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The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices.The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is onl...
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... of drugs and vaccines, it is important for the design of devices and for understanding the administration techniques. and its surroundings in order to determine the major three- dimensional facial landmarks. These may be obtained into x, y and z coordinates of the nose [2,3]. Among about 50 facial landmarks, 12 are related to the nose as shown in (Fig. 1). These landmarks may be used to estimate facial volumes and areas by the mean of several tetrahedral and triangles [4][5][6]. Using the linear and angular measurements, the differences in the nose and nostrils [7] may be analyzed and character- ized as shown in (Fig. 2). The soft tissue component of the outer nose (nasus exter- nus) is ...
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... fenestrated veins beneath the mucous mem- brane. The fenestrae always face the respiratory epithelium and are believed to be one of the sources of fluid for humidi- fication. The epithelium is also supplied with a dense net- work of erectile tissue, which is also cavernous and particu- larly well developed over the conchae and septum as shown in (Fig. 10). The vascular bed is especially high in density over the lower part of the septum and over the middle and inferior conchae, which provides a promising condition for drug absorption. Due to the large veins the lamina propria and the mucosa is particularly thick over the surfaces of the middle and inferior conchae. Constriction of the ...
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... by the blood flow in the region under normal and pathological conditions. The structure of the blood vessels of the nasal mucosa is of major importance for the function of the nose. The capil- laries are fenestrated and the porosity of the endothelial basement membrane is one of the characteristics of the nasal blood vessels as shown in (Fig. ...
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... lymphatic system includes lymphatic vessels and glands through which they pass. The lymphatics have the property of absorbing materials from the tissues and convey- ing them into the circulation as shown in (Fig. 12). Lipids and lipid soluble compounds are examples of compounds absorbed by the lymphatic system. Due to the watery fluid (called lym- pha), the lymphatics are delicate transparent vessels. The lym- phatic vessels begin as close-ended vessels called lymphatic capillaries and are found throughout the nasal mucosa (Fig. 12). Fig. (12). The ...
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... circulation as shown in (Fig. 12). Lipids and lipid soluble compounds are examples of compounds absorbed by the lymphatic system. Due to the watery fluid (called lym- pha), the lymphatics are delicate transparent vessels. The lym- phatic vessels begin as close-ended vessels called lymphatic capillaries and are found throughout the nasal mucosa (Fig. 12). Fig. (12). The relationship between the lymphatic system and the blood capillaries as well as the drainage of fluid into the lymphatic ...
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... as shown in (Fig. 12). Lipids and lipid soluble compounds are examples of compounds absorbed by the lymphatic system. Due to the watery fluid (called lym- pha), the lymphatics are delicate transparent vessels. The lym- phatic vessels begin as close-ended vessels called lymphatic capillaries and are found throughout the nasal mucosa (Fig. 12). Fig. (12). The relationship between the lymphatic system and the blood capillaries as well as the drainage of fluid into the lymphatic ...
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... from the anterior part of the nose drain through the nostrils with lymphatics of the skin to subman- dibular lymph nodes, but in the middle and the posterior part of the nasal cavity the lymph drainage is mainly to the lateral pharyngeal lymph nodes, the deep cervical lymph nodes and to the jugulofacial lymph nodes as shown in (Fig. 13). The buccal nodes and the mandibular nodes collect drainage from the mucous membrane of the nose and bring it further to the submandibular nodes (Fig. 13). The nose-associated lym- phoid system (NALT) around the nasal and buccal cavity, which are a combination of occasional M-cell clusters or lymph corpuscles and the adenoid tissue (as ...
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... and the posterior part of the nasal cavity the lymph drainage is mainly to the lateral pharyngeal lymph nodes, the deep cervical lymph nodes and to the jugulofacial lymph nodes as shown in (Fig. 13). The buccal nodes and the mandibular nodes collect drainage from the mucous membrane of the nose and bring it further to the submandibular nodes (Fig. 13). The nose-associated lym- phoid system (NALT) around the nasal and buccal cavity, which are a combination of occasional M-cell clusters or lymph corpuscles and the adenoid tissue (as well as the ton- sils in the pharynx) has been called Waldeyer's ring. Due to this lymphoid tissue, polyps may be found growing from the outer wall of the ...
