Intranasal Drug Delivery for Brain Targeting: An Updated Review of Emerging Strategies

Intranasal drug delivery is an ancient form of therapy which finds its roots in the ancient Indian medicinal science of Ayurveda. In Ayurveda, medicinal formulations are delivered via the nasal passage in a form of therapy known as Nasya Karma. In this form of therapy, a number of formulations such as oils, powders, extracts of herbs, vapours, and medicinal smoke are delivered via the nasal passage for the treatment of both localized and systemic diseases [1]. In the past, over thirty different forms of therapeutic practices have been described in the form of Nasya therapy for the treatment of a number of different diseases and disorders.  In modern pharmaceutical science, the intranasal route of drug delivery is considered a promising route for the delivery of drugs for both localized and systemic effects. The intranasal route is most commonly used for the treatment of localized diseases such as allergic rhinitis, sinusitis, nasal congestion, and the common cold. A number of different classes of drugs are delivered via the intranasal route, such as antihistamines, decongestants, corticosteroids, and antimicrobials for the symptomatic relief of localized diseases such as the common cold. [2] One of the significant benefits of using the nasal route is that the nasal mucosa is a highly vascular area, thereby facilitating the quick absorption of the drug into the bloodstream. The nasal cavity has a large surface area and a permeable membrane, thereby allowing a quick absorption of the drug, thus producing a quick therapeutic effect [3]. In addition, the nasal route of drug administration has an added advantage of avoiding first-pass metabolism, thereby increasing the bioavailability of a drug that is extensively metabolized when given orally. The other advantage of using the nasal route is that, unlike other routes, drug administration via the nasal route is not an invasive procedure, thereby making patient compliance quite easy. Unlike parenteral administration, intranasal administration is painless, thereby avoiding all complications associated with parenteral administration, such as pain, tissue damage, and transmission of blood-borne viruses such as hepatitis B and HIV [4].  Moreover, the nasal route has been identified as a promising route for the delivery of acid-labile substances, which include peptides, proteins, and hormones. These substances have poor bioavailability when given orally. In addition, substances with poor bioavailability or those that undergo extensive metabolism in the gut can be given nasally to improve their bioavailability. Drugs with poor bioavailability or those undergoing extensive metabolism in the gut can be given nasally to improve their bioavailability. The poor bioavailability or extensive metabolism of drugs in the gut can be improved by the nasal route [5]. This can be achieved by the use of permeation enhancers and mucoadhesive agents to improve drug absorption in the nasal mucosa.Recent advances in pharmaceutical technology have led to the development of innovative drug administration systems, which have improved the potential of the intranasal route in drug delivery. The innovative drug delivery systems include liposomes, cyclodextrin inclusion complexes, in situ gels, nanoparticles, microemulsions, and nanoemulsions, which have improved drug solubility and bioavailability, and drug release. The advanced drug delivery systems have improved the potential of the intranasal route in drug delivery [6].

2. Function and Anatomy of Nose

2.1. External Composition

The external Nose is the part of the nasal apparatus exposed to the external environment, and its function is to serve as the entrance for inhaled air. The external nose has a root, a dorsum, an apex, alae, and a columella. The nostrils, also known as the anterior nares, open to the nasal cavity. This structure acts as a protective mechanism, filters, and is aesthetically pleasing [7].

Figure 1 shows a representation of the anatomy of the nose. The internal and external structures of the nose are illustrated in the image, showing how the nose opens into the nasal cavity which is surrounded by nasal bones and cartilages. There are also the conchae of the nose, the superior, middle, and inferior conchae that are responsible for humidifying and filtering air. There are frontal and sphenoid sinuses shown as air cavities, and their role includes resonating the voice and draining the nasal cavity.

Fig. 1: Human nose anatomy and physiology showing internal structures of nasal cavity and sinuses

2.2. Nasal Skeleton

The nasal skeleton is made up of the bony and cartilaginous components of the nose. The bony part of the nose is made up of the nasal bones, the frontal process of the maxilla, and the perpendicular plate of the ethmoid. The cartilaginous part of the nose is made up of the septal cartilage, the lateral cartilages, and the alar cartilages. This framework is essential for maintaining patency and shape of the airway [8]. The figure 2 indicates the anatomical structures of the nasal septum which separates the nasal cavity into two parts. The septum consists of anterior septal cartilage and superior perpendicular plate of ethmoid bone.

