Synthesis and evaluation of amide prodrugs of mefenamic acid for colon targeting

Prodrug approach is one of the important approaches for targeting drugs to colon. Prodrug design has paved a way to overcome the undesirable properties associated with the existing drug and successful site-specific drug delivery to varied organs and tissues. Colon-specific drug delivery through colon-specific prodrug activation may be accomplished by the utilization of high activity of certain enzymes at the target site relative to non-target tissues for prodrug to drug conversion. For the present studies mefenamic acid was selected because of being curative agents for most prevalent colon disease namely intestinal bowel disease due to any reason. Anti-inflammatory therapy, at present, involves use of corticosteroids, as all NSAIDs are absorbed in the stomach and they do not reach to colon. Most of the NSAIDs have free carboxylic acid groups, although, it is important for their activity but they can be targeted to colon via formation of mutual prodrugs ( amide). Hydrolytic enzymes of stomach to ileum do not hydrolyze such mutual prodrugs. Absorption of the NSAIDs primarily takes place in the stomach and followed with jejunum due to lipophilicity of the unionized form. Thus, they do not reach to the colon and also ulcerogenic which can also be avoided by formation of their mutual prodrugs. Ordinary treatment of IBD requires frequent intake of anti-inflammatory drugs at higher doses. Most of these drugs are rapidly absorbed from small intestine with very small fraction actually reaching the site of action i.e. colon. Interaction with non-targeted sites leads to significant adverse effects. Therefore, out of the need to overcome this formidable barrier of GIT, colon-targeted delivery has evolved as an ideal drug delivery system for the topical treatment of local diseases of colon like inflammatory bowel disease. Minimizing drug-induced side effects and mortality are the main challenges during management of IBD.