Peroral polypeptide delivery. A comparative in vitro study of mucolytic agents

Besides the absorption and enzymatic barrier, the diffusion barrier based on the mucus gel layer covering gastrointestinal (GI) epithelia represents the third major factor being responsible for a very poor bioavailability of orally administered (poly)peptide drugs. In order to overcome the latter ones, the mucus liquefying action of various types of mucolytic agents and their influence on the model polypeptide drug insulin has been evaluated in a comparative in vitro study. The results demonstrated that the proteases pronase (EC 3.4.24.31) and papain (EC 3.4.22.2) cause a relative reduction in mucus viscosity of 75.9 +/- 6.8% and 51.1 +/- 3.3% (n = 3) after 6 h of incubation at pH 5.0, respectively, whereas the mucolytic effect of the detergents Triton X-100 (octoxinol) and Tween 20 (polysorbate 20) was markedly lower. Mucolytic proteases and well established mucolytic sulfhydryl compounds, however, caused a rapid degradation of insulin. Therefore these two types of mucolytic agents can only be used if the (poly)peptide drug proves stable towards degradation. The results indicate the strict need of novel mucolytic agents for the peroral administration of therapeutic (poly)peptides.