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... region there is an anatomical relationship between the olfactory nerves and the extracranial lymphatics through the foramina in the cribriform plate. The lymphatics form a collar around the root of the olfactory nerve within the cribriform plate, so there is very limited leakage or drain- age of cerebrospinal fluid into the nasal submucosa (Fig. 13). In addition, the lymphatics are able to guard the entrance from the nose to the brain, taking part in the defense system by protecting the brain from slowly moving molecules from being transported from the nasal ...
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... si- nuses, the nasal cavity and the integument of the nose [25]. The ophthalmic nerve divides into three branches just after passing through the sphenoidal fissure, where one is the na- sal nerve, a deeply placed nerve that enters the cavity through the anterior ethmoidal foramen and via a shallow opening on the front of the cribriform plate (Fig. 14). After entering into the nasal cavity it divides into two branches, an internal and an external branch. The internal branch supplies the mucous membrane near the anterior part of the septum of the nose. The external branch supplies the mucous mem- brane covering the anterior part of the outer wall of the nos- trils. When it leaves the ...
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... ganglion supporting nerves to the nasal cavity is the pterygopalatine ganglion or the Meckel's ganglion (Fig. 14). Four branches enter from Meckel's ganglion where two of them supply the nose: the internal branch to the nose and the posterior branch to the nasal cavity and the pharynx. The ascending branch supplies the mucous membrane of the si- nuses such as posterior ethmoidal sinuses and the sphenoidal sinuses. The descending or palatine branch ...
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... superior conchae. The olfactory nerves are made by non-medullated fibers and are not protected by the white substance of Schwann. They convey nerve im- pulses arising from the bipolar olfactory neurons in the olfac- tory mucosa and through the axons the impulse is brought to a synapse in the olfactory bulb, as presented by Dr. Cajal in 1894 in (Fig. ...
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... vomeronasal organ is another chemoreceptor organ found in the nasal cavity. It detects external chemical signals and is connected to the terminalis nerve to the brain, through the vomeronasal-termianlis nerve (Fig. 16) [28]. The vo- meronasal organ is essential for promoting bonding between newborn and mother [29], eliciting and maintaining male and female sexual behaviour, influencing the onset of puberty, the oestrus cycle, gestation, maternal behaviour and social behaviour [30][31][32]. It also influences mood changes in woman [33]. In adults the ...
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... newborn and mother [29], eliciting and maintaining male and female sexual behaviour, influencing the onset of puberty, the oestrus cycle, gestation, maternal behaviour and social behaviour [30][31][32]. It also influences mood changes in woman [33]. In adults the vomeronasal organ is a tube-like membranous organ, 2-10 mm long, located as shown in (Fig. 16). It opens into the nasal cavity through a small ori- fice (about 1 mm in diameter) as a small depression of the nasal mucosa, close to the base of the nasal ...
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... These are small scattered serous glands, the structure of which re- sembles that of the serous salivary glands (parotid gland) with a large opening (0.1-0.4 mm in diameter). This fluid is commonly visible in cold weather as droplets hanging from ones nose. In the other part of the nasal cavity there are numerous seromucous glands (Fig. 17), secreting proteineous secretion where large amounts of mucus are added. The density of glands differs depending on age and location. At birth there are about 34 glands per mm 2 . When growing, the area of the nasal cavity increases and the density decreases, being around 17-18 glands per mm 2 at age one, 13 glands/mm 2 at age 5 and ...
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... the olfactory region there are numerous olfactory glands, called Bowman's glands (Fig. 17). These are tubu- loalveolar serous glands that deliver watery, although pro- teineous secretions onto the olfactory surface. Their secre- tion is important for the function of the olfactory region, both as a trap but also as a solvent for odoriferous substances. Constant flow from the glands keeps the mucosa clean so that new scents ...
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... of the anterior vestibule and nostrils are covered by skin, containing large stiff hair called vibrissae that guard the entrance into the nasal cavity by collecting airborne dust and bacteria. About is covered by a squamous epithelium anteriorly, followed by transitional epithelium (Fig. ...
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... cavity, which is the lympoid tissue, where occasional M-cells or M-cell clusters (lymph corpuscles) may be found in the epithelium. Their main density is posterior in the ade- noid tissue. The epithelium covering the paranasal sinuses is similar to respiratory mucosa, but less vascular, thinner, and more loosely attached to the bony walls [11]. Fig. (18). The structure of a squamous (left) and transitional (right) ...
