Nasal Spray: Review Article

 Corresponding author: Lokesh Janardhan Sayam Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Nasal Spray: Review Article Shreya Ravindra Sarve, Lokesh Janardhan Sayam *, Sayyad Faizan Sayyad Roshan and Archana KajaleKulkarni Department of Pharmaceutics, Yavatmal Zilla Vikas Samiti's Pataldhamal Wadhwani College of Pharmacy, Yavatmal. Sant Gadge Baba Amravati University. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 Publication history: Received on 12 September 2025; revised on 19 October 2025; accepted on 22 October 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.24.1.0913 Abstract A nasal spray is a liquid medication delivered into the nasal cavity through a spray device for local or systemic therapeutic effects. It is a non-invasive drug delivery system that offers several advantages, including ease of administration, rapid onset of action, avoidance of first-pass metabolism, and improved patient compliance. The nasal cavity has a rich blood supply and a large surface area, which enables quick absorption of drugs directly into the bloodstream. Additionally, nasal sprays can deliver drugs directly to the brain through the olfactory and trigeminal nerve pathways, bypassing the blood–brain barrier. This makes them suitable not only for treating local conditions such as allergic rhinitis, nasal congestion, and sinusitis but also for systemic conditions like migraines, hormonal deficiencies, and certain neurological disorders. Nasal sprays can be formulated as solutions, suspensions, emulsions, or dry powders and often contain excipients to enhance drug absorption, stability, and patient comfort. Their user-friendly design allows for self-administration, making them a convenient and effective alternative to oral or injectable routes of drug delivery. With ongoing advancements in nanotechnology, biotechnology, and formulation science, nasal sprays are expected to play an even larger role in drug delivery. Innovations such as mucoadhesive nanoparticles, thermosensitive gels, and targeted delivery systems are expanding the potential of nasal drug delivery for complex conditions, including neurodegenerative diseases and systemic infections. This review discusses the key parameters influencing nasal spray performance, emphasizing the morphological, physiological, histological characteristics of the nasal cavity, Ideal drug candidates, possible drugs for nasal spray, nasal spray devices that are used to introduced drug into nasal cavity. Components of nasal spray container and that affect drug formulations and pharmacokinetics. Keywords: Nasal Spray; Nasal Cavity; Epithelium; Buffers; Allergic Reaction; Ph; Viscosity 1. Introduction Nasal spray formulations are an increasingly popular method for delivering both local and systemic therapies. They are commonly used for treating conditions such as allergic rhinitis, nasal congestion, and more recently for systemic treatments like migraines and hormone replacement therapy. The nasal route offers significant advantages, including rapid drug absorption due to the rich blood supply in the nasal mucosa, and the avoidance of first pass metabolism. These features make nasal sprays a convenient and effective option for patients. [1] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 379 Figure 1 Nasal spray – for childs Figure 2 Nasal spray – for adults About 2% of the drugs that are conveyed through nasal route due to the reason for availability of large surface area. In comparison to alternative routes of drug delivery, nasal route is found more prominent. Drug substance like xylometazoline, which is of imidazole class, acts on alpha-adrenergic receptors of nasal mucosal arterioles leading to decrease of blood flow. It reduces the swelling of nasal turbinate’s, relating to amplification of nasal lumen. Various excipients were used in novel drug delivery system with aim of taking specific roles in drug delivery system such as carriers, bioavailability enhancers, masking of taste, stabilizer, solubilizer etc. [2] Now a day’s multiple types of formulation are used to administer drug by nasal rout, which includes nasal spray, nasal drop, nasal powder, nasal gels and nasal insert etc. Administration of drugs through the nose in the spray dosage form is a non-invasive method that gives rapid onset of drug action. Because the nasals spray dosage form is cost-effective, easy to use/carry and self-administrable, it has high patient compliance. Therefore, nasal drug delivery has become a popular