The effect of mucin on supersaturation of poorly water-soluble drugs with different crystallization behavior and in vitro-in vivo correlation

Drug delivery systems such as lipids, solid dispersions, or nanocrystals have been proposed to improve the ab-sorption and bioavailability of poorly water-soluble drugs with different crystallization behavior by polymers in a spring-parachute model, which generate and stabilize the drug supersaturation. Mucins, synthesized by specialized epithelial cells, have characteristics of high molecular polymer and electrostatic or hydrophobic interactions with drugs. Our study aims to investigate the effect of mucin on supersaturation of poorly water-soluble drugs with different crystallization behavior in fasted state simulated intestinal fluid (FaSSIF) and in vitro-in vivo correlation (IVIVC). The solubility of poorly water-soluble drugs was tested. The experiment of supersaturation stability was performed by solvent-shift method. The experiment of crystallization was observed by polarized light microscope analysis. The animal pharmacokinetic experiment was conducted, and the IVIVC was analyzed by linear regression. There was no significant difference in solubility between FaSSIF without and with mucin. It showed significant differences in Tss or AUC of naproxen (nifedipine, itraconazole) between FaSSIF without and with mucin (p < 0.05, p < 0.01). There was no significant difference in Tss of ritonavir between FaSSIF without and with mucin, except for significant differences in AUC (p < 0.01). In the presence of mucin, crystallization time was prolonged in FaSSIF. The SSR of drugs in FaSSIF with mucin and Fain rat showed a better level of IVIVC with a higher r value, compared with that between FaSSIF and rat. Mucin prolonged the super -saturation of poorly water-soluble drugs with different crystallization behavior, without the change of solubility, by inhibiting the drug nucleation (or crystal growth) or forming the mucin-drug interaction. It showed the role of mucin widely existed in poorly water-soluble drugs in vivo condition.