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... mucosal membrane is thickest over the conchaes and the center of the septum due to highly vascularised mucosa which is also linked to the erectile tissue in the nose, particu- larly in the middle and inferior chonchae as shown in (Fig. 10), which enables the airways to widen or narrow. This autonomically controlled vasculature of the nasal tissue, in combination with its rich supply of secretory cells is of importance in the modification of inspired ...
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... ciliated cells (Fig. 19) are the most frequent cell type in the nasal cavity, their function is e.g. to provide a coordi- nated sweeping motion of the mucus coat to the throat, called ciliary escalator or ciliary clearance. This function is an im- portant protective mechanism for removing mucus and trapped inhaled particles. Due to this clearance, inhaled ...
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... about 300 microvilli, which are fingerlike cytoplasmic expansions on the surface of the cells in addition to the cilia. These microvilli are uniformly distributed on the entire api- cal surface [16], increasing the surface area significantly. The microvilli also prevent drying of the surface by retaining moisture essential for ciliary function. Fig. (19). The anatomy of a ciliated cell and schematic diagrams showing the molecular structure of ...
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... ciliated cell contains about 100-250 mobile cellular appendage called cilia, 0.3 m wide and 5 m in length as shown in (Fig. 19). Their function is to help transporting fluid or the carpet of mucus towards the throat where after it is swallowed. The cilia contain a motor protein called dynein and microtubules, which are composed of linear polymers of globular proteins called tubulin. The core of each of the structures is termed the axoneme and contains two ...
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... to move along the surface of the adjacent microtubule. The ciliary activity is based on the movement of the doublet microtubules in relation to one another, initiated by the dynein arms. Hydrolysis of ATP produces a sliding movement along the microtubule, where the dynein molecules produce a continuous shear force slid- ing toward the ciliary tip (Fig. 19), a movement called the effective stroke. At the same time, a passive elastic connec- tions provided by nexin and the radial spokes accumulate the energy necessary to bring the cilia back to the straight posi- tion (recovery ...
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... columnar cells (Fig. 21) are like ciliated cells, on the basement membrane and stretch to the airway lumen where they bear microvilli. The microvilli are slender fingerlike cytoplasmic expansions of the cell membrane that have the capability to absorb compounds. It has been shown that a number of drug substances, proteins are absorbed through the columnar ...
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... cells (Fig. 21), also called mucus cells or chalice cells, are interspersed among the ciliated and columnar cells throughout the epithelium. They appear to be formed by a modification of the columnar cell. They form granules which consist of mucin or mucigen inside the cell and in the upper part of the cell, while the nucleus is pressed down towards ...
Citations
... Intranasal delivery of drugs can directly enter the brain, reducing drug exposures to peripheral organs and tissues, avoiding drug degradation in the circulation and enhancing the bioavailability of delivered drugs [26]. It was reported that daily intranasal administration of a novel PEI-conjugated R 8 -Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits in PS-1/APP mice AD model [27]. The intranasal delivery of full-length anti-Nogo-A antibody could promote growth and compensatory sprouting of corticofugal projections and enhance functional recovery in a rat stroke model [28]. ...
... Nevertheless, there are still several disadvantages of intranasal administration. AD is a chronic disorder, repeated intranasal administration may cause irreversible damage to the nasal epithelium, nasal mucosa and nerves in the cavity since their surface area is limited [30]. Future investigations are warranted to evaluate the safety, efficacy and therapeutic effects of intranasal administration in passive immunotherapy in AD and other human neurodegenerative diseases. ...
Passive immunotherapy with specific antibodies targeting Amyloid β (Aβ) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer’s disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aβ peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aβ antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aβ antibodies, such as lecanemab (a humanized mAb binds to soluble Aβ protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aβ peptides) and aducanumab (a human mAb binds to the aggregated form of Aβ), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aβ antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aβ antibodies and other pharmaceutical agents should also be explored.
... Like the respiratory epithelium, the olfactory epithelium is constituted of ciliated columnar cells coated by a mucus layer. Nevertheless, in the olfactory epithelium, the cilia are immobile and exhibit greater length compared to those present in the respiratory epithelium [27]. Within the olfactory epithelium, regenerating neurons involve two distinct categories of basal cells: horizontal basal cells and globose basal cells. ...