route of drug administration and has strong growth opportunity. [3] The nasal delivery also appears to be a good approach to get over the barriers for blooda brain barrier (BBB) that permits direct medication delivery the central nervous system (CNS)-active bio phase compounds. It has also been regarded as one of vaccination administration. [4] The current review describes the key parameters influencing nasal spray, as well as the morphological, physiological, and histological characteristics of the nasal cavity features of medication formulations and drug attributes decisively ascertain nasal pharmacokinetics preparations. Figure 3 Evolution of Nasal spray 1.1. Anatomy and physiology of Nasal cavity In humans and other animal species, the major functions of the nasal cavity are breathing and olfaction. It also affords an important protective activity once it filters, heat and humidifies the inhaled air before reaching the lowest airways. The human nasal cavity has a total volume of 1520 ml (about 51.4 oz) and a total surface area of approximately 150 cm. The nose is separated in two nasal cavities by the septum. The volume of each cavity is about 7.5 ml (about 0.25 oz) and has a surface area around 75 cm (about 2.46 ft) pH of the mucosal secretions ranges from 5.0 to 6.7 in children and 5.5 World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 380 to 6.5 in adults. The nasal passage epithelium is covered by a mucus layer that is renewed every 10 to 15 min. From the nose, mucus moves at a rate of 5 to 6 mm/min resulting in particle clearance within the nose every 20 min. 1.2. Three regions can be distinguished in each part 1.2.1. Respiratory region The nasal respiratory region is the largest part of the nasal cavity, also called conchae. The respiratory region is the most important for systemic drug delivery. The respiratory epithelium is composed of four types of cells, namely, nonciliated and ciliated columnar cells, basal cells and goblet cells. The respiratory region contains three nasal turbinates superior, middle, and inferior which project from the lateral wall of each of the nasal cavity. For systemic drug delivery, nasal respiratory mucosa is considered the most important section. 1.2.2. Vestibular region Most anterior part of the nasal cavity is nasal vestibule, just inside the nostrils, and presents an area of about 0.6 cm this nasal portion is covered by a stratified squamous and keratinized epithelium with sebaceous glands is responsible for filtering out the airborne particles. It is considered to be less important in the three regions concerning drug absorption.[5] Figure 4 Anatomy Of human nasal cavity. [5] 1.2.3. Olfactory region The olfactory region is located in the roof of the nasal cavity and extends a short way down the septum and lateral wall it is of about 10 cm2 in surface area and it plays a vital role in transportation of drugs to the brain and the CSF. When the drug is administered internally, it can enter into the brain via three different paths. The first one is the systemic pathway by which the drug is absorbed into the systemic circulation and subsequently reaches the brain by crossing BBB [especially lipophilic drug]. The others are the olfactory region and the trigeminal neural pathway by which drug is transported directly from the nasal cavity to CNS [cerebrospinal fluid and brain tissue]. There are different mechanism by which the drugs across the olfactory membrane to reach CNS. The first mechanism involves direct transfer of the drug to primary neurons of the olfactory epithelium and transport to the olfactory bulb by intracellular axonal transport with subsequent possible distribution into more distant brain tissues. The second mechanism depends on the drug permeation across the olfactory sustentacular epithelial cells, either by transcellular or paracellular mechanisms followed by uptake into CNS. The last one employs pinocytosis by olfactory neurons. [6] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 381 Figure 5 Cell types of the nasal epithelium showing ciliated cell [6] 1.3. Blood supply to nasal cavity Nasal vasculature is ever such supplied with blood to implement the essential functions of the nasal cavity like as heating and humidification, olfaction, mucociliary clearance and immunological functions. Blood provides comes from branches of both the internal and external carotid artery including branches of the facial artery and maxillary artery. The named arteries of the nose are • Sphenopalatine artery, a branch of maxillary artery. • Anteriorethmoidal artery, a branch of ophthalmic artery. Branches of the facial artery supplying the vestibule of the nasal cavity. The lamina propria in the nasal mucosa is rich in blood vessels. They differ from the vasculature in the tracheobronchial tree in three ways. First is venous sinusoid in the nose. Second is arteriovenous anastomosis in the nose. Third are the nasal vasculature shows cyclical nature. 