Abstract by Janni Støvring Mortensen

The mucus barrier that surface-lines the gastrointestinal tract (GIT), protects the underlying epithelium by limiting the diffusion of endogenous and exogenous compounds such as biopharmaceuticals (BPs), and thus challenges successful oral delivery of BPs. Drug delivery systems (DDSs) containing functional excipients are used to counteract the low stability and poor epithelial permeation of BPs. To enhance the latter, excipients such as permeation enhancers (PEs) are often utilized in DDSs. Yet, the interplay between functional excipients such as PEs and the mucus barrier is to date poorly understood nor studied in representative and reliable mucus models.

This thesis aimed to investigate the interactions between, and effects of, the frequently used lipid-based PEs, sodium 8-[(2-hydroxybenzoyl)amino]octanoate (SNAC) and sodium decanoate (C10) in gastrointestinal (GI) mucus from pigs and in a biosimilar mucus (BM) model. Additionally, this work also aimed to investigate if the regional site of mucus, as well as age and maturity of the donor pig, would affect the interactions between PEs and mucus.

Overall, the addition of SNAC or C10 to ex vivo porcine intestinal mucus (PIM) enhanced the barrier properties of PIM, as the exposure to SNAC or C10 increased the mucus retention and viscosity of PIM, leading to decreased nanoparticle (NP) diffusion due to a more dense microstructural network of PIM, and thus increased confinement of NPs in PIM. In contrast, the permeation of hydrophilic macromolecules through PIM was not affected by the presence of SNAC. Interestingly, the viscosity of ex vivo porcine gastric mucus (PGM) was not affected by the presence of SNAC, which differed from the observation in PIM. Additionally, the degree to which SNAC and C10 induced NP confinement in PIM depended highly on the donor pig’s age and maturity. Permeation of a wide range of molecular weights and charged hydrophilic macromolecules through BM was similar to that through PIM, yet the effects of SNAC and C10 in BM differed from the effects observed in PIM.

Overall, this thesis emphasizes the need for more knowledge of how excipients such as PEs affect the mucus barrier and that careful selection of the mucus models for such studies is needed. Furthermore, information on how different regional mucus sites or conditions such as age and maturity may impact mucus interactions with DDS and excipients is required to create efficient DDSs for oral delivery of BPs that may permeate the mucus barrier to improve oral drug delivery of BPs.