Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid

Cristiano, Claudia; Cavanagh, Robert J.; Cuzzucoli Crucitti, Valentina; Moloney, Cara; Axioti, Eleni; Dixon, Emily; Jacob, Philippa L.; Schiano, Marica Erminia; Cuozzo, Mariarosaria; Liguori, Fabrizio Maria; Rolando, Barbara; Russo, Roberto; Taresco, Vincenzo; Sodano, Federica; Rimoli, Maria Grazia

Abstract

Objective: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). Methods: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. Results: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. Conclusions: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

Citation

Cristiano, C., Cavanagh, R. J., Cuzzucoli Crucitti, V., Moloney, C., Axioti, E., Dixon, E., …Rimoli, M. G. (2024). Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid. Biomedicine and Pharmacotherapy, 175, Article 116647. https://doi.org/10.1016/j.biopha.2024.116647

• Journal Article Type: Article
• Acceptance Date: Apr 24, 2024
• Online Publication Date: May 3, 2024
• Publication Date: 2024-06
• Deposit Date: May 16, 2024
• Publicly Available Date: May 16, 2024
• Journal: Biomedicine and Pharmacotherapy
• Print ISSN: 0753-3322
• Electronic ISSN: 1950-6007
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 175
• Article Number: 116647
• DOI: https://doi.org/10.1016/j.biopha.2024.116647
• Keywords: Galactosylated prodrugs; Poly (glycerol adipate); Polymer-drug solid dispersion; Ulcerogenicity; Cytotoxicity; Anti-inflammatory activity
• Public URL: https://nottingham-repository.worktribe.com/output/34849698
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0753332224005316?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid; Journal Title: Biomedicine & Pharmacotherapy; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.biopha.2024.116647; Content Type: article; Copyright: © 2024 The Authors. Published by Elsevier Masson SAS.