1.4. Mechanism of Drug Permeation/Absorption by Nasal Route The absorbed drugs from the nasal cavity must pass through the mucus layer. It is the first step in absorption. Small, unchanged drugs easily pass through this layer but large, charged drugs are difficult to cross it. The principal protein of the mucus is mucin which has the tendency to bind to the solutes, hindering diffusion. Additionally, structural changes in the mucus layer are possible because of environmental changes. The two mechanisms are as follows 1.4.1. First mechanism It involves an aqueous route of transport, which is also known as paracellular route but slow and passive. There is an inverse log-log correlation between intranasal absorption and the molecular weight of water-soluble compounds. The molecular weight greater than 1000 Daltons show poor bioavailability. 1.4.2. Second mechanism It involves transport through a lipoidal route known as the transcellular process. It is responsible for the transport of lipophilic drugs that show a rate dependency on their lipophilicity. Drugs can also cross cell membranes by an active World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 382 transport route via carriermediated means or transport through the opening of tight junctions. For example, chitosan, a natural biopolymer from shell fish opening of tight junctions between epithelial cells to facilitate drug transport. [7] Figure 6 Mechanism of drug absorption by nasal route [7] 1.5. Barriers to nasal absorption 1.5.1. Low bioavailability Lipophilic drugs are generally well absorbed from the nasal cavity compared to polar drugs. It is due to low membrane permeability. 1.5.2. Low membrane transport Rapid clearance of the administered formulation from the nasal cavity due to the mucociliary clearance mechanism. This is especially the case for drugs that are not easily absorbed across the nasal membrane. 1.5.3. Enzymatic Degradation Low transport of especially peptides and proteins across the nasal membrane is the possibility of an enzymatic degradation of the molecule either within the lumen of the nasal cavity or during passage across the epithelial barrier by exopeptidase and endopeptidase. [8] • Advantages o Absorption of drug is rapid due to highly vascularized mucosa. o Availability of large nasal mucosal surface area. o Onset of action is rapid. o Administration of dose is easy and Non-invasive. o Bypass the Blood Brain Barrier. o Degradation of drug observed in GIT is avoided. o Hepatic first pass metabolism is absent. o Nasal bioavailability of small drug molecules is good. o Bioavailability of large drug molecules can be increased by means of absorption enhancers. (9) o Alternate to parenteral route especially for proteins and peptides. o For the patient on long term therapy this route convenient. o Improved bioavailability as compared to oral route. o Side effects are minimum due to low dose. o Patient convenience and compliance is improved. o A self-administration of drug dose is possible. o Direct transport into systemic circulation and CNS is possible. [10] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 383 • Disadvantages o Delivery volume in nasal cavity is restricted to 25– 200 μl. o Systemic toxicity occurring due to absorption enhancers is yet not established. o High molecular weight compounds cannot be delivered through this route [mass cut off~1kDa]. o Large interspecies variability is observed in this route. o Normal defense mechanisms like mucociliary clearance and ciliary beating affects the permeability of drug. [11] o Drugs like Budesonide, Azilactine are liable to cause irritation of nasal mucosa. o Limited understanding of mechanisms and less developed models at this stage. o Smaller absorption surface compared with GIT. o Possibility of nasal irritation hence inconvenient compared with oral route. o Enzymatic barrier to permeability of drug. [12] Limitations • The relatively small area available for drug absorption limits the dose. • There is a finite amount of time for drug absorption. • Drug effectiveness is hampered by nasal disease absorption. • The substances that increase absorption are nasal medication delivery system toxicity in histology that is yet unclear established. • There is less surface area for absorption compared to GIT. • Nasal sensitivity. [13] 1.5.4. ‘Ideal’ drug candidate for nasal delivery An ideal nasal drug candidate should possess the following attributes • Appropriate aqueous solubility to provide the desired dose in a 25–150 ml volume of formulation administration per nostril. • Appropriate nasal absorption properties. • No nasal irritation from the drug. • A suitable clinical rationale for nasal dosage forms, e.g. rapid onset of action. • Low dose. Generally, below 25 mg per dose. • No toxic nasal metabolites. • No offensive odour/aroma associated with the drug. • Suitable stability characteristics. [14] 1.6. Reasons Behind Nasal Spray Formulation Nasal spray formulations are widely used to treat nasal irritation-related diseases such as allergic rhinitis, nasal congestion, sinusitis, and rhinosinusitis. They deliver drugs directly to the nasal mucosa, providing a rapid onset of action and reducing systemic side effects compared to oral medications. They are particularly effective because the nasal cavity offers a large surface area, rich vascular supply, and bypass of first-pass metabolism, which enhances drug absorption. 1.6.1. Diseases related to Nasal Cavity • Allergic Rhinitis: Allergic rhinitis is an inflammation of the membranes lining the nose, often triggered by allergens such as pollen, dust mites, mold, or pet dander. • Symptoms: Sneezing, runny or congested nose, itchy eyes, postnasal drip, watery eyes, and fatigue. • Causes: Immune system overreaction to allergens like pollen, dust mites, animal dander, mold, or certain foods. • Nasal Polyps: Nasal polyps are soft, painless, noncancerous growths that develop on the lining of the nasal passages or sinuses due to chronic inflammation. • Symptoms: Chronic nasal congestion, runny nose, postnasal drip, reduced or lost sense of smell, and facial pressure. • Causes: Chronic inflammation of the nasal mucosa due to asthma, allergies, or chronic sinus infections. [15] • Chronic Sinusitis: Chronic sinusitis is characterized by inflammation of the sinuses lasting 12 weeks or longer. It can result from infections, nasal polyps, or swelling of the sinus lining. Symptoms: Nasal congestion, facial pain or pressure, thick nasal discharge, reduced sense of smell, headache, and cough. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 384 • Causes: Infections (bacterial, viral, or fungal), nasal polyps, structural abnormalities (e.g.deviated septum), or persistent inflammation. [16] • Deviated Nasal Septum: A deviated septum occurs when the nasal septum, the cartilage and bone dividing the nasal cavity, is displaced to one side. • Symptoms: Nasal obstruction (difficulty breathing through one or both nostrils), frequent sinus infections, snoring, and nosebleeds. • Causes: Congenital (present from birth) or trauma to the nose causing displacement of the septum. [17] • Epistaxis (Nosebleeds): Nosebleeds can result from various factors, including trauma, dry air, allergies, and underlying health conditions. They are characterized by bleeding from the nostrils and may require medical attention if recurrent or severe. • Symptoms: Bleeding from the nose, sometimes associated with pain or swelling if trauma is involved. • Causes: Trauma, dry air, nasal infections, hypertension, blood disorders, or use of anticoagulant drugs. [18] • Nasal Vestibulitis: Nasal vestibulitis is an infection of the nasal vestibule, often caused by bacteria like Staphylococcus aureus. It can lead to redness, swelling, and pain at the entrance of the nose. • Symptoms: Redness, swelling, pain at the entrance of the nose, crusting, and sometimes pus discharge. • Causes: Bacterial infection (commonly Staphylococcus aureus) in the nasal vestibule, often due to nose-picking or injury. [19] • Formulation of nasal spray: Formulations play a significant role in nasal spray performance. In addition to the Active Pharmaceutical Ingredient (API), the physical characteristics of the emitted spray are critical to therapeutic outcomes and critical in vitro spray characteristics. Formulation factors, such as the viscosity and the presence of excipients, can lead to distinct spray characteristics and deposition and absorption behavior in the nasal cavity. [20] 1.6.2. Possible Methods of formulations of Nasal Spray Aqueous solution sprays Excipients include Preservatives