An ex-vivo model for transsynovial drug permeation of intraarticular injectables in naive and arthritic synovium
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 mode...
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Published in | Journal of controlled release Vol. 332; pp. 581 - 591 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
10.04.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•ex-vivo synovial explant model allows quantification of drug leakage from the joint.•LPS induced synovitis partially mimics inflammatory permeability changes in-vivo.•porcine ex-vivo model shows superiority in IVIVC over usual artificial membranes.•assessment of the substance-dependent permeability in terms of size or charge. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0168-3659 1873-4995 |
DOI: | 10.1016/j.jconrel.2021.03.008 |