelerated conditions. These differences may be attributed to the improved emulsification method, particularly the use of ultrasonication for particle size reduction\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe findings of this study are in line with those of other studies. The nanoemulsion droplet sizes measured here fall within the nanometer range, similar to the values observed by Đorđević et al. for risperidone nanoemulsions and other studies on curcumin nanoemulsions\u003csup\u003e[\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]\u003c/sup\u003e.Additionally, although slightly higher, the PDI values reflected comparable trends in droplet size distribution and uniformity. This alignment with prior studies supports the reliability of the formulation and characterization methods used, indicating that the developed nanoemulsions possess physicochemical properties that are suitable for effective drug delivery.\u003c/p\u003e\u003cp\u003eAlthough the results are promising, this study had some limitations. One major constraint is the lack of in vivo validation, as the study primarily focused on in vitro evaluation\u003csup\u003e[\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e]\u003c/sup\u003e. Additionally, although the stability of the formulation was assessed under accelerated conditions, further long-term studies are needed to confirm its long-term stability and effectiveness in clinical settings. To increase the applicability of the findings, it is crucial to address these limitations in future studies\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe implications of this research extend beyond the theoretical findings, offering practical applications that could significantly impact the treatment of neurological disorders. By refining and optimizing intranasal nanoemulsion formulations, this study provides a foundation for future advancements in drug delivery to the CNS. Future studies should focus on in vivo testing, clinical trials, and large-scale production to fully exploit the benefits of this approach. If successfully translated into clinical practice, these findings could play a pivotal role in the pharmaceutical industry, particularly for developing non-invasive therapies for neurological disorders such as depression, schizophrenia, and epilepsy, thereby improving treatment outcomes and minimizing systemic side effects\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e"},{"header":"6 Conclusion","content":"\u003cp\u003eThis study successfully formulated and evaluated mirtazapine-loaded nanoemulsions for potential nose-to-brain delivery, demonstrating significant advantages over conventional oral delivery. Among the formulations, F4 exhibited the highest drug release (92.28%), whereas F1 had the lowest (64.21%), highlighting the impact of formulation composition on drug release profiles. Stability assessments confirmed that F1, F2,F3, and F4 were stable under freeze-thaw and centrifugation tests, while F4 showed instability in the latter. SEM revealed spherical, well-separated nanoparticles, and DSC confirmed the transformation of mirtazapine into an amorphous form, which enhanced its solubility. FTIR analysis maintained the structural integrity of the drug, with slight variations due to excipient interactions. The zeta potential and PDI values indicated good stability and size distribution for most of the formulations. Notably, nose-to-brain delivery offers distinct advantages over oral delivery, including bypassing the blood-brain barrier, faster drug action, reduced systemic side effects, and improved bioavailability, making it a promising approach for treating central nervous system disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICAL STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN.A.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors agree to publish the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data is available in the article file\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN.A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.A.W. supervised the project, contributed to the methodology, and was involved in the project administration.