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

• Published in: Journal of controlled release 2019-02, Vol.296, p.107-113
• Main Authors: Yeap, Yan Yan, Lock, Jaclyn, Lerkvikarn, Sean, Semin, Tanner, Nguyen, Nicholas, Carrier, Rebecca L.
• Format: Article
• Language: English
• Subjects: absorption; Animals; Carvedilol - chemistry; Cell Line, Tumor; Chemical Precipitation; coculture; dispersions; drug delivery systems; drugs; high performance liquid chromatography; Humans; Intestinal mucus; intestines; Intestines - chemistry; Ion-selective electrodes; microsatellite repeats; Mucin; Mucins; mucus; Mucus - chemistry; pharmacokinetics; Piroxicam - chemistry; Polymeric precipitation inhibitors; polymers; Poorly water-soluble drugs; Solubility; specific ion electrodes; Supersaturation; Swine; Water - chemistry; water solubility
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2018.11.023

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 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. [Display omitted] •The potential for intestinal mucus to stabilize drug supersaturation was evaluated.•Mucin and porcine mucus delayed the precipitation of carvedilol (CVDL) and piroxicam.•Supersaturated CVDL was absorbed to a greater extent in mucus-producing monolayers.