Hot melt extrusion for enhanced dissolution and intestinal absorption of hydrochlorothiazide

Hydrochlorothiazide (HTZ) is a potent thiazide diuretic that is used in the management of hypertension. However, HTZ suffers from low and variable oral bioavailability owing to its poor dissolution and limited intestinal permeability. Thus, the aim of this study was to enhance the dissolution rate of HTZ using hot melt extrusion (HME). The goal was to employ excipients capable of improving intestinal permeability of HTZ and modulate the physical properties of the extrudate including its disintegration rate. Formulations comprising HTZ, Kollidon® VA 64, Avicel and either Cremophore RH 40 or Poloxamer 188 were prepared using HME.

The formulations were characterized using differential scanning calorimetry, X-ray diffraction, scanning electron microscopy and in vitro dissolution testing. The intestinal permeability was assessed using in situ rabbit intestinal perfusion technique. Analysis suggested that HTZ was either molecularly dispersed or in its amorphous form within the formulation. Dissolution testing reflected significant enhancement in HTZ dissolution rate after HME. In situ intestinal absorption studies revealed site dependent absorption of HTZ.

The absorption decreased as it moves down the small intestine before increasing again at the colon contrasting the regional expression of P-glycoprotein transporters. Co-perfusion of HTZ with either poloxamer188 or cremophore RH40 improved the intestinal absorption from jejunum and ileum with the enhancement being significant in ileum segment. Intestinal absorption enhancement was associated with a significant increase in HTZ transcellular absorption reflecting modulation of the drug P-glycoprotein efflux and fluidization of the intestinal membrane. This study demonstrates the potential of HME as a tool for enhancing the dissolution and bioavailability of HTZ.

2.1. Materials

Hydrochlorothiazid (HTZ) and Kolliphor®P 188 (Poloxamer 188) were purchased from Sigma Aldrich, USA. Kollidon® VA 64 (Vinylpyrrolidone-vinyl acetate co-polymer) and Cremophore RH 40 is a gift sample from BASF (Ludwigshafen, Germany). Avicel PH 102 (microcrystalline cellulose) was a gift from FMC corp., Pennsylvania, USA.

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Ebtessam Essa, Manna Amin, Amal Sultan, Mona Arafa, Gamal El Maghraby, Christopher McConville, Hot melt extrusion for enhanced dissolution and intestinal absorption of hydrochlorothiazide, Journal of Drug Delivery Science and Technology, Volume 88, 2023, 104895, ISSN 1773-2247,
https://doi.org/10.1016/j.jddst.2023.104895.