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Nasal mucociliary clearance as a factor in nasal drug delivery
Abstract
The nasal mucociliary clearance system transports the mucus layer that covers the nasal epithelium towards the nasopharynx by ciliary beating. Its function is to protect the respiratory system from damage by inhaled substances. Impairment of nasal mucociliary clearance can result in diseases of the upper airways. Therefore, it is important to study the effects of drugs and drug excipients on nasal mucociliary clearance. A large number of methods are used to assess mucociliary clearance. These methods study the effects of drug and excipients on the mucociliary system in vitro or in vivo in animals and humans. In some cases, the results of different in vitro and in vivo measurements do not correlate well. In vitro methods, especially ciliary beat frequency measurements, have been demonstrated to be valuable tools for toxicity screening. However, in vivo studies are essential to confirm the safety of nasal drug formulations. Nasal mucociliary clearance also has implications for nasal drug absorption. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in fast systemic drug absorption. Several approaches are discussed to increase the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. However, more experimental evidence is needed to support the conclusion that this improved absorption is caused by a longer residence time of the nasal drug formulation.
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“Samples taken from 30 minutes onwards, however, cannot reflect spiking, as substances that are not absorbed across the nasal membrane are transported to the back of the throat, and then swallowed within 15 minutes [14].”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [14]
In the citing paper
“Hence, taking saliva samples at 15 minutes creates the risk of collecting saliva that is ‘spiked’ with IN-OT (indeed this may be why other saliva studies have chosen 30 minutes as their first measurement, as this allows almost double the length of time of average mucociliary transport [14]).”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [14]
In the citing paper
“This process of clearing substances from the nasal cavity to the back of the throat, called mucociliary transport, takes 12–15 minutes in healthy individuals [14].”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [14]
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“Certain synthetic opioids and opioid-like substances, such as tramadol and propoxyphene, have a dose-dependent response to naloxone and escape detection from our standard urine toxicologic screens [21].”
BackgroundChallenges and innovations of drug delivery in older age
Khan, M. S., & Roberts, M. S. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.09.003 · Cited by 79
Advancements in Nanoemulsion-Based Drug Delivery Across Different Administration Routes
Chatzidaki, M. D., & Mitsou, E. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17030337 · Cited by 85
“However, the nasal mucosa also presents challenges, as its mucus layer traps foreign substances [130] and the rapid removal of formulations occurs through the mucociliary clearance process.”
Pozzoli, M., Ong, H. X., Morgan, L. C., Sukkar, M. B., Traini, D., Young, P. M., & Sonvico, F. (2016) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2016.07.010 · Cited by 74
Antoine Minne, A., Louahed, J., Mehauden, S., Baras, B., Renauld, J., & Rita Vanbever, A. (2007) · Immunology · doi:10.1111/j.1365-2567.2007.02641.x · Cited by 73
Kaur, P., Garg, T., Vaidya, B., Prakash, A. K., Rath, G., & Goyal, A. K. (2014) · Journal of drug targeting · doi:10.3109/1061186x.2014.994097 · Cited by 70
“Main problem with nasal delivery is the mucociliary clearance, which facilitates the clearance of nasally applied dosage forms from nose [24].”
BackgroundLuppi, B., Bigucci, F., Mercolini, L., Musenga, A., Sorrenti, M., Catenacci, L., & Zecchi, V. (2009) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.61.02.0003 · Cited by 69
“A major problem of nasal drug delivery is the mucociliary clearance mechanism, which rapidly removes non-mucoadhesive dosage forms from the absorption site.([4]) Mucoadhesive polymers can be used to prevent rapid clearance of the drug formulation, increasing the nasal residence time and thereby allowing longer absorpt…”
BackgroundClassification of Cilio‐Inhibiting Effects of Nasal Drugs
Merkus, P., Romeijn, S. G., Verhoef, J. C., Merkus, F. W. H. M., & Schouwenburg, P. F. (2001) · The Laryngoscope · doi:10.1097/00005537-200104000-00008 · Cited by 69
“Nasivin® Oxymetazoline, BAC, EDTA 2 (5) 4 (10) Ciliostatic”
Carvalho, F. C., Barbi, M. D. S., Sarmento, V. H. V., Chiavacci, L. A., Netto, F. M., & Gremião, M. P. D. (2010) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.62.04.0004 · Cited by 68
“Nasal mucociliary clearance largely determines the absorption profile of nasal drug delivery, since the residence time of drugs delivered to the nasal cavity is limited by this mechanism.([6,7]) To optimize nasal uptake, bioadhesive drug delivery systems have been studied.”
