title: Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases.
abstract: Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer Tmax, low Cmaxafter the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases.
authors.affiliation: Cellix Bio Pvt Ltd, Plot No 1177B, Road Number 56, Jubilee Hills, Hyderabad 500033, India. Electronic address: kmahesh@cellixbio.com.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kandula
authors.affiliation: Cellix Bio Pvt Ltd, Plot No 1177B, Road Number 56, Jubilee Hills, Hyderabad 500033, India. Electronic address: kbsunil@cellixbio.com.
authors.forename: K B
authors.initials: KB
authors.lastname: Sunil Kumar
authors.affiliation: Cellix Bio Pvt Ltd, Plot No 1177B, Road Number 56, Jubilee Hills, Hyderabad 500033, India. Electronic address: sivanesanp@cellixbio.com.
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Palanichamy
authors.affiliation: Cellix Bio Pvt Ltd, Plot No 1177B, Road Number 56, Jubilee Hills, Hyderabad 500033, India. Electronic address: rampala@cellixbio.com.
authors.forename: Ashok
authors.initials: A
authors.lastname: Rampal
mesh_terms: D000636:Aminosalicylic Acids / Q000627:therapeutic use*; D000818:Animals; D002210:Caprylates / Q000138:chemical synthesis / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D019804:Mesalamine / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012460:Sulfasalazine / Q000627:therapeutic use
chemical_list: D000636:Aminosalicylic Acids; C000617191:CLX-103; D002210:Caprylates; D011355:Prodrugs; D012460:Sulfasalazine; D019804:Mesalamine; D016264:Dextran Sulfate; D015118:Eicosapentaenoic Acid; C031492:octanoic acid
keywords: CLX-103; Fatty acid conjugate; Inflammatory bowel diseases; Mesalamine; Ulcerative colitis