The development journey of an artificial intestinal model predicting oral drug absorption: the mucus-PVPA model

Abstract

Oral drug administration is the most convenient route to systemically deliver drugs because of its cost-effectiveness, ease of administration and high patient compliance. However, when a drug is orally administered it will be exposed to the different physiological processes and environments found along the gastrointestinal (GI) tract, which will determine its ability of being absorbed and reach the systemic blood circulation. For this reason, a close evaluation of the impact of the GI physiology on drug absorption should be carried out when new drugs and formulations are being developed. As a result of this, the need for reliable in vitro models able to mimic both the GI processes and environment has become ever so evident. To answer the above-mentioned need, this thesis focused on the development of an in vitro model that could be employed to study drug permeation in an intestinally relevant environment. The construction of the model was stepwise. Firstly, the already established in vitro PVPA (Phospholipid Vesicle-based Permeation Assay) barriers were implemented by the addition of a mucus layer to simulate the intestinal mucosa, leading to the mucus-PVPA model. This model demonstrated the ability to distinguish between the permeabilities of drugs with different physicochemical properties. Secondly, intestinally relevant pH conditions were added to the mucus-PVPA model to account for their impact on drug absorption, and commercially available simulated intestinal fluids were also used to increase the biorelevance of the model during permeation studies. The final step was to couple the assessment of drug permeation with in vitro lipolysis to produce a model capable of mimicking both intestinal processes and unraveling the impact of lipid digestion on the permeation of drugs contained in lipid-based formulations. The lipolysis-permeation model demonstrated to predict in vivo drug absorption in rats for three lipid-based formulations, underlining its potential use in the assessment of the performance of novel drugs and formulations.