Fig. 2: Anatomy of the Nasal Septum

2.3. Nasal orifice

The nasal orifices, or anterior nares, are the openings that provide for the entry of air into the nasal cavity. The anterior nares lead to the nasal vestibule is covered by stratified squamous epithelial tissue and vibrissae (nasal hairs). These hairs trap large dust particles and microbes, serving as the first line of defence [9].

2.4. Mucous membrane of the nose

 The nasal cavity is lined by a highly vascularized mucous membrane composed of pseudostratified ciliated columnar epithelium with goblet cells. This lining performs key functions such as:

• Humidification and warming of inspired air
• Mucociliary clearance of trapped particles
• Secretion of mucus for protection

The rich blood supply enhances heat exchange, while ciliary movement helps transport mucus toward the nasopharynx [10].

2.5. Olfactory epithelium

 The Olfactory epithelium region spans approximately 2,370 mm², situated partially on the nasal partition and partially over the superior nasal concha [11]. A vestigial structure known as Jacobson's organ, or the vomeronasal organ, appears as a blind pouch alongside the compartment. Inside humans, in existence definitive evidence of centralised connectivity for this organ, although it is functional in other mammals, such as rats [10]. The olfactory neuroepithelium comprises olfactory sensory neurons surrounded by supporting cells, which regulate ECF K+ levels essential for neuroelectric movement, and progenitor cells, which regenerate" the neuronal epithelium near about every six weeks" The sensory olfactory neurons are bipolar Neurons with Spherical Soma bodies and dendrites that have a Ciliary range of 10 to 23, each extending up to 200 µm, often overlapping with cilia from adjacent neurons. These cilia feature a characteristic nine-plus-two microtubule structure typical of motile cilia, although the central pair diminishes at the apex. The olfactory structure is remarkable in the neural network due to its uninterrupted contact with the surroundings and its potential to restore harmed or missing nerve cells.”  Olfactory sensory neurons transform into unmyelinated nerve fibres that connect within the olfactory bulb. Base cells, tiny angular cells connected to the basement layer of the membrane, serve as differentiated cells for recipient cells and auxiliary cells, potentially aiding in the recovery of tissue after viral injury. The lower lamina propria houses olfactory nerve fibres and Bowman’s tubular-alveolar glands. "As nerve fibres enter the cribriform layer, they are wrapped by Schwann cells. Myelinated Schwann cells contain 5 to 10 fibres, sometimes as many as 100. Olfactory sensory neurons have a bipolar configuration, and approximately 15,000 olfactory receptor neurons synapse onto a single mitral or tufted cell within the olfactory bulb...The olfactory bulb measures 12.2 mm in length (ranging from 6 to 16 mm) . Mitral and tufted cells project a single primary dendrite into a specific glomerulus, while also extending several secondary dendrites into the external plexiform layer... cells surrounding the glomeruli, granular neurons, and cells with short axons are interneurons that connect the glomeruli. Granular neurons bind to Olfactory bulb neurons and restrict them. The primary axons from the olfactory tract originate in the Olfactory bulb neurons or their bundles and form pathways that extend to the olfactory tubercle, with subsequent projections reaching the amygdala, prepiriform cortex, anterior olfactory nucleus, and entorhinal cortex [11]. The structure of the olfactory epithelium in the nasal cavity is shown in Figure 3. This consists of olfactory receptor cells (sense receptors), which have cilia to identify smells; supporting cells to provide support and basal cells for renewal. Below this, there is lamina propria, which has Bowman’s glands, secreting fluids to dissolve odorants.

