An ex-vivo model for transsynovial drug permeation of intraarticular injectables in naive and arthritic synovium

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TitreAn ex-vivo model for transsynovial drug permeation of intraarticular injectables in naive and arthritic synovium
Type de publicationJournal Article
Year of Publication2021
AuteursSiefen T, Lokhnauth J, Liang A, Larsen CCasper, Lamprecht A
JournalJOURNAL OF CONTROLLED RELEASE
Volume332
Pagination581-591
Date PublishedAPR 10
Type of ArticleArticle
ISSN0168-3659
Mots-clésFormulation development, Franz-cell, Joint residence time, Permeability, synovitis
Résumé

Estimation of joint residence time of a drug is a key requirement for rational development of intraarticular therapeutics. There is a great need for a predictive model to reduce the high number of animal experiments in early stage development. Here, a Franz-cell based porcine ex-vivo permeation model is proposed, and transsynovial permeation of fluorescently-labeled dextrans in the range of potential drug candidates (10?150 kDa), as well as a small molecule (fluorescein sodium) and charged dextran derivates, have been determined. In addition, a lipopolysaccharide (LPS) -induced synovitis model was assessed for inflammatory biomarker levels and its effect on permeation of the solutes. Size-dependent permeability was observed for the analytes, which distinctly differed from findings with an artificial polycarbonate membrane, which is a widely used model. LPS was found to successfully stimulate an inflammatory response and led to a reduced size selectivity of the synovial membrane. 150 kDa dextran flux was accelerated approximately 2.5-fold in the inflamed state, whereas the permeation of smaller molecules was little affected. Moreover, by varying the LPS concentrations, the ex-vivo model was shown to produce varying degrees of synovitis-like inflammation. A simple and highly relevant ex-vivo tool for investigation of transsynovial permeation was developed, offering the further advantage of mimicking synovitis-induced permeability changes. Thus, this model provides a promising method for formulation screening, while reducing the need for animal experiments.

DOI10.1016/j.jconrel.2021.03.008