Development and Rheological Profiling of Biosimilar Mucus

This article presents the development of a biosimilar mucus mixture for assessment of the effect of mucus on drug absorption. The biosimilar mucus was optimized to represent a rheological profile similar to that of porcine intestinal mucus. This was obtained with a mixture of mucin, polyacrylic acid, lipids and BSA. INTRODUCTION The viscoelastic mucus layers covering the epithelial surfaces are likely to constitute a barrier to mucosal drug delivery. The viscosity and the network structure of mucus can physically constitute a barrier to the diffusion of drugs and drug delivery systems and thereby decrease or prevent transmucosal drug absorption. Furthermore, the net negative charge and hydrophilicity of mucus and the interactions between mucus components and drugs amplify the barrier properties of mucus. It is crucial to have suitable models to assess the effect of mucus on drug absorption. Mucus is composed of ~95 % water, ~5 % mucin, small amounts of proteins, lipids, DNA and electrolytes. Mucins are high molecular weight, heavily glycosylated proteins that are responsible for the rheological properties of mucus. The selection of commercially available mucin is limited to mucin that is isolated from porcine stomach or bovine submaxillary glands and subjected to a purification process, this however reduces the molecular weight of the mucins. It has been demonstrated that commercial porcine gastric mucin in itself does not represent the rheological properties of native mucus. Mucus is a non-Newtonian viscoelastic gel with shear-thinning properties and dominant elastic behavior irrespective of its physiological origin. However, the viscosity of mucus from different physiological locations appear to vary, which might be due to variation in pH and ionic strength that influence the viscosity or it might correlate with differences in the detailed composition of mucus, but this has not yet been systematically investigated. Generally, the knowledge on variation in mucus between species, individuals, physiological sites and health/disease states with respect to content and rheological profile is sparse. This is mainly due to the difficulties in obtaining truly representative mucus and in isolating the large, highly polydisperse and complex mucins for analysis. The inaccessibility to obtaining native mucus have led to the development of several different simulated mucus mixtures and use of cell cultures as e.g. Calu-3 cells, which can secrete mucus, in contrast to the standard model for assessing intestinal absorption, the Caco-2 cells. In rare cases, the simulated mucus mixture is based on a preceding analysis on Development and Rheological Profiling of Biosimilar Mucus Marie Boegh, Stefania G. Baldursdottir, Maja H. Nielsen, Anette Müllertz and Hanne M. Nielsen Department of Pharmacy, Faculty of Health and Medical Sciences University of Copenhagen, Copenhagen, Denmark