Fig. 3: Structure of the olfactory epithelium in the nasal cavity

2.6. Ethmoid sinuses

 The ethmoid sinuses consist of multiple air-filled cavities (ethmoidal air cells) The sinuses are situated between the nasal cavity and the eyes, and are categorized into anterior, middle, and posterior groups.  These sinuses:

• Reduce skull weight
• Contribute to voice resonance
• Assist in mucus production and drainage

They open into the nasal cavity and are lined by respiratory mucosa [12]

 2.7. Sphenoid sinus

 The sphenoid sinus is situated deep within the skull. in the body of the sphenoid bone, posterior to the nasal cavity. It drains into the sphenoethmoidal recess. Due to its proximity to critical structures such as the pituitary gland and optic nerve, it has clinical importance. It also contributes to air humidification and resonance [13]

3. Potential factors affecting the nasal delivery

This route has recently gained attention as a promising alternative systemic and brain-targeted Drug delivery is enhanced because of the extensive surface area available, high vascularisation, and Bypassing hepatic first-pass metabolism. However, there are many physiological, physicochemical, and formulation-related factors that can affect the efficiency of drug absorption. It is important to understand these factors to design an efficient drug delivery system.

3.1. Nasal Physiology and Blood Flow

This is because the nasal cavity is characterized by its extensive surface area with rich vascularization membrane. It increases the rate of absorption+ of the drug into the systemic circulation. The blood supply to the drug in the respiratory region increases the permeability of the drug through the nasal membrane. It enables the drug to act rapidly. Differences in blood flow to the nasal region may affect the rate of drug absorption [14] The nasal mucous membrane has a good blood supply, which makes it suitable for drug absorption. Improved blood circulation enhances the efficiency of drug absorption and facilitates its distribution throughout the body. The blood flow inside the nose is responsible for heat adjustment and moisturization of inhaled air, too [15]

3.2. Mucociliary Clearance

Mucociliary clearance serves as a key defence system of the nasal cavity that removes inhaled particles and drug formulations. The coordinated movement of cilia transports mucus and trapped substances toward the nasopharynx, thereby reducing the residence time of drugs in the nasal cavity. Rapid mucociliary clearance may limit drug absorption and reduce bioavailability [16]. Mucociliary clearance can be described as the removal process occurring in both the upper and lower airways, driven by the interaction between mucus and the rhythmic beating of cilia. The respiratory mucosa produces approximately 200 g to 2 L of mucus daily [36] and ciliary beating. The efficiency of this process depends not only on the biochemical, physical, and chemical characteristics of mucus but also on the number, structure, and synchronized movement of cilia. Nasal mucus is composed of a weak, flexible, three-dimensional gel-like network formed by hydrated mucin molecules. This structure is stabilized through disulfide linkages and additional secondary chemical interactions between ions. The mucus environment is slightly acidic, typically maintaining a pH range of 5.5–6.5, which helps in preventing infections and provides limited buffering capacity as a chemical buffer. Due to the presence of hydroxyl (–OH) groups and oligosaccharide chains, nasal mucus carries a net negative charge. Its highly hydrated nature and glycoprotein network allow it to form nonspecific interactions with various substances, including pathogens and drug molecules. The viscosity, adhesiveness, and cohesiveness of mucus are largely determined by glycoproteins, which consist of protein cores linked to oligosaccharide chains, typically with a molecular weight around 200 kDa. These components also contribute to the overall negative charge of nasal mucus. [17].

3.3. Enzymatic Degradation

The nasal mucosa contains variety metabolic enzymes including proteases, peptidases, and cytochrome P450 enzymes, which can metabolize drugs before systemic absorption. This enzymatic activity can significantly affect the stability and bioavailability of certain drugs, especially peptide and protein-based therapeutics [18] Enzymes present in the nasal cavity may reduce the effectiveness of administered drugs by breaking them down. Peptide- and protein-based drugs are especially susceptible, as aminopeptidases and proteases can degrade them. Additionally, enzymes such as serine and cysteine endopeptidases cleave internal peptide bonds, while exopeptidases (including mono- and di-aminopeptidases) act on the terminal ends of peptide chains. [19]

3.4. Physicochemical Properties of the Drug

Similarly, the characteristics of the drug, such as the molecular weight, lipophilicity, solubility, and degree of ionization (pKa value), affect the nasal absorption process. In general, lipophilic drugs with low molecular weights are easily absorbed through the nasal membrane, while hydrophilic compounds with high molecular weights are poorly absorbed [20].

3.5. Formulation Factors

The formulation parameters such as pH, viscosity, osmolarity, drug concentration, and presence of absorption enhancers or mucoadhesive polymers, etc., also have a significant impact on drug delivery through the nasal route. All these factors can influence drug stability, permeability, and residence time in the nasal cavity [21].

