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

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.

Highlights

• Need to develop an oral solution of ONC201 for glioma treatment.
• Unfavorable chemical properties of ONC201 leading to a specific development.
• Design of a hydrotropic based formulation driven by theory and experiment.
• Characterization of the hydrotropic system by DSC, TGA, NMR and PXRD.
• Assessment of the performance of the formulation by LC-MS/MS.

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.

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Materials

ONC201 base and dihydrochloride (ONC201·2HCl; batch #S22S02C27; purity > 99 %) were purchased from MedKoo Biosciences (Morrisville, USA). Analytical grade acetonitrile came from Sigma-Aldrich (St Quentin-Fallavier, France). Ultrapure water was produced by the Direct-Q® 3 UV system (Merck, Guyancourt, France). Nicotinamide (also known as vitamin PP or B3) was obtained from Cooper (Melun, France). Strawberry flavors and bitter masking agent were purchased from IFF (New York, NY, USA); sucralose from Sigma-Aldrich (St Quentin-Fallavier, France) and citric acid from Cooper (Melun, France). Hydroxypropyl-β-cyclodextrin (HP-β-CD, KLEPTOSE HPB Oral Grade) and Hydroxypropyl-γ-cyclodextrin (HP-γ-CD, CAVASOL W8 HP Pharma) were kindly provided by Roquette and Ashland respectively.

Maxime Annereau, Philippe-Henri Secretan, Marina Vignes, Stéphanie Ramos, Jacques Grill, Thomas Bizien, Christina Sizun, Alexandre Michelet, André Rieutord, François-Xavier Legrand, Bernard Do, Development of a pediatric oral solution of ONC201 using nicotinamide to enhance solubility and stability, International Journal of Pharmaceutics, Volume 667, Part B, 2024, 124965, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124965.

Read also our introduction article on Flavour / Flavor here: