Intestinal mucus is capable of stabilizing supersaturation of poorly water-soluble drugs

Abstract

The utilization of polymers to stabilize drug supersaturation and enhance oral drug absorption has recently garnered considerable interest. The potential role of intestinal mucus in stabilizing drug supersaturation, however, has not been previously explored. The ability for intestinal mucus to stabilize drug supersaturation and delay drug precipitation is potentially useful in enhancing the absorption of orally dosed compounds from drug delivery systems that generate supersaturation within the gastrointestinal tract (e.g., solid dispersions, lipid-based drug delivery systems). This work aims to evaluate the precipitation-delaying abilities of intestinal mucus using carvedilol (CVDL) and piroxicam (PXM) as model drugs. In supersaturation-precipitation (S-P) experiments, CVDL and PXM supersaturation were induced in test media (0, 0.1, 0.2, 0.4 %w/v mucin and 8 %w/v native pig intestinal mucus (PIM)) via the solvent-shift method at supersaturation ratios (SSR) of 5 and 6, respectively. Time to drug precipitation was assessed using ion-selective electrodes and HPLC. The S-P experiments showed that increasing mucin concentration led to increasingly delayed CVDL precipitation, while PXM precipitation was prevented at all mucin concentrations studied. The ability of mucus-stabilized CVDL supersaturation to translate into enhanced CVDL absorption was evaluated in transport experiments using mucus-producing (90% Caco-2:10% HT29-MTX-E12 co-cultures) vs. non-mucus-producing intestinal monolayers (100% Caco-2 cultures). The absorption enhancement of CVDL (SSR = 5 relative to SSR = 1) was higher across mucus-producing than non-mucus-producing intestinal monolayers. This work demonstrates for the first time the potential for intestinal mucus to delay the precipitation and enhance the absorption of poorly water-soluble compounds, suggesting that drug supersaturation can be stabilized in close proximity to the absorptive site, thereby presenting a possible novel approach for targeted supersaturating drug delivery systems.

Simultaneous assessment of in vitro lipolysis and permeation in the mucus-PVPA model to predict oral absorption of a poorly water soluble drug in SNEDDSs

“…The good IVIVC obtained using the mucus-PVPA model (Fig. 4) together with the results described by Yeap and colleagues (Yeap et al, 2019) highlight the importance of having a mucus layer lining the permeation barrier when studying the permeation of supersaturated PWSD. This is especially relevant as the supersaturation stabilization process could be seen as an intrinsic mechanism of action for lipid-based formulations, and it should thus be taken into consideration in the development of novel drug delivery systems.…”

“…to play an important role in stabilizing drug supersaturation. In fact, it has been found that mucin and pig intestinal mucus were both able to delay precipitation during supersaturation-permeation experiments for two PWSD (Yeap et al, 2019). It has been proposed that the mechanisms enabling the stabilization of supersaturation exerted by the mucus layer were drug-specific.…”

“…It has been proposed that the mechanisms enabling the stabilization of supersaturation exerted by the mucus layer were drug-specific. In particular, it has been shown that the presence of mucin and pig intestinal mucus delayed carvedilol and piroxicam precipitation, and that the absorption of carvedilol from a supersaturated solution was higher across mucus-producing co-culture of Caco-2 cell-layers compared to non-mucus-producing ones (Yeap et al, 2019). Therefore, the absence of biosimilar mucus in the HTP dispersion/lipolysis setup (Section 3.1) could be another reason why the in vitro lipolysis evaluation did not correlate with in vivo data, as the stabilization of drug supersaturation could not be carried out by the mucus layer.…”

“…However, all of the mentioned models except one (Keemink and Bergström, 2018) lack the presence of a mucus layer on top of the permeation barriers, thus not being able to closely mimic the physiology of the GI mucosa (Falavigna et al, 2020a;Lechanteur et al, 2018). Notably, it has been shown that the presence of the mucus layer can stabilize supersaturation of PWSDs after in vitro lipolysis of lipid-based formulations, and it has been proposed that this could be one of the intrinsic mechanisms of action of these formulations (Yeap et al, 2013;Yeap et al, 2019). Further, several studies have pointed at the influence that mucus has on the diffusion and permeation of PWSDs, thus further emphasizing the importance of taking this additional barrier into account (Falavigna et al, 2020b;Miyazaki et al, 2019).…”

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

“…In addition, rapid intestinal absorption reduces supersaturation and prevents rapid precipitation in the small intestine [ 94 , 95 , 96 ]. Furthermore, in vivo intestinal fluid components such as mucus can inhibit drug precipitation [ 97 ]. Taken together, in the case of free weak base drugs, it can be a good approximation to neglect particle growth and precipitation.…”