3.6. Pathophysiological Conditions

Nasal disorders like rhinitis, sinusitis, allergies, and infections may cause disruption in the normal physiological state of the nasal mucosa. These disorders may interfere with mucociliary clearance, mucus secretion, and membrane permeability, which may in turn affect the efficiency of drug delivery in the nose [22].

4.Physiology of the respiratory mucosa

The nasal cavity has a number of important physiological functions that facilitate breathing and protect the lower respiratory system. An average of 10,000-12,000 litres of air is passed through the nasal passages daily in adults, where air is warmed, humidified, and filtered before reaching the lungs [23] The nasal mucosa consists of pseudostratified ciliated columnar epithelium that has goblet cells and mucous glands. The mucous glands produce mucus, which traps inhaled particles such as dust, allergens, and microorganisms.. The coordinated beating of cilia transports this mucus toward the nasopharynx for elimination, a process known as mucociliary clearance [24] The nose and paranasal sinuses also function as a resonance chamber for speech and contribute to the production of nitric oxide (NO), which plays an important role in host defence, antimicrobial activity, and regulation of pulmonary function In addition, the nasal cavity acts as a chemosensory organ, detecting irritants and environmental chemicals that trigger protective reflex responses such as sneezing and increased mucus secretion.

4.1Cleaning Function

The cleaning function of the respiratory mucosa is primarily carried out by the mucociliary clearance (MCC) system, which serves as a key innate defence mechanism of the upper respiratory tract. It involves the coordinated interaction between nasal mucus and ciliated epithelial cells. Inhaled air contains dust, pathogens, and particulate matter, most of which are trapped in the sticky mucus layer covering the nasal epithelium. The cilia beat in a synchronized, wave-like (metachronous) motion, propelling the mucus along with trapped particles toward the nasopharynx, where it is either swallowed or expelled [25] Larger particles such as pollen, dust, and environmental debris are trapped by the nasal hairs (vibrissae) and mucus layer covering the respiratory epithelium. Although filtration efficiency decreases for smaller particles, the nasal mucosa still removes a considerable proportion through mucociliary transport mechanisms. When aerosolized liquids are inhaled through the nose, approximately 90–95% of these particles are removed in the upper respiratory tract, whereas mouth breathing reduces this clearance efficiency significantly [17] As a result, the dose of inhaled gases reaching the pulmonary alveoli is much lower during nasal breathing than during oral breathing. This filtration and clearance mechanism provides an important protective barrier for the lower respiratory tract.

4.2 Sneeze Reflex

Sneezing is an important protective reflex that helps remove irritants and foreign particles from the nasal cavity. This reflex is mediated by the exposure of irritant substances to sensory receptors in the nasal mucosa, especially histamine H1 receptors on trigeminal nerve endings [26] The sensory signals are transmitted through the trigeminal nerve, which reaches the sneeze center in the brainstem. The process starts with a deep inhalation, along with closure of the glottis. Then, there is a strong contraction of the chest and abdominal muscles. Finally, there is a sudden opening of the glottis, which causes air to rush through the nose and mouth, carrying with it mucus and other particles. The speed of this rushing air can go up to 40-50 m/s [27]

4.3 Nasolacrimal Reflex

The nasolacrimal reflex occurs when chemical or mechanical stimulation of the nasal mucosa results in increased lacrimal gland secretion, leading to tearing of the eyes. This reflex serves as a protective response to irritants and allergens entering the nasal cavity (Baroody, 2011).[29] The reflex pathway involves afferent sensory neurons of the trigeminal nerve, which transmit impulses to The superior salivatory nucleus is located within the brainstem. From there, Parasympathetic fibres travel via the greater petrosal Nerve and pterygopalatine ganglion to reach the lacrimal gland. Activation of this neural pathway stimulates lacrimal secretion. Stimulation of one nasal cavity generally produces a stronger ipsilateral response, although a weaker response may also occur on the contralateral side [28]