\u003c/p\u003e\n\u003cp\u003eM.K. conceptualized the study, performed the formal analysis, and contributed to writing, reviewing, and editing the manuscript.\u003c/p\u003e\n\u003cp\u003eR.K. contributed to conceptualization and participated in writing, reviewing, and editing the manuscript.\u003c/p\u003e\n\u003cp\u003eA.A. curated the data and conducted formal analysis.\u003c/p\u003e\n\u003cp\u003eS.Z. assisted with validation and contributed to data curation.\u003c/p\u003e\n\u003cp\u003eA.S.A. contributed to validation and participated in methodology development.\u003c/p\u003e\n\u003cp\u003eB.A.contributed to the conceptualization and conducted formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN.A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data has been mentioned in the article file\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eK\u0026ouml;nig, H.; K\u0026ouml;nig, H.-H.; Konnopka, A., The excess costs of depression: a systematic review and meta-analysis. \u003cem\u003eEpidemiology and psychiatric sciences \u003c/em\u003e\u003cstrong\u003e2020,\u003c/strong\u003e \u003cem\u003e29\u003c/em\u003e, e30.\u003c/li\u003e\n\u003cli\u003eIbrahim, M. M.; Basalious, E. B.; El-Nabarawi, M. A.; Makhlouf, A. I.; Sayyed, M. E.; Ibrahim, I. T. J. D. D.; Research, T., Nose to brain delivery of mirtazapine via lipid nanocapsules: Preparation, statistical optimization, radiolabeling, in vivo biodistribution and pharmacokinetic study. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (9), 2539-2557.\u003c/li\u003e\n\u003cli\u003eJin, Y.; Cui, R.; Zhao, L.; Fan, J.; Li, B., Mechanisms of Panax ginseng action as an antidepressant. \u003cem\u003eCell proliferation \u003c/em\u003e\u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e52\u003c/em\u003e (6), e12696.\u003c/li\u003e\n\u003cli\u003eAlaayedi, M. H.; Maraie, N. K., Lomustine\u0026rsquo;s nanoemulsion as nose-to-brain drug delivery system for CNS tumor treatment. \u003cem\u003eSaudi Pharmaceutical Journal \u003c/em\u003e\u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e31\u003c/em\u003e (8), 101692.\u003c/li\u003e\n\u003cli\u003eMago, R.; Tripathi, N.; Andrade, C., Cardiovascular adverse effects of newer antidepressants. \u003cem\u003eExpert review of neurotherapeutics \u003c/em\u003e\u003cstrong\u003e2014,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (5), 539-551.\u003c/li\u003e\n\u003cli\u003eBeach, S. R.; Kostis, W. J.; Celano, C. M.; Januzzi, J. L.; Ruskin, J. N.; Noseworthy, P. A.; Huffman, J. C., Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. \u003cem\u003eThe Journal of clinical psychiatry \u003c/em\u003e\u003cstrong\u003e2014,\u003c/strong\u003e \u003cem\u003e75\u003c/em\u003e (5), 11731.\u003c/li\u003e\n\u003cli\u003eMisra, S. K.; Pathak, K. J. C.; Interfaces, Nose-to-brain targeting via nanoemulsion: significance and evidence. \u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e7\u003c/em\u003e (1), 23.\u003c/li\u003e\n\u003cli\u003eSpindelegger, C. J.; Papageorgiou, K.; Grohmann, R.; Engel, R.; Greil, W.; Konstantinidis, A.; Agelink, M. W.; Bleich, S.; Ruether, E.; Toto, S., Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010. \u003cem\u003eInternational journal of neuropsychopharmacology \u003c/em\u003e\u003cstrong\u003e2015,\u003c/strong\u003e \u003cem\u003e18\u003c/em\u003e (4), pyu080.\u003c/li\u003e\n\u003cli\u003eBrambilla, P.; Cipriani, A.; Hotopf, M.; Barbui, C., Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. \u003cem\u003ePharmacopsychiatry \u003c/em\u003e\u003cstrong\u003e2005,\u003c/strong\u003e \u003cem\u003e38\u003c/em\u003e (02), 69-77.\u003c/li\u003e\n\u003cli\u003eEl Sisi, A. M.; Eissa, E. M.; Hassan, A. H.; Bekhet, M. A.; El-Ela, F. I. A.; Roh, E. J.; Kharshoum, R. M.; Ali, A. A. J. P., Nose-to-Brain Delivery of Chitosan-Grafted Leciplexes for Promoting the Bioavailability and Antidepressant Efficacy of Mirtazapine: In Vitro Assessment and Animal Studies. \u003cstrong\u003e2025,\u003c/strong\u003e \u003cem\u003e18\u003c/em\u003e (1), 46.\u003c/li\u003e\n\u003cli\u003eVoican, C. S.; Corruble, E.; Naveau, S.; Perlemuter, G., Antidepressant-induced liver injury: a review for clinicians. \u003cem\u003eAmerican Journal of Psychiatry \u003c/em\u003e\u003cstrong\u003e2014,\u003c/strong\u003e \u003cem\u003e171\u003c/em\u003e (4), 404-415.