are used in the formulation (e.g., benzalkonium chloride) Buffers are added (e.g., phosphate buffer) to maintain pH (typically 4.5–6.5). Tonicity agents are use (e.g., sodium chloride) for isotonicity, Solubilizers or stabilizers needed. Dissolve the API in a suitable portion of purified water (e.g., Water for Injection [WFI]). Add required excipients (preservatives, buffers, tonicity agents) and adjust pH (5.5) Make up the solution volume with purified water, Mix thoroughly to ensure uniformity. Pass the solution through a sterile membrane filter (0.22 μm pore size) to remove any particulate matter and microorganisms. Using aseptic technique or a clean environment (e.g., laminar flow hood), fill the sterile solution into sterile nasal spray bottles ,Ensure correct volume per spray (e.g., 100 μL per actuation). World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 385 In the last Seal containers with appropriate spray pumps and caps. Label as per regulatory requirements, Store in suitable conditions [21] 1.7. Suspension sprays Choose a suitable drug that is poorly soluble in aqueous media and intended for local or systemic nasal delivery (e.g., Mometasone Furoate). Select preservatives (e.g., Benzalkonium Chloride), tonicity agents (e.g., Sodium Chloride), pH adjusters (e.g., Sodium Hydroxide, Hydrochloric Acid), and stabilizers. Disperse the suspending agent (e.g., Carbopol 974P) in purified water under continuous stirring accurately weigh the API and micronize if necessary to obtain uniform particle size (target size: ~10–50 μm). Slowly incorporate the API into the hydrated suspension base under continuous stirring to avoid agglomeration. Homogenization or high-shear mixing may be applied to ensure uniform dispersion. Measure pH of the suspension, Adjust pH to nasal physiological range (typically 4.5–6.5) using suitable pH modifiers. Adjust tonicity with sodium chloride or similar agents to achieve isotonicity (~0.9% NaCl equivalent). Add preservative agents like Benzalkonium Chloride (0.01–0.02%) to prevent microbial growth. Fill the suspension into suitable nasal spray containers (e.g., polyethylene bottles with spray pumps). Ensure uniform filling and avoid air bubbles, Close tightly with suitable nasal spray pump. Store at controlled room temperature (15–25°C) in amber-colored containers to prevent degradation. World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 386 Label with batch number, manufacturing date, expiry date, storage conditions and usage instruction. [22] 1.8. Dry powder nasal sprays Perform compatibility studies using DSC (Differential Scanning Calorimetry) and FTIR (Fourier Transform Infrared Spectroscopy) to ensure no interactions. Selection of Drug and Excipients Drug Properties: Should be stable in dry state, preferably micronized (<10 µm). Excipients Commonly used carriers include lactose, mannitol, starch, and microcrystalline cellulose. Micronize the drug to achieve the target particle size (generally 1–5 ) . Milling ensures uniformity of particles and enhances bioavailability. Accurately weigh drug and excipients according to the desired formulation. Blend under controlled conditions (e.g., in a Turbula mixer). Blend time is critical to avoid over-mixing which can cause segregation. The dry powder is filled into a nasal spray device designed for powders. Typical devices include single-dose capsules or multi-dose reservoirs equipped with a powder dispersion system. Ensure minimal powder loss during filling, typically done in low-humidity environments (RH < 40%). Assemble the nasal spray device under aseptic and controlled conditions, seal proper to prevent moisture ingress. Label the device according to regulations, Use moisture-resistant packaging (e.g., aluminum blisters, HDPE containers). [23] World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 393 The nozzle design ensures atomization into droplets of optimal size (20–100 µm), which deposit in the anterior and posterior nasal cavity without reaching the lungs. Each actuation delivers a metered dose, ensuring reproducible administration. [42] 1.16. EVALUATION PARAMETERS 1.16.1. Appearance, Colour, and Clarity The appearance of the content of the container (i.e., formulation) and the container closure system (e.g., pump components, inside of the container) should conform to their respective descriptions as an indication of the drug product integrity. If any color is associated with the formulation (either present initially or from degradative processes occurring during shelf life) then a quantitative test with appropriate acceptance criteria should be established for the drug product by the manufacturer. 