... The anatomy of the nose clearly indicates the olfactory zone ( Fig. 1) and the interface of CNS which interacts directly with the peripheral area within the brain. With an expanse of around 160 cm 2 (microvilli comprise 96,000 cm 2 ), the intranasal route has been thoroughly researched for systemic and topical-related deliveries [27]. It houses olfactory receptors and neurons that link to the olfactory bulb. ...
... This approach takes advantage of the intricate neural networks associated with olfaction comprising area of approximately 5 cm 2 with around 3000 cm 2 microvilli, providing a targeted means of delivering therapeutic agents [27]. The journey of drug delivery begins in the nasal cavity, a complex anatomical region with distinct epithelial structures, which serve as entry points for therapeutic agents. ...
Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood–brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.
... The middle diagram shows area proportion of the nasal epithelium and cell proportion in rat (left) and human (right) tracheal, bronchial, bronchiolar and alveolar regions. Information collected fromMercer et al. (1994),Gizurarson (2012), and Parent ...
... Activation of V1a receptors that are present on vascular smooth muscle cells produces contraction of vascular smooth muscle cells [20]. This may contribute to its topical effect through contraction of smooth muscles of nasal arterioles as the nasal tissues are highly vascular [21]. ...
Background
A bloodless surgical field coupled with stable hemodynamics is pivotal for successful surgical intervention, especially in endonasal surgeries. This study investigates the effect of intranasal desmopressin spray in reducing surgical bleeding and on hemodynamics compared with topical epinephrine in patients scheduled for endonasal dacryocystorhinostomy (DCR).
Methods
Fifty-two patients were randomly allocated into two groups in this double-blind clinical study: Desmopressin group ( n =26): patients received two puffs of desmopressin acetate 10 μg/puff in the side of the nasal cavity ipsilateral to the obstructed lacrimal duct (20 µg totally) 60 min before the surgery. Epinephrine group ( n =26): patients received topical 1 : 100 000 epinephrine in the nasal cavity ipsilateral to the obstructed lacrimal duct via 3 soaked packs placed in the middle meatus for 5 min after induction of general anesthesia and before the start of surgery.
Results
The median clarity of the surgical field based on the BOEZAART grading system was significantly clearer in the desmopressin group compared with epinephrine group. The duration of surgery was significantly shorter in the desmopressin group (66.92±5.04 min) compared with epinephrine group (71.73±5.45 min). Mean arterial blood pressure (MABP) and heart rate (HR) were statistically significant higher in epinephrine group compared to the desmopressin group at 2 and 5 min after topical epinephrine compared with desmopressin group.
Conclusion
Pre-emptive 20 ug single dose of intranasal desmopressin provides a clear surgical field with no hemodynamics effects compared with topical epinephrine in patients undergoing endonasal dacryocystorhinostomy. Clinicaltrial.gov (ref: NCT05507476, date of registration: 18-8–2022).
... This paper reviews research studies in the last 7 years focussed on the use of poly (lactic-co-glycolic acid) (PLGA) NPs in nasal delivery, exploring the designs and properties of these NPs. This review does not cover the anatomy and the physiological functions of the nasal cavity as this has been extensively covered in previously published papers [6][7][8][9]. The first section of this review covers the challenges faced in achieving efficient nasal therapeutic delivery. ...
... Nasal irritation and pain. It has been reported that some of the side effects observed with IN delivery is due to the nerves that innervate the nasal cavity [8]. The trigeminal nerve senses pain and irritation after nasal administration, while the facial nerve responds to this irritation by stimulating glands and facial expressions in the subject [8]. ...
... It has been reported that some of the side effects observed with IN delivery is due to the nerves that innervate the nasal cavity [8]. The trigeminal nerve senses pain and irritation after nasal administration, while the facial nerve responds to this irritation by stimulating glands and facial expressions in the subject [8]. It is important to note that the high permeability of the nasal epithelium predisposes it to the adverse effects of drugs and excipients in the nasal formulation [34]. ...
The nasal route has routinely been used in the local delivery of drugs, however with innovations in nanotechnology, there has been increased interest in exploring this route more for systemic, and brain/CNS delivery. This is because this route is safe, non-invasive, and medications can be self-administered to achieve rapid therapeutic drug levels with minimal doses. Polymeric nanoparticles (NPs) such as PLGA NPs have a wide range of applications in drug delivery, due to their large surface area and surface modification of the NPs with targeting ligands and polymers which enhances drug delivery, cellular uptake, and bioavailability at target sites. This review covers recent research on the use of PLGA nanoparticles in the delivery of small molecule drugs and macromolecules via the nasal route. It covers some background information about the challenges in delivering drugs via this route. The most common targeting ligands and polymer coatings used in the surface modification of PLGA NPs are highlighted. Finally, recent patents and clinical trials of PLGA NPs in nasal drug delivery are also covered.
... It also can bypass hepatic metabolism and decrease several off-target adverse effects, and therefore, it appears as an interesting administration route [13,14]. Nasal cavity is supplied by six branches of arteries that may improve drugs systemic absorption; furthermore, existence of the olfactory area may offer a way to target the brain directly [15]. The combination of all those factors along with high surface area in the nasal cavity may help to improve medication absorption. ...
... Mice were carefully set at a tilted posture during administration so that they could inhale the formulation. Three mice from every group were slaughtered at predefined time intervals (5,15,30,60,120, and 180 min post-delivery) [63]. Samples of blood were taken via heart punctures while the remaining organs involving brain were dissected, removed from sticking tissues and fluids, rinsed with normal saline, weighed, then their radioactivity caused by 131 I-MZP absorption was determined using NaI gamma rays scintillation counter. ...
Mirtazapine (MZPc) is an antidepressant drug which is approved by the FDA. It has low bioavailability, which is only 50%, in spite of its rapid absorption when orally administered owing to high first-pass metabolism. This study was oriented towards delivering intranasal (IN) mirtazapine by a direct route to the brain by means of preparing lipid nanocapsules (LNCs) as a targeted drug delivery system. MZP-LNCs were constructed by solvent-free phase inversion temperature technique applying D-Optimal mixture design to study the impact of 3 formulation variables on the characterization of the formulated nanocapsules. Independent variables were percentage of Labrafac oil, percentage of Solutol and percentage of water. Dependent variables were particle size, polydispersity index (PDI), Zeta potential and solubilization capacity. Nanocapsules of the optimized formula loaded with MZP were of spherical shape as confirmed by transmission electron microscopy with particle diameter of 20.59 nm, zeta potential of − 5.71, PDI of 0.223 and solubilization capacity of 7.21 mg/g. The in vivo pharmacokinetic behavior of intranasal MZP-LNCs in brain and blood was correlated to MZP solution after intravenous (IV) and intranasal administration in mice. In vivo biodistribution of the drug in mice was assessed by a radiolabeling technique using radioiodinated mirtazapine ( ¹³¹ I-MZP). Results showed that intranasal MZP-LNCs were able to deliver higher amount of MZP to the brain with less drug levels in blood when compared to the MZP solution after IV and IN administration. Moreover, the percentage of drug targeting efficiency (%DTE) of the optimized MZP-LNCs was 332.2 which indicated more effective brain targeting by the intranasal route. It also had a direct transport percentage (%DTP) of 90.68 that revealed a paramount contribution of the nose to brain pathway in the drug delivery to the brain.
Graphical Abstract
... Nasal respiratory mucosa is composed of a pseudostratified columnar epithelium containing ciliary epithelial cells, goblet mucus-producing cells, and basal stem cells [13][14][15], a membrane basement, and the underlying lamina propria, comprising stromal cells such as fibroblasts and immune cells [16]. The MucilAir™ nasal model is a 3D in vitro model of the human nasal epithelium that closely mimics the biology of the nasal barrier. ...
... To estimate the flow rate in an in vivo 0.33 cm 2 nasal area, it is also necessary to consider additional assumptions, namely that the flow rate is the same through all nasal areas. Estimations of the total surface area of both nasal cavities are about 160 cm 2 [15] or 150 cm 2 [43], and if the paranasal sinuses are included, about 400 cm 2 [41]. Considering all these assumptions, we conclude that in our study of the 0.33 cm 2 insert, the applied flow rate was 6.0× to 80.0× lower than in vivo settings (Table S1), using the low flow rate of 2 mL/min recommended by the manufacturer. ...
... Table S1. Estimation of flow rate in in vivo 0.33 cm 2 human nasal epithelium [15,[40][41][42][43]. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. ...
