{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:33:32Z","timestamp":1792089212592,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Drug administration to the vaginal site has gained increasing attention in past decades, highlighting the need for reliable in vitro methods to assess the performance of novel formulations. To optimize formulations destined for the vaginal site, it is important to evaluate the drug retention within the vagina as well as its permeation across the mucosa, particularly in the presence of vaginal fluids. Herewith, the vaginal-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model was validated as a tool to evaluate the permeation of the anti-inflammatory drug ibuprofen from liposomal formulations (i.e., plain and chitosan-coated liposomes). Drug permeation was assessed in the presence and absence of mucus and simulated vaginal fluid (SVF) at pH conditions mimicking both the healthy vaginal premenopausal conditions and vaginal infection\/pre-puberty\/post-menopause state. The permeation of ibuprofen proved to depend on the type of formulation (i.e., chitosan-coated liposomes exhibited lower drug permeation), the mucoadhesive formulation properties and pH condition. This study highlights both the importance of mucus and SVF in the vaginal model to better understand and predict the in vivo performance of formulations destined for vaginal administration, and the suitability of the vaginal-PVPA model for such investigations.<\/jats:p>","DOI":"10.3390\/pharmaceutics12060568","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T10:43:58Z","timestamp":1592563438000},"page":"568","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The Vaginal-PVPA: A Vaginal Mucosa-Mimicking In Vitro Permeation Tool for Evaluation of Mucoadhesive Formulations"],"prefix":"10.3390","volume":"12","author":[{"given":"Margherita","family":"Falavigna","sequence":"first","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Pattacini","sequence":"additional","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Troms\u00f8, Norway"},{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco, Universit\u00e0 di Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wibel","sequence":"additional","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-1456","authenticated-orcid":false,"given":"Fabio","family":"Sonvico","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco, Universit\u00e0 di Parma, Parco Area delle Scienze 27\/a, 43124 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-2840","authenticated-orcid":false,"given":"Natasa","family":"\u0160kalko-Basnet","sequence":"additional","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0934-9773","authenticated-orcid":false,"given":"G\u00f8ril Eide","family":"Flaten","sequence":"additional","affiliation":[{"name":"Drug Transport and Delivery Research Group, Department of Pharmacy, UiT The Arctic University of Norway, Universitetsvegen 57, 9037 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1080\/17425247.2019.1645117","article-title":"Recent advances in the mucus-interacting approach for vaginal drug delivery: From mucoadhesive to mucus-penetrating nanoparticles","volume":"16","author":"Rossi","year":"2019","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_2","unstructured":"Sarmento, B. (2016). Cell-based in vitro models for vaginal permeability studies. Concepts and Models for Drug Permeability Studies\u2014Cell Tissue Based in Vitro Culture Models, Woodhead Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rai, M., and dos Santos, C.A. (2017). Nanoformulations for vaginal therapy. Nanotechnology Applied to Pharmaceutical Technology, Springer International Publishing AG.","DOI":"10.1007\/978-3-319-70299-5"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.addr.2015.06.008","article-title":"New strategies for local treatment of vaginal infections","volume":"92","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1021\/mp300408m","article-title":"Interactions of Microbicide Nanoparticles with a Simulated Vaginal Fluid","volume":"9","author":"Rocha","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"J\u00f8raholmen, M.W., Bhargava, A., Julin, K., Johannessen, M., and Skalko-Basnet, N. (2020). The Antimicrobial Properties of Chitosan Can Be Tailored by Formulation. Mar. Drugs, 18.","DOI":"10.3390\/md18020096"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijsu.2019.10.015","article-title":"The current state of animal models in research: A review","volume":"72","author":"Robinson","year":"2019","journal-title":"Int. J. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ejpb.2015.01.005","article-title":"Methods to determine the interactions of micro- and nanoparticles with mucus","volume":"96","author":"Cattoz","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0010-7824(99)00010-4","article-title":"A vaginal fluid simulant","volume":"59","author":"Owen","year":"1999","journal-title":"Contraception"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5957","DOI":"10.2147\/IJN.S211691","article-title":"Azithromycin-liposomes as a novel approach for localized therapy of cervicovaginal bacterial infections","volume":"14","author":"Vanic","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ijpharm.2017.12.038","article-title":"Mucus-PVPA (mucus Phospholipid Vesicle-based Permeation Assay): An artificial permeability tool for drug screening and formulation development","volume":"537","author":"Falavigna","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ejps.2019.02.035","article-title":"Mimicking regional and fasted\/fed state conditions in the intestine with the mucus-PVPA in vitro model: The impact of pH and simulated intestinal fluids on drug permeability","volume":"132","author":"Falavigna","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1002\/jps.23845","article-title":"Improved Permeability of Acyclovir: Optimization of Mucoadhesive Liposomes Using the Phospholipid Vesicle-Based Permeation Assay","volume":"103","author":"Naderkhani","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jconrel.2017.12.004","article-title":"Polymeric gels for intravaginal drug delivery","volume":"270","author":"Cook","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.resmic.2017.04.004","article-title":"Aerobic vaginitis: No longer a stranger","volume":"168","author":"Donders","year":"2017","journal-title":"Res. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejpb.2014.02.006","article-title":"Mucoadhesive liposomes as new formulation for vaginal delivery of curcumin","volume":"87","author":"Berginc","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ijpharm.2014.06.016","article-title":"Chitosan-coated liposomes for topical vaginal therapy: Assuring localized drug effect","volume":"472","author":"Vanic","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ejps.2005.08.007","article-title":"Drug permeability across a phospholipid vesicle based barrier: A novel approach for studying passive diffusion","volume":"27","author":"Flaten","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ejps.2015.09.007","article-title":"Resveratrol-loaded liposomes for topical treatment of the vaginal inflammation and infections","volume":"79","author":"Acharya","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ejps.2018.04.016","article-title":"Drug permeability profiling using cell-free permeation tools: Overview and applications","volume":"119","author":"Berben","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5601","DOI":"10.2147\/IJN.S141949","article-title":"Stratum corneum lipid liposome-encapsulated panomycocin: Preparation, characterization, and the determination of antimycotic efficacy against Candida spp. isolated from patients with vulvovaginitis in an in vitro human vaginal epithelium tissue model","volume":"12","author":"Bayram","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"J\u00f8raholmen, M.W., Basnet, P., Tostrup, M.J., Moueffaq, S., and Skalko-Basnet, N. (2019). Localized Therapy of Vaginal Infections and Inflammation: Liposomes-In-Hydrogel Delivery System for Polyphenols. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11020053"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Andersen, T., Mishchenko, E., Flaten, G.E., Sollid, J.U.E., Mattsson, S., Tho, I., and Skalko-Basnet, N. (2017). Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes. Mar. Drugs, 15.","DOI":"10.3390\/md15030064"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giordani, B., Basnet, P., Mishchenko, E., Luppi, B., and Skalko-Basnet, N. (2019). Utilizing Liposomal Quercetin and Gallic Acid in Localized Treatment of Vaginal Candida Infections. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12010009"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1007\/s13346-017-0395-2","article-title":"Vaginal drug delivery for the localised treatment of cervical cancer","volume":"7","author":"Major","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"52001","DOI":"10.1088\/1361-6528\/28\/5\/052001","article-title":"Application of nanotechnology for the development of microbicides","volume":"28","author":"Brako","year":"2016","journal-title":"Nanotechnology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1208\/s12248-011-9290-9","article-title":"BDDCS Applied to Over 900 Drugs","volume":"13","author":"Benet","year":"2011","journal-title":"AAPS J."},{"key":"ref_28","first-page":"17","article-title":"Thin-Film Hydration Followed by Extrusion Method for Liposome Preparation","volume":"Volume 1522","author":"Zhang","year":"2016","journal-title":"Advanced Structural Safety Studies"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijpharm.2004.07.010","article-title":"Liposome formulation of poorly water soluble drugs: Optimisation of drug loading and ESEM analysis of stability","volume":"285","author":"Mohammed","year":"2004","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/wnan.144","article-title":"Mucoadhesive nanosystems for vaginal microbicide development: Friend or foe?","volume":"3","author":"Amiji","year":"2011","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3390\/md13010222","article-title":"Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy","volume":"13","author":"Andersen","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ijpharm.2005.06.028","article-title":"Effectiveness of submicron-sized, chitosan-coated liposomes in oral administration of peptide drugs","volume":"303","author":"Takeuchi","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1002\/jps.23954","article-title":"Development of a Biomimetic Phospholipid Vesicle-based Permeation Assay for the Estimation of Intestinal Drug Permeability","volume":"103","author":"Naderkhani","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ijbiomac.2012.09.013","article-title":"Ibuprofen-loaded chitosan and chemically modified chitosans\u2014Release features from tablet and film forms","volume":"52","author":"Vieira","year":"2013","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Avdeef, A. (2003). Charge State. Absorption and Drug Development: Solubility, Permeability, and Charge State, John Wiley & Sons Inc.","DOI":"10.1002\/047145026X"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"118739","DOI":"10.1016\/j.ijpharm.2019.118739","article-title":"The effect of freeze-drying on mucoadhesion and transport of acrylated chitosan nanoparticles","volume":"573","author":"Eliyahu","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1700060","DOI":"10.1002\/mabi.201700060","article-title":"A Polymer Chemistry Point of View on Mucoadhesion and Mucopenetration","volume":"17","author":"Schattling","year":"2017","journal-title":"Macromol. Biosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1128\/MMBR.68.1.132-153.2004","article-title":"Diversity of Microbial Sialic Acid Metabolism","volume":"68","author":"Vimr","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/S0006-3495(99)77288-7","article-title":"pH-dependent conformational change of gastric mucin leads to sol-gel transition","volume":"76","author":"Cao","year":"1999","journal-title":"Biophys. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.3390\/polym3041875","article-title":"Biomedical Activity of Chitin\/Chitosan Based Materials\u2014Influence of Physicochemical Properties Apart from Molecular Weight and Degree of N-Acetylation","volume":"3","author":"Kumirska","year":"2011","journal-title":"Polymers"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Falavigna, M., Stein, P.C., Flaten, G.E., and Di Cagno, M.P. (2020). Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020168"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejps.2015.03.017","article-title":"Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids","volume":"73","author":"Naderkhani","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"312","DOI":"10.18433\/J3HP41","article-title":"Strategies to prolong the intravaginal residence time of drug delivery systems","volume":"12","author":"Baloglu","year":"2009","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ejps.2011.06.007","article-title":"Engineering tenofovir loaded chitosan nanoparticles to maximize microbicide mucoadhesion","volume":"44","author":"Meng","year":"2011","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jpba.2018.04.041","article-title":"Rheological analysis and mucoadhesion: A 30 year-old and still active combination","volume":"156","author":"Rossi","year":"2018","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/6\/568\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:40:43Z","timestamp":1760175643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/6\/568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,19]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["pharmaceutics12060568"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12060568","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,19]]}}}