1.16.2. Identification A specific identification test is recommended to verify the identity of the drug substance in the drug product. Chromatographic retention time alone is not an adequate method to ensure the identity of the drug substance in the drug product. If the drug substance is a single enantiomer, then at least one of the methods should be specific for this property. 1.16.3. Drug Content (Assay) The assay of drug substance in the entire container should be determined analytically with a stability indicating procedure. This test provides assurance of consistent manufacturing (e.g., formulation, filling, sealing). The acceptance criteria (assay limits as specified in official books) should be tight enough to ensure conformance in other related attributes (e.g., spray content uniformity). A suitable assay procedure should be designed to address any degradation of the drug substance, adherence of the drug substance to the container and closure components, and the potential effect of formulation evaporation and/or leakage. [43] 1.16.4. Impurities and Degradation Products The levels of degradation products and impurities should be determined by means of stability indicating procedure. Acceptance criteria should be set for individual and total degradation products and impurities. For identification and qualification thresholds, refer to the appropriate guidance. All related impurities appearing at levels of 0.1 percent or greater should be specified. Specified impurities and degradation products are those, either identified or unidentified, that are individually listed and limited in the drug product specification. 1.16.5. Preservatives If preservatives, antioxidants, chelating agents, or other stabilizing excipients (e.g, benzalkonium chloride, phenylethyl alcohol, edetate) are used in the formulation, there should be a specific assay for these components with associated acceptance criteria (At a concentration of 0.10 percent or 1.0 milligram per day). 1.16.6. Pump Delivery Pump delivery volume to determine pump delivery volume of CPS Technology Platform spray pump (Aptar Pharma, Illinois, USA), 5 spray pumps were filled with 10 gm nasal spray. These were then primed, followed by 5 test actuations and weighed prior to and after each test actuation using analytical balance (Shimadzu, Japan). Pump delivery was determined using formula: • p𝑢𝑚𝑝 𝑑𝑒𝑙𝑖𝑣𝑒𝑟𝑦 = (𝑊1−𝑊2) 𝐷 • Where, W1 = Initial weight • W2 = Weight after actuation • D = Density of liquid formulation (1.032 g/ml) g . 1.16.7. Spray pattern For spray pattern determination, FDandC Blue No. 2 dye was dissolved in the formulated nasal spray in concentration such that it does not affect nasal spray properties. This was filled in nasal spray bottles, and the pumps were actuated World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 394 manually. The resultant spray was captured on a white cardboard sheet located at 3 or 6 cm above the tip of spray nozzle. The longest chord (LL) and shortest chord (LS) were measured across the spray pattern and ratio of LL to LS was also calculated. This ratio, defined as the ovality ratio, characterizes the general shape of each pattern. Each sample was tested in triplicate. [44] 1.16.8. Plume geometry Plume geometry was measured using a Spray VIEW™ NSP system and analyzed by Spray VIEW™ software version 3.6.1 (Proveris Scientific Corporation, USA). All units were actuated with an automated NSx Actuation Station. The Spray NSP combines laser sheet illumination and high-speed digital imaging and is designed specifically to characterize pharmaceutical nasal spray pumps. The plume geometry was characterized by the following metrics: spray angle (the angle of emitted plume measured from vertex of the spray cone and spray nozzle) and plume width (the width of plume at a given distance from the spray nozzle). 1.16.9. Droplet size distribution Droplet size distribution was determined by laser diffraction technique employing HELOS BR instrument with SPRAYER module and force actuator (Sympatech GmbH, Clausthal-Zellerfeld, Germany). Various instrumental parameters were varied and effect of such parameters in droplet size distribution of nasal spray was studied. The spraying angle was either 30°, 60° or 90° while the actuation force was kept 35 or 45 N. Actuation distance was set as 3 or 6 cm and hold time was kept either 1, 2 or 3 sec. Time resolved measurement was performed and data were analyzed by Fraunhofer theory. 