BackgroundKhatri, D. K., Preeti, K., Tonape, S., Bhattacharjee, S., Patel, M., Shah, S., Singh, P. K., Srivastava, S., Gugulothu, D., Vora, L., et al. (2023) · Current Neuropharmacology · doi:10.2174/1570159x20666220507022701 · Cited by 75
Ramvikas, M., Arumugam, M., Chakrabarti, S. R., & Jaganathan, K. S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-39981-4.00015-4 · Cited by 70
“• Normal defense mechanisms like mucociliary clearance and ciliary beating affect the permeability of the drug.(15)”
Deruyver, L., Rigaut, C., Lambert, P., Haut, B., & Goole, J. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113826 · Cited by 67
“It is reported that a mucociliary transit greater than 30 minutes may be considered abnormal and could signify a potential alteration of the nasal mucosa [106].”
BackgroundLi, R., Huang, Y., Chen, L., Zhou, H.-H., Zhang, M., Chang, L., Shen, H. Y., Zhou, M., Su, P., & Zhu, D. (2018) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2018.10.013 · Cited by 68
Antimicrobial Essential Oil Formulation: Chitosan Coated Nanoemulsions for Nose to Brain Delivery
Rinaldi, F., Oliva, A., Sabatino, M., Imbriano, A., Hanieh, P. N., Garzoli, S., Mastroianni, C. M., Angelis, M. D., Miele, M. C., Arnaut, M., et al. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12070678 · Cited by 65
Nose-to-brain delivery of antipsychotics using nanotechnology: a review
Tan, M. S. A., Parekh, H. S., Pandey, P. M., Siskind, D. J., & Falconer, J. R. (2020) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2020.1762563 · Cited by 68
“After intranasal liquid or suspension-based drug administration, mucociliary clearance mechanisms are triggered, which typically remove the formulation from mucosa within 15–30 minutes at an average velocity of 5–8 mm per minute [33,34,40].”
BackgroundSingh, R. M. P., Kumar, A., & Pathak, K. (2013) · AAPS PharmSciTech · doi:10.1208/s12249-013-9921-9 · Cited by 65
Mucoadhesive and mucus-penetrating interpolyelectrolyte complexes for nose-to-brain drug delivery
Porfiryeva, N. N., Ивановна, С. И., Анясович, С. И., Moustafine, R. I., & Khutoryanskiy, V. V. (2021) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2021.102432 · Cited by 64
“system, characterised by the presence of a mucus blanket that continuously being reformed through the production of mucins and movement as a result of mucociliary clearance.(49,50) This”
BackgroundDevelopment and evaluation of in situ nasal gel formulations of loratadine.
Sherafudeen, S. P., & Vasantha, P. V. (2015) · Europe PMC (PubMed Central) · Cited by 63
Spray dried powders for nasal delivery: Process and formulation considerations
Henriques, P., Fortuna, A. C., & Doktorovová, S. (2022) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2022.05.002 · Cited by 66
Mucoadhesive Polymeric Hydrogels for Nasal Delivery of Acyclovir
Alsarra, I. A., Hamed, A. Y., Mahrous, G. M., Maghraby, G. M. E., Al-Robayan, A. A., & Alanazi, F. K. (2008) · Drug Development and Industrial Pharmacy · doi:10.1080/03639040802360510 · Cited by 63
Nanotechnology for CNS delivery of bio-therapeutic agents
Shah, L. K., Yadav, S. K., & Amiji, M. M. (2013) · Drug Delivery and Translational Research · doi:10.1007/s13346-013-0133-3 · Cited by 64
“Another major factor is the mucocilliary clearance which is a self-clearing mechanism where external agents once bound to the mucus are transported to the nasophayrnx and eventually to the gastrointestinal tract [56].”
