One of the main limitations associated with nasal absorption is the rapid removal of a drug from the nasal cavity by ciliated cells. The cylindrical cilia lining the surface of the nasal mucosa sway at a speed of 5∼6 mm/min in order to move mucus from the nasal cavity to the pharynx and to eliminate substances adhered to the surface of the nasal mucosa. Although this process is a protective mechanism for maintaining optimal respiratory system functionality, it can also shorten the contact time between a drug and the nasal mucosa, directly affecting the efficiency of drug absorption through the nose, as a drug molecule typically remains within the nasal cavity for a period of approximately 20–30 min after administration (Du et al., 2023). To counteract the effects of this clearance mechanism, it is usually possible to extend the drug adhesion time and increase drug absorption by selecting appropriate dosage forms, using bioadhesive materials, or modifying the surface of drug carriers, such as nanoparticles (Badran et al., 2023), liposomes (Kannavou et al., 2023), and microemulsions (Pailla et al., 2022) with specific ligands.

Efflux mechanisms involving transport proteins expressed in the nasal mucosa, such as multidrug resistance protein 1, breast cancer resistance protein, and P-glycoprotein (P-gp), can limit the absorption of certain drugs. Therefore, inhibiting the synthesis and expression of these proteins can reduce drug clearance (Chen et al., 2018). For example, a previous study demonstrated that P-gp plays an important role in drug absorption and efflux in the nasal cavity, and treatment with PSC-833, a specific P-gp inhibitor, increased the amount of quinidine (a P-gp substrate used as a model drug) reaching the brain via the nasal nerves (Bors et al., 2020).

Many enzyme systems catalyze the biological processes occurring within the nasal mucosa; these systems include cytochrome enzyme subunits, epoxidases, polymerases, peptidases, and proteases, all of which can lead to drug degradation in the nasal cavity, producing a “pseudo-first pass effect” that limits the amount of peptide- and protein-based drugs that might otherwise enter the brain (Oliveira et al., 2016). Administration of enzyme inhibitors can reduce the expression or activity of enzymes, thereby increasing drug uptake (Khatri et al., 2023).

The abundance of capillaries in the nasal cavity can increase the amount of a drug being absorbed into the bloodstream, resulting in high drug concentrations in the general circulation. However, this also reduces the probability of direct drug entry into the brain and increases the likelihood of side effects (Kumar et al., 2016). The use of vasoconstrictors at the administration site can, to some extent, prevent excessive drug diffusion into the bloodstream, thereby increasing brain-targeted drug delivery.

Under normal circumstances, a higher molecular weight will lower the efficiency of drug absorption (Fortuna et al., 2014). For lipid-soluble drugs, the rate of absorption across the nasal mucosa is nearly 100%; however, these rates are also affected by the molecular weight of a drug, with the absorption efficiency being significantly reduced when the molecular weight exceeds 1 kDa. For macromolecular water-soluble drugs, the concentration of drugs entering the CSF decreases as the relative molecular weight increases. In addition, the absorption efficiency of polar drugs is affected by the molecular weight; for example, when the molecular weight of a polar drug is less than 300 Da, the absorption efficiency is mostly unaffected by the drug’s physical and chemical properties, whereas the absorption efficiency is highly affected by the physical and chemical properties of a drug whose molecular weight exceeds 300 Da (Appu et al., 2016).

Before a drug can be absorbed through the nasal mucosa, it must first dissolve in nasal secretions. In terms of composition, water accounts for 90% of the components of nasal secretions, with the remainder comprising small amounts of mucin, proteins, inorganic salts, and lipids, among other factors (Hussain et al., 2023). Therefore, drugs with high water solubility will also be soluble in nasal secretions. However, for drugs with low water solubility, carriers such as cyclodextrins (De Gaetano et al., 2022), microemulsions (Pires et al., 2021), and nanoparticles (Abla and Mehanna, 2023) can be selected as drug delivery vectors, allowing the carrier instead of the drug to come into direct contact with the nasal mucosa. The shells of these carriers have good hydrophilicity, which improves their solubility in mucus.

The smooth and rapid absorption of drugs across the mucosal layer is dependent on their liposolubility. Usually, drugs with high lipid solubility have good compatibility with the nasal mucosa and are more likely to be absorbed. However, the high fat solubility of a drug can also be detrimental as it can facilitate entry into the general circulation after absorption through the nasal cavity, which is not conducive for drug entry into the brain (Chen et al., 2022; Tanna et al., 2023).

In general, drugs with an appropriate viscosity should be more likely to remain in contact with the nasal mucosa for longer periods of time, thereby improving the absorption efficiency (Bseiso et al., 2022). However, a previous study that explored the effect of viscosity on absorption efficiency of metoclopramide hydrochloride drugs reported that although the retention time of a drug in the nasal cavity was prolonged as the viscosity increased, the absorption efficiency actually decreased (Zaki et al., 2007). Most new drug carriers, such as microspheres, gels, and nanoparticles, have been developed with an appropriate drug viscosity in mind, improving both the retention time of drugs in the nasal cavity as well as the absorption efficiency.

