Synthesis, hydrolysis studies and pharmacodynamic profile of novel colon-specific mutual prodrug of Aceclofenac with amino acids
By Arun Rasheed, I. Theja, C.K. Ashok Kumar, Y. Lavanya, P. Ravindra Royal, S. Vamsee Krishna
The colon specific drug delivery of non steroidal anti-inflammatory drugs involves targeting the drug to the colon, thereby lowering the required dose, reducing the systemic side effects, and thus resulting in a more effective therapy system. The gastric side effect of aceclofenac is due to the presence of free carboxylic group. The present study aimed at reducing the side effects of aceclofenac by masking the carboxylic acid group with methyl esters of amino acids through the formation of amide linkage. The amino acids like histidine, alanine, tyrosine and glycine were chosen as promoiety because they had broad spectrum of anti-inflammatory, cytoprotective and immunomodulatory properties and therefore would synergize the effect of prodrug. The structures of synthesized prodrugs were confirmed by elemental analysis, IR, 1H NMR, 13C NMR and mass spectroscopy. In vitro reconversion of prodrugs carried out in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF) showed that the prodrugs remained intact in SGF and SIF, except SCF. In SCF, the rat fecal content containing colonic enzyme (amidase) hydrolyzed the amide linkage of synthesized prodrugs and free aceclofenac was released Marked reduction of ulcer index and an increase in anti-inflammatory activities were observed for the prodrugs and proved to be better in action in the colon as compared to the parent drug.
Keywords : NSAIDs, aceclofenac, amide prodrug, mutual prodrugs, pharmacokinetics, ulcerogenicity