Sulfurous thermal waters (STWs) are used as a complementary treatment for allergic rhinitis. However, there is scant data on the effects of STW on nasal epithelial cells, and in vitro models are warranted. The main aim of this study was to evaluate the dose and time effects of exposure to 3D nasal inserts (MucilAirTM-HF allergic rhinitis model) with STW or isotonic sodium chloride solution (ISCS) aerosols. Transepithelial electrical resistance (TEER) and histology were assessed before and after nebulizations. Chemokine/cytokine levels in the basal supernatants were assessed by enzyme-linked immunosorbent assay. The results showed that more than four daily nebulizations of four or more minutes compromised the normal epithelial integrity. In contrast, 1 or 2 min of STW or ISCS nebulizations had no toxic effect up to 3 days. No statistically significant changes in release of inflammatory chemokines MCP-1/CCL2 > IL-8/CXCL8 > MIP-1α/CCL3, no meaningful release of “alarmins” (IL-1α, IL-33), nor of anti-inflammatory IL-10 cytokine were observed. We have characterized safe time and dose conditions for aerosol nebulizations using a novel in vitro 3D nasal epithelium model of allergic rhinitis patients. This may be a suitable in vitro setup to mimic in vivo treatments of chronic rhinitis with STW upon triggering an inflammatory stimulus in the future.
... 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). ...
The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood–brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).
... 3 Due to the complex structure of the sinonasal cavity, including the narrow anterior valve and many convoluted meatus, it is challenging to achieve efficient and convenient drug delivery within the sinonasal cavity. 8 Nasal inhalation from nebulizers has been utilized to improve delivery to the upper posterior nasal segments, with the major disadvantages of significant inhalation to the lungs and poor dose control. 9,10 Drops may achieve better deposition beyond the nasal valve, but cumbersome delivery procedures are required. ...
Objectives
To compare the deposition patterns within the nasal cavity between the bi‐directional and unilateral nasal delivery systems. And to summarize the clinical application of the bi‐directional nasal drug delivery devices.
Data source
PubMed, Cochrane Library, Embase, and Web of Science databases.
Methods
A scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA). We included studies exploring patterns and influencing factors of particle depositions within the nasal cavity among patients, healthy controls, and nose cast models using the bi‐directional and unilateral nasal delivery system. The clinical application of the bi‐directional delivery devices was also summarized.
Results
A total of 24 studies were included in this review. Bi‐directional nasal delivery systems utilize forced exhalation to power the delivery of drugs to deeper areas of the nasal cavity and paranasal sinuses. Unilateral nasal delivery systems included traditional liquid spray pumps, the aerosol mask system, nebulization, and conventional nasal inhalation. Compared with unilateral delivery systems, the bi‐directional nasal delivery system provided a more extensive and efficient nasal deposition in the nasal cavity, especially in the olfactory cleft, without lung deposition. Several parameters, including particle size, pulsatile flow, and nasal geometry, could significantly influence nasal deposition. The bi‐directional nasal delivery system enables better delivery of steroids or sumatriptan to the sinonasal cavity's high and deep target sites. This bi‐directional delivery device demonstrated an effective and well‐tolerated treatment that produced high drug utilization, rapid absorption, and sustained symptom improvement among patients with chronic rhinosinusitis (CRS) or migraine.
Conclusion
The bi‐directional nasal drug delivery systems demonstrated significantly higher drug deposition in superior and posterior regions of the nasal cavity than unilateral nasal delivery systems. Further studies should explore its potential role in delivering drugs to the olfactory cleft among patients with olfactory disorders and central nervous system diseases.
Level of evidence
N/A.
... Moreover, an accumulating evidence demonstrates that drugs deposited in the nasal cavity escape the usual rapid clearance by enzymatic degradation and the mucociliary system, undergo uptake into cells of the olfactory and trigeminal pathways, or are absorbed into the systemic circulation. [36][37][38][39] This pathway via the trigeminal pathway can be an important direct pathway for drug delivery to the brain, 38 and this pathway transports only particles of small size (< 200 nm) via a direct passage from the nasal cavity to the brain (passive diffusion). 40 We also measured whether the nasal administration of MF microcrystal dispersions, which is smaller size particles (< 200 nm), delivered to blood and brain in this study. ...
Purpose
We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF).
Methods
MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice.
Results
The particle size range of MF prepared with the bead mill treatment was 80–200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions.
Conclusion
We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.