Both the pH of a nasal preparation and the composition of the surface of the nasal cavity affect the dissolution, absorption, and penetration of a drug, with the optimal absorption occurring when a drug is in a non-dissipative state (Yu et al., 2011). The pH of nasal secretions is approximately 5.5–6.5, and preparations with a pH too far outside this range will irritate the nasal cavity (England et al., 1999). Ideally, the pH of the nasal cavity should be maintained at approximately 4.5–6.5 for optimal buffering.

A change in osmotic pressure not only causes the contraction or relaxation of nasal epithelial cells and affects drug absorption, but it may also exacerbate nasal mucosal edema and reduce the beat frequency of ciliated cells in the nasal cavity (Lemoine et al., 2005). Any drugs administered via the nasal cavity should be isotonic with the nasal mucosa (i.e., equivalent to 0.9% sodium chloride solution).

Common formulations currently used for the nasal administration of drugs include nasal drops, sprays, powders, gels, microspheres, membranes, emulsions, liposomes, nanoparticles, and micelles (Khan et al., 2017). The physical properties of a drug delivery system can affect the dissolution and retention time of drugs in the nasal cavity. Nasal sprays generally result in significantly higher bioavailability of a drug compared with that of drugs administered via nasal drops, which are quickly cleared by nasal cilia. In contrast, drugs administered via nasal sprays are mainly deposited within the front portion of the nasal cavity, with only a small proportion being slowly cleared into the throat, thereby extending the retention time of drugs in the nasal cavity, facilitating absorption, and improving the bioavailability (Kumar et al., 2017). Powder-based formulations tend to result in stronger and more prolonged contact with the mucosa than solution-based formulations, leading to higher concentration gradients on both sides of the mucosa, thereby increasing drug absorption and brain bioavailability. Many other new dosage forms, such as gel or microsphere preparations, emulsions, liposomes, nanoparticles, and micelles are also conducive to improving the nasal absorption of drugs (Marcello and Chiono, 2023). In summary, an appropriate dosage form should be selected based on the aforementioned specifications on a case-by-case basis depending on the properties of the drug being administered.

Some commonly used preservatives in nasal preparations include benzalkonium chloride, ethylenediaminetetraacetic acid, ethylparaben, and thiomersal. Improper selection of a preservative can affect the absorption of drugs across the nasal mucosa (Li et al., 2018). Lipophilic preservatives such as ethylparaben can reversibly accelerate or reduce the frequency of movement of ciliated cells in the nasal cavity, whereas polar preservatives, such as benzalkonium chloride, tend to reduce the movement of cilia in the nasal cavity.

Typically, a higher dosage of a drug will lead to greater absorption and improve the efficacy. However, higher drug concentrations may irritate the nasal mucosa. Moreover, the volume of the nasal cavity is limited, and a dosage that is too high can lead to overflow from the nostrils or entry into the pharynx, causing discomfort. According to a previous study, the appropriate nasal administration volume is 0.05–0.15 mL, and the maximum volume should not exceed 0.20 mL (Mittal et al., 2014).

For humans, the method of administration primarily depends on the dosage form (Krishnan et al., 2017). When using nasal drops, for example, the head should be tilted back at an appropriate angle before the medication is administered. Sprays should be directly administered into the nasal cavity, and a plaster must be applied to the inner wall of the nasal cavity. In experimental animals, medications are usually administered directly.

Pz-peptidase has been shown to promote drug permeability, and the enzyme can instantly and reversibly induce the opening of tight junctions (Chikuma et al., 1993).

Cell-penetrating peptides are short peptides that can penetrate the cell and/or nuclear membrane to guide any connected peptides, proteins, or other bioactive molecules into cells (Kamei, 2017). Although the precise transmembrane mechanism of cell-penetrating peptides is not fully understood, the effects are likely mediated via signal transduction pathways and endocytosis (Kamei et al., 2021).

The cations present in the amino groups of chitosan can bind to anions in the mucosa, thereby improving the permeability of epithelial cell membranes and promoting the opening of the tight junctions between epithelial cells and enhancing drug absorption (Shim and Yoo, 2020). Chitosan functions as a mucosal adhesive and has a good safety profile, which has led to it being extensively investigated in recent years for its potential therapeutic applications (Hard et al., 2023).

