Development of a pediatric oral solution of ONC201 using nicotinamide to enhance solubility and stability.

Autor: Annereau M; Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, CNRS, Institut des Sciences Moléculaires d'Orsay, Orsay 91405, France., Secretan PH; Université Paris-Saclay, Matériaux et santé, Orsay 91400, France. Electronic address: philippe-henri.secretan@universite-paris-saclay.fr., Vignes M; Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France., Ramos S; Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France., Grill J; Department of Pediatric and Adolescent Oncology and INSERM Unit 981, Gustave Roussy Institute and University of Paris Saclay, Villejuif, France., Bizien T; Université Paris-Saclay, Synchrotron Soleil, Saint-Aubin 91190, France., Sizun C; Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Gif-sur-Yvette 91198, France., Michelet A; Applications Developement Lab, PekinElmer, Villebon-sur-Yvette 91140, France., Rieutord A; Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France., Legrand FX; Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, Orsay 91400, France., Do B; Department of clinical pharmacy, Gustave Roussy Cancer Campus, Villejuif 94800, France; Université Paris-Saclay, CNRS, Institut des Sciences Moléculaires d'Orsay, Orsay 91405, France.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Dec 25; Vol. 667 (Pt B), pp. 124965. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1016/j.ijpharm.2024.124965
Abstrakt: Diffuse intrinsic pontine glioma (DIPG) poses a significant treatment challenge in pediatric patients due to its aggressive nature and difficulty in crossing the blood-brain barrier with effective therapies. ONC201 (dordaviprone) shows promises in inducing apoptosis in cancer cells but suffers from poor water solubility and stability issues. Moreover, conventional solubilizing agents acceptable in formulations intended for adult patients are not suitable for pediatric use. So, this study aims to develop a stable, concentrated oral solution of ONC201 suitable for pediatric dosing without harmful excipients and efficient taste masking. Based on Molecular Dynamics simulations, a first screening among a selection of hydrotropes was carried out and, from the results obtained, nicotinamide was selected for experimental study. Given ONC201's challenges of poor solubility and stability, the formulation's physical and chemical properties were meticulously optimized. Extensive analyses, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and nuclear magnetic resonance (NMR) spectroscopy, confirmed the solution's stability across various storage conditions, with no evidence of precipitation or significant degradation. This newly formulated solution is now used inside daily practice in the French compassionate Use Program to give access to ONC201 allowing treating patients who suffer from swallowing disorders.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: