Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease

Abstract

Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.

Keywords: 4-Aminosalicylic acid, 5-Aminosalicylic acid, Sulfasalazine, Colon-specific prodrug, Inflammatory bowel disease, Ulcerative colitis, 2,4,6-trinitrobenzene sulphonic acid, Experimental colitis

Core tip: Anti-inflammatory activity of antitubercular drug 4-aminosalicylic acid (ASA) was first described by Lover in 1984. Since then, numerous clinical trials were carried out to establish its efficacy in left-sided and active/quiescent ulcerative colitis. It is 50% more potent than 5-ASA against inflammation and does not produce 5-ASA-induced immunoallergic acute pancreatitis. 4-ASA is a stable and inexpensive alternative to 5-ASA in patients with acute pancreatitis. Despite all these positive findings, an extensive literature review surprisingly revealed few colon-targeting delivery systems for 4-ASA. The present review presents a complete profile of 4-ASA and its colon-specific prodrugs for inflammatory bowel disease.