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Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Research Article

An Ex vivo Investigation on Drug Permeability of Sheep Nasal Epithelial Tissue Membranes from the Respiratory and Olfactory Regions

Author(s): Anja Haasbroek-Pheiffer*, Alvaro Viljoen, Jan Steenekamp, Weiyang Chen and Josias Hamman

Volume 21, Issue 1, 2024

Published on: 23 January, 2023

Page: [115 - 125] Pages: 11

DOI: 10.2174/1567201820666221214105836

Price: $65

Abstract

Background: Besides systemic drug delivery, the intranasal route of administration has shown potential for direct nose-to-brain drug delivery, which has gained popularity because it bypasses the blood-brain barrier.

Objective: The region in the nose from which the epithelial tissue membrane is excised to conduct ex vivo permeation studies for nasal drug delivery studies may be of importance, but the permeability of the epithelium from the different nasal regions has not yet been investigated in the sheep model.

Methods: The permeation of five selected model compounds (i.e., atenolol, caffeine, Rhodamine 123, FITC-dextran, and Lucifer Yellow) was measured across epithelial tissues that were excised from two different areas of the sheep nasal cavity, namely the ventral nasal concha (representing respiratory epithelium) and the ethmoid nasal concha (representing olfactory epithelium).

Results: Although the selected compounds' permeation was generally slightly higher across the olfactory epithelial tissues than across the respiratory epithelial tissues, it was not statistically significant except in the case of atenolol.

Conclusion: The presence of olfactory nerves and supporting cells and the gaps between them in the olfactory epithelial tissues may have contributed to the higher permeation of atenolol, but this needs to be further investigated to elucidate the precise mechanism.

