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Oral transmucosal delivery of eletriptan for neurological diseases.
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.ORCID iD: 0000-0002-2535-7108
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
Malmö University, Faculty of Health and Society (HS), Department of Biomedical Science (BMV). Malmö University, Biofilms Research Center for Biointerfaces.
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2022 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 627, article id 122222Article in journal (Refereed) Published
Abstract [en]

Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 627, article id 122222
Keywords [en]
Caffeine, Cell uptake, Digitonin, Dissolution, Eletriptan hydrobromide, Enhancer, FITC-labeled dextran, Oral transmucosal delivery, Permeation pathway, Tissue integrity, Triptans
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:mau:diva-56096DOI: 10.1016/j.ijpharm.2022.122222ISI: 000886537500005PubMedID: 36155795Scopus ID: 2-s2.0-85139046757OAI: oai:DiVA.org:mau-56096DiVA, id: diva2:1711478
Available from: 2022-11-17 Created: 2022-11-17 Last updated: 2024-02-05Bibliographically approved

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Valetti, SabrinaPrgomet, ZdenkaEngblom, JohanBjörklund, Sebastian

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Valetti, SabrinaRiaz, AzraPrgomet, ZdenkaEngblom, JohanBjörklund, Sebastian
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Department of Biomedical Science (BMV)Biofilms Research Center for BiointerfacesFaculty of Odontology (OD)
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