\u003c/li\u003e\n\u003cli\u003eSalam, A.-M. S. T. Nose to Brain Delivery of Antiepileptic Drugs Using Nanoemulsions. University of Toledo, 2015.\u003c/li\u003e\n\u003cli\u003eAtmaca, M., Selective serotonin reuptake inhibitor-induced sexual dysfunction: current management perspectives. \u003cem\u003eNeuropsychiatric disease and treatment \u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, 1043-1050.\u003c/li\u003e\n\u003cli\u003ePires, P. C.; Paiva-Santos, A. C.; Veiga, F. J. P., Nano and microemulsions for the treatment of depressive and anxiety disorders: An efficient approach to improve solubility, brain bioavailability and therapeutic efficacy. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (12), 2825.\u003c/li\u003e\n\u003cli\u003eVitorino, C.; Silva, S.; Bicker, J.; Falc\u0026atilde;o, A.; Fortuna, A. J. D. D. T., Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e24\u003c/em\u003e (9), 1911-1923.\u003c/li\u003e\n\u003cli\u003eHassanein, E. H.; Althagafy, H. S.; Baraka, M. A.; Abd-Alhameed, E. K.; Ibrahim, I. M. J. N.-s. s. A. o. P., Pharmacological update of mirtazapine: a narrative literature review. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e397\u003c/em\u003e (5), 2603-2619.\u003c/li\u003e\n\u003cli\u003eSharma, A.; Alam, M. A.; Kaur, A.; Sharma, S.; Yadav, S. J. C. P. R.; Reviews, R. F. C. P., Psychopharmacological Treatment of Depression and Anxiety and their Different Drug Delivery Targets. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e20\u003c/em\u003e (4), 297-322.\u003c/li\u003e\n\u003cli\u003eSachan, N.; Bahadur, S.; Sharma, P. K. J. D. D. L., Recent advances and novel approaches for nose to brain drug delivery for treatment of migraine. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e (3), 182-198.\u003c/li\u003e\n\u003cli\u003eJilani, T.; Gibbons, J.; Faizy, R.; Saadabadi, A. J. S., Mirtazapine. \u003cstrong\u003e2024\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eMujtaba, M. A.; Rashid, M. A.; Godbole, M. D.; Alhamhoom, Y.; Shende, D. S.; Alshehri, S.; Akbar, M. J.; Kaleem, M.; Mahajan, U. N.; Shahzad, N. J. F. i. P., Escitalopram oxalate-loaded chitosan nanoparticle in situ gel formulation intended for direct nose-to-brain delivery: in vitro, ex vivo, and in vivo pharmacokinetic evaluation. \u003cstrong\u003e2025,\u003c/strong\u003e \u003cem\u003e16\u003c/em\u003e, 1577331.\u003c/li\u003e\n\u003cli\u003eAlberto, M.; Paiva-Santos, A. C.; Veiga, F.; Pires, P. C. J. P., Lipid and polymeric nanoparticles: Successful strategies for nose-to-brain drug delivery in the treatment of depression and anxiety disorders. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (12), 2742.\u003c/li\u003e\n\u003cli\u003eShah, B.; Khunt, D.; Misra, M. J. F. J. o. P. S., Comparative evaluation of intranasally delivered quetiapine loaded mucoadhesive microemulsion and polymeric nanoparticles for brain targeting: Pharmacokinetic and gamma scintigraphy studies. \u003cstrong\u003e2021,\u003c/strong\u003e \u003cem\u003e7\u003c/em\u003e, 1-12.\u003c/li\u003e\n\u003cli\u003eNaji, L.; Dennis, B.; Rosic, T.; Wiercioch, W.; Paul, J.; Worster, A.; Thabane, L.; Samaan, Z. J. D.; Dependence, A., Mirtazapine for the treatment of amphetamine and methamphetamine use disorder: A systematic review and meta-analysis. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e232\u003c/em\u003e, 109295.\u003c/li\u003e\n\u003cli\u003eShah, B. J. J. o. P. I., Microemulsion as a promising carrier for nose to brain delivery: Journey since last decade. \u003cstrong\u003e2021\u003c/strong\u003e, 1-24.\u003c/li\u003e\n\u003cli\u003eKarami, Z.; Zanjani, M. R. S.; Hamidi, M. J. D. d. t., Nanoemulsions in CNS drug delivery: recent developments, impacts and challenges. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e24\u003c/em\u003e (5), 1104-1115.\u003c/li\u003e\n\u003cli\u003eSusa, F.; Arpicco, S.; Pirri, C. F.; Limongi, T. J. P., An Overview on the Physiopathology of the Blood\u0026ndash;Brain Barrier and the Lipid-Based Nanocarriers for Central Nervous System Delivery. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e16\u003c/em\u003e (7), 849.\u003c/li\u003e\n\u003cli\u003eGupta, A.; Eral, H. B.; Hatton, T. A.; Doyle, P. S. J. S. m., Nanoemulsions: formation, properties and applications. \u003cstrong\u003e2016,\u003c/strong\u003e \u003cem\u003e12\u003c/em\u003e (11), 2826-2841.\u003c/li\u003e\n\u003cli\u003eSingh, Y.; Meher, J. G.; Raval, K.; Khan, F. A.; Chaurasia, M.; Jain, N. K.; Chourasia, M. K. J. J. o. c. r., Nanoemulsion: Concepts, development and applications in drug delivery. \u003cstrong\u003e2017,\u003c/strong\u003e \u003cem\u003e252\u003c/em\u003e, 28-49.\u003c/li\u003e\n\u003cli\u003ePavoni, L.; Perinelli, D. R.; Bonacucina, G.; Cespi, M.; Palmieri, G. F. J. N., An overview of micro-and nanoemulsions as vehicles for essential oils: Formulation, preparation and stability. \u003cstrong\u003e2020,\u003c/strong\u003e \u003cem\u003e10\u003c/em\u003e (1), 135.\u003c/li\u003e\n\u003cli\u003eGrosso, C.; Silva, A.; Delerue-Matos, C.; Barroso, M. F. J. P., Single and multitarget systems for drug delivery and detection: up-to-date strategies for brain disorders. \u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e16\u003c/em\u003e (12), 1721.\u003c/li\u003e\n\u003cli\u003eEissa, E. M.; El Sisi, A. M.; Bekhet, M. A.; El-Ela, F. I. A.; Kharshoum, R. M.; Ali, A. A.; Alrobaian, M.; Ali, A. M. A., pH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy. \u003cem\u003ePharmaceuticals \u003c/em\u003e\u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e17\u003c/em\u003e (8), 978.\u003c/li\u003e\n\u003cli\u003ePailla, S. R.; Talluri, S.; Rangaraj, N.; Ramavath, R.; Challa, V. S.; Doijad, N.; Sampathi, S. J. D. J. o. P. S., Intranasal Zotepine Nanosuspension: Intended for improved brain distribution in rats. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e27\u003c/em\u003e, 541-556.\u003c/li\u003e\n\u003cli\u003eAlbaqshi, L.; Singh, A.; Khan, S.; Kumar, M.; Kour, J.; Pottathil, S.; Aldhubiab, B.; Tiwari, A.; Nair, A. B. J. I. J. P. E. R., Formulation and optimization of aripiprazole-loaded nanostructured lipid carriers for nose-to-brain delivery. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e58\u003c/em\u003e (2), 579-588.\u003c/li\u003e\n\u003cli\u003eKakkar, V.; Modgill, N.; Kumar, M. J. H. M. i. D. T. M. t. I. D. D., Novel drug delivery systems for herbal antidepressants. \u003cstrong\u003e2016\u003c/strong\u003e, 529-556.\u003c/li\u003e\n\u003cli\u003eClementino, A. R.; Pellegrini, G.; Banella, S.; Colombo, G.; Cantù, L.; Sonvico, F.; Del Favero, E., Structure and fate of nanoparticles designed for the nasal delivery of poorly soluble drugs. \u003cem\u003eMolecular Pharmaceutics \u003c/em\u003e\u003cstrong\u003e2021,\u003c/strong\u003e \u003cem\u003e18\u003c/em\u003e (8), 3132-3146.\u003c/li\u003e\n\u003cli\u003eKenneth, E. M.; Xaveir, S. N.; John, M. C.; Patience, O. O.; Krause, R., Evaluation of Accelerated Stability Testing of a Mirtazapine-loaded Nanoemulsion as per International Conference on Harmonization (ich) Protocols. \u003cem\u003eAmerican Journal of Nanoscience and Nanotechnology Research \u003c/em\u003e\u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e6\u003c/em\u003e (1), 8-17.\u003c/li\u003e\n\u003cli\u003eMohammed, M. A.; Syeda, J. T.; Wasan, K. M.; Wasan, E. K., An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. \u003cem\u003ePharmaceutics \u003c/em\u003e\u003cstrong\u003e2017,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e (4), 53.\u003c/li\u003e\n\u003cli\u003eAbdulbaqi, M. R.; Albadri, A. A.; Abdulelah, F. M., Nanoemulsion Preparation, Identification and Evaluation Review. \u003cem\u003eJournal of Global Pharma Technology \u003c/em\u003e\u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e11\u003c/em\u003e (07), 198-206.\u003c/li\u003e\n\u003cli\u003eOkoturo, O.; VanderNoot, T., Temperature dependence of viscosity for room temperature ionic liquids. \u003cem\u003eJournal of Electroanalytical Chemistry \u003c/em\u003e\u003cstrong\u003e2004,\u003c/strong\u003e \u003cem\u003e568\u003c/em\u003e, 167-181.\u003c/li\u003e\n\u003cli\u003eKenneth, E. M.; Xavier, S. N.; John, M. C.; Patience, O. O.; Krause, R., Evaluation of accelerated stability testing of a mirtazapine-loaded nanoemulsion as per. \u003cem\u003eAm J Nanosci Nanotechnol Res \u003c/em\u003e\u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e6\u003c/em\u003e, 1-10.\u003c/li\u003e\n\u003cli\u003eBhatt, P.; Bhatt, T.; Jain, V.; Jain, R.; Bigoniya, P., Nanoemulsion through cold emulsification: An advanced cold manufacturing process for a stable and advanced drug delivery system. \u003cem\u003eJournal of Applied Pharmaceutical Science \u003c/em\u003e\u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e (5), 012-021.\u003c/li\u003e\n\u003cli\u003eKakad, S. P.; Gangurde, T. D.; Kshirsagar, S. J.; Mundhe, V. G., Nose to brain delivery of nanosuspensions with first line antiviral agents is alternative treatment option to Neuro-AIDS treatment. \u003cem\u003eHeliyon \u003c/em\u003e\u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e8\u003c/em\u003e (7).\u003c/li\u003e\n\u003cli\u003eAlgahtani, M. S.; Ahmad, M. Z.; Ahmad, J., Investigation of factors influencing formation of nanoemulsion by spontaneous emulsification: impact on droplet size, polydispersity index, and stability. \u003cem\u003eBioengineering \u003c/em\u003e\u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e (8), 384.\u003c/li\u003e\n\u003cli\u003ePreeti; Sambhakar, S.; Malik, R.; Bhatia, S.; Al Harrasi, A.; Rani, C.; Saharan, R.; Kumar, S.; Geeta; Sehrawat, R., Nanoemulsion: An Emerging Novel Technology for Improving the Bioavailability of Drugs. \u003cem\u003eScientifica (Cairo) \u003c/em\u003e\u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e2023\u003c/em\u003e, 6640103.\u003c/li\u003e\n\u003cli\u003eVerma, N. K.; Yadav, A.; Yadav, V., Recent Advances In Nanoemulsion Based Drug Delivery System: A Review. \u003cstrong\u003e2022\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eTscharnuter, W., Photon Correlation Spectroscopy in Particle Sizing. 2006.\u003c/li\u003e\n\u003cli\u003eEid, A.; Elmarzugi, N.; El Enshasy, H., Preparation and evaluation of olive oil nanoemulsion using sucrose monoester. \u003cem\u003eInternational Journal of Pharmacy and Pharmaceutical Sciences \u003c/em\u003e\u003cstrong\u003e2013,\u003c/strong\u003e \u003cem\u003e5\u003c/em\u003e, 434-440.\u003c/li\u003e\n\u003cli\u003eKamble, S.; Agrawal, S.; Cherumukkil, S.; Sharma, V.; Jasra, R. V.; Munshi, P., Revisiting zeta potential, the key feature of interfacial phenomena, with applications and recent advancements. \u003cem\u003eChemistrySelect \u003c/em\u003e\u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e7\u003c/em\u003e (1), e202103084.\u003c/li\u003e\n\u003cli\u003eGurpreet, K.; Singh, S., Review of nanoemulsion formulation and characterization techniques. \u003cem\u003eIndian Journal of Pharmaceutical Sciences \u003c/em\u003e\u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e80\u003c/em\u003e (5).\u003c/li\u003e\n\u003cli\u003eWaqar, M. A.; Zaman, M.; Hameed, H.; Jamshaid, M.; Irfan, A.; Shazly, G. A.; Paiva-Santos, A. C.; Bin Jardan, Y. A., Formulation, characterization, and evaluation of \u0026beta;-Cyclodextrin functionalized hypericin loaded nanocarriers. \u003cem\u003eACS omega \u003c/em\u003e\u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e8\u003c/em\u003e (41), 38191-38203.\u003c/li\u003e\n\u003cli\u003eDutta, A., Fourier transform infrared spectroscopy. \u003cem\u003eSpectroscopic methods for nanomaterials characterization \u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, 73-93.\u003c/li\u003e\n\u003cli\u003eAbdelbary, G. A.; Tadros, M. I., Brain targeting of olanzapine via intranasal delivery of core\u0026ndash;shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies. \u003cem\u003eInternational journal of pharmaceutics \u003c/em\u003e\u003cstrong\u003e2013,\u003c/strong\u003e \u003cem\u003e452\u003c/em\u003e (1-2), 300-310.\u003c/li\u003e\n\u003cli\u003ePu, X.; Sun, J.; Han, J.; Lian, H.; Zhang, P.; Yan, Z.; He, Z., Nanosuspensions of 10-hydroxycamptothecin that can maintain high and extended supersaturation to enhance oral absorption: preparation, characterization and in vitro/in vivo evaluation. \u003cem\u003eJournal of nanoparticle research \u003c/em\u003e\u003cstrong\u003e2013,\u003c/strong\u003e \u003cem\u003e15\u003c/em\u003e, 1-13.