1.16.10. Particle Size Distribution For suspension nasal sprays, the specification should include tests and acceptance criteria for the particle size distribution of the drug substance particles in the formulation. For example, microscopic evaluation can be used, and such an examination can provide information and data on the presence of large particles, changes in morphology of the drug substance particles, extent of agglomerates, and crystal growth. 1.16.11. Impurities and Degradation Products The levels of impurities and degradation products should be determined by a validated analytical procedure or procedures. Acceptance criteria should be set for individual and total impurities and degradation products. All related impurities appearing at levels of 0.1 percent or greater should be specified according to ICH guideline for impurities. [45] 2. Factors influencing nasal drug absorption Various factors moving the general bioavailability of drug that are administered through the nasal route. Those are physiochemical properties of the drug, the anatomical and physiological properties of the nasal cavity and also the kind and characteristics of nasal drug delivery system. 2.1. Physiochemical properties of drug • Molecular size • Enzymatic degradation in nasal cavity • Lipophilic-hydrophilic balance 2.2. Delivery effect • Drug distribution and deposition • Formulation (Concentration, pH) • Viscosity 2.3. Nasal effect • Environmental pH • Cold, rhinitis • Membrane permeability World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 395 2.4. Molecular size The molecular size of the drug affects absorption of the drug through the nasal route. The lipotropic drug has direct relationship between the relative molecular mass and drug permeation whereas water soluble compound shave inverse relationship. The speed of permeation is extremely sensitive to molecular size for compounds with MW ≥ 300 Daltons. 2.5. Enzymatic degradation in nasal cavity Nasal cavity having exo-peptidases and end peptidases, exo-peptidases. Exopeptidases capability to cleave peptides at their N and C terminal and endopeptidases like aminoalkanoic acid and amino acid, which might attack internal amide bonds. Drugs like peptides and proteins are having low bioavailability across the nasal cavity; therefore, this drug might have risk to endure catalyst degradation of the drug molecule within the lumen of the nasal cavity or throughout passage through the epithelial barrier. [46] 2.6. Lipophilic-hydrophilic balance The HLB nature of the drug affects the absorption method. By increasing lipophilicity, the permeation of the compound commonly will increase through nasal mucous membrane.Though the nasal mucous membrane was found to own some deliquescent character, it seems that this mucous membrane is primarily lipotropic in nature, and the lipid domain plays a very important role within the barrier operate of those membranes. Lipophilic drug like buprenorphine, androgenic hormone and 17a-ethinylestrogen are nearly fully absorbed once administered intranasal route. 2.7. Formulation (pH, Concentration) The pH of the formulation will have an effect on drug permeation. To avoid nasal irritation, the PH of the nasal formulation ought to be adjusted to 4.5–6.5 because of enzyme is found in nasal secretions, that is to blame for destroying bound microorganism at acidic pH. Underneath alkaline conditions, lysozyme is inactivated and the tissue is prone to microbic infection. In addition to avoiding irritation, it leads to getting economical drug permeation and prevents the expansion of microorganism. Concentration gradient plays vital role within the permeation method of drug through the nasal membrane because of nasal mucosal damage. 2.8. Viscosity A higher viscosity of the formulation will increase contact time between the drug and the nasal mucous membrane there by increasing the time for permeation. At identical time, extremely viscous formulations interfere with the traditional functions like ciliary beating or mucociliary clearance and therefore alter the permeability of drug. The viscosity of nasal spray is 80-500 CP. [47] 2.9. Drug distribution and deposition The drug distribution within the bodily cavity affects the potency of nasal absorption. The mode of drug administration may influence the distribution of drug in bodily cavity that successively can confirm the absorption potency of drug. The absorption and bioavailability of the nasal dose forms depend on the positioning of disposition. The anterior portion of the nose provides a protracted nasal residential time for disposition of formulation; it enhances the absorption of the drug. The posterior chamber of bodily cavity can use for the deposition of dose kind and drug is eliminated by the mucociliary clearance method and thus how’s low bioavailability. The positioning of disposition and distribution of the dose forms are depending on delivery device, mode of administration, physicochemical properties of drug molecule. 