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Nose-to-Brain Drug Delivery: History
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Subjects: Pharmacology & Pharmacy
Contributor:
Linh Thi-Thao Nguyen
, Van-An Duong

Nose-to-brain drug delivery is an innovative approach that leverages the unique anatomical pathways connecting the nasal cavity to the brain, including the olfactory and trigeminal nerve routes. This method bypasses the blood–brain barrier, enabling direct and efficient transport of therapeutic agents to the central nervous system. It offers significant advantages, such as rapid drug action, reduced systemic side effects, and improved patient compliance through non-invasive administration. This entry summarizes factors affecting the nose-to-brain delivery of drugs and the recent development of nanoparticle-based nose-to-brain delivery.

  • nose-to-brain
  • blood–brain barrier
  • bioavailability
  • drug delivery
  • nanoparticle
  • polymeric nanoparticles
  • SLNs
  • NLCs
  • emulsions
  • liposomes
Nose-to-brain drug delivery is an approach to directly deliver therapeutic agents from the nasal cavity to the brain, bypassing the blood–brain barrier (BBB) [1][2]. The BBB is a highly selective structure that prevents most drugs from reaching the brain when administered through conventional routes, such as oral or parenteral methods [3][4]. The anatomical connection between the nasal cavity and the brain, primarily through the olfactory and trigeminal nerve pathways, offers a unique route for drug delivery that avoids the challenges posed by the BBB [5][6][7]. This approach has emerged as a promising non-invasive technique for treating various central nervous system (CNS) disorders, including Alzheimer’s disease, Parkinson’s disease, brain tumors, epilepsy, and psychiatric conditions [8][9][10].
Intranasal (IN) administration has several advantages over traditional drug delivery routes. It bypasses the gastrointestinal tract and liver metabolism, eliminating the risk of drug degradation during first-pass metabolism, improving bioavailability [11][12]. Furthermore, IN delivery allows for rapid drug absorption and onset of action, making it particularly beneficial in conditions requiring immediate therapeutic effects [10][13]. The localized administration also minimizes systemic side effects, as the drug is directed specifically to the brain. Additionally, the ease of self-administration makes IN delivery a patient-friendly option, enhancing compliance and accessibility for chronic or acute treatments [14][15].
The underlying mechanism of nose-to-brain delivery involves the olfactory and trigeminal nerve pathways [16]. The olfactory nerve, located in the upper nasal cavity, provides a direct connection to the brain’s olfactory bulb, allowing drugs to bypass the systemic circulation and enter the CNS directly [17][18]. Similarly, the trigeminal nerve, which innervates the nasal mucosa, also facilitates drug transport to various brain regions [19]. These pathways enable therapeutic agents to reach the brain quickly and effectively, bypassing the restrictive barriers that would otherwise impede drug delivery [20]. They are considered direct nose-to-brain delivery pathways. The lymphatic pathway is an emerging route in nose-to-brain drug delivery, offering an alternative to direct neuronal transport via the olfactory and trigeminal nerves. Drugs administered intranasally can enter the nasal lymphatic vessels and reach the CNS through cerebrospinal fluid exchange or perivascular spaces [21]. This route may be especially useful for delivering large molecules or biologics that are otherwise restricted by the BBB. By reducing systemic exposure and enabling more targeted CNS delivery, the lymphatic pathway holds promise for enhancing the efficacy and safety of IN therapeutics [22]. Besides these routes, IN-administered drugs can reach the brain via indirect pathways. A part of the drug administered intranasally is distributed in the respiratory region and absorbed by respiratory epithelia to the systemic circulation. It can also be distributed to the lungs and gastrointestinal tract and then absorbed into the blood stream [23][24]. From the blood, the drug can cross the BBB to enter the brain. However, BBB has many efflux pumps to prevent drugs from entering the brain [6][25][26]. Figure 1 presents direct and indirect routes for nose-to-brain delivery.
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Figure 1. Direct and indirect routes of nose-to-brain delivery. Created in BioRender.
Despite its advantages, nose-to-brain delivery poses certain challenges that must be addressed during formulation development [27]. The nasal cavity’s limited surface area and small volume capacity restrict the amount of drug that can be delivered at a time [28]. Additionally, the mucociliary clearance mechanism rapidly removes foreign substances, limiting the residence time of formulations in the nasal cavity [29][30][31]. The enzymatic degradation of drugs and variability in absorption due to individual nasal conditions also present significant obstacles [32]. To overcome these limitations, researchers have developed different nanoparticle (NP)-based drug delivery systems, such as liposomes [33], nanoemulsions [34], solid lipid nanoparticles (SLNs) [35][36], nanostructured-lipid carriers [37], polymeric NPs [38][39], and micelles [40], to improve drug solubility, stability, and retention in the nasal cavity [32][41][42].
In this entry, the authors summarize the key factors influencing the efficiency and effectiveness of nose-to-brain drug delivery. Additionally, the authors highlight the recent advancements in nanotechnology-based delivery systems that have been developed to overcome current challenges in nose-to-brain delivery, thereby providing a deeper understanding of how these advanced drug delivery systems are paving the way for more effective treatments of central nervous system disorders through the intranasal route.

This entry is adapted from the peer-reviewed paper 10.3390/encyclopedia5030091

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