\u003c/li\u003e\n\u003cli\u003eAzeem, A.; Rizwan, M.; Ahmad, F. J.; Iqbal, Z.; Khar, R. K.; Aqil, M.; Talegaonkar, S., Nanoemulsion components screening and selection: a technical note. \u003cem\u003eAaps Pharmscitech \u003c/em\u003e\u003cstrong\u003e2009,\u003c/strong\u003e \u003cem\u003e10\u003c/em\u003e, 69-76.\u003c/li\u003e\n\u003cli\u003eNemade, S.; Kakad, S.; Kshirsagar, S.; Padole, T., Development of nanoemulsion of antiviral drug for brain targeting in the treatment of neuro-AIDS. \u003cem\u003eBeni-Suef University Journal of Basic and Applied Sciences \u003c/em\u003e\u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e11\u003c/em\u003e (1), 138.\u003c/li\u003e\n\u003cli\u003eZaman, M.; Hanif, M., In vitro and ex vivo assessment of hydrophilic polymer- and plasticizer-based thin buccal films designed by using central composite rotatable design for the delivery of meloxicam. \u003cem\u003eAdvances in Polymer Technology \u003c/em\u003e\u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e37\u003c/em\u003e (6), 1823-1836.\u003c/li\u003e\n\u003cli\u003eZahra, S.; Zaib, S.; Khan, I. J. I. J. o. B. M., Identification of isobenzofuranone derivatives as promising antidiabetic agents: Synthesis, in vitro and in vivo inhibition of \u0026alpha;-glucosidase and \u0026alpha;-amylase, computational docking analysis and molecular dynamics simulations. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e259\u003c/em\u003e, 129241.\u003c/li\u003e\n\u003cli\u003ePires, P. C.; Santos, A. O., Nanosystems in nose-to-brain drug delivery: A review of non-clinical brain targeting studies. \u003cem\u003eJournal of controlled release \u003c/em\u003e\u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e270\u003c/em\u003e, 89-100.\u003c/li\u003e\n\u003cli\u003eAffandi, M.; Julianto, T.; Majeed, A., Development and stability evaluation of astaxanthin nanoemulsion. \u003cem\u003eAsian J Pharm Clin Res \u003c/em\u003e\u003cstrong\u003e2011,\u003c/strong\u003e \u003cem\u003e4\u003c/em\u003e (1), 142-148.\u003c/li\u003e\n\u003cli\u003eBaboota, S.; Shakeel, F.; Ahuja, A.; Ali, J.; Shafiq, S. J. A. p., Design, development and evaluation of novel nanoemulsion formulations for transdermal potential of celecoxib. \u003cstrong\u003e2007,\u003c/strong\u003e \u003cem\u003e57\u003c/em\u003e (3), 315.\u003c/li\u003e\n\u003cli\u003eTrott, O.; Olson, A. J. J. J. o. c. c., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. \u003cstrong\u003e2010,\u003c/strong\u003e \u003cem\u003e31\u003c/em\u003e (2), 455-461.\u003c/li\u003e\n\u003cli\u003eVitorino, C.; Silva, S.; Gouveia, F.; Bicker, J.; Falc\u0026atilde;o, A.; Fortuna, A. J. E. j. o. p.; biopharmaceutics, QbD-driven development of intranasal lipid nanoparticles for depression treatment. \u003cstrong\u003e2020,\u003c/strong\u003e \u003cem\u003e153\u003c/em\u003e, 106-120.\u003c/li\u003e\n\u003cli\u003eTawfik, M. A.; Eltaweel, M. M.; Fatouh, A. M.; Shamsel-Din, H. A.; Ibrahim, A. B. J. D. D.; Research, T., Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique. \u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e13\u003c/em\u003e (12), 3059-3076.\u003c/li\u003e\n\u003cli\u003eNigam, K.; Kaur, A.; Tyagi, A.; Nematullah, M.; Khan, F.; Gabrani, R.; Dang, S. J. D. d.; research, t., Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e, 879-890.\u003c/li\u003e\n\u003cli\u003eSharma, D.; Sharma, R. K.; Sharma, N.; Gabrani, R.; Sharma, S. K.; Ali, J.; Dang, S. J. A. p., Nose-to-brain delivery of PLGA-diazepam nanoparticles. \u003cstrong\u003e2015,\u003c/strong\u003e \u003cem\u003e16\u003c/em\u003e, 1108-1121.\u003c/li\u003e\n\u003cli\u003eJena, D.; Srivastava, N.; Yasir, M.; Dan, D. J. C. N., Intranasal delivery of lipid nanoparticles: A ground-breaking approach for brain targeting. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e (3), 209-223.\u003c/li\u003e\n\u003cli\u003eKomane, P. P.; Kumar, P.; Choonara, Y. E., Nanoparticles and treatment of depression. In \u003cem\u003eNatural Molecules in Neuroprotection and Neurotoxicity\u003c/em\u003e, Elsevier: 2024; pp 1959-1987.