Graphical Abstract

[1]
Alexander, A.; Agrawal, M.; Chougule, M.B.; Saraf, S.; Saraf, S. Nose-to-brain drug delivery: An alternative approach for effective brain drug targeting. In: Nanopharmaceuticals: Expectations and Realities of Multifunctional Drug Delivery Systems, 1st ed; Shegokar, R., Ed.; Elsevier: Cambridge, UK, 2020; pp. 175-200.
[http://dx.doi.org/10.1016/B978-0-12-817778-5.00009-9]
[2]
Aderibigbe, B. In situ-based gels for nose to brain delivery for the treatment of neurological diseases. Pharmaceutics, 2018, 10(2), 40.
[http://dx.doi.org/10.3390/pharmaceutics10020040] [PMID: 29601486]
[3]
Gizurarson, S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr. Drug Deliv., 2012, 9, 566-582.
[http://dx.doi.org/10.2174/156720112803529828] [PMID: 22788696]
[4]
Patel, A.A.; Patel, R.J.; Patel, S.R. Nanomedicine for intranasal delivery to improve brain uptake. Curr. Drug Deliv., 2018, 15(4), 461-469.
[http://dx.doi.org/10.2174/1567201814666171013150534] [PMID: 29034836]
[5]
Sosnik, A. Tissue-based in vitro and ex vivo models for nasal permeability studies. In: Concepts and models for drug permeability studies, 1st ed; Sarmento, B., Ed.; Woodhead Publishing: Cambridge, UK, 2015; pp. 237-254.
[6]
Kashyap, K.; Shukla, R. Drug delivery and targeting to the brain through nasal route: Mechanisms, applications and challenges. Curr. Drug Deliv., 2019, 16, 887-901.
[http://dx.doi.org/10.2174/1567201816666191029122740] [PMID: 31660815]
[7]
Shah, P.; Sarolia, J.; Vyas, B.; Wagh, P.; Ankur, K.; Kumar, M.A. PLGA nanoparticles for nose to brain delivery of clonazepam: Formulation, optimization by 32 factorial design, in vitro and in vivo evaluation. Curr Drug Deliv, 2021, 18, 805-824.
[http://dx.doi.org/10.2174/1567201817666200708115627]
[8]
Pardeshi, C.V.; Belgamwar, V.S. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: An excellent platform for brain targeting. Expert Opin. Drug Deliv., 2013, 10(7), 957-972.
[http://dx.doi.org/10.1517/17425247.2013.790887] [PMID: 23586809]
[9]
Guennoun, R.; Fréchou, M.; Gaignard, P.; Liere, P.; Slama, A.; Schumacher, M.; Denier, C.; Mattern, C. Intranasal administration of progesterone: A potential efficient route of delivery for cerebroprotection after acute brain injuries. Neuropharmacology, 2019, 145((Pt B)), 283-291.
[http://dx.doi.org/10.1016/j.neuropharm.2018.06.006] [PMID: 29885423]
[10]
Gautam, D.; Singh, S.; Maurya, P.; Singh, M.; Kushwaha, S.; Saraf, S.A. Appraisal of nano-lipidic astaxanthin cum thermoreversible gel and its efficacy in haloperidol induced Parkinsonism. Curr. Drug Deliv., 2021, 18, 1550-1562.
[http://dx.doi.org/10.2174/1567201818666210510173524] [PMID: 33970844]
[11]
Abd-Elrasheed, E.; El-Helaly, S.N.; EL-Ashmoony, M.M.; Salah, S. Brain targeted intranasal zaleplon nano-emulsion: In vitro characterization and assessment of gamma aminobutyric acid levels in rabbits’ brain and plasma at low and high doses. Curr. Drug Deliv., 2018, 15, 898-906.
[http://dx.doi.org/10.2174/1567201814666171130121732] [PMID: 29189154]
[12]
Lochhead, J.J.; Thorne, R.G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev., 2012, 64(7), 614-628.
[http://dx.doi.org/10.1016/j.addr.2011.11.002] [PMID: 22119441]
[13]
Fransén, N.; Espefält Westin, U.; Nyström, C.; Björk, E. The in vitro transport of dihydroergotamine across porcine nasal respiratory and olfactory mucosa and the effect of a novel powder formulation. J. Drug Deliv. Sci. Technol., 2007, 17(4), 267-271.
[http://dx.doi.org/10.1016/S1773-2247(07)50094-8]
[14]
Abdelrahman, F.E.; Elsayed, I.; Gad, M.K.; Badr, A.; Mohamed, M.I. Investigating the cubosomal ability for transnasal brain targeting: In vitro optimization, ex vivo permeation and in vivo biodistribution. Int. J. Pharm., 2015, 490(1-2), 281-291.
[http://dx.doi.org/10.1016/j.ijpharm.2015.05.064] [PMID: 26026251]
[15]
Chatzitaki, A.T.; Jesus, S.; Karavasili, C.; Andreadis, D.; Fatouros, D.G.; Borges, O. Chitosan-coated PLGA nanoparticles for the nasal delivery of ropinirole hydrochloride: In vitro and ex vivo evaluation of efficacy and safety. Int. J. Pharm., 2020, 589, 119776.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119776] [PMID: 32818538]
[16]
Du, G.; Gao, Y.; Nie, S.; Pan, W. The permeation of nalmefene hydrochloride across different regions of ovine nasal mucosa. Chem. Pharm. Bull. (Tokyo), 2006, 54(12), 1722-1724.
[http://dx.doi.org/10.1248/cpb.54.1722] [PMID: 17139110]
[17]
