Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

Abstract

Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments

“…Facilitation of dissolution is thought of as providing 81 an initial ''spring'', while inclusion of solubilising excipients or 82 precipitation inhibitors can act as a ''parachute'', retarding the 83 transition back to a lower energy, crystalline form. Critically [12][13][14]. 116 Fenofibrate is an orally active, lipid regulating, BCS class II com-117 pound, and is a good model for the assessment of formulation 118 strategies to enhance bioavailability and eliminate food effect 119 [12,13].…”

“…In particular, 531 nanonisation of fenofibrate has proved quite successful, resulting 532 in a commercial preparation which has allowed dose reduction 533 and food state independent dosing through the increased bioavail-534 ability [7,15]. Furthermore, it appears that in the case of the non-ionisable com-603 pound such as fenofibrate, the risk of reduced in vivo absorption due to digestion-induced drug precipitation is low [14,23,31]. 605 However, in the case of weak bases, in particular, there is potential 606 for formulation digestion by intestinal lipases to result in a loss of 607 solubilisation and cause precipitation [32,33].…”

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

“…A later study by Stillhart et al proposed an explicit consideration of the impact of lipids and lipolysis kinetics on drug solubility and distribution in the GI environment (i.e. in the lipid emulsions or in the micelle-rich aqueous environment) by considering a linear contribution of each of the lipids and lipid digestion products on drug concentration during lipolysis [198]. The authors reported excellent agreement between experimental and modeled drug solubility profiles for three different types of fenofibrate-loaded LBFs, attesting to the robustness of the mechanism and kinetic model.…”

Analytical technologies for real-time drug dissolution and precipitation testing on a small scale

“…An interesting approach is to compare in‐vitro results with and without a drug absorption sink. The interplay of drug solubilisation and permeation has recently been highlighted by several research groups [65–69]. These studies used different experimental methods to assess the absorption effect.…”

“…The interplay of drug solubilisation and permeation has recently been highlighted by several research groups. [65][66][67][68][69] These studies used different experimental methods to assess the absorption effect. While the aforementioned μFlux system is based on a membrane separating the donor and acceptor compartments, it is also possible to employ a parallel artificial membrane permeability assay, a cell layer, or an absorption sink that is mathematically simulated.…”