4.4 Nasal Cycle

Nasal cycle is defined as a spontaneous and reciprocal change of nasal congestion without a change of the total nasal airflow. R. Kayser first described it in 1895 [29]. According to literature, the nasal cycle can be detected in 70–90% of humans [29] [30]. The nasal cycle is regulated by the hypothalamus [31], with efferents running along the vidian nerve and showing an asymmetrical activity in controls[32]. Changes of volume in the erectile tissue of the septum, the inferior and middle turbinates, and even in the paranasal sinuses can be demonstrated. [33]

5. Nose to Brain Drug Delivery System

Nose-to-brain Drug Delivery System is an emerging non-invasive strategy designed to deliver therapeutic agents directly from the nasal cavity to the brain, thereby bypassing the blood–brain barrier (BBB). The BBB is a highly selective barrier formed by tight junctions between endothelial cells, which restricts the entry of most drugs into the central nervous system (CNS). As a result, nearly 98% of small molecules and almost all large biomolecules fail to reach the brain in therapeutic concentrations through conventional routes such as oral or intravenous administration.[34] The intranasal route provides a unique anatomical connection between the nasal cavity and the brain through the olfactory and trigeminal nerve pathways, enabling direct transport of drugs to the CNS. In the case where the drug is administered intranasally, it is possible for the drug to be absorbed through the nasal membrane and subsequently carried via these neuronal pathways to the tissues in the brain, thus avoiding the systemic circulation and the BBB,[35] This approach also has several advantages, such as quick onset of action, bypassing the hepatic first-pass effect, increased bioavailability, and increased compliance due to the non-invasive route. In addition, the nasal passage is known to have a large surface area, high vascularisation, and permeability, which enhance the absorption of the drug[36]. Despite these advantages, nose-to-brain delivery is associated with several physiological and formulation problems. These include a limited dose capacity of the nasal cavity (usually 25-200 μL), rapid mucociliary clearance, enzymatic degradation, and limited residence time in the nasal cavity, which may impair drug absorption and therapeutic efficiency. In addition, physicochemical properties of a drug, including molecular weight, solubility, and lipophilicity, play a crucial role in nasal absorption and brain targeting [37]. Figure 4 presents a lateral view of the nasal cavity along with other associated structures. The air moves into the nose from the nasal vestibule through the nasal cavity, which has the conchae (turbinates) that expand its surface area for warming and moistening of air. Frontal and Sphenoid sinuses are hollow spaces filled with air to make the skull light and provide voice resonance. The nasal cavity structure is provided by the ethmoid bone. Below it lies the oral cavity containing the tongue and palatine velum..

Fig.4: Sagittal Section of Nasal Cavity

5.1 Concept of Nose-to-Brain Drug Delivery

The term 'Nose to Brain Drug Delivery' has recently been proposed as a new, non-invasive method of drug delivery to the CNS. The conventional drug delivery systems, which include both oral and intravenous routes of drug administration, are found to be ineffective in achieving therapeutic drug concentration in the Brain due to the presence of a blood-Brain barrier (BBB). The BBB is a selective physiological barrier composed of tightly sealed endothelial cells, which prevents most of the drugs from crossing over into the Brain, thus limiting the treatment of CNS disorders [38]. Intranasal administration provides a unique opportunity for targeting the brain because the nasal cavity and the central nervous system are directly connected via the olfactory and trigeminal nerve pathways. It is possible to cross the BBB and target the brain by using the neuronal pathways. This is helpful in the rapid transport of the drug to the target site, which enhances the efficiency of the drug. Nasal Cavity is the best site for drug delivery because it provides a large surface area with high vascularization and permeability. When the drug is placed in the upper part of the nasal cavity, it can be delivered to the brain via the olfactory bulb using the olfactory pathway. It is possible to transport the drug to the different parts of the brain using the trigeminal nerve pathway by placing the drug in the respiratory region. [39]

5.2 Anatomy of the Nasal Cavity Relevant to Brain Targeting

The nasal cavity is an important site for nose-to-brain delivery, as it acts as an anatomical route between the external environment and the central nervous system. The nasal cavity is an important route for the absorption of various physiological functions, with an absorptive surface area of about 150-200 cm². The nasal route is also well-perfused, which is advantageous for the quick absorption of the administered dose. The nasal cavity is anatomically divided into three main areas on the basis of its anatomical and functional characteristics. The areas include the Vestibular region, the respiratory region, and the olfactory region. Each region is characterized by unique structural features. [40, 41]

