SYNTHESIS AND IN-VITRO EVALUATION OF PEPTIDE LINKED PRODRUGS OF SELECTED CEPHALOSPORIN

Cephalosporins are drug of choice for many infectious microorganisms even against many antibiotic resistant cases. Ceftriaxone, a third generation cephalosporin is effective in many infections including fluoro-quinolone resistant strains of Salmonella typhi, the causative pathogen for enteric fever (typhoid). The antibiotic is supposed to act in the intestinal cells but gastric instability limits the oral use of ceftriaxone. Present research aims to develop an orally bioavailable formulation of ceftriaxone which is otherwise available as parenteral owing to its gastric instability. Natural polysaccharides have been used as excipients and drug delivery carriers since long but are not good for linking to form prodrugs. Hydrolysis resistant fraction of Almond gum, whose structure has been elucidated as a trisaccharide is used to synthesize the prodrugs of ceftriaxone. Two peptide linkers i.e., glycine and phenylalanine have been used to link the trisaccharide with the cephalosporin in three steps. Both the prodrugs were characterized and evaluated in-vitro. IR and NMR data confirmed the synthesis of polymeric prodrugs and in-vitro evaluation shows sustained drug delivery without degradation of the drug. Results of assessment in simulated gastric fluid and intestinal fluid suggests that the drug was released by action of GI enzymes on the peptide linker. This research work resulted into development of enzyme specific prodrugs of ceftriaxone using natural polysaccharide as well as the concept can be further used to design new class of antibiotics.