Sridhar, V., Wairkar, S., Gaud, R. S., Bajaj, A., & Meshram, P. V. (2017) · Journal of drug targeting · doi:10.1080/1061186x.2017.1350858 · Cited by 62
“However, intranasal delivery would be effective only when the drug is in contact with nasal epithelium for a sufficient period to diffuse into the olfactory projections [25].”
BackgroundWorkman, A. D., & Cohen, N. A. (2014) · American Journal of Rhinology and Allergy · doi:10.2500/ajra.2014.28.4092 · Cited by 60
Lipid emulsions as vehicles for enhanced nasal delivery of insulin
Mitra, R., Pezron, I., Chu, W. A., & Mitra, A. K. (2000) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(00)00506-8 · Cited by 59
Cao, S., Zhang, Q., & Jiang, X. (2007) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2007.00540.x · Cited by 58
Oh, D.-H., Chun, K.-H., Jeon, S.-O., Kang, J. W., & Lee, S. K. (2011) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2011.05.010 · Cited by 58
Improved nasal bioavailability of elcatonin by insoluble powder formulation
Ishikawa, F., Katsura, M., Tamai, I., & Tsuji, A. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(01)00736-0 · Cited by 58
“In contrast, although the dry powder formulation using water-soluble lactose as a drug carrier is available for the pulmonary dry powder inhalation ( Malcolmson and Embleton, 1998 ), this apparently does not increase the absorption of polar molecules via the nasal route (Nagai et al., 1984; Ugwoke et al., 2000).”
BackgroundA gellan gum derivative as in-situ gelling cationic polymer for nasal drug delivery
Jelkmann, M., Leichner, C., Zaichik, S., Laffleur, F., & Bernkop‐Schnürch, A. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.04.114 · Cited by 57
Abbas, Z., & Marihal, S. (2014) · Journal of Pharmacy And Bioallied Sciences · doi:10.4103/0975-7406.142959 · Cited by 57
“NMCC is one of the most important limiting factor for nasal drug delivery as it severely limits the time allowed for drug absorption to occur and effectively rules out the option of sustained nasal drug administration.[10] Several approaches are discussed in the literature to increase the residence time of drug formul…”
Nasal drug delivery: Design of a novel mucoadhesive and in situ gelling polymer
Menzel, C., Jelkmann, M., Laffleur, F., & Bernkop‐Schnürch, A. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.11.055 · Cited by 57
Intranasal delivery of antipsychotic drugs
Katare, Y. K., Piazza, J. E., Bhandari, J., Daya, R. P., Akilan, K., Simpson, M. J., Hoare, T. R., & Mishra, R. K. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.11.027 · Cited by 57
Metadata
- Authors
- Marttin, E., Schipper, N. G. M., Verhoef, J. C., & Merkus, F. W. H. M.
- Corresponding author
- Merkus, Frans W.H.M
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 1998-01
- Volume
- 29
- Issue
- 1-2
- Pages
- 13-38
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W2089895093
- Cited by
- 469
- References
- 255
- Citations by year
- 2026: 24 · 2025: 45 · 2024: 26 · 2023: 40 · 2022: 32 · 2021: 34 · 2020: 26 · 2019: 16 · 2018: 27 · 2017: 15 · 2016: 18 · 2015: 14 · 2014: 24 · 2013: 17 · 2012: 15
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Health Sciences › Medicine › Otorhinolaryngology › Sinusitis and nasal conditions
- Keywords
- nasal mucociliary clearance, intranasal drug delivery, ciliary beat frequency, mucus transport, pharmaceutical excipients, nasal drug absorption, residence time, toxicity screening, upper airway diseases, in vitro-in vivo correlation
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