Cyclodextrins are cyclic compounds composed of D-glucose molecules connected by 1,4-glycosidic bonds; they are water-soluble, non-reducing, molecules that take the form of a white crystalline powder (Rassu et al., 2021). Commonly used α-, β-, and γ-cyclodextrins are composed of six, seven, and eight glucose molecules, respectively (Papakyriakopoulou et al., 2021). The unique spatial structure of cyclodextrins allows them to form inclusion complexes with many substances, especially those that are lipophilic. Thus, cyclodextrins can be used as nasal mucosal absorption enhancers, solubilizers, or stabilizers to promote drug absorption, either directly or indirectly (Papakyriakopoulou et al., 2021).

As described in several studies, various types of chitosan and hydroxypropyl methylcellulose can also be used as mucosal adhesives to facilitate nasal drug administration (Nižić et al., 2020; Kamali et al., 2023).

To increase the nose-to-brain delivery of nanoscale drugs, selecting appropriate ligands for surface modification of the formulation can increase the affinity between the drug delivery system and the mucosa, leading to enhanced mucosal adsorption. The most commonly used targeting ligands are proteins whose receptors are expressed in the olfactory region, namely lactoferrin (Li et al., 2023) or certain glycoproteins (Pernet et al., 2023). Several lectins, such as wheat germ agglutinin (Su et al., 2020) and solanum tuberosum lectin (Chen et al., 2012), have also been used to promote nose-to-brain drug delivery.

Liposomes are novel dosage forms of targeted drug delivery systems. Liposomes are enclosed bilayer membranes of phospholipids (such as lecithin and cholesterol) that contain hydrophilic cores and possess the characteristics and functions of biofilms (Duong et al., 2023). Lipid-soluble compounds can be embedded in phospholipid bilayer membranes, whereas water-soluble compounds can be encapsulated in hydrophilic parts; therefore, liposomes can carry both lipid- and water-soluble drugs (Duong et al., 2023). Owing to their surface charge, liposomes increase the contact time with the mucosa and improve the bioavailability of drugs while also protecting encapsulated biomolecules from degradation by enzymes in the nasal mucosa (Semyachkina-Glushkovskaya et al., 2022). Liposomes cause only slight or no damage to the nasal mucosa, without inducing irritation or ciliary toxicity, and they are suitable for long-term administration (Semyachkina-Glushkovskaya et al., 2022).

An in situ gel, also known as an in vivo gel, is a polymer that can undergo a phase change at the drug delivery site into a liquid or semi-solid form (Tang et al., 2011). Such preparations can effectively extend the retention time of drugs in the nasal cavity and increase drug concentrations in brain tissue (He et al., 2008). Depending on the factor that induces the phase change, in situ gels can be classified as temperature-, pH-, and ionic-type gels (He et al., 2008). These gels have a highly hydrophilic three-dimensional network structure, which increases the absorption of drugs across the nasal mucosa by increasing the water permeability. The gels can induce their effects without damaging the mucosal surface because the drugs are transported through the paracellular pathway along with the flow of water (Agrawal et al., 2020). Therefore, in recent decades, researchers have been focusing on optimizing the properties of these gels and improving the understanding of the processes through which they exert their effects.

Microspheres are a new dosage form developed in recent years involving a particle dispersion system formed by drug dispersion and absorption in a polymer matrix (Rassu et al., 2018). Microspheres are a spherical drug delivery system composed of various materials, including but not limited to, albumin, gelatin, polylactides, and starches (Rassu et al., 2018). Microspheres act as strong bio-adhesives and can extend the retention time of drugs in the nasal cavity to 4 h (Pandey et al., 2020). In addition, they can protect drugs from enzymatic metabolism, thereby greatly enhancing their bioavailability (Pandey et al., 2020).

An emulsion is a heterogeneous dispersion system composed of two or more immiscible or partially miscible liquids (Gizurarson, 2012). The particle size of a microemulsion ranges from 10 to 100 nm, they have a transparent appearance, and they contain surfactants and cosurfactants in a thermodynamically and dynamically stable system (Froelich et al., 2021). Microemulsions are capable of carrying large amounts of lipophilic and water-soluble drugs while simultaneously protecting them from degradation, hydrolysis, and oxidation (Froelich et al., 2021).

Nanoparticles are drug delivery systems with a particle size of 10–100 nm that are generated using polymer materials as carriers to adsorb or encapsulate drugs within the carrier material (Antunes et al., 2023). Nanoparticles can protect encapsulated drugs from degradation, preventing their unintended removal from the nasal cavity, extending the residence time of drugs in the nasal mucosa, and promoting the direct transport of certain drugs from the nasal cavity to the brain, without increasing drug concentrations within the general circulation; thus, nanoparticles can help facilitate brain-targeted drug delivery (Ferreira et al., 2023). Although the precise mechanism remains unknown, the transportation of nanoparticles to the brain may involve receptor-mediated endocytosis into cerebral capillary endothelial cells (Montegiove et al., 2022).