2.10. Environmental pH The environmental pH conjointly affects the potency of nasal drug absorption. The unionized lipotropic kind crosses the nasal epithelial barrier via transcellular route, whereas the additional lipotropic ionizing kind passes through the aqueous para cellular route. The environmental pH is 4.5-6.5. 2.11. Membrane permeability Nasal membrane permeability is that the necessary issue that affects the absorption of the drug through the nasal route. The water-soluble drugs and notably massive relative molecular mass drug like peptides and proteins are having the low membrane permeability are in the main absorbed through the endocytotic transport and by passive diffusion through the aqueous pores (i.e. tight junctions). World Journal of Biology Pharmacy and Health Sciences, 2025, 24(01), 378-398 396 2.12. Cold, rhinitis The symptoms hyper secretion, itching and instinctive reflex primarily caused by the viruses, microorganism or irritants. Inflammation could be a most often associated common unwellness, it influences the bioavailability of the drug. It’s caused by chronic or acute inflammation of the tissue layer of the nose. These conditions influence the absorption of drug through the mucous secretion membrane due the inflammation. [48] 3. Conclusion The nasal drug delivery systems are particularly effective because of nasal cavity offers large surface area and enhances drug absorption. It is non invasive drug delivery system. They improve bioavailability as compared to oral routes. The present study of nasal spray summaries possible method of formulation of nasal spray. The choice of method depends on the type of drug and its solubility. In formulation polymers are used to improve viscosity, control drug release, and increase nasal contact time. This review also discusses about evaluation of nasal spray for the effective management of allergic rhinitis, nasal polyps, chronic sinusitis, deviated nasal spectrum. This review discusses about the possible method of formulation of nasal spray. This study identify drug directly delivered into nasal mucosa and providing rapid onset of action and reducing side effect compared to oral medications. In this review Oxymethazolin, phenylephrine is describing as possible drug candidate. Compliance with ethical standards Acknowledgments We express our sincere thanks to Prof. Dr. A. V. Chandewar sir, the principal of P Wadhwani College of Pharmacy, Yavatmal for making available facilities in the college for making this project. With reverence, we sincerely accentuate our everlasting heartfelt gratitude and in arrange to our guide Prof Dr. Archana Kajale-Kulkarni Madam for her valuable guidance, keen interest, constructive criticism and encouragement throughout the period of project. It gives us immense pleasure to express our sincere thanks to our fellow classmate specially our friends, for maintaining a scientific and cordial atmosphere, and extending timely help at various stages of this project work. We extend our profound respect and heartfelt gratitude to our parents and family members for their blessings, moral support and ever encouraging attitude Finally, we thank to all those who helped us directly or indirectly in completion of our project. Disclosure of conflict of interest No conflict of interest to be disclosed References [1] Payal Ramesh Gaikwad, Sanjana Shridhar Walwante, Nandkishor Deshmukh, Dr. Swati Deshmukh, “Excipients Used In Nasal Spray Formulation”, Indo American Journal of Pharmaceuticals Sciences, 2025, 12(01), 249-256. [2] Falgun Bhuva and L.D. Patel, “Pediatric Nasal Spray Solution: Factorial Design Development and Evaluation”, Journal of Drug Delivery and Therapeutics, 2018, 8(5), 355-365. [3] Santosh Thorat, “Formulation and Product Development of Nasal Spray”, Scholars Journal of Applied Medical Sciences, 2016, 4(8D), 2976-2985. [4] Mr. Nilesh Bhaskar Khairnar, Ms. Rajeshwari K. Thokal, Dr. Gajanan S. 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