5.2.1. Vestibular Region

The vestibular region is the front part of the nasal cavity, located immediately inside the nostrils. This region is lined with stratified squamous epithelium. The structures present in the vestibular region include hair follicles, sebaceous glands, and mucus glands. The main function of the vestibular region is the filtration of the inhaled material, such that the material is not allowed to enter the respiratory system. The surface area available for the passage of the material is less, as the epithelial layer is thick. Therefore, the vestibular region is not considered an important region for the passage of the drug. [42]

5.2.2. Respiratory Region

 The respiratory region is the largest portion of the nasal cavity and accounts for approximately 90% of the total nasal surface area. It is lined by pseudostratified ciliated columnar epithelium with the presence of goblet cells that produce mucus. This region is highly vascularized and plays an essential role in warming, humidifying, and filtering inhaled air. Due to its extensive surface area and abundant vascularization, the respiratory region serves as is the primary site for systemic drug absorption through the nasal route. However, drug delivery through this region generally results in systemic circulation rather than direct brain targeting. The presence of mucociliary clearance mechanisms can also reduce drug residence time and limit absorption efficiency [ 43]

5.2.3. Olfactory Region

The olfactory region is located at the roof of the nasal cavity and represents only about  5–10% of the total nasal surface area. Despite its small size, this region is extremely important for direct nose-to-brain drug delivery. It contains specialised olfactory sensory neurone that extend from the nasal mucosa to the olfactory bulb in the brain. Drugs deposited in the olfactory region can be transported directly to the brain via olfactory neuronal pathways, bypassing the blood–brain barrier. This unique anatomical connection makes the olfactory region the most important site for brain-targeted nasal drug delivery. However, reaching this region effectively remains challenging due to its limited accessibility and location deep within the nasal cavity .[41, 44]

5.3 Mechanisms of Nose-to-Brain Drug Transport

The nasal cavity provides a unique approach that enables direct drug transport to the brain, circumventing the restrictive blood–brain barrier (BBB). Drugs administered intranasally can be absorbed across the nasal epithelium and transported to the central nervous system through different mechanisms. Among these mechanisms, transcellular transport and paracellular transport are the two major pathways through which drugs cross the nasal epithelial barrier. The efficiency of these pathways depends on the Physiochemical Properties of the drug and the structural characteristics of the nasal mucosa.

5.3.1. Transcellular Transport

Transcellular transport refers to the movement of drug molecules through the epithelial cell of the nasal mucosa. In this mechanism, the drugs move through the apical membrane, the cytoplasm, the basolateral membrane, the tissues, and the neuronal pathways. This mechanism is generally through the process of passive diffusion. This mechanism is favoured by those drugs that are lipophilic in nature, i.e., the ability of the drug to dissolve in the lipid layer of the cell membrane is high. The permeability of small, lipophilic molecules with low molecular mass is generally good for the transcellular pathway. In the context of nose-to-brain delivery, the drugs absorbed through the transcellular pathway can also reach the olfactory neurons as well as the nerve endings of the trigeminal nerve, thus reaching the brain. Therefore, the transcellular pathway is considered the most important mechanism for the absorption of the drug through the nasal route [45, 46]

5.3.2. Paracellular Transport

Paracellular transport is the transport of the drug through the space between two adjacent cells using the tight junction pathway. In this Pathway, the drug diffuses through the space between the cells. Paracellular transport is restricted to small hydrophilic drug molecules because the Tight junctions between the cells in the nasal membrane limit the transport of larger drug molecules. The permeability of the Paracellular pathway is low compared to the transcellular pathway because the Tight junctions between the cells act as a barrier to the. The entry of Potentially harmful substance. Nevertheless, the permeation enhancers, surfactants, and mucoadhesive polymers can be used to facilitate the Paracellular transport. This pathway is being studied to improve the delivery of the drug to the brain. [47, 48]

5.4 Nose-to-Brain Pathways

Nose-to-brain drug delivery has emerged as a promising route for the delivery of therapeutic agents to the central nervous system (CNS) in a non-invasive manner. The nasal cavity has been found to be anatomically linked to the brain through multiple neural and vascular routes, which allow the drug to avoid the blood–brain barrier (BBB) during intranasal administration. The major routes of nose-to-brain transport include the olfactory neural route, the trigeminal nerve route, and the vascular route. These routes help in the direct or indirect transport of the drug from the nasal mucosa to the brain.

