In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations

Abstract

Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (J) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (J) and, subsequently, the effective diffusion constant (D) were calculated using the plasma concentrations. J was, like J, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

Enabling formulations of aprepitant: in vitro and in vivo comparison of nanocrystalline, amorphous and deep eutectic solvent based formulations

“…This suggests that the in vivo absorption mechanism of aprepitant from the nanocrystalline formulation is different than from the amorphous and DES formulations. A previous study of the absorption mechanism of aprepitant has suggested that the nanocrystals are able to reduce the resistance of the aqueous boundary layer next to the intestinal barrier ( Roos et al, 2017 ). Another study proposed that particle diffusion through the mucus layer increases the absorption of aprepitant ( Roos et al, 2018b ).…”

“…Several mechanistic pharmacokinetic studies have classified aprepitant as a biopharmaceutical classification system (BCS) class II drug, with solubility-limited oral drug absorption ( Wu et al, 2004 ; Litou et al, 2019 ; Shono et al, 2010 ). It has been suggested that the increased absorption of aprepitant from the nanocrystalline formulation is caused by increased diffusion of dissolved drug, colloid structures and nanoparticles in the aqueous boundary layer ( Roos et al, 2018a ; Roos et al, 2017 ; Roos et al, 2018b ).…”

Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states

“…The AAFE and AFE for each simulation are presented in Table 3. [37] In the present study, dissolution experiments in the Level II biorelevant media proved more useful than the equilibrium solubility experiments for identifying the relevant apparent solubility of the marketed aprepitant formulation. Thus, the experimental results demonstrated not only that the final concentration of aprepitant in the dissolution experiments was well above the equilibrium solubility, but also that application of the plateau values from the dissolution experiments led to a more accurate simulation of the plasma profiles.…”

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

“…Jejunal and colonic lumen-to-blood effective permeability (P eff ) of the four model compounds was determined based on a modification of the method described by Sjögren et al, 2015 [18]. This method has been successfully implemented in human, dog and rat [4,[18][19][20][21]. In short, an input rate was acquired by deconvolution of the plasma concentration-time profiles following the intestinal perfusion using Phoenix software version 8.2 (Certara USA, Princeton, NJ, USA).…”