Duygu Yilmaz Usta, Seval Olgac, Murside Ayse Demirel, Serdar Kula, Cigdem Elmas, Perihan Sezginer, Akif Kavgaci, Zeynep Safak Teksin
Gazi University. Alanya Alaadin Keykubat University.
Turkey
European Journal of Pharmaceutics and Biopharmaceutics
Eur J Pharma Biopharma 2025;
DOI: 10.1016/j.ejpb.2025.114725
Abstract
Bosentan monohydrate (BOS) is the most preferred molecule for treating the rare pulmonary arterial hypertension (PAH) disease. BOS shows low solubility and high variability when administered orally. This study evaluated the pharmacodynamic biodistribution, echocardiography, and histology results of BOS-loaded SNEDDS and BOS-loaded S-SNEDDS tablets. Pharmacodynamic biodistribution studies were conducted with male Balb/c mice (8 weeks old, 18-20 g) after oral administration. XenoLightTM DiR and VivoTag® 680XL fluorescent dyes were used to monitor biological distribution and absorption with the In Vivo Imaging System® (IVIS®). Pharmacodynamic echocardiography and histology studies were carried out with Wistar rats (8-10 weeks old, 250-300 g). The PAH rat model was successfully induced with monocrotaline (MCT), which is one dose (60 mg/kg) was intraperitoneally injected. The reference drug (Tracleer® 125 mg tablet) and BOS-loaded SNEDDS and S-SNEDDS tablets were administered as 50 mg/kg; 2 mL per os to the treatment groups. Pharmacodynamic biodistribution studies showed that real-time biodistribution in the body, ex-vivo region of interest (ROI) values of organs, and total fluorescence emission were increased (p < 0.05). It has been confirmed that the formulations enter the systemic circulation via the lymphatic system, do not have a first-pass effect in the liver, and show no emission in the liver. The echocardiographic study was performed for up to 14 days and no difference was found between the treatment groups which are the reference tablet (Tracleer®), BOS-loaded SNEDDS, and BOS-loaded S-SNEDDS tablet (p > 0.05). Hematoxylin and Eosin (H&E) and Immunohistochemical (IHC) staining were done for the histology studies. These studies showed that the BOS-loaded formulations have a similar therapeutic effect on histopathological phenomena in lung and liver tissues. As the histological evaluation results, lower-dose formulations were found to be more effective than the same dose reference tablet in terms of improvements in histological parameters (p < 0.05). Comprehensive and comparative in vitro and in vivo studies indicate that BOS-loaded formulations could be an alternative oral drug delivery system for PAH treatment compared to the reference product.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Medical Therapy. Pharmacokinetics and Pharmacology
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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