{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:34:50Z","timestamp":1790361290765,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","award":["75F40120C00150"],"award-info":[{"award-number":["75F40120C00150"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. Food and Drug Administration were quantified using the human-derived sublingual HO-1-u-1 and buccal EpiOral\u2122 in vitro tissue models. Methods: Epithelial barrier properties were monitored using propranolol and Lucifer Yellow as prototypic transcellular and paracellular markers. APIs were dissolved in artificial saliva, pH 6.7, and transepithelial flux from the apical to the basolateral compartment was quantified using HPLC. Results: Apparent permeability coefficients (Papp) calculated for these APIs in the sublingual HO-1-u-1 tissue model varied from Papp = 2.72 \u00b1 0.06 \u00d7 10\u22125 cm\/s for asenapine to Papp = 6.21 \u00b1 2.60 \u00d7 10\u22125 cm\/s for naloxone. In contrast, the buccal EpiOral\u2122 tissue model demonstrated greater discrimination power in terms of permeation properties for the same APIs, with values ranging from Papp = 3.31 \u00b1 0.83 \u00d7 10\u22127 cm\/s for acyclovir to Papp = 2.56 \u00b1 0.68 \u00d7 10\u22125 cm\/s for sufentanil. The tissue-associated dose fraction recovered at the end of the transport experiment was significantly increased in the buccal EpiOral\u2122 tissue model, reaching up to 8.5% for sufentanil. Conclusions: Experimental permeation data collected for selected APIs in FDA-approved oral cavity products will serve as a training set to aid the development of predictive computational models for improving algorithms that describe drug absorption from the oral cavity. Following a robust in vitro\u2013in vivo correlation analysis, it is expected that such innovative in silico modeling strategies will the accelerate development of generic oral cavity products by facilitating the utility of model-integrated evidence to support decision making in generic drug development and regulatory approval.<\/jats:p>","DOI":"10.3390\/pharmaceutics17070924","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T13:00:51Z","timestamp":1752757251000},"page":"924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In Vitro Oral Cavity Permeability Assessment to Enable Simulation of Drug Absorption"],"prefix":"10.3390","volume":"17","author":[{"given":"Pankaj","family":"Dwivedi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in Saint Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyata","family":"Kalra","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc., Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc., Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khondoker","family":"Alam","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Tsakalozou","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manar","family":"Al-Ghabeish","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Kelchen","sequence":"additional","affiliation":[{"name":"Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-4964","authenticated-orcid":false,"given":"Giovanni M.","family":"Pauletti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in Saint Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ibarra, M., Troc\u00f3niz, I.F., and Fagiolino, P. (2021). Enteric reabsorption processes and their impact on drug pharmacokinetics. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-85174-w"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/mds.870060304","article-title":"Absorption of apomorphine by various routes in parkinsonism","volume":"6","author":"Gancher","year":"1991","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1517\/14656566.2010.506188","article-title":"Evaluation of the clinical efficacy of asenapine in schizophrenia","volume":"11","author":"Minassian","year":"2010","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1586\/14787210.2014.880337","article-title":"Acyclovir Lauriad\u00ae: A muco-adhesive buccal tablet for the treatment of recurrent herpes labialis","volume":"12","author":"Downing","year":"2014","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2165\/00063030-200519030-00003","article-title":"Oral delivery of peptide drugs: Barriers and developments","volume":"19","author":"Hamman","year":"2005","journal-title":"BioDrugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1479568","DOI":"10.1080\/21688370.2018.1479568","article-title":"Cell culture models of oral mucosal barriers: A review with a focus on applications, culture conditions and barrier properties","volume":"6","author":"Bierbaumer","year":"2018","journal-title":"Tissue Barriers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0378-5173(99)00091-5","article-title":"A mechanistic analysis to characterize oramucosal permeation properties","volume":"184","author":"Chen","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_8","unstructured":"U.S. Food and Drug Administration (FDA) (2025). Approved Drug Products with Therapeutic Equivalence Evaluations, Orange Book."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1208\/pt0804106","article-title":"Influence of a niosomal formulation on the oral bioavailability of acyclovir in rabbits","volume":"8","author":"Attia","year":"2007","journal-title":"AAPS PharmSciTech"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Marquet, P. (2002). Pharmacology of high-dose buprenorphine. Buprenorphine Therapy of Opiate Addiction, Humana Press.","DOI":"10.1007\/978-1-59259-282-1_1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1097\/00000542-199108000-00009","article-title":"Absorption and bioavailability of oral transmucosal fentanyl citrate","volume":"75","author":"Streisand","year":"1991","journal-title":"Anesthesiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"360","DOI":"10.5414\/CP201646","article-title":"Low absolute bioavailability of oral naloxone in healthy subjects","volume":"50","author":"Smith","year":"2012","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.clinthera.2014.11.001","article-title":"Pharmacokinetic properties of single- and repeated-dose sufentanil sublingual tablets in healthy volunteers","volume":"37","author":"Willsie","year":"2015","journal-title":"Clin. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2165\/00003495-199040020-00008","article-title":"Zolpidem","volume":"40","author":"Langtry","year":"1990","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1002\/1097-0142(19871215)60:12<2927::AID-CNCR2820601214>3.0.CO;2-0","article-title":"Monoclonal antibodies against human oral squamous cell carcinoma reacting with keratin proteins","volume":"60","author":"Myoken","year":"1987","journal-title":"Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijpharm.2008.11.010","article-title":"HO-1-u-1 model for screening sublingual drug delivery\u2014Influence of pH, osmolarity and permeation enhancer","volume":"370","author":"Wang","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_17","first-page":"6","article-title":"Preparation of artificial saliva formulation","volume":"2","author":"Amal","year":"2015","journal-title":"Pharm. Technol."},{"key":"ref_18","first-page":"284652","article-title":"Development and Validation of Acyclovir HPLC External Standard Method in Human Plasma: Application to Pharmacokinetic Studies","volume":"2014","author":"Muralidharan","year":"2014","journal-title":"Adv. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.2147\/DDDT.S116848","article-title":"Stability of apomorphine in solutions containing selected antioxidant agents","volume":"10","author":"Ang","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3797\/scipharm.1112-07","article-title":"Stability-indicating liquid chromatographic method for the quantification of the new antipsychotic agent asenapine in bulk and in pharmaceutical formulation","volume":"80","author":"Chhalotiya","year":"2012","journal-title":"Sci. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.talanta.2008.09.024","article-title":"Development and validation of a HPLC method for the determination of buprenorphine hydrochloride, naloxone hydrochloride and noroxymorphone in a tablet formulation","volume":"77","author":"Mostafavi","year":"2009","journal-title":"Talanta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0731-7085(00)00312-5","article-title":"Development and validation of an HPLC assay for fentanyl, alfentanil, and sufentanil in swab samples","volume":"23","author":"Lambropoulos","year":"2000","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_23","first-page":"1909","article-title":"Development of a Validated HPLC Method for the Estimation of Metformin HCl and Propranolol HCl","volume":"4","author":"Meka","year":"2014","journal-title":"J. Pharm. Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357890","DOI":"10.1155\/2013\/357890","article-title":"Development and Validation of a Reversed-Phase HPLC Method for the Estimation of Zolpidem in Bulk Drug and Tablets","volume":"2013","author":"Konoz","year":"2013","journal-title":"J. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.archoralbio.2009.02.004","article-title":"Whole saliva flow rate and body profile in healthy young adults","volume":"54","author":"Yamamoto","year":"2009","journal-title":"Arch. Oral Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1208\/s12249-020-1618-2","article-title":"Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin","volume":"21","author":"Eleraky","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.1002\/jps.22674","article-title":"Development of a new permeability assay using low-efflux MDCKII cells","volume":"100","author":"Di","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1016\/j.xphs.2021.01.029","article-title":"Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space","volume":"110","author":"Huth","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.tiv.2007.01.024","article-title":"Organotypic human oral tissue models for toxicological studies","volume":"21","author":"Klausner","year":"2007","journal-title":"Toxicol. Vitr."},{"key":"ref_30","first-page":"E24","article-title":"High glucose concentration in isotonic media alters caco-2 cell permeability","volume":"5","author":"Shertzer","year":"2003","journal-title":"AAPS PharmSciTech"},{"key":"ref_31","first-page":"237","article-title":"Cellular and molecular basis of barrier function in oral epithelium","volume":"8","author":"Wertz","year":"1991","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1208\/s12248-010-9227-8","article-title":"Application of method suitability for drug permeability classification","volume":"12","author":"Volpe","year":"2010","journal-title":"AAPS J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"124998","DOI":"10.1016\/j.ijpharm.2024.124998","article-title":"Sublingual permeability of model drugs in New Zealand White Rabbits: In Vitro-In vivo correlation","volume":"668","author":"Kaur","year":"2025","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wanasathop, A., Patel, P.B., Choi, H.A., and Li, S.K. (2021). Permeability of Buccal Mucosa. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111814"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.xphs.2018.10.006","article-title":"Physicochemical QSAR analysis of passive permeability across Caco-2 monolayers","volume":"108","author":"Lanevskij","year":"2019","journal-title":"J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"661","DOI":"10.2165\/00003088-200241090-00003","article-title":"Oral mucosal drug delivery: Clinical pharmacokinetics and therapeutic applications","volume":"41","author":"Zhang","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1208\/s12249-012-9839-7","article-title":"Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine","volume":"13","author":"Bartlett","year":"2012","journal-title":"AAPS PharmSciTech"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:13Z","timestamp":1760033473000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["pharmaceutics17070924"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17070924","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]}}}