Optimizing therapeutics: A novel mutual prodrug of ketoprofen and Chlorzoxazone for enhanced efficacy and safety

Abstract

The development of mutual prodrugs signifies a pivotal advancement in the optimization of therapeutic profiles for established pharmaceuticals. This study explores the synthesis and evaluation of an innovative mutual prodrug combining the nonsteroidal anti-inflammatory drug (NSAID) Ketoprofen and the skeletal muscle relaxant Chlorzoxazone. Designed to alleviate gastric irritation inherent to NSAIDs while capitalizing on the synergistic benefits of both agents, the synthesized mutual prodrug was characterized and confirmed through extensive physicochemical and spectroscopic studies. Solubility and partition coefficient analyses indicated heightened lipophilicity, enhancing the prodrug's suitability for oral administration compared to its parent drugs. Additionally, protein binding studies revealed a low binding affinity, suggesting improved bioavailability. Subsequent in vitro hydrolysis studies assessed the prodrug's stability across various pH levels (1.2, 3, 5 and 7.4) simulated gastric and intestinal fluids, plasma and rat liver homogenate, with quantitative evaluation performed by high-performance liquid chromatography. The prodrug remained stable and unhydrolyzed in the stomach after absorption, but underwent rapid cleavage by esterase's in blood and rat liver homogenate, releasing the active parent drugs. Our investigation underscores the transformative potential of mutual prodrug design in optimizing the efficacy and safety profile of combining NSAIDs with muscle relaxants. This approach offers a novel therapeutic strategy that enhances patient outcomes while minimizing adverse effects, paving the way for innovative treatments in managing musculoskeletal conditions and improving overall quality of life.