5.4.1. Olfactory Neural Pathway

The olfactory neural pathway is considered to be the main route for direct drug delivery. The direct drug delivery from the nasal cavity to the brain occurs in the olfactory region, which is located in the upper portion of the nasal cavity and consists of specialized structures that help in drug delivery. The drug delivery in this region occurs through specialized olfactory receptor neurons, which extend from the nasal epithelium to the brain. The drug can be transported intracellularly or extracellularly Once it reaches the olfactory bulb, the drug is transported even further into the central nervous system. Once this occurs, the drug is able to distribute itself into other parts of the brain, such as the cerebral cortex and limbic system. This method allows for the rapid and direct delivery of drugs into the brain without having to cross the BBB and is especially useful for the treatment of Alzheimer’s and Parkinson’s diseases. [49] As seen in figure 5 below, the transport process of substances, whether biomolecules or drugs, into the brain through the olfactory route after nasal delivery is depicted. The molecules will pass through the mucosal membrane and move across the olfactory epithelium using either transcellular, paracellular, or intracellular pathways. They will then move from the olfactory nerve to the olfactory bulb and cerebrospinal fluid (CSF).

Fig. 5: Olfactory Pathway

5.4.2. Trigeminal Nerve Pathways

 The trigeminal nerve pathway is yet another significant pathway for nose-to-brain drug delivery. The trigeminal nerve innervates the respiratory and olfactory regions of the nasal cavity and extends to different parts of the brain, including the brainstem and spinal cord. Drugs absorbed through the nasal mucosa can be transported along the branches of the trigeminal nerve to reach deeper brain structures. Compared with the olfactory pathway, the trigeminal pathway mainly facilitates drug transport to the brainstem and posterior brain regions. This pathway, therefore complements the olfactory route and enhances overall drug distribution within the CNS [50] Figure 6 provides a diagrammatic representation of the path taken by biomolecules when delivered into the brain via intranasal administration without passing through the blood-brain barrier. Figure 6 (left) gives an illustration of intranasal drug administration together with the anatomical association between the nasal area and the trigeminal nerve, whereas Figure 6 (right) shows a close-up view of the delivery of drugs across the respiratory epithelium and cribriform plate to the brain stem.

Fig. 6: Trigeminal Nerve Pathways

5.4.3. Vascular Pathway

The vascular pathway involves drug absorption through the highly vascularized nasal mucosa, particularly in the respiratory region. After absorption, drugs enter the systemic circulation through the nasal blood vessels and may subsequently reach the brain through the bloodstream. Although this pathway does not provide direct transport to the brain like neuronal pathways, it contributes to drug delivery to the CNS when drugs are able to cross the BBB after entering systemic circulation. However, systemic absorption may lead to reduced targeting efficiency and potential systemic side effects. Therefore, modern formulation strategies often aim to enhance direct neuronal transport while minimizing systemic exposure [51]

Table 1 summarizes the major nose-to-brain drug transport pathways, highlighting their transport route, speed, targeted brain regions, and relative importance in intranasal brain delivery.

Table No 1: Pathways for Intranasal Drug Delivery to the Brain

Figure 7 illustrates the major pathways involved in intranasal nose-to-brain drug delivery, including olfactory, trigeminal, and systemic transport routes that facilitate drug targeting to brain tissue while partially bypassing the blood–brain barrier (BBB).

Fig. 7: Multiple pathways involved in nose-to-brain drug delivery via intranasal administration.

