Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Abstract

Vactosertib is a novel inhibitor of transforming growth factor-β signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

• Authors: Su Young Jung, Ju-Hwan Park, Min-Jun Baek, Gyu-Ho Kim, Jaehwan Kim, Hong-Mei Zheng, Jae-Min Kim, Il-Mo Kang, Dae-Duk Kim, Jangik I Lee
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 578 Pg. 119103 (Mar 30 2020) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 32036008 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Aniline Compounds
• Anti-Inflammatory Agents, Non-Steroidal
• Delayed-Action Preparations
• Powders
• Triazoles
• Bentonite
• vactosertib

Topics

• Administration, Oral
• Aniline Compounds (chemistry, pharmacokinetics, pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacokinetics, pharmacology)
• Area Under Curve
• Bentonite (chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Chemistry, Pharmaceutical (methods)
• Colitis, Ulcerative (drug therapy)
• Delayed-Action Preparations (chemistry, pharmacokinetics, pharmacology)
• Drug Liberation (drug effects)
• Freeze Drying (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Powders (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rodentia
• Therapeutic Equivalency
• Triazoles (chemistry, pharmacokinetics, pharmacology)