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

Abstract

Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:βCD 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:βCD 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 NaK-ATPase channel. Thus, it is postulated that the CS/HCT:βCD 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.

The Potential of Chitosan in Nanomedicine: An Overview of the Cytotoxicity of Chitosan Based Nanoparticles

“…No toxicity or structural damage was detected in any of the ex vivo studies ( Onnainty et al, 2016 ; Shah et al, 2016 ; Wardani et al, 2018 ; Tzeyung et al, 2019 ). One of them demonstrated that an active ingredient (hydrochlorothiazid) became less toxic when incorporated into chitosan nanoparticles, compared to the free form ( Onnainty et al, 2016 ), and another study showed that chitosan nanoparticles exhibited a protective effect against free radicals ( Wardani et al, 2018 ). An in vivo study in mice demonstrated that the chitosan nanoparticles were well tolerated, as no inflammation or pathological changes were detected ( Sonaje et al, 2009 ).…”

“…Several of the papers demonstrated that chitosan in nanoparticle form was less cytotoxic than chitosan in free form ( Amidi et al, 2006 ; Yin et al, 2009 ; Pistone et al, 2017b ; Facchinatto et al, 2021 ). The active ingredient (clotrimazole and hydrochlorothiazide) also showed less cytotoxicity when incorporated in chitosan nanoparticles ( Onnainty et al, 2016 ; Facchinatto et al, 2021 ). Reduced toxicity of the active ingredient (Centella asiatica) was also seen after incorporation into chitosan nanoparticles ex vivo ( Haroon et al, 2021 ).…”

New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity

“…The reported aqueous solubility is 0.7 g/L, and logP – 0.07 . HCT is reported as a BCS class IV drug in a number of reports. − However, according to the WHO essential medicine list, BCS is a class III drug . Sanphui et al reported five cocrystals of HCT, and their solubility and permeability properties were extensively studied .…”

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

“…The intestinal permeation of HCT was studied by applying the everted rat gut sac technique (Onnainty et al, ; Quevedo & Briñón, ; Quevedo, Nieto, & Briñón, ; Raposo, ). The medium was TC199, pH 7.4, and with 95% O 2 –5% CO 2 gas bubbling at 37°C.…”