Prediction of subcutaneous drug absorption - do we have reliable data to design a simulated interstitial fluid?

For many years subcutaneous (SC) administration has represented the main route for delivering biopharmaceuticals. However, little information exists about the milieu in the subcutaneous tissue, especially about the properties/composition of the fluid present in this tissue, the interstitial fluid (ISF), which is one of the key elements for the drug release and absorption. Better knowledge on SC ISF composition, properties and dynamics may provide better insight into in vivo drug performance. In addition, a simulated SC ISF, which allows better prediction of in vivo absorption of drugs after subcutaneous administration based on in vitro release experiments, would help to improve formulation design, and reduce the number of animal studies and clinical trials required to obtain marketing authorization. To date, a universal medium for predicting drug solubility/release in the interstitial space does not exist. This review provides an overview of the currently available information on composition and physicochemical properties of SC ISF and critically discusses different isolation techniques in the context of information that could be gained from the isolated fluid. Moreover, it surveys current in vitro release media aiming to mimic SC ISF composition and highlights information gaps that need to be filled for designing a meaningful artificial SC ISF.