Eid, H.M.; Elkomy, M.H.; El Menshawe, S.F.; Salem, H.F. Transfersomal nanovesicles for nose-to-brain delivery of ofloxacin for better management of bacterial meningitis: Formulation, optimization by Box-Behnken design, characterization and in vivo pharmacokinetic study. J. Drug Deliv. Sci. Technol., 2019, 54, 101304.
[http://dx.doi.org/10.1016/j.jddst.2019.101304]
[18]
Karasulu, E.; Yavaşoğlu, A.; Evrenşanal, Z.; Uyanıkgil, Y.; Karasulu, H.Y. Permeation studies and histological examination of sheep nasal mucosa following administration of different nasal formulations with or without absorption enhancers. Drug Deliv., 2008, 15(4), 219-225.
[http://dx.doi.org/10.1080/10717540802006377] [PMID: 18446567]
[19]
Karavasili, C.; Bouropoulos, N.; Sygellou, L.; Amanatiadou, E.P.; Vizirianakis, I.S.; Fatouros, D.G. PLGA/DPPC/trimethylchitosan spray-dried microparticles for the nasal delivery of ropinirole hydrochloride: In vitro, ex vivo and cytocompatibility assessment. Mater. Sci. Eng. C, 2016, 59, 1053-1062.
[http://dx.doi.org/10.1016/j.msec.2015.11.028] [PMID: 26652464]
[20]
Nour, S.A.; Abdelmalak, N.S.; Naguib, M.J.; Rashed, H.M.; Ibrahim, A.B. Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: In vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies. Drug Deliv., 2016, 23(9), 3681-3695.
[http://dx.doi.org/10.1080/10717544.2016.1223216] [PMID: 27648847]
[21]
Pund, S.; Rasve, G.; Borade, G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur. J. Pharm. Sci., 2013, 48(1-2), 195-201.
[http://dx.doi.org/10.1016/j.ejps.2012.10.029] [PMID: 23159662]
[22]
Seju, U.; Kumar, A.; Sawant, K.K. Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: In vitro and in vivo studies. Acta Biomater., 2011, 7(12), 4169-4176.
[http://dx.doi.org/10.1016/j.actbio.2011.07.025] [PMID: 21839863]
[23]
Sood, S.; Jain, K.; Gowthamarajan, K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf. B Biointerfaces, 2014, 113, 330-337.
[http://dx.doi.org/10.1016/j.colsurfb.2013.09.030] [PMID: 24121076]
[24]
Wheatley, M.A.; Dent, J.; Wheeldon, E.B.; Smith, P.L. Nasal drug delivery: An in vitro characterization of transepithelial electrical properties and fluxes in the presence or absence of enhancers. J. Control. Release, 1988, 8(2), 167-177.
[http://dx.doi.org/10.1016/0168-3659(88)90043-0]
[25]
Salade, L.; Wauthoz, N.; Goole, J.; Amighi, K. How to characterize a nasal product. The state of the art of in vitro and ex vivo specific methods. Int. J. Pharm., 2019, 561, 47-65.
[http://dx.doi.org/10.1016/j.ijpharm.2019.02.026] [PMID: 30822505]
[26]
Berben, P.; Bauer-Brandl, A.; Brandl, M.; Faller, B.; Flaten, G.E.; Jacobsen, A.C.; Brouwers, J.; Augustijns, P. Drug permeability profiling using cell-free permeation tools: Overview and applications. Eur. J. Pharm. Sci., 2018, 119, 219-233.
[http://dx.doi.org/10.1016/j.ejps.2018.04.016] [PMID: 29660464]
[27]
Rinaki, E.; Valsami, G.; Macheras, P. Quantitative biopharmaceutics classification system: The central role of dose/solubility ratio. Pharm. Res., 2003, 20(12), 1917-1925.
[http://dx.doi.org/10.1023/B:PHAM.0000008037.57884.11] [PMID: 14725354]
[28]
Song, I.S.; Choi, Y.A.; Choi, M.K. Comparison of gastrointestinal permeability of caffeine, propranolol, atenolol, ofloxacin, and quinidine measured using ussing chamber system and Caco-2 cell monolayer. Mass Spectrom. Lett., 2017, 8(2), 34-38.
[29]
Chen, X.; Slättengren, T.; de Lange, E.C.M.; Smith, D.E.; Hammarlund-Udenaes, M. Revisiting atenolol as a low passive permeability marker. Fluids Barriers CNS, 2017, 14(1), 30.
[http://dx.doi.org/10.1186/s12987-017-0078-x] [PMID: 29089037]
[30]
Ladel, S.; Schlossbauer, P.; Flamm, J.; Luksch, H.; Mizaikoff, B.; Schindowski, K. Improved in vitro model for intranasal mucosal drug delivery: Primary olfactory and respiratory epithelial cells compared with the permanent Nasal cell line RPMI 2650. Pharmaceutics, 2019, 11(8), 367.
[http://dx.doi.org/10.3390/pharmaceutics11080367] [PMID: 31374872]
[31]
Bhushani, J.A.; Karthik, P.; Anandharamakrishnan, C. Nanoemulsion based delivery system for improved bioaccessibility and Caco-2 cell monolayer permeability of green tea catechins. Food Hydrocoll., 2016, 56, 372-382.
[http://dx.doi.org/10.1016/j.foodhyd.2015.12.035]
[32]
Irvine, J.D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J.W.; Selick, H.E.; Grove, J.R. Jr. MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. J. Pharm. Sci., 1999, 88(1), 28-33.
[http://dx.doi.org/10.1021/js9803205] [PMID: 9874698]
[33]
Shikanga, E.; Hamman, J.; Chen, W.; Combrinck, S.; Gericke, N.; Viljoen, A. In vitro permeation of mesembrine alkaloids from Sceletium tortuosum across porcine buccal, sublingual, and intestinal mucosa. Planta Med., 2012, 78(3), 260-268.
[http://dx.doi.org/10.1055/s-0031-1280367] [PMID: 22105579]
[34]
ICH. Validation of analytical procedures: Text and methodology Q2(R1). Available from: https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf (Accessed on: 2022 Mar 7).
[35]
Wahlang, B.; Pawar, Y.B.; Bansal, A.K. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur. J. Pharm. Biopharm., 2011, 77(2), 275-282.
[http://dx.doi.org/10.1016/j.ejpb.2010.12.006] [PMID: 21147222]
[36]
Gerber, W.; Steyn, D.; Kotzé, A.; Svitina, H.; Weldon, C.; Hamman, J. Capsaicin and piperine as functional excipients for improved drug delivery across nasal epithelial models. Planta Med., 2019, 85, 1114-1123.
[http://dx.doi.org/10.1055/a-0978-5172] [PMID: 31340396]
[37]
Haasbroek, A. Drug absorption enhancement capacities and mechanisms of action of Aloe vera gel materials., MSc Dissertation, North-West University: Potchefstroom, 2018.
[38]
Barrios, A.W.; Sanchez Quinteiro, P.; Salazar, I. The nasal cavity of the sheep and its olfactory sensory epithelium. Microsc. Res. Tech., 2014, 77(12), 1052-1059.
[http://dx.doi.org/10.1002/jemt.22436] [PMID: 25213000]
[39]
Deferme, S.; Annaert, P.; Augutijns, P. In vitro screening models to assess intestinal drug absorption and metabolism. In: Drug absorption studies: In situ, in vitro and in silico models,, 1st ed; Ehrhard, C.; Kim, K.J., Eds.; Springer Science & Business Media: New York, USA,, 2008; pp. 182-215.
[http://dx.doi.org/10.1007/978-0-387-74901-3_8]
[40]
Palumbo, P.; Picchini, U.; Beck, B.; van Gelder, J.; Delbar, N.; DeGaetano, A. A general approach to the apparent permeability index. J. Pharmacokinet. Pharmacodyn., 2008, 35(2), 235-248.
[http://dx.doi.org/10.1007/s10928-008-9086-4] [PMID: 18351296]
[41]
Hansen, T.S.; Nilsen, O.G. Echinacea purpurea and P-glycoprotein drug transport in Caco-2 cells. Phytother. Res., 2009, 23(1), 86-91.www.interscience.wiley.com
[http://dx.doi.org/10.1002/ptr.2563] [PMID: 18688789]
[42]
Gerber, W.; Svitina, H.; Steyn, D.; Peterson, B.; Kotzé, A.; Weldon, C.; Hamman, J.H. Comparison of RPMI 2650 cell layers and excised sheep nasal epithelial tissues in terms of nasal drug delivery and immunocytochemistry properties. J. Pharmacol. Toxicol. Methods, 2022, 113, 107131.
[http://dx.doi.org/10.1016/j.vascn.2021.107131] [PMID: 34699972]
[43]
Crowe, T.P.; Greenlee, M.H.W.; Kanthasamy, A.G.; Hsu, W.H. Mechanism of intranasal drug delivery directly to the brain. Life Sci., 2018, 195, 44-52.
[http://dx.doi.org/10.1016/j.lfs.2017.12.025] [PMID: 29277310]
[44]
Djupesland, P.G.; Messina, J.C.; Mahmoud, R.A. The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview. Ther. Deliv., 2014, 5(6), 709-733.
[http://dx.doi.org/10.4155/tde.14.41] [PMID: 25090283]
[45]
Keller, L.A.; Merkel, O.; Popp, A. Intranasal drug delivery: Opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res., 2022, 12(4), 735-757.
[http://dx.doi.org/10.1007/s13346-020-00891-5] [PMID: 33491126]
[46]
Illum, L. Nasal drug delivery - Possibilities, problems and solutions. J. Control. Release, 2003, 87, 187-198.
[http://dx.doi.org/10.1016/S0168-3659(02)00363-2] [PMID: 12618035]
[47]
Fortuna, A.; Alves, G.; Falcão, A. In vitro and in vivo relevance of the P-glycoprotein probe substrates in drug discovery and development: Focus on rhodamine 123, digoxin and talinolol. J. Bioequivalence Availab., 2011, 01(02), 1-23.
[http://dx.doi.org/10.4172/jbb.S2-001]
[48]
Sharma, B.; Luhach, K.; Kulkarni, G.T. In vitro and in vivo models of BBB to evaluate brain targeting drug delivery. In: Gao H, Gao X, editors.Brain targeted Drug Delivery Systems: A Focus on Nanotechnology and Nanoparticles, 1st ed; London, UK: Elsevier Academic Press, 2019, pp. 53-101.
[49]
E Kratzing, J. The olfactory mucosa of the sheep. Aust. J. Biol. Sci., 1970, 23(2), 447-458.
[http://dx.doi.org/10.1071/BI9700447]
[50]
Ibrahim, D.; Nakamuta, N.; Taniguchi, K.; Yamamoto, Y.; Taniguchi, K. Histological and lectin histochemical studies on the olfactory and respiratory mucosae of the sheep. J. Vet. Med. Sci., 2014, 76(3), 339-346.
[http://dx.doi.org/10.1292/jvms.13-0436] [PMID: 24200894]
[51]
Kavoi, B.; Makanya, A.; Hassanali, J.; Carlsson, H.E.; Kiama, S. Comparative functional structure of the olfactory mucosa in the domestic dog and sheep. Ann. Anat., 2010, 192(5), 329-337.
[http://dx.doi.org/10.1016/j.aanat.2010.07.004] [PMID: 20801626]

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