\u003c/li\u003e\n\u003cli\u003eVăruț, R. M.; Popescu, A. I. S.; Gaman, S.; Niculescu, C. E.; Niculescu, A. Ș.; Dop, D.; Stepan, M. D.; Ionovici, N.; Singer, C. E.; Popescu, C. J. P., Cyclodextrin-Based Drug Delivery Systems for Depression: Improving Antidepressant Bioavailability and Targeted Central Nervous System Delivery. \u003cstrong\u003e2025,\u003c/strong\u003e \u003cem\u003e17\u003c/em\u003e (3), 355.\u003c/li\u003e\n\u003cli\u003eVirmani, R.; Virmani, T.; Pathak, K., Nanovesicles for delivery of central nervous system drugs. In \u003cem\u003eApplications of Nanovesicular Drug Delivery\u003c/em\u003e, Elsevier: 2022; pp 315-339.\u003c/li\u003e\n\u003cli\u003eSharma, S.; Dang, S. J. C. p. d., Neuropsychological disorders and their nanocarriers. \u003cstrong\u003e2020,\u003c/strong\u003e \u003cem\u003e26\u003c/em\u003e (19), 2247-2256.\u003c/li\u003e\n\u003cli\u003eIBRAHIM, M.; BASALIOUS, E.; El-NABARAWI, M.; MAKHLOUF, A. J. J. o. R. i. P., Lipid nanocapsules: A Novel Strategy for Brain Targeting via Nasal Administration. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e28\u003c/em\u003e (2).\u003c/li\u003e\n\u003cli\u003eGhazwani, M.; Vasudevan, R.; Kandasamy, G.; Manusri, N.; Devanandan, P.; Puvvada, R. C.; Veeramani, V. P.; Paulsamy, P.; Venkatesan, K.; Chidmabaram, K. J. G., Formulation of intranasal mucoadhesive thermotriggered in situ gel containing mirtazapine as an antidepressant drug. \u003cstrong\u003e2023,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e (6), 457.\u003c/li\u003e\n\u003cli\u003ePatel, M. S.; Mandal, S. D.; Mandal, S.; Faldu, S.; Patel, J. J. T. J. o. P. S., Nasotransmucosal Delivery of Curcumin-Loaded Mucoadhesive Microemulsions for Treating Inflammation-Related CNS Disorders. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e19\u003c/em\u003e (5), 560.\u003c/li\u003e\n\u003cli\u003eChavda, V. P.; Balar, P. C.; Bezbaruah, R.; Vaghela, D. A.; Rynjah, D.; Bhattacharjee, B.; Sugandhi, V. V.; Paiva-Santos, A. C. J. N., Nanoemulsions: summary of a decade of research and recent advances. \u003cstrong\u003e2024,\u003c/strong\u003e \u003cem\u003e19\u003c/em\u003e (6), 519-536.\u003c/li\u003e\n\u003cli\u003eMandal, S.; Mandal, S. D.; Chuttani, K.; Dharamsi, A.; bhushan Subudhi, B. J. J. o. D. D. S.; Technology, Transnasomucosal mucoadhesive microemulsion of zaltoprofen: A comparative brain distribution study. \u003cstrong\u003e2017,\u003c/strong\u003e \u003cem\u003e39\u003c/em\u003e, 237-246.\u003c/li\u003e\n\u003cli\u003eThakkar, H.; Patel, A.; Chauhan, N. J. C. o. Y. S., Formulation and optimization of mucoadhesive microemulsion containing mirtazapine for intranasal delivery. \u003cstrong\u003e2014,\u003c/strong\u003e \u003cem\u003e5\u003c/em\u003e (1), 25-25.\u003c/li\u003e\n\u003cli\u003eGadhave, D.; Choudhury, H.; Kokare, C. J. A. N., Neutropenia and leukopenia protective intranasal olanzapine-loaded lipid-based nanocarriers engineered for brain delivery. \u003cstrong\u003e2019,\u003c/strong\u003e \u003cem\u003e9\u003c/em\u003e, 151-168.\u003c/li\u003e\n\u003cli\u003eJain, A. S.; Bavaskar, K. R.; Rokade, P. B.; Rane, B. R.; Morani, D. O. J. J. o. P. S.; Research, Fabrication and Evaluation of Amitriptyline HC1 Loaded Nanostructured Lipid Carriers and In-Vitro Characterization. \u003cstrong\u003e2025,\u003c/strong\u003e \u003cem\u003e17\u003c/em\u003e (1), 1-8.\u003c/li\u003e\n\u003cli\u003ePatel, D.; Thakkar, H. J. T. d., Formulation considerations for improving intranasal delivery of CNS acting therapeutics. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e13\u003c/em\u003e (7), 371-381.\u003c/li\u003e\n\u003cli\u003eMandlik, S. K.; Ranpise, N. S.; Mohanty, B. S.; Chaudhari, P. R. J. D. D.; Research, T., A coupled bimodal SPECT-CT imaging and brain kinetics studies of zolmitriptan-encapsulated nanostructured polymeric carriers. \u003cstrong\u003e2018,\u003c/strong\u003e \u003cem\u003e8\u003c/em\u003e, 797-805.\u003c/li\u003e\n\u003cli\u003eAkilo, O. D. Exploration of an Electro-Magneto-Responsive Polymeric Drug Delivery System for Enhanced Nose-To-Brain Delivery. University of the Witwatersrand, Johannesburg (South Africa), 2016.\u003c/li\u003e\n\u003cli\u003eCui, J.; Li, M.; Wei, Y.; Li, H.; He, X.; Yang, Q.; Li, Z.; Duan, J.; Wu, Z.; Chen, Q. J. F. i. p., Inhalation aromatherapy via brain-targeted nasal delivery: Natural volatiles or essential oils on mood disorders. \u003cstrong\u003e2022,\u003c/strong\u003e \u003cem\u003e13\u003c/em\u003e, 860043.\u003c/li\u003e\n\u003cli\u003eAhmad, N.; Ahmad, R.; Al Qatifi, S.; Alessa, M.; Al Hajji, H.; Sarafroz, M. J. B. c., A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy. \u003cstrong\u003e2020,\u003c/strong\u003e \u003cem\u003e14\u003c/em\u003e, 1-15.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bionanoscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnsc","sideBox":"Learn more about [BioNanoScience](http://link.springer.com/journal/12668)","snPcode":"12668","submissionUrl":"https://submission.nature.com/new-submission/12668/3","title":"BioNanoScience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Nanoemulsion, Mirtazapine, Depression, Behavior, Intranasal Delivery, Brain Targeting","lastPublishedDoi":"10.21203/rs.3.rs-7282569/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7282569/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeurological disorders, such as depression, are difficult to manage owing to limited brain drug delivery and suboptimal therapies. This study developed and evaluated lavender oil-based mirtazapine-loaded nanoemulsions for direct nose-to-brain targeting to enhance therapeutic efficiency and reduce systemic side effects. Nanoemulsions were prepared using homogenization-sonication, incorporating lavender oil, Tween-80, Span-80, ethanol, and distilled water. They exhibited spherical, uniformly distributed nanosized globules with nasal pH compatibility (6.14–6.19). Among the formulations, F4 showed optimal results with a zeta potential of –10.4 ± 0.9, ideal viscosity, high drug entrapment, and excellent \u003cem\u003ein-vitro\u003c/em\u003e(92.78%) and \u003cem\u003eex-vivo\u003c/em\u003e (93.28%) mucosal penetration. Molecular docking confirmed the stable binding of mirtazapine to the dopamine receptor (PDB ID: 6CM4) via multiple hydrophobic and π-interactions. All formulations demonstrated stability under centrifugation and freeze-thaw conditions. Overall, this study supports mirtazapine nanoemulsions as a promising, non-invasive strategy for central nervous system drug delivery, improving bioavailability while minimizing systemic toxicity.\u003c/p\u003e","manuscriptTitle":"Lavender Oil-Infused Mirtazapine Nanoemulsion for Direct Nose- to-Brain Targeting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-18 17:38:39","doi":"10.21203/rs.3.rs-7282569/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-16T00:55:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-26T15:50:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134569718179021469985438539035841677858","date":"2025-09-13T05:58:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-11T02:24:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-12T05:46:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-12T02:02:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"BioNanoScience","date":"2025-08-03T09:45:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bionanoscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnsc","sideBox":"Learn more about [BioNanoScience](http://link.springer.com/journal/12668)","snPcode":"12668","submissionUrl":"https://submission.nature.com/new-submission/12668/3","title":"BioNanoScience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f8b6d2f2-15c3-4b25-bd1d-69d4ff349ff3","owner":[],"postedDate":"September 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:01:45+00:00","versionOfRecord":{"articleIdentity":"rs-7282569","link":"https://doi.org/10.1007/s12668-026-02443-6","journal":{"identity":"bionanoscience","isVorOnly":false,"title":"BioNanoScience"},"publishedOn":"2026-02-26 15:57:31","publishedOnDateReadable":"February 26th, 2026"},"versionCreatedAt":"2025-09-18 17:38:39","video":"","vorDoi":"10.1007/s12668-026-02443-6","vorDoiUrl":"https://doi.org/10.1007/s12668-026-02443-6","workflowStages":[]},"version":"v1","identity":"rs-7282569","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7282569","identity":"rs-7282569","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}