Effect of Ingested Lipids on Drug Dissolution and Release with Concurrent Digestion: A Modeling Approach

Abstract

Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.

Size selectivity of intestinal mucus to diffusing particulates is dependent on surface chemistry and exposure to lipids

“…Simulated intestinal contents were prepared using maleate buffer at physiologically relevant pH level (6.5) and Ca 2+ concentration (10 mM), and model bile components at levels representative of the fed state 29 , including bile salt (sodium taurodeoxycholate, NaTDC) and phospholipid (L-alpha-phosphatidylcholine, lecithin from egg yolk). To simulate food-associated lipid intake, soybean oil, sodium oleate and monoglycerol were added to the model bile/maleate buffer solution (Table 1).…”

Food-associated stimuli enhance barrier properties of gastrointestinal mucus

“…Amine-, carboxylate-, and sulfate-modified microspheres (200 nm diameter, 2% solids in distilled water with 2 mM azide) were diluted in various test media (Table 1)[29] for a final particle concentration of 0.0025 wt.-%. The different particle surface functionalities were utilized to test the impact of varied chemistries on interaction with mucus components during transport through mucus.…”

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

“…Electron paramagnetic resonance (EPR) has recently been employed to measure compound partitioning in lipid-based systems [78–81]. EPR spectra reflect the nature of the microenvironment of a molecule of interest.…”

“…The vast majority of drugs are thus not detectable by this method. Commercially available stable radicals (spin probes) can be used as “model drugs,” to study partitioning behavior in the presence of lipids and simulated intestinal fluids and also to understand changes in the physicochemical nature of intestinal fluids during lipid digestion [81]. Spin probes can also be covalently linked to drugs to allow their detection by EPR [82].…”

“…This expression can be modified to account for the impact of LBF digestion on drug release, with the fraction of drug released due to digestion being proportional to the fraction of the emulsion droplet digested [81]: $$\frac{d{C}_{\mathit{\text{aq}}}}{dt}=-\frac{A_{\mathit{\text{em}}}{P}_{\mathit{\text{rel}}}}{V}true(C_{\mathit{\text{aq}}}-C_{\mathit{\text{aq}}}^{\prime }true)+k_{\mathit{\text{dig}}}\frac{A_{\text{italicem}}}{V}\frac{V_{\text{italicem}}}{n_{FA}}{C}_{\mathit{\text{em}}}$$ where V em is the total emulsion volume, n FA is the number of moles of FA produced due to lipolysis, k dig is the lipolysis rate constant (see eqn 9 below), and C em is the drug concentration inside the lipid emulsions.…”