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

• Published in: Journal of controlled release Vol. 332; pp. 581 - 591
• Main Authors: Siefen, Tobias, Lokhnauth, John, Liang, Alfred, Larsen, Crilles Casper, Lamprecht, Alf
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.04.2021
• Subjects: Formulation development; Franz-cell; Joint residence time; Permeability; Synovitis; Formulation development; Synovitis; Joint residence time; Permeability; Franz-cell
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.03.008

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. [Display omitted] •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.