Exploring a new free-standing polyelectrolyte (PEM) thin film as a predictive tool for drug-mucin interactions: Insights on drug transport through mucosal surfaces.

The main objective of the present work was to design a biomimetic free-standing multilayered PEM film, constructed by the layer-by-layer (LbL) assembly approach, based on natural biopolymers and intended to recreate the complex mucus-mimetic matrices in order to provide mechanistic insights into biophysical interactions between drugs and the physiological gel-forming mucin network of mucus that covers the mucosal epithelia named as(CS/ALG)/(PGM) PEM film. The obtained results indicate that mucin may delay or increase drug precipitation on the mucus layer, depending on specific drug-mucin interactions driving drug supersaturation or drug crystallization phenomena. It was found that the drug lipophilicity characteristics governed the mucin binding degree, which had an influencing role on the drug translocation across this gel-like hydrogel. Moreover, the ionization of these drugs did not have a significant role on the drug binding ability to mucin as much as the lipophilicity properties did. The (CS/ALG)/(PGM) PEM film may be a promising tool to routine testing drug-mucus interactions to evaluate biophysical interactions between this protective barrier of the organism against different drug therapeutic products or external aggressive agents, leading to the optimization of drug delivery products or drugs for particular disease states.

Development and validation of a reversed-phase high-performance liquid chromatographic method with solid-phase extraction for the quantification of hydrochlorothiazide in ex vivo permeation studies.

Hydrochlorothiazide (HCT) is a diuretic used to treat hypertension. In order to study its intestinal permeation behavior applying an ex vivo methodology, a rapid, sensitive and selective reversed-phase liquid chromatography (RP-HPLC) method coupled with UV detection (RP-HPLC UV) was developed for the analysis of HCT in TC199 culture medium used as mucosal and serosal solutions in the everted rat intestinal sac model. Also, analytical procedures for the quantification of HCT by RP-HPLC with UV detection required a sample preparation step by solid-phase extraction. The method was validated in the concentration range of 8.05 × 10-7 to 3.22 × 10-5 m for HCT. Chromatographic parameters, namely carry-over, lower limit of quantification (1.4491 × 10-7 m), limit of detection (3.8325 × 10-8 m), selectivity, inter- and intraday precision and extraction recovery, were determined and found to be adequate for the intended purposes. The validated method was successfully used for permeability assays across rat intestinal epithelium applying the ex vivo everted rat gut sac methodology to study the permeation behavior of HCT.

Permeability Profiles and Intestinal Toxicity Assessment of Hydrochlorothiazide and Its Inclusion Complex with ß-Cyclodextrin Loaded into Chitosan Nanoparticles.

Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):ß-cyclodextrin (ßCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:ßCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:ßCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na+/K+-ATPase channel. Thus, it is postulated that the CS/HCT:ßCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium; consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.