Development and pharmacokinetic evaluation of Neusilin® US2-based S-SNEDDS tablets for bosentan: Fasted and fed states bioavailability, IVIS® real-time biodistribution, and ex-vivo imaging
The study reported here aimed to develop and optimize the S-SNEDDS tablet of bosentan (BOS) and to investigate its pharmacokinetic and biodistribution properties. The BOS-loaded SNEDDS have been developed and characterized in a previous study. The BOS-loaded SNEDDS formulation was converted to S-SNEDDS using Neusilin® US2. The S-SNEDDS tablets were obtained using the direct compression technique, and in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies of the tablets were performed. The S-SNEDDS tablet and reference tablet (Tracleer®) were administered to male Wistar rats at 50 mg/kg dose by oral gavage in fasted and fed state conditions. The biodistribution of the S-SNEDDS tablet was investigated in Balb/C mice using fluorescent dye. The tablets were dispersed in distilled water before administration to animals. The relationship between in vitro dissolution data and in vivo plasma concentration was examined. The S-SNEDDS tablets showed 2.47, 7.49, 3.70, and 4.39 increases in the percentages of cumulative dissolution in FaSSIF, FeSSIF, FaSSIF-V2, and
FeSSIF-V2, respectively, when compared to the reference, and increased the Cmax and AUC 2.65 and 1.28-fold and 4.73 and 2.37-fold in fasted and fed states, respectively, when compared to the reference. S-SNEDDS tablets also significantly reduced interindividual variability in both fasted and fed states (p<0.05). The XenoLight™ DiR and VivoTag® 680XL labeled S-SNEDDS tablet formulation increased the real-time biodistribution in the body by factors of 2.4 and 3.4 and organ uptake and total emission increased by factors of 2.8 and 3.1, respectively. The IVIVR has been successfully established for S-SNEDDS tablets (R2>0.9). The present study confirms the potential of the S-SNEDDS tablet to enhance the in vitro and in vivo performance of BOS.
Materials
BOS and etodolac were kindly supplied by Abdi İbrahim (Türkiye) and Nobel Pharmaceuticals (Türkiye), respectively. Sodium lauryl sulfate, triethylamine, and acetonitrile were purchased from Merck (Germany). Polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) was purchased from BASF (Germany). Caprylocaproyl polyoxyl-8 glycerides (Labrasol®) and glyceryl monolinoleate (Maisine®) were received as gift samples by Gattefossé (France). The biorelevant media (originally known as “SIF Powder”) was
Micromeritic properties of self-nanoemulsifying powders
A self-nanoemulsifying powder was prepared to overcome the disadvantages associated with liquid SNEDDS. In this study, 1 g of SNEDDS formulation with a droplet size of 17 nm, a PDI of 0.180, consisting of 10.11% Maisine®, 80.90% Cremophor® RH 40, and 8.99% Labrasol®, and 30 mg BOS (Yilmaz Usta et al., 2022), were converted to S-SNEDDS using adsorbent Neusilin® US2. Neusilin® US2, which has a large surface area due to its small particles, has a high capacity to adsorb oils.
Read more
Duygu YILMAZ USTA, Seval OLGAC, Burcu TIMUR, Zeynep Safak TEKSIN, Development and pharmacokinetic evaluation of Neusilin® US2-based S-SNEDDS tablets for bosentan: Fasted and fed states bioavailability, IVIS® real-time biodistribution, and ex-vivo imaging, International Journal of Pharmaceutics, 2023, 123219, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2023.123219.