6. Formulation Approaches for Nose to Brain Drug Delivery

The effectiveness of nose-to-brain drug delivery largely depends on the formulation strategy used to overcome physiological barriers of the nasal cavity such as mucociliary clearance, enzymatic degradation, and limited residence time. Several traditional and innovative approaches to formulation design have been explored to improve the stability, permeability, and targeting efficiency of the administered drug in the brain. The approaches focus on the improvement of the absorption of the administered drug through the nasal membrane and the direct delivery of the drug to the CNS [52]

6.1. Conventional Nasal Formulations

The conventional nasal dosage forms include nasal solutions, suspensions, and powders. These dosage forms can be easily formulated and offer rapid drug absorption because of the highly vascular nature of the nasal cavity. However, these dosage forms have some disadvantages, which include the short residence time and rapid mucociliary clearance. For these dosage forms to be more efficient, they can be formulated with enhancers or mucoadhesive agents to increase drug retention in the nasal cavity. [53]

6.2. Mucoadhesive Formulations

Mucoadhesive drug delivery systems are designed to adhere to the mucosal surfaces, thereby increasing the retention time and absorption of the drug. Polymers such as chitosan, Carbopol, and hydroxypropyl methyl cellulose (HPMC) are generally used for mucoadhesive systems. Polymers have also shown an improvement in the permeability of the drug by interacting with the mucosal surfaces and temporarily opening the tight junctions of the epithelial cells. Therefore, mucoadhesive systems have shown a significant improvement in the bioavailability of the drug and the efficiency of brain targeting [54]

6.3. Nano-Based Drug Delivery Systems

Nanotechnology-based drug delivery formulations have also been highlighted for the delivery of the drug to the brain via the nose. They can improve the stability, permeability, and targeting efficiency of the drug. Nano-emulsion, polymeric nanoparticles, and solid lipid nanoparticles can be referred to as Nanocarriers. They can entrap the drug, which can be shielded against degradation and environmental factors. They can protect the drug from enzymatic degradation in the nasal cavity. Moreover, the size of the drug is small, which can improve the surface area for absorption and targeting. [55]

6.4. Liposomal and Vesicular Systems

Liposomal formulations and other vesicular systems such as niosomes and transfersomes have also been explored for intranasal drug delivery. These systems consist of lipid Bilayer vesicles are capable of simultaneously entrapping both water-soluble (hydrophilic) and fat-soluble (lipophilic) drugs. Liposomes can enhance drug penetration through the nasal mucosa and improve drug stability. Furthermore, their biocompatibility and ability to fuse with biological membranes make them promising carriers for delivering drugs directly to the brain [56].

6.5. Nano-emulsions

Nano-emulsions (NEs) differ from microemulsions in that they are essentially conventional emulsions with extremely small droplet sizes and a narrow particle distribution. These systems are thermodynamically unstable and consist of two immiscible liquid phases. Nano-emulsions may exist as either water-in-oil (W/O) or oil-in-water (O/W) types, with O/W systems being particularly valuable for pharmaceutical and drug delivery applications. Similar to microemulsions, surfactants and co-surfactants are incorporated to enhance stability during formulation. Various techniques are employed for the preparation of nano-emulsions. These include low-energy methods such as phase inversion composition, phase inversion temperature, and solvent displacement, as well as high-energy methods like high-pressure homogenization and ultrasonication. In high-pressure homogenization, the oil and aqueous phases are driven through a narrow gap under elevated pressure, resulting in the formation of fine droplets; increasing the pressure further reduces droplet size. The micro fluidization technique also utilizes high pressure, where a specialized device forces the emulsion through microchannels to produce a uniform nano-sized dispersion [57].

6.6. Micro-emulsion

Microemulsions are thermodynamically stable, isotropic and transparent dispersions of oil, water, surfactant, and often a co-surfactant. They typically have droplet size range of 10-100, which distinguishes them from conventional emulsions. Due to their small droplet size and high surface area, microemulsions provide enhanced drug solubilization and improved bioavailability, making them highly suitable for drug delivery applications  [58] Microemulsions are classified into different types based on their composition, including oil-in-water (O/W), water-in-oil (W/O), and bicontinuous systems. The formation of microemulsions requires a proper balance between hydrophilic and lipophilic components, which is often achieved using surfactants such as Tween or Span, along with co-surfactants like ethanol or propylene glycol. These components help in reducing interfacial tension and facilitate the spontaneous formation of the microemulsion system [59].

Figure 8 presents the commonly explored formulation approaches for intranasal nose-to-brain drug delivery, including nanoemulsions, microemulsions, liposomes, lipid and polymeric nanoparticles, in situ gels, and nasal sprays designed to enhance brain targeting efficiency.

Fig. 8